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Sample records for retinoic acid isomers

  1. Effects of retinoic acid isomers on proteomic pattern in human breast cancer MCF-7 cell line

    Czech Academy of Sciences Publication Activity Database

    Flodrová, Dana; Benkovská, Dagmar; Macejová, D.; Bialešová, L.; Bobálová, Janette; Brtko, J.

    2013-01-01

    Roč. 47, č. 4 (2013), s. 205-209 ISSN 1210-0668 R&D Projects: GA MŠk(CZ) 7AMB12SK151 Institutional support: RVO:68081715 Keywords : retinoic acid isomers * retinoid * breast cancer * malignant cells * proteomic analysis Subject RIV: CB - Analytical Chemistry, Separation

  2. Rapid determination of retinoic acid and its main isomers in plasma by second-order high-performance liquid chromatography data modeling.

    Science.gov (United States)

    Teglia, Carla M; Cámara, María S; Goicoechea, Héctor C

    2014-12-01

    This paper reports the development of a method based on high-performance liquid chromatography (HPLC) coupled to second-order data modeling with multivariate curve resolution-alternating least-squares (MCR-ALS) for quantification of retinoic acid and its main isomers in plasma in only 5.5 min. The compounds retinoic acid (RA), 13-cis-retinoic acid, 9-cis-retinoic acid, and 9,13-di-cis-retinoic acid were partially separated by use of a Poroshell 120 EC-C18 (3.0 mm × 30 mm, 2.7 μm particle size) column. Overlapping not only among the target analytes but also with the plasma interferents was resolved by exploiting the second-order advantage of the multi-way calibration. A validation study led to the following results: trueness with recoveries of 98.5-105.9 % for RA, 95.7-110.1 % for 13-cis-RA, 97.1-110.8 % for 9-cis-RA, and 99.5-110.9 % for 9,13-di-cis-RA; repeatability with RSD of 3.5-3.1 % for RA, 3.5-1.5 % for 13-cis-RA, 4.6-2.7 % for 9-cis-RA, and 5.2-2.7 % for 9,13-di-cis-RA (low and high levels); and intermediate precision (inter-day precision) with RSD of 3.8-3.0 % for RA, 2.9-2.4 % for 13-cis-RA, 3.6-3.2 % for 9,13-di-cis-RA, and 3.2-2.9 % for 9-cis-RA (low and high levels). In addition, a robustness study revealed the method was suitable for monitoring patients with dermatological diseases treated with pharmaceutical products containing RA and 13-cis-RA.

  3. Study of apoptotic mechanisms induced by all-trans retinoic acid and its 13-cis isomer on cellular lines of human hepato carcinoma Hep3B and HepG2

    International Nuclear Information System (INIS)

    Arce Vargas, Frederick

    2006-01-01

    Two cellular lines of liver cancer (Hep3B and HepG2) were incubated during different periods of time with some concentrations of two retinoic acid isomers (ATRA and 13-cis AR) and with 5-fu chemotherapeutic agents, cisplatin and paclitaxel. It was determined if these substances leaded cytotoxicity, apoptosis and if they modified the expression of different genes related to cellular death by apoptosis, in order to explain the hepatocellular carcinoma resistance to these drugs. HepG2 cells showed more resistance than Hep3B cells to 72 hours of treatment, as much ATRA as the 13-cis AR were toxic and produced apoptosis in two cellular lines. This type of cellular death seems to be mediated by a decrease in Bcl-xL concentration in Hep3B cells treated with both retinoids an increase in bax concentration in HepG2 cells treated with 13-cis AR. It were observed 3 and 8 proteolysis of procaspase in Hep3B cells, suggesting extrinsic via activation of the apoptosis, while cellular death in HepG2 cells seems to be independent of caspases. Cisplatin and paclitaxel leaded cytotoxicity to 48 hours of treatment, with significant differences between two cellular lines only in case of paclitaxel. Hep3B cells treated with cisplatin and HepG2 cells treated with paclytaxel suffered apoptosis. 5-FU produced toxicity only when it was used to high concentrations and the mechanism of cellular death induced by this agent seems to be primarily necrosis in Hep3B cells and apoptosis in HepG2. There was decrease in the Bcl-xL concentration in two cellular lines when it was treated with cisplatin and in HepG2 cells treated with 5-FU. Bax concentration there no was modified with no treatment. Activation of the 3 caspases seems to happen only in HepG2 cells with 5-FU and paclytaxel. These two agents, also, decreased the survivin concentration of HepG2 cells. Treatments of the three drugs produced an increase in the expression of this gen in Hep3B cells, which might explain partially the resistance

  4. Retinoic acid synthesis and functions in early embryonic development

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    Kam Richard Kin Ting

    2012-03-01

    Full Text Available Abstract Retinoic acid (RA is a morphogen derived from retinol (vitamin A that plays important roles in cell growth, differentiation, and organogenesis. The production of RA from retinol requires two consecutive enzymatic reactions catalyzed by different sets of dehydrogenases. The retinol is first oxidized into retinal, which is then oxidized into RA. The RA interacts with retinoic acid receptor (RAR and retinoic acid X receptor (RXR which then regulate the target gene expression. In this review, we have discussed the metabolism of RA and the important components of RA signaling pathway, and highlighted current understanding of the functions of RA during early embryonic development.

  5. Azadirachtin interacts with retinoic acid receptors and inhibits retinoic acid-mediated biological responses.

    Science.gov (United States)

    Thoh, Maikho; Babajan, Banaganapalli; Raghavendra, Pongali B; Sureshkumar, Chitta; Manna, Sunil K

    2011-02-11

    Considering the role of retinoids in regulation of more than 500 genes involved in cell cycle and growth arrest, a detailed understanding of the mechanism and its regulation is useful for therapy. The extract of the medicinal plant Neem (Azadirachta indica) is used against several ailments especially for anti-inflammatory, anti-itching, spermicidal, anticancer, and insecticidal activities. In this report we prove the detailed mechanism on the regulation of retinoic acid-mediated cell signaling by azadirachtin, active components of neem extract. Azadirachtin repressed all trans-retinoic acid (ATRA)-mediated nuclear transcription factor κB (NF-κB) activation, not the DNA binding but the NF-κB-dependent gene expression. It did not inhibit IκBα degradation, IκBα kinase activity, or p65 phosphorylation and its nuclear translocation but inhibited NF-κB-dependent reporter gene expression. Azadirachtin inhibited TRAF6-mediated, but not TRAF2-mediated NF-κB activation. It inhibited ATRA-induced Sp1 and CREB (cAMP-response element-binding protein) DNA binding. Azadirachtin inhibited ATRA binding with retinoid receptors, which is supported by biochemical and in silico evidences. Azadirachtin showed strong interaction with retinoid receptors. It suppressed ATRA-mediated removal of retinoid receptors, bound with DNA by inhibiting ATRA binding to its receptors. Overall, our data suggest that azadirachtin interacts with retinoic acid receptors and suppresses ATRA binding, inhibits falling off the receptors, and activates transcription factors like CREB, Sp1, NF-κB, etc. Thus, azadirachtin exerts anti-inflammatory and anti-metastatic responses by a novel pathway that would be beneficial for further anti-inflammatory and anti-cancer therapies.

  6. Azadirachtin Interacts with Retinoic Acid Receptors and Inhibits Retinoic Acid-mediated Biological Responses*

    Science.gov (United States)

    Thoh, Maikho; Babajan, Banaganapalli; Raghavendra, Pongali B.; Sureshkumar, Chitta; Manna, Sunil K.

    2011-01-01

    Considering the role of retinoids in regulation of more than 500 genes involved in cell cycle and growth arrest, a detailed understanding of the mechanism and its regulation is useful for therapy. The extract of the medicinal plant Neem (Azadirachta indica) is used against several ailments especially for anti-inflammatory, anti-itching, spermicidal, anticancer, and insecticidal activities. In this report we prove the detailed mechanism on the regulation of retinoic acid-mediated cell signaling by azadirachtin, active components of neem extract. Azadirachtin repressed all trans-retinoic acid (ATRA)-mediated nuclear transcription factor κB (NF-κB) activation, not the DNA binding but the NF-κB-dependent gene expression. It did not inhibit IκBα degradation, IκBα kinase activity, or p65 phosphorylation and its nuclear translocation but inhibited NF-κB-dependent reporter gene expression. Azadirachtin inhibited TRAF6-mediated, but not TRAF2-mediated NF-κB activation. It inhibited ATRA-induced Sp1 and CREB (cAMP-response element-binding protein) DNA binding. Azadirachtin inhibited ATRA binding with retinoid receptors, which is supported by biochemical and in silico evidences. Azadirachtin showed strong interaction with retinoid receptors. It suppressed ATRA-mediated removal of retinoid receptors, bound with DNA by inhibiting ATRA binding to its receptors. Overall, our data suggest that azadirachtin interacts with retinoic acid receptors and suppresses ATRA binding, inhibits falling off the receptors, and activates transcription factors like CREB, Sp1, NF-κB, etc. Thus, azadirachtin exerts anti-inflammatory and anti-metastatic responses by a novel pathway that would be beneficial for further anti-inflammatory and anti-cancer therapies. PMID:21127062

  7. Retinoic acid signaling in axonal regeneration

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    Radhika ePuttagunta

    2012-01-01

    Full Text Available Following an acute central nervous system injury, axonal regeneration and functional recovery are extremely limited. This is due to an extrinsic inhibitory growth environment and the lack of intrinsic growth competence. Retinoic acid (RA signaling, essential in developmental dorsoventral patterning and specification of spinal motor neurons, has been shown through its receptor, the transcription factor RA receptor β2 (RARß2, to induce axonal regeneration following spinal cord injury (SCI. Recently, it has been shown that in dorsal root ganglia neurons, cAMP levels were greatly increased by lentiviral RARβ2 expression and contributed to neurite outgrowth. Moreover, RARβ agonists, in cerebellar granule neurons and in the brain in vivo, induced phosphoinositide 3-kinase dependent phosphorylation of AKT that was involved in RARβ-dependent neurite outgrowth. More recently, RA-RARß pathways were shown to directly transcriptionally repress a member of the inhibitory Nogo receptor complex, Lingo-1, under an axonal growth inhibitory environment in vitro as well as following spinal injury in vivo. This perspective focuses on these newly discovered molecular mechanisms and future directions in the field.

  8. New discovery of cryptorchidism: Decreased retinoic acid in testicle

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    Jinpu Peng

    2016-05-01

    Full Text Available This study focuses on investigation of cryptorchidism induced by flutamide (Flu and its histopathological damage, and detects retinoic acid concentration in testicle tissue, in order to find a new method for clinical treatment to infertility caused by cryptorchidism. Twenty SD (Sprague Dawley pregnant rats were randomly divided into Flu cryptorchidism group (n = 10 and normal control group (n = 10. HE stained for observing morphological difference. Transmission electron microscope (TEM was used for observing the tight junction structure between Sertoli cells. Epididymal caudal sperms were counted and observed in morphology. The expression of stimulated by retinoic acid gene 8 (Stra8 was detected using immunohistochemistry, western blot, and Q-PCR. High performance liquid chromatography (HPLC analysis was made on retinoic acid content. Sperm count and morphology observation confirmed cryptorchidism group was lower than normal group in sperm quantity and quality. The observation by TEM showed a loose structure of tight junctions between Sertoli cells. Immunohistochemistry, western blot, and Q-PCR showed that cryptorchidism group was significantly lower than normal group in the expression of Stra8. HPLC showed that retinoic acid content was significantly lower in cryptorchid testis than in normal testis. In the cryptorchidism model, retinoic acid content in testicular tissue has a significant reduction; testicles have significant pathological changes; damage exists in the structure of tight junctions between Sertoli cells; Stra8 expression has a significant reduction, perhaps mainly contributing to spermatogenesis disorder.

  9. Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis

    DEFF Research Database (Denmark)

    Wendland, Kerstin; Niss, Kristoffer; Kotarsky, Knut

    2018-01-01

    Despite the essential role of thymic epithelial cells (TEC) in T cell development, the signals regulating TEC differentiation and homeostasis remain incompletely understood. In this study, we show a key in vivo role for the vitamin A metabolite, retinoic acid (RA), in TEC homeostasis. In the abse......Despite the essential role of thymic epithelial cells (TEC) in T cell development, the signals regulating TEC differentiation and homeostasis remain incompletely understood. In this study, we show a key in vivo role for the vitamin A metabolite, retinoic acid (RA), in TEC homeostasis...

  10. Retinoic acid in developmental toxicology: Teratogen, morphogen and biomarker.

    NARCIS (Netherlands)

    Piersma, Aldert H; Hessel, Ellen V; Staal, Yvonne C

    This review explores the usefulness retinoic acid (RA) related physiological factors as possible biomarkers of embryotoxicity. RA is involved in the morphogenesis of the early embryo as well as in the development and maturation of a wide variety of organ anlagen. The region-specific homeostasis of

  11. Comparative proteomic analysis of colon cancer cell HCT-15 in response to all-trans retinoic acid treatment.

    Science.gov (United States)

    Zhao, Jie; Wen, Gaotian; Ding, Ming; Pan, Jian-Yi; Yu, Mei-Lan; Zhao, Fukun; Weng, Xia-Lian; Du, Jiang-Li

    2012-12-01

    Colon cancer is one of the most common malignances. In vitro and in vivo study show that retinoic acids inhibit a wide variety of cancer cells but the molecular mechanism of their anti-tumor effects are not yet fully understood. Alltrans retinoic acid (ATRA), an isomer of retinoic acid, can inhibit the proliferation of HCT-15 human colon cancer cell line. A proteomic analysis was performed using HCT-15 treated with ATRA to further elucidate the retinoic acid signaling pathway and its anti-tumor effect mechanism. MTT results showed that the growth of HCT-15 cells were significantly inhibited by ATRA. The alkaline phosphatase activity assay showed that ATRA failed to induce the differentiation of HCT-15. The DNA ladder detection showed that ATRA induced apoptosis in HCT-15. Two-dimensional gel electrophoresis coupled with MALDI-TOF/TOF mass spectrometry identified 13 differentially expressed proteins in HCT-15 cells after all-trans retinoic acid treatment. Among the identified differentially expressed proteins, there were four scaffold proteins (YWHAE, SFN, YWHAB, and YWHAZ), two ubiquitin modification related proteins (ISG-15 and UBE2N), two translational initiation factors (EIF1AX and EIF3K), two cytoskeleton related proteins (EZRI and CNN3), two proteinmodification related proteins (TXNDC17 and PIMT), and one enzyme related to phospholipid metabolism (PSP). Both EZRI and UBE2N were rendered to western-blot validation and the results were consistent with the two-dimension electrophoresis analysis. In this study, the differentially expressed proteins in HCT-15 treated by ATRA were identified, which will assist the further elucidation of the anti-tumor mechanism of retinoic acids.

  12. E1A FUNCTIONS AS A COACTIVATOR OF RETINOIC ACID-DEPENDENT RETINOIC ACID RECEPTOR-BETA-2 PROMOTER ACTIVATION

    NARCIS (Netherlands)

    KRUYT, FAE; FOLKERS, GE; WALHOUT, AJM; VANDERLEEDE, BM; VANDERSAAG, PT; Kruyt, Frank

    The retinoic acid (RA) receptor (RAR) beta2 promoter is strongly activated by RA in embryonal carcinoma (EC) cells. We examined this activation in the P19 EC-derived END-2 cell line and in E1A-expressing counterparts and found strong RA-dependent RARbeta2 promoter activation in the E1A-expressing

  13. Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity

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    Paulo Czarnewski

    2017-01-01

    Full Text Available Vitamin A (VA is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders. In particular, VA metabolite all-trans retinoic acid (atRA has been shown to be crucial in inducing gut tropism in lymphocytes and modulating T helper differentiation. In addition to the widely recognized role in adaptive immunity, increasing evidence identifies atRA as an important modulator of innate immune cells, such as tolerogenic dendritic cells (DCs and innate lymphoid cells (ILCs. Here, we focus on the role of retinoic acid in differentiation, trafficking and the functions of innate immune cells in health and inflammation associated disorders. Lastly, we discuss the potential involvement of atRA during the plausible crosstalk between DCs and ILCs.

  14. Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor alpha

    Science.gov (United States)

    Hall, J.A.; Cannons, J.L.; Grainger, J.R.; Santos, L.M. Dos; Hand, T.W.; Naik, S.; Wohlfert, E.A.; Chou, D.B.; Oldenhove, G.; Robinson, M.; Grigg, M.E.; Kastenmayer, R.; Schwartzberg, P.L.; Belkaid, Y.

    2012-01-01

    SUMMARY Vitamin A and its metabolite, retinoic acid (RA), have recently been implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells. Here we show that RA is also required to elicit proinflammatory CD4+ helper T cell responses to infection and mucosal vaccination. Retinoic acid receptor alpha (RARα) is the critical mediator of these effects. Strikingly, antagonism of RAR signaling and deficiency in RARα(Rara−/−) results in a cell autonomous CD4+ T cell activation defect. Altogether, these findings reveal a fundamental role for the RA/RARα axis in the development of both regulatory and inflammatory arms of adaptive immunity and establish nutritional status as a broad regulator of adaptive T cell responses. PMID:21419664

  15. Disruption of retinoic acid receptor alpha reveals the growth promoter face of retinoic acid.

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    Giulia Somenzi

    2007-09-01

    Full Text Available Retinoic acid (RA, the bioactive derivative of Vitamin A, by epigenetically controlling transcription through the RA-receptors (RARs, exerts a potent antiproliferative effect on human cells. However, a number of studies show that RA can also promote cell survival and growth. In the course of one of our studies we observed that disruption of RA-receptor alpha, RARalpha, abrogates the RA-mediated growth-inhibitory effects and unmasks the growth-promoting face of RA (Ren et al., Mol. Cell. Biol., 2005, 25:10591. The objective of this study was to investigate whether RA can differentially govern cell growth, in the presence and absence of RARalpha, through differential regulation of the "rheostat" comprising ceramide (CER, the sphingolipid with growth-inhibitory activity, and sphingosine-1-phosphate (S1P, the sphingolipid with prosurvival activity.We found that functional inhibition of endogenous RARalpha in breast cancer cells by using either RARalpha specific antagonists or a dominant negative RARalpha mutant hampers on one hand the RA-induced upregulation of neutral sphingomyelinase (nSMase-mediated CER synthesis, and on the other hand the RA-induced downregulation of sphingosine kinase 1, SK1, pivotal for S1P synthesis. In association with RA inability to regulate the sphingolipid rheostat, cells not only survive, but also grow more in response to RA both in vitro and in vivo. By combining genetic, pharmacological and biochemical approaches, we mechanistically demonstrated that RA-induced growth is, at least in part, due to non-RAR-mediated activation of the SK1-S1P signaling.In the presence of functional RARalpha, RA inhibits cell growth by concertedly, and inversely, modulating the CER and S1P synthetic pathways. In the absence of a functional RARalpha, RA-in a non-RAR-mediated fashion-promotes cell growth by activating the prosurvival S1P signaling. These two distinct, yet integrated processes apparently concur to the growth-promoter effects

  16. Endogenous retinoic acid activity in principal cells and intercalated cells of mouse collecting duct system.

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    Yuen Fei Wong

    2011-02-01

    Full Text Available Retinoic acid is the bioactive derivative of vitamin A, which plays an indispensible role in kidney development by activating retinoic acid receptors. Although the location, concentration and roles of endogenous retinoic acid in post-natal kidneys are poorly defined, there is accumulating evidence linking post-natal vitamin A deficiency to impaired renal concentrating and acidifying capacity associated with increased susceptibility to urolithiasis, renal inflammation and scarring. The aim of this study is to examine the presence and the detailed localization of endogenous retinoic acid activity in neonatal, young and adult mouse kidneys, to establish a fundamental ground for further research into potential target genes, as well as physiological and pathophysiological roles of endogenous retinoic acid in the post-natal kidneys.RARE-hsp68-lacZ transgenic mice were employed as a reporter for endogenous retinoic acid activity that was determined by X-gal assay and immunostaining of the reporter gene product, β-galactosidase. Double immunostaining was performed for β-galactosidase and markers of kidney tubules to localize retinoic acid activity. Distinct pattern of retinoic acid activity was observed in kidneys, which is higher in neonatal and 1- to 3-week-old mice than that in 5- and 8-week-old mice. The activity was present specifically in the principal cells and the intercalated cells of the collecting duct system in all age groups, but was absent from the glomeruli, proximal tubules, thin limbs of Henle's loop and distal tubules.Endogenous retinoic acid activity exists in principal cells and intercalated cells of the mouse collecting duct system after birth and persists into adulthood. This observation provides novel insights into potential roles for endogenous retinoic acid beyond nephrogenesis and warrants further studies to investigate target genes and functions of endogenous retinoic acid in the kidney after birth, particularly in the

  17. Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain

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    Maden Malcolm

    2007-12-01

    Full Text Available Abstract Background Human retinoic acid teratogenesis results in malformations of dorsally derived hindbrain structures such as the cerebellum, noradrenergic hindbrain neurons and the precerebellar system. These structures originate from the rhombic lip and adjacent dorsal precursor pools that border the fourth ventricle roofplate. While retinoic acid synthesis is known to occur in the meninges that blanket the hindbrain, the particular sensitivity of only dorsal structures to disruptions in retinoid signalling is puzzling. We therefore looked for evidence within the neural tube for more spatiotemporally specific signalling pathways using an in situ hybridisation screen of known retinoic acid pathway transcripts. Results We find that there are highly restricted domains of retinoic acid synthesis and breakdown within specific hindbrain nuclei as well as the ventricular layer and roofplate. Intriguingly, transcripts of cellular retinoic acid binding protein 1 are always found at the interface between dividing and post-mitotic cells. By contrast to earlier stages of development, domains of synthesis and breakdown in post-mitotic neurons are co-localised. At the rhombic lip, expression of the mRNA for retinoic acid synthesising and catabolising enzymes is spatially highly organised with respect to the Cath1-positive precursors of migratory precerebellar neurons. Conclusion The late developing hindbrain shows patterns of retinoic acid synthesis and use that are distinct from the well characterised phase of rostrocaudal patterning. Selected post-mitotic populations, such as the locus coeruleus, appear to both make and break down retinoic acid suggesting that a requirement for an autocrine, or at least a highly localised paracrine signalling network, might explain its acute sensitivity to retinoic acid disruption. At the rhombic lip, retinoic acid is likely to act as a dorsalising factor in parallel with other roofplate signalling pathways. While its

  18. Gonadotropin Regulation of Retinoic Acid Activity in the Testis

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    Seyedmehdi Nourashrafeddin

    2018-02-01

    Full Text Available Initiation of spermatogenesis in primates is triggered at puberty by an increase in gonadotropins; i.e., follicle-stimulating hormone (FSH and luteinizing hormone (LH. Prior to puberty, testis of the monkey contains only undifferentiated germ cells. However, sermatogonial differentiation and spermatogenesis may be initiated prior to puberty after stimulation with exogenous LH and FSH. Retinoic acid (RA signaling is considered to be a major component that drives spermatogonial differentiation. We were interested in evaluating the relative role of LH and FSH, either alone or in combination, in regulating the retinoic acid signaling in monkey testis. Sixteen juvenile male rhesus monkeys (Macaca mulatta were infused with intermittent recombinant single chain human LH (schLH or recombinant human FSH (rhFSH or a combination of both for 11 days. We then analyzed the expression of the several putative RA signaling pathway related genes; i.e. RDH10, RDH11, ALDH1A1, ALDH1A2, CYP26B1, CRABP1, CRABP2, STRA6, STRA8 in the testis after 11 days of stimulation with vehicle, LH, FSH and combination LH/FSH using quantitative real-time PCR (qPCR. The qPCR results analysis showed that administration of gonadotropins affected a significant change in expression of some RA signaling related genes in the monkey testis. The gonadotropins, either alone or in combination dramatically increased expression of CRABP2 (p≤0.001, whereas there was a decrease in ALDH1A2 expression (p≤0.001. Moreover, combined gonadotropin treatment led to the significant decrease in CRABP1 expression (p≤0.05. These findings are the first evidence that the activity of retinoic acid signaling in the monkey testis is regulated through gonadotropins (LH/FSH levels.

  19. Retinoic Acid and Immune Homeostasis: A Balancing Act.

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    Erkelens, Martje N; Mebius, Reina E

    2017-03-01

    In the immune system, the vitamin A metabolite retinoic acid (RA) is known for its role in inducing gut-homing molecules in T and B cells, inducing regulatory T cells (Tregs), and promoting tolerance. However, it was suggested that RA can have a broad spectrum of effector functions depending on the local microenvironment. Under specific conditions, RA can also promote an inflammatory environment. We discuss the dual role of RA in immune responses and how this might be regulated. Furthermore, we focus on the role of RA in autoimmune diseases and whether RA might be used as a therapeutic agent. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. The role of retinoic acid in tolerance and immunity.

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    Hall, Jason A; Grainger, John R; Spencer, Sean P; Belkaid, Yasmine

    2011-07-22

    Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. A third human retinoic acid receptor, hRAR-γ

    International Nuclear Information System (INIS)

    Krust, A.; Kastner, Ph.; Petkovich, M.; Zelent, A.; Chambon, P.

    1989-01-01

    Retinoic acid receptors (RARs) are retinoic acid (RA)-inducible enhancer factors belonging to the superfamily of steroid/thyroid nuclear receptors. The authors have previously characterized two human RAR (hRAR-α and hRAR-β) cDNAs and have recently cloned their murine cognates (mRAR-α and mRAR-β) together with a third RAR (mRAR-γ) whose RNA was detected predominantly in skin, a well-known target for RA. mRAR-γ cDNA was used here to clone its human counterpart (hRAR-γ) from a T47D breast cancer cell cDNA library. Using a transient transfection assay in HeLa cells and a reporter gene harboring a synthetic RA responsive element, they demonstrate that hRAR-γ cDNA indeed encodes a RA-inducible transcriptional trans-activator. Interestingly, comparisons of the amino acid sequences of all six human and mouse RARs indicate that the interspecies conservation of a given member of the RAR subfamily (either α, β, or γ) is much higher than the conservation of all three receptors within a given species. These observations indicate that RAR-α, -β, and -γ may perform specific functions. They show also that hRAR-γ RNA is the predominant RAR RNA species in human skin, which suggests that hRAR-γ mediates some of the retinoid effects in this tissue

  2. All-trans retinoic acid inhibits craniopharyngioma cell growth: study on an explant cell model.

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    Li, Qiang; You, Chao; Zhou, Liangxue; Sima, Xiutian; Liu, Zhiyong; Liu, Hao; Xu, Jianguo

    2013-05-01

    The ratio between FABP5 and CRABPII determines cellular response to physiological level of retinoic acid; tumor cells undergo proliferation with high level of FABP5 and apoptosis with high level of CRABPII. We intended to study FABP5 and CRABPII expression in craniopharyngiomas, to establish craniopharyngioma cell model using explants method, and to study the effect of pharmacological dose of retinoic acid on craniopharyngioma cells. Expression of FABP5 and CRABPII in craniopharyngioma tissue from 20 patients was studied using immunohistochemistry. Primary craniopharyngioma cell cultures were established using tissue explants method. Craniopharyngioma cells were treated using various concentrations of all-trans retinoic acid, and cell growth curve, apoptosis, expression of FABP5, CRABPII and NF-κB were assayed in different groups. FABP5/CRABPII ratio was significantly higher in adamatinomatous group than that in papillary group. Cell cultures were established in 19 cases (95 %). Pharmacological level retinoic acid inhibited cell growth and induced cellular apoptosis in dose dependent manner, and apoptosis rate cells treated with 30 μM retinoic acid for 24 h was 43 %. Also, retinoic acid increased CRABPII, and decreased FABP5 and NF-κB expression in craniopharyngioma cells. High FABP5/CRABPII ratio is observed in adamatinomatous craniopharyngioma. Retinoic acid at pharmacological level induced craniopharyngioma cell apoptosis via increasing FABP5/CRABPII ratio and inhibiting NF-κB signaling pathway. Our study demonstrated that all-trans retinoic acid might be a candidate for craniopharyngioma adjuvant chemotherapy in future.

  3. Retinoic acid modulation of ultraviolet light-induced epidermal ornithine decarboxylase activity

    International Nuclear Information System (INIS)

    Lowe, N.J.; Breeding, J.

    1982-01-01

    Irradiation of skin with ultraviolet light of sunburn range (UVB) leads to a large and rapid induction of the polyamine biosynthetic enzyme ornithine decarboxylase in the epidermis. Induction of epidermal ornithine decarboxylase also occurs following application of the tumor promoting agent 12-0-tetradecanoylphorbol-13 acetate and topical retinoic acid is able to block both this ornithine decarboxylase induction and skin tumor promotion. In the studies described below, topical application of retinoic acid to hairless mouse skin leads to a significant inhibition of UVB-induced epidermal ornithine decarboxylase activity. The degree of this inhibition was dependent on the dose, timing, and frequency of the application of retinoic acid. To show significant inhibition of UVB-induced ornithine decarboxylase the retinoic acid had to be applied within 5 hr of UVB irradiation. If retinoic acid treatment was delayed beyond 7 hr following UVB, then no inhibition of UVB-induced ornithine decarboxylase was observed. The quantities of retinoic acid used (1.7 nmol and 3.4 nmol) have been shown effective at inhibiting 12-0-tetradecanoyl phorbol-13 acetate induced ornithine decarboxylase. The results show that these concentrations of topical retinoic acid applied either before or immediately following UVB irradiation reduces the UVB induction of epidermal ornithine decarboxylase. The effect of retinoic acid in these regimens on UVB-induced skin carcinogenesis is currently under study

  4. Retinoic Acid-Induced Epidermal Transdifferentiation in Skin

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    Yoshihiro Akimoto

    2014-06-01

    Full Text Available Retinoids function as important regulatory signaling molecules during development, acting in cellular growth and differentiation both during embryogenesis and in the adult animal. In 1953, Fell and Mellanby first found that excess vitamin A can induce transdifferentiation of chick embryonic epidermis to a mucous epithelium (Fell, H.B.; Mellanby, E. Metaplasia produced in cultures of chick ectoderm by high vitamin A. J. Physiol. 1953, 119, 470–488. However, the molecular mechanism of this transdifferentiation process was unknown for a long time. Recent studies demonstrated that Gbx1, a divergent homeobox gene, is one of the target genes of all-trans retinoic acid (ATRA for this transdifferentiation. Furthermore, it was found that ATRA can induce the epidermal transdifferentiation into a mucosal epithelium in mammalian embryonic skin, as well as in chick embryonic skin. In the mammalian embryonic skin, the co-expression of Tgm2 and Gbx1 in the epidermis and an increase in TGF-β2 expression elicited by ATRA in the dermis are required for the mucosal transdifferentiation, which occurs through epithelial-mesenchymal interaction. Not only does retinoic acid (RA play an important role in mucosal transdifferentiation, periderm desquamation, and barrier formation in the developing mammalian skin, but it is also involved in hair follicle downgrowth and bending by its effect on the Wnt/β-catenin pathway and on members of the Runx, Fox, and Sox transcription factor families.

  5. In silico discovery of novel Retinoic Acid Receptor agonist structures

    Directory of Open Access Journals (Sweden)

    Samuels Herbert H

    2001-06-01

    Full Text Available Abstract Background Several Retinoic Acid Receptors (RAR agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. Results We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually to the structure of the receptor with the Internal Coordinates Mechanics (ICM program. Thirty ligand candidates were tested in vitro. Conclusions Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

  6. Retinoic acid from the meninges regulates cortical neuron generation.

    Science.gov (United States)

    Siegenthaler, Julie A; Ashique, Amir M; Zarbalis, Konstantinos; Patterson, Katelin P; Hecht, Jonathan H; Kane, Maureen A; Folias, Alexandra E; Choe, Youngshik; May, Scott R; Kume, Tsutomu; Napoli, Joseph L; Peterson, Andrew S; Pleasure, Samuel J

    2009-10-30

    Extrinsic signals controlling generation of neocortical neurons during embryonic life have been difficult to identify. In this study we demonstrate that the dorsal forebrain meninges communicate with the adjacent radial glial endfeet and influence cortical development. We took advantage of Foxc1 mutant mice with defects in forebrain meningeal formation. Foxc1 dosage and loss of meninges correlated with a dramatic reduction in both neuron and intermediate progenitor production and elongation of the neuroepithelium. Several types of experiments demonstrate that retinoic acid (RA) is the key component of this secreted activity. In addition, Rdh10- and Raldh2-expressing cells in the dorsal meninges were either reduced or absent in the Foxc1 mutants, and Rdh10 mutants had a cortical phenotype similar to the Foxc1 null mutants. Lastly, in utero RA treatment rescued the cortical phenotype in Foxc1 mutants. These results establish RA as a potent, meningeal-derived cue required for successful corticogenesis.

  7. Interaction between cellular retinoic acid-binding protein II and histone hypoacetylation in renal cell carcinoma

    OpenAIRE

    Viroj Wiwanitkit

    2008-01-01

    Renal cell carcinoma is a rare but serious malignancy. Since a reduction in the level of retinoic acid receptor beta 2 (RARbeta2) expression in cancer cells due in part to histone hypoacetylation which is controlled by histone deacetylase (HD), the study on the interaction between cellular retinoic acid-binding proteins II (CRABP II), which is proposed to have its potential influence on retinoic acid (RA) response, and HD can be useful. Comparing to CARBP II and HD, the CARBP II-HD poses the ...

  8. Study of apoptotic mechanisms induced by all-trans retinoic acid and its 13-cis isomer on cellular lines of human hepato carcinoma Hep3B and HepG2; Estudio de los mecanismos apoptoticos inducidos por el acido retinoico todo-trans y su isomero 13-cis en las lineas celulares de hepatocarcinoma humano Hep3B y HepG2

    Energy Technology Data Exchange (ETDEWEB)

    Arce Vargas, Frederick [Costa Rica

    2006-07-01

    Two cellular lines of liver cancer (Hep3B and HepG2) were incubated during different periods of time with some concentrations of two retinoic acid isomers (ATRA and 13-cis AR) and with 5-fu chemotherapeutic agents, cisplatin and paclitaxel. It was determined if these substances leaded cytotoxicity, apoptosis and if they modified the expression of different genes related to cellular death by apoptosis, in order to explain the hepatocellular carcinoma resistance to these drugs. HepG2 cells showed more resistance than Hep3B cells to 72 hours of treatment, as much ATRA as the 13-cis AR were toxic and produced apoptosis in two cellular lines. This type of cellular death seems to be mediated by a decrease in Bcl-xL concentration in Hep3B cells treated with both retinoids an increase in bax concentration in HepG2 cells treated with 13-cis AR. It were observed 3 and 8 proteolysis of procaspase in Hep3B cells, suggesting extrinsic via activation of the apoptosis, while cellular death in HepG2 cells seems to be independent of caspases. Cisplatin and paclitaxel leaded cytotoxicity to 48 hours of treatment, with significant differences between two cellular lines only in case of paclitaxel. Hep3B cells treated with cisplatin and HepG2 cells treated with paclytaxel suffered apoptosis. 5-FU produced toxicity only when it was used to high concentrations and the mechanism of cellular death induced by this agent seems to be primarily necrosis in Hep3B cells and apoptosis in HepG2. There was decrease in the Bcl-xL concentration in two cellular lines when it was treated with cisplatin and in HepG2 cells treated with 5-FU. Bax concentration there no was modified with no treatment. Activation of the 3 caspases seems to happen only in HepG2 cells with 5-FU and paclytaxel. These two agents, also, decreased the survivin concentration of HepG2 cells. Treatments of the three drugs produced an increase in the expression of this gen in Hep3B cells, which might explain partially the resistance

  9. Preparation of N, N, N-trimethyl chitosan-functionalized retinoic acid ...

    African Journals Online (AJOL)

    nanocarrier (TR-SLNs) with enhanced anti-cancer activity. ... Retinoic acid (RA), a derivative of vitamin A, is a potential ... intravenous (i.v.) administration; therefore, RA ... °C. Preparation of TMC. TMC was synthesized by reductive methylation.

  10. Role of retinoic acid receptors in squamous-cell carcinoma in human esophagus

    DEFF Research Database (Denmark)

    Bergheim, I.; Wolfgarten, E.; Bollschweiler, E.

    2005-01-01

    BACKGROUND: Worldwide, cancer in the esophagus ranks among the 10 most common cancers. Alterations of retinoic acid receptors (e.g. RARalpha, beta, gamma, and RXRalpha, beta, gamma) expression is considered to play an important role in development of squamous-cell carcinoma (SCC), which is the most...... common esophageal cancer. Alcohol consumption and smoking, which can alter retinoic acid receptor levels, have been identified as key risk factors in the development of carcinoma in the aero-digestive tract. Therefore, the aim of the present study was to evaluate protein levels of retinoic acid receptors...... were found for RARalpha, beta, and RXRbeta protein levels between normal esophageal tissue of patients and that of controls. CONCLUSION: In conclusion, results of the present study suggest that alterations of retinoic acid receptors protein may contribute in the development of SCC in esophagus...

  11. Retinoic acid for treatment of systemic sclerosis and morphea: A literature review.

    Science.gov (United States)

    Thomas, Renee M; Worswick, Scott; Aleshin, Maria

    2017-03-01

    Systemic sclerosis and morphea are connective tissue diseases characterized by tightening, thickening, and hardening of the skin, leading to significant morbidity. Unfortunately, current treatment options have limited efficacy for many patients. Cutaneous manifestations of these diseases arise from excess collagen deposition and fibrosis in the skin, through pathogenic mechanisms which have yet to be extensively detailed at the causal immune and cellular levels. Research elucidating the mechanism of action of retinoic acid on collagen production in the skin and case series highlighting the success of retinoic acid on the skin manifestations of systemic sclerosis and on morphea demonstrate its promise as a treatment. Herein they will briefly review the treatment options for both systemic sclerosis and morphea, and will discuss the potential of retinoic acid as a therapy and the supporting evidence from the literature, highlighting the previously published basic science and clinical studies investigating the role of retinoic acid in the treatment of sclerotic skin diseases. © 2016 Wiley Periodicals, Inc.

  12. Preparation of N, N, N-trimethyl chitosan-functionalized retinoic acid ...

    African Journals Online (AJOL)

    encapsulated solid lipid nanoparticles for the effective treatment of glioma. Methods: Retinoic acid-loaded solid lipid nanoparticles (R-SLNs) were prepared using homogenization followed by sonication. R-SLN surfaces were functionalized electrostatically ...

  13. Retinoic acid modulates chondrogenesis in the developing mouse cranial base.

    Science.gov (United States)

    Kwon, Hyuk-Jae; Shin, Jeong-Oh; Lee, Jong-Min; Cho, Kyoung-Won; Lee, Min-Jung; Cho, Sung-Won; Jung, Han-Sung

    2011-12-15

    The retinoic acid (RA) signaling pathway is known to play important roles during craniofacial development and skeletogenesis. However, the specific mechanism involving RA in cranial base development has not yet been clearly described. This study investigated how RA modulates endochondral bone development of the cranial base by monitoring the RA receptor RARγ, BMP4, and markers of proliferation, programmed cell death, chondrogenesis, and osteogenesis. We first examined the dynamic morphological and molecular changes in the sphenooccipital synchondrosis-forming region in the mouse embryo cranial bases at E12-E16. In vitro organ cultures employing beads soaked in RA and retinoid-signaling inhibitor citral were compared. In the RA study, the sphenooccipital synchondrosis showed reduced cartilage matrix and lower BMP4 expression while hypertrophic chondrocytes were replaced with proliferating chondrocytes. Retardation of chondrocyte hypertrophy was exhibited in citral-treated specimens, while BMP4 expression was slightly increased and programmed cell death was induced within the sphenooccipital synchondrosis. Our results demonstrate that RA modulates chondrocytes to proliferate, differentiate, or undergo programmed cell death during endochondral bone formation in the developing cranial base. Copyright © 2011 Wiley Periodicals, Inc., A Wiley Company.

  14. Retinoic acid activates two pathways required for meiosis in mice.

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    Jana Koubova

    2014-08-01

    Full Text Available In all sexually reproducing organisms, cells of the germ line must transition from mitosis to meiosis. In mice, retinoic acid (RA, the extrinsic signal for meiotic initiation, activates transcription of Stra8, which is required for meiotic DNA replication and the subsequent processes of meiotic prophase. Here we report that RA also activates transcription of Rec8, which encodes a component of the cohesin complex that accumulates during meiotic S phase, and which is essential for chromosome synapsis and segregation. This RA induction of Rec8 occurs in parallel with the induction of Stra8, and independently of Stra8 function, and it is conserved between the sexes. Further, RA induction of Rec8, like that of Stra8, requires the germ-cell-intrinsic competence factor Dazl. Our findings strengthen the importance of RA and Dazl in the meiotic transition, provide important details about the Stra8 pathway, and open avenues to investigate early meiosis through analysis of Rec8 induction and function.

  15. Bovine cumulus-granulosa cells contain biologically active retinoid receptors that can respond to retinoic acid

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    Malayer Jerry

    2003-11-01

    Full Text Available Abstract Retinoids, a class of compounds that include retinol and its metabolite, retinoic acid, are absolutely essential for ovarian steroid production, oocyte maturation, and early embryogenesis. Previous studies have detected high concentrations of retinol in bovine large follicles. Further, administration of retinol in vivo and supplementation of retinoic acid during in vitro maturation results in enhanced embryonic development. In the present study, we hypothesized that retinoids administered either in vivo previously or in vitro can exert receptor-mediated effects in cumulus-granulosa cells. Total RNA extracted from in vitro cultured cumulus-granulosa cells was subjected to reverse transcription polymerase chain reaction (RT-PCR and mRNA expression for retinol binding protein (RBP, retinoic acid receptor alpha (RARalpha, retinoic acid receptor beta (RARbeta, retinoic acid receptor gamma (RARgamma, retinoid X receptor alpha (RXRalpha, retinoid X receptor beta (RXRbeta, retinaldehyde dehydrogenase-2 (RALDH-2, and peroxisome proliferator activated receptor gamma (PPARgamma. Transcripts were detected for RBP, RARalpha, RARgamma, RXRalpha, RXRbeta, RALDH-2, and PPARgamma. Expression of RARbeta was not detected in cumulus-granulosa cells. Using western blotting, immunoreactive RARalpha, and RXRbeta protein was also detected in bovine cumulus-granulosa cells. The biological activity of these endogenous retinoid receptors was tested using a transient reporter assay using the pAAV-MCS-betaRARE-Luc vector. Addition of 0.5 and 1 micro molar all-trans retinoic acid significantly (P trans retinol stimulated a mild increase in reporter activity, however, the increase was not statistically significant. Based on these results we conclude that cumulus cells contain endogenously active retinoid receptors and may also be competent to synthesize retinoic acid using the precursor, retinol. These results also indirectly provide evidence that retinoids

  16. Separation behavior of octadecadienoic acid isomers and identification of cis- and trans-isomers using gas chromatography.

    Science.gov (United States)

    Shibamoto, Shigeaki; Gooley, Andrew; Yamamoto, Kouhei

    2015-01-01

    Using a strongly polar cyanopropyl capillary column we have investigated the gas chromatography (GC) separation behaviors of 24 octadecadienoic acid methyl ester (18:2ME) isomers compared against saturated methyl stearate (18:0ME) and arachidic acid methyl ester (20:0ME), and the dependency on the GC column temperature. The 24 isomers were obtained by performing cis-to trans-isomerization of six regioisomers: five of the 18:2ME isomers were prepared by the partial reduction of methyl α-linolenate and methyl γ-linolenate C18 trienoic acids with different double bond positions, whereas the sixth isomer, 18:2ME (c5, c9), was obtained from a raw constituent fatty acid methyl ester (FAME) sample extracted from Japanese yew seeds. There are no reference standards commercially available for 18:2ME isomers, and in elucidating the elution order of these isomers this study should help the future identification of cis- and trans-type of 18:2ME. We also report the identification method of cis- and trans-type of FAME using equivalent chain lengths and attempt the identification of cis- and trans-type of 18:2ME isomers from partially hydrogenated canola oil.

  17. Neutrophils are immune cells preferentially targeted by retinoic acid in elderly subjects

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    Minet-Quinard Régine

    2010-08-01

    Full Text Available Abstract Background The immune system gradually deteriorates with age and nutritional status is a major factor in immunosenescence. Of the many nutritional factors implicated in age-related immune dysfunction, vitamin A may be a good candidate, since vitamin A concentrations classically decrease during aging whereas it may possess important immunomodulatory properties via its active metabolites, the retinoic acids. This prompted us to investigate the immune response induced by retinoids in adults and elderly healthy subjects. Before and after oral supplementation with 13cis retinoic acid (0.5 mg/kg/day during 28 days, whole blood cells were phenotyped, and functions of peripheral blood mononuclear cells (PBMC and polymorphonuclear cells (PMN were investigated by flow cytometry and ELISA tests. Results In both young adults (n = 20, 25 ± 4 years and older subjects (n = 20, 65 ± 4 years, retinoic acid supplementation had no effect on the distribution of leukocyte subpopulations or on the functions of PBMC (Il-2 and sIl-2R production, membrane expression of CD25. Concerning PMN, retinoic acid induced an increase in both spontaneous migration and cell surface expression of CD11b in the two different age populations, whereas bactericidal activity and phagocytosis remained unchanged. Conclusions We demonstrated that retinoic acid induces the same intensity of immune response between adult and older subjects, and more specifically affects PMN functions, i.e. adhesion and migration, than PBMC functions.

  18. Retinoic acid signaling: a new piece in the spoken language puzzle

    Directory of Open Access Journals (Sweden)

    Jon-Ruben eVan Rhijn

    2015-11-01

    Full Text Available Speech requires precise motor control and rapid sequencing of highly complex vocal musculature. Despite its complexity, most people produce spoken language effortlessly. This is due to activity in distributed neuronal circuitry including cortico-striato-thalamic loops that control speech-motor output. Understanding the neuro-genetic mechanisms that encode these pathways will shed light on how humans can effortlessly and innately use spoken language and could elucidate what goes wrong in speech-language disorders.FOXP2 was the first single gene identified to cause speech and language disorder. Individuals with FOXP2 mutations display a severe speech deficit that also includes receptive and expressive language impairments. The underlying neuro-molecular mechanisms controlled by FOXP2, which will give insight into our capacity for speech-motor control, are only beginning to be unraveled. Recently FOXP2 was found to regulate genes involved in retinoic acid signaling and to modify the cellular response to retinoic acid, a key regulator of brain development. Herein we explore the evidence that FOXP2 and retinoic acid signaling function in the same pathways. We present evidence at molecular, cellular and behavioral levels that suggest an interplay between FOXP2 and retinoic acid that may be important for fine motor control and speech-motor output. We propose that retinoic acid signaling is an exciting new angle from which to investigate how neurogenetic mechanisms can contribute to the (spoken language ready brain.

  19. Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor.

    Directory of Open Access Journals (Sweden)

    Barbara Hämmerle

    Full Text Available Neuroblastma cell lines contain a side-population of cells which express stemness markers. These stem-like cells may represent the potential underlying mechanism for resistance to conventional therapy and recurrence of neuroblastoma in patients.To develop novel strategies for targeting the side-population of neurobastomas, we analyzed the effects of 13-cis-retinoic acid (RA combined with the proteasome inhibitor MG132. The short-term action of the treatment was compared with effects after a 5-day recovery period during which both chemicals were withdrawn. RA induced growth arrest and differentiation of SH-SY5Y and SK-N-BE(2 neuroblastoma cell lines. Inhibition of the proteasome caused apoptosis in both cell lines, thus, revealing the critical role of this pathway in the regulated degradation of proteins involved in neuroblastoma proliferation and survival. The combination of RA with MG132 induced apoptosis in a dose-dependent manner, in addition to promoting G2/M arrest in treated cultures. Interestingly, expression of stem cell markers such as Nestin, Sox2, and Oct4 were reduced after the recovery period of combined treatment as compared with untreated cells or treated cells with either compound alone. Consistent with this, neurosphere formation was significantly impaired by the combined treatment of RA and MG132.Given that stem-like cells are associated with resistant to conventional therapy and are thought to be responsible for relapse, our results suggest that dual therapy of RA and proteasome inhibitor might be beneficial for targeting the side-population of cells associated residual disease in high-risk neuroblastoma.

  20. Teratogenic effects of retinoic acid on neurulation in mice embryos.

    Science.gov (United States)

    Nobakht, M; Zirak, A; Mehdizadeh, M; Tabatabaeei, P

    2006-02-21

    Retinoic acids (RA) are natural chemicals that exert a hormone-like activity and a variety of biological effects on early development of mouse. In this study, the probable teratogenic effects of RA on CNS have been investigated in pregnant mice (n = 20) divided into four groups: (1) untreated controls, (2) controls which received a single dose of DMSO, (3) a group that received 40 mg/kg, and (4) a group that received 60 mg/kg of all-trans RA in DMSO, respectively on the eighth day of gestation. Embryos whose dams had received 40 and 60 mg/kg doses of RA, showed malformations and decreased size. At 40 mg/kg dosage level, 50% of the embryos had closed neural tubes while at 60 mg/kg dosage level the neural tube failed to close. The neuroblast mantle layers were disorganized in the 40 mg/kg and even more in the 60 mg/kg exposed group compared to the controls. In mitosis, the density of chromatin was increased in the 60 mg/kg dose group. Compared to controls the 40 and 60 mg/kg dose groups of RA treated dams decreases in the luminal longitudinal and internal measures were observed. Also the thickness of ventricular, mantle and marginal layers was smaller. Wide intercellular spaces due to the degenerated cells at high doses of RA as well as an accumulation of intercellular fluid were observed. Therefore, the wedge shape of neuroepithelium was abolished, preventing the elevation of the neural wall.

  1. Neofunctionalization in vertebrates: the example of retinoic acid receptors.

    Directory of Open Access Journals (Sweden)

    Hector Escriva

    2006-07-01

    Full Text Available Understanding the role of gene duplications in establishing vertebrate innovations is one of the main challenges of Evo-Devo (evolution of development studies. Data on evolutionary changes in gene expression (i.e., evolution of transcription factor-cis-regulatory elements relationships tell only part of the story; protein function, best studied by biochemical and functional assays, can also change. In this study, we have investigated how gene duplication has affected both the expression and the ligand-binding specificity of retinoic acid receptors (RARs, which play a major role in chordate embryonic development. Mammals have three paralogous RAR genes--RAR alpha, beta, and gamma--which resulted from genome duplications at the origin of vertebrates. By using pharmacological ligands selective for specific paralogues, we have studied the ligand-binding capacities of RARs from diverse chordates species. We have found that RAR beta-like binding selectivity is a synapomorphy of all chordate RARs, including a reconstructed synthetic RAR representing the receptor present in the ancestor of chordates. Moreover, comparison of expression patterns of the cephalochordate amphioxus and the vertebrates suggests that, of all the RARs, RAR beta expression has remained most similar to that of the ancestral RAR. On the basis of these results together, we suggest that while RAR beta kept the ancestral RAR role, RAR alpha and RAR gamma diverged both in ligand-binding capacity and in expression patterns. We thus suggest that neofunctionalization occurred at both the expression and the functional levels to shape RAR roles during development in vertebrates.

  2. Interaction between cellular retinoic acid-binding protein II and histone hypoacetylation in renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Viroj Wiwanitkit

    2008-04-01

    Full Text Available Renal cell carcinoma is a rare but serious malignancy. Since a reduction in the level of retinoic acid receptor beta 2 (RARbeta2 expression in cancer cells due in part to histone hypoacetylation which is controlled by histone deacetylase (HD, the study on the interaction between cellular retinoic acid-binding proteins II (CRABP II, which is proposed to have its potential influence on retinoic acid (RA response, and HD can be useful. Comparing to CARBP II and HD, the CARBP II-HD poses the same function and biological process as HD. This can confirm that HD has a significant suppressive effect on the expression of CARBP II. Therefore, reduction in the level of RARbeta2 expression in cancer cells can be expected and this can lead to failure in treatment of renal cell carcinoma with RA. The author hereby purpose that additional HD inhibitor should be added into the regiment of RA to increase the effectiveness of treatment.

  3. In Vivo Imaging of Retinoic Acid Receptor Activity using a Sodium/Iodide Symporter and Luciferase Dual Imaging Reporter Gene

    Directory of Open Access Journals (Sweden)

    Min Kyung So

    2004-07-01

    Full Text Available Retinoic acids are natural derivatives of vitamin A, and play important roles in modulating tumor cell growth by regulating differentiation, thus suggesting the potential use of these derivatives in cancer therapy and prevention. To visualize the intranuclear responses of functional retinoic acid receptors, we have developed a dual-imaging reporter gene system based on the use of sodium/iodide symporter (NIS and luciferase in cancer cell lines. NIS and luciferase genes were linked with an internal ribosome entry site, and placed under the control of an artificial cis-acting retinoic acid responsive element (pRARE/NL. After retinoic acid treatment, I-125 uptake by pRARE/NL transfected cells was found to have increased by up to about five times that of nontreated cells. The bioluminescence intensity of pRARE/NL transfected cells showed dose-dependency. In vivo luciferase images showed higher intensity in retinoic acid treated SK-RARE/NL tumors, and scintigraphic images of SK-RARE/NL tumors showed increased Tc-99m uptake after retinoic acid treatment. The NIS/luciferase imaging reporter system was sufficiently sensitive to allow the visualization of intranuclear retinoic acid receptor activity. This cis-enhancer imaging reporter system may be useful in vitro and in vivo for the evaluation of retinoic acid responses in such areas as cellular differentiation and chemoprevention.

  4. Effect of retinoic acid on proteoglycan turnover in bovine articular cartilage cultures

    International Nuclear Information System (INIS)

    Campbell, M.A.; Handley, C.J.

    1987-01-01

    This paper describes proteoglycan catabolism by adult bovine articular cartilage treated with retinoic acid as a means of stimulating the loss of this macromolecule from the extracellular matrix of cartilage. Addition of retinoic acid (10(-12)-10(-6) M) to adult bovine articular cartilage which had been labeled with [ 35 S]sulfate for 6 h after 5 days in culture, resulted in a dose-dependent increase in the rate of loss of 35 S-labeled proteoglycans from the matrix of the tissue. Concomitant with this loss was a decrease in the proteoglycan content of the tissue. Incubation of cultures treated with 1 microM retinoic acid, at 4 degrees C, or with 0.5 mM cycloheximide, resulted in a significant decrease in the rate of retinoic acid-induced loss of proteoglycans and demonstrated cellular involvement in this process. Analysis of the 35 S-labeled proteoglycans remaining in the matrix showed that the percentage of radioactivity associated with the small proteoglycan species extracted from the matrix of articular cartilage explants labeled with [ 35 S]sulfate after 5 days in culture was 15% and this increased to 22% in tissue maintained in medium alone. In tissue treated with 1 microM retinoic acid for 6 days, the percentage of radioactivity associated with the small proteoglycan was 58%. Approximately 93% of the 35 S-labeled proteoglycans released into the medium of control and retinoic acid-treated cultures was recovered in high density fractions after CsCl gradient centrifugation and eluted on Sepharose CL-2B as a broad peak with a Kav of 0.30-0.37. Less than 17% of these proteoglycans was capable of aggregating with hyaluronate. These results indicate that in both control and retinoic acid-treated cultures the larger proteoglycan species is lost to the medium at a greater rate than the small proteoglycan species. The effect of retinoic acid on proteoglycan turnover was shown to be reversible

  5. BIOLOGICAL ROLE OF ALDO-KETO REDUCTASES IN RETINOIC ACID BIOSYNTHESIS AND SIGNALING

    Directory of Open Access Journals (Sweden)

    F. Xavier eRuiz

    2012-04-01

    Full Text Available Several aldo-keto reductase (AKR enzymes from subfamilies 1B and 1C show retinaldehyde reductase activity, having low Km and kcat values. Only AKR1B10 and 1B12, with all-trans-retinaldehyde, and AKR1C3, with 9-cis-retinaldehyde, display high catalytic efficiency. Major structural determinants for retinaldehyde isomer specificity are located in the external loops (A and C for AKR1B10, and B for AKR1C3, as assessed by site-directed mutagenesis and molecular dynamics. Cellular models have shown that AKR1B and 1C enzymes are well suited to work in vivo as retinaldehyde reductases and to regulate retinoic acid (RA biosynthesis at hormone pre-receptor level. An additional physiological role for the retinaldehyde reductase activity of these enzymes, consistent with their tissue localization, is their participation in β-carotene absorption. Retinaldehyde metabolism may be subjected to subcellular compartmentalization, based on enzyme localization. While retinaldehyde oxidation to RA takes place in the cytosol, reduction to retinol could take place in the cytosol by AKRs or in the membranes of endoplasmic reticulum by microsomal retinaldehyde reductases. Upregulation of some AKR1 enzymes in different cancer types may be linked to their induction by oxidative stress and to their participation in different signaling pathways related to cell proliferation. AKR1B10 and AKR1C3, through their retinaldehyde reductase activity, trigger a decrease in the RA biosynthesis flow, resulting in RA deprivation and consequently lower differentiation, with an increased cancer risk in target tissues. Rational design of selective AKR inhibitors could lead to development of novel drugs for cancer treatment as well as reduction of chemotherapeutic drug resistance.

  6. Metabolism of all-trans-retinoic acid and all-trans-retinyl acetate. Demonstration of common physiological metabolites in rat small intestinal mucosa and circulation

    International Nuclear Information System (INIS)

    Cullum, M.E.; Zile, M.H.

    1985-01-01

    The kinetics and metabolism of physiological doses of all-trans-retinoic acid were examined in blood and small intestinal mucosa of vitamin A-depleted rats. A major portion of intrajugularly injected retinoic acid is rapidly (within 2 min) sequestered by tissues; subsequently 13-cis-retinoic acid and polar metabolites are released into circulation. All-trans-retinoic acid appears in small intestinal epithelium within 2 min after dosing and is the major radioactive compound there for at least 2 h. Retinoyl glucuronide and 13-cis-retinoic acid are early metabolites of all-trans-retinoic acid in the small intestine of bile duct-cannulated rats. Retinoyl glucuronide, the major metabolite of retinoic acid intestinal epithelium, in contrast to other polar metabolites, was not detected in circulation. An examination of [ 3 H]retinyl acetate metabolites under steady state conditions in vitamin A-repleted rats demonstrates the occurrence of all-trans-retinoic acid and 13-cis-retinoic acid in circulation and in intestinal epithelium, in a pattern similar to that found after injection of retinoic acid into vitamin A-depleted rats. These data establish that all-trans-retinoic acid, 13-cis-retinoic acid, and retinoyl glucuronide are physiological metabolites of vitamin A in target tissues, and therefore are important candidates as mediators of the biological effect of the vitamin

  7. Comparative Effects of Retinoic Acid or Glycolic Acid Vehiculated in Different Topical Formulations

    Science.gov (United States)

    Maia Campos, Patrícia Maria Berardo Gonçalves; Gaspar, Lorena Rigo; Gonçalves, Gisele Mara Silva; Pereira, Lúcia Helena Terenciane Rodrigues; Semprini, Marisa; Lopes, Ruberval Armando

    2015-01-01

    Retinoids and hydroxy acids have been widely used due to their effects in the regulation of growth and in the differentiation of epithelial cells. However, besides their similar indication, they have different mechanisms of action and thus they may have different effects on the skin; in addition, since the topical formulation efficiency depends on vehicle characteristics, the ingredients of the formulation could alter their effects. Thus the objective of this study was to compare the effects of retinoic acid (RA) and glycolic acid (GA) treatment on the hairless mouse epidermis thickness and horny layer renewal when added in gel, gel cream, or cream formulations. For this, gel, gel cream, and cream formulations (with or without 6% GA or 0.05% RA) were applied in the dorsum of hairless mice, once a day for seven days. After that, the skin was analyzed by histopathologic, morphometric, and stereologic techniques. It was observed that the effects of RA occurred independently from the vehicle, while GA had better results when added in the gel cream and cream. Retinoic acid was more effective when compared to glycolic acid, mainly in the cell renewal and the exfoliation process because it decreased the horny layer thickness. PMID:25632398

  8. Three conazoles increase hepatic microsomal retinoic acid metabolism and decrease mouse hepatic retinoic acid levels in vivo

    International Nuclear Information System (INIS)

    Chen, P.-J.; Padgett, William T.; Moore, Tanya; Winnik, Witold; Lambert, Guy R.; Thai, Sheau-Fung; Hester, Susan D.; Nesnow, Stephen

    2009-01-01

    Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with cancer-preventative properties (Ward et al., Toxicol. Pathol. 2006; 34:863-78). The goals of this study were to examine effects of propiconazole, triadimefon, and myclobutanil, three triazole-containing conazoles, on the microsomal metabolism of atRA, the associated hepatic cytochrome P450 (P450) enzyme(s) involved in atRA metabolism, and their effects on hepatic atRA levels in vivo. The in vitro metabolism of atRA was quantitatively measured in liver microsomes from male CD-1 mice following four daily intraperitoneal injections of propiconazole (210 mg/kg/d), triadimefon (257 mg/kg/d) or myclobutanil (270 mg/kg/d). The formation of both 4-hydroxy-atRA and 4-oxo-atRA were significantly increased by all three conazoles. Propiconazole-induced microsomes possessed slightly greater metabolizing activities compared to myclobutanil-induced microsomes. Both propiconazole and triadimefon treatment induced greater formation of 4-hydroxy-atRA compared to myclobutanil treatment. Chemical and immuno-inhibition metabolism studies suggested that Cyp26a1, Cyp2b, and Cyp3a, but not Cyp1a1 proteins were involved in atRA metabolism. Cyp2b10/20 and Cyp3a11 genes were significantly over-expressed in the livers of both triadimefon- and propiconazole-treated mice while Cyp26a1, Cyp2c65 and Cyp1a2 genes were over-expressed in the livers of either triadimefon- or propiconazole-treated mice, and Cyp2b10/20 and Cyp3a13 genes were over-expressed in the livers of myclobutanil-treated mice. Western blot analyses indicated conazole induced-increases in Cyp2b and Cyp3a proteins. All three conazoles decreased hepatic atRA tissue levels ranging from 45-67%. The possible implications of these changes in hepatic atRA levels

  9. The Expression of Bone Morphogenetic Protein 2 and Matrix Metalloproteinase 2 through Retinoic Acid Receptor Beta Induced by All-Trans Retinoic Acid in Cultured ARPE-19 Cells.

    Directory of Open Access Journals (Sweden)

    Zhenya Gao

    Full Text Available All-trans retinoic acid (ATRA plays an important role in ocular development. Previous studies found that retinoic acid could influence the metabolism of scleral remodeling by promoting retinal pigment epithelium (RPE cells to secrete secondary signaling factors. The purpose of this study was to investigate whether retinoic acid affected secretion of bone morphogenetic protein 2 (BMP-2 and matrix metalloproteinase 2 (MMP-2 and to explore the signaling pathway of retinoic acid in cultured acute retinal pigment epithelial 19 (ARPE-19 cells.The effects of ATRA (concentrations from 10-9 to 10-5 mol/l on the expression of retinoic acid receptors (RARs in ARPE-19 cells were examined at the mRNA and protein levels using reverse transcription-polymerase chain reaction (RT-PCR and western blot assay, respectively. The effects of treating ARPE-19 cells with ATRA concentrations ranging from 10-9 to 10-5 mol/l for 24 h and 48 h or with 10-6mol/l ATRA at different times ranging from 6h to 72h were assessed using real-time quantitative PCR (qPCR and enzyme-linked immunosorbent assay (ELISA. The contribution of RARβ-induced activation of ARPE-19 cells was confirmed using LE135, an antagonist of RARβ.RARβ mRNA levels significantly increased in the ARPE-19 cells treated with ATRA for 24h and 48h. These increases in RARβ mRNA levels were dose dependent (at concentrations of 10-9 to 10-5 mol/l with a maximum effect observed at 10-6 mol/l. There were no significant changes in the mRNA levels of RARα and RARγ. Western blot assay revealed that RARβ protein levels were increased significantly in a time-dependent manner in ARPE-19 cells treated with 10-6 mol/l ATRA from 12 h to 72 h, with a marked increase observed at 24 h and 48 h. The upregulation of RARβ and the ATRA-induced secretion in ARPE-19 cells could be inhibited by the RARβ antagonist LE135.ATRA induced upregulation of RARβ in ARPE-19 cells and stimulated these cells to secrete BMP-2 and MMP-2.

  10. Topical retinoic acid changes the epidermal cell surface glycosylation pattern towards that of a mucosal epithelium

    DEFF Research Database (Denmark)

    Griffiths, C E; Dabelsteen, Erik; Voorhees, J J

    1996-01-01

    Topical all-trans retinoic acid (RA) produces a number of epidermal changes which are indistinguishable from those observed following treatment with a local irritant, namely sodium lauryl sulphate (SLS). This observation has led to criticism that the efficacy of RA in disorders such as photoageing...

  11. Retinoic acid and Cyp26b1 are critical regulators of osteogenesis in the axial skeleton

    NARCIS (Netherlands)

    Spoorendonk, K.M.; Peterson-Maduro, J.; Renn, J.; Trowe, T.; Kranenbarg, S.; Winkler, C.; Schulte-Merker, S.

    2008-01-01

    Retinoic acid (RA) plays important roles in diverse biological processes ranging from germ cell specification to limb patterning. RA ultimately exerts its effect in the nucleus, but how RA levels are being generated and maintained locally is less clear. Here, we have analyzed the zebrafish

  12. Retinoic acid: an educational "vitamin elixir" for gut-seeking T cells.

    Science.gov (United States)

    Mora, J Rodrigo; von Andrian, Ulrich H

    2004-10-01

    T cell priming by dendritic cells (DC) from gut-associated lymphoid tissues gives rise to effector cells with pronounced gut tropism. The mechanism for DC-dependent imprinting of gut specificity has remained unknown. New findings point to retinoic acid, which is uniquely produced by intestinal DC, but not by DC from other lymphoid organs.

  13. Novel retinoic acid receptor alpha agonists for treatment of kidney disease.

    Directory of Open Access Journals (Sweden)

    Yifei Zhong

    Full Text Available Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs: RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1 in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN. Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN.

  14. ISOLATION AND CHARACTERIZATION OF AXOLOTL NPDC-1 AND ITS EFFECTS ON RETINOIC ACID RECEPTOR SIGNALING

    Science.gov (United States)

    Theodosiou, Maria; Monaghan, James R; Spencer, Michael L; Voss, S Randal; Noonan, Daniel J

    2009-01-01

    Retinoic acid, a key morphogen in early vertebrate development and tissue regeneration, mediates its effects through the binding of receptors that act as ligand-induced transcription factors. These binding events function to recruit an array of transcription co-regulatory proteins to specific gene promoters. One such co-regulatory protein, neuronal proliferation and differentiation control-1 (NPDC-1), is broadly expressed during mammalian development and functions as an in vitro repressor of retinoic acid receptor (RAR)-mediated transcription. To obtain comparative and developmental insights about NPDC-1 function, we cloned the axolotl (Ambystoma mexicanum) orthologue and measured transcript abundances among tissues sampled during the embryonic and juvenile phases of development, and also during spinal cord regeneration. Structurally, the axolotl orthologue of NPDC-1 retained sequence identity to mammalian sequences in all functional domains. Functionally, we observed that axolotl NPDC-1 mRNA expression peaked late in embryogenesis, with highest levels of expression occurring during the time of limb development, a process regulated by retinoic acid signaling. Also similar to what has been observed in mammals, axolotl NPDC-1 directly interacts with axolotl RAR, modulates axolotl RAR DNA binding, and represses cell proliferation and axolotl RAR-mediated gene transcription. These data justify axolotl as a model to further investigate NPDC-1 and its role in regulating retinoic acid signaling. PMID:17331771

  15. Disabled-2 Mediation of Retinoic Acid Cell Growth Arrest Signal in Breast Cancer

    Science.gov (United States)

    2002-08-01

    C. Cohen, L. E. Mendez , I. R. Horowitz, ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. A. I Godwin, and X X. Xu, submitted for publication. T...trans., 9-cis-retinoic acid) and P- caro - forming units of adenovirus were added to the cells in medium with low tene were purchased from Sigma

  16. Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema.

    Science.gov (United States)

    Hind, Matthew; Stinchcombe, Sian

    2009-11-01

    Emphysema is characterized by the destruction of alveoli and alveolar ducts within the lungs. Retinoid signaling is believed to play a role in alveologenesis, with the retinoic acid receptor gamma thought to be required for alveolar formation. Based on this hypothesis, Roche Holding AG is developing palovarotene (R-667, RO-3300074), a selective retinoic acid receptor gamma agonist for the treatment of emphysema. In small animal studies, palovarotene was claimed to reverse the structural, functional and inflammatory features of cigarette smoke-induced emphysema. Phase I clinical trials of palovarotene in patients with emphysema demonstrated that the drug is well tolerated, with improvements observed in markers of emphysema progression. Unlike all-trans retinoic acid, the pharmacokinetic profile of palovarotene appears to be dose-proportional. At the time of publication, a phase II, placebo-controlled trial was ongoing, and was expected to report prospective measurements of exercise, gas transfer and lung densitometry endpoints. The development of a selective retinoic acid receptor gamma agonist for the treatment of emphysema represents the first of a new class of small-molecule regenerative therapies that may prove useful for the treatment of destructive or age-related lung disease.

  17. Increased Toxicity of Chemotherapeutic Drugs by All-Trans Retinoic Acid in Cd44 Cells

    Directory of Open Access Journals (Sweden)

    A Abbasi

    2016-03-01

    Full Text Available BACKGROUND AND OBJECTIVE: In recent studies, undifferentiated CD44 cells have been introduced as the major cause of chemotherapeutic drug resistance in esophageal cancer. In this study, we aimed to evaluate the effects of all-trans retinoic acid on reducing chemotherapeutic drug resistance and improving the associated toxic effects. METHODS: In this clinical study, CD44+ and CD44- cells were separated from KYSE-30 cell line, using magnetic-activated cell sorting (MACS method. The cytotoxic effects of retinoic acid treatment, combined with cisplatin and 5-fluorouracil, were separately evaluated in two cell groups, i.e., CD44+ and CD44-. Cytotoxicity was determined by identifying cellular metabolic activity, acridine orange/ethidium bromide staining, and flow cytometry. FINDINGS: In this study, CD44 marker was expressed in 6.25% of the cell population in KYSE-30 cell line. The results of flow cytometry revealed that treatment with a combination of retinoic acid and chemotherapeutic drugs could improve cell cycle arrest in CD44+ cells (p<0.05, unlike CD44- cells. Determination of cellular metabolic activity, increased cell apoptosis along with decreased half maximal inhibitory concentration (IC50, and acridine orange/ethidium bromide staining were indicative of the increased percentage of primary and secondary apoptotic CD44+ cells. However, in CD44- cells, these effects were only observed by using a combination of retinoic acid and cisplatin (p<0.05. CONCLUSION: The present results showed that all-trans retinoic acid could increase the toxicity of cisplatin and 5-fluorouracil in CD44+ cells.

  18. Synthesis of two possible ligature for the receivers of the acid retinoic

    International Nuclear Information System (INIS)

    Coto Quintana, T.

    1997-01-01

    The retinoic acid and their similar, play an important part in the control of the growth of the cellular diferenciation. This biological activity is due to its interaction with the nuclear receivers of the retinoic acid (RARs and RXRs). In this work was synthesized two similar of the retinoic acid: the acid (E)-3-(3 - [(5,6,7,8-tetrathido-3,5,5,8,8-pentametil-2-naftil)cartonil] fenil)-2-butenoico (1) and the acid (AND) -3-(3 - [(5,6,7,8-tethahiddro-3,5,5,8,8-pentametil-2-naftil)etenil] enil)-2-butenoico (2). The elaboration of (1) required six synthetic steps and involved a study of the joining Heck with paladio being evaluated the use of two different methods, one direct and the other one indirect. The structural elucidation of (1), (2), the synthetic precursor (6) and the isolation of four secondary compounds were interesting, being reached conclusions with regard to regal aspects - and estereoquimical of the corresponding reactions. The ceto-acid (1) resulted active with the receiving RAR, showing selectivity for the subtypes β and γ [es

  19. Are conjugated linolenic acid isomers an alternative to conjugated linoleic acid isomers in obesity prevention?

    Science.gov (United States)

    Miranda, Jonatan; Arias, Noemi; Fernández-Quintela, Alfredo; del Puy Portillo, María

    2014-04-01

    Despite its benefits, conjugated linoleic acid (CLA) may cause side effects after long-term administration. Because of this and the controversial efficacy of CLA in humans, alternative biomolecules that may be used as functional ingredients have been studied in recent years. Thus, conjugated linolenic acid (CLNA) has been reported to be a potential anti-obesity molecule which may have additional positive effects related to obesity. According to the results reported in obesity, CLNA needs to be given at higher doses than CLA to be effective. However, because of the few studies conducted so far, it is still difficult to reach clear conclusions about the potential use of these CLNAs in obesity and its related changes (insulin resistance, dyslipidemia, or inflammation). Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.

  20. Triphenyl phosphate-induced developmental toxicity in zebrafish: Potential role of the retinoic acid receptor

    Energy Technology Data Exchange (ETDEWEB)

    Isales, Gregory M.; Hipszer, Rachel A.; Raftery, Tara D. [Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC (United States); Chen, Albert; Stapleton, Heather M. [Division of Environmental Sciences and Policy, Nicholas School of the Environment, Duke University, Durham, NC (United States); Volz, David C., E-mail: volz@mailbox.sc.edu [Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC (United States)

    2015-04-15

    Highlights: • Triphenyl phosphate-induced toxicity in zebrafish embryos is enhanced in the presence of a retinoic acid receptor antagonist. • Triphenyl phosphate uptake or metabolism within zebrafish embryos is not altered in the presence of a retinoic acid receptor antagonist. • Triphenyl phosphate decreases expression of cytochrome P450 26a1 in zebrafish embryos. • Triphenyl phosphate inhibits retinoic acid-induced activation of human retinoic acid receptors. - Abstract: Using zebrafish as a model, we previously reported that developmental exposure to triphenyl phosphate (TPP) – a high-production volume organophosphate-based flame retardant – results in dioxin-like cardiac looping impairments that are independent of the aryl hydrocarbon receptor. Using a pharmacologic approach, the objective of this study was to investigate the potential role of retinoic acid receptor (RAR) – a nuclear receptor that regulates vertebrate heart morphogenesis – in mediating TPP-induced developmental toxicity in zebrafish. We first revealed that static exposure of zebrafish from 5–72 h post-fertilization (hpf) to TPP in the presence of non-toxic concentrations of an RAR antagonist (BMS493) significantly enhanced TPP-induced toxicity (relative to TPP alone), even though identical non-toxic BMS493 concentrations mitigated retinoic acid (RA)-induced toxicity. BMS493-mediated enhancement of TPP toxicity was not a result of differential TPP uptake or metabolism, as internal embryonic doses of TPP and diphenyl phosphate (DPP) – a primary TPP metabolite – were not different in the presence or absence of BMS493. Using real-time PCR, we then quantified the relative change in expression of cytochrome P450 26a1 (cyp26a1) – a major target gene for RA-induced RAR activation in zebrafish – and found that RA and TPP exposure resulted in a ∼5-fold increase and decrease in cyp26a1 expression, respectively, relative to vehicle-exposed embryos. To address whether TPP may

  1. Retinoic acid reduces human neuroblastoma cell migration and invasiveness: effects on DCX, LIS1, neurofilaments-68 and vimentin expression

    International Nuclear Information System (INIS)

    Messi, Elio; Florian, Maria C; Caccia, Claudio; Zanisi, Mariarosa; Maggi, Roberto

    2008-01-01

    Neuroblastoma is a severe pediatric tumor, histologically characterised by a variety of cellular phenotypes. One of the pharmacological approaches to neuroblastoma is the treatment with retinoic acid. The mechanism of action of retinoic acid is still unclear, and the development of resistance to this differentiating agent is a great therapy problem. Doublecortin, a microtubule-associated protein involved in neuronal migration, has recently been proposed as a molecular marker for the detection of minimal residual disease in human neuroblastoma. Nevertheless, no information is available on the expression of doublecortin in the different cell-types composing human neuroblastoma, its correlation with neuroblastoma cell motility and invasiveness, and the possible modulations exerted by retinoic acid treatment. We analysed by immunofluorescence and by Western blot analysis the presence of doublecortin, lissencephaly-1 (another protein involved in neuronal migration) and of two intermediate filaments proteins, vimentin and neurofilament-68, in SK-N-SH human neuroblastoma cell line both in control conditions and under retinoic acid treatment. Migration and cell invasiveness studies were performed by wound scratch test and a modified microchemotaxis assay, respectively. Doublecortin is expressed in two cell subtypes considered to be the more aggressive and that show high migration capability and invasiveness. Vimentin expression is excluded by these cells, while lissencephaly-1 and neurofilaments-68 are immunodetected in all the cell subtypes of the SK-N-SH cell line. Treatment with retinoic acid reduces cell migration and invasiveness, down regulates doublecortin and lissencephaly-1 expression and up regulates neurofilament-68 expression. However, some cells that escape from retinoic acid action maintain migration capability and invasiveness and express doublecortin. a) Doublecortin is expressed in human neuroblastoma cells that show high motility and invasiveness; b

  2. Oleic Acid enhances all-trans retinoic Acid loading in nano-lipid emulsions.

    Science.gov (United States)

    Chinsriwongkul, Akhayachatra; Opanasopit, Praneet; Ngawhirunpat, Tanasait; Rojanarata, Theerasak; Sila-On, Warisada; Ruktanonchai, Uracha

    2010-01-01

    The aim of this study was to investigate the enhancement of all-trans retinoic acid (ATRA) loading in nano-lipid emulsions and stability by using oleic acid. The effect of formulation factors including initial ATRA concentration and the type of oil on the physicochemical properties, that is, percentage yield, percentage drug release, and photostability of formulations, was determined. The solubility of ATRA was increased in the order of oleic acid > MCT > soybean oil > water. The physicochemical properties of ATRA-loaded lipid emulsion, including mean particle diameter and zeta potential, were modulated by changing an initial ATRA concentration as well as the type and mixing ratio of oil and oleic acid as an oil phase. The particles of lipid emulsions had average sizes of less than 250 nm and negative zeta potential. The addition of oleic acid in lipid emulsions resulted in high loading capacity. The photodegradation rate was found to be dependent on the initial drug concentration but independent of the type of oily phase used in this study. The release rates were not affected by initial ATRA concentration but were affected by the type of oil, where oleic acid showed the highest release rate of ATRA from lipid emulsions.

  3. Comparison of efficacy of chemical peeling with 25% trichloroacetic acid and 0.1% retinoic acid for facial rejuvenation

    Directory of Open Access Journals (Sweden)

    Selda Yildirim

    2016-06-01

    Full Text Available Introduction : Skin aging is a problem which negatively affects the psyche of the person, social relations, as well as work life and health and which compels the patients to find appropriate treatment methods. Numerous treatment methods have been developed in order to delay aging and to reduce the aging effects in addition to having a younger, healthier and more beautiful facial appearance. Aim : To compare the efficiency, cosmetic results and possible adverse effects of the peeling treatment with 25% trichloroacetic acid (TCA and 0.1% retinoic acid for facial rejuvenation in patients presenting with skin aging. Material and methods: Fifty female patients in total presenting with medium and advanced degree skin aging were subject to this study. Two separate treatment groups were formed; the first group underwent chemical skin treatment with 25% TCA while the other group was applied with 0.1% retinoic acid treatment. Following the 4 months’ treatment the patients were controlled three times in total for post lesional hypopigmentation, hyperpigmentation, scars, skin irritation and other possible changes per month. The pretreatment and first follow-up visit, and final control images were comparatively evaluated by three observers via specific software. Results : The healing rates of the group subject to retinoic acid were statistically higher (p 0.05. The frequency of TCA- and retinoic acid-associated adverse effects was similar in both groups (p > 0.05. As a result of both treatments, a reduction in the quality of life scores as well as a pronounced recovery (p = 0.001 in the quality of life of those patients with skin aging was observed. Conclusions : The photo aging treatment option with 0.1% retinoic acid is cheaper and more feasible for patients compared to 25% TCA, and it is also as reliable and effective as TCA.

  4. Comparative evaluation of retinoic acid, benzoyl peroxide and erythromycin lotion in acne vulgarils

    Directory of Open Access Journals (Sweden)

    Dogra A

    1993-01-01

    Full Text Available Ninety three patients suffering from acne vulgaris were treated with 0.05% retinoic acid (23 patients, 10% benzyoyl peroxide (24 patients, 2% erythromycin lotin (25 patients and 50% glycerine in methylated spirit (21 patients used as a control, for a period of 6 weeks. The patients were evaluated at 2 weeks and 6 weeks by spot counting of the lesions and diagrammatic representations. Good to excellent results were obtained in 69.6% of patients of erythromycin lotion. Retinoic acid was more effective in reducing noninflammatory lesions (75.2% whereas inflammatory lesions showed better response (73.6% with erythromycin lotion and benzoyl peroxide was almost equally effective in both types of lesions.

  5. Retinoic acid, hemin and hexamethylen bisacetamide interference with "in vitro" differentiation of chick embryo chondrocytes.

    Science.gov (United States)

    Manduca, P; Abelmoschi, M L

    1992-01-01

    We have investigated the effect of all-trans Retinoic acid, and of substances (Hemine and Hexamethylene bisacetamide) which interfere with "in vitro" differentiation of mesenchyme derived cell lineages on the expression of specific markers of hyperthrophy in "in vitro" differentiating chick embryo chondrocytes. (Castagnola P., et al., 1986). Continuous treatment of chondrogenic cells in conditions allowing differentiation "in vitro" with Retinoic acid resulted in persistence of type I collagen synthesis and in lack of type X collagen and Ch 21 protein expression. Hemin treated cells secreted a reduced amount of type X collagen. HMBA treatment inhibited type X collagen expression and caused reduction of the ratio between type II collagen and Ch 21 synthesized. The data indicate an independent regulation of these markers during chondrocyte differentiation.

  6. ISOLATION AND CHARACTERIZATION OF AXOLOTL NPDC-1 AND ITS EFFECTS ON RETINOIC ACID RECEPTOR SIGNALING

    OpenAIRE

    Theodosiou, Maria; Monaghan, James R; Spencer, Michael L; Voss, S Randal; Noonan, Daniel J

    2007-01-01

    Retinoic acid, a key morphogen in early vertebrate development and tissue regeneration, mediates its effects through the binding of receptors that act as ligand-induced transcription factors. These binding events function to recruit an array of transcription co-regulatory proteins to specific gene promoters. One such co-regulatory protein, neuronal proliferation and differentiation control-1 (NPDC-1), is broadly expressed during mammalian development and functions as an in vitro repressor of ...

  7. Effect of retinoic acid on midkine gene expression in rat anterior pituitary cells.

    Science.gov (United States)

    Maliza, Rita; Fujiwara, Ken; Azuma, Morio; Kikuchi, Motoshi; Yashiro, Takashi

    2017-06-29

    Retinoic acid (RA) is converted from retinal by retinaldehyde dehydrogenases (RALDHs) and is an essential signaling molecule in embryonic and adult tissue. We previously reported that RALDH1 was produced in the rat anterior pituitary gland and hypothesized that RA was generated in the gland. Midkine (MK) is an RA-inducible growth factor, and MK production in the rat anterior pituitary gland was recently reported. However, the mechanism that regulates gene expression of MK in the pituitary gland has not been determined. To investigate regulation of MK production in the anterior pituitary gland, we analyzed changes in MK mRNA in cultured rat anterior pituitary cells. We identified MK-expressing cells by double-staining with in situ hybridization and immunohistochemical techniques for RALDH1. MK mRNA was expressed in RALDH1-producing cells in the anterior pituitary gland. Using isolated anterior pituitary cells of rats, we examined the effect of RA on gene expression of MK. Quantitative real-time PCR revealed that 72 h exposure to a concentration of 10 -6 M of retinal and all-trans retinoic acid increased MK mRNA levels by about 2-fold. Moreover, the stimulatory effect of all-trans retinoic acid was mimicked by the RA receptor agonist Am80. This is the first report to show that RA is important in regulating MK expression in rat anterior pituitary gland.

  8. All-trans retinoic acid increases oxidative metabolism in mature adipocytes

    DEFF Research Database (Denmark)

    Mercader, Josep; Madsen, Lise; Felipe, Francisco

    2007-01-01

    BACKGROUND/AIMS: In rodents, retinoic acid (RA) treatment favors loss of body fat mass and the acquisition of brown fat features in white fat depots. In this work, we sought to examine to what extent these RA effects are cell autonomous or dependent on systemic factors. METHODS: Parameters of lipid......), and to an increased expression of proteins favoring fat oxidation (peroxisome proliferator-activated receptor gamma coactivator-1alpha, uncoupling protein 2, fasting-induced adipose factor, enzymes of mitochondrial fatty acid oxidation). These changes paralleled inactivation of the retinoblastoma protein and were...

  9. Kinetics of photoirradiation-induced synthesis of soy oil-conjugated linoleic acid isomers.

    Science.gov (United States)

    Jain, Vishal P; Proctor, Andrew

    2007-02-07

    Photoirradiation of soy oil with UV/visible light has been shown to produce significant amounts of trans,trans conjugated linoleic acid (CLA) isomers through conversion of various synthesized intermediate cis,trans isomers. The objective of this study was to determine the kinetics of CLA isomers synthesis to better understand the production of various isomers. Soy oil was irradiated with UV/visible light for 144 h in the presence of an iodine catalyst and CLA isomers analyzed by gas chromatography (GC). Arrhenius plots were developed for the conversion of soy oil linoleic acid (A) to form cis-, trans/trans-, cis-CLA (B), conversion of cis-, trans/trans-, cis-CLA to form trans,trans-CLA (C) with respect to B, and formation of trans,trans-CLA isomers with respect to C. The kinetics of consumption of linoleic acid (LA) to form cis-, trans/trans-, cis-CLA was found to be of second-order with a rate constant of 9.01 x 10-7 L/mol s. The rate of formation of cis-, trans/trans-, cis-CLA isomers depends on the rate of formation from LA and its rate of consumption to form trans,trans-CLA isomers. The conversion of cis-, trans/trans-, cis-CLA isomers to trans,trans-CLA isomers was found to be of first-order with a rate constant of 2.75 x 10-6 s-1. However, the formation of thermodynamically stable trans,trans-CLA isomers (C) with respect to C was found to be a zero-order reaction with a rate constant of 10.66 x 10-7 mol/L s. The consumption of LA was found to be the rate-determining step in the CLA isomers formation reaction mechanism. The findings provide a better understanding of the mechanism of CLA isomers synthesis by photoirradiation and the factors controlling the ratio of various isomers.

  10. Allosteric Regulation in the Ligand Binding Domain of Retinoic Acid Receptorγ.

    Directory of Open Access Journals (Sweden)

    Yassmine Chebaro

    Full Text Available Retinoic acid (RA plays key roles in cell differentiation and growth arrest through nuclear retinoic acid receptors (RARs, which are ligand-dependent transcription factors. While the main trigger of RAR activation is the binding of RA, phosphorylation of the receptors has also emerged as an important regulatory signal. Phosphorylation of the RARγ N-terminal domain (NTD is known to play a functional role in neuronal differentiation. In this work, we investigated the phosphorylation of RARγ ligand binding domain (LBD, and present evidence that the phosphorylation status of the LBD affects the phosphorylation of the NTD region. We solved the X-ray structure of a phospho-mimetic mutant of the LBD (RARγ S371E, which we used in molecular dynamics simulations to characterize the consequences of the S371E mutation on the RARγ structural dynamics. Combined with simulations of the wild-type LBD, we show that the conformational equilibria of LBD salt bridges (notably R387-D340 are affected by the S371E mutation, which likely affects the recruitment of the kinase complex that phosphorylates the NTD. The molecular dynamics simulations also showed that a conservative mutation in this salt bridge (R387K affects the dynamics of the LBD without inducing large conformational changes. Finally, cellular assays showed that the phosphorylation of the NTD of RARγ is differentially regulated by retinoic acid in RARγWT and in the S371N, S371E and R387K mutants. This multidisciplinary work highlights an allosteric coupling between phosphorylations of the LBD and the NTD of RARγ and supports the importance of structural dynamics involving electrostatic interactions in the regulation of RARs activity.

  11. Process for separating the ortho- and para- isomers of hydroxymandelic acid or a salt thereof, the isomers thus obtained, the use of the ortho-isomer for the preparation of eddha

    NARCIS (Netherlands)

    Hoefnagel, A.J.; Van Bekkum, H.

    1994-01-01

    Abstract of WO 9414746 (A1) The invention relates to a method for separating the ortho- and para-isomers of hydroxymandelic acid or a salt thereof. For that purpose the starting material is a solid mixture of these ortho- and para-isomers in the alkali metal salt form. This mixture is extracted with

  12. Metabolic characteristics of 13-cis-retinoic acid (isotretinoin) and anti-tumour activity of the 13-cis-retinoic acid metabolite 4-oxo-13-cis-retinoic acid in neuroblastoma.

    Science.gov (United States)

    Sonawane, Poonam; Cho, Hwang Eui; Tagde, Ashujit; Verlekar, Dattesh; Yu, Alice L; Reynolds, C Patrick; Kang, Min H

    2014-12-01

    Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA. Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples. Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-β mRNA and protein levels. We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma. © 2014 The British Pharmacological Society.

  13. Identifying the receptor subtype selectivity of retinoid X and retinoic acid receptors via quantum mechanics.

    Science.gov (United States)

    Tsuji, Motonori; Shudo, Koichi; Kagechika, Hiroyuki

    2017-03-01

    Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands.

  14. Treatment of refractory undifferentiated acute myelogenous leukemia with all-trans-retinoic acid.

    Science.gov (United States)

    Griggs, J J; Henley, S E; Rowe, J M

    1994-02-01

    A patient is described with undifferentiated acute myeloblastic leukemia refractory to two courses of daunorubicin and cytosine arabinoside. Because some the myeloblasts developed morphologic features of promyelocytes, the patient was treated with all-trans-retinoic acid (ATRA) in an attempt to promote maturation. Cytogenetic studies and sensitive molecular analysis did not reveal any abnormality classically associated with acute promyelocytic leukemia. Serial bone marrow biopsies demonstrated myeloid maturation, and the patient uneventfully went into a sustained complete remission. A review of the literature confirms this to be an apparently hitherto undescribed response to ATRA that may have therapeutic implications in similar patients.

  15. Influence of retinoic acid on mesenchymal stem cell differentiation in amyloid hydrogels

    Directory of Open Access Journals (Sweden)

    Reeba Susan Jacob

    2015-12-01

    Full Text Available This paper presents data related to the research article “Self healing hydrogels composed of amyloid nano fibrils for cell culture and stem cell differentiation” [1]. Here we probed the collective influence of all-trans retinoic acid (RA and substrate properties (amyloid hydrogel on human mesenchymal stem cell (hMSC differentiation. Stem cells were cultured on soft amyloid hydrogels [1,2] in the presence and absence of matrix encapsulated RA. The cell morphology was imaged and assessed via quantification of circularity. Further immunostaining and quantitative real time PCR was used to quantify various markers of differentiation in the neuronal lineage.

  16. Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut

    OpenAIRE

    Kim, Myung H.; Taparowsky, Elizabeth J.; Kim, Chang H.

    2015-01-01

    Distinct groups of innate lymphoid cells (ILCs) such as ILC1, ILC2 and ILC3 populate the intestine, but how these ILCs develop tissue tropism for this organ is unclear. We report that prior to migration to the intestine ILCs first undergo a `switch' in their expression of homing receptors from lymphoid to gut homing receptors. This process is regulated by mucosal dendritic cells and the gut-specific tissue factor retinoic acid (RA). This change in homing receptors is required for long-term po...

  17. Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

    Science.gov (United States)

    Cook, Donald N.; Kang, Hong Soon; Jetten, Anton M.

    2015-01-01

    In this overview, we provide an update on recent progress made in understanding the mechanisms of action, physiological functions, and roles in disease of retinoic acid related orphan receptors (RORs). We are particularly focusing on their roles in the regulation of adaptive and innate immunity, brain function, retinal development, cancer, glucose and lipid metabolism, circadian rhythm, metabolic and inflammatory diseases and neuropsychiatric disorders. We also summarize the current status of ROR agonists and inverse agonists, including their regulation of ROR activity and their therapeutic potential for management of various diseases in which RORs have been implicated. PMID:26878025

  18. Retinoic Acid-Related Orphan Receptors (RORs: Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

    Directory of Open Access Journals (Sweden)

    Donald N. Cook

    2015-12-01

    Full Text Available In this overview, we provide an update on recent progress made in understanding the mechanisms of action, physiological functions, and roles in disease of retinoic acid related orphan receptors (RORs. We are particularly focusing on their roles in the regulation of adaptive and innate immunity, brain function, retinal development, cancer, glucose and lipid metabolism, circadian rhythm, metabolic and inflammatory diseases and neuropsychiatric disorders. We also summarize the current status of ROR agonists and inverse agonists, including their regulation of ROR activity and their therapeutic potential for management of various diseases in which RORs have been implicated.

  19. Acitretin systemic and retinoic acid 0.1% cream supression of basal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Xi-Bao Zhang

    2010-03-01

    Full Text Available Retinoids have been used for years as monotherapy and/or in combination for treatment and suppression of cutaneous malignancies in patients with basal cell nevus syndrome, xeroderma pigmentosum, or cutaneous T-cell lymphoma (CTCL basal cell carcinoma (BCC. We report 4 cases with BCC confirmed by histopathology who were treated by short-term systemic acitretin combined with retinoic acid 0.1% cream. The 4 cases with BCC showed good response to the treatment without severe adverse effects during treatment and follow-up. The finding suggests that acitretin may be an appropriate treatment option for elderly patients who require less invasive treatment for BCC.

  20. Potential role of nuclear receptor ligand all-trans retinoic acids in the treatment of fungal keratitis

    Directory of Open Access Journals (Sweden)

    Hong-Yan Zhou

    2015-08-01

    Full Text Available Fungal keratitis (FK is a worldwide visual impairment disease. This infectious fungus initiates the primary innate immune response and, later the adaptive immune response. The inflammatory process is related to a variety of immune cells, including macrophages, helper T cells, neutrophils, dendritic cells, and Treg cells, and is associated with proinflammatory, chemotactic and regulatory cytokines. All-trans retinoic acids (ATRA have diverse immunomodulatory actions in a number of inflammatory and autoimmune conditions. These retinoids regulate the transcriptional levels of target genes through the activation of nuclear receptors. Retinoic acid receptor α (RAR α, retinoic acid receptor γ (RAR γ, and retinoid X receptor α (RXR α are expressed in the cornea and immune cells. This paper summarizes new findings regarding ATRA in immune and inflammatory diseases and analyzes the perspective application of ATRA in FK.

  1. Differential retinoic acid inhibition of ornithine decarboxylase induction by 12-O-tetradecanoylphorbol-13-acetate and by germicidal ultraviolet light

    International Nuclear Information System (INIS)

    Lichti, U.; Patterson, E.; Hennings, H.; Yuspa, S.H.

    1981-01-01

    Several retinoids including retinoic acid effectively inhibit phorbol ester-mediated tumor promotion and ornithine decarboxylase (ODC) induction in mouse epidermis. To understand better the possible cellular site of action of retinoids, the inhibitory action of retinoic acid on the induction of ODC was compared for two distinctly different inducers, namely, 12-O-tetradecanoylphorbol-13-acetate (TPA) and germicidal ultraviolet light (uv), in primary mouse epidermal cell cultures. It was found that the induction of ODC by TPA is almost completely prevented by retinoic acid while the induction by uv is only moderately inhibited. The differential inhibition of enzyme induction cannot be accounted for by selective retinoid inhibition of DNA, RNA, or protein synthesis either alone or in concert with TPA or uv. These agents possibly act at transcription or translation, both of which are required for ODC induction by TPA or uv

  2. Chicken homeobox gene Msx-1: structure, expression in limb buds and effect of retinoic acid.

    Science.gov (United States)

    Yokouchi, Y; Ohsugi, K; Sasaki, H; Kuroiwa, A

    1991-10-01

    A chicken gene carrying a homeobox highly homologous to the Drosophila muscle segment homeobox (msh) gene was isolated and designated as Msx-1. Conceptual translation from the longest ORF gave a protein of 259 amino acids lacking the conserved hexapeptide. Northern analysis detected a single 2.6 kb transcript. As early as day 2 of incubation, the transcript was detected but was not found in adult tissue. In situ hybridization analysis revealed that Msx-1 expression is closely related to a particular mesenchymal cell lineage during limb bud formation. In early stage embryos, Msx-1 was expressed in the somatopleure. When primordial mesenchyme cells for limb bud were generated from the Wolffian ridge of the somatopleure, Msx-1 expression began to diminish in the posterior half of the limb bud then in the presumptive cartilage-forming mesenchyme. In developing limb buds, remarkable expression was seen in the apical ectodermal ridge (AER), which is responsible for the sustained outgrowth and development of the limb. The Msx-1 transcripts were found in the limb mesenchymal cells in the region covering the necrotic zone and ectodermal cells overlying such mesenchymal cells. Both ectodermal and mesenchymal expression in limb bud were rapidly suppressed by local treatment of retinoic acid which can generate mirror-image duplication of digits. This indicates that retinoic acid alters the marginal presumptive non-cartilage forming mesenchyme cell lineage through suppression of Msx-1 expression.

  3. Inhibitory effect of all-trans retinoic acid on human hepatocellular carcinoma cell proliferation

    Institute of Scientific and Technical Information of China (English)

    Yun-Feng Piao; Yang Shi; Pu-Jun Gao

    2003-01-01

    AIM: To study the inhibitory effect of all-trans retinoic acid on human hepatocellular carcinoma cell line SMMC-7721and to explore the mechanism of its effect.METHODS: SMMC-7721 cells were divided into two groups, one treated with all-trans retinoic acid (ATRA) for 5 days and the other as a control group. Light microscope and electron microscope were used to observe the morphological changes. Telomerase activity was analyzed with silver-stained telomere repeated assay protocal (TRAP). Expression of Caspase-3 was demonstrated with western blot.RESULTS: ATRA-treated cells showed differentiation features including small and pyknotic nuclei, densely stained chromatin and fewer microvilli. Besides, ATRA could inhibit the activity of telomerase, promote the expression of Caspase-3 and its activation.CONCLUSION: Telomerase activity and Caspase-3expression are changed in human hepatocellular carcinoma cell line SMMC-7721 treated with all-trans retinioc acid.The inhibition of telomerase activity and the activation of Caspase-3 may be the key steps through which ATRA inhibits the proliferation of SMMC-7721 cell line.

  4. Chemometric deconvolution of gas chromatographic unresolved conjugated linoleic acid isomers triplet in milk samples.

    Science.gov (United States)

    Blasko, Jaroslav; Kubinec, Róbert; Ostrovský, Ivan; Pavlíková, Eva; Krupcík, Ján; Soják, Ladislav

    2009-04-03

    A generally known problem of GC separation of trans-7;cis-9; cis-9,trans-11; and trans-8,cis-10 CLA (conjugated linoleic acid) isomers was studied by GC-MS on 100m capillary column coated with cyanopropyl silicone phase at isothermal column temperatures in a range of 140-170 degrees C. The resolution of these CLA isomers obtained at given conditions was not high enough for direct quantitative analysis, but it was, however, sufficient for the determination of their peak areas by commercial deconvolution software. Resolution factors of overlapped CLA isomers determined by the separation of a model CLA mixture prepared by mixing of a commercial CLA mixture and CLA isomer fraction obtained by the HPLC semi-preparative separation of milk fatty acids methyl esters were used to validate the deconvolution procedure. Developed deconvolution procedure allowed the determination of the content of studied CLA isomers in ewes' and cows' milk samples, where dominant isomer cis-9,trans-11 is eluted between two small isomers trans-7,cis-9 and trans-8,cis-10 (in the ratio up to 1:100).

  5. A case of all-trans retinoic acid-induced myositis in the treatment of acute promyelocytic leukaemia.

    Science.gov (United States)

    Chan, K H; Yuen, S L S; Joshua, D

    2005-12-01

    The use of all-trans retinoic acid (ATRA) is now standard therapy for the treatment of acute promyelocytic leukaemia (APML). There have been increasing reports of ATRA-induced myositis, with its frequent association with retinoic acid syndrome and Sweet's syndrome. We report a case of a young man with APML who developed ATRA-induced myositis characterized by unexplained fevers, bilateral leg swelling and a non-painful purpuric, petechial rash, with prompt resolution of symptoms and signs with high-dose steroids and cessation of ATRA. Rapid recognition of this adverse reaction and prompt institution of steroids is of prime importance given its potentially fatal course.

  6. Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis

    Directory of Open Access Journals (Sweden)

    Ana Cañete

    2017-02-01

    Full Text Available Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA, acting through nuclear retinoic acid receptors (RARs, is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells. Furthermore, defective RA/RARα signaling is involved in the pathogenesis of acute promyelocytic leukemia due to a failure in differentiation of promyelocytes. This review focuses on the different roles played by vitamin A/RA signaling in physiological and pathological mouse hematopoiesis duddurring both, embryonic and adult life, and the consequences of vitamin A deficiency for the blood system.

  7. Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid

    Energy Technology Data Exchange (ETDEWEB)

    Van Wauwe, J.P.; Coene, M.C.; Goossens, J.; Van Nijen, G.; Cools, W.; Lauwers, W.

    1988-05-01

    Ketoconazole, an antifungal agent and inhibitor of certain mammalian cytochrome P-450-dependent enzymes, was studied for its effects on the in vitro and in vivo metabolism of all-trans-retinoic acid (RA). In vitro, ketoconazole (Ki = 0.75 microM) inhibited, in an apparently competitive manner, the cytochrome P-450-mediated metabolism to 4-hydroxy- and 4-keto-retinoic acids by hamster liver microsomes. In vivo, ketoconazole suppressed the formation of polar RA metabolites by normal rats dosed intrajugularly with 200 ng of (/sup 3/H)RA. After p.o. treatment with ketoconazole (2.5-40 mg/kg) given 1 hr before the (/sup 3/H)RA injection, the radioactivity extracted from the liver consisted of 25 to 50% polar metabolites (control 66 +/- 1%) and 50 to 75% undegraded RA (control 34 +/- 1%) as evidenced by reverse-phase high-performance liquid chromatography. Time course experiments showed that ketoconazole's inhibitory effects lasted for 3 hr. Our data indicate the quantitative importance of the cytochrome P-450 enzymatic pathway in the biotransformation of RA. They also suggest that ketoconazole is capable of prolonging the biological half-life of RA and of improving the tissue levels of this compound.

  8. Combinatorial roles for zebrafish retinoic acid receptors in the hindbrain, limbs and pharyngeal arches

    Science.gov (United States)

    Linville, Angela; Radtke, Kelly; Waxman, Joshua S.; Yelon, Deborah; Schilling, Thomas F.

    2011-01-01

    Retinoic acid (RA) signaling regulates multiple aspects of vertebrate embryonic development and tissue patterning, in part through the local availability of nuclear hormone receptors called retinoic acid receptors (RARs) and retinoid receptors (RXRs). RAR/RXR heterodimers transduce the RA signal, and loss-of-function studies in mice have demonstrated requirements for distinct receptor combinations at different stages of embryogenesis. However, the tissue-specific functions of each receptor and their individual contributions to RA signaling in vivo are only partially understood. Here we use morpholino oligonucleotides to deplete the four known zebra fish RARs (raraa, rarab, rarga, and rargb). We show that while all four are required for anterior–posterior patterning of rhombomeres in the hindbrain, there are unique requirements for rarga in the cranial mesoderm for hindbrain patterning, and rarab in lateral plate mesoderm for specification of the pectoral fins. In addition, the alpha subclass (raraa, rarab) is RA inducible, and of these only raraa expression is RA-dependent, suggesting that these receptors establish a region of particularly high RA signaling through positive-feedback. These studies reveal novel tissue-specific roles for RARs in controlling the competence and sensitivity of cells to respond to RA. PMID:18929555

  9. Extracellular calcium alters the effects of retinoic acid on DNA synthesis in cultured murine keratinocytes

    International Nuclear Information System (INIS)

    Tong, P.; Mayes, D.; Wheeler, L.

    1986-01-01

    The rate of proliferation of epidermal keratinocytes was manipulated by growing the cells in medium containing high or low concentrations of calcium. Keratinocytes cultured in high extracellular Ca ++ (1.4 mM and 2.8 mM) proliferated twice as fast as those grown in low Ca ++ medium (0.09 mM) as measured by incorporation of [ 3 H] thymidine into DNA. Exposure of high calcium keratinocytes to all-trans retinoic acid for 4 days caused a dose-related inhibition of DNA synthesis with an IC 50 of about 10 μM. In contrast, incubating low calcium keratinocytes with all-trans retinoic acid caused a dose-related stimulation of DNA synthesis with maximum increase of 278% over control at 10 μM. This increase was accompanied by increases in culture confluency with maximum increase of 109% in cell number of control at 10 μM. These results are of importance since they suggest Ca ++ may influence the effect of retinoids on keratinocytes

  10. The ancestral retinoic acid receptor was a low-affinity sensor triggering neuronal differentiation

    KAUST Repository

    Handberg-Thorsager, Mette

    2018-02-22

    Retinoic acid (RA) is an important intercellular signaling molecule in vertebrate development, with a well-established role in the regulation of hox genes during hindbrain patterning and in neurogenesis. However, the evolutionary origin of the RA signaling pathway remains elusive. To elucidate the evolution of the RA signaling system, we characterized RA metabolism and signaling in the marine annelid Platynereis dumerilii, a powerful model for evolution, development, and neurobiology. Binding assays and crystal structure analyses show that the annelid retinoic acid receptor (RAR) binds RA and activates transcription just as vertebrate RARs, yet with a different ligand-binding pocket and lower binding affinity, suggesting a permissive rather than instructive role of RA signaling. RAR knockdown and RA treatment of swimming annelid larvae further reveal that the RA signal is locally received in the medial neuroectoderm, where it controls neurogenesis and axon outgrowth, whereas the spatial colinear hox gene expression in the neuroectoderm remains unaffected. These findings suggest that one early role of the new RAR in bilaterian evolution was to control the spatially restricted onset of motor and interneuron differentiation in the developing ventral nerve cord and to indicate that the regulation of hox-controlled anterior-posterior patterning arose only at the base of the chordates, concomitant with a high-affinity RAR needed for the interpretation of a complex RA gradient.

  11. ATP7A is a novel target of retinoic acid receptor β2 in neuroblastoma cells

    Science.gov (United States)

    Bohlken, A; Cheung, B B; Bell, J L; Koach, J; Smith, S; Sekyere, E; Thomas, W; Norris, M; Haber, M; Lovejoy, D B; Richardson, D R; Marshall, G M

    2009-01-01

    Increased retinoic acid receptor β (RARβ2) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RARβ2 expression is a common feature of many human cancers, suggesting that RARβ2 may act as a tumour suppressor gene in the absence of supplemented retinoid. We have previously shown that low RARβ2 expression is a feature of advanced neuroblastoma. Here, we demonstrate that the ABC domain of the RARβ2 protein alone was sufficient for the growth inhibitory effects of RARβ2 on neuroblastoma cells. ATP7A, the copper efflux pump, is a retinoid-responsive gene, was upregulated by ectopic overexpression of RARβ2. The ectopic overexpression of the RARβ2 ABC domain was sufficient to induce ATP7A expression, whereas, RARβ2 siRNA blocked the induction of ATP7A expression in retinoid-treated neuroblastoma cells. Forced downregulation of ATP7A reduced copper efflux and increased viability of retinoid-treated neuroblastoma cells. Copper supplementation enhanced cell growth and reduced retinoid-responsiveness, whereas copper chelation reduced the viability and proliferative capacity. Taken together, our data demonstrates ATP7A expression is regulated by retinoic acid receptor β and it has effects on intracellular copper levels, revealing a link between the anticancer action of retinoids and copper metabolism. PMID:19127267

  12. The efficacy of 9-cis retinoic acid in experimental models of cancer.

    Science.gov (United States)

    Gottardis, M M; Lamph, W W; Shalinsky, D R; Wellstein, A; Heyman, R A

    1996-01-01

    9-cis retinoic acid (9-cis RA) is a retinoid receptor pan-agonist that binds with high affinity to both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Using a variety of in vivo and in vitro cancer models, we present experimental data that 9-cis RA has activity as a potential chemotherapeutic agent. Treatment of the human promyelocytic leukemia cell line HL-60 with 9-cis RA decreases cell proliferation, increases cell differentiation, and increases apoptosis. Induction of apoptosis correlates with an increase in tissue transglutaminase (type II) activity. In vivo, 9-cis RA induces complete tumor regression of an early passage human lip squamous cell carcinoma xenograft. Finally, 9-cis RA inhibits the anchorage-independent growth of the human breast cancer cell lines MCF-7 and LY2 (an antiestrogen-resistant MCF-7 variant). Transient co-transfection assays indicate that 9-cis RA inhibits estrogen receptor transcription of an ERE-tk-LUC reporter through RAR or RXR receptors. These data suggest that retinoid receptors can antagonize estrogen-dependent transcription and provides one possible mechanism for the inhibition of cell growth by 9-cis RA in breast cancer cell lines. In summary, these findings present evidence that 9-cis RA has a wide range of activities in human cancer models.

  13. Retinoic acid temporally orchestrates colonization of the gut by vagal neural crest cells.

    Science.gov (United States)

    Uribe, Rosa A; Hong, Stephanie S; Bronner, Marianne E

    2018-01-01

    The enteric nervous system arises from neural crest cells that migrate as chains into and along the primitive gut, subsequently differentiating into enteric neurons and glia. Little is known about the mechanisms governing neural crest migration en route to and along the gut in vivo. Here, we report that Retinoic Acid (RA) temporally controls zebrafish enteric neural crest cell chain migration. In vivo imaging reveals that RA loss severely compromises the integrity and migration of the chain of neural crest cells during the window of time window when they are moving along the foregut. After loss of RA, enteric progenitors accumulate in the foregut and differentiate into enteric neurons, but subsequently undergo apoptosis resulting in a striking neuronal deficit. Moreover, ectopic expression of the transcription factor meis3 and/or the receptor ret, partially rescues enteric neuron colonization after RA attenuation. Collectively, our findings suggest that retinoic acid plays a critical temporal role in promoting enteric neural crest chain migration and neuronal survival upstream of Meis3 and RET in vivo. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. The ancestral retinoic acid receptor was a low-affinity sensor triggering neuronal differentiation

    Science.gov (United States)

    Handberg-Thorsager, Mette; Gutierrez-Mazariegos, Juliana; Arold, Stefan T.; Kumar Nadendla, Eswar; Bertucci, Paola Y.; Germain, Pierre; Tomançak, Pavel; Pierzchalski, Keely; Jones, Jace W.; Albalat, Ricard; Kane, Maureen A.; Bourguet, William; Laudet, Vincent; Arendt, Detlev; Schubert, Michael

    2018-01-01

    Retinoic acid (RA) is an important intercellular signaling molecule in vertebrate development, with a well-established role in the regulation of hox genes during hindbrain patterning and in neurogenesis. However, the evolutionary origin of the RA signaling pathway remains elusive. To elucidate the evolution of the RA signaling system, we characterized RA metabolism and signaling in the marine annelid Platynereis dumerilii, a powerful model for evolution, development, and neurobiology. Binding assays and crystal structure analyses show that the annelid retinoic acid receptor (RAR) binds RA and activates transcription just as vertebrate RARs, yet with a different ligand-binding pocket and lower binding affinity, suggesting a permissive rather than instructive role of RA signaling. RAR knockdown and RA treatment of swimming annelid larvae further reveal that the RA signal is locally received in the medial neuroectoderm, where it controls neurogenesis and axon outgrowth, whereas the spatial colinear hox gene expression in the neuroectoderm remains unaffected. These findings suggest that one early role of the new RAR in bilaterian evolution was to control the spatially restricted onset of motor and interneuron differentiation in the developing ventral nerve cord and to indicate that the regulation of hox-controlled anterior-posterior patterning arose only at the base of the chordates, concomitant with a high-affinity RAR needed for the interpretation of a complex RA gradient. PMID:29492455

  15. Synthesis of Similars of the Retinoic Acid with Anti-Cancer Potential

    International Nuclear Information System (INIS)

    Marin Cordoba, R.

    2001-01-01

    Three precursors were synthesized in the route toward new structures similar of the retinoic acid. They are the bromocetones 15, 35 and 36. Two new similar of the retinoic acid were synthesized; they are the acids 39 and 40. The mechanism for the formation of 1,1,4,4-tetramethyl-1, 2,3,4-tetrahydronaphthalene (17), starting from benzene and 2,5-dimethyl-2, 5-dichlorine-hexane was studied. This reaction intended to be carried out in four elementary reactions. Under the used conditions, the product is isolated in 95%. Also, the effect of the dilution in the yield of the tetramethyltehydro-naphthalene was studied; the good relationship of benzene to the compound dichloride was of 29:1. It is determined that the bromocetones 15, 35 and 36 are little reactive toward the joining of Heck when the crotonic acid is used. Probably, the presence of the groups metoxyle and hydroxyle to the halogen in the bromocetones 15 and 36, respectively, affect the reactivity. In the case of the bromocetone 35, to make this reaction, the group protective acilo gets lost before being made the vinylation of Heck, becoming the bromocetone 36. The joining of Heck between the acrylic acid and the bromocetone 15 in an isolated yield of 33% was possible to be made. It indicates that besides the electronic effects that affect to the bromocetone in this type of reaction, the vinyllic methyl in the crotonic acid causes a low reactivity in this joining, for this substrate in particular. (Author) [es

  16. Androgen and retinoic acid interaction in LNCaP cells, effects on cell proliferation and expression of retinoic acid receptors and epidermal growth factor receptor

    International Nuclear Information System (INIS)

    Li, Ming-tang; Richter, Frank; Chang, Chawnshang; Irwin, Robert J; Huang, Hosea FS

    2002-01-01

    Modulation of the expression of retinoic acid receptors (RAR) α and γ in adult rat prostate by testosterone (T) suggests that RAR signaling events might mediate some of the androgen effects on prostate cells. In this study, we examined the interactions between T and retinoic acid (RA) in cell growth of human prostate carcinoma cells, LNCaP, and their relationship with the expression of RAR and epidermal growth factor receptor (EGF-R). Both T and RA, when administered alone, stimulated 3 H-thymidine incorporation in LNCaP cells in a dose-dependent manner; the effect of each agent was reciprocally attenuated by the other agent. Testosterone treatment of LNCaP cells also resulted in dose dependent, biphasic increases in RAR α and γ mRNAs; increases paralleled that of 3 H-thymidine incorporation and were attenuated by the presence of 100 nM RA. These results suggest a link between RAR signaling and the effect of T on LNCaP cell growth. Gel electrophoretic mobility shift assays revealed the presence of putative androgen responsive element (ARE) in the promoter region of RAR α gene, suggesting that a direct AR-DNA interaction might mediate the effects of T on RAR α gene. Furthermore, treatment of LNCaP cells with 20 nM T resulted in an increase in EGF-R. In contrast, EGF-R was suppressed by 100 nM RA that also suppressed the effect of T. Current results demonstrate interactions between T and RA in the expression of RARs and cell growth in LNCaP cells. The presence of putative ARE in the promoter of the RAR α gene suggests that AR-DNA interaction might mediate the effects of T on RAR α gene. The opposite effects of T and RA on the expression of RAR and EGF-R suggest that signal events of these receptors might be involved in the interaction between T and RA in the control of LNCaP cell growth

  17. Androgen and retinoic acid interaction in LNCaP cells, effects on cell proliferation and expression of retinoic acid receptors and epidermal growth factor receptor

    Directory of Open Access Journals (Sweden)

    Irwin Robert J

    2002-06-01

    Full Text Available Abstract Background Modulation of the expression of retinoic acid receptors (RAR α and γ in adult rat prostate by testosterone (T suggests that RAR signaling events might mediate some of the androgen effects on prostate cells. Method In this study, we examined the interactions between T and retinoic acid (RA in cell growth of human prostate carcinoma cells, LNCaP, and their relationship with the expression of RAR and epidermal growth factor receptor (EGF-R. Results Both T and RA, when administered alone, stimulated 3H-thymidine incorporation in LNCaP cells in a dose-dependent manner; the effect of each agent was reciprocally attenuated by the other agent. Testosterone treatment of LNCaP cells also resulted in dose dependent, biphasic increases in RAR α and γ mRNAs; increases paralleled that of 3H-thymidine incorporation and were attenuated by the presence of 100 nM RA. These results suggest a link between RAR signaling and the effect of T on LNCaP cell growth. Gel electrophoretic mobility shift assays revealed the presence of putative androgen responsive element (ARE in the promoter region of RAR α gene, suggesting that a direct AR-DNA interaction might mediate the effects of T on RAR α gene. Furthermore, treatment of LNCaP cells with 20 nM T resulted in an increase in EGF-R. In contrast, EGF-R was suppressed by 100 nM RA that also suppressed the effect of T. Conclusions Current results demonstrate interactions between T and RA in the expression of RARs and cell growth in LNCaP cells. The presence of putative ARE in the promoter of the RAR α gene suggests that AR-DNA interaction might mediate the effects of T on RAR α gene. The opposite effects of T and RA on the expression of RAR and EGF-R suggest that signal events of these receptors might be involved in the interaction between T and RA in the control of LNCaP cell growth.

  18. Proteomic analysis of changes in the protein composition of MCF-7 human breast cancer cells induced by all-trans retinoic acid, 9-cis retinoic acid, and their combination

    Czech Academy of Sciences Publication Activity Database

    Flodrová, Dana; Benkovská, Dagmar; Macejová, D.; Bialesova, L.; Hunakova, L.; Brtko, J.; Bobálová, Janette

    2015-01-01

    Roč. 232, č. 1 (2015), s. 226-232 ISSN 0378-4274 R&D Projects: GA MŠk(CZ) 7AMB12SK151 Institutional support: RVO:68081715 Keywords : retinoic acid * polyacrylamide gel electrophoresis * MALDI TOF MS Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 3.522, year: 2015

  19. Synthesis of 1-[13CD3]-9-cis-retinoic acid

    International Nuclear Information System (INIS)

    Bennani, Y.L.

    1995-01-01

    1-[ 13 CD 3 ]-9-cis-Retinoic acid was prepared in 8 steps from 2,6-dimethylcyclohexanone. Alkylation of 2,6-dimethylcyclohexanone under LiHMDS/MnBr 2 / 13 CD 3 I gave the corresponding labeled 2-[ 13 CD 3 ]-2,2,6-trimethylcyclohexanone 4 in good yield. Further functionalization of 4 to 6-[ 13 CD 3 ]-β-cyclocitral 6 proceeded through a Shapiro reaction. Aldehyde 6 was condensed with ethyl 3,3-dimethylacrylate to afford the corresponding bicyclic pyranone 7. Reduction of 7 to lactol 8, followed by acid-catalyzed ring opening gave the 9-cis-aldehyde 9. Wittig-Horner olefination and saponification afforded the title compound in good overall yield and in excellent isotopic purity. (Author)

  20. Synthesis of 1-[{sup 13}CD{sub 3}]-9-cis-retinoic acid

    Energy Technology Data Exchange (ETDEWEB)

    Bennani, Y.L. [Ligand Pharmaceuticals Inc., San Diego, CA (United States). Dept. of Medicinal Chemistry

    1995-12-31

    1-[{sup 13}CD{sub 3}]-9-cis-Retinoic acid was prepared in 8 steps from 2,6-dimethylcyclohexanone. Alkylation of 2,6-dimethylcyclohexanone under LiHMDS/MnBr{sub 2}/{sup 13}CD{sub 3}I gave the corresponding labeled 2-[{sup 13}CD{sub 3}]-2,2,6-trimethylcyclohexanone 4 in good yield. Further functionalization of 4 to 6-[{sup 13}CD{sub 3}]-{beta}-cyclocitral 6 proceeded through a Shapiro reaction. Aldehyde 6 was condensed with ethyl 3,3-dimethylacrylate to afford the corresponding bicyclic pyranone 7. Reduction of 7 to lactol 8, followed by acid-catalyzed ring opening gave the 9-cis-aldehyde 9. Wittig-Horner olefination and saponification afforded the title compound in good overall yield and in excellent isotopic purity. (Author).

  1. Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease.

    Science.gov (United States)

    Liu, Yan; Chen, Hongen; Wang, Jingjing; Zhou, Wenjing; Sun, Ruifang; Xia, Min

    2015-07-01

    Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis. Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263. © 2015 American Society for Nutrition.

  2. Analysis of the interplay between all-trans retinoic acid and histone deacetylase inhibitors in leukemic cells

    DEFF Research Database (Denmark)

    Noack, Katrin; Mahendrarajah, Nisintha; Hennig, Dorle

    2017-01-01

    The treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) induces granulocytic differentiation. This process renders APL cells resistant to cytotoxic chemotherapies. Epigenetic regulators of the histone deacetylases (HDACs) family, which comprise four classes (I–IV),...

  3. A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans

    DEFF Research Database (Denmark)

    Brophy, Patrick D.; Rasmussen, Maria; Parida, Mrutyunjaya

    2017-01-01

    investigations have identified several gene variants that cause RA, including EYA1, LHX1, and WT1 However, whereas compound null mutations of genes encoding α and γ retinoic acid receptors (RARs) cause RA in mice, to date there have been no reports of variants in RAR genes causing RA in humans. In this study, we...... in humans....

  4. Effects of 13- cis-retinoic acid on the tamoxifen induced uterine histological changes in the rabbit

    International Nuclear Information System (INIS)

    Hamid, S.; Minhas, L.A.; Khan, M.Y.

    2013-01-01

    Objective: To study the effects of 13-cis-retinoic acid on the tamoxifen induced uterine histological changes in the rabbit. Study Design: Experimental - randomized controlled trial. Place and Duration of study: The study was conducted for 4 months at the department of Anatomy, Army Medical College and National Institute of Health in 2007. Material and Methods: The animals were randomly divided into three groups, a control group A, and two experimental groups B and C, consisting of thirty rabbits each. The experimental groups were treated with tamoxifen only and tamoxifen plus retinoic acid, respectively. The animals were sacrificed after three months. The uteri were then processed for paraffin embedding. Sections were then assessed for the luminal epithelial height, endometrial area and percentage of mitotic figures. Results: The results obtained were suggestive of uterine proliferation by tamoxifen. The adjuvant administration of 13-cis-retinoic acid produced a statistically significant (p = 0.002) inhibitory effect on the tamoxifen induced increase in the area of endometrium, whereas no significant suppressive effect of this drug has been observed on the other parameters when compared with Group B. Conclusion: 13-cis Retinoic acid has not shown a significant role in the reversal of tamoxifen induced changes in the uterine tissue after a short term administration of three months. (author)

  5. Beneficial effects of retinoic acid on extracellular matrix degradation and attachment behaviour in follicular thyroid carcinoma cell lines

    NARCIS (Netherlands)

    Havekes, B.; Schröder van der Elst, J. P.; van der Pluijm, G.; Goslings, B. M.; Romijn, J. A.; Smit, J. W.

    2000-01-01

    The prognosis of patients with metastasised follicular thyroid carcinoma (FTC) is limited, necessitating the search for new treatment options. Beneficial effects of retinoids have been suggested in thyroid cancer and the present study was performed to investigate the effects of retinoic acid (RA) on

  6. The mucosal factors retinoic acid and TGF-B induce phenotypically and functionally distinct dendritic cell types

    NARCIS (Netherlands)

    Hartog, den C.G.; Altena, van S.E.C.; Savelkoul, H.F.J.; Neerven, van R.J.J.

    2013-01-01

    Non-inflammatory dendritic cell (DC) subsets play an essential role in preventing massive inflammation in mucosal tissues. We investigated whether mucosa-related factors, namely retinoic acid (RA) and transforming growth factor-ß (TGF-ß1), can induce such DC types. DCs were differentiated from

  7. Preparation, isolation and identification of non-conjugated C18:2 fatty acid isomers.

    Science.gov (United States)

    Fardin-Kia, Ali Reza

    2016-12-01

    Non-conjugated geometric/positional isomers of linoleic acid (c9,c12-18:2) are often present in processed foods and oils. The following work presents a simple addition/elimination reaction for preparation of non-conjugated 18:2 fatty acid isomers. A mixture containing positional and geometric isomers of C18:2 fatty acids was produced by addition of hydrobromic acid to the fatty acid double bonds, followed by its elimination with a strong sterically hindered base. Pure 8,12-, 8,13-, 9,12-, and 9,13-18:2 fatty acid methyl esters were isolated from the synthetic mixture by a combination of sub-ambient RP-HPLC and Ag + -HPLC. The determination of the double bond position was achieved by GC-MS using picolinyl esters derivatives. The determination of the fatty acid double bond geometric configuration was obtained by partial hydrogenation of the isolated isomer with hydrazine, followed by the GC-FID analysis. Published by Elsevier Ireland Ltd.

  8. Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid.

    Science.gov (United States)

    Subongkot, Thirapit; Ngawhirunpat, Tanasait

    2017-01-01

    This study was aimed to develop a novel microemulsion that contained oleth-5 as a surfactant to enhance the oral absorption of all-trans retinoic acid (ATRA). The prepared microemulsion was evaluated for its particle size, shape, zeta potential, in vitro release, in vitro intestinal absorption, intestinal membrane cytotoxicity and stability. The obtained microemulsion was spherical in shape with a particle size of microemulsion was best fit with the zero-order model. This microemulsion significantly improved the intestinal absorption of ATRA. Confocal laser scanning microscopy analysis using a fluorescent dye-loaded microemulsion also confirmed the intestinal absorption result. The intestinal membrane cytotoxicity of the ATRA-loaded microemulsion did not differ from an edible oil (fish oil). Stability testing showed that the ATRA-loaded microemulsion was more stable at 25°C than 40°C.

  9. Alterations in vitamin A/retinoic acid homeostasis in diet-induced obesity and insulin resistance.

    Science.gov (United States)

    Mody, Nimesh

    2017-11-01

    Vitamin A is an essential micronutrient for life and the phytochemical β-carotene, also known as pro-vitamin A, is an important dietary source of this vitamin. Vitamin A (retinol) is the parent compound of all bioactive retinoids but it is retinoic acid (RA) that is the active metabolite of vitamin A. The plasma concentration of retinol is maintained in a narrow range and its normal biological activities strictly regulated since excessive intake can lead to toxicity and thus also be detrimental to life. The present review will give an overview of how vitamin A homeostasis is maintained and move on to focus on the link between circulating vitamin A and metabolic disease states. Finally, we will examine how pharmacological or genetic alterations in vitamin A homeostasis and RA-signalling can influence body fat and blood glucose levels including a novel link to the liver secreted hormone fibroblast growth factor 21, an important metabolic regulator.

  10. Ultrasound-enhanced delivery of doxorubicin/all-trans retinoic acid-loaded nanodiamonds into tumors.

    Science.gov (United States)

    Li, Huanan; Zeng, Deping; Wang, Zhenyu; Fang, Liaoqiong; Li, Faqi; Wang, Zhibiao

    2018-03-14

    To build up a combined therapy strategy to address limitations of the enhanced permeability and retention (EPR) effect and improve the efficiency of tumor therapy. A pH-sensitive nanocomplex for co-delivery of doxorubicin (DOX) and all-trans retinoic acid (ATRA) was developed based on nanodiamonds (DOX/ATRA-NDs) to enhance intracellular retention of drugs. Meanwhile, ultrasound was employed to enhance tumor vascular penetration of DOX-ATRA-NDs. The distribution of DOX/ATRA-NDs in the tumor tissues increased threefold when ultrasound was applied at 1 MHz and 0.6 W/cm 2 . Comparing with unmodified chemotherapeutics, the combined therapy induced more tumor cells apoptosis and greater tumor growth inhibition in both liver and breast tumor models. DOX-ATRA-NDs demonstrate great potential in clinical applications.

  11. Thyroid hormone and retinoic acid nuclear receptors: specific ligand-activated transcription factors

    International Nuclear Information System (INIS)

    Brtko, J.

    1998-01-01

    Transcriptional regulation by both the thyroid hormone and the vitamin A-derived 'retinoid hormones' is a critical component in controlling many aspects of higher vertebrate development and metabolism. Their functions are mediated by nuclear receptors, which comprise a large super-family of ligand-inducible transcription factors. Both the thyroid hormone and the retinoids are involved in a complex arrangement of physiological and development responses in many tissues of higher vertebrates. The functions of 3,5,3'-triiodothyronine (T 3 ), the thyromimetically active metabolite of thyroxine as well as all-trans retinoic acid, the biologically active vitamin A metabolite are mediated by nuclear receptor proteins that are members of the steroid/thyroid/retinoid hormone receptor family. The functions of all members of the receptor super family are discussed. (authors)

  12. Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signalling

    DEFF Research Database (Denmark)

    Arregi, Igor; Climent, Maria; Iliev, Dobromir

    2016-01-01

    Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here we show that Retinol dehydrogenase-10 (Rdh......10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis...... and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early...

  13. Effect of isomers of hydroxybenzoic acid on the growth and metabolism of Chlorella vulgaris Beijerinck (Chlorophyceae

    Directory of Open Access Journals (Sweden)

    Andrzej Bajguz

    2014-01-01

    Full Text Available The isomers o-, m-, and p- of hydroxybenzoic acid (HBA in the concentration range 10-1-10-4 M in the unicellular green alga Chlorella vulgaris (Chlorophyceae display marked biological activity. The o-HBA isomer, commonly known as salicylic acid, in a concentration of 10-4 M exerted the most stimulating effect on the parameters analysed (the number of cells, dry mass, the content of chlorophylls a and h, carotenoids, soluble proteins and their secretion, monosaccharides, DNA and RNA whereas p-HBA had weak stimulating properties. On the other hand, m-HBA had a weak inhibitory effect on the growth of C. vulgaris and all the biochemical parameters analysed in comparison with the control culture of algae devoid of HBA isomers.

  14. Expression of a retinoic acid signature in circulating CD34 cells from coronary artery disease patients

    Directory of Open Access Journals (Sweden)

    van der Laan Anja M

    2010-06-01

    Full Text Available Abstract Background Circulating CD34+ progenitor cells have the potential to differentiate into a variety of cells, including endothelial cells. Knowledge is still scarce about the transcriptional programs used by CD34+ cells from peripheral blood, and how these are affected in coronary artery disease (CAD patients. Results We performed a whole genome transcriptome analysis of CD34+ cells, CD4+ T cells, CD14+ monocytes, and macrophages from 12 patients with CAD and 11 matched controls. CD34+ cells, compared to other mononuclear cells from the same individuals, showed high levels of KRAB box transcription factors, known to be involved in gene silencing. This correlated with high expression levels in CD34+ cells for the progenitor markers HOXA5 and HOXA9, which are known to control expression of KRAB factor genes. The comparison of expression profiles of CD34+ cells from CAD patients and controls revealed a less naïve phenotype in patients' CD34+ cells, with increased expression of genes from the Mitogen Activated Kinase network and a lowered expression of a panel of histone genes, reaching levels comparable to that in more differentiated circulating cells. Furthermore, we observed a reduced expression of several genes involved in CXCR4-signaling and migration to SDF1/CXCL12. Conclusions The altered gene expression profile of CD34+ cells in CAD patients was related to activation/differentiation by a retinoic acid-induced differentiation program. These results suggest that circulating CD34+ cells in CAD patients are programmed by retinoic acid, leading to a reduced capacity to migrate to ischemic tissues.

  15. Alterations of Intercellular Junctions in Peritoneal Mesothelial Cells from Patients Undergoing Dialysis: Effect of Retinoic Acid

    Science.gov (United States)

    Retana, Carmen; Sanchez, Elsa; Perez-Lopez, Alejandro; Cruz, Armando; Lagunas, Jesus; Cruz, Carmen; Vital, Socorro; Reyes, Jose L.

    2015-01-01

    ♦ Background: Dialysis patients are classified according to their peritoneal permeability as low transporter (LT, low solute permeability) or high transporter (HT, high solute permeability). Tight junction (TJ) proteins are critical to maintain ions, molecules and water paracellular transport through peritoneum. Exposure to peritoneal dialysis solutions causes damage to TJ in human peritoneal mesothelial cells (HPMCs). We analyzed the quantity, distribution and function of TJ proteins: claudin-1, -2 and -8, ZO-1 and occludin, in HPMC cultures from LT and HT patients. Since all-trans retinoic acid (ATRA) might modify the expression of TJ proteins, we studied its effect on HPMCs. ♦ Methods: Control HPMCs were isolated from human omentum, while HT or LT cells were obtained from dialysis effluents. Cells were cultured in presence of ATRA 0, 50 or 100 nM. Transepithelial electrical resistance (TER) measurement, immunostaining and Western blot analyses were performed. ♦ Results: HT exhibited lower TER than control and LT monolayers. Immunofluorescence for TJ was weak and discontinuous along the cell contour, in LT and HT. Furthermore, claudin-1, occludin and ZO-1 expressions were decreased. In all groups, claudin-2 was localized at nuclei. We observed that ATRA improved TJ distribution and increased TJ expression in HT. This retinoid did not modify claudin-2 and -8 expressions. All-trans retinoic acid decreased TER in HT, but had no effect in LT. ♦ Conclusions: Tight junctions were altered in HPMCs from dialyzed patients. The HT monolayer has lower TER than LT, which might be associated with the peritoneal permeability in these patients. ATRA might be a therapeutic alternative to maintain mesothelial integrity, since it improved TJ localization and expression. PMID:24584604

  16. Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles.

    Science.gov (United States)

    Santos, Tiago; Ferreira, Raquel; Quartin, Emanuel; Boto, Carlos; Saraiva, Cláudia; Bragança, José; Peça, João; Rodrigues, Cecília; Ferreira, Lino; Bernardino, Liliana

    2017-09-01

    Neurogenic niches constitute a powerful endogenous source of new neurons that can be used for brain repair strategies. Neuronal differentiation of these cells can be regulated by molecules such as retinoic acid (RA) or by mild levels of reactive oxygen species (ROS) that are also known to upregulate RA receptor alpha (RARα) levels. Data showed that neural stem cells from the subventricular zone (SVZ) exposed to blue light (405nm laser) transiently induced NADPH oxidase-dependent ROS, resulting in β-catenin activation and neuronal differentiation, and increased RARα levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis both in vitro and in vivo, while offering a temporal and spatial control of RA release. In conclusion, this combinatory treatment offers great advantages to potentiate neuronal differentiation, and provides an innovative and efficient application for brain regenerative therapies. Controlling the differentiation of stem cells would support the development of promising brain regenerative therapies. Blue light transiently increased reactive oxygen species, resulting in neuronal differentiation and increased retinoic acid receptor (RARα) levels. Additionally, the same blue light stimulation was capable of triggering the release of RA from light-responsive nanoparticles (LR-NP). The synergy between blue light and LR-NP led to amplified neurogenesis, while offering a temporal and spatial control of RA release. In this sense, our approach relying on the modulation of endogenous stem cells for the generation of new neurons may support the development of novel clinical therapies. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  17. Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Green, A.C. [St Vincent' s Institute, Fitzroy, Victoria 3065 (Australia); Department of Medicine at St. Vincent' s Hospital, The University of Melbourne, Victoria 3065 (Australia); Kocovski, P.; Jovic, T.; Walia, M.K. [St Vincent' s Institute, Fitzroy, Victoria 3065 (Australia); Chandraratna, R.A.S. [IO Therapeutics, Inc., Santa Ana, CA 92705 (United States); Martin, T.J.; Baker, E.K. [St Vincent' s Institute, Fitzroy, Victoria 3065 (Australia); Department of Medicine at St. Vincent' s Hospital, The University of Melbourne, Victoria 3065 (Australia); Purton, L.E., E-mail: lpurton@svi.edu.au [St Vincent' s Institute, Fitzroy, Victoria 3065 (Australia); Department of Medicine at St. Vincent' s Hospital, The University of Melbourne, Victoria 3065 (Australia)

    2017-01-01

    Low and high serum retinol levels are associated with increased fracture risk and poor bone health. We recently showed retinoic acid receptors (RARs) are negative regulators of osteoclastogenesis. Here we show RARs are also negative regulators of osteoblast and adipocyte differentiation. The pan-RAR agonist, all-trans retinoic acid (ATRA), directly inhibited differentiation and mineralisation of early osteoprogenitors and impaired the differentiation of more mature osteoblast populations. In contrast, the pan-RAR antagonist, IRX4310, accelerated differentiation of early osteoprogenitors. These effects predominantly occurred via RARγ and were further enhanced by an RARα agonist or antagonist, respectively. RAR agonists similarly impaired adipogenesis in osteogenic cultures. RAR agonist treatment resulted in significant upregulation of the Wnt antagonist, Sfrp4. This accompanied reduced nuclear and cytosolic β-catenin protein and reduced expression of the Wnt target gene Axin2, suggesting impaired Wnt/β-catenin signalling. To determine the effect of RAR inhibition in post-natal mice, IRX4310 was administered to male mice for 10 days and bones were assessed by µCT. No change to trabecular bone volume was observed, however, radial bone growth was impaired. These studies show RARs directly influence osteoblast and adipocyte formation from mesenchymal cells, and inhibition of RAR signalling in vivo impairs radial bone growth in post-natal mice. - Graphical abstract: Schematic shows RAR ligand regulation of osteoblast differentiation in vitro. RARγ antagonists±RARα antagonists promote osteoblast differentiation. RARγ and RARα agonists alone or in combination block osteoblast differentiation, which correlates with upregulation of Sfrp4, and downregulation of nuclear and cytosolic β-catenin and reduced expression of the Wnt target gene Axin2. Red arrows indicate effects of RAR agonists on mediators of Wnt signalling.

  18. Regional differentiation of retinoic acid-induced human pluripotent embryonic carcinoma stem cell neurons.

    Directory of Open Access Journals (Sweden)

    Dennis E Coyle

    Full Text Available The NTERA2 cl D1 (NT2 cell line, derived from human teratocarcinoma, exhibits similar properties as embryonic stem (ES cells or very early neuroepithelial progenitors. NT2 cells can be induced to become postmitotic central nervous system neurons (NT2N with retinoic acid. Although neurons derived from pluripotent cells, such as NT2N, have been characterized for their neurotransmitter phenotypes, their potential suitability as a donor source for neural transplantation also depends on their ability to respond to localized environmental cues from a specific region of the CNS. Therefore, our study aimed to characterize the regional transcription factors that define the rostocaudal and dorsoventral identity of NT2N derived from a monolayer differentiation paradigm using quantitative PCR (qPCR. Purified NT2N mainly expressed both GABAergic and glutamatergic phenotypes and were electrically active but did not form functional synapses. The presence of immature astrocytes and possible radial glial cells was noted. The NT2N expressed a regional transcription factor code consistent with forebrain, hindbrain and spinal cord neural progenitors but showed minimal expression of midbrain phenotypes. In the dorsoventral plane NT2N expressed both dorsal and ventral neural progenitors. Of major interest was that even under the influence of retinoic acid, a known caudalization factor, the NT2N population maintained a rostral phenotype subpopulation which expressed cortical regional transcription factors. It is proposed that understanding the regional differentiation bias of neurons derived from pluripotent stem cells will facilitate their successful integration into existing neuronal networks within the CNS.

  19. PPARα activators down-regulate CYP2C7, a retinoic acid and testosterone hydroxylase

    International Nuclear Information System (INIS)

    Fan Liqun; Brown-Borg, Holly; Brown, Sherri; Westin, Stefan; Mode, Agneta; Corton, J. Christopher

    2004-01-01

    Peroxisome proliferators (PP) are a large class of structurally diverse chemicals that mediate their effects in the liver mainly through the peroxisome proliferator-activated receptor α (PPARα). Exposure to PP results in down-regulation of CYP2C family members under control of growth hormone and sex steroids including CYP2C11 and CYP2C12. We hypothesized that PP exposure would also lead to similar changes in CYP2C7, a retinoic acid and testosterone hydroxylase. CYP2C7 gene expression was dramatically down-regulated in the livers of rats treated for 13 weeks by WY-14,643 (WY; 500 ppm) or gemfibrozil (GEM; 8000 ppm). In the same tissues, exposure to WY and GEM and to a lesser extent di-n-butyl phthalate (20 000 ppm) led to decreases in CYP2C7 protein levels in both male and female rats. An examination of the time and dose dependence of CYP2C7 protein changes after PP exposure revealed that CYP2C7 was more sensitive to compound exposure compared to other CYP2C family members. Protein expression was decreased after 1, 5 and 13 weeks of PP treatment. CYP2C7 protein expression was completely abolished at 5 ppm WY, the lowest dose tested. GEM and DBP exhibited dose-dependent decreases in CYP2C7 protein expression, becoming significant at 1000 ppm or 5000 ppm and above, respectively. These results show that PP exposure leads to changes in CYP2C7 mRNA and protein levels. Thus, in addition to known effects on steroid metabolism, exposure to PP may alter retinoic acid metabolism

  20. Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan.

    Science.gov (United States)

    Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Takagi, Mai; Sei, Kazunari; Yang, Min; Hirotsuji, Junji; Hu, Jianying; Nishikawa, Jun-ichi; Nakanishi, Tsuyoshi; Ike, Michihiko

    2010-04-01

    This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) alpha in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan. To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARalpha agonist contamination in the river basins. RARalpha agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARalpha agonists are always present and widespread in the rivers. Comparative investigation of RARalpha and estrogen receptor alpha agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARalpha agonist contamination was entirely different from that of the estrogenic compound contamination. This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARalpha agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARalpha agonists in the rivers. Although a trial conducted to identify RARalpha agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARalpha agonistic activity were not RAs (natural RAR ligands) and 4-oxo-RAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China. These findings suggest that there are unknown RARalpha agonists with high

  1. PI3K/AKT and ERK regulate retinoic acid-induced neuroblastoma cellular differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Qiao, Jingbo [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Paul, Pritha; Lee, Sora [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Qiao, Lan; Josifi, Erlena; Tiao, Joshua R. [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Chung, Dai H., E-mail: dai.chung@vanderbilt.edu [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer Retinoic acid (RA) induces neuroblastoma cells differentiation, which is accompanied by G0/G1 cell cycle arrest. Black-Right-Pointing-Pointer RA resulted in neuroblastoma cell survival and inhibition of DNA fragmentation; this is regulated by PI3K pathway. Black-Right-Pointing-Pointer RA activates PI3K and ERK1/2 pathway; PI3K pathway mediates RA-induced neuroblastoma cell differentiation. Black-Right-Pointing-Pointer Upregulation of p21 is necessary for RA-induced neuroblastoma cell differentiation. -- Abstract: Neuroblastoma, the most common extra-cranial solid tumor in infants and children, is characterized by a high rate of spontaneous remissions in infancy. Retinoic acid (RA) has been known to induce neuroblastoma differentiation; however, the molecular mechanisms and signaling pathways that are responsible for RA-mediated neuroblastoma cell differentiation remain unclear. Here, we sought to determine the cell signaling processes involved in RA-induced cellular differentiation. Upon RA administration, human neuroblastoma cell lines, SK-N-SH and BE(2)-C, demonstrated neurite extensions, which is an indicator of neuronal cell differentiation. Moreover, cell cycle arrest occurred in G1/G0 phase. The protein levels of cyclin-dependent kinase inhibitors, p21 and p27{sup Kip}, which inhibit cell proliferation by blocking cell cycle progression at G1/S phase, increased after RA treatment. Interestingly, RA promoted cell survival during the differentiation process, hence suggesting a potential mechanism for neuroblastoma resistance to RA therapy. Importantly, we found that the PI3K/AKT pathway is required for RA-induced neuroblastoma cell differentiation. Our results elucidated the molecular mechanism of RA-induced neuroblastoma cellular differentiation, which may be important for developing novel therapeutic strategy against poorly differentiated neuroblastoma.

  2. Analysis of conjugated linoleic acid and trans 18:1 isomers in synthetic and animal products.

    Science.gov (United States)

    Kramer, John K G; Cruz-Hernandez, Cristina; Deng, Zeyuan; Zhou, Jianqiang; Jahreis, Gerhard; Dugan, Michael E R

    2004-06-01

    The chemistry of conjugated fatty acids, specifically octadecadienoic acids (18:2; commonly referred to as conjugated linoleic acid, or CLA), has provided many challenges to lipid analysts because of their unique physical properties and the many possible positional and geometric isomers. After the acid-labile properties of CLAs during analytic procedures were overcome, it became evident that natural products, specifically dairy fats, contain one dominant (c9,t11-CLA), 3 intermediate (t7,c9-, t9,c11-, and t11,c13-CLA), and up to 20 more minor CLA isomers. The best analytic techniques to date include a combination of gas chromatography that uses 100-m highly polar capillary columns, silver ion-HPLC, and a combination of silver ion-thin-layer chromatography and gas chromatography to analyze the CLA and trans 18:1 isomers, because some of them serve as precursors of CLA in biological systems. These analytic techniques have assisted commercial suppliers to prepare pure CLA isomers and have permitted the evaluation of individual CLA isomers for their nutritional and biological activity in animal and human systems. It is increasingly evident that different CLA isomers have distinctly different physiologic and biochemical properties. These techniques are essential to evaluate dairy fats for their CLA content, to design experimental diets to increase the amount of CLA in dairy fats, and to determine the CLA profile in these CLA-enriched dairy fats. These improved techniques are used to evaluate the CLA profile in pork products from pigs fed different commercial CLA mixtures.

  3. All-Trans Retinoic Acid plus Arsenic Trioxide versus All-Trans Retinoic Acid plus Chemotherapy for Newly Diagnosed Acute Promyelocytic Leukemia: A Meta-Analysis.

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    Yafang Ma

    Full Text Available Recently, the all-trans retinoic acid (ATRA plus arsenic trioxide (ATO protocol has become a promising first-line therapeutic approach in patients with newly diagnosed acute promyelocytic leukemia (APL, but its benefits compared with standard ATRA plus chemotherapy regimen needs to be proven. Herein, we conducted a meta-analysis comparing the efficacy of ATRA plus ATO with ATRA plus chemotherapy for adult patients with newly diagnosed APL.We systematically searched biomedical electronic databases and conference proceedings through February 2016. Two reviewers independently assessed all studies for relevance and validity.Overall, three studies were eligible for inclusion in this meta-analysis, which included a total of 585 patients, with 317 in ATRA plus ATO group and 268 in ATRA plus chemotherapy group. Compared with patients who received ATRA and chemotherapy, patients who received ATRA plus ATO had a significantly better event-free survival (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.22-0.67, p = 0.009, overall survival (HR = 0.44, 95% CI: 0.24-0.82, p = 0.009, complete remission rate (relative risk [RR] = 1.05; 95% CI: 1.01-1.10; p = 0.03. There were no significant differences in early mortality (RR = 0.48; 95% CI: 0.22-1.05; p = 0.07.Thus, this analysis indicated that ATRA plus ATO protocol may be preferred to standard ATRA plus chemotherapy protocol, particularly in low-to-intermediate risk APL patients. Further larger trials were needed to provide more evidence in high-risk APL patients.

  4. Expression of the helix-loop-helix protein inhibitor of DNA binding-1 (ID-1) is activated by all-trans retinoic acid in normal human keratinocytes

    International Nuclear Information System (INIS)

    Villano, C.M.; White, L.A.

    2006-01-01

    The ID (inhibitor of differentiation or DNA binding) helix-loop-helix proteins are important mediators of cellular differentiation and proliferation in a variety of cell types through regulation of gene expression. Overexpression of the ID proteins in normal human keratinocytes results in extension of culture lifespan, indicating that these proteins are important for epidermal differentiation. Our hypothesis is that the ID proteins are targets of the retinoic acid signaling pathway in keratinocytes. Retinoids, vitamin A analogues, are powerful regulators of cell growth and differentiation and are widely used in the prevention and treatment of a variety of cancers in humans. Furthermore, retinoic acid is necessary for the maintenance of epithelial differentiation and demonstrates an inhibitory action on skin carcinogenesis. We examined the effect of all-trans retinoic acid on expression of ID-1, -2, -3, and -4 in normal human keratinocytes and found that exposure of these cells to all-trans retinoic acid causes an increase in both ID-1 and ID-3 gene expression. Furthermore, our data show that this increase is mediated by increased transcription involving several cis-acting elements in the distal portion of the promoter, including a CREB-binding site, an Egr1 element, and an YY1 site. These data demonstrate that the ID proteins are direct targets of the retinoic acid signaling pathway. Given the importance of the ID proteins to epidermal differentiation, these results suggest that IDs may be mediating some of the effects of all-trans retinoic acid in normal human keratinocytes

  5. Non-genomic actions of retinoic acid induce pi3k signaling pathway and phosphorylation of nuclear proteins

    OpenAIRE

    Laserna Mendieta, Emilio J.; Masiá, Susana; Barettino, Domingo

    2007-01-01

    Retinoic acid (RA), the active form of vitamin A, induces neuroblastoma cells SH-SY5Y to differentiate. In addition to its classical transcriptional actions regulating the expression of specific genes, RA acts in an extra-genomic way, modulating the activity of relevant signalling cascades. In particular, RA treatment of SH-SY5Y neuroblastoma cells results in activation of phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, and this activation is required for RA-induced differentiation (...

  6. Delayed translocation of NGFI-B/RXR in glutamate stimulated neurons allows late protection by 9-cis retinoic acid

    International Nuclear Information System (INIS)

    Mathisen, Gro H.; Fallgren, Asa B.; Strom, Bjorn O.; Boldingh Debernard, Karen A.; Mohebi, Beata U.; Paulsen, Ragnhild E.

    2011-01-01

    Highlights: → NGFI-B and RXR translocate out of the nucleus after glutamate treatment. → Arresting NGFI-B/RXR in the nucleus protects neurons from excitotoxicity. → Late protection by 9-cis RA is possible due to a delayed translocation of NGFI-B/RXR. -- Abstract: Nuclear receptor and apoptosis inducer NGFI-B translocates out of the nucleus as a heterodimer with RXR in response to different apoptosis stimuli, and therefore represents a potential pharmacological target. We found that the cytosolic levels of NGFI-B and RXRα were increased in cultures of cerebellar granule neurons 2 h after treatment with glutamate (excitatory neurotransmitter in the brain, involved in stroke). To find a time-window for potential intervention the neurons were transfected with gfp-tagged expressor plasmids for NGFI-B and RXR. The default localization of NGFI-Bgfp and RXRgfp was nuclear, however, translocation out of the nucleus was observed 2-3 h after glutamate treatment. We therefore hypothesized that the time-window between treatment and translocation would allow late protection against neuronal death. The RXR ligand 9-cis retinoic acid was used to arrest NGFI-B and RXR in the nucleus. Addition of 9-cis retinoic acid 1 h after treatment with glutamate reduced the cytosolic translocation of NGFI-B and RXRα, the cytosolic translocation of NGFI-Bgfp observed in live neurons, as well as the neuronal death. However, the reduced translocation and the reduced cell death were not observed when 9-cis retinoic acid was added after 3 h. Thus, late protection from glutamate induced death by addition of 9-cis retinoic acid is possible in a time-window after apoptosis induction.

  7. 9-cis-retinoic Acid and troglitazone impacts cellular adhesion, proliferation, and integrin expression in K562 cells.

    Science.gov (United States)

    Hanson, Amanda M; Gambill, Jessica; Phomakay, Venusa; Staten, C Tyler; Kelley, Melissa D

    2014-01-01

    Retinoids are established pleiotropic regulators of both adaptive and innate immune responses. Recently, troglitazone, a PPAR gamma agonist, has been demonstrated to have anti-inflammatory effects. Separately, retinoids and troglitazone are implicated in immune related processes; however, their combinatory role in cellular adhesion and proliferation has not been well established. In this study, the effect of 9-cis-retinoic acid (9-cis-RA) and troglitazone on K562 cellular adhesion and proliferation was investigated. Troglitazone exposure decreased K562 cellular adhesion to RGD containing extracellular matrix proteins fibronectin, FN-120, and vitronectin in a concentration and time-dependent manner. In the presence of troglitazone, 9-cis-retinoic acid restores cellular adhesion to levels comparable to vehicle treatment alone on fibronectin, FN-120, and vitronectin substrates within 72 hours. Due to the prominent role of integrins in attachment to extracellular matrix proteins, we evaluated the level of integrin α5 subunit expression. Troglitazone treatment results in decrease in α5 subunit expression on the cell surface. In the presence of both agonists, cell surface α5 subunit expression was restored to levels comparable to vehicle treatment alone. Additionally, troglitazone and 9-cis-RA mediated cell adhesion was decreased in the presence of a function blocking integrin alpha 5 inhibitor. Further, through retinoid metabolic profiling and HPLC analysis, our study demonstrates that troglitazone augments retinoid availability in K562 cells. Finally, we demonstrate that troglitazone and 9-cis-retinoic acid synergistically dampen cellular proliferation in K562 cells. Our study is the first to report that the combination of troglitazone and 9-cis-retinoic acid restores cellular adhesion, alters retinoid availability, impacts integrin expression, and dampens cellular proliferation in K562 cells.

  8. Oridonin stabilizes retinoic acid receptor alpha through ROS-activated NF-κB signaling.

    Science.gov (United States)

    Cao, Yang; Wei, Wei; Zhang, Nan; Yu, Qing; Xu, Wen-Bin; Yu, Wen-Jun; Chen, Guo-Qiang; Wu, Ying-Li; Yan, Hua

    2015-04-10

    Retinoic acid receptor alpha (RARα) plays an essential role in the regulation of many biological processes, such as hematopoietic cell differentiation, while abnormal RARα function contributes to the pathogenesis of certain diseases including cancers, especially acute promyelocytic leukemia (APL). Recently, oridonin, a natural diterpenoid isolated from Rabdosia rubescens, was demonstrated to regulate RARα by increasing its protein level. However, the underlying molecular mechanism for this action has not been fully elucidated. In the APL cell line, NB4, the effect of oridonin on RARα protein was analyzed by western blot and real-time quantitative RT-PCR analyses. Flow cytometry was performed to detect intracellular levels of reactive oxygen species (ROS). The association between nuclear factor-kappa B (NF-κB) signaling and the effect of oridonin was assessed using specific inhibitors, shRNA gene knockdown, and immunofluorescence assays. In addition, primary leukemia cells were treated with oridonin and analyzed by western blot in this study. RARα possesses transcriptional activity in the presence of its ligand, all-trans retinoic acid (ATRA). Oridonin remarkably stabilized the RARα protein, which retained transcriptional activity. Oridonin also moderately increased intracellular ROS levels, while pretreatment with the ROS scavenger, N-acetyl-l-cysteine (NAC), dramatically abrogated RARα stabilization by oridonin. More intriguingly, direct exposure to low concentrations of H2O2 also increased RARα protein but not mRNA levels, suggesting a role for ROS in oridonin stabilization of RARα protein. Further investigations showed that NAC antagonized oridonin-induced activation of NF-κB signaling, while the NF-κB signaling inhibitor, Bay 11-7082, effectively blocked the oridonin increase in RARα protein levels. In line with this, over-expression of IκΒα (A32/36), a super-repressor form of IκΒα, or NF-κB-p65 knockdown inhibited oridonin or H2O2-induced

  9. Clinical Significance of Retinoic Acid Receptor Beta Promoter Methylation in Prostate Cancer: A Meta-Analysis.

    Science.gov (United States)

    Dou, MengMeng; Zhou, XueLiang; Fan, ZhiRui; Ding, XianFei; Li, LiFeng; Wang, ShuLing; Xue, Wenhua; Wang, Hui; Suo, Zhenhe; Deng, XiaoMing

    2018-01-01

    Retinoic acid receptor beta (RAR beta) is a retinoic acid receptor gene that has been shown to play key roles during multiple cancer processes, including cell proliferation, apoptosis, migration and invasion. Numerous studies have found that methylation of the RAR beta promoter contributed to the occurrence and development of malignant tumors. However, the connection between RAR beta promoter methylation and prostate cancer (PCa) remains unknown. This meta-analysis evaluated the clinical significance of RAR beta promoter methylation in PCa. We searched all published records relevant to RAR beta and PCa in a series of databases, including PubMed, Embase, Cochrane Library, ISI Web of Science and CNKI. The rates of RAR beta promoter methylation in the PCa and control groups (including benign prostatic hyperplasia and normal prostate tissues) were summarized. In addition, we evaluated the source region of available samples and the methods used to detect methylation. To compare the incidence and variation in RAR beta promoter methylation in PCa and non-PCa tissues, the odds ratio (OR) and 95% confidence interval (CI) were calculated accordingly. All the data were analyzed with the statistical software STATA 12.0. Based on the inclusion and exclusion criteria, 15 articles assessing 1,339 samples were further analyzed. These data showed that the RAR beta promoter methylation rates in PCa tissues were significantly higher than the rates in the non-PCa group (OR=21.65, 95% CI: 9.27-50.57). Subgroup analysis according to the source region of samples showed that heterogeneity in Asia was small (I2=0.0%, P=0.430). Additional subgroup analysis based on the method used to detect RAR beta promoter methylation showed that the heterogeneity detected by MSP (methylation-specific PCR) was relatively small (I2=11.3%, P=0.343). Although studies reported different rates for RAR beta promoter methylation in PCa tissues, the total analysis demonstrated that RAR beta promoter methylation

  10. Clinical Significance of Retinoic Acid Receptor Beta Promoter Methylation in Prostate Cancer: A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    MengMeng Dou

    2018-03-01

    Full Text Available Background/Aims: Retinoic acid receptor beta (RAR beta is a retinoic acid receptor gene that has been shown to play key roles during multiple cancer processes, including cell proliferation, apoptosis, migration and invasion. Numerous studies have found that methylation of the RAR beta promoter contributed to the occurrence and development of malignant tumors. However, the connection between RAR beta promoter methylation and prostate cancer (PCa remains unknown. This meta-analysis evaluated the clinical significance of RAR beta promoter methylation in PCa. Materials and Methods: We searched all published records relevant to RAR beta and PCa in a series of databases, including PubMed, Embase, Cochrane Library, ISI Web of Science and CNKI. The rates of RAR beta promoter methylation in the PCa and control groups (including benign prostatic hyperplasia and normal prostate tissues were summarized. In addition, we evaluated the source region of available samples and the methods used to detect methylation. To compare the incidence and variation in RAR beta promoter methylation in PCa and non-PCa tissues, the odds ratio (OR and 95% confidence interval (CI were calculated accordingly. All the data were analyzed with the statistical software STATA 12.0. Results: Based on the inclusion and exclusion criteria, 15 articles assessing 1,339 samples were further analyzed. These data showed that the RAR beta promoter methylation rates in PCa tissues were significantly higher than the rates in the non-PCa group (OR=21.65, 95% CI: 9.27-50.57. Subgroup analysis according to the source region of samples showed that heterogeneity in Asia was small (I2=0.0%, P=0.430. Additional subgroup analysis based on the method used to detect RAR beta promoter methylation showed that the heterogeneity detected by MSP (methylation-specific PCR was relatively small (I2=11.3%, P=0.343. Conclusion: Although studies reported different rates for RAR beta promoter methylation in PCa

  11. Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation.

    Science.gov (United States)

    Peinemann, Frank; van Dalen, Elvira C; Enk, Heike; Berthold, Frank

    2017-08-25

    Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review. To evaluate the efficacy and safety of additional retinoic acid as part of a postconsolidation therapy after high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT), compared to placebo retinoic acid or to no additional retinoic acid in people with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11), MEDLINE in PubMed (1946 to 24 November 2016), and Embase in Ovid (1947 to 24 November 2016). Further searches included trial registries (on 22 December 2016), conference proceedings (on 23 March 2017) and reference lists of recent reviews and relevant studies. We did not apply limits by publication year or languages. Randomised controlled trials (RCTs) evaluating additional retinoic acid after HDCT followed by HSCT for people with high-risk neuroblastoma compared to placebo retinoic acid or to no additional retinoic acid. Primary outcomes were overall survival and treatment-related mortality. Secondary outcomes were progression-free survival, event-free survival, early toxicity, late toxicity, and health-related quality of life. We used standard

  12. The meninges is a source of retinoic acid for the late-developing hindbrain.

    Science.gov (United States)

    Zhang, Jinghua; Smith, Deborah; Yamamoto, Miyuki; Ma, Lanhua; McCaffery, Peter

    2003-08-20

    One general function for retinoic acid (RA) is pattern organization in the CNS. This regulatory factor has an essential role in spinal cord motor neuron and early posterior hindbrain development. In the anterior CNS, however, there is only a limited number of foci of RA synthesis, and less attention has been placed on regions such as the anterior hindbrain where RA synthesizing enzymes are absent. This study shows that a rich source of RA lies around the hindbrain from the RA synthetic enzyme retinaldehyde dehydrogenase-2 (RALDH2) present in the surrounding meninges and mesenchyme by embryonic day 13. RALDH2 is not distributed uniformly throughout the meninges but is restricted to territories over the developing hindbrain, suggesting that RA signaling may be localized to those regions. Further regulation of RA signaling is provided by the presence of a RA sink in the form of the CYP26B1 RA catabolic enzyme expressed in deeper regions of the brain. As a guide to the neural anatomy of hindbrain RA signaling, we used a mouse transgenic for a lacZ reporter gene driven by a RA response element (RAREhsplacZ) to identify regions of RA signaling. This reporter mouse provides evidence that RA signaling in the hindbrain after embryonic day 13 occurs in the regions of the cerebellum and precerebellar system adjacent to sources of RA, including the inferior olive and the pontine nuclei.

  13. Effects of tracheal occlusion with retinoic acid administration on normal lung development.

    Science.gov (United States)

    Delabaere, Amélie; Marceau, Geoffroy; Coste, Karen; Blanchon, Loïc; Déchelotte, Pierre-Jean; Blanc, Pierre; Sapin, Vincent; Gallot, Denis

    2017-05-01

    Tracheal occlusion (TO) is an investigational therapy for severe congenital diaphragmatic hernia that decreases pulmonary hypoplasia, but sustained TO also induces deficient surfactant synthesis. Intramuscular maternal administration of retinoic acid (RA) in a surgical rabbit model of congenital diaphragmatic hernia showed a beneficial effect on lung maturation. We evaluated the potential of RA delivery into the trachea and studied the combined effects of TO and RA on normal lung development. Experiments were performed on normal rabbit fetuses. Liposomes and capric triglyceride (Miglyol ® ), alone and with RA, were administered in the trachea just before TO (d26). Lung morphology and surfactant production were studied at term (d30). Tracheal occlusion increased lung weight and enhanced alveolar development but increased apoptotic activity and decreased surfactant expression. Tracheal injection of RA improved surfactant production to levels of normal controls. We established the potential of liposome and Miglyol as RA vehicle for delivering this bioactive molecule in the fetal airways. Tracheal RA injection seems to oppose the effects of TO in fetuses with normal lungs. © 2017 John Wiley & Sons, Ltd. © 2017 John Wiley & Sons, Ltd.

  14. Transcriptional Elongation Factor Elongin A Regulates Retinoic Acid-Induced Gene Expression during Neuronal Differentiation

    Directory of Open Access Journals (Sweden)

    Takashi Yasukawa

    2012-11-01

    Full Text Available Elongin A increases the rate of RNA polymerase II (pol II transcript elongation by suppressing transient pausing by the enzyme. Elongin A also acts as a component of a cullin-RING ligase that can target stalled pol II for ubiquitylation and proteasome-dependent degradation. It is not known whether these activities of Elongin A are functionally interdependent in vivo. Here, we demonstrate that Elongin A-deficient (Elongin A−/− embryos exhibit abnormalities in the formation of both cranial and spinal nerves and that Elongin A−/− embryonic stem cells (ESCs show a markedly decreased capacity to differentiate into neurons. Moreover, we identify Elongin A mutations that selectively inactivate one or the other of the aforementioned activities and show that mutants that retain the elongation stimulatory, but not pol II ubiquitylation, activity of Elongin A rescue neuronal differentiation and support retinoic acid-induced upregulation of a subset of neurogenesis-related genes in Elongin A−/− ESCs.

  15. Apoptotic and anti-proliferative effects of all-trans retinoic acid

    International Nuclear Information System (INIS)

    Zamora, Monica; Ortega, Juan Alberto; Alana, Lide; Vinas, Octavi; Mampel, Teresa

    2006-01-01

    We examined the apoptotic and anti-proliferative effects of all-trans retinoic acid (atRA) in HeLa cells. Our results demonstrated that HeLa cells were more sensitive to the anti-proliferative effects of atRA than to its apoptotic effects. Furthermore, we demonstrated that caspase inhibition attenuates cell death but does not alter the atRA-dependent reduction in cell proliferation, which suggests that atRA-induced apoptosis is independent of the arrest in cell proliferation. To check whether ANT proteins mediated these atRA effects, we transiently transfected cells with expression vectors encoding for individual ANT (adenine nucleotide translocase 1-3). Our results revealed that ANT1 and ANT3 over-expressing HeLa cells increased their atRA sensitivity. Thus, our results not only demonstrate the different functional activities of ANT isoforms, but also contribute to a better understanding of the properties of atRA as an anti-tumoral agent used in cancer therapy

  16. Retinoic acid signaling in B-cells is essential for oral immunization and microflora composition

    Science.gov (United States)

    Pantazi, Eirini; Marks, Ellen; Stolarczyk, Emilie; Lycke, Nils; Noelle, Randolph J.; Elgueta, Raul

    2015-01-01

    Retinoic acid (RA)3 is a critical regulator of the intestinal adaptive immune response. However, the intrinsic impact of RA on B cell differentiation in the regulation of gut humoral immunity in vivo has never been directly shown. To address this issue, we have been able to generate a mouse model where B-cells specifically express a dominant negative receptor α for RA. Here, we show that the silencing of RA signaling in B-cells reduces the numbers of IgA+ antibody secreting cells (ASC) both in vitro and in vivo, suggesting that RA has a direct effect on IgA plasma cell (PC) differentiation. Moreover, the lack of RA signaling in B-cells abrogates Ag-specific IgA responses after oral immunization and affects the microbiota composition. In conclusion, these results suggest that RA signaling in B-cells through the RA receptor α is important to generate an effective gut humoral response and to maintain a normal microbiota composition. PMID:26163586

  17. Cutting Edge: Retinoic Acid Signaling in B Cells Is Essential for Oral Immunization and Microflora Composition.

    Science.gov (United States)

    Pantazi, Eirini; Marks, Ellen; Stolarczyk, Emilie; Lycke, Nils; Noelle, Randolph J; Elgueta, Raul

    2015-08-15

    Retinoic acid (RA) is a critical regulator of the intestinal adaptive immune response. However, the intrinsic impact of RA on B cell differentiation in the regulation of gut humoral immunity in vivo has never been directly shown. To address this issue, we have been able to generate a mouse model where B cells specifically express a dominant-negative receptor α for RA. In this study, we show that the silencing of RA signaling in B cells reduces the numbers of IgA(+) Ab-secreting cells both in vitro and in vivo, suggesting that RA has a direct effect on IgA plasma cell differentiation. Moreover, the lack of RA signaling in B cells abrogates Ag-specific IgA responses after oral immunization and affects the microbiota composition. In conclusion, these results suggest that RA signaling in B cells through the RA receptor α is important to generate an effective gut humoral response and to maintain a normal microbiota composition. Copyright © 2015 by The American Association of Immunologists, Inc.

  18. Dexamethasone, all trans retinoic acid and interferon alpha 2a in patients with refractory multiple myeloma.

    Science.gov (United States)

    Avilés, A; Rosas, A; Huerta-Guzmán, J; Talavera, A; Cleto, S

    1999-02-01

    Few effective regimen are available for patients with refractory multiple myeloma (RMM). Generally, responses are scarce and disease free survival is very short. We developed a new therapeutic option in these patients using dexamethasone (40 mg/m2, i.v., daily, days 1 to 4), all-trans retinoic acid (45 mg/m2, po, daily, days 5 to 14) and interferon alpha 2a (9.0 MU, daily, subcutaneously, days 5 to 14). The treatment was administered every 21 days for 6 cycles. In a pilot study, 12 patients, heavily treated with chemotherapy and radiotherapy and in some cases with interferon, were allocated to receive the afore mentioned treatment. Response was observed in 10 patients (83%). With a median follow-up of 36.1 months (range 27 to 41), seven patients remain alive and disease-free without any treatment. Two patients were failures and have died due to tumor progression. Toxicity was mild and all patients received treatment according to the planned doses of drugs. The use of biological modifiers in combination with dexamethasone offer a safe and effective therapeutic option in patients with refractory multiple myeloma. More studies are warranted to define the role of this type of treatment.

  19. Newborn serum retinoic acid level is associated with variants of genes in the retinol metabolism pathway.

    Science.gov (United States)

    Manolescu, Daniel C; El-Kares, Reyhan; Lakhal-Chaieb, Lajmi; Montpetit, Alexandre; Bhat, Pangala V; Goodyer, Paul

    2010-06-01

    Retinoic acid (RA) is a critical regulator of gene expression during embryonic development. In rodents, moderate maternal vitamin A deficiency leads to subtle morphogenetic defects and inactivation of RA pathway genes causes major disturbances of embryogenesis. In this study, we quantified RA in umbilical cord blood of 145 healthy full-term Caucasian infants from Montreal. Sixty seven percent of values were ROL). However, we found that the (A) allele of the rs12591551 single nucleotide polymorphism (SNP) in the ALDH1A2 gene (ALDH1A2rs12591551(A)), occurring in 19% of newborns, was associated with 2.5-fold higher serum RA levels. ALDH1A2 encodes retinaldehyde dehydrogenase (RALDH) 2, which synthesizes RA in fetal tissues. We also found that homozygosity for the (A) allele of the rs12724719 SNP in the CRABP2 gene (CRABP2rs12724719(A/A)) was associated with 4.4-fold increase in umbilical cord serum RA. CRABP2 facilitates RA binding to its cognate receptor complex and transfer to the nucleus. We hypothesize that individual variation in RA pathway genes may account for subtle variations in RA-dependent human embryogenesis.

  20. Retinoic acid functions as a key GABAergic differentiation signal in the basal ganglia.

    Directory of Open Access Journals (Sweden)

    Christina Chatzi

    2011-04-01

    Full Text Available Although retinoic acid (RA has been implicated as an extrinsic signal regulating forebrain neurogenesis, the processes regulated by RA signaling remain unclear. Here, analysis of retinaldehyde dehydrogenase mutant mouse embryos lacking RA synthesis demonstrates that RA generated by Raldh3 in the subventricular zone of the basal ganglia is required for GABAergic differentiation, whereas RA generated by Raldh2 in the meninges is unnecessary for development of the adjacent cortex. Neurospheres generated from the lateral ganglionic eminence (LGE, where Raldh3 is highly expressed, produce endogenous RA, which is required for differentiation to GABAergic neurons. In Raldh3⁻/⁻ embryos, LGE progenitors fail to differentiate into either GABAergic striatal projection neurons or GABAergic interneurons migrating to the olfactory bulb and cortex. We describe conditions for RA treatment of human embryonic stem cells that result in efficient differentiation to a heterogeneous population of GABAergic interneurons without the appearance of GABAergic striatal projection neurons, thus providing an in vitro method for generation of GABAergic interneurons for further study. Our observation that endogenous RA is required for generation of LGE-derived GABAergic neurons in the basal ganglia establishes a key role for RA signaling in development of the forebrain.

  1. Tributyltin and triphenyltin inhibit osteoclast differentiation through a retinoic acid receptor-dependent signaling pathway

    International Nuclear Information System (INIS)

    Yonezawa, Takayuki; Hasegawa, Shin-ichi; Ahn, Jae-Yong; Cha, Byung-Yoon; Teruya, Toshiaki; Hagiwara, Hiromi; Nagai, Kazuo; Woo, Je-Tae

    2007-01-01

    Organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), have been widely used in agriculture and industry. Although these compounds are known to have many toxic effects, including endocrine-disrupting effects, their effects on bone resorption are unknown. In this study, we investigated the effects of organotin compounds, such as monobutyltin (MBT), dibutyltin (DBT), TBT, and TPT, on osteoclast differentiation using mouse monocytic RAW264.7 cells. MBT and DBT had no effects, whereas TBT and TPT dose-dependently inhibited osteoclast differentiation at concentrations of 3-30 nM. Treatment with a retinoic acid receptor (RAR)-specific antagonist, Ro41-5253, restored the inhibition of osteoclastogenesis by TBT and TPT. TBT and TPT reduced receptor activator of nuclear factor-κB ligand (RANKL) induced nuclear factor of activated T cells (NFAT) c1 expression, and the reduction in NFATc1 expression was recovered by Ro41-5253. Our results suggest that TBT and TPT suppress osteoclastogenesis by inhibiting RANKL-induced NFATc1 expression via an RAR-dependent signaling pathway

  2. All-trans retinoic acid negatively regulates cytotoxic activities of nature killer cell line 92

    International Nuclear Information System (INIS)

    Li Ang; He Meilan; Wang Hui; Qiao Bin; Chen Ping; Gu Hua; Zhang Mengjie; He Shengxiang

    2007-01-01

    NK cells are key components of innate immune systems and their activities are regulated by cytokines and hormones. All-trans retinoic acid (ATRA), as a metabolite of vitamin A and an immunomodulatory hormone, plays an important role in regulating immune responses. In the present study, we investigated the effect of ATRA on human NK cell line NK92. We found that ATRA dose-dependently suppressed cytotoxic activities of NK92 cells without affecting their proliferation. To explore the mechanisms underlying the ATRA influence on NK92 cells, we examined the production of cytokines (TNF-α, IFN-γ), gene expression of cytotoxic-associated molecules (perforin, granzyme B, nature killer receptors (NCRs), and NKG2D), and the activation of NF-κB pathways related with immune response. Our results demonstrated that ATRA suppressed NF-κB activity and prevented IκBα degradation in a dose-dependent way, inhibited IFN-γ production and gene expression of granzyme B and NKp46. Our findings suggest that ATRA is a negative regulator of NK92 cell activation and may act as a potential regulator of anti-inflammatory functions in vivo

  3. ZRF1 controls the retinoic acid pathway and regulates leukemogenic potential in acute myeloid leukemia.

    Science.gov (United States)

    Demajo, S; Uribesalgo, I; Gutiérrez, A; Ballaré, C; Capdevila, S; Roth, M; Zuber, J; Martín-Caballero, J; Di Croce, L

    2014-11-27

    Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in transcriptional regulation, is highly overexpressed in human AML, but it is not known whether it plays a role in leukemia progression. Here, we demonstrate that ZRF1 depletion decreases cell proliferation, induces apoptosis and enhances cell differentiation in human AML cells. Treatment with retinoic acid (RA), a differentiating agent currently used to treat certain AMLs, leads to a functional switch of ZRF1 from a negative regulator to an activator of differentiation. At the molecular level, ZRF1 controls the RA-regulated gene network through its interaction with the RA receptor α (RARα) and its binding to RA target genes. Our genome-wide expression study reveals that ZRF1 regulates the transcription of nearly half of RA target genes. Consistent with our in vitro observations that ZRF1 regulates proliferation, apoptosis, and differentiation, ZRF1 depletion strongly inhibits leukemia progression in a xenograft mouse model. Finally, ZRF1 knockdown cooperates with RA treatment in leukemia suppression in vivo. Taken together, our data reveal that ZRF1 is a key transcriptional regulator in leukemia progression and suggest that ZRF1 inhibition could be a novel strategy to be explored for AML treatment.

  4. Evidence for the presence of a retinoic acid receptor in rat osteosarcoma cells

    International Nuclear Information System (INIS)

    Atkins, K.B.; Beitz, D.C.; Horst, R.L.; Reinhardt, T.A.

    1990-01-01

    Research has shown that ROS 17/2.8 cells respond to retinoic acid (RA) and do not express the cellular binding protein (CRABP) for RA. Initial experiments indicated the presence of a cytosolic and nuclear RA-binding activity. Both cytosolic and nuclear extracts were centrifuged (230,000g), and the supernatants labeled with [ 3 H]-RA±100-fold excess RA. Sucrose gradient analysis of the nuclear extract showed a specific RA-binding activity sedimenting at 3.3S. Scatchard analysis of the nuclear extract showed a single binding component with an apparent K d of 10 -9 M and an estimate of 1,700-3,000 copies/cell. The molecular weight of putative RAR was estimated to be 51KD by gel filtration. The cytosolic RA-binding activity co-sediments (2.0S) on a sucrose gradient with the cytosolic RA-binding activity from rat testis. Scatchard analysis resulted in an apparent Kd of 10 -8 M with an estimated 60,000 copies of CRABP/cell. These data indicate ROS 17/2.8 cells express both RAR and CRABP

  5. A novel retinoic acid chalcone reverses epithelial‑mesenchymal transition in prostate cancer cells

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    Jian Zhong

    2015-06-01

    Full Text Available The present study was performed to investigate the effect of retinoic acid fluoro chalcone (RAFC on lipopolysaccharide (LPS induced epithelial-mesenchymal transition (EMT in PC3 and CWR22rv1 prostate cell lines. Lipo-polysaccharide (LPS was used to induce epithelial-mesenchymal transition in prostate carcinoma cell lines. The results revealed that treatment of PC3 and CWR22rv1 cells with LPS resulted in significant changes in the morphological features of the EMT. The mesenchymal marker, vimentin expression was significantly increased whereas the expression level of E‑cadherin was markedly decreased after the treatment. We also observed increased cell motility and higher level of transcription factor glioma‑associated oncogene homolog 1 (Gli1 expression on LPS treatment. Treatment of prostate cells with RAFC reversed the morphological changes induced by LPS in prostate cells. RAFC also reduced the expression of EMT markers induced by LPS and suppressed the Gli1 expression. The resultant effect of these changes was the suppression of motility and invasiveness of the prostrate cells. Thus, RAFC exhibited anti‑invasive effect on prostrate cells by inhibition of the EMT process via Hedgehog signaling pathway.

  6. Cell Identity Switching Regulated by Retinoic Acid Signaling Maintains Homogeneous Segments in the Hindbrain.

    Science.gov (United States)

    Addison, Megan; Xu, Qiling; Cayuso, Jordi; Wilkinson, David G

    2018-06-04

    The patterning of tissues to form subdivisions with distinct and homogeneous regional identity is potentially disrupted by cell intermingling. Transplantation studies suggest that homogeneous segmental identity in the hindbrain is maintained by identity switching of cells that intermingle into another segment. We show that switching occurs during normal development and is mediated by feedback between segment identity and the retinoic acid degrading enzymes, cyp26b1 and cyp26c1. egr2, which specifies the segmental identity of rhombomeres r3 and r5, underlies the lower expression level of cyp26b1 and cyp26c1 in r3 and r5 compared with r2, r4, and r6. Consequently, r3 or r5 cells that intermingle into adjacent segments encounter cells with higher cyp26b1/c1 expression, which we find is required for downregulation of egr2b expression. Furthermore, egr2b expression is regulated in r2, r4, and r6 by non-autonomous mechanisms that depend upon the number of neighbors that express egr2b. These findings reveal that a community regulation of retinoid signaling maintains homogeneous segmental identity. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program.

    Science.gov (United States)

    Tasseff, Ryan; Jensen, Holly A; Congleton, Johanna; Dai, David; Rogers, Katharine V; Sagar, Adithya; Bunaciu, Rodica P; Yen, Andrew; Varner, Jeffrey D

    2017-10-30

    In this study, we present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes reinforcing feedback between an ATRA-inducible signalsome complex involving many proteins including Vav1, a guanine nucleotide exchange factor, and the activation of the mitogen activated protein kinase (MAPK) cascade. We decomposed the effective model into three modules; a signal initiation module that sensed and transformed an ATRA signal into program activation signals; a signal integration module that controlled the expression of upstream transcription factors; and a phenotype module which encoded the expression of functional differentiation markers from the ATRA-inducible transcription factors. We identified an ensemble of effective model parameters using measurements taken from ATRA-induced HL-60 cells. Using these parameters, model analysis predicted that MAPK activation was bistable as a function of ATRA exposure. Conformational experiments supported ATRA-induced bistability. Additionally, the model captured intermediate and phenotypic gene expression data. Knockout analysis suggested Gfi-1 and PPARg were critical to the ATRAinduced differentiation program. These findings, combined with other literature evidence, suggested that reinforcing feedback is central to hyperactive signaling in a diversity of cell fate programs.

  8. Inhibition of matrix metalloproteinases expression in human dental pulp cells by all-trans retinoic acid

    Institute of Scientific and Technical Information of China (English)

    Jin Man Kim; Sang Wook Kang; Su-Mi Shin; Duck Su Kim; Kyong-Kyu Choi; Eun-Cheol Kim; Sun-Young Kim

    2014-01-01

    All-trans retinoic acid (ATRA) inhibits matrix metalloproteinase (MMP)-2 and MMP-9 in synovial fibroblasts, skin fibroblasts, bronchoalveolar lavage cells and cancer cells, but activates MMP-9 in neuroblast and leukemia cells. Very little is known regarding whether ATRA can activate or inhibit MMPs in human dental pulp cells (HDPCs). The purpose of this study was to determine the effects of ATRA on the production and secretion of MMP-2 and-9 in HDPCs. The productions and messenger RNA (mRNA) expressions of MMP-2 and-9 were accessed by gelatin zymography and real-time polymerase chain reaction (PCR), respectively. ATRA was found to decrease MMP-2 level in a dose-dependent manner. Significant reduction in MMP-2 mRNA expression was also observed in HDPCs treated with 25 mmol?L21 ATRA. However, HDPCs treated with ATRA had no effect on the pattern of MMP-9 produced or secreted in either cell extracts or conditioned medium fractions. Taken together, ATRA had an inhibitory effect on MMP-2 expression in HDPCs, which suggests that ATRA could be a candidate as a medicament which could control the inflammation of pulp tissue in vital pulp therapy and regenerative endodontics.

  9. Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development

    Science.gov (United States)

    Lenti, Elisa; Farinello, Diego; Penkov, Dmitry; Castagnaro, Laura; Lavorgna, Giovanni; Wuputra, Kenly; Tjaden, Naomi E. Butler; Bernassola, Francesca; Caridi, Nicoletta; Wagner, Michael; Kozinc, Katja; Niederreither, Karen; Blasi, Francesco; Pasini, Diego; Trainor, Paul A.

    2016-01-01

    The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome P450 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insights into the molecular determinants of human congenital asplenia. PMID:27214556

  10. Carotenoid supplementation and retinoic acid in immunoglobulin A regulation of the gut microbiota dysbiosis.

    Science.gov (United States)

    Lyu, Yi; Wu, Lei; Wang, Fang; Shen, Xinchun; Lin, Dingbo

    2018-04-01

    Dysbiosis, a broad spectrum of imbalance of the gut microbiota, may progress to microbiota dysfunction. Dysbiosis is linked to some human diseases, such as inflammation-related disorders and metabolic syndromes. However, the underlying mechanisms of the pathogenesis of dysbiosis remain elusive. Recent findings suggest that the microbiome and gut immune responses, like immunoglobulin A production, play critical roles in the gut homeostasis and function, and the progression of dysbiosis. In the past two decades, much progress has been made in better understanding of production of immunoglobulin A and its association with commensal microbiota. The present minireview summarizes the recent findings in the gut microbiota dysbiosis and dysfunction of immunoglobulin A induced by the imbalance of pathogenic bacteria and commensal microbiota. We also propose the potentials of dietary carotenoids, such as β-carotene and astaxanthin, in the improvement of the gut immune system maturation and immunoglobulin A production, and the consequent promotion of the gut health. Impact statement The concept of carotenoid metabolism in the gut health has not been well established in the literature. Here, we review and discuss the roles of retinoic acid and carotenoids, including pro-vitamin A carotenoids and xanthophylls in the maturation of the gut immune system and IgA production. This is the first review article about the carotenoid supplements and the metabolites in the regulation of the gut microbiome. We hope this review would provide a new direction for the management of the gut microbiota dysbiosis by application of bioactive carotenoids and the metabolites.

  11. Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo.

    Science.gov (United States)

    Hirobe, Sachiko; Otsuka, Risa; Iioka, Hiroshi; Quan, Ying-Shu; Kamiyama, Fumio; Asada, Hideo; Okada, Naoki; Nakagawa, Shinsaku

    2017-01-01

    Pigmented lesions such as of seborrheic keratosis and senile lentigo, which are commonly seen on skin of people>50years of age, are considered unattractive and disfiguring because of their negative psychological impact. Drug therapy using all-trans retinoic acid (ATRA) is an attractive option for self-treatment at home. We have developed an ATRA-loaded microneedle patch (ATRA-MN) and confirmed the pharmacological effects of ATRA-MN application in mice. Here, we describe a clinical study to evaluate the safety and efficacy of ATRA-MN in subjects with seborrheic keratosis or senile lentigo. ATRA-MN was applied to the lesion site of each subject for 6h once per week for 4weeks. The skin irritation reaction was scored to assess adverse reactions and blood tests were performed to evaluate the presence of systemic adverse reactions. To assess the treatment effect using ATRA-MN, the desquamation and whitening ability of the investigational skin was observed. Desquamation of the stratum corneum was observed following four ATRA-MN applications at 1-week intervals, but ATRA-MN applications did not induce severe local or systemic adverse effects. These results showed that ATRA-MN treatment is promising as a safe and effective therapy for seborrheic keratosis and senile lentigo. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Synergistic effects of retinoic acid and tamoxifen on human breast cancer cells: Proteomic characterization

    International Nuclear Information System (INIS)

    Wang Ying; He Qingyu; Chen Hongming; Chiu Jenfu

    2007-01-01

    The anti-estrogen tamoxifen and vitamin A-related compound, all-trans retinoic acid (RA), in combination act synergistically to inhibit the growth of MCF-7 human breast cancer cells. In the present study, we applied two-dimensional gel electrophoresis based proteomic approach to globally analyze this synergistic effect of RA and tamoxifen. Proteomic study revealed that multiple clusters of proteins were involved in RA and tamoxifen-induced apoptosis in MCF-7 breast cancer cells, including post-transcriptional and splicing factors, proteins related to cellular proliferation or differentiation, and proteins related to energy production and internal degradation systems. The negative growth factor-transforming growth factor β (TGFβ) was secreted by RA and/or tamoxifen treatment and was studies as a potential mediator of the synergistic effects of RA and tamoxifen in apoptosis. By comparing protein alterations in treatments of RA and tamoxifen alone or in combination to those of TGFβ treatment, or co-treatment with TGFβ inhibitor SB 431542, proteomic results showed that a number of proteins were involved in TGFβ signaling pathway. These results provide valuable insights into the mechanisms of RA and tamoxifen-induced TGFβ signaling pathway in breast cancer cells

  13. Anti-Inflammatory Strategy for M2 Microglial Polarization Using Retinoic Acid-Loaded Nanoparticles

    Directory of Open Access Journals (Sweden)

    Marta Machado-Pereira

    2017-01-01

    Full Text Available Inflammatory mechanisms triggered by microglial cells are involved in the pathophysiology of several brain disorders, hindering repair. Herein, we propose the use of retinoic acid-loaded polymeric nanoparticles (RA-NP as a means to modulate microglia response towards an anti-inflammatory and neuroprotective phenotype (M2. RA-NP were first confirmed to be internalized by N9 microglial cells; nanoparticles did not affect cell survival at concentrations below 100 μg/mL. Then, immunocytochemical studies were performed to assess the expression of pro- and anti-inflammatory mediators. Our results show that RA-NP inhibited LPS-induced release of nitric oxide and the expression of inducible nitric oxide synthase and promoted arginase-1 and interleukin-4 production. Additionally, RA-NP induced a ramified microglia morphology (indicative of M2 state, promoting tissue viability, particularly neuronal survival, and restored the expression of postsynaptic protein-95 in organotypic hippocampal slice cultures exposed to an inflammatory challenge. RA-NP also proved to be more efficient than the free equivalent RA concentration. Altogether, our data indicate that RA-NP may be envisioned as a promising therapeutic agent for brain inflammatory diseases.

  14. All trans retinoic acid abrogates spontaneous monocytic growth in juvenile chronic myelomonocytic leukaemia.

    Science.gov (United States)

    Cambier, N; Menot, M L; Schlageter, M H; Balitrand, N; Leblanc, T; Bordigoni, P; Rohrlich, P; Lamagnère, J P; Donadieu, J; Herbelin, C; Puissant, C; Gourand, F; Baruchel, A; Chomienne, C

    2001-01-01

    All trans retinoic acid, the active metabolite of vitamin A, exerts profound effects on cell differentiation. On normal myeloid progenitors, retinoids switch the differentiation program of granulo-macrophagic progenitors towards the granulocytic lineage and consequently reduce CFU-M colony formation. Bone marrow and peripheral blood mononuclear cells from children with Juvenile Chronic Myelomonocytic Leukaemia show typical spontaneous monocytic growth. We questioned whether in this disease, retinoids could switch myelomonocytic growth and inhibit the abnormal CFU-M colony proliferation. Ten JCML samples were studied in the presence of ATRA in methyl cellulose colony assay, before (CFU-C) or after (pre-CFU) liquid suspension culture. In vitro characteristics of JCML such as spontaneous monocytic growth in the absence of growth factor was noted in all patients. In the presence of leucocyte-conditioned medium, nine samples showed only CFU-M growth and one sample CFU-GM growth. Incubation with ATRA inhibited CFU-M colony formation in nine cases. Enhancement of granulocytic differentiation (CFU-G) was noted in nine cases. ATRA also inhibited CD34+ JCML monocytic growth and GM-CSF hypersensitivity. These data suggest that, in JCML progenitors, retinoid pathways are functional and inhibition of immature monocytic progenitors cells may be achieved with retinoids, without impeding granulocytic cell growth.

  15. Retinoic Acid Differentially Regulates the Migration of Innate Lymphoid Cell Subsets to the Gut.

    Science.gov (United States)

    Kim, Myung H; Taparowsky, Elizabeth J; Kim, Chang H

    2015-07-21

    Distinct groups of innate lymphoid cells (ILCs) such as ILC1, ILC2, and ILC3 populate the intestine, but how these ILCs develop tissue tropism for this organ is unclear. We report that prior to migration to the intestine ILCs first undergo a "switch" in their expression of homing receptors from lymphoid to gut homing receptors. This process is regulated by mucosal dendritic cells and the gut-specific tissue factor retinoic acid (RA). This change in homing receptors is required for long-term population and effector function of ILCs in the intestine. Only ILC1 and ILC3, but not ILC2, undergo the RA-dependent homing receptor switch in gut-associated lymphoid tissues. In contrast, ILC2 acquire gut homing receptors in a largely RA-independent manner during their development in the bone marrow and can migrate directly to the intestine. Thus, distinct programs regulate the migration of ILC subsets to the intestine for regulation of innate immunity. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Anti-apoptotic role of retinoic acid in the inner ear of noise-exposed mice

    International Nuclear Information System (INIS)

    Ahn, Joong Ho; Kang, Hun Hee; Kim, Young-Jin; Chung, Jong Woo

    2005-01-01

    Exposure to loud noise can induce temporary or permanent hearing loss, and acoustic trauma is the major cause of hearing impairment in industrial nations. However, the mechanisms underlying the death of hair cells after acoustic trauma remain unclear. In addition to its involvement in cellular stress and apoptosis, the c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, is involved in cell survival, transformation, embryonic morphogenesis, and differentiation. JNK is primarily activated by various environmental stresses including noise, and the phenotypic result appears be to cell death. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A that regulates a wide range of biological processes, including cell proliferation, differentiation, and morphogenesis. We evaluated the role of ATRA in preserving hearing in mice exposed to noise that can induce permanent hearing loss. Mice fed with ATRA before and during 3 consecutive days of noise exposure had a more preserved hearing threshold than mice fed sesame oil or saline. Histological and TUNEL staining of the cochlea showed significantly enhanced preservation of the organ of Corti, including outer hair cells and relatively low apoptotic nuclei, in mice-fed ATRA than in mice-fed sesame oil or saline. Phospho-JNK immunohistochemistry showed that ATRA inhibited the activation of JNK. These results suggest that ATRA has an anti-apoptotic effect on cochleae exposed to noise

  17. Autophagic dedifferentiation induced by cooperation between TOR inhibitor and retinoic acid signals in budding tunicates.

    Science.gov (United States)

    Kawamura, Kaz; Yoshida, Takuto; Sekida, Satoko

    2018-01-15

    Asexual bud development in the budding tunicate Polyandrocarpa misakiensis involves transdifferentiation of multipotent epithelial cells, which is triggered by retinoic acid (RA), and thrives under starvation after bud isolation from the parent. This study aimed to determine cell and molecular mechanisms of dedifferentiation that occur during the early stage of transdifferentiation. During dedifferentiation, the numbers of autophagosomes, lysosomes, and secondary lysosomes increased remarkably. Mitochondrial degradation and exosome discharge also occurred in the atrial epithelium. Autophagy-related gene 7 (Atg7) and lysosomal proton pump A gene (PumpA) were activated during the dedifferentiation stage. When target of rapamycin (TOR) inhibitor was administered to growing buds without isolating them from the parent, phagosomes and secondary lysosomes became prominent. TOR inhibitor induced Atg7 only in the presence of RA. In contrast, when growing buds were treated with RA, lysosomes, secondary lysosomes, and mitochondrial degradation were prematurely induced. RA significantly activated PumpA in a retinoid X receptor-dependent manner. Our results indicate that in P. misakiensis, TOR inhibition and RA signals act in synergy to accomplish cytoplasmic clearance for dedifferentiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Somite-Derived Retinoic Acid Regulates Zebrafish Hematopoietic Stem Cell Formation.

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    Laura M Pillay

    Full Text Available Hematopoietic stem cells (HSCs are multipotent progenitors that generate all vertebrate adult blood lineages. Recent analyses have highlighted the importance of somite-derived signaling factors in regulating HSC specification and emergence from dorsal aorta hemogenic endothelium. However, these factors remain largely uncharacterized. We provide evidence that the vitamin A derivative retinoic acid (RA functions as an essential regulator of zebrafish HSC formation. Temporal analyses indicate that RA is required for HSC gene expression prior to dorsal aorta formation, at a time when the predominant RA synthesis enzyme, aldh1a2, is strongly expressed within the paraxial mesoderm and somites. Previous research implicated the Cxcl12 chemokine and Notch signaling pathways in HSC formation. Consequently, to understand how RA regulates HSC gene expression, we surveyed the expression of components of these pathways in RA-depleted zebrafish embryos. During somitogenesis, RA-depleted embryos exhibit altered expression of jam1a and jam2a, which potentiate Notch signaling within nascent endothelial cells. RA-depleted embryos also exhibit a severe reduction in the expression of cxcr4a, the predominant Cxcl12b receptor. Furthermore, pharmacological inhibitors of RA synthesis and Cxcr4 signaling act in concert to reduce HSC formation. Our analyses demonstrate that somite-derived RA functions to regulate components of the Notch and Cxcl12 chemokine signaling pathways during HSC formation.

  19. Cellular retinoic acid bioavailability in various pathologies and its therapeutic implication.

    Science.gov (United States)

    Osanai, Makoto

    2017-06-01

    Retinoic acid (RA), an active metabolite of vitamin A, is a critical signaling molecule in various cell types. We found that RA depletion caused by expression of the RA-metabolizing enzyme CYP26A1 promotes carcinogenesis, implicating CYP26A1 as a candidate oncogene. Several studies of CYP26s have suggested that the biological effect of RA on target cells is primarily determined by "cellular RA bioavailability", which is defined as the RA level in an individual cell, rather than by the serum concentration of RA. Consistently, stellate cells store approximately 80% of vitamin A in the body, and the state of cellular RA bioavailability regulates their function. Based on the similarities between stellate cells and astrocytes, we demonstrated that retinal astrocytes regulate tight junction-based endothelial integrity in a paracrine manner. Since diabetic retinopathy is characterized by increased vascular permeability in its early pathogenesis, RA normalized retinal astrocytes that are compromised in diabetes, resulting in suppression of vascular leakiness. RA also attenuated the loss of the epithelial barrier in murine experimental colitis. The concept of "cellular RA bioavailability" in various diseases will be directed at understanding various pathologies caused by RA insufficiency, implying the potential feasibility of a therapeutic strategy targeting the stellate cell system. © 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

  20. Rotavirus nonstructural protein 1 antagonizes innate immune response by interacting with retinoic acid inducible gene I

    Directory of Open Access Journals (Sweden)

    Qin Lan

    2011-12-01

    Full Text Available Abstract Background The nonstructural protein 1 (NSP1 of rotavirus has been reported to block interferon (IFN signaling by mediating proteasome-dependent degradation of IFN-regulatory factors (IRFs and (or the β-transducin repeat containing protein (β-TrCP. However, in addition to these targets, NSP1 may subvert innate immune responses via other mechanisms. Results The NSP1 of rotavirus OSU strain as well as the IRF3 binding domain truncated NSP1 of rotavirus SA11 strain are unable to degrade IRFs, but can still inhibit host IFN response, indicating that NSP1 may target alternative host factor(s other than IRFs. Overexpression of NSP1 can block IFN-β promoter activation induced by the retinoic acid inducible gene I (RIG-I, but does not inhibit IFN-β activation induced by the mitochondrial antiviral-signaling protein (MAVS, indicating that NSP1 may target RIG-I. Immunoprecipitation experiments show that NSP1 interacts with RIG-I independent of IRF3 binding domain. In addition, NSP1 induces down-regulation of RIG-I in a proteasome-independent way. Conclusions Our findings demonstrate that inhibition of RIG-I mediated type I IFN responses by NSP1 may contribute to the immune evasion of rotavirus.

  1. Providing theoretical data for detection of four formamidic acid isomers in astrophysical media

    Science.gov (United States)

    Vichietti, R. M.; da Silva, A. B. F.; Haiduke, R. L. A.

    2018-03-01

    We present a theoretical study, so that molecular data (geometrical parameters, vibrational frequencies, infrared intensities, electronic energies, enthalpies, and Gibbs energies) of four formamidic acid (FA) isomers (labeled here as FA1, FA2, FA3, and FA4) and formamide (HCONH2) are obtained from CCSD/cc-pVTZ, CCSD/aug-cc-pVTZ, CCSD/cc-pVQZ, and CCSD(T)/cc-pVTZ calculations. Furthermore, on the basis of insufficient or even lacking theoretical and experimental results in the literature, we employed the aforementioned theory levels to determine benchmark values of dipole moments and rotational constants for these four FA isomers in order to contribute for their detection in astrophysical environments. Besides, we provide for the first time data about forward and reverse rate constants (200-4000 K) and Arrhenius' parameters for each interconversion reaction between pairs of FA isomers as well as for the tautomeric process involving FA4 and formamide, which were calculated from a Complete Basis Set (CBS) extrapolation equation obtained at CCSD/cc-pVTZ optimized geometries. Our kinetic analysis indicated a faster interconversion between the FA structures in comparison with the FA4 ↔ HCONH2 process, suggesting that these isomers could co-exist in astrophysical media. Finally, we estimated that these isomers may be detected with relative abundances, [FAx]/[HCONH2] (x = 1, 2, 3, and 4), between ∼0.01 and ∼0.1% in astrophysical sources at chemical equilibrium conditions and temperatures around 1000 K. However, these ratios can become as high as ∼1, ∼3, and ∼5%, respectively, in hotter regions with temperatures around 2000, 3000, and 4000 K (expected, for example, in massive star-forming regions).

  2. Ethanol induced hepatic mitochondrial dysfunction is attenuated by all trans retinoic acid supplementation.

    Science.gov (United States)

    Nair, Saritha S; Prathibha, P; Rejitha, S; Indira, M

    2015-08-15

    Alcoholics have reduced vitamin A levels in serum since vitamin A and ethanol share the same metabolic pathway. Vitamin A supplementation has an additive effect on ethanol induced toxicity. Hence in this study, we assessed the impact of supplementation of all trans retinoic acid (ATRA), an active metabolite of vitamin A on ethanol induced disruptive alterations in liver mitochondria. Male Sprague Dawley rats were grouped as follows: I: Control; II: Ethanol (4 g/kg b.wt./day); III: ATRA (100 μg/kg b.wt./day); and IV: Ethanol (4 g/kg b.wt./day)+ATRA (100 μg/kg b.wt./day). Duration of the experiment was 90 days, after which the animals were sacrificed for the study. The key enzymes of energy metabolism, reactive oxygen species, mitochondrial membrane potential and hepatic mRNA expressions of Bax, Bcl-2, c-fos and c-jun were assessed. Ethanol administration increased the reactive oxygen species generation in mitochondria. It also decreased the activities of the enzymes of citric acid cycle and oxidative phosphorylation. ATP content and mitochondrial membrane potential were decreased and cytosolic cytochrome c was increased consequently enhancing apoptosis. All these alterations were altered significantly on ATRA supplementation along with ethanol. These results were reinforced by our histopathological studies. ATRA supplementation to ethanol fed rats, led to reduction in oxidative stress, decreased calcium overload in the matrix and increased mitochondrial membrane potential, which might have altered the mitochondrial energy metabolism and elevated ATP production thereby reducing the apoptotic alterations. Hence ATRA supplementation seemed to be an effective intervention against alcohol induced mitochondrial dysfunction. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Comparative molecular pathology of cadmium- and all-trans-retinoic acid-induced postaxial forelimb ectrodactyly

    International Nuclear Information System (INIS)

    Liao Xiaoyan; Lee, Grace S.; Shimizu, Hirohito; Collins, Michael D.

    2007-01-01

    Cadmium chloride (CdCl 2 ) and all-trans-retinoic acid (RA) induce postaxial forelimb ectrodactyly in C57BL/6N mice when administered during early limb development, and co-administration yields a synergistic response suggesting a common final pathway to the defect. In the current study, forelimb buds from embryos given high maternal teratogenic doses of CdCl 2 or RA, or the combination of both agents at low doses were collected at various time points after treatment on GD 9.5 and examined for cellular apoptosis, proliferation, and patterning genes. Some cellular perturbations detected in the developing limb bud were similar for both teratogens, whereas other alterations were unique to each agent. For example, at 12 and 18 h, CdCl 2 treatment increased apoptotic cells in the mesenchyme underneath the apical ectodermal ridge (AER), whereas RA caused apoptosis in the AER and proximal mesenchyme. Further, the combined low-dose treatment increased cell death synergistically in all three regions. CdCl 2 and the low-dose combined treatment inhibited mesenchymal proliferation at 12 h, which was associated with induction of p21 cip1 and inhibition of phospho-c-Jun. In contrast, RA did not inhibit mesenchymal proliferation and did not induce p21 cip1 expression or change c-Jun phosphorylation. All three treatment groups showed a delay in the patterning of distal chondrogenesis centers as indicated by Sox9 expression. There was also common inhibition in the expression of AER markers, Fgf8 and Fgf4, and the mesenchymal marker Msx1 involved in the maintenance of epithelial-mesenchymal interactions. Collectively, a model is hypothesized where limb patterning can be perturbed by insults to both ectoderm and mesoderm

  4. Methylation and silencing of the retinoic acid receptor-β2 gene in cervical cancer

    International Nuclear Information System (INIS)

    Ivanova, Tatyana; Petrenko, Anatolii; Gritsko, Tatyana; Vinokourova, Svetlana; Eshilev, Ernest; Kobzeva, Vera; Kisseljov, Fjodor; Kisseljova, Natalia

    2002-01-01

    Expression of the retinoic acid receptor β2 (RAR-β2), a putative tumor suppressor gene, is reduced in various human cancers, including squamous cell carcinomas (SCC) of the uterine cervix. The mechanism of the inhibition of RAR-β2 expression remains obscure. We examined whether methylation of RAR-β2 gene could be responsible for this silencing in cervical SCC. Expression of RAR-β2 mRNA and methylation status of the 5' region of RAR-β2 gene were examined in 20 matched specimens from patients with cervical SCC and in three cervical cancer cell lines by Northern blot analysis and methylation-specific PCR (MSP) assay or Southern blot analysis respectively. In 8 out 20 cervical SCC (40%) the levels of RAR-β2 mRNA were decreased or undetectable in comparison with non-neoplastic cervix tissues. All 8 tumors with reduced levels of RAR-β2 mRNA expression showed methylation of the promoter and the first exon expressed in the RAR-β2 transcript. The RAR-β2 gene from non-neoplastic cervical tissues was mostly unmethylated and expressed, but methylated alleles of the gene were found in three samples of the morphologically normal tissues adjacent to the tumors. Three cervical cancer cell lines with extremely low level of RAR-β2 mRNA expression, SiHA, HeLA and CaSki, also showed methylation of this region of the RAR-β2 gene. These findings suggest that methylation of the 5' region of RAR-β2 gene may contribute to gene silencing and that methylation of this region may be an important and early event in cervical carcinogenesis. These findings may be useful to make retinoids more effective as preventive and therapeutic agents in combination with inhibitors of DNA methylation

  5. The effects of retinoic acid on immunoglobulin synthesis: Role of interleukin 6

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    Ballow, M.; Xiang, Shunan; Wang, Weiping; Brodsky, L. [Children`s Hospital of Buffalo, NY (United States)]|[State Univ. of New York, Buffalo, NY (United States)

    1996-05-01

    Retinoic acid (RA) and its parent compound, retinol (ROH, vitamin A), have been recognized as important immunopotentiating agents. Previous studies from our laboratory have demonstrated that PA can augment formalin-treated Staphylococcus aureus (SAC) stimulated immunoglobulin (Ig) synthesis of cord blood mononuclear cells (CBMC). To determine the mechanism(s) by which RA modulates Ig synthesis, we studied the effects of RA on B cells and cytokine production. The addition of RA (10{sup -5} to 10{sup -10} M) to Epstein-Barr virus (EBV)-transformed B-cell clones derived from either adult or cord blood B cells augmented Ig secretion twofold. In contrast, cell proliferation was inhibited as measured by {sup 3}H-thymidine incorporation. We evaluated two cytokines known to be constitutively produced by EBV cell lines, IL-1 and IL-6. While RA had no effect on IL-1 production, IL-6 synthesis was greatly enhanced (20- to 45-fold), which was also reflected by an increase in steady-state mRNA levels for IL-6 but not TNF-{alpha} or TGF-{beta} on Northern blot analysis. Polyclonal rabbit anti-IL-6 antibodies were used to block the augmenting effects of RA on Ig synthesis of adenoidal B cells. RA-induced augmentation in IgG and IgA synthesis was blocked 58 and 29%, respectively, by anti-IL-6 antibodies. These studies suggest that the enhancing effects of RA on Ig synthesis are mediated, at least in part, by the autocrine or paracrine effects of IL-6 on B-cell differentiation. 37 refs., 5 figs.

  6. 9-Cis retinoic acid protects against methamphetamine-induced neurotoxicity in nigrostriatal dopamine neurons.

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    Reiner, David J; Yu, Seong-Jin; Shen, Hui; He, Yi; Bae, Eunkyung; Wang, Yun

    2014-04-01

    Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. 9-Cis retinoic acid (9cRA), a biologically active derivative of vitamin A, has protective effects against damage caused by H(2)O(2) and oxygen-glucose deprivation in vitro as well as infarction and terminal deoxynucleotidyl transferase-mediated dNTP nick-end labeling (TUNEL) labeling in ischemic brain. The purpose of this study was to examine if there was a protective role for 9cRA against MA toxicity in nigrostriatal dopaminergic neurons. Primary dopaminergic neurons, prepared from rat embryonic ventral mesencephalic tissue, were treated with MA. High doses of MA decreased tyrosine hydroxylase (TH) immunoreactivity while increasing TUNEL labeling. These toxicities were significantly reduced by 9cRA. 9cRA also inhibited the export of Nur77 from nucleus to cytosol, a response that activates apoptosis. The interaction of 9cRA and MA in vivo was next examined in adult rats. 9cRA was delivered intracerebroventricularly; MA was given (5 mg/kg, 4×) one day later. Locomotor behavior was measured 2 days after surgery for a period of 48 h. High doses of MA significantly reduced locomotor activity and TH immunoreactivity in striatum. Administration of 9cRA antagonized these changes. Previous studies have shown that 9cRA can induce bone morphogenetic protein-7 (BMP7) expression and that administration of BMP7 attenuates MA toxicity. We demonstrated that MA treatment significantly reduced BMP7 mRNA expression in nigra. Noggin (a BMP antagonist) antagonized 9cRA-induced behavioral recovery and 9cRA-induced normalization of striatal TH levels. Our data suggest that 9cRA has a protective effect against MA-mediated neurodegeneration in dopaminergic neurons via upregulation of BMP.

  7. Polydimethylsiloxane (PDMS) modulates CD38 expression, absorbs retinoic acid and may perturb retinoid signalling.

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    Futrega, Kathryn; Yu, Jianshi; Jones, Jace W; Kane, Maureen A; Lott, William B; Atkinson, Kerry; Doran, Michael R

    2016-04-21

    Polydimethylsiloxane (PDMS) is the most commonly used material in the manufacture of customized cell culture devices. While there is concern that uncured PDMS oligomers may leach into culture medium and/or hydrophobic molecules may be absorbed into PDMS structures, there is no consensus on how or if PDMS influences cell behaviour. We observed that human umbilical cord blood (CB)-derived CD34(+) cells expanded in standard culture medium on PDMS exhibit reduced CD38 surface expression, relative to cells cultured on tissue culture polystyrene (TCP). All-trans retinoic acid (ATRA) induces CD38 expression, and we reasoned that this hydrophobic molecule might be absorbed by PDMS. Through a series of experiments we demonstrated that ATRA-mediated CD38 expression was attenuated when cultures were maintained on PDMS. Medium pre-incubated on PDMS for extended durations resulted in a time-dependant reduction of ATRA in the medium and increasingly attenuated CD38 expression. This indicated a time-dependent absorption of ATRA into the PDMS. To better understand how PDMS might generally influence cell behaviour, Ingenuity Pathway Analysis (IPA) was used to identify potential upstream regulators. This analysis was performed for differentially expressed genes in primary cells including CD34(+) haematopoietic progenitor cells, mesenchymal stromal cells (MSC), and keratinocytes, and cell lines including prostate cancer epithelial cells (LNCaP), breast cancer epithelial cells (MCF-7), and myeloid leukaemia cells (KG1a). IPA predicted that the most likely common upstream regulator of perturbed pathways was ATRA. We demonstrate here that ATRA is absorbed by PDMS in a time-dependent manner and results in the concomitant reduced expression of CD38 on the cell surface of CB-derived CD34(+) cells.

  8. Retinoic acid-treated pluripotent stem cells undergoing neurogenesis present increased aneuploidy and micronuclei formation.

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    Rafaela C Sartore

    Full Text Available The existence of loss and gain of chromosomes, known as aneuploidy, has been previously described within the central nervous system. During development, at least one-third of neural progenitor cells (NPCs are aneuploid. Notably, aneuploid NPCs may survive and functionally integrate into the mature neural circuitry. Given the unanswered significance of this phenomenon, we tested the hypothesis that neural differentiation induced by all-trans retinoic acid (RA in pluripotent stem cells is accompanied by increased levels of aneuploidy, as previously described for cortical NPCs in vivo. In this work we used embryonal carcinoma (EC cells, embryonic stem (ES cells and induced pluripotent stem (iPS cells undergoing differentiation into NPCs. Ploidy analysis revealed a 2-fold increase in the rate of aneuploidy, with the prevalence of chromosome loss in RA primed stem cells when compared to naïve cells. In an attempt to understand the basis of neurogenic aneuploidy, micronuclei formation and survivin expression was assessed in pluripotent stem cells exposed to RA. RA increased micronuclei occurrence by almost 2-fold while decreased survivin expression by 50%, indicating possible mechanisms by which stem cells lose their chromosomes during neural differentiation. DNA fragmentation analysis demonstrated no increase in apoptosis on embryoid bodies treated with RA, indicating that cell death is not the mandatory fate of aneuploid NPCs derived from pluripotent cells. In order to exclude that the increase in aneuploidy was a spurious consequence of RA treatment, not related to neurogenesis, mouse embryonic fibroblasts were treated with RA under the same conditions and no alterations in chromosome gain or loss were observed. These findings indicate a correlation amongst neural differentiation, aneuploidy, micronuclei formation and survivin downregulation in pluripotent stem cells exposed to RA, providing evidence that somatically generated chromosomal

  9. Retinoic acid-induced alveolar cellular growth does not improve function after right pneumonectomy.

    Science.gov (United States)

    Dane, D Merrill; Yan, Xiao; Tamhane, Rahul M; Johnson, Robert L; Estrera, Aaron S; Hogg, Deborah C; Hogg, Richard T; Hsia, Connie C W

    2004-03-01

    To determine whether all-trans retinoic acid (RA) treatment enhances lung function during compensatory lung growth in fully mature animals, adult male dogs (n = 4) received 2 mg x kg(-1) x day(-1) po RA 4 days/wk beginning the day after right pneumonectomy (R-PNX, 55-58% resection). Litter-matched male R-PNX controls (n = 4) received placebo. After 3 mo, transpulmonary pressure (TPP)-lung volume relationship, diffusing capacities for carbon monoxide and nitric oxide, cardiac output, and septal volume (V(tiss-RB)) were measured under anesthesia by a rebreathing technique at two lung volumes. Lung air and tissue volumes (V(air-CT) and V(tiss-CT)) were also measured from high-resolution computerized tomographic (CT) scans at a constant TPP. In RA-treated dogs compared with controls, TPP-lung volume relationships were similar. Diffusing capacities for carbon monoxide and nitric oxide were significantly impaired at a lower lung volume but similar at a high lung volume. Whereas V(tiss-RB) was significantly lower at both lung volumes in RA-treated animals, V(air-CT) and V(tiss-CT) were not different between groups; results suggest uneven distribution of ventilation consistent with distortion of alveolar geometry and/or altered small airway function induced by RA. We conclude that RA does not improve resting pulmonary function during the early months after R-PNX despite histological evidence of its action in enhancing alveolar cellular growth in the remaining lung.

  10. Retinoic acid and cAMP inhibit rat hepatocellular carcinoma cell proliferation and enhance cell differentiation

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    Ionta, M. [Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas MG (Brazil); Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo SP (Brazil); Rosa, M.C.; Almeida, R.B.; Freitas, V.M.; Rezende-Teixeira, P.; Machado-Santelli, G.M. [Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo SP (Brazil)

    2012-05-25

    Hepatocellular carcinoma (HCC) is the third highest cause of cancer death worldwide. In general, the disease is diagnosed at an advanced stage when potentially curative therapies are no longer feasible. For this reason, it is very important to develop new therapeutic approaches. Retinoic acid (RA) is a natural derivative of vitamin A that regulates important biological processes including cell proliferation and differentiation. In vitro studies have shown that RA is effective in inhibiting growth of HCC cells; however, responsiveness to treatment varies among different HCC cell lines. The objective of the present study was to determine if the combined use of RA (0.1 µM) and cAMP (1 mM), an important second messenger, improves the responsiveness of HCC cells to RA treatment. We evaluated the proliferative behavior of an HCC cell line (HTC) and the expression profile of genes related to cancer signaling pathway (ERK and GSK-3β) and liver differentiation [E-cadherin, connexin 26 (Cx26), and connexin 32 (Cx32)]. RA and cAMP were effective in inhibiting the proliferation of HTC cells independently of combined use. However, when a mixture of RA and cAMP was used, the signals concerning the degree of cell differentiation were increased. As demonstrated by Western blot, the treatment increased E-cadherin, Cx26, Cx32 and Ser9-GSK-3β (inactive form) expression while the expression of Cx43, Tyr216-GSK-3β (active form) and phosphorylated ERK decreased. Furthermore, telomerase activity was inhibited along treatment. Taken together, the results showed that the combined use of RA and cAMP is more effective in inducing differentiation of HTC cells.

  11. Conditional RARα Knockout Mice Reveal Acute Requirement for Retinoic Acid and RARα in Homeostatic Plasticity

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    Federica eSarti

    2012-02-01

    Full Text Available All-trans retinoic acid (RA plays important roles in brain development through regulating gene transcription. Recently, a novel postdevelopmental role of RA in mature brain was proposed. Specifically, RA rapidly enhanced excitatory synaptic transmission independent of transcriptional regulation. RA synthesis was induced when excitatory synaptic transmission was chronically blocked, and RA then activated dendritic protein synthesis and synaptic insertion of homomeric GluA1 AMPA receptors, thereby compensating for the loss of neuronal activity in a homeostatic fashion. This action of RA was suggested to be mediated by its canonical receptor RARα but no genetic evidence was available. Thus, we here tested the fundamental requirement of RARα in homeostatic plasticity using conditional RARα knockout mice, and additionally performed a structure-function analysis of RARα. We show that acutely deleting RARα in neurons eliminated RA’s effect on excitatory synaptic transmission, and inhibited activity blockade-induced homeostatic synaptic plasticity. By expressing various RARα rescue constructs in RARα knockout neurons, we found that the DNA-binding domain of RARα was dispensable for its role in regulating synaptic strength, further supporting the notion that RA and RARα act in a non-transcriptional manner in this context. By contrast, the ligand-binding domain (LBD and the mRNA-binding domain (F-domain are both necessary and sufficient for the function of RARα in homeostatic plasticity. Furthermore, we found that homeostatic regulation performed by the LBD/F domains leads to insertion of calcium-permeable AMPA receptors. Our results confirm with unequivocal genetic approaches that RA and RARα perform essential non-transcriptional functions in regulating synaptic strength, and establish a functional link between the various domains of RARα and their involvement in regulating protein synthesis and excitatory synaptic transmission during

  12. Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives

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    McCulloch D

    2017-03-01

    Full Text Available Derek McCulloch, Christina Brown, Harry Iland Institute of Hematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia Abstract: Acute promyelocytic leukemia (APL is a distinct subtype of acute myeloid leukemia (AML with a unique morphological appearance, associated coagulopathy and canonical balanced translocation of genetic material between chromosomes 15 and 17. APL was first described as a distinct subtype of AML in 1957 by Dr Leif Hillestad who recognized the pattern of an acute leukemia associated with fibrinolysis, hypofibrinogenemia and catastrophic hemorrhage. In the intervening years, the characteristic morphology of APL has been described fully with both classical hypergranular and variant microgranular forms. Both are characterized by a balanced translocation between the long arms of chromosomes 15 and 17, [t(15;17(q24;q21], giving rise to a unique fusion gene PML-RARA and an abnormal chimeric transcription factor (PML-RARA, which disrupts normal myeloid differentiation programs. The success of current treatments for APL is in marked contrast to the vast majority of patients with non-promyelocytic AML. The overall prognosis in non-promyelocytic AML is poor, and although there has been an improvement in overall survival in patients aged <60 years, only 30%–40% of younger patients are still alive 5 years after diagnosis. APL therapy has diverged from standard AML therapy through the empirical discovery of two agents that directly target the molecular basis of the disease. The evolution of treatment over the last 4 decades to include all-trans retinoic acid and arsenic trioxide, with chemotherapy limited to patients with high-risk disease, has led to complete remission in 90%–100% of patients in trials and rates of overall survival between 86% and 97%. Keywords: acute promyelocytic leukemia, ATRA, arsenic trioxide

  13. Plasticity of photoreceptor-generating retinal progenitors revealed by prolonged retinoic acid exposure

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    Cameron David A

    2011-08-01

    Full Text Available Abstract Background Retinoic acid (RA is important for vertebrate eye morphogenesis and is a regulator of photoreceptor development in the retina. In the zebrafish, RA treatment of postmitotic photoreceptor precursors has been shown to promote the differentiation of rods and red-sensitive cones while inhibiting the differentiation of blue- and UV-sensitive cones. The roles played by RA and its receptors in modifying photoreceptor fate remain to be determined. Results Treatment of zebrafish embryos with RA, beginning at the time of retinal progenitor cell proliferation and prior to photoreceptor terminal mitosis, resulted in a significant alteration of rod and cone mosaic patterns, suggesting an increase in the production of rods at the expense of red cones. Quantitative pattern analyses documented increased density of rod photoreceptors and reduced local spacing between rod cells, suggesting rods were appearing in locations normally occupied by cone photoreceptors. Cone densities were correspondingly reduced and cone photoreceptor mosaics displayed expanded and less regular spacing. These results were consistent with replacement of approximately 25% of positions normally occupied by red-sensitive cones, with additional rods. Analysis of embryos from a RA-signaling reporter line determined that multiple retinal cell types, including mitotic cells and differentiating rods and cones, are capable of directly responding to RA. The RA receptors RXRγ and RARαb are expressed in patterns consistent with mediating the effects of RA on photoreceptors. Selective knockdown of RARαb expression resulted in a reduction in endogenous RA signaling in the retina. Knockdown of RARαb also caused a reduced production of rods that was not restored by simultaneous treatments with RA. Conclusions These data suggest that developing retinal cells have a dynamic sensitivity to RA during retinal neurogenesis. In zebrafish RA may influence the rod vs. cone cell fate

  14. Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon

    International Nuclear Information System (INIS)

    Dunst, Jeurgen; Heansgen, Gabriele; Lautenschleager, Christine; Feuchsel, Glenn; Becker, Axel

    1999-01-01

    Purpose: We have evaluated the tumor tissue pO 2 in cervical cancers during radiotherapy with special emphasis on the course of the pO 2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-α-2a. Methods and Materials: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitve radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO 2 with an Eppendorf pO 2 -histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-α-2a (IFN-α-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-α-2a in a dosage of 6 x 10 6 I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3 x 10 6 I.U. IFN-α-2a subcutaneously three times weekly until the end of the radiation treatment). pO 2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. Results: A poor oxygenation defined as a median pO 2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO 2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO 2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO 2 from 6.0 ± 3.1 mm Hg to 20.7 ± 21.2 mm Hg was found, p 2 was more pronounced in patients with radiotherapy plus additional cRA/IFN treatment as compared to patients treated

  15. NR4A orphan nuclear receptors influence retinoic acid and docosahexaenoic acid signaling via up-regulation of fatty acid binding protein 5

    International Nuclear Information System (INIS)

    Volakakis, Nikolaos; Joodmardi, Eliza; Perlmann, Thomas

    2009-01-01

    The orphan nuclear receptor (NR) Nurr1 is expressed in the developing and adult nervous system and is also induced as an immediate early gene in a variety of cell types. In silico analysis of human promoters identified fatty acid binding protein 5 (FABP5), a protein shown to enhance retinoic acid-mediated PPARβ/δ signaling, as a potential Nurr1 target gene. Nurr1 has previously been implicated in retinoid signaling via its heterodimerization partner RXR. Since NRs are commonly involved in cross-regulatory control we decided to further investigate the regulatory relationship between Nurr1 and FABP5. FABP5 expression was up-regulated by Nurr1 and other NR4A NRs in HEK293 cells, and Nurr1 was shown to activate and bind to the FABP5 promoter, supporting that FABP5 is a direct downstream target of NR4A NRs. We also show that the RXR ligand docosahexaenoic acid (DHA) can induce nuclear translocation of FABP5. Moreover, via up-regulation of FABP5 Nurr1 can enhance retinoic acid-induced signaling of PPARβ/δ and DHA-induced activation of RXR. We also found that other members of the NR4A orphan NRs can up-regulate FABP5. Thus, our findings suggest that NR4A orphan NRs can influence signaling events of other NRs via control of FABP5 expression levels.

  16. NR4A orphan nuclear receptors influence retinoic acid and docosahexaenoic acid signaling via up-regulation of fatty acid binding protein 5

    Energy Technology Data Exchange (ETDEWEB)

    Volakakis, Nikolaos; Joodmardi, Eliza [Ludwig Institute for Cancer Research Ltd., Box 240, S-17177 Stockholm (Sweden); Perlmann, Thomas, E-mail: thomas.perlmann@licr.ki.se [Ludwig Institute for Cancer Research Ltd., Box 240, S-17177 Stockholm (Sweden); The Department of Cell and Molecular Biology, Karolinska Institute, S-17177 Stockholm (Sweden)

    2009-12-25

    The orphan nuclear receptor (NR) Nurr1 is expressed in the developing and adult nervous system and is also induced as an immediate early gene in a variety of cell types. In silico analysis of human promoters identified fatty acid binding protein 5 (FABP5), a protein shown to enhance retinoic acid-mediated PPAR{beta}/{delta} signaling, as a potential Nurr1 target gene. Nurr1 has previously been implicated in retinoid signaling via its heterodimerization partner RXR. Since NRs are commonly involved in cross-regulatory control we decided to further investigate the regulatory relationship between Nurr1 and FABP5. FABP5 expression was up-regulated by Nurr1 and other NR4A NRs in HEK293 cells, and Nurr1 was shown to activate and bind to the FABP5 promoter, supporting that FABP5 is a direct downstream target of NR4A NRs. We also show that the RXR ligand docosahexaenoic acid (DHA) can induce nuclear translocation of FABP5. Moreover, via up-regulation of FABP5 Nurr1 can enhance retinoic acid-induced signaling of PPAR{beta}/{delta} and DHA-induced activation of RXR. We also found that other members of the NR4A orphan NRs can up-regulate FABP5. Thus, our findings suggest that NR4A orphan NRs can influence signaling events of other NRs via control of FABP5 expression levels.

  17. Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn's Disease.

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    Karin Fransén

    Full Text Available Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD, but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1 is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD and Ulcerative Colitis (UC. DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T allele, relative to homozygous carriers of the minor (C allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.

  18. Exogenous Modulation of Retinoic Acid Signaling Affects Adult RGC Survival in the Frog Visual System after Optic Nerve Injury.

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    Mildred V Duprey-Díaz

    Full Text Available After lesions to the mammalian optic nerve, the great majority of retinal ganglion cells (RGCs die before their axons have even had a chance to regenerate. Frog RGCs, on the other hand, suffer only an approximately 50% cell loss, and we have previously investigated the mechanisms by which the application of growth factors can increase their survival rate. Retinoic acid (RA is a vitamin A-derived lipophilic molecule that plays major roles during development of the nervous system. The RA signaling pathway is also present in parts of the adult nervous system, and components of it are upregulated after injury in peripheral nerves but not in the CNS. Here we investigate whether RA signaling affects long-term RGC survival at 6 weeks after axotomy. Intraocular injection of all-trans retinoic acid (ATRA, the retinoic acid receptor (RAR type-α agonist AM80, the RARβ agonist CD2314, or the RARγ agonist CD1530, returned axotomized RGC numbers to almost normal levels. On the other hand, inhibition of RA synthesis with disulfiram, or of RAR receptors with the pan-RAR antagonist Ro-41-5253, or the RARβ antagonist LE135E, greatly reduced the survival of the axotomized neurons. Axotomy elicited a strong activation of the MAPK, STAT3 and AKT pathways; this activation was prevented by disulfiram or by RAR antagonists. Finally, addition of exogenous ATRA stimulated the activation of the first two of these pathways. Future experiments will investigate whether these strong survival-promoting effects of RA are mediated via the upregulation of neurotrophins.

  19. Phenothiourea sensitizes zebrafish cranial neural crest and extraocular muscle development to changes in retinoic acid and IGF signaling.

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    Brenda L Bohnsack

    Full Text Available 1-Phenyl 2-thiourea (PTU is a tyrosinase inhibitor commonly used to block pigmentation and aid visualization of zebrafish development. At the standard concentration of 0.003% (200 µM, PTU inhibits melanogenesis and reportedly has minimal other effects on zebrafish embryogenesis. We found that 0.003% PTU altered retinoic acid and insulin-like growth factor (IGF regulation of neural crest and mesodermal components of craniofacial development. Reduction of retinoic acid synthesis by the pan-aldehyde dehydrogenase inhibitor diethylbenzaldehyde, only when combined with 0.003% PTU, resulted in extraocular muscle disorganization. PTU also decreased retinoic acid-induced teratogenic effects on pharyngeal arch and jaw cartilage despite morphologically normal appearing PTU-treated controls. Furthermore, 0.003% PTU in combination with inhibition of IGF signaling through either morpholino knockdown or pharmacologic inhibition of tyrosine kinase receptor phosphorylation, disrupted jaw development and extraocular muscle organization. PTU in and of itself inhibited neural crest development at higher concentrations (0.03% and had the greatest inhibitory effect when added prior to 22 hours post fertilization (hpf. Addition of 0.003% PTU between 4 and 20 hpf decreased thyroxine (T4 in thyroid follicles in the nasopharynx of 96 hpf embryos. Treatment with exogenous triiodothyronine (T3 and T4 improved, but did not completely rescue, PTU-induced neural crest defects. Thus, PTU should be used with caution when studying zebrafish embryogenesis as it alters the threshold of different signaling pathways important during craniofacial development. The effects of PTU on neural crest development are partially caused by thyroid hormone signaling.

  20. A retinoic acid receptor β2 agonist reduces hepatic stellate cell activation in nonalcoholic fatty liver disease.

    Science.gov (United States)

    Trasino, Steven E; Tang, Xiao-Han; Jessurun, Jose; Gudas, Lorraine J

    2016-10-01

    Hepatic stellate cells (HSCs) are an important cellular target for the development of novel pharmacological therapies to prevent and treat nonalcoholic fatty liver diseases (NAFLD). Using a high fat diet (HFD) model of NAFLD, we sought to determine if synthetic selective agonists for retinoic acid receptor β2 (RARβ2) and RARγ can mitigate HSC activation and HSC relevant signaling pathways during early stages of NAFLD, before the onset of liver injury. We demonstrate that the highly selective RARβ2 agonist, AC261066, can reduce the activation of HSCs, marked by decreased HSC expression of α-smooth muscle actin (α-SMA), in mice with HFD-induced NAFLD. Livers of HFD-fed mice treated with AC261066 exhibited reduced steatosis, oxidative stress, and expression of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFα), interleukin 1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1). Kupffer cell (macrophage) expression of transforming growth factor-β1 (TGF-β1), which plays a critical role in early HSC activation, was markedly reduced in AC261066-treated, HFD-fed mice. In contrast, HFD-fed mice treated with an RARγ agonist (CD1530) showed no decreases in steatosis, HSC activation, or Kupffer cell TGF-β1 levels. In conclusion, our data demonstrate that RARβ2 is an attractive target for development of NAFLD therapies. • Hepatic stellate cells (HSCs) are an important pharmacological target for the prevention of nonalcoholic fatty liver diseases (NAFLD). • Retinoids and retinoic acid receptors (RARs) possess favorable metabolic modulating properties. • We show that an agonist for retinoic acid receptor-β2 (RARβ2), but not RARγ, mitigates HSC activation and NAFLD.

  1. Intermittent apnea elicits inactivity-induced phrenic motor facilitation via a retinoic acid- and protein synthesis-dependent pathway.

    Science.gov (United States)

    Baertsch, Nathan A; Baker, Tracy L

    2017-11-01

    Respiratory motoneuron pools must provide rhythmic inspiratory drive that is robust and reliable, yet dynamic enough to respond to respiratory challenges. One form of plasticity that is hypothesized to contribute to motor output stability by sensing and responding to inadequate respiratory neural activity is inactivity-induced phrenic motor facilitation (iPMF), an increase in inspiratory output triggered by a reduction in phrenic synaptic inputs. Evidence suggests that mechanisms giving rise to iPMF differ depending on the pattern of reduced respiratory neural activity (i.e., neural apnea). A prolonged neural apnea elicits iPMF via a spinal TNF-α-induced increase in atypical PKC activity, but little is known regarding mechanisms that elicit iPMF following intermittent neural apnea. We tested the hypothesis that iPMF triggered by intermittent neural apnea requires retinoic acid and protein synthesis. Phrenic nerve activity was recorded in urethane-anesthetized and -ventilated rats treated intrathecally with an inhibitor of retinoic acid synthesis (4-diethlyaminobenzaldehyde, DEAB), a protein synthesis inhibitor (emetine), or vehicle (artificial cerebrospinal fluid) before intermittent (5 episodes, ~1.25 min each) or prolonged (30 min) neural apnea. Both DEAB and emetine abolished iPMF elicited by intermittent neural apnea but had no effect on iPMF elicited by a prolonged neural apnea. Thus different patterns of reduced respiratory neural activity elicit phenotypically similar iPMF via distinct spinal mechanisms. Understanding mechanisms that allow respiratory motoneurons to dynamically tune their output may have important implications in the context of respiratory control disorders that involve varied patterns of reduced respiratory neural activity, such as central sleep apnea and spinal cord injury. NEW & NOTEWORTHY We identify spinal retinoic acid and protein synthesis as critical components in the cellular cascade whereby repetitive reductions in respiratory

  2. Activation of RAS/ERK alone is insufficient to inhibit RXRα function and deplete retinoic acid in hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ai-Guo, E-mail: wangaiguotl@hotmail.com; Song, Ya-Nan; Chen, Jun; Li, Hui-Ling; Dong, Jian-Yi; Cui, Hai-Peng; Yao, Liang; Li, Xue-Feng; Gao, Wen-Ting; Qiu, Ze-Wen; Wang, Fu-Jin; Wang, Jing-Yu, E-mail: wangjingyus@163.com

    2014-09-26

    Highlights: • The activation of RAS/ERK is insufficient to inhibit RXRα function and deplete RA. • The retinoid metabolism-related genes are down-regulated by ras oncogene. • The atRA has no effect on preventing hepatic tumorigenesis or curing the developed hepatic nodules. - Abstract: Activation of RAS/ERK signaling pathway, depletion of retinoid, and phosphorylation of retinoid X receptor alpha (RXRα) are frequent events found in liver tumors and thought to play important roles in hepatic tumorigenesis. However, the relationships among them still remained to be elucidated. By exploring the transgenic mouse model of hepatic tumorigenesis induced by liver-specific expression of H-ras12V oncogene, the activation of RAS/ERK, the mRNA expression levels of retinoid metabolism-related genes, the contents of retinoid metabolites, and phosphorylation of RXRα were determined. RAS/ERK signaling pathway was gradually and significantly activated in hepatic tumor adjacent normal liver tissues (P) and hepatic tumor tissues (T) of H-ras12V transgenic mice compared with normal liver tissues (Wt) of wild type mice. On the contrary, the mRNA expression levels of retinoid metabolism-related genes were significantly reduced in P and T compared with Wt. Interestingly, the retinoid metabolites 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (atRA), the well known ligands for nuclear transcription factor RXR and retinoic acid receptor (RAR), were significantly decreased only in T compared with Wt and P, although the oxidized polar metabolite of atRA, 4-keto-all-trans-retinoic-acid (4-keto-RA) was significantly decreased in both P and T compared with Wt. To our surprise, the functions of RXRα were significantly blocked only in T compared with Wt and P. Namely, the total protein levels of RXRα were significantly reduced and the phosphorylation levels of RXRα were significantly increased only in T compared with Wt and P. Treatment of H-ras12V transgenic mice at 5-week

  3. Morphological Differentiation Towards Neuronal Phenotype of SH-SY5Y Neuroblastoma Cells by Estradiol, Retinoic Acid and Cholesterol

    OpenAIRE

    Teppola, Heidi; Sarkanen, Jertta-Riina; Jalonen, Tuula O.; Linne, Marja-Leena

    2015-01-01

    Human SH-SY5Y neuroblastoma cells maintain their potential for differentiation and regression in culture conditions. The induction of differentiation could serve as a strategy to inhibit cell proliferation and tumor growth. Previous studies have shown that differentiation of SH-SY5Y cells can be induced by all-trans-retinoic-acid (RA) and cholesterol (CHOL). However, signaling pathways that lead to terminal differentiation of SH-SY5Y cells are still largely unknown. The goal of this study was...

  4. Morphological Differentiation Towards Neuronal Phenotype of SH-SY5Y Neuroblastoma Cells by Estradiol, Retinoic Acid and Cholesterol

    OpenAIRE

    Teppola, Heidi; Sarkanen, Jertta-Riina; Jalonen, Tuula; Linne, Marja-Leena

    2016-01-01

    Human SH-SY5Y neuroblastoma cells maintain their potential for differentiation and regression in culture conditions. The induction of differentiation could serve as a strategy to inhibit cell proliferation and tumor growth. Previous studies have shown that differentiation of SH-SY5Y cells can be induced by all-trans-retinoic-acid (RA) and cholesterol (CHOL). However, signaling pathways that lead to terminal differentiation of SH-SY5Y cells are still largely unknown. The goal of this study was...

  5. A retinoic acid-inducible mRNA from F9 teratocarcinoma cells encodes a novel protease inhibitor homologue.

    Science.gov (United States)

    Wang, S Y; Gudas, L J

    1990-09-15

    We have previously isolated several cDNA clones specific for mRNA species that increase in abundance during the retinoic acid-associated differentiation of F9 teratocarcinoma stem cells. One of these mRNAs, J6, encodes a approximately 40 kDa protein as assayed by hybrid selection and in vitro translation (Wang, S.-Y., LaRosa, G., and Gudas, L. J. (1985) Dev. Biol. 107, 75-86). The time course of J6 mRNA expression is similar to those of both laminin B1 and collagen IV (alpha 1) messages following retinoic acid addition. To address the functional role of this protein, we have isolated a full-length cDNA clone complementary to this approximately 40-kDa protein mRNA. Sequence analysis reveals an open reading frame of 406 amino acids (Mr 45,652). The carboxyl-terminal portion of this predicted protein contains a region that is homologous to the reactive sites found among members of the serpin (serine protease inhibitor) family. The predicted reactive site (P1-P1') of this J6 protein is Arg-Ser, which is the same as that of antithrombin III. Like ovalbumin and human monocyte-derived plasminogen activator inhibitor (mPAI-2), which are members of the serpin gene family, the J6 protein appears to have no typical amino-terminal signal sequence.

  6. A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene.

    OpenAIRE

    Lee, M O; Liu, Y; Zhang, X K

    1995-01-01

    The lactoferrin gene is highly expressed in many different tissues, and its expression is controlled by different regulators. In this report, we have defined a retinoic acid response element (RARE) in the 5'-flanking region of the lactoferrin gene promoter. The lactoferrin-RARE is composed of two AGGTCA-like motifs arranged as a direct repeat with 1-bp spacing (DR-1). A gel retardation assay demonstrated that it bound strongly with retinoid X receptor (RXR) homodimers and RXR-retinoic acid re...

  7. Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle

    Science.gov (United States)

    Lapteva, Maria; Möller, Michael; Gurny, Robert; Kalia, Yogeshvar N.

    2015-11-01

    Acne vulgaris is a highly prevalent dermatological disease of the pilosebaceous unit (PSU). An inability to target drug delivery to the PSU results in poor treatment efficacy and the incidence of local side-effects. Cutaneous application of nanoparticulate systems is reported to induce preferential accumulation in appendageal structures. The aim of this work was to prepare stable polymeric micelles containing retinoic acid (RA) using a biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) and to evaluate their ability to deliver RA to skin. An innovative punch biopsy sample preparation method was developed to selectively quantify follicular delivery; the amounts of RA present were compared to those in bulk skin, (i.e. without PSU), which served as the control. RA was successfully incorporated into micelle nanocarriers and protected from photoisomerization by inclusion of Quinoline Yellow. Incorporation into the spherical, homogeneous and nanometer-scale micelles (dn 400-fold. Drug delivery experiments in vitro showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A® Micro (0.04%), a marketed gel containing RA loaded microspheres, (7.1 +/- 1.1% vs. 0.4 +/- 0.1% and 7.5 +/- 0.8% vs. 0.8 +/- 0.1% of the applied dose, respectively). In contrast to a non-colloidal RA solution, Effederm® (0.05%), both the RA loaded MPEG-dihexPLA polymeric micelles (0.005%) and Retin-A® Micro (0.04%) displayed selectivity for delivery to the PSU with 2-fold higher delivery to PSU containing samples than to control samples. Moreover, the micelle formulation outperformed Retin-A® Micro in terms of delivery efficiency to PSU presenting human skin (10.4 +/- 3.2% vs. 0.6 +/- 0.2%, respectively). The results indicate that the polymeric micelle formulation enabled an increased and targeted delivery of RA to the PSU, potentially translating to a safer and more efficient

  8. Postnatal Ablation of Synaptic Retinoic Acid Signaling Impairs Cortical Information Processing and Sensory Discrimination in Mice.

    Science.gov (United States)

    Park, Esther; Tjia, Michelle; Zuo, Yi; Chen, Lu

    2018-06-06

    Retinoic acid (RA) and its receptors (RARs) are well established essential transcriptional regulators during embryonic development. Recent findings in cultured neurons identified an independent and critical post-transcriptional role of RA and RARα in the homeostatic regulation of excitatory and inhibitory synaptic transmission in mature neurons. However, the functional relevance of synaptic RA signaling in vivo has not been established. Here, using somatosensory cortex as a model system and the RARα conditional knock-out mouse as a tool, we applied multiple genetic manipulations to delete RARα postnatally in specific populations of cortical neurons, and asked whether synaptic RA signaling observed in cultured neurons is involved in cortical information processing in vivo Indeed, conditional ablation of RARα in mice via a CaMKIIα-Cre or a layer 5-Cre driver line or via somatosensory cortex-specific viral expression of Cre-recombinase impaired whisker-dependent texture discrimination, suggesting a critical requirement of RARα expression in L5 pyramidal neurons of somatosensory cortex for normal tactile sensory processing. Transcranial two-photon imaging revealed a significant increase in dendritic spine elimination on apical dendrites of somatosensory cortical layer 5 pyramidal neurons in these mice. Interestingly, the enhancement of spine elimination is whisker experience-dependent as whisker trimming rescued the spine elimination phenotype. Additionally, experiencing an enriched environment improved texture discrimination in RARα-deficient mice and reduced excessive spine pruning. Thus, RA signaling is essential for normal experience-dependent cortical circuit remodeling and sensory processing. SIGNIFICANCE STATEMENT The importance of synaptic RA signaling has been demonstrated in in vitro studies. However, whether RA signaling mediated by RARα contributes to neural circuit functions in vivo remains largely unknown. In this study, using a RARα conditional

  9. Cellular alterations and enhanced induction of cleft palate after coadministration of retinoic acid and TCDD

    International Nuclear Information System (INIS)

    Abbott, B.D.; Birnbaum, L.S.

    1989-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and retinoic acid (RA) are both teratogenic in mice. TCDD is a highly toxic, stable environmental contaminant, while RA is a naturally occurring form of vitamin A. Exposure to TCDD induces hydronephrosis and cleft palate, and exposure to RA induces limb defects and cleft palate. Teratology studies previously have shown that the incidence of clefting is higher after exposure to RA + TCDD than would be observed for the same doses of either compound given alone. This study examines the cellular effects which result in cleft palate, after po administration on gestation Day (GD) 10 or 12 of RA + TCDD in corn oil (10 ml/kg total volume). Exposure on GD 10 to 6 micrograms TCDD + 40 mg RA/kg inhibited early growth of the shelves and clefting was due to a failure of shelves to meet and fuse. This effect on mesenchyme was observed in previous studies to occur after exposure on GD 10 to 40 mg/kg RA alone, but not after TCDD alone. After exposure on GD 12 to 6 micrograms TCDD + 80 mg RA/kg, clefting was due to a failure of shelves to fuse after making contact, because the medial cells differentiated into an oral-like epithelium. This response was observed in previous studies to occur after exposure to TCDD alone, but RA alone on GD 12 resulted in differentiation toward nasal-like cells. The interaction between TCDD and RA results in RA-like clefting after exposure on GD 10 and TCDD-like clefting after exposure on GD 12, and this clefting occurs at higher incidences than would occur after the same levels of either agent alone. After exposure on either GD 10 or 12 to RA + TCDD, the programmed cell death of the medial cells does not occur, and these cells continue to express EGF receptors and to bind 125I-EGF. The effects of RA and TCDD may involve modulation of the cells responses to embryonic growth and differentiation factors

  10. Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad.

    Directory of Open Access Journals (Sweden)

    Andrew J Childs

    Full Text Available The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment. Germ cells in the fetal testis enter mitotic arrest, whilst those in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to mesonephros-derived retinoic acid (RA. Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however. We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad. Expression of the three RA-synthesising enzymes, ALDH1A1, 2 and 3 in the fetal ovary and testis was equal to or greater than that in the mesonephros at 8-9 weeks gestation, indicating an intrinsic capacity within the gonad to synthesise RA. Using immunohistochemistry to detect RA receptors RARα, β and RXRα, we find germ cells to be the predominant target of RA signalling in the fetal human ovary, but also reveal widespread receptor nuclear localization indicative of signalling in the testis, suggesting that human fetal testicular germ cells are not efficiently shielded from RA by the action of the RA-metabolising enzyme CYP26B1. Consistent with this, expression of CYP26B1 was greater in the human fetal ovary than testis, although the sexually-dimorphic expression patterns of the germ cell-intrinsic regulators of meiotic initiation, STRA8 and NANOS2, appear conserved. Finally, we demonstrate that RA induces a two-fold increase in STRA8 expression in cultures of human fetal testis, but is not sufficient to cause widespread meiosis-associated gene expression. Together, these data indicate that while local production of RA within the fetal ovary may

  11. Retinoic Acid Signalling and the Control of Meiotic Entry in the Human Fetal Gonad

    Science.gov (United States)

    Kinnell, Hazel L.; Anderson, Richard A.; Saunders, Philippa T. K.

    2011-01-01

    The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment. Germ cells in the fetal testis enter mitotic arrest, whilst those in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to mesonephros-derived retinoic acid (RA). Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however. We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad. Expression of the three RA-synthesising enzymes, ALDH1A1, 2 and 3 in the fetal ovary and testis was equal to or greater than that in the mesonephros at 8–9 weeks gestation, indicating an intrinsic capacity within the gonad to synthesise RA. Using immunohistochemistry to detect RA receptors RARα, β and RXRα, we find germ cells to be the predominant target of RA signalling in the fetal human ovary, but also reveal widespread receptor nuclear localization indicative of signalling in the testis, suggesting that human fetal testicular germ cells are not efficiently shielded from RA by the action of the RA-metabolising enzyme CYP26B1. Consistent with this, expression of CYP26B1 was greater in the human fetal ovary than testis, although the sexually-dimorphic expression patterns of the germ cell-intrinsic regulators of meiotic initiation, STRA8 and NANOS2, appear conserved. Finally, we demonstrate that RA induces a two-fold increase in STRA8 expression in cultures of human fetal testis, but is not sufficient to cause widespread meiosis-associated gene expression. Together, these data indicate that while local production of RA within the fetal ovary may be important in

  12. Retinoic acid signaling plays a restrictive role in zebrafish primitive myelopoiesis.

    Directory of Open Access Journals (Sweden)

    Dong Liang

    Full Text Available Retinoic acid (RA is known to regulate definitive myelopoiesis but its role in vertebrate primitive myelopoiesis remains unclear. Here we report that zebrafish primitive myelopoiesis is restricted by RA in a dose dependent manner mainly before 11 hpf (hours post fertilization when anterior hemangioblasts are initiated to form. RA treatment significantly reduces expressions of anterior hemangioblast markers scl, lmo2, gata2 and etsrp in the rostral end of ALPM (anterior lateral plate mesoderm of the embryos. The result indicates that RA restricts primitive myelopoiesis by suppressing formation of anterior hemangioblasts. Analyses of ALPM formation suggest that the defective primitive myelopoiesis resulting from RA treatment before late gastrulation may be secondary to global loss of cells for ALPM fate whereas the developmental defect resulting from RA treatment during 10-11 hpf should be due to ALPM patterning shift. Overexpressions of scl and lmo2 partially rescue the block of primitive myelopoiesis in the embryos treated with 250 nM RA during 10-11 hpf, suggesting RA acts upstream of scl to control primitive myelopoiesis. However, the RA treatment blocks the increased primitive myelopoiesis caused by overexpressing gata4/6 whereas the abolished primitive myelopoiesis in gata4/5/6 depleted embryos is well rescued by 4-diethylamino-benzaldehyde, a retinal dehydrogenase inhibitor, or partially rescued by knocking down aldh1a2, the major retinal dehydrogenase gene that is responsible for RA synthesis during early development. Consistently, overexpressing gata4/6 inhibits aldh1a2 expression whereas depleting gata4/5/6 increases aldh1a2 expression. The results reveal that RA signaling acts downstream of gata4/5/6 to control primitive myelopoiesis. But, 4-diethylamino-benzaldehyde fails to rescue the defective primitive myelopoiesis in either cloche embryos or lycat morphants. Taken together, our results demonstrate that RA signaling restricts

  13. Uptake and metabolism of [11-3H] all-trans retinoic acid by rabbit tracheal epithelial cells

    International Nuclear Information System (INIS)

    Bhat, P.V.; Jetten, A.M.

    1986-01-01

    Retinoic acid (RA) inhibits squamous cell differentiation of rabbit tracheal epithelial cells in culture at concentrations as low as 10 -9 - 10 -10 M. These cells take up 11-[ 3 H]-RA readily when added to the cells either as free RA or as RA complexed to serum retinol binding protein (SRBP) or albumin. The uptake of RA by RTE cells as SRBP or albumin complexes was significantly lower than that of free RA. Metabolites were analyzed by high pressure liquid chromatography. This analysis showed that RTE cells metabolized RA to polar metabolites (Peak I) and to a less polar metabolite (Peak III). The metabolite in Peak III constituted 13-20% of the cell-associated radioactivity after 24 hrs. incubation with RA. Formation of the Peak I and Peak III metabolites from RA was observed both in undifferentiated as well as in cells that underwent terminal differentiation to squamous cells and their synthesis appeared constitutive. When cells were treated for 6 hrs with 3 H-RA and then further in the absence of RA 75% of the cell-associated radioactivity was released in the medium within 24 hrs, thereafter the release was slow. Analysis of the metabolites secreted by the cells into the medium showed only the presence of Peak I metabolites. The authors data show that RTE cells metabolize RA into polar metabolites which are rapidly released into the medium and into a less polar metabolite, possibly an ester of retinoic acid, which is retained by the cell

  14. Cell-Type-Specific Regulation of the Retinoic Acid Receptor Mediated by the Orphan Nuclear Receptor TLX†

    Science.gov (United States)

    Kobayashi, Mime; Yu, Ruth T.; Yasuda, Kunio; Umesono, Kazuhiko

    2000-01-01

    Malformations in the eye can be caused by either an excess or deficiency of retinoids. An early target gene of the retinoid metabolite, retinoic acid (RA), is that encoding one of its own receptors, the retinoic acid receptor β (RARβ). To better understand the mechanisms underlying this autologous regulation, we characterized the chick RARβ2 promoter. The region surrounding the transcription start site of the avian RARβ2 promoter is over 90% conserved with the corresponding region in mammals and confers strong RA-dependent transactivation in primary cultured embryonic retina cells. This response is selective for RAR but not retinoid X receptor-specific agonists, demonstrating a principal role for RAR(s) in retina cells. Retina cells exhibit a far higher sensitivity to RA than do fibroblasts or osteoblasts, a property we found likely due to expression of the orphan nuclear receptor TLX. Ectopic expression of TLX in fibroblasts resulted in increased sensitivity to RA induction, an effect that is conserved between chick and mammals. We have identified a cis element, the silencing element relieved by TLX (SET), within the RARβ2 promoter region which confers TLX- and RA-dependent transactivation. These results indicate an important role for TLX in autologous regulation of the RARβ gene in the eye. PMID:11073974

  15. Cell-type-specific regulation of the retinoic acid receptor mediated by the orphan nuclear receptor TLX.

    Science.gov (United States)

    Kobayashi, M; Yu, R T; Yasuda, K; Umesono, K

    2000-12-01

    Malformations in the eye can be caused by either an excess or deficiency of retinoids. An early target gene of the retinoid metabolite, retinoic acid (RA), is that encoding one of its own receptors, the retinoic acid receptor beta (RARbeta). To better understand the mechanisms underlying this autologous regulation, we characterized the chick RARbeta2 promoter. The region surrounding the transcription start site of the avian RARbeta2 promoter is over 90% conserved with the corresponding region in mammals and confers strong RA-dependent transactivation in primary cultured embryonic retina cells. This response is selective for RAR but not retinoid X receptor-specific agonists, demonstrating a principal role for RAR(s) in retina cells. Retina cells exhibit a far higher sensitivity to RA than do fibroblasts or osteoblasts, a property we found likely due to expression of the orphan nuclear receptor TLX. Ectopic expression of TLX in fibroblasts resulted in increased sensitivity to RA induction, an effect that is conserved between chick and mammals. We have identified a cis element, the silencing element relieved by TLX (SET), within the RARbeta2 promoter region which confers TLX- and RA-dependent transactivation. These results indicate an important role for TLX in autologous regulation of the RARbeta gene in the eye.

  16. TRIM32 promotes retinoic acid receptor α-mediated differentiation in human promyelogenous leukemic cell line HL60

    International Nuclear Information System (INIS)

    Sato, Tomonobu; Okumura, Fumihiko; Iguchi, Akihiro; Ariga, Tadashi; Hatakeyama, Shigetsugu

    2012-01-01

    Highlights: ► TRIM32 enhanced RARα-mediated transcriptional activity even in the absence of RA. ► TRIM32 stabilized RARα in the human promyelogenous leukemic cell line HL60. ► Overexpression of TRIM32 in HL60 cells induced granulocytic differentiation. ► TRIM32 may function as a coactivator for RARα-mediated transcription in APL cells. -- Abstract: Ubiquitination, one of the posttranslational modifications, appears to be involved in the transcriptional activity of nuclear receptors including retinoic acid receptor α (RARα). We previously reported that an E3 ubiquitin ligase, TRIM32, interacts with several important proteins including RARα and enhances transcriptional activity of RARα in mouse neuroblastoma cells and embryonal carcinoma cells. Retinoic acid (RA), which acts as a ligand to nuclear receptors including RARα, plays crucial roles in development, differentiation, cell cycles and apoptosis. In this study, we found that TRIM32 enhances RARα-mediated transcriptional activity even in the absence of RA and stabilizes RARα in the human promyelogenous leukemic cell line HL60. Moreover, we found that overexpression of TRIM32 in HL60 cells suppresses cellular proliferation and induces granulocytic differentiation even in the absence of RA. These findings suggest that TRIM32 functions as one of the coactivators for RARα-mediated transcription in acute promyelogenous leukemia (APL) cells, and thus TRIM32 may become a potentially therapeutic target for APL.

  17. 9-cis-retinoic acid increases apolipoprotein AI secretion and mRNA expression in HepG2 cells.

    Science.gov (United States)

    Haghpassand, M; Moberly, J B

    1995-10-01

    HepG2 cells were studied as a model for regulation of hepatic apolipoprotein AI (apo AI) secretion and gene expression by 9-cis-retinoic acid. HepG2 cells cultured on plastic dishes were exposed to 9-cis-retinoic acid (9-cis-RA) for 48 h with a complete media change at 24 h. Apo AI mass in cultured media was determined by ELISA, by quantitative immunoblotting and by steady-state 35S-methionine labeling. Messenger RNA levels were determined by RNase protection using probes for apo AI and the housekeeping gene, glyceraldehyde 3-phosphate dehydrogenase (G3PDH). 9-cis-RA increased secretion of apo AI by 52% at doses of 10 and 1 microM (6.3 +/- 0.6 vs. 4.2 +/- 0.3; P G3PDH mRNA was slightly decreased (14%, P < 0.05). Thus, 9-cis-RA stimulates apo AI expression in HepG2 cells, suggesting a role for retinoids in activating endogenous apo AI gene expression.

  18. Absorption Kinetics of the Main Conjugated Linoleic Acid Isomers in Commercial-Rich Oil after Oral Administration in Rats.

    Science.gov (United States)

    Rodríguez-Alcalá, Luís M; Ares, Irma; Fontecha, Javier; Martínez-Larrañaga, María-Rosa; Anadón, Arturo; Martínez, María-Aránzazu

    2017-09-06

    This study aimed to assess the oral absorption and plasma kinetics of two main isomers contained in commercial conjugated linoleic acid (CLA)-rich oil (Tonalin TG-80), rumenic acid (RA), and C18:2 trans-10, cis-12. The isomer plasma disposition after the single oral dose of 3000 mg of Tonalin TG-80/kg, containing 1200 mg/kg of each isomer, was studied in rats. The isomer plasma concentrations were determined by gas chromatography with flame ionization detection. The plasma kinetics showed rapid oral absorption of RA and C18:2 trans-10, cis-12 (t 1/2a 0.34 ± 0.09 and 0.53 ± 0.01 h) and slow elimination (t 1/2β 25.68 ± 3.29 and 18.12 ± 1.71 h); the maximal isomer plasma concentrations (C max ) of 8.48 ± 0.98 and 7.67 ± 0.80 μg mL -1 , respectively, were estimated at 2.08 ± 0.14 and 2.26 ± 0.11 h. Our results from a preclinical kinetic study in rats help to design future studies in humans for evaluating the CLA isomer dose-response.

  19. Altered sensitivity to ellagic acid in neuroblastoma cells undergoing differentiation with 12-O-tetradecanoylphorbol-13-acetate and all-trans retinoic acid.

    Science.gov (United States)

    Alfredsson, Christina Fjæraa; Rendel, Filip; Liang, Qui-Li; Sundström, Birgitta E; Nånberg, Eewa

    2015-12-01

    Ellagic acid has previously been reported to induce reduced proliferation and activation of apoptosis in several tumor cell lines including our own previous data from non-differentiated human neuroblastoma SH-SY5Y cells. The aim of this study was now to investigate if in vitro differentiation with the phorbol ester 12-O- tetradecanoylphorbol-13-acetate or the vitamin A derivative all-trans retinoic acid altered the sensitivity to ellagic acid in SH-SY5Y cells. The methods used were cell counting and LDH-assay for evaluation of cell number and cell death, flow cytometric analysis of SubG1- and TUNEL-analysis for apoptosis and western blot for expression of apoptosis-associated proteins. In vitro differentiation was shown to reduce the sensitivity to ellagic acid with respect to cell detachment, loss of viability and activation of apoptosis. The protective effect was phenotype-specific and most prominent in all-trans retinoic acid-differentiated cultures. Differentiation-dependent up-regulation of Bcl-2 and integrin expression is introduced as possible protective mechanisms. The presented data also point to a positive correlation between proliferative activity and sensitivity to ellagic-acid-induced cell detachment. In conclusion, the presented data emphasize the need to consider degree of neuronal differentiation and phenotype of neuroblastoma cells when discussing a potential pharmaceutical application of ellagic acid in tumor treatment. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  20. Trans fatty acid isomers and the trans-9/trans-11 index in fat containing foods

    Science.gov (United States)

    Kuhnt, Katrin; Baehr, Melanie; Rohrer, Carsten; Jahreis, Gerhard

    2011-01-01

    To determine trans fatty acid (TFA) distribution of contemporary foods, especially regarding individual trans octadecenoic acids (trans C18:1), 339 German foods of six categories (semi-solid fats, deep-fried potato products, bakery products, confectioneries, instant products and butter) were analysed using two GC methods. Results showed a high variation of TFA content between and within the categories containing between 0 and 40.5% of FAME except in butter, which is a source of natural TFA. The mean TFA values were below 2.0% of FAME, however, bakery products contained 4.5% and butter fat 3.2%, respectively. In addition, the distribution of individual trans C18:1 differed. In samples containing ruminant fat (butter and various confectioneries), vaccenic acid (t11-C18:1, t11) predominated, while in foods containing industrially hydrogenated fats, elaidic acid (trans-9, t9-) and t10-C18:1 were the major trans isomers.. This was reflected by a low t9/t11 index of 0.3 and 0.5 in butter and ruminant fat containing confectioneries, respectively, whilst the highest index was observed in shortenings and deep-fried potato products at 5.2 and 6.8, respectively. In conclusion, the TFA content of foods available on the German market is generally declining, but substantial variations are present. The t9/t11 index could be used as an indicator to determine ruminant fat. Practical applications: A number of studies provide evidence that a high TFA intake, particularly of industrial origin, adversely affects human health. The TFA content of foods could be reduced due to the introduction of several mandatory regulations and modifications regarding the hydrogenation process of oils. The most abundant dietary TFA are the isomers of trans C18:1. Unfortunately, the differentiation of these isomers is not yet very common, though the trans C18:1 profile differs depending on its origin (bacterial hydrogenation in the rumen or industrial hydrogenation). To date, data for TFA content

  1. RETINOIC ACID INDUCTION OF CLEFT PALATE IN EGF AND TGF-ALPHA KNOCKOUT MICE: STAGE SPECIFIC INFLUENCES OF GROWTH FACTOR EXPRESSION

    Science.gov (United States)

    ABBOTT, B. D., LEFFLER, K.E. AND BUCKALEW, A.R, Reproductive Toxicology Division, NHEERL, ORD, US EPA, Research Triangle Park, North Carolina. Retinoic acid induction of cleft palate (CP) in EGF and TGF knockout mice: Stage specific influences of growth factor expression.<...

  2. The Effectiveness of a 5% Retinoic Acid Peel Combined with Microdermabrasion for Facial Photoaging: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

    Science.gov (United States)

    Faghihi, Gita; Fatemi-Tabaei, Saghi; Abtahi-Naeini, Bahareh; Siadat, Amir Hossein; Sadeghian, Giti; Ali Nilforoushzadeh, Mohammad; Mohamadian-Shoeili, Hamed

    2017-01-01

    Background . Tretinoin has been shown to improve photoaged skin. This study was designed to evaluate the efficacy and tolerability of a 5% retinoic acid peel combined with microdermabrasion for facial photoaging. Materials and Methods . Forty-five patients, aged 35-70, affected by moderate-to-severe photodamage were enrolled in this trial. All patients received 3 sessions of full facial microdermabrasion and 3 sessions of either 5% retinoic acid peel or placebo after the microdermabrasion. Efficacy was measured using the Glogau scale. Patients were assessed at 2 weeks and 1, 2, and 6 months after treatment initiation. Results . The mean ± SD age of participants was 49.55 ± 11.61 years, and the majorities (73.3%) were female. Between 1 month and 2 months, participants reported slight but statistically significant improvements for all parameters ( P < 0.001). In terms of adverse effects, there were statistically significant differences reported between the 5% retinoic acid peel groups and the control group ( P < 0.001). The majority of adverse effects reported in the study were described as mild and transient. Conclusion . This study demonstrated that 5% retinoic acid peel cream combined with microdermabrasion was safe and effective in the treatment of photoaging in the Iranian population. This trial is registered with IRCT2015121112782N8.

  3. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens

    NARCIS (Netherlands)

    Montesinos, Pau; Rayon, Chelo; Vellenga, Edo; Brunet, Salut; Gonzalez, Jose; Gonzalez, Marcos; Holowiecka, Aleksandra; Esteve, Jordi; Bergua, Juan; Gonzalez, Jose D.; Rivas, Concha; Tormo, Mar; Rubio, Vicente; Bueno, Javier; Manso, Felix; Milone, Gustavo; de la Serna, Javier; Perez, Inmaculada; Perez-Encinas, Manuel; Krsnik, Isabel; Ribera, Josep M.; Escoda, Lourdes; Lowenberg, Bob; Sanz, Miguel A.

    2011-01-01

    The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and

  4. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all- trans retinoic acid and anthracycline chemotherapy: Characteristics, outcome, and prognostic factors

    NARCIS (Netherlands)

    P. Montesinos (Pau); J.M. Bergua (Juan Miguel); E. Vellenga (Edo); C. Rayón (Chelo); R. Parody (Ricardo); J. de Serna (Javier); A. León (Angel); J. Esteve (Jordi); G. Milone (Gustavo); G. Debén (Guillermo); C. Rivas (Concha); M. González (Marcos); M. Tormo (Mar); D.M. Joaquín; J.D. González (José David); S. Negri (Silvia); E. Amutio (Elena); S. Brunet (Salut); B. Löwenberg (Bob); M.A. Sanz (Miguel Angel)

    2009-01-01

    textabstractDifferentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all- trans retinoic acid (ATRA). Detailed knowl- edge about DS has remained limited. We present an analysis of the incidence, char-

  5. Localization of the cellular retinoic acid binding protein (CRABP) gene relative to the acute promyelocytic leukemia-associated breakpoint on human chromosome 15

    NARCIS (Netherlands)

    A.H.M. Geurts van Kessel (Ad); H. de Leeuw (H.); E.J. Dekker (Erik Jan); J.M. Rijks (Jolianne); N. Spurr (N.); A.M. Ledbetter (Andrew M.); E. Kootwijk (E.); M.J. Vaessen (Marie-Josée)

    1991-01-01

    textabstractA human genomic fragment comprising the cellular retinoic acid binding protein (CRABP) gene was isolated. By using a panel of somatic cell hybrids, this gene could be assigned to human chromosome 15. Subsequently, a possible involvement of the CRABP gene in translocation (15;17)

  6. MicroRNA-10a is reduced in breast cancer and regulated in part through retinoic acid

    International Nuclear Information System (INIS)

    Khan, Sonja; Wall, Deirdre; Curran, Catherine; Newell, John; Kerin, Michael J; Dwyer, Roisin M

    2015-01-01

    MicroRNAs (miRNAs) are short non-coding RNA molecules that play a critical role in mRNA cleavage and translational repression, and are known to be altered in many diseases including breast cancer. MicroRNA-10a (miR-10a) has been shown to be deregulated in various cancer types. The aim of this study was to investigate miR-10a expression in breast cancer and to further delineate the role of retinoids and thyroxine in regulation of miR-10a. Following informed patient consent and ethical approval, tissue samples were obtained during surgery. miR-10a was quantified in malignant (n = 103), normal (n = 30) and fibroadenoma (n = 35) tissues by RQ-PCR. Gene expression of Retinoic Acid Receptor beta (RARβ) and Thyroid Hormone receptor alpha (THRα) was also quantified in the same patient samples (n = 168). The in vitro effects of all-trans Retinoic acid (ATRA) and L-Thyroxine (T 4 ) both individually and in combination, on miR-10a expression was investigated in breast cancer cell lines, T47D and SK-BR-3. The level of miR-10a expression was significantly decreased in tissues harvested from breast cancer patients (Mean (SEM) 2.1(0.07)) Log 10 Relative Quantity (RQ)) compared to both normal (3.0(0.16) Log 10 RQ, p < 0.001) and benign tissues (2.6(0.17) Log 10 RQ, p < 0.05). The levels of both RARβ and THRα gene expression were also found to be decreased in breast cancer patients compared to controls (p < 0.001). A significant positive correlation was determined between miR-10a and RARβ (r = 0.31, p < 0.001) and also with THRα (r = 0.32, p < 0.001). In vitro stimulation assays revealed miR-10a expression was increased in both T47D and SK-BR-3 cells following addition of ATRA (2 fold (0.7)). While T 4 alone did not stimulate miR-10a expression, the combination of T 4 and ATRA was found to have a positive synergistic effect. The data presented supports a potential tumour suppressor role for miR-10a in breast cancer, and highlights retinoic acid as a positive regulator of the

  7. HIC1 links retinoic acid signalling to group 3 innate lymphoid cell-dependent regulation of intestinal immunity and homeostasis

    Science.gov (United States)

    Antignano, Frann; Korinek, Vladimir; Underhill, T. Michael

    2018-01-01

    The intestinal immune system must be able to respond to a wide variety of infectious organisms while maintaining tolerance to non-pathogenic microbes and food antigens. The Vitamin A metabolite all-trans-retinoic acid (atRA) has been implicated in the regulation of this balance, partially by regulating innate lymphoid cell (ILC) responses in the intestine. However, the molecular mechanisms of atRA-dependent intestinal immunity and homeostasis remain elusive. Here we define a role for the transcriptional repressor Hypermethylated in cancer 1 (HIC1, ZBTB29) in the regulation of ILC responses in the intestine. Intestinal ILCs express HIC1 in a vitamin A-dependent manner. In the absence of HIC1, group 3 ILCs (ILC3s) that produce IL-22 are lost, resulting in increased susceptibility to infection with the bacterial pathogen Citrobacter rodentium. Thus, atRA-dependent expression of HIC1 in ILC3s regulates intestinal homeostasis and protective immunity. PMID:29470558

  8. Retinoic acid combined with spermatogonial stem cell conditions facilitate the generation of mouse germ-like cells

    DEFF Research Database (Denmark)

    Dong, Guoyi; Shang, Zhouchun; Liu, Longqi

    2017-01-01

    Spermatogenic lineage has been directly generated in spermatogonial stem cell (SSC) conditions from human pluripotent stem cells (PSCs). However, it remains unknown whether mouse embryonic stem cells (ESCs) can directly differentiate into advanced male germ cell lineage in the same conditions. Here......, we showed rather low efficiency of germ-like cell generation from mouse ESCs in SSC conditions. Interestingly, addition of retinoic acid (RA) into SSC conditions enabled efficient differentiation of mouse ESCs into germ-like cells, as shown by the activation of spermatogenesis-associated genes...... such as Mvh, Dazl, Prdm14, Stella, Scp1, Scp3, Stra8 and Rec8. In contrast, for cells cultured in control medium, the activation of the above genes barely occurred. In addition, RA with SSC conditions yielded colonies of Acrosin-expressing cells and the positive ratio reached a peak at day 6. Our work thus...

  9. Detection of Promyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARα Fusion Gene with Functionalized Graphene Oxide

    Directory of Open Access Journals (Sweden)

    Hongwei Wang

    2013-06-01

    Full Text Available An attempt was made to use functionalized graphene oxide (GO to detect the Promyelocytic leukemia/Retinoic acid receptor α fusion gene (PML/RARα fusion gene, a marker gene of acute promyelocytic leukemia. The functionalized GO was prepared by chemical exfoliation method, followed by a polyethylene glycol grafting. It is found that the functionalized GO can selectively adsorb the fluorescein isothiocyanate (FITC-labeled single-stranded DNA probe and quench its fluorescence. The probe can be displaced by the PML/RARα fusion gene to restore the fluorescence, which can be detected by laser confocal microscopy and flow cytometry. These can be used to detect the presence of the PML/RARα fusion gene. This detection method is verified to be fast, simple and reliable.

  10. A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity.

    Science.gov (United States)

    Pino-Lagos, Karina; Guo, Yanxia; Brown, Chrysothemis; Alexander, Matthew P; Elgueta, Raúl; Bennett, Kathryn A; De Vries, Victor; Nowak, Elizabeth; Blomhoff, Rune; Sockanathan, Shanthini; Chandraratna, Roshantha A; Dmitrovsky, Ethan; Noelle, Randolph J

    2011-08-29

    It is known that vitamin A and its metabolite, retinoic acid (RA), are essential for host defense. However, the mechanisms for how RA controls inflammation are incompletely understood. The findings presented in this study show that RA signaling occurs concurrent with the development of inflammation. In models of vaccination and allogeneic graft rejection, whole body imaging reveals that RA signaling is temporally and spatially restricted to the site of inflammation. Conditional ablation of RA signaling in T cells significantly interferes with CD4(+) T cell effector function, migration, and polarity. These findings provide a new perspective of the role of RA as a mediator directly controlling CD4(+) T cell differentiation and immunity. © 2011 Pino-Lagos et al.

  11. Uptake of Retinoic Acid-Modified PMMA Nanoparticles in LX-2 and Liver Tissue by Raman Imaging and Intravital Microscopy.

    Science.gov (United States)

    Yildirim, Turgay; Matthäus, Christian; Press, Adrian T; Schubert, Stephanie; Bauer, Michael; Popp, Jürgen; Schubert, Ulrich S

    2017-10-01

    A primary amino-functionalized methyl methacrylate-based statistical copolymer is covalently coupled with retinoic acid (RA) and a fluorescent dye (DY590) in order to investigate the feasibility of the RA containing polymeric nanoparticles for Raman imaging studies and to study the possible selectivity of RA for hepatic stellate cells via intravital microscopy. Cationic nanoparticles are prepared by utilizing the nanoprecipitation method using modified polymers. Raman studies show that RA functional nanoparticles can be detectable in all tested cells without any need of additional label. Moreover, intravital microscopy indicates that DY590 is eliminated through the hepatobiliary route but not if used as covalently attached tracing molecule for nanoparticles. However, it is a suitable probe for sensitive detection of polymeric nanoparticles. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Dynamic changes in nicotinamide pyridine dinucleotide content in normal human epidermal keratinocytes and their effect on retinoic acid biosynthesis

    International Nuclear Information System (INIS)

    Pinkas-Sarafova, Adriana; Markova, N.G.; Simon, M.

    2005-01-01

    The function of many enzymes that regulate metabolism and transcription depends critically on the nicotinamide pyridine dinucleotides. To understand the role of NAD(P)(H) in physiology and pathophysiology, it is imperative to estimate both their amount and ratios in a given cell type. In human epidermis and in cultured epidermal keratinocytes, we found that the total dinucleotide content is in the low millimolar range. The dinucleotide pattern changes during proliferation and maturation of keratinocytes in culture. Differences in the concentrations of NAD(P)(H) of 1.5- to 12-fold were observed. This resulted in alteration of the NAD(P)H/NAD(P) ratio, which could impact the differential regulation of both transcriptional and metabolic processes. In support of this notion, we provide evidence that the two-step oxidation of retinol to retinoic acid, a nuclear hormone critical for epidermal homeostasis, can be regulated by the relative physiological amounts of the pyridine dinucleotides

  13. Immunomodulatory effects of testosterone evaluated in all-trans retinoic acid differentiated HL-60 cells, granulocytes, and monocytes

    DEFF Research Database (Denmark)

    Boje, Alex; Moesby, Lise; Timm, Michael

    2012-01-01

    The sex hormones are known to affect innate immunity in humans. In this study we evaluated the immunomodulatory effects of testosterone in a model system comprising of all-trans retinoic acid differentiated HL-60 cells, and confirmed the results in human granulocytes and monocytes. Results showed...... that testosterone at pharmacological doses reduced the production of interleukin-8 and reactive oxygen species from differentiated HL-60 cells in a concentration dependent manner without affecting phagocytosis. The cells were stimulated with zymosan, lipopolysaccharide, or Bacillus subtilis. At the highest...... concentration of testosterone (120 µM), interleukin-8 secretion was reduced 42-80%, and production of reactive oxygen species was reduced 32-46%. Flutamide, an antagonist of the classical intracellular androgen receptor, was unable to antagonize the immunosuppressive effect of testosterone. We further...

  14. Retinoic acid signalling is required for the pathogenicity of effector CD4+ T cells during the development of intestinal inflammation

    DEFF Research Database (Denmark)

    Rivollier, Aymeric Marie Christian; Pool, Lieneke; Frising, Ulrika

    The vitamin A metabolite retinoic acid (RA) seems to be a double-edge sword in CD4+ T cell biology, sustaining the development of foxp3+ Treg cells, but also being essential for the stability of the Th1 lineage. Here we explored the role of RA signalling in CD4+ T cells during the development...... of intestinal inflammation in the T cell transfer colitis model. RA signalling-deficient CD4+ T cells are less potent at inducing intestinal inflammation compared to their RA signalling-proficient counterparts and exhibit a differentiation skewing towards more IL-17+ and foxp3+ cells, while their capacity......-deficient and –proficient Tregs are equally competent to inhibit colitis development. Together our results indicate that RA, through its receptor RARα, negatively regulates the early expansion of CD4+ T cells during colitis and is necessary for the generation of colitogenic Th1/Th17 cells, while it is dispensable...

  15. Molecular characterization and chromosomal assignment of equine cartilage derived retinoic acid sensitive protein (CD-RAP)/melanoma inhibitory activity (MIA)

    DEFF Research Database (Denmark)

    Berg, Lise Charlotte; Mata, Xavier; Thomsen, Preben Dybdahl

    2008-01-01

    Cartilage-derived retinoic acid sensitive protein (CD-RAP) also known as melanoma inhibitory activity (MIA) has already been established as a marker for chondrocyte differentiation and a number of cancerous condition sin humans. Studies have also shown that CD-RAP/MIA is a potential marker of joint......RNA in articular cartilage and chondrocytes from horses with no signs of joint disease. The expression decreased as the cells dedifferentiated in monolayer culture. We also identified an equine CD-RAP/MIA splioce variant similar to that reported in humans. The CD_RAP/MIA protein was detected in equine synovial...... fluid, serum and culture medium from chondrocyte cultures. In conclusion, CD-RAP/MIA is expressed in equine cartilage and chondrocytes, and the protein can be detected in equine serum, synovial fluid and in culture medium from chondrocyte cultures. The equine gene and resulting protein share great...

  16. Radiochemically pure [1-14C]valproic acid--a mixture of labeled structural isomers

    International Nuclear Information System (INIS)

    Dickinson, R.G.; Wood, B.T.; Kluck, R.M.; Hooper, W.D.

    1986-01-01

    Ongoing studies of the disposition of valproic acid (VPA) and its glucuronide conjugate required the radiolabeled drug for greater sensitivity and tracing of oxidation metabolites. [1- 14 C]VPA hereinafter called LABEL (radiochemical purity greater than 98% as determined by paper and thin layer chromatography) was purchased from Amersham International, U.K. Quantitative analysis of VPA and VPA-glucuronide in bile and urine samples from rats given VPA and tracer LABEL by our standard gas chromatographic assay showed gross discrepancies with the results obtained by liquid scintillation counting of the same extracts. Examination of the purity of LABEL was therefore undertaken. Equilibration of LABEL between various organic-aqueous solvent pairs was identical to that of authentic VPA. However, gas chromatographic-mass spectrometric analysis of the trimethylsilyl derivative of LABEL revealed it to be a mixture of labeled 2-methylheptanoic acid (approximately 60%), 2-ethylhexanoic acid (approximately 30%), and 2-propylpentanoic acid (i.e., VPA, 5-10%). The origin of the isomers of VPA in LABEL was logically traced to the synthetic procedure--coupling of the Grignard reagent of (an isomeric mixture of 2-, 3-, and 4-) chloroheptane(s) with [ 14 C]carbon dioxide. This result highlights the inadequacy of the quality control procedures used and reinforces the necessity for caution in accepting the quoted purity of radiolabeled drugs

  17. Vitamin A active metabolite, all-trans retinoic acid, induces spinal cord sensitization. II. Effects after intrathecal administration

    Science.gov (United States)

    Alique, M; Lucio, F J; Herrero, J F

    2006-01-01

    Background and purpose: In our previous study (see accompanying paper) we observed that all-trans retinoic acid (ATRA) p.o. induces changes in spinal cord neuronal responses similar to those observed in inflammation-induced sensitization. In the present study we assessed the it. effects of ATRA, and its mechanisms of action. Experimental approach: The effects of all drugs were studied after it. administration in nociceptive withdrawal reflexes using behavioural tests in awake male Wistar rats. Key results: The administration of ATRA in normal rats induced a dose-dependent enhancement of nociceptive responses to noxious mechanical and thermal stimulation, as well as responses to innocuous stimulation. The intensity of the responses was similar to that observed in non-treated animals after carrageenan-induced inflammation. The effect induced by ATRA was fully prevented by the previous administration of the retinoic acid receptor (RAR) pan-antagonist LE540 but not by the retinoid X receptor (RXR) pan-antagonist HX531, suggesting a selective action on spinal cord RARs. The COX inhibitor dexketoprofen and the interleukin-1 receptor antagonist IL-1ra inhibited ATRA effect. The results indicate that COX and interleukin-1 are involved in the effects of ATRA in the spinal cord, similar to that seen in inflammation. Conclusions and implications: In conclusion, ATRA induces changes in the spinal cord similar to those observed in inflammation. The sensitization-like effect induced by ATRA was mediated by RARs and associated with a modulation of COX-2 and interleukin-1 activities. ATRA might be involved in the mechanisms underlying the initiation and/or maintenance of sensitization in the spinal cord. PMID:16847438

  18. Cleft lip with or without cleft palate: Associations with transforming growth factor alpha and retinoic acid receptor loci

    Energy Technology Data Exchange (ETDEWEB)

    Chenevix-Trench, G.; Jones, K. (Queensland Inst. of Medical Research (Australia) Univ. of Queensland (Australia)); Green, A.C.; Duffy, D.L.; Martin, N.G. (Queensland Inst. of Medical Research (Australia))

    1992-12-01

    The first association study of cleft lip with or without cleft palate (CL/P), with candidate genes, found an association with the transforming growth-factor alpha (TGFA) locus. This finding has since been replicated, in whole or in part, in three independent studies. Here the authors extend their original analysis of the TGFA TaqI RFLP to two other TGFA RFLPs and seven other RFLPs at five candidate genes in 117 nonsyndromic cases of CL/P and 113 controls. The other candidate genes were the retinoic acid receptor (RARA), the bcl-2 oncogene, and the homeobox genes 2F, 2G, and EN2. Significant associations with the TGFA TaqI and BamHI RFLPs were confirmed, although associations of clefting with previously reported haplotypes did not reach significance. Of particular interest, in view of the known teratogenic role of retinoic acid, was a significant association with the RARA PstI RFLP (P = .016; not corrected for multiple testing). The effect on risk of the A2 allele appears to be additive, and although the A2A2 homozygote only has an odds ratio of about 2 and recurrence risk to first-degree relatives ([lambda][sub 1]) of 1.06, because it is so common it may account for as much as a third of the attributable risk of clefting. There is no evidence of interaction between the TGFA and RARA polymorphisms on risk, and jointly they appear to account for almost half the attributable risk of clefting. 43 refs., 1 fig., 4 tabs.

  19. Antimetastatic gene expression profiles mediated by retinoic acid receptor beta 2 in MDA-MB-435 breast cancer cells

    International Nuclear Information System (INIS)

    Wallden, Brett; Emond, Mary; Swift, Mari E; Disis, Mary L; Swisshelm, Karen

    2005-01-01

    The retinoic acid receptor beta 2 (RARβ2) gene modulates proliferation and survival of cultured human breast cancer cells. Previously we showed that ectopic expression of RARβ2 in a mouse xenograft model prevented metastasis, even in the absence of the ligand, all-trans retinoic acid. We investigated both cultured cells and xenograft tumors in order to delineate the gene expression profiles responsible for an antimetastatic phenotype. RNA from MDA-MB-435 human breast cancer cells transduced with RARβ2 or empty retroviral vector (LXSN) was analyzed using Agilent Human 1A Oligo microarrays. The one hundred probes with the greatest differential intensity (p < 0.004, jointly) were determined by selecting the top median log ratios from eight-paired microarrays. Validation of differences in expression was done using Northern blot analysis and quantitative RT-PCR (qRT-PCR). We determined expression of selected genes in xenograft tumors. RARβ2 cells exhibit gene profiles with overrepresentation of genes from Xq28 (p = 2 × 10 -8 ), a cytogenetic region that contains a large portion of the cancer/testis antigen gene family. Other functions or factors impacted by the presence of exogenous RARβ2 include mediators of the immune response and transcriptional regulatory mechanisms. Thirteen of fifteen (87%) of the genes evaluated in xenograft tumors were consistent with differences we found in the cell cultures (p = 0.007). Antimetastatic RARβ2 signalling, direct or indirect, results in an elevation of expression for genes such as tumor-cell antigens (CTAG1 and CTAG2), those involved in innate immune response (e.g., RIG-I/DDX58), and tumor suppressor functions (e.g., TYRP1). Genes whose expression is diminished by RARβ2 signalling include cell adhesion functions (e.g, CD164) nutritional or metabolic processes (e.g., FABP6), and the transcription factor, JUN

  20. The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-induced differentiation of colon cancer cells

    International Nuclear Information System (INIS)

    Bengtsson, Astrid M; Jönsson, Gunilla; Magnusson, Cecilia; Salim, Tavga; Axelsson, Cecilia; Sjölander, Anita

    2013-01-01

    Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT 1 R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT 2 R) is lost. Further, our previous data indicate that patients with high CysLT 1 R and low CysLT 2 R expression have a poor prognosis. In this study, we examined whether the balance between CysLT 1 R and CysLT 2 R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA). To determine the effect of ATRA on CysLT 2 R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions. ATRA treatment induces CysLT 2 R mRNA and protein expression without affecting CysLT 1 R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor (RAR) dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C 4 synthase, the enzyme responsible for the production of the ligand for CysLT 2 R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT 2 R-specific inhibitor. This study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway

  1. Retinoic acid receptor gamma impacts cellular adhesion, Alpha5Beta1 integrin expression and proliferation in K562 cells.

    Science.gov (United States)

    Kelley, Melissa D; Phomakay, Raynin; Lee, Madison; Niedzwiedz, Victoria; Mayo, Rachel

    2017-01-01

    The interplay between cellular adhesion and proliferation is complex; however, integrins, particularly the α5β1 subset, play a pivotal role in orchestrating critical cellular signals that culminate in cellular adhesion and growth. Retinoids modify the expression of a variety of adhesive/proliferative signaling proteins including α5β1 integrins; however, the role of specific retinoic acid receptors involved in these processes has not been elucidated. In this study, the effect of all-trans-retinoic acid receptor (RAR) agonists on K562 cellular adhesion, proliferation, and α5β1 integrin cell surface expression was investigated. RARγ agonist exposure increased K562 cellular adhesion to RGD containing extracellular matrix proteins fibronectin and FN-120 in a time- and concentration dependent manner, while RARα or RARβ agonist treatment had no effect on cellular adhesion. Due to the novel RARγ- dependent cellular adhesion response exhibited by K562 cells, we examined α5 and β1 integrin subunit expression when K562 cells were exposed to retinoid agonists or vehicle for 24, 48, 72 or 96 hours. Our data demonstrates no differences in K562 cell surface expression of the α5 integrin subunit when cells were exposed to RARα, RARβ, or RARγ agonists for all time points tested. In contrast, RARγ agonist exposure resulted in an increase in cell surface β1 integrin subunit expression within 48 hours that was sustained at 72 and 96 hours. Finally, we demonstrate that while exposure to RARα or RARβ agonists have no effect on K562 cellular proliferation, the RARγ agonist significantly dampens K562 cellular proliferation levels in a time- and concentration- dependent manner. Our study is the first to report that treatment with a RARγ specific agonist augments cellular adhesion to α5β1 integrin substrates, increases cell surface levels of the β1 integrin subunit, and dampens cellular proliferation in a time and concentration dependent manner in a human

  2. Detection of biologically active isomers of conjugated linoleic acid in kaymak

    Directory of Open Access Journals (Sweden)

    Ökten, Sevtap

    2005-12-01

    Full Text Available Numerous physiological effects are attributed to conjugated linoleic acids (CLA. Biologically active isomers of CLA ( cis -9, trans -11 (C18:2 and trans- 10, cis- 12 (C18:2 have been reported to have anticarcinogenic, antioxidative and antiatherosclerotic properties. Relatively rich sources of CLA include milk fat-containing foods such as kaymak. Kaymak is a kind of concentrated cream which is traditionally manufactured from buffalo or cow's milk mainly in Turkey . The objective of this study was to determine CLA concentrations during kaymak production. Kaymak was manufactured from cow's milk which was enriched with unfermented cream. Biologically active isomers of CLA in raw milk, cream and kaymak were analyzed using gas chromatography. The method was quick, repeatable and sensitive for the CLA determination of samples. Significant differences were found among the concentrations of both isomer and total CLA during the production process (pNumerosos efectos fisiológicos se atribuyen a los ácidos linoleico conjugados (CLA. Así los isómeros biológicamente activos ( cis -9, trans -11 (C18:2 y trans- 10, cis del ácido linoleico han sido descritos con propiedades anticarcinogénicas, antioxidantes y antiarterioscleróticas. Fuentes relativamente ricas de CLA incluyen alimentos con grasas lácteas tales como el kaymak. El kaymak es una crema concentrada elaborada de leche de búfalo o vaca principalmente en Turquía. El objetivo de este estudio fue la determinación de la concentración de CLA durante la producción de kaymak. El kaymak objeto de estudio fue elaborado a partir de leche de vaca que fue enriquecida con crema no fermentada. Los isómeros biológicamente activos del CLA fueron analizados por cromatografía gaseosa en leche cruda, crema y kaymak. El método empleado fue rápido, reproducible y sensible. Se encontraron diferencias significativas en las concentraciones de ambos isómeros y de CLA total durante el proceso de producci

  3. Further evidence of a relationship between the retinoic acid receptor alpha locus and nonsyndromic cleft lip with or without cleft palate (CL [+-] P)

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, D.; Field, L. (Univ. of Calgary (Canada)); Ray, A. (Univ. of Toronto (Canada)); Marazita, M. (Medical College of Virginia, Richmond, VA (United States))

    1993-11-01

    Chenevix-Trench et al. (1992) reported a significant difference between nonsyndromic cleft lip with or without cleft palate (CL [+-] P) cases and unrelated controls in the frequency of alleles at the retinoic acid receptor alpha (RARA) PstI RFLP located at 17q21.1. They also observed borderline significant (P = .055) differences between allele frequencies in subjects with cleft lip and palate (CL + P) compared with those with cleft lip only (CL). Retinoic acid (RA) is a known teratogen capable of producing cleft palate in rodents (Abbott and Birnbaum 1990). Chenevix-Tench et al. (1992) hypothesized that variation in susceptibility to the effects of RA in humans may result from alterations at the RARA locus. We have investigated association and linkage between CL [+-] P and a microsatellite marker (D17S579) located at 17q21 (Hall et al. 1992), selected for its proximity to RARA, in 14 extended multiplex families from rural West Bengal, India.

  4. Anti-inflammatory effects of conjugated linoleic acid isomers and essential fatty acids in bovine mammary epithelial cells.

    Science.gov (United States)

    Dipasquale, D; Basiricò, L; Morera, P; Primi, R; Tröscher, A; Bernabucci, U

    2018-01-09

    Fatty acids are important modulators of inflammatory responses, in particular, n-3 and n-6 essential fatty acids and CLA have received particular attention for their ability to modulate inflammation. The objectives of this study were to compare the effects of CLA and essential fatty acids on the expression of pro and anti- inflammatory cytokines and their protective efficacy against inflammatory status in mammary gland by an in vitro model based on bovine mammary epithelial cells (BME-UV1). Bovine mammary epithelial cells were treated with complete medium containing either 50 µM of cis-9, trans-11 CLA (c9,t11 CLA) or trans-10, cis-12 CLA (t10,c12 CLA) or (α)-linolenic acid (aLnA) or (γ)-linolenic acid (gLnA) or linoleic acid (LA). After 48 h by fatty acids administration the cells were treated for 3 h with 20 µM of lipopolysaccharide (LPS) to induce inflammatory stimulus. Reactive oxygen species (ROS) production after treatments was assessed to verify and to compare the potential protection of different fatty acids against LPS-induced oxidative stress. The messenger RNA abundance of bovine pro and anti-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukine-10 (IL-10)) and peroxisome proliferator receptor-α/γ (PPARγ/α) were determined in BME-UV1 by real-time PCR. The results showed that cells treated with fatty acids and LPS increased ROS production compared with control cells. Among treatments, cells treated with c9,t11 CLA and t10,c12 CLA isomers revealed significant lower levels of ROS production compared with other fatty acids. All fatty acids reduced the gene expression of pro- and anti-inflammatory cytokines. Among fatty acids, t10,c12 CLA, LA and gLnA showed an homogeneous reduction of the three pro-inflammatory cytokines and this may correspond to more balanced and efficient physiological activity and may trigger a better protective effect. The PPARγ gene expression was

  5. Use of Magnetic Folate-Dextran-Retinoic Acid Micelles for Dual Targeting of Doxorubicin in Breast Cancer

    Directory of Open Access Journals (Sweden)

    J. Varshosaz

    2013-01-01

    Full Text Available Amphiphilic copolymer of folate-conjugated dextran/retinoic acid (FA/DEX-RA was self-assembled into micelles by direct dissolution method. Magnetic iron oxide nanoparticles (MNPs coated with oleic acid (OA were prepared by hydrothermal method and encapsulated within the micelles. Doxorubicin HCl was loaded in the magnetic micelles. The characteristics of the magnetic micelles were determined by Fourier transform infrared (FT-IR spectroscopy, thermogravimetric analysis (TGA, transmission electron microscopy (TEM, and vibrating sample magnetometer (VSM. The crystalline state of OA-coated MNPs and their heat capacity were analyzed by X-ray diffraction (XRD and differential scanning calorimetry (DSC methods, respectively. The iron content of magnetic micelles was determined using inductively coupled plasma optical emission spectrometry (ICP-OES. Bovine serum albumin (BSA was used to test the protein binding of magnetic micelles. The cytotoxicity of doxorubicin loaded magnetic micelles was studied on MCF-7 and MDA-MB-468 cells using MTT assay and their quantitative cellular uptake by fluorimetry method. TEM results showed the MNPs in the hydrophobic core of the micelles. TGA results confirmed the presence of OA and FA/DEX-RA copolymer on the surface of MNPs and micelles, respectively. The magnetic micelles showed no significant protein bonding and reduced the IC50 of the drug to about 10 times lower than the free drug.

  6. Role of chemical carcinogens in epithelial and mesenchymal neoplasms with tumor initiation-promotion protocol and the effect of 13-cis retinoic acid in chemo prevention

    International Nuclear Information System (INIS)

    Bukhari, S.M.H.; Shahzad, S.Q.; Naeem, S.; Qureshi, G.R.; Naveed, I.A.

    2002-01-01

    Objective: To study the effects of chemical carcinogens on epithelial and mesenchymal tumorigenesis with tumor initiation-promotion protocol and the use of 13-cis retinoic acid as a chemo preventive agent. Design: It was an experimental study. Place and Duration of Study: The study was conducted at Postgraduate Medical Institute (PGML) Lahore for 20 weeks. Materials and Methods: Sixty albino rats were divided into six groups of ten of animals each. First group of animals (control) was not given carcinogens and 13-cis retinoic acid in second group DMBA was applied on the dorsal skin in repeated dos of 100 mu g/ml in acetone, twice a weak. In the third group DMBA was given 100 mu g/ml as single dose while TPA was given 10 mu g//ml in acetone, twice a weak after two weeks of DMBA applications. In fourth group only DMBA 100 mu g/ml in acetone was applied as a single dose. In fifth and sixth groups 13-cis retinoic acid was given topically before and after the application of DMBA and TPA. Results: First and fourth groups did not develop any tumor. In second groups 2 animals developed malignant fibrous histiocytoma, 4 squamous cell carcinoma while 1 dysphasia and 1 carcinoma in situ. Third group developed osteoma (3 animals), papilloma (3 animals, squamous cell carcinoma (01) and dysplasia (01). Conclusion: Our results showed that DMBA acts as tumor initiator while TPA as promoter. DMBA also produces tumors itself when given alone in repeated doses. The chemical carcinogens are not only a cause of epithelial carcinogenesis but also responsible for mesenchymal tumorigenesis. 13 cis retinoic acid was equally effective in both stages of tumorigenesis. It also prevents malignant conversion of chemically induced benign tumors. (author)

  7. Trichoplax adhaerens reveals a network of nuclear receptors sensitive to 9-cis-retinoic acid at the base of metazoan evolution

    Czech Academy of Sciences Publication Activity Database

    Novotný, J.F.; Chughtai, A.A.; Kostrouchová, M.; Kostrouchová, V.; Kostrouch, D.; Kaššák, F.; Kaňa, Radek; Schierwater, B.; Kostrouchová, M.; Kostrouch, Z.

    2017-01-01

    Roč. 5, SEP 29 (2017), s. 1-29, č. článku e3789. ISSN 2167-8359 R&D Projects: GA ČR(CZ) GA16-10088S; GA MŠk(CZ) ED2.1.00/19.0392 Institutional support: RVO:61388971 Keywords : Trichoplax adhaerens * RXR * 9-cis retinoic acid Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 2.177, year: 2016

  8. Retinoic Acid Signaling Mediates Hair Cell Regeneration by Repressing p27kip and sox2 in Supporting Cells.

    Science.gov (United States)

    Rubbini, Davide; Robert-Moreno, Àlex; Hoijman, Esteban; Alsina, Berta

    2015-11-25

    During development, otic sensory progenitors give rise to hair cells and supporting cells. In mammalian adults, differentiated and quiescent sensory cells are unable to generate new hair cells when these are lost due to various insults, leading to irreversible hearing loss. Retinoic acid (RA) has strong regenerative capacity in several organs, but its role in hair cell regeneration is unknown. Here, we use genetic and pharmacological inhibition to show that the RA pathway is required for hair cell regeneration in zebrafish. When regeneration is induced by laser ablation in the inner ear or by neomycin treatment in the lateral line, we observe rapid activation of several components of the RA pathway, with dynamics that position RA signaling upstream of other signaling pathways. We demonstrate that blockade of the RA pathway impairs cell proliferation of supporting cells in the inner ear and lateral line. Moreover, in neuromast, RA pathway regulates the transcription of p27(kip) and sox2 in supporting cells but not fgf3. Finally, genetic cell-lineage tracing using Kaede photoconversion demonstrates that de novo hair cells derive from FGF-active supporting cells. Our findings reveal that RA has a pivotal role in zebrafish hair cell regeneration by inducing supporting cell proliferation, and shed light on the underlying transcriptional mechanisms involved. This signaling pathway might be a promising approach for hearing recovery. Hair cells are the specialized mechanosensory cells of the inner ear that capture auditory and balance sensory input. Hair cells die after acoustic trauma, ototoxic drugs or aging diseases, leading to progressive hearing loss. Mammals, in contrast to zebrafish, lack the ability to regenerate hair cells. Here, we find that retinoic acid (RA) pathway is required for hair cell regeneration in vivo in the zebrafish inner ear and lateral line. RA pathway is activated very early upon hair cell loss, promotes cell proliferation of progenitor cells

  9. Sorption of a branched nonylphenol isomer and perfluorooctanoic acid on geosorbents and carbon nanotubes

    Energy Technology Data Exchange (ETDEWEB)

    Li, Chengliang

    2011-10-13

    As metabolites of organic surfactants, both nonylphenol (NP) and perfluorooctanoic acid (PFOA) are toxic and ubiquitous in the environment. Their sorption on soils and sediments is of importance for their fate and transport in the environment. Especially in China, there is still a lack of consolidated knowledge on the sorption behavior of NP and PFOA on geosorbents such as Yangtze River sediments. Thus, the present thesis investigates the sorption of a branched NP isomer [4-(1-ethyl-1, 3-dimethylpentyl) phenol] (NP111) and PFOA on Yangtze River sediments and their model components, i.e. a clay mineral (illite), metal oxides (goethite and {delta}-Al{sub 2}O{sub 3}) and organic matter (isolated from Yangtze River sediments and commercial organic matter) by both batch and dialysis techniques. NP111 is the most environmentally relevant NP isomer and its fate in the environment is unknown. Because PFOA is weakly adsorbed on geosorbents, multi-walled carbon nanotubes (MWCNTs) were studied as promising adsorbents. One of the MWCNTs studied contained traces of metal catalyst on the outer surface. Sorption isotherms of NP111 and PFOA on the sediments and their model components were fitted well by the Freundlich model. Sorption of NP111 on the sediments depended largely on their organic carbon content, resulting in organic carbon-normalized sorption coefficient (K{sub OC}) values between 6.3 x 10{sup 3} and 1.1 x 10{sup 4} L kg{sup -1}. The sorption of NP111 on {delta}-Al{sub 2}O{sub 3} and illite was comparable to that on sediments, but significantly lower than that on goethite. In contrast, the sorption of PFOA on the sediments was significantly lower. The affinity of PFOA to goethite and {delta}-Al{sub 2}O{sub 3} was slightly higher than to the sediments, but it was negligible to natural organic matter and illite. The results suggest that the organic carbon content of the sediments plays a dominant role in the sorption of NP111, whereas goethite acts as a potential sink

  10. Effect of Temperature on Oscillatory Behaviour of the System Containing Isomers of Hydroxybenzoic Acid in Batch Reactor

    Directory of Open Access Journals (Sweden)

    Masood A. Nath

    2008-01-01

    Full Text Available In the present paper a thorough study of temperature dependence on oscillatory behaviour of the Belousov-Zhabotinsky (BZ system containing the isomers of hydroxybenzoic acids + BrO3-+ Mn(II in aqueous acid medium (1.0 M H2SO4 at a fixed concentration of reacting species has been reported. On varying temperature, the oscillatory parameters like induction time, time period and number of oscillations show marked changes. These changes arise due to the position and number of hydroxyl groups in these isomers which affect the oscillations. Experimental observations have satisfactorily been explained by FKN mechanism and kinetic parameters. The oscillatory characteristics depend on the temperature dependence of the rate constant of the reaction controlling the inhibitory reaction steps (negative feedback

  11. Molecular mechanism of 9-cis-retinoic acid inhibition of adipogenesis in 3T3-L1 cells

    International Nuclear Information System (INIS)

    Sagara, Chiaki; Takahashi, Katsuhiko; Kagechika, Hiroyuki; Takahashi, Noriko

    2013-01-01

    Highlights: ► We examined the effects of 9-cis-RA on adipogenesis in mouse preadipocyte 3T3-L1. ► 9-cis-RA inhibited lipid accumulation in adipogenetically-induced 3T3-L1 cells. ► A RXR pan-antagonist suppressed the inhibitory effects of 9-cis-RA on adipogenesis. ► This antagonist had no effects on RXRα and PPARγ levels in 9-cis-RA-treated cells. ► 9-cis-RA-induced decrease in both RXRα and PPARγ was independent of RXR activation. -- Abstract: Retinoic acid (RA) signaling is mediated by specific nuclear hormone receptors. Here we examined the effects of 9-cis-RA on adipogenesis in mouse preadipocyte 3T3-L1 cells. 9-cis-RA inhibits the lipid accumulation of adipogenetically induced 3T3-L1 cells. The complex of retinoid X receptor α (RXRα) with peroxisome proliferator-activated receptor γ (PPARγ) is a major transcription factor in the process of adipogenesis, and the levels of these molecules were decreased by 9-cis-RA treatment. A RXR pan-antagonist suppressed 9-cis-RA’s inhibitory effects on adipogenesis, but not on the intracellular levels of both RXRα and PPARγ. These results suggest that 9-cis-RA could inhibit adipogenesis by activating RXR, and decrease both RXR and PPARγs levels in a RXR activation-independent manner

  12. Novel insights into a retinoic-acid-induced cleft palate based on Rac1 regulation of the fibronectin arrangement.

    Science.gov (United States)

    Tang, Qinghuang; Li, Liwen; Lee, Min-Jung; Ge, Qing; Lee, Jong-Min; Jung, Han-Sung

    2016-03-01

    Retinoic acid (RA)-induced cleft palate results from both extrinsic obstructions by the tongue and internal factors within the palatal shelves. Our previous study showed that the spatiotemporal expression of Rac1 regulates the fibronectin (FN) arrangement through cell density alterations that play an important role in palate development. In this study, we investigate the involvement of the Rac1 regulation of the FN arrangement in RA-induced cleft palate. Our results demonstrate that RA-induced intrinsic alterations in palatal shelves, including a delayed progress of cell condensation, delay palate development, even after the removal of the tongue. Further analysis shows that RA treatment diminishes the region-distinctive expression of Rac1 within the palatal shelves, which reversely alters the fibrillar arrangement of FN. Furthermore, RA treatment disrupts the formation of lamellipodia, which are indicative structures of cell migration that are regulated by Rac1. These results suggest that the Rac1 regulation of the FN arrangement is involved in RA-induced cleft palate through the regulation of cell migration, which delays the progress of cell condensation and subsequently influences the FN arrangement, inducing a delay in palate development. Our study provides new insights into the RA-induced impairment of palatal shelf elevation based on cell migration dynamics.

  13. A retinoic acid receptor cDNA probe (RAR2) identifies a moderately frequent RFLP on chromosome 17

    Energy Technology Data Exchange (ETDEWEB)

    Bale, A E; Weinberger, C; McBride, O W [National Cancer Institute, Bethesda, MD (USA)

    1988-08-11

    RAR2, a 0.72 kb EcoRI, PvuII fragment from the 5{prime} end of the retinoic acid receptor cDNA probe was isolated. PstI identifies a constant band at 0.87 kb and a simple two allele polymorphism with a band at either 3.3 kb (A1) or 2.9 kb (A2). In 38 random blood donors, the frequency of the 3.3 kb allele (A1) was 0.29 and of the 2.9 kb allele (A2) was 0.71. The polymorphic bands and the 0.87 kb constant band segregated with chromosome 17 in 88 human-rodent somatic cell hybrids. Co-dominant inheritance was shown in 35 individuals from 5 informative families. Weak constant bands at 6.4 kb, 4.0 kb and 1.4 kb did not cosegregate with the polymorphic bands in somatic cell hybrids and could be eliminated by increasing the wash stringency.

  14. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia

    Science.gov (United States)

    Boutzen, Héléna; Saland, Estelle; Larrue, Clément; de Toni, Fabienne; Gales, Lara; Castelli, Florence A.; Cathebas, Mathilde; Zaghdoudi, Sonia; Stuani, Lucille; Kaoma, Tony; Riscal, Romain; Yang, Guangli; Hirsch, Pierre; David, Marion; De Mas-Mansat, Véronique; Delabesse, Eric; Vallar, Laurent; Delhommeau, François; Jouanin, Isabelle; Ouerfelli, Ouathek; Le Cam, Laurent; Linares, Laetitia K.; Junot, Christophe; Portais, Jean-Charles; Vergez, François; Récher, Christian

    2016-01-01

    Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD–Scid–IL2rγnull mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies. PMID:26951332

  15. Effect of Quercetin on Bone Mineral Status and Markers of Bone Turnover in Retinoic Acid-Induced Osteoporosis

    Directory of Open Access Journals (Sweden)

    Oršolić Nada

    2018-06-01

    Full Text Available Retinoic acid-induced osteoporosis (RBM is one of the most common causes of secondary osteoporosis. This study tested the anti-osteoporetic effect of quercetin in RBM-induced bone loss model (RBM. After 14-day supplementation of 13cRA to induce RBM, rats were administered with quercetin (100 mg/kg or alendronate (40 mg/kg. We analysed changes in body and uterine weight of animals, femoral geometric characteristics, calcium and phosphorus content, bone weight index, bone hystology, bone mineral density (BMD, markers of bone turnover, lipid peroxidation, glutathione levels and SOD, CAT activity of liver, kidney spleen, and ovary as well as biochemical and haematological variables. In comparison to the control RBM rats, the treatment with quercetin increased bone weight index, BMD, osteocalcin level, femoral geometric characteristics, calcium and phosphorus content in the 13cRA-induced bone loss model. Histological results showed its protective action through promotion of bone formation. According to the results, quercetin could be an effective substitution for alendronate in 13cRA-induced osteoporosis. Good therapeutic potential of quercetin on rat skeletal system is based partly on its antioxidant capacity and estrogenic activity.

  16. Effect of STI-571 (imatinib mesylate) in combination with retinoic acid and γ-irradiation on viability of neuroblastoma cells

    International Nuclear Information System (INIS)

    Roessler, Jochen; Zambrzycka, Izabella; Lagodny, Jeanette; Kontny, Udo; Niemeyer, Charlotte Marie

    2006-01-01

    Neuroblastoma (NB) expresses the tyrosine kinase receptors c-Kit, PDGFR-α and -β-targets for STI-571.We investigated a possible combination therapy of STI-571 with retinoic acid (RA) and γ-irradiation on NB cell viability in vitro. Expression of tyrosine kinase receptors and their ligands was examined in 6 NB cell lines by RT-PCR and FACS. The effect on cell viability was determined by MTT assay. Cell viability of all 6 NB cell lines was significantly inhibited after treatment with 20 μM STI-571 for 72 h, two cell lines responding already to 10 μM. Cell lines responded irrespective of their mRNA status or cell surface expression of c-Kit, PDGFR-α and -β. Co-incubation with 9-cis RA sensitized cells to the inhibitory effects of STI-571. However, pre-treatment with 9-cis RA resulted in resistance of NB cell lines to STI-571 and γ-irradiation. Treatment of NB with STI-571 in combination with 9-cis RA might be a therapeutic strategy for patients in consolidation therapy who have completed γ-irradiation therapy

  17. Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program.

    Science.gov (United States)

    Brown, Chrysothemis C; Esterhazy, Daria; Sarde, Aurelien; London, Mariya; Pullabhatla, Venu; Osma-Garcia, Ines; Al-Bader, Raya; Ortiz, Carla; Elgueta, Raul; Arno, Matthew; de Rinaldis, Emanuele; Mucida, Daniel; Lord, Graham M; Noelle, Randolph J

    2015-03-17

    CD4(+) T cells differentiate into phenotypically distinct T helper cells upon antigenic stimulation. Regulation of plasticity between these CD4(+) T-cell lineages is critical for immune homeostasis and prevention of autoimmune disease. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARα, sustains stable expression of Th1 lineage specifying genes, as well as repressing genes that instruct Th17-cell fate. RA signaling is essential for limiting Th1-cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our study identifies RA-RARα as a key component of the regulatory network governing maintenance and plasticity of Th1-cell fate and defines an additional pathway for the development of Th17 cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Retinoic Acid Signaling in B Cells Is Required for the Generation of an Effective T-Independent Immune Response.

    Science.gov (United States)

    Marks, Ellen; Ortiz, Carla; Pantazi, Eirini; Bailey, Charlotte S; Lord, Graham M; Waldschmidt, Thomas J; Noelle, Randolph J; Elgueta, Raul

    2016-01-01

    Retinoic acid (RA) plays an important role in the balance of inflammation and tolerance in T cells. Furthermore, it has been demonstrated that RA facilitates IgA isotype switching in B cells in vivo . However, it is unclear whether RA has a direct effect on T-independent B cell responses in vivo . To address this question, we generated a mouse model where RA signaling is specifically silenced in the B cell lineage. This was achieved through the overexpression of a dominant negative receptor α for RA (dnRARα) in the B cell lineage. In this model, we found a dramatic reduction in marginal zone (MZ) B cells and accumulation of transitional 2 B cells in the spleen. We also observed a reduction in B1 B cells in the peritoneum with a defect in the T-independent B cell response against 2,4,6-trinitrophenyl. This was not a result of inhibited development of B cells in the bone marrow, but likely the result of both defective expression of S1P 1 in MZ B cells and a defect in the development of MZ and B1 B cells. This suggests that RARα expression in B cells is important for B cell frequency in the MZ and peritoneum, which is crucial for the generation of T-independent humoral responses.

  19. Retinoic Acid Is Essential for Th1 Cell Lineage Stability and Prevents Transition to a Th17 Cell Program

    Science.gov (United States)

    Brown, Chrysothemis C.; Esterhazy, Daria; Sarde, Aurelien; London, Mariya; Pullabhatla, Venu; Osma-Garcia, Ines; al-Bader, Raya; Ortiz, Carla; Elgueta, Raul; Arno, Matthew; de Rinaldis, Emanuele; Mucida, Daniel; Lord, Graham M.; Noelle, Randolph J.

    2015-01-01

    Summary CD4+ T cells differentiate into phenotypically distinct T helper cells upon antigenic stimulation. Regulation of plasticity between these CD4+ T-cell lineages is critical for immune homeostasis and prevention of autoimmune disease. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARα, sustains stable expression of Th1 lineage specifying genes, as well as repressing genes that instruct Th17-cell fate. RA signaling is essential for limiting Th1-cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our study identifies RA-RARα as a key component of the regulatory network governing maintenance and plasticity of Th1-cell fate and defines an additional pathway for the development of Th17 cells. PMID:25769610

  20. Retinoic Acid Signaling in B Cells Is Required for the Generation of an Effective T-Independent Immune Response

    Science.gov (United States)

    Marks, Ellen; Ortiz, Carla; Pantazi, Eirini; Bailey, Charlotte S.; Lord, Graham M.; Waldschmidt, Thomas J.; Noelle, Randolph J.; Elgueta, Raul

    2016-01-01

    Retinoic acid (RA) plays an important role in the balance of inflammation and tolerance in T cells. Furthermore, it has been demonstrated that RA facilitates IgA isotype switching in B cells in vivo. However, it is unclear whether RA has a direct effect on T-independent B cell responses in vivo. To address this question, we generated a mouse model where RA signaling is specifically silenced in the B cell lineage. This was achieved through the overexpression of a dominant negative receptor α for RA (dnRARα) in the B cell lineage. In this model, we found a dramatic reduction in marginal zone (MZ) B cells and accumulation of transitional 2 B cells in the spleen. We also observed a reduction in B1 B cells in the peritoneum with a defect in the T-independent B cell response against 2,4,6-trinitrophenyl. This was not a result of inhibited development of B cells in the bone marrow, but likely the result of both defective expression of S1P1 in MZ B cells and a defect in the development of MZ and B1 B cells. This suggests that RARα expression in B cells is important for B cell frequency in the MZ and peritoneum, which is crucial for the generation of T-independent humoral responses. PMID:28066447

  1. Cell fate specification in the lingual epithelium is controlled by antagonistic activities of Sonic hedgehog and retinoic acid.

    Science.gov (United States)

    El Shahawy, Maha; Reibring, Claes-Göran; Neben, Cynthia L; Hallberg, Kristina; Marangoni, Pauline; Harfe, Brian D; Klein, Ophir D; Linde, Anders; Gritli-Linde, Amel

    2017-07-01

    The interaction between signaling pathways is a central question in the study of organogenesis. Using the developing murine tongue as a model, we uncovered unknown relationships between Sonic hedgehog (SHH) and retinoic acid (RA) signaling. Genetic loss of SHH signaling leads to enhanced RA activity subsequent to loss of SHH-dependent expression of Cyp26a1 and Cyp26c1. This causes a cell identity switch, prompting the epithelium of the tongue to form heterotopic minor salivary glands and to overproduce oversized taste buds. At developmental stages during which Wnt10b expression normally ceases and Shh becomes confined to taste bud cells, loss of SHH inputs causes the lingual epithelium to undergo an ectopic and anachronic expression of Shh and Wnt10b in the basal layer, specifying de novo taste placode induction. Surprisingly, in the absence of SHH signaling, lingual epithelial cells adopted a Merkel cell fate, but this was not caused by enhanced RA signaling. We show that RA promotes, whereas SHH, acting strictly within the lingual epithelium, inhibits taste placode and lingual gland formation by thwarting RA activity. These findings reveal key functions for SHH and RA in cell fate specification in the lingual epithelium and aid in deciphering the molecular mechanisms that assign cell identity.

  2. All-trans retinoic acid promotes neural lineage entry by pluripotent embryonic stem cells via multiple pathways

    Directory of Open Access Journals (Sweden)

    Fang Bo

    2009-07-01

    Full Text Available Abstract Background All-trans retinoic acid (RA is one of the most important morphogens with pleiotropic actions. Its embryonic distribution correlates with neural differentiation in the developing central nervous system. To explore the precise effects of RA on neural differentiation of mouse embryonic stem cells (ESCs, we detected expression of RA nuclear receptors and RA-metabolizing enzymes in mouse ESCs and investigated the roles of RA in adherent monolayer culture. Results Upon addition of RA, cell differentiation was directed rapidly and exclusively into the neural lineage. Conversely, pharmacological interference with RA signaling suppressed this neural differentiation. Inhibition of fibroblast growth factor (FGF signaling did not suppress significantly neural differentiation in RA-treated cultures. Pharmacological interference with extracellular signal-regulated kinase (ERK pathway or activation of Wnt pathway effectively blocked the RA-promoted neural specification. ERK phosphorylation was enhanced in RA-treated cultures at the early stage of differentiation. Conclusion RA can promote neural lineage entry by ESCs in adherent monolayer culture systems. This effect depends on RA signaling and its crosstalk with the ERK and Wnt pathways.

  3. Immunomodulation by Bifidobacterium infantis 35624 in the murine lamina propria requires retinoic acid-dependent and independent mechanisms.

    Directory of Open Access Journals (Sweden)

    Patrycja Konieczna

    Full Text Available Appropriate dendritic cell processing of the microbiota promotes intestinal homeostasis and protects against aberrant inflammatory responses. Mucosal CD103(+ dendritic cells are able to produce retinoic acid from retinal, however their role in vivo and how they are influenced by specific microbial species has been poorly described. Bifidobacterium infantis 35624 (B. infantis feeding to mice resulted in increased numbers of CD103(+retinaldehyde dehydrogenase (RALDH(+ dendritic cells within the lamina propria (LP. Foxp3(+ lymphocytes were also increased in the LP, while TH1 and TH17 subsets were decreased. 3,7-dimethyl-2,6-octadienal (citral treatment of mice blocked the increase in CD103(+RALDH(+ dendritic cells and the decrease in TH1 and TH17 lymphocytes, but not the increase in Foxp3(+ lymphocytes. B. infantis reduced the severity of DSS-induced colitis, associated with decreased TH1 and TH17 cells within the LP. Citral treatment confirmed that these effects were RALDH mediated. RALDH(+ dendritic cells decreased within the LP of control inflamed animals, while RALDH(+ dendritic cells numbers were maintained in the LP of B. infantis-fed mice. Thus, CD103(+RALDH(+ LP dendritic cells are important cellular targets for microbiota-associated effects on mucosal immunoregulation.

  4. Morphological Differentiation Towards Neuronal Phenotype of SH-SY5Y Neuroblastoma Cells by Estradiol, Retinoic Acid and Cholesterol.

    Science.gov (United States)

    Teppola, Heidi; Sarkanen, Jertta-Riina; Jalonen, Tuula O; Linne, Marja-Leena

    2016-04-01

    Human SH-SY5Y neuroblastoma cells maintain their potential for differentiation and regression in culture conditions. The induction of differentiation could serve as a strategy to inhibit cell proliferation and tumor growth. Previous studies have shown that differentiation of SH-SY5Y cells can be induced by all-trans-retinoic-acid (RA) and cholesterol (CHOL). However, signaling pathways that lead to terminal differentiation of SH-SY5Y cells are still largely unknown. The goal of this study was to examine in the RA and CHOL treated SH-SY5Y cells the additive impacts of estradiol (E2) and brain-derived neurotrophic factor (BDNF) on cell morphology, cell population growth, synaptic vesicle recycling and presence of neurofilaments. The above features indicate a higher level of neuronal differentiation. Our data show that treatment for 10 days in vitro (DIV) with RA alone or when combined with E2 (RE) or CHOL (RC), but not when combined with BDNF (RB), significantly (p differentiation.

  5. Interleukin-33-Activated Islet-Resident Innate Lymphoid Cells Promote Insulin Secretion through Myeloid Cell Retinoic Acid Production.

    Science.gov (United States)

    Dalmas, Elise; Lehmann, Frank M; Dror, Erez; Wueest, Stephan; Thienel, Constanze; Borsigova, Marcela; Stawiski, Marc; Traunecker, Emmanuel; Lucchini, Fabrizio C; Dapito, Dianne H; Kallert, Sandra M; Guigas, Bruno; Pattou, Francois; Kerr-Conte, Julie; Maechler, Pierre; Girard, Jean-Philippe; Konrad, Daniel; Wolfrum, Christian; Böni-Schnetzler, Marianne; Finke, Daniela; Donath, Marc Y

    2017-11-21

    Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Involvement of apoptotic cell death and cell cycle perturbation in retinoic acid-induced cleft palate in mice

    International Nuclear Information System (INIS)

    Okano, Junko; Suzuki, Shigehiko; Shiota, Kohei

    2007-01-01

    Retinoic acid (RA), a metabolite of vitamin A, plays a key role in a variety of biological processes and is essential for normal embryonic development. On the other hand, exogenous RA could cause cleft palate in offspring when it is given to pregnant animals at either the early or late phases of palatogenesis, but the pathogenetic mechanism of cleft palate caused by excess RA remains not fully elucidated. The aim of the present study was to investigate the effects of excess of RA on early palatogenesis in mouse fetuses and analyze the teratogenic mechanism, especially at the stage prior to palatal shelf elevation. We gave all-trans RA (100 mg/kg) orally to E11.5 ICR pregnant mice and observed the changes occurring in the palatal shelves of their fetuses. It was found that apoptotic cell death increased not only in the epithelium of the palatal shelves but also in the tongue primordium, which might affect tongue withdrawal movement during palatogenesis and impair the horizontal elevation of palatal shelves. In addition, RA was found to prevent the G 1 /S progression of palatal mesenchymal cells through upregulation of p21 Cip1 , leading to Rb hypophospholylation. Thus, RA appears to cause G 1 arrest in palatal mesenchymal cells in a similar manner as in various cancer and embryonic cells. It is likely that apoptotic cell death and cell cycle disruption are involved in cleft palate formation induced by RA

  7. Isotretinoin (13-cis-retinoic acid) alters learning and memory, but not anxiety-like behavior, in the adult rat.

    Science.gov (United States)

    Dopheide, Marsha M; Morgan, Russell E

    2008-12-01

    Isotretinoin (ISO, 13-cis-retinoic acid) is commonly prescribed as Accutane for the treatment of acne. ISO is a known teratogen and the physical side effects of the drug have been well documented. However, possible psychological risks associated with the drug have yet to be determined. Retinoid receptors are abundant in the striatum and hippocampus, brain structures involved in implicit and explicit memory processes, respectively. The current study examined whether ISO influenced implicit or explicit memory processes using a two-stage radial-arm maze (RAM) task. The two stages were identical, except for the method of presenting arm choices to the rats: one at a time (Stage 1) or in pairs (Stage 2). Male rats (n=12/group) were tested on both stages of the RAM during chronic oral treatment with ISO (0, 5, 10, or 15 mg/kg/day). Performance indicated that ISO impaired explicit memory in Stage 2, but retention tests one month after ISO exposure ended, indicated recovery from this explicit memory impairment and evidence of enhanced implicit memory in the 10 mg and 15 mg ISO rats. These data indicate extensive, enduring memory effects from oral ISO treatment at doses likely to produce serum levels within the range typically used to treat acne in humans.

  8. Effect of graphene oxide on undifferentiated and retinoic acid-differentiated SH-SY5Y cells line

    Science.gov (United States)

    Lv, Min; Zhang, Yujie; Liang, Le; Wei, Min; Hu, Wenbing; Li, Xiaoming; Huang, Qing

    2012-06-01

    Graphene oxide (GO), has created an unprecedented opportunity for development and application in biology, due to its abundant functional groups and well water solubility. Recently, the potential toxicity of GO in the environment and in humans has garnered more and more attention. In this paper, we systematically studied the cytotoxicity of GO nanosheets via examining the effect of GO on the morphology, viability and differentiation of a human neuroblastoma SH-SY5Y cell line, which was an ideal model used to study neuronal disease in vitro. The results suggested that GO had no obvious cytotoxicity at low concentration (cells exhibited dose- and time-dependent decreases at high concentration (>=80 μg mL-1). Moreover, GO did not induce apoptosis. Very interestingly, GO significantly enhanced the differentiation of SH-SY5Y induced-retinoic acid (RA) by evaluating neurite length and the expression of neuronal marker MAP2. These data provide a promising application for neurodegenerative diseases.

  9. Addition of all-trans-retinoic acid to omeprazole and sucralfate therapy improves the prognosis of gastric dysplasia.

    Science.gov (United States)

    Jin, Jianjun; Li, Xiaozhen; Xing, Luqi; Chang, Yongchao; Wu, Lijuan; Jin, Zhe; Su, Xiuli; Bai, Yanli; Zheng, Yufeng; Jiang, Yalin; Zhao, Xiao; Lu, Lan; Gao, Qiang

    2015-04-01

    To investigate the efficacy of all-trans retinoic acid (ATRA) in human gastric dysplasia. In this double-blind study, patients with precancerous gastric dysplasia with or without intestinal metaplasia (IM) received either conventional treatment consisting of omeprazole and sucralfate (control group) or conventional treatment plus ATRA. Gastric mucosal biopsies were performed before and after drug treatment and were analysed histologically; expression of retinoblastoma (Rb) protein and HER2 protein in gastric mucosa were measured using immunohistochemistry. A total of 122 patients were included in the study, 63 in the ATRA group and 59 in the control group. In the ATRA group, dysplasia was attenuated in 43 out of 63 patients (68%) compared with 22 out of 59 patients (37%) in the control group; however, IM was not affected by treatment in either group. ATRA treatment was associated with significantly increased Rb expression and decreased HER2 expression in gastric mucosa. The use of conventional therapy plus ATRA for gastric dysplasia was associated with improved efficacy compared with conventional therapy alone. It was also accompanied by increased Rb expression and decreased HER2 expression in gastric mucosa. The addition of ATRA to conventional therapy for gastritis may improve the prognosis of gastric dysplasia. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  10. Mediator complex cooperatively regulates transcription of retinoic acid target genes with Polycomb Repressive Complex 2 during neuronal differentiation.

    Science.gov (United States)

    Fukasawa, Rikiya; Iida, Satoshi; Tsutsui, Taiki; Hirose, Yutaka; Ohkuma, Yoshiaki

    2015-11-01

    The Mediator complex (Mediator) plays key roles in transcription and functions as the nexus for integration of various transcriptional signals. Previously, we screened for Mediator cyclin-dependent kinase (CDK)-interacting factors and identified three proteins related to chromatin regulation. One of them, SUZ12 is required for both stability and activity of Polycomb Repressive Complex 2 (PRC2). PRC2 primarily suppresses gene expression through histone H3 lysine 27 trimethylation, resulting in stem cell maintenance and differentiation; perturbation of this process leads to oncogenesis. Recent work showed that Mediator contributes to the embryonic stem cell state through DNA loop formation, which is strongly associated with chromatin architecture; however, it remains unclear how Mediator regulates gene expression in cooperation with chromatin regulators (i.e. writers, readers and remodelers). We found that Mediator CDKs interact directly with the PRC2 subunit EZH2, as well as SUZ12. Known PRC2 target genes were deregulated by Mediator CDK knockdown during neuronal differentiation, and both Mediator and PRC2 complexes co-occupied the promoters of developmental genes regulated by retinoic acid. Our results provide a mechanistic link between Mediator and PRC2 during neuronal differentiation. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  11. Trim24 (Tif1 alpha): an essential 'brake' for retinoic acid-induced transcription to prevent liver cancer.

    Science.gov (United States)

    Khetchoumian, Konstantin; Teletin, Marius; Tisserand, Johan; Herquel, Benjamin; Ouararhni, Khalid; Losson, Régine

    2008-12-01

    Retinoic acid (RA), the active derivative of vitamin A, is an important signaling molecule that controls various developmental processes and influence the proliferation and differentiation of a variety of cell types. RA exerts its biological functions primarily through binding to and activating nuclear RA receptors (RARs, which include the RAR alpha, beta and gamma isotypes RARA, RARB and RARC). Aberrant expression or impaired function of these nuclear receptors has been linked to diverse types of cancer. RARs are RA-dependent transcription factors that regulate gene expression through the recruitment of different co-regulators (co-activators and co-repressors). TRIM24 (formerly known as TIF1 alpha) was among the first co-regulators identified as interacting with RARs in a ligand-dependent fashion, and it was recently shown to function in mice as a potent liver-specific tumor suppressor by attenuating Rara-mediated transcription. The fact that Trim24(-/-), but not Trim24(-/-)Rara(+/-), mutant mice are highly predisposed to the development of hepatocellular carcinoma (HCC) has significant implications in cancer research. This result, along with the observation that in response to pharmacological inhibition of the RA signaling, hepatocytes lacking Trim24 loose their ability to proliferate, strongly implicates Rara as a proto-oncogene in hepatocytes and demonstrates that overactivated RA signaling is deleterious to liver homeostasis.

  12. Promotive Effect of Minoxidil Combined with All-trans Retinoic Acid (tretinoin) on Human Hair Growth in Vitro

    Science.gov (United States)

    Kwon, Oh Sang; Pyo, Hyun Keol; Oh, Youn Jin; Han, Ji Hyun; Lee, Se Rah; Chung, Jin Ho; Eun, Hee Chul

    2007-01-01

    Minoxidil induces hair growth in male pattern baldness and prolongs the anagen phase. All-trans retinoic acid (ATRA) has been reported to act synergistically with minoxidil in vivo: they can enhance more dense hair regrowth than either compound alone. We evaluated the effect of minoxidil combined with ATRA on hair growth in vitro. The effect of co-treatment of minoxidil and ATRA on hair growth was studied in hair follicle organ culture. In cultured human dermal papilla cells (DPCs) and normal human epidermal keratinocytes, the expressions of Erk, Akt, Bcl-2, Bax, P53 and P21 were evaluated by immunoblot analysis. Minoxidil plus ATRA additively promoted hair growth in vitro, compared with minoxidil alone. In addition, minoxidil plus ATRA elevated phosphorylated Erk, phosphorylated Akt and the ratio of Bcl-2/Bax, but decreased the expressions of P53 and P21 more effectively than by minoxidil alone. Our results suggest that minoxidil plus ATRA would additively enhance hair growth by mediating dual functions: 1) the prolongation of cell survival by activating the Erk and Akt signaling pathways, and 2) the prevention of apoptosis of DPCs and epithelial cells by increasing the ratio of Bcl-2/Bax and downregulating the expressions of P53 and P21. PMID:17449938

  13. Mechanism underlying the suppressor activity of retinoic acid on IL4-induced IgE synthesis and its physiological implication.

    Science.gov (United States)

    Seo, Goo-Young; Lee, Jeong-Min; Jang, Young-Saeng; Kang, Seung Goo; Yoon, Sung-Il; Ko, Hyun-Jeong; Lee, Geun-Shik; Park, Seok-Rae; Nagler, Cathryn R; Kim, Pyeung-Hyeun

    2017-12-01

    The present study extends an earlier report that retinoic acid (RA) down-regulates IgE Ab synthesis in vitro. Here, we show the suppressive activity of RA on IgE production in vivo and its underlying mechanisms. We found that RA down-regulated IgE class switching recombination (CSR) mainly through RA receptor α (RARα). Additionally, RA inhibited histone acetylation of germ-line ε (GL ε) promoter, leading to suppression of IgE CSR. Consistently, serum IgE levels were substantially elevated in vitamin A-deficient (VAD) mice and this was more dramatic in VAD-lecithin:retinol acyltransferase deficient (LRAT -/- ) mice. Further, serum mouse mast cell protease-1 (mMCP-1) level was elevated while frequency of intestinal regulatory T cells (Tregs) were diminished in VAD LRAT -/- mice, reflecting that deprivation of RA leads to allergic immune response. Taken together, our results reveal that RA has an IgE-repressive activity in vivo, which may ameliorate IgE-mediated allergic disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages.

    Science.gov (United States)

    Seifart, C; Muyal, J P; Plagens, A; Yildirim, A Ö; Kohse, K; Grau, V; Sandu, S; Reinke, C; Tschernig, T; Vogelmeier, C; Fehrenbach, H

    2011-08-01

    All-trans retinoic acid (ATRA) is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase model and hypothesised that beneficial effects should be reflected by increased alveolar surface area, elastin expression and downregulation of inflammatory mediators and matrix metalloproteinases (MMPs). Emphysema was induced by porcine pancreatic elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 μg · kg(-1) body weight) versus olive oil. Lungs were removed at day 38. Rat alveolar epithelial L2 cells were incubated with/without elastase followed by ATRA- or vehicle-treatment, respectively. ATRA only partially ameliorated structural defects. Alveolar walls exhibited irregular architecture: increased arithmetic mean thickness, reduction in surface coverage by alveolar epithelial cells type II. ATRA only partially restored reduced soluble elastin. It tended to increase the ratio of ED1(+):ED2(+) macrophages. Bronchoalveolar lavage (BAL) cells exhibited a proinflammatory state and high expression of interleukin-1β, cytokine-induced neutrophil chemoattractant-1, tumour necrosis factor-α, nuclear factor-κB, MMP-2, MMP-9, MMP-12, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in emphysema, with ATRA exerting only few effects. MMP-7 was highly induced by ATRA in healthy but not in emphysematous lungs. ATRA reduced both MMP-2 and TIMP-1 activity in BAL fluid of emphysematous lungs. ATRA-therapy may bear the risk of unwanted side-effects on alveolar septal architecture in emphysematous lungs.

  15. Lack of retinoic acid leads to increased langerin-expressing dendritic cells in gut-associated lymphoid tissues.

    Science.gov (United States)

    Chang, Sun-Young; Cha, Hye-Ran; Chang, Jae-Hoon; Ko, Hyun-Jeong; Yang, Hyungjun; Malissen, Bernard; Iwata, Makoto; Kweon, Mi-Na

    2010-04-01

    Retinoic acid (RA) is a crucial factor for maintaining homeostasis in the gut, including lymphocyte homing, immunoglobulin (Ig) A production, and T regulatory cells (Treg) and T helper cell 17 (T(H)17) generation. Until now, most attention has focused on the function of dendritic cells (DCs) to initiate adaptive immunity including T and B lymphocytes through RA. To investigate the effects of RA on DCs of gut-associated lymphoid tissue (GALT), we analyzed the phenotype and function of DC subsets from GALT of vitamin A-deficient (VAD) mice. VAD mice were prepared by feeding them a VAD diet over 12 weeks from gestational days 10-14. Here, we report that tremendous increase of langerin(+) DCs occurred in the mesenteric lymph nodes (MLNs) and gut lamina propria of VAD mice dependent on CCR7 signaling. Langerin(+) DCs have phenotypes more similar to those of bone marrow-derived dermal langerin(+) DCs than epidermal Langerhans cells. Moreover, RA receptor antagonists enhance the differentiation of langerin(+) DCs from mouse and human precursors of bone marrow and peripheral blood. Langerin(+) DCs were highly differentiated but less inflammatory than langerin(-) DCs of MLNs of VAD mice. Moreover, tolerance to orally delivered antigen was completely abrogated by depletion of langerin(+) DCs in the VAD mice. These results suggest that generation of langerin(+) DCs in the GALT is tightly regulated by RA and that the microenvironment of tissues determines the phenotype of DCs. 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Temperature-controlled continuous production of all-trans retinoic acid-loaded solid lipid nanoparticles using static mixers

    Science.gov (United States)

    Shao, Wenyao; Yan, Mengwen; Chen, Tingting; Chen, Yuqing; Xiao, Zongyuan

    2017-04-01

    This work aims to develop a temperature-controlled continuous solvent emulsification-diffusion process to synthesize all-trans retinoic acid (ATRA)-loaded solid lipid nanoparticles (SLNs) using static mixers. ATRA-loaded SLNs of around 200 nm were obtained when the flow rates of the organic and aqueous phases were 50 ml min-1 and 500 ml min-1, respectively. It was found that the lipid concentration played a dominant role in the size of the obtained SLNs, and higher drug concentration resulted in relatively low entrapment efficiency. The encapsulation of ATRA in the SLNs was effective in improving its stability according to the photo-degradation test. The in vitro release of SLN was slow without an initial burst. This study demonstrates that the solvent emulsification-diffusion technique with static mixing is an effective method of producing SLNs, and could easily be scaled up for industrial applications. Highlights Higher lipid concentration leads to larger SLNs. SLN transformation occurs due to Ostwald ripening. The ATRA-loaded SLNs around 200 nm were successfully produced with static mixers. ATRA-loaded SLNs show better stability towards sunlight. ATRA in SLNs exhibited a relatively slow release rate without a significant initial burst.

  17. Catalase Induced by All-Trans Retinoic Acid Is Involved in Antiproliferation of 36B10 Cells

    International Nuclear Information System (INIS)

    Park, Woo Yoon; Yu, Jae Ran

    2010-01-01

    All-trans retinoic acid (ATRA) has antiproliferative effects against brain tumor cells. Recently, ATRA has been reported to induce catalase. We investigated whether catalase induction by ATRA is associated with its antiproliferative effects. 36B10 cells were exposed to 0-50μM ATRA for 24 or 48 hours and mRNA, protein, and activity of catalase were measured. Reactive oxygen species (ROS) were measured using 2',7'-dichlorofluorescin diacetate. A clonogenic assay was used to confirm the cytotoxic effect. The mRNA, protein, and activity of catalase were found to increase in a concentration- and incubation- time-dependent manner. The increase in catalase activity induced by ATRA was decreased by the addition of 3-amino-1,2,4-triazole (ATZ). ROS was also increased with ATRA and decreased by the addition of ATZ. The decrease in cell survival induced by ATRA was partly rescued by ATZ. Catalase induction by ATRA is involved in ROS overproduction and thus inhibits the proliferation of 36B10 cells.

  18. Cell fate specification in the lingual epithelium is controlled by antagonistic activities of Sonic hedgehog and retinoic acid.

    Directory of Open Access Journals (Sweden)

    Maha El Shahawy

    2017-07-01

    Full Text Available The interaction between signaling pathways is a central question in the study of organogenesis. Using the developing murine tongue as a model, we uncovered unknown relationships between Sonic hedgehog (SHH and retinoic acid (RA signaling. Genetic loss of SHH signaling leads to enhanced RA activity subsequent to loss of SHH-dependent expression of Cyp26a1 and Cyp26c1. This causes a cell identity switch, prompting the epithelium of the tongue to form heterotopic minor salivary glands and to overproduce oversized taste buds. At developmental stages during which Wnt10b expression normally ceases and Shh becomes confined to taste bud cells, loss of SHH inputs causes the lingual epithelium to undergo an ectopic and anachronic expression of Shh and Wnt10b in the basal layer, specifying de novo taste placode induction. Surprisingly, in the absence of SHH signaling, lingual epithelial cells adopted a Merkel cell fate, but this was not caused by enhanced RA signaling. We show that RA promotes, whereas SHH, acting strictly within the lingual epithelium, inhibits taste placode and lingual gland formation by thwarting RA activity. These findings reveal key functions for SHH and RA in cell fate specification in the lingual epithelium and aid in deciphering the molecular mechanisms that assign cell identity.

  19. Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor.

    Directory of Open Access Journals (Sweden)

    Aurore Gely-Pernot

    2015-10-01

    Full Text Available All-trans retinoic acid (ATRA is instrumental to male germ cell differentiation, but its mechanism of action remains elusive. To address this question, we have analyzed the phenotypes of mice lacking, in spermatogonia, all rexinoid receptors (RXRA, RXRB and RXRG or all ATRA receptors (RARA, RARB and RARG. We demonstrate that the combined ablation of RXRA and RXRB in spermatogonia recapitulates the set of defects observed both upon ablation of RAR in spermatogonia. We also show that ATRA activates RAR and RXR bound to a conserved regulatory region to increase expression of the SALL4A transcription factor in spermatogonia. Our results reveal that this major pluripotency gene is a target of ATRA signaling and that RAR/RXR heterodimers are the functional units driving its expression in spermatogonia. They add to the mechanisms through which ATRA promote expression of the KIT tyrosine kinase receptor to trigger a critical step in spermatogonia differentiation. Importantly, they indicate also that meiosis eventually occurs in the absence of a RAR/RXR pathway within germ cells and suggest that instructing this process is either ATRA-independent or requires an ATRA signal originating from Sertoli cells.

  20. 9-cis-retinoic acid represses estrogen-induced expression of the very low density apolipoprotein II gene.

    Science.gov (United States)

    Schippers, I J; Kloppenburg, M; Snippe, L; Ab, G

    1994-11-01

    The chicken very low density apolipoprotein II (apoVLDLII) gene is estrogen-inducible and specifically expressed in liver. We examined the possible involvement of the retinoid X receptor (RXR) and its ligand 9-cis-retinoic acid (9-cis-RA) in the activation of the apoVLDLII promoter. We first concentrated on a potential RXR recognition site, which deviates at only one position from a perfect direct A/GGGTCA repeat spaced by one nucleotide (DR-1) and was earlier identified as a common HNF-4/COUP-TF recognition site. However, band shift analysis revealed that this imperfect DR-1 motif does not interact with RXR alpha-homodimers. In accordance with this observation we found that this regulatory element does not mediate transactivation through RXR alpha in the presence of 9-cis-RA. However, our experiments revealed another, unexpected, effect of 9-cis-RA. Instead of stimulating, 9-cis-RA attenuated estrogen-induced expression of transfected estrogen-responsive VLDL-CAT reporter plasmids. This repression appeared to take place through the main estrogen response element (ERE) of the gene. Importantly, 9-cis-RA also strongly repressed the estrogen-induced expression of the endogenous apoVLDLII gene in cultured chicken hepatoma cells.

  1. Suppressive role of OGT-mediated O-GlcNAcylation of BAP1 in retinoic acid signaling.

    Science.gov (United States)

    Moon, Seungtae; Lee, Yong-Kyu; Lee, Sang-Wang; Um, Soo-Jong

    2017-10-07

    BRCA1-associated protein 1 (BAP1) has been implicated in diverse biological functions, including tumor suppression. However, its regulation via glycosylation and its role in embryonic stem (ES) cells are poorly defined. BAP1 was recently reported to interact with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). Here, we confirmed the physical interaction and investigated its functional significance. The O-GlcNAcylation of BAP1, which requires OGT, was examined in vivo and in vitro, and was proven using alloxan, an OGT inhibitor. OGT promoted the BAP1-induced repression of retinoic acid (RA)-induced RA receptor (RAR) activation. The repressive activity of BAP1 was relieved by alloxan but exacerbated by PUGNAc, an O-GlcNAcase (OGA) inhibitor. Finally, we addressed the role of O-GlcNAcylation in the RA-induced differentiation of murine ES cells. Alkaline phosphatase staining revealed the cooperation of RA and alloxan for impairing the pluripotency of ES cells. This cooperation was also observed by measuring the size of embryonic bodies and the expression of Sox2, a pluripotency marker. Overall, our data suggest that OGT-mediated O-GlcNAcylation of BAP1 prefers the maintenance of pluripotency, whereas its inhibition facilitates RA-induced differentiation in ES cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Ectopic cross-talk between thyroid and retinoic acid signaling: A possible etiology for spinal neural tube defects.

    Science.gov (United States)

    Li, Huili; Bai, Baoling; Zhang, Qin; Bao, Yihua; Guo, Jin; Chen, Shuyuan; Miao, Chunyue; Liu, Xiaozhen; Zhang, Ting

    2015-12-01

    Previous studies have highlighted the connections between neural tube defects (NTDs) and both thyroid hormones (TH) and vitamin A. However, whether the two hormonal signaling pathways interact in NTDs has remained unclear. We measured the expression levels of TH signaling genes in human fetuses with spinal NTDs associated with maternal hyperthyroidism as well as levels of retinoic acid (RA) signaling genes in mouse fetuses exposed to an overdose of RA using NanoString or real-time PCR on spinal cord tissues. Interactions between the two signaling pathways were detected by ChIP assays. The data revealed attenuated DIO2/DIO3 switching in fetuses with NTDs born to hyperthyroid mothers. The promoters of the RA signaling genes CRABP1 and RARB were ectopically occupied by increased RXRG and RXRB but displayed decreased levels of inhibitory histone modifications, suggesting that elevated TH signaling abnormally stimulates RA signaling genes. Conversely, in the mouse model, the observed decrease in Dio3 expression could be explained by increased levels of inhibitory histone modifications in the Dio3 promoter region, suggesting that overactive RA signaling may ectopically derepress TH signaling. This study thus raises in vivo a possible abnormal cross-promotion between two different hormonal signals through their common RXRs and the subsequent recruitment of histone modifications, prompting further investigation into their involvement in the etiology of spinal NTDs. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Potential for all-trans retinoic acid (tretinoin) to enhance interferon-alpha treatment response in chronic myelogenous leukemia, melanoma, myeloma and renal cell carcinoma.

    Science.gov (United States)

    Kast, Richard E

    2008-10-01

    This note mechanistically accounts for recent unexplained findings that all-trans retinoic acid (ATRA, also termed tretinoin) exerts an anti-viral effect against hepatitis C virus (HCV) in chronically infected patients, in whom ATRA also showed synergy with interferon-alpha. How HCV replication was suppressed was unclear. Both effects of ATRA can be accounted for by ATRA's upregulation of RIG protein, an 18 kDa product of retinoic induced gene-1. Increased RIG then couples ATRA to increased Type 1 interferons' production. Details of this mechanism predict that ATRA will similarly augment interferon-a activity in treating chronic myelogenous leukemia, melanoma, myeloma and renal cell carcinoma and that the addition of ribavirin and/or bexarotene will each incrementally enhance interferon-a responses in these cancers.

  4. Estimated pKa values for the environmentally relevant C1 through C8 perfluorinated sulfonic acid isomers.

    Science.gov (United States)

    Rayne, Sierra; Forest, Kaya

    2016-10-14

    In order to estimate isomer-specific acidity constants (pKa) for the perfluorinated sulfonic acid (PFSA) environmental contaminants, the parameterization method 6 (PM6) pKa prediction method was extensively validated against a wide range of carbon oxyacids and related sulfonic/sulfinic acids. Excellent pKa prediction performance was observed for the carbon oxyacids using the PM6 method, but this approach was found to have a severe positive bias for sulfonic/sulfinic acids. To overcome this obstacle, a correlation was developed between non-adjusted PM6 pKa values and the corresponding experimentally obtained/estimated acidity constants for a range of representative alkyl, aryl and halogen-substituted sulfonic acids. Application of this correction to the PM6 values allows for extension of this computational method to a new acid functional group. When used to estimate isomer-specific pKa values for the C1 through C8 PFSAs, the modified PM6 approach suggests an adjusted pKa range from -5.3 to -9.0, indicating that all members of this class of well-known environmental contaminants will be effectively completely dissociated in aquatic systems.

  5. Effect of all-trans retinoic acid on newly diagnosed acute promyelocytic leukemia patients: results of a Brazilian center

    Directory of Open Access Journals (Sweden)

    B.C. de-Medeiros

    1998-12-01

    Full Text Available Thirty-seven patients with acute promyelocytic leukemia (APL were treated with all-trans retinoic acid (ATRA. Patients received 45 mg m-2 day-1 po of ATRA until complete remission (CR was achieved, defined as: a presence of less than 5% blasts in the bone marrow, with b white blood cells >103/mm3, c platelets >105/mm3 and d hemoglobin concentration >8 g/dl, with no blood or platelet transfusions. Thirty-one (83.7% patients achieved CR by day 50, and 75% of these before day 30. Correction of the coagulopathy, achieved between days 2 and 10 (mean, 3 days, was the first evidence of response to treatment. Only one patient had been previously treated with chemotherapy and three had the microgranular variant M3 form. Dryness of skin and mucosae was the most common side effect observed in 82% of the patients. Thrombosis, hepatotoxicity and retinoid acid syndrome (RAS were observed in 7 (19%, 6 (16% and 4 (11% patients, respectively. Thirteen (35% patients had to be submitted to chemotherapy due to hyperleukocytosis (above 40 x 103/mm3 and six of these presented with new signs of coagulopathy after chemotherapy. Four (11% patients died secondarily to intracerebral hemorrhage (IH and two (5.4% dropped out of the protocol due to severe ATRA side effects (one RAS and one hepatotoxicity. RAS and IH were related strictly to hyperleukocytosis. The reduced use of platelets and fresh frozen plasma probably lowered the total cost of treatment. We conclude that ATRA is an effective agent for inducing complete remission in APL patients.

  6. Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells

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    Niu Chao

    2010-08-01

    Full Text Available Abstract Objective To investigate the effect of all-trans retinoic acid(ATRA on the proliferation and differentiation of brain tumor stem cells(BTSCs in vitro. Methods Limiting dilution and clonogenic assay were used to isolate and screen BTSCs from the fresh specimen of human brain glioblastoma. The obtained BTSCs, which were cultured in serum-free medium, were classified into four groups in accordance with the composition of the different treatments. The proliferation of the BTSCs was evaluated by MTT assay. The BTSCs were induced to differentiate in serum-containing medium, and classified into the ATRA group and control group. On the 10th day of induction, the expressions of CD133 and glial fibrillary acidic protein (GFAP in the differentiated BTSCs were detected by immunofluorescence. The differentiated BTSCs were cultured in serum-free medium, the percentage and the time required for formation of brain tumor spheres (BTS were observed. Results BTSCs obtained by limiting dilution were all identified as CD133-positive by immunofluorescence. In serum-free medium, the proliferation of BTSCs in the ATRA group was observed significantly faster than that in the control group, but slower than that in the growth factor group and ATRA/growth factor group, and the size of the BTS in the ATRA group was smaller than that in the latter two groups(P P P P Conclusion ATRA can promote the proliferation and induce the differentiation of BTSCs, but the differentiation is incomplete, terminal differentiation cannot be achieved and BTSs can be formed again.

  7. Retinoic acid regulates cell-shape and -death of E-FABP (FABP5)-immunoreactive septoclasts in the growth plate cartilage of mice.

    Science.gov (United States)

    Bando, Yasuhiko; Yamamoto, Miyuki; Sakiyama, Koji; Sakashita, Hide; Taira, Fuyoko; Miyake, Genki; Iseki, Shoichi; Owada, Yuji; Amano, Osamu

    2017-09-01

    Septoclasts, which are mononuclear and spindle-shaped cells with many processes, have been considered to resorb the transverse septa of the growth plate (GP) cartilage at the chondro-osseous junction (COJ). We previously reported the expression of epidermal-type fatty acid-binding protein (E-FABP, FABP5) and localization of peroxisome proliferator-activated receptor (PPAR)β/δ, which mediates the cell survival or proliferation, in septoclasts. On the other hand, retinoic acid (RA) can bind to E-FABP and is stored abundantly in the GP cartilage. From these information, it is possible to hypothesize that RA in the GP is incorporated into septoclasts during the cartilage resorption and regulates the growth and/or death of septoclasts. To clarify the mechanism of the cartilage resorption induced by RA, we administered an overdose of RA or its precursor vitamin A (VA)-deficient diet to young mice. In mice of both RA excess and VA deficiency, septoclasts decreased in the number and cell size in association with shorter and lesser processes than those in normal mice, suggesting a substantial suppression of resorption by septoclasts in the GP cartilage. Lack of PPARβ/δ-expression, TUNEL reaction, RA receptor (RAR)β, and cellular retinoic acid-binding protein (CRABP)-II were induced in E-FABP-positive septoclasts under RA excess, suggesting the growth arrest/cell-death of septoclasts, whereas cartilage-derived retinoic acid-sensitive protein (CD-RAP) inducing the cell growth arrest or morphological changes was induced in septoclasts under VA deficiency. These results support and do not conflict with our hypothesis, suggesting that endogenous RA in the GP is possibly incorporated in septoclasts and utilized to regulate the activity of septoclasts resorbing the GP cartilage.

  8. A PU.1 suppressive target gene, metallothionein 1G, inhibits retinoic acid-induced NB4 cell differentiation.

    Directory of Open Access Journals (Sweden)

    Naomi Hirako

    Full Text Available We recently revealed that myeloid master regulator SPI1/PU.1 directly represses metallothionein (MT 1G through its epigenetic activity of PU.1, but the functions of MT1G in myeloid differentiation remain unknown. To clarify this, we established MT1G-overexpressing acute promyelocytic leukemia NB4 (NB4MTOE cells, and investigated whether MT1G functionally contributes to all-trans retinoic acid (ATRA-induced NB4 cell differentiation. Real-time PCR analyses demonstrated that the inductions of CD11b and CD11c and reductions in myeloperoxidase and c-myc by ATRA were significantly attenuated in NB4MTOE cells. Morphological examination revealed that the percentages of differentiated cells induced by ATRA were reduced in NB4MTOE cells. Since G1 arrest is a hallmark of ATRA-induced NB4 cell differentiation, we observed a decrease in G1 accumulation, as well as decreases in p21WAF1/CIP1 and cyclin D1 inductions, by ATRA in NB4MTOE cells. Nitroblue tetrazolium (NBT reduction assays revealed that the proportions of NBT-positive cells were decreased in NB4MTOE cells in the presence of ATRA. Microarray analyses showed that the changes in expression of several myeloid differentiation-related genes (GATA2, azurocidin 1, pyrroline-5-carboxylate reductase 1, matrix metallopeptidase -8, S100 calcium-binding protein A12, neutrophil cytosolic factor 2 and oncostatin M induced by ATRA were disturbed in NB4MTOE cells. Collectively, overexpression of MT1G inhibits the proper differentiation of myeloid cells.

  9. Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis.

    Directory of Open Access Journals (Sweden)

    Lizhi Wu

    Full Text Available UAB30 is an RXR selective agonist that has been shown to have potential cancer chemopreventive properties. Due to high efficacy and low toxicity, it is currently being evaluated in human Phase I clinical trials by the National Cancer Institute. While UAB30 shows promise as a low toxicity chemopreventive drug, the mechanism of its action is not well understood. In this study, we investigated the effects of UAB30 on gene expression in human organotypic skin raft cultures and mouse epidermis. The results of this study indicate that treatment with UAB30 results in upregulation of genes responsible for the uptake and metabolism of all-trans-retinol to all-trans-retinoic acid (ATRA, the natural agonist of RAR nuclear receptors. Consistent with the increased expression of these genes, the steady-state levels of ATRA are elevated in human skin rafts. In ultraviolet B (UVB irradiated mouse skin, the expression of ATRA target genes is found to be reduced. A reduced expression of ATRA sensitive genes is also observed in epidermis of mouse models of UVB-induced squamous cell carcinoma and basal cell carcinomas. However, treatment of mouse skin with UAB30 prior to UVB irradiation prevents the UVB-induced decrease in expression of some of the ATRA-responsive genes. Considering its positive effects on ATRA signaling in the epidermis and its low toxicity, UAB30 could be used as a chemoprophylactic agent in the treatment of non-melanoma skin cancer, particularly in organ transplant recipients and other high risk populations.

  10. Comparison of anthracycline-based combination chemotherapy with or without all-trans retinoic acid in acute promyelocytic leukemia

    International Nuclear Information System (INIS)

    Raza, S.; Ahmed, P.; Khan, B.

    2008-01-01

    To compare survival in Acute Promyelocytic Leukemia (APL) patients treated with or without All-Trans Retinoic Acid (ATRA). Longitudinal, comparative study. All consecutive newly diagnosed patients of acute promyelocytic leukemia, treated at Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan, between May 2001 and April 2007, were included and given chemotherapy according to availability of ATRA. Diagnosis was confirmed on morphology/ karyotyping/ molecular analysis. Eligibility criteria included confirmed morphologic diagnosis and/or by demonstration of t(15;17) and/or PML/RAR macro re-arrangement, no prior chemotherapy, normal hepatic and renal function, Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 and no contraindications to ATRA (history of sensitivity to Vit. A or other retinoids). All patients having history of cardiac failure (LVEF 150 macro mol/L and pregnancy were excluded from this study. Survival was calculated from the date of chemotherapy to death or last follow-up according to Kaplan-Meier and Cox (Proportional hazard) regression analysis methods. During the 6 years study period, 31 newly diagnosed patients with acute promyelocytic leukemia received treatment at AFBMTC. Seventeen patients received anthracycline-based remission induction and consolidation chemotherapy, while 14 received ATRA-based remission induction, consolidation and by two years maintenance therapy. Overall Survival (OS), Disease Free Survival (DFS) and mortality were 29.4%, 29.4% and 70.6% respectively in 17 patients who received anthracycline based chemotherapy, whereas in patients who received ATRA-based chemotherapy OS, DFS and mortality was 71.4%, 64.2% and 28.6% respectively. Major causes of mortality were septicemia and chemotherapy related toxicity. Response to ATRA-based chemotherapy in patient cohort was better as compared with anthracycline based chemotherapy (71.4% vs. 29.4%) in terms of survival and mortality. (author)

  11. Local sequence information in cellular retinoic acid-binding protein I: specific residue roles in beta-turns.

    Science.gov (United States)

    Rotondi, Kenneth S; Gierasch, Lila M

    2003-01-01

    We have recently shown that two of the beta-turns (III and IV) in the ten-stranded, beta-clam protein, cellular retinoic acid-binding protein I (CRABP I), are favored in short peptide fragments, arguing that they are encoded by local interactions (K. S. Rotondi and L. M. Gierasch, Biochemistry, 2003, Vol. 42, pp. 7976-7985). In this paper we examine these turns in greater detail to dissect the specific local interactions responsible for their observed native conformational biases. Conformations of peptides corresponding to the turn III and IV fragments were examined under conditions designed to selectively disrupt stabilizing interactions, using pH variation, chaotrope addition, or mutagenesis to probe specific side-chain influences. We find that steric constraints imposed by excluded volume effects between near neighbor residues (i,i+2), favorable polar (i,i+2) interactions, and steric permissiveness of glycines are the principal factors accounting for the observed native bias in these turns. Longer-range stabilizing interactions across the beta-turns do not appear to play a significant role in turn stability in these short peptides, in contrast to their importance in hairpins. Additionally, our data add to a growing number of examples of the 3:5 type I turn with a beta-bulge as a class of turns with high propensity to form locally defined structure. Current work is directed at the interplay between the local sequence information in the turns and more long-range influences in the mechanism of folding of this predominantly beta-sheet protein. Copyright 2004 Wiley Periodicals, Inc.

  12. Paradoxical effects of all-trans-retinoic acid on lupus-like disease in the MRL/lpr mouse model.

    Directory of Open Access Journals (Sweden)

    Xiaofeng Liao

    Full Text Available Roles of all-trans-retinoic acid (tRA, a metabolite of vitamin A (VA, in both tolerogenic and immunogenic responses are documented. However, how tRA affects the development of systemic autoimmunity is poorly understood. Here we demonstrate that tRA have paradoxical effects on the development of autoimmune lupus in the MRL/lpr mouse model. We administered, orally, tRA or VA mixed with 10% of tRA (referred to as VARA to female mice starting from 6 weeks of age. At this age, the mice do not exhibit overt clinical signs of lupus. However, the immunogenic environment preceding disease onset has been established as evidenced by an increase of total IgM/IgG in the plasma and expansion of lymphocytes and dendritic cells in secondary lymphoid organs. After 8 weeks of tRA, but not VARA treatment, significantly higher pathological scores in the skin, brain and lung were observed. These were accompanied by a marked increase in B-cell responses that included autoantibody production and enhanced expression of plasma cell-promoting cytokines. Paradoxically, the number of lymphocytes in the mesenteric lymph node decreased with tRA that led to significantly reduced lymphadenopathy. In addition, tRA differentially affected renal pathology, increasing leukocyte infiltration of renal tubulointerstitium while restoring the size of glomeruli in the kidney cortex. In contrast, minimal induction of inflammation with tRA in the absence of an immunogenic environment in the control mice was observed. Altogether, our results suggest that under a predisposed immunogenic environment in autoimmune lupus, tRA may decrease inflammation in some organs while generating more severe disease in others.

  13. All-trans retinoic acid directs urothelial specification of murine embryonic stem cells via GATA4/6 signaling mechanisms.

    Directory of Open Access Journals (Sweden)

    Joshua R Mauney

    2010-07-01

    Full Text Available The urinary bladder and associated tract are lined by the urothelium, a transitional epithelium that acts as a specialized permeability barrier that protects the underlying tissue from urine via expression of a highly specific group of proteins known as the uroplakins (UP. To date, our understanding of the developmental processes responsible for urothelial differentiation has been hampered due to the lack of suitable models. In this study, we describe a novel in vitro cell culture system for derivation of urothelial cells from murine embryonic stem cells (ESCs following cultivation on collagen matrices in the presence all trans retinoic acid (RA. Upon stimulation with micromolar concentrations of RA, ESCs significantly downregulated the pluripotency factor OCT-4 but markedly upregulated UP1A, UP1B, UP2, UP3A, and UP3B mRNA levels in comparison to naïve ESCs and spontaneously differentiating controls. Pan-UP protein expression was associated with both p63- and cytokeratin 20-positive cells in discrete aggregating populations of ESCs following 9 and 14 days of RA stimulation. Analysis of endodermal transcription factors such as GATA4 and GATA6 revealed significant upregulation and nuclear enrichment in RA-treated UP2-GFP+ populations. GATA4-/- and GATA6-/- transgenic ESC lines revealed substantial attenuation of RA-mediated UP expression in comparison to wild type controls. In addition, EMSA analysis revealed that RA treatment induced formation of transcriptional complexes containing GATA4/6 on both UP1B and UP2 promoter fragments containing putative GATA factor binding sites. Collectively, these data suggest that RA mediates ESC specification toward a urothelial lineage via GATA4/6-dependent processes.

  14. Antisense oligonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Xu, Qin; Zhang, Zhiyuan; Zhang, Ping; Chen, Wantao

    2008-01-01

    Antisense oligonucleotides against hTR (As-ODN-hTR) have shown promising results as treatment strategies for various human malignancies. All-trans retinoic acid (ATRA) is a signalling molecule with important roles in differentiation and apoptosis. Biological responses to ATRA are currently used therapeutically in various human cancers. The aim of this study was to evaluate the anti-tumor effects of As-ODN-hTR combined with ATRA in vivo. In situ human oral squamous cell carcinoma (OSCC) models were established by subcutaneous injection of Tca8113 cells. Mice were treated with sense oligonucleotides against hTR(S-ODN-hTR) alone, As-ODN-hTR alone, ATRA alone, As-ODN-hTR plus ATRA, or S-ODN-hTR plus ATRA. Tumor size and weight were assessed in the mice. Telomerase activity was detected by a TRAP assay, apoptotic cells were evaluated with a Tunel assay, the expression of apoptosis-related proteins (Bcl-2 and Bax) was evaluated by immunohistochemistry and ultrastructural morphological changes in the tumor specimen were examined. Both As-ODN-hTR and ATRA can significantly inhibit tumor growth in this OSCC xenograft solid-tumor model, and the combination of the two agents had a synergistic anti-tumorogenic effect. We also demonstrated that this anti-tumor effect correlated with inhibition of telomerase activity. Furthermore, significant increases in the number of apoptotic cells, typical apoptotic morphology and a downregulation of the anti-apoptotic protein, bcl-2 were observed in the treated tissues. The combination of As-ODN-hTR and ATRA has a synergistic anti-tumor effect. This anti-tumor effect can be mainly attributed to apoptosis induced by a decrease in telomerase activity. Bcl-2 plays an important role in this process. Therefore, combining As-ODN-hTR and ATRA may be an approach for the treatment of human oral squamous cell carcinoma

  15. Increased catalase activity by all-trans retinoic acid and its effect on radiosensitivity in rat glioma cells

    International Nuclear Information System (INIS)

    Jin, Hua; Jeon, Ha Yeun; Park, Woo Yoon; Kim, Won Dong; Ahn, Hee Yul; Yu, Jae Ran

    2005-01-01

    It has been reported that all-trans retinoic acid (ATRA) can inhibit glioma growing in vitro. However, clinical trials with ATRA alone in gliomas revealed modest results. ATRA has been shown to increase radiosensitivity in other tumor types, so combining radiation and ATRA would be one of alternatives to increase therapeutic efficacy in malignant gliomas. Thus, we intended to know the role of catalase, which is induced by ATRA, for radiosensitivity. If radiation-reduced reactive oxygen species (ROS) is removed by catalase, the effect of radiation will be reduced. A rat glioma cell line (36B10) was used for this study. The change of catalase activity and radiosensitivity by ATRA, with or without 3-amino-1, 2, 4-triazole (ATZ), a chemical inhibitor of catalase were measured. Catalase activity was measured by the decomposition of H 2 O 2 spectrophotometrically. Radiosensitivity was measured with clonogenic assay. Also ROS was measured using a 2, 7-dichlorofluores-cein diacetate spectrophotometrically. When 36B10 cells were exposed to 10, 25 and 50 μ M of ATRA for 48 h, the expression of catalase activity were increased with increasing concentration and incubation time of ATRA. Catalase activity was decreased with increasing the concentration of AT (1, 10 mM) dose-dependently. ROS was increased with ATRA and it was augmented with the combination of ATRA and radiation. ATZ decreased ROS production and increased cell survival in combination of ATRA and radiation despite the reduction of catalase. The increase of ROS is one of the reasons for the increased radiosensitivity in combination with ATRA. The catalase that is induced by ATRA doesn't decrease ROS production and radiosensitivity

  16. Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes

    Directory of Open Access Journals (Sweden)

    Deep-Dixit Vishwa

    2006-11-01

    Full Text Available Abstract Background Vitamin A (VA deficiency induces a type 1 cytokine response and exogenously provided retinoids can induce a type 2 cytokine response both in vitro and in vivo. The precise mechanism(s involved in this phenotypic switch are inconsistent and have been poorly characterized in humans. In an effort to determine if retinoids are capable of inducing Th2 cytokine responses in human T cell cultures, we stimulated human PBMCs with immobilized anti-CD3 mAb in the presence or absence of all-trans retinoic acid (ATRA or 9-cis-RA. Results Stimulation of human PBMCs and purified T cells with ATRA and 9-cis-RA increased mRNA and protein levels of IL-4, IL-5, and IL-13 and decreased levels of IFN-γ, IL-2, IL-12p70 and TNF-α upon activation with anti-CD3 and/or anti-CD28 mAbs. These effects were dose-dependent and evident as early as 12 hr post stimulation. Real time RT-PCR analysis revealed a dampened expression of the Th1-associated gene, T-bet, and a time-dependent increase in the mRNA for the Th2-associated genes, GATA-3, c-MAF and STAT6, upon treatment with ATRA. Besides Th1 and Th2 cytokines, a number of additional proinflammatory and regulatory cytokines including several chemokines were also differentially regulated by ATRA treatment. Conclusion These data provide strong evidence for multiple inductive roles for retinoids in the development of human type-2 cytokine responses.

  17. Transcriptional up-regulation of restin by all-trans retinoic acid through STAT1 in cancer cell differentiation process

    International Nuclear Information System (INIS)

    Fu Haiyan; Yang Guodong; Lu Fan; Wang Ruihua; Yao Libo; Lu Zifan

    2006-01-01

    RESTIN, a member of the melanoma-associated antigen superfamily, is a nuclear protein induced by atRA (all-trans retinoic acid) in HL60 cells. HeLa cells stably transfected with restin results in G1 cell cycle arrest. How this gene is regulated by atRA in the cell differentiation process is still unclear. In this study, we observed that up-regulation of restin was present during the atRA-induced HL60 cell differentiation process, suggesting the functional relevance between RESTIN and atRA-induced cellular effects. In order to further define the transcriptional regulation of restin by atRA, we analyzed the promoter region of restin. About 2.1 kb 5' flanking sequence of this gene was cloned into vector pGL3 and its core promoter region was identified through systemic deletions. Interestingly, restin promoter containing several potential consensus-binding sites of STAT-1α was activated by atRA in ER + MCF-7 cells but not in ER - MDA-MB-231 cells, over-expression of STAT-1α in latter rescued the activation effect of restin promoter in response to atRA and IFNγ. Our evidence supported that STAT-1α plays an important role in the atRA-induced transcriptional up-regulation of restin, which was associated with the atRA-induced HL60 cell differentiation and potentially mediated the downstream effects of atRA signal pathway via STAT-1α in some cancer cells

  18. Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia

    Science.gov (United States)

    Ferreira, R.; Fonseca, M. C.; Santos, T.; Sargento-Freitas, J.; Tjeng, R.; Paiva, F.; Castelo-Branco, M.; Ferreira, L. S.; Bernardino, L.

    2016-04-01

    Stroke is one of the leading causes of death and disability worldwide. However, current therapies only reach a small percentage of patients and may cause serious side effects. We propose the therapeutic use of retinoic acid-loaded nanoparticles (RA-NP) to safely and efficiently repair the ischaemic brain by creating a favourable pro-angiogenic environment that enhances neurogenesis and neuronal restitution. Our data showed that RA-NP enhanced endothelial cell proliferation and tubule network formation and protected against ischaemia-induced death. To evaluate the effect of RA-NP on vascular regulation of neural stem cell (NSC) survival and differentiation, endothelial cell-conditioned media (EC-CM) were collected. EC-CM from healthy RA-NP-treated cells reduced NSC death and promoted proliferation while EC-CM from ischaemic RA-NP-treated cells decreased cell death, increased proliferation and neuronal differentiation. In parallel, human endothelial progenitor cells (hEPC), which are part of the endogenous repair response to vascular injury, were collected from ischaemic stroke patients. hEPC treated with RA-NP had significantly higher proliferation, which further highlights the therapeutic potential of this formulation. To conclude, RA-NP protected endothelial cells from ischaemic death and stimulated the release of pro-survival, proliferation-stimulating factors and differentiation cues for NSC. RA-NP were shown to be up to 83-fold more efficient than free RA and to enhance hEPC proliferation. These data serve as a stepping stone to use RA-NP as vasculotrophic and neurogenic agents for vascular disorders and neurodegenerative diseases with compromised vasculature.

  19. A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid.

    Science.gov (United States)

    Zhou, Ru; Horai, Reiko; Mattapallil, Mary J; Caspi, Rachel R

    2011-10-15

    The eye is an immunologically privileged and profoundly immunosuppressive environment. Early studies reported inhibition of T cell proliferation, IFN-γ production, and generation of regulatory T cells (Tregs) by aqueous humor (AH) and identified TGF-β as a critical factor. However, T cell subsets including Foxp3(+) Treg and Th17 were unknown at that time, as was the role of retinoic acid (RA) in Treg induction. Consequently, the effect of the ocular microenvironment on T cell lineage commitment and function, and the role of RA in this process, had not been explored. We now use gene-manipulated mice and highly purified T cell populations to demonstrate that AH suppresses lineage commitment and acquisition of Th1 and Th17 effector function of naive T cells, manifested as reduction of lineage-specific transcription factors and cytokines. Instead, AH promoted its massive conversion to Foxp3(+) Tregs that expressed CD25, GITR, CTLA-4, and CD103 and were functionally suppressive. TGF-β and RA were both needed and synergized for Treg conversion by AH, with TGF-β-enhancing T cell expression of RA receptor α. Newly converted Foxp3(+) Tregs were unstable, but were stabilized upon continued exposure to AH or by the DNA demethylating agent 5-aza-2'-deoxycytidine. In contrast, T cells already committed to effector function were resistant to the suppressive and Treg-inducing effects of AH. We conclude that RA in the eye plays a dual role: in vision and in immune privilege. Nevertheless, primed effector T cells are relatively insensitive to AH, helping to explain their ability to induce uveitis despite an inhibitory ocular microenvironment.

  20. Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

    Science.gov (United States)

    Kojima, Hiroyuki; Takeda, Yukimasa; Muromoto, Ryuta; Takahashi, Miki; Hirao, Toru; Takeuchi, Shinji; Jetten, Anton M.; Matsuda, Tadashi

    2018-01-01

    The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. In this study, we investigated the effects of isoflavones on RORα/γ activity and the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In doxycycline-inducible CHO stable cell lines, we found that four isoflavones, biochanin A (BA), genistein, formononetin, and daidzein, enhanced RORα- or RORγ-mediated transcriptional activity in a dose-dependent manner. In an activation assay of the Il17a promoter using Jurkat cells, these compounds enhanced the RORα- or RORγ-mediated activation of the Il17a promoter at concentrations of 1 × 10−6 M to 1 × 10−5 M. In mammalian two-hybrid assays, the four isoflavones enhanced the interaction between the RORα- or RORγ-ligand binding domain and the co-activator LXXLL peptide in a dose-dependent manner. In addition, these isoflavones potently enhanced Il17a mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin, but showed slight enhancement of Il17a gene expression in RORα/γ-knockdown EL4 cells. Immunoprecipitation and immunoblotting assays also revealed that BA enhanced the interaction between RORγt and SRC-1, which is a co-activator for nuclear receptors. Taken together, these results suggest that the isoflavones have the ability to enhance IL-17 gene expression by stabilizing the interactions between RORα/γ and co-activators. This also provides the first evidence that dietary chemicals can enhance IL-17 gene expression in immune cells. PMID:25583575

  1. All-trans retinoic acid increases oxidative metabolism in mature adipocytes

    DEFF Research Database (Denmark)

    Mercader, Josep; Madsen, Lise; Felipe, Francisco

    2007-01-01

    ), and to an increased expression of proteins favoring fat oxidation (peroxisome proliferator-activated receptor gamma coactivator-1alpha, uncoupling protein 2, fasting-induced adipose factor, enzymes of mitochondrial fatty acid oxidation). These changes paralleled inactivation of the retinoblastoma protein and were...

  2. Retinoic acid attenuates the mild hyperoxic lung injury in newborn mice

    Czech Academy of Sciences Publication Activity Database

    Zimová-Herknerová, M.; Mysliveček, J.; Potměšil, Petr

    2008-01-01

    Roč. 57, č. 1 (2008), s. 33-40 ISSN 0862-8408 Institutional research plan: CEZ:AV0Z50390512 Keywords : Retionic acid * Hyperoxia * Lung injury Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 1.653, year: 2008

  3. Post-surgical treatment of thyroid carcinoma in dogs with retinoic ...

    African Journals Online (AJOL)

    tulyasys

    2016-01-20

    Jan 20, 2016 ... In humans it is well known that therapeutic options for TC and prognosis after ..... Molecular pathways: current role and future directions of the retinoic acid ... Potential of retinoic acid derivatives for the treatment of corticotroph ...

  4. Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis: A Human Pilot Study.

    Science.gov (United States)

    Assis, David N; Abdelghany, Osama; Cai, Shi-Ying; Gossard, Andrea A; Eaton, John E; Keach, Jill C; Deng, Yanhong; Setchell, Kenneth D R; Ciarleglio, Maria; Lindor, Keith D; Boyer, James L

    2017-02-01

    To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline. In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).

  5. Genetic variation in toll-like receptors and retinoic acid-inducible gene I and outcome of hepatitis C virus infection

    DEFF Research Database (Denmark)

    Clausen, L N; Ladelund, S; Weis, N

    2014-01-01

    We evaluated the effects of genetic variation in toll-like receptors (TLR), retinoic acid-inducible gene I (RIG-I) and their signalling pathways on spontaneous hepatitis C virus (HCV) resolution. We screened 95 single-nucleotide polymorphisms (SNPs) in 22 genes. SNPs significantly associated...... with resolution in the discovery cohort were genotyped in a validation cohort. Multivariate logistic regression adjusted for sex, hepatitis B surface antigen, HIV infection and the interleukin-28B rs12979860 SNP was performed in the combined cohort. Haplotype reconstruction and linkage disequilibrium analysis...

  6. Herpes simplex virus infection is sensed by both Toll-like receptors and retinoic acid-inducible gene- like receptors, which synergize to induce type I interferon production

    DEFF Research Database (Denmark)

    Rasmussen, Simon B; Jensen, Søren B; Nielsen, Christoffer

    2009-01-01

    The innate antiviral response is initiated by pattern recognition receptors, which recognize viral pathogen-associated molecular patterns. Here we show that retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) in cooperation with Toll-like receptor (TLR) 9 is required for expression of type I...... interferons (IFNs) after infection with herpes simplex virus (HSV). Our work also identified RNase L as a critical component in IFN induction. Moreover, we found that TLR9 and RLRs activate distinct, as well as overlapping, intracellular signalling pathways. Thus, RLRs are important for recognition of HSV...

  7. PKC δ Regulates Translation Initiation through PKR and eIF2 α in Response to Retinoic Acid in Acute Myeloid Leukemia Cells

    OpenAIRE

    Ozpolat, Bulent; Akar, Ugur; Tekedereli, Ibrahim; Alpay, S. Neslihan; Barria, Magaly; Gezgen, Baki; Zhang, Nianxiang; Coombes, Kevin; Kornblau, Steve; Lopez-Berestein, Gabriel

    2012-01-01

    Translation initiation and activity of eukaryotic initiation factor-alpha (eIF2 α ), the rate-limiting step of translation initiation, is often overactivated in malignant cells. Here, we investigated the regulation and role of eIF2 α in acute promyelocytic (APL) and acute myeloid leukemia (AML) cells in response to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), the front-line therapies in APL. ATRA and ATO induce Ser-51 phosphorylation (inactivation) of eIF2 α , through the induct...

  8. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial.

    Science.gov (United States)

    Platzbecker, Uwe; Avvisati, Giuseppe; Cicconi, Laura; Thiede, Christian; Paoloni, Francesca; Vignetti, Marco; Ferrara, Felicetto; Divona, Mariadomenica; Albano, Francesco; Efficace, Fabio; Fazi, Paola; Sborgia, Marco; Di Bona, Eros; Breccia, Massimo; Borlenghi, Erika; Cairoli, Roberto; Rambaldi, Alessandro; Melillo, Lorella; La Nasa, Giorgio; Fiedler, Walter; Brossart, Peter; Hertenstein, Bernd; Salih, Helmut R; Wattad, Mohammed; Lübbert, Michael; Brandts, Christian H; Hänel, Mathias; Röllig, Christoph; Schmitz, Norbert; Link, Hartmut; Frairia, Chiara; Pogliani, Enrico Maria; Fozza, Claudio; D'Arco, Alfonso Maria; Di Renzo, Nicola; Cortelezzi, Agostino; Fabbiano, Francesco; Döhner, Konstanze; Ganser, Arnold; Döhner, Hartmut; Amadori, Sergio; Mandelli, Franco; Ehninger, Gerhard; Schlenk, Richard F; Lo-Coco, Francesco

    2017-02-20

    Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 10 9 /L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.

  9. Application of Attenuated Total Reflectance-Fourier Transformed Infrared (ATR-FTIR) Spectroscopy To Determine the Chlorogenic Acid Isomer Profile and Antioxidant Capacity of Coffee Beans.

    Science.gov (United States)

    Liang, Ningjian; Lu, Xiaonan; Hu, Yaxi; Kitts, David D

    2016-01-27

    The chlorogenic acid isomer profile and antioxidant activity of both green and roasted coffee beans are reported herein using ATR-FTIR spectroscopy combined with chemometric analyses. High-performance liquid chromatography (HPLC) quantified different chlorogenic acid isomer contents for reference, whereas ORAC, ABTS, and DPPH were used to determine the antioxidant activity of the same coffee bean extracts. FTIR spectral data and reference data of 42 coffee bean samples were processed to build optimized PLSR models, and 18 samples were used for external validation of constructed PLSR models. In total, six PLSR models were constructed for six chlorogenic acid isomers to predict content, with three PLSR models constructed to forecast the free radical scavenging activities, obtained using different chemical assays. In conclusion, FTIR spectroscopy, coupled with PLSR, serves as a reliable, nondestructive, and rapid analytical method to quantify chlorogenic acids and to assess different free radical-scavenging capacities in coffee beans.

  10. Highly efficient high-performance liquid chromatographic separation of xylene isomers and phthalate acid esters on a homemade DUT-67(Zr) packed column.

    Science.gov (United States)

    Chen, Sha; Li, Xiao-Xin; Feng, Fan; Li, Sumei; Han, Jia-Hui; Jia, Zi-Yi; Shu, Lun; Somsundaran, P; Li, Jian-Rong

    2018-04-16

    In this study, the baseline separations of xylene isomers and phthalate acid esters on a homemade DUT-67(Zr) packed column were achieved, respectively. The high selectivity for xylene isomers and phthalate acid esters was obtained with the increase of temperature and decrease of the retention time. The hydrophobicity of xylene isomers and phthalate acid esters caused the different separation time on the DUT-67(Zr) packed column. The relative standard deviation values of retention time, peak area, peak height and half peak width for five repeat separation of the xylene isomers were 0.26-0.35, 2.11-2.26, 1.51-2.03, and 0.29-0.77%, and the values of the phthalate acid esters on DUT-67(Zr) column were 0.1-0.4, 4.4-5.2, 3.9-6.3, and 0.6-2.1%, respectively. The thermodynamic properties indicated that the separation of xylene isomers was controlled by ΔH and ΔS, but the separation of phthalate acid esters was mainly controlled by ΔS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  11. Effect of retinoic acid on the radiosensitivity of normal human oral keratinocyte

    International Nuclear Information System (INIS)

    Lee, Jean; Heo, Min Suk; Lee, Sam Sun; Oh, Sung Ook; Choi, Soon Chul; Park, Tae Won; Lee, Sul Mi; Choi, Hang Moon

    2003-01-01

    To evaluate the effect of all-trans-retinotic acid (ATRA) on the radiosensitivity of normal human oral keratinocyte (NHOK). Relative cell survival fraction including SF2 (survival fraction at 2 Gy) was calculated on the basis of colony formation assay. Data were fitted to the linear-quadratic model to establish the survival curve and calculate α and β values. Using flow cytometry at 1, 2, 3, 4, and 5 days after exposure to 2 and 10 Gy irradiation, cell cycle arrest and apoptosis were analysed. To understand the molecular mechanism of the radiosensitization of ATRA on NHOK, proteins related with apoptosis and cell cycle arrest were investigated by Western blot analysis. Treatment with ATRA resulted in a significant decrease of SF2 value for NHOK from 0.63 to 0.27, and increased α and β value, indicating that ATRA increased radiosensitivity of NHOK. ATRA increased LDH significantly, but increasing irradiation dose decreased LDH, suggesting that the radiosensitizing effect of ATRA is not directly related with increasing cell necrosis by ATRA. ATRA did not induce appotosis but increased G2 arrest after 10 Gy irradiation, implying that the increased radiosensitivity of NHOK may be due to a decrease in mitosis caused by increasing G2 arrest. ATRA inhibited the reduction of p53 at 3 days after 10 Gy irradiation and increased p21 at 1 day after 10 Gy irradiation. Further study is required to determine the precise relationship between this effect and the radiosensitizing effect of ATRA. These results suggested that ATRA increase radiosensitivity by inhibiting mitosis caused by increasing G2 arrest.

  12. Influence of the geometric isomers on the radical scavenging properties of 3,5-dica®eoylquinic acid: A DFT study in vacuo and in solution

    CSIR Research Space (South Africa)

    Makola, MM

    2016-09-01

    Full Text Available 3,5-Dica®eoylquinic acid (diCQA) is a part of the chlorogenic acid group of compounds, largely isolated from food sources and possessing potent antioxidant activity. Only the trans–trans isomer exists in nature, however, abiotic stresses, such as UV...

  13. All-trans retinoic acid protects against arsenic-induced uterine toxicity in female Sprague–Dawley rats

    International Nuclear Information System (INIS)

    Chatterjee, A.; Chatterji, U.

    2011-01-01

    Background and purpose: Arsenic exposure frequently leads to reproductive failures by disrupting the rat uterine histology, hormonal integrity and estrogen signaling components of the rat uterus, possibly by generating reactive oxygen species. All-trans retinoic acid (ATRA) was assessed as a prospective therapeutic agent for reversing reproductive disorders. Experimental approach: Rats exposed to arsenic for 28 days were allowed to either recover naturally or were treated simultaneously with ATRA for 28 days or treatment continued up to 56 days. Hematoxylin–eosin double staining was used to evaluate changes in the uterine histology. Serum gonadotropins and estradiol were assayed by ELISA. Expression of the estrogen receptor (ERα), an estrogen responsive gene vascular endothelial growth factor (VEGF), and cell cycle regulatory proteins, cyclin D1 and CDK4, was assessed by RT-PCR, immunohistochemistry and western blot analysis. Key results: ATRA ameliorated sodium arsenite-induced decrease in circulating estradiol and gonadotropin levels in a dose- and time-dependent manner, along with recovery of luminal epithelial cells and endometrial glands. Concomitant up regulation of ERα, VEGF, cyclin D1, CDK4 and Ki-67 was also observed to be more prominent for ATRA-treated rats as compared to the rats that were allowed to recover naturally for 56 days. Conclusions and implications: Collectively, the results reveal that ATRA reverses arsenic-induced disruption of the circulating levels of gonadotropins and estradiol, and degeneration of luminal epithelial cells and endometrial glands of the rat uterus, indicating resumption of their functional status. Since structural and functional maintenance of the pubertal uterus is under the influence of estradiol, ATRA consequently up regulated the estrogen receptor and resumed cellular proliferation, possibly by an antioxidant therapeutic approach against arsenic toxicity. Highlights: ► Arsenic disrupts the uterine histology and

  14. Retinoic acid morpholine amide (RAMA) inhibits expression of Fas ligand through EP1 receptor in colon cancer cells.

    Science.gov (United States)

    Chen, Shao-Xuan; Du, Shi-Yu; Wang, Yun-Ting; Zhao, Hong-Chuan; Zhang, Yan-Li; Yao, Li

    2016-01-01

    Among the members of tumour necrosis factor family Fas ligand on binding to its receptor strongly induces apoptosis of tumour-infiltrating lymphocytes (TIL). Thus, FasL acts as an inhibitor of anti-tumour immune response. The present study demonstrates that retinoic acid morpholine amide (RAMA) significantly suppresses FasL expression in colon cancer cells in a dose- and time-dependent manner. The suppression of FasL mRNA and proteins was significant at a concentration of 30 μM after 48 h in CLT85 and HT26 colon cancer cells. There was around 2.6- and 3.2-fold decrease in FasL mRNA after incubation with 30 μM of RAMA in CLT85 cells and HT26 cells, respectively. The results from Western blot showed a decrease in FasL mRNA and protein expression in both CLT85 and HT26 cells after suppression of cyclooxygenase (COX)-2 and COX-1 by RNAi. However, when COX-2-specific silencer RNA (siCOX-2)- and siCOX-1-treated CLT85 and HT26 cells were exposed to RAMA, inhibition of FasL expression was further suppressed. The siCOX-2-treated CLT85 and HT26 cells on exposure to RAMA showed ∼87 and ∼54 % reduction in FasL mRNA, respectively. Co-culture of Jurkat T cells with RAMA-treated HT26 and CLT85 cells decreased the viability of Jurkat T cells by only 2 and 4.3 %, respectively, compared to 19.5 and 37.3 % in control HT26 and CLT85 cells. The results from real-time reverse transcription polymerase chain reaction (RT-PCR) and immunoblotting showed that suppression of EP1 prevented RAMA-induced FasL suppression in CLT85 cells at both the mRNA and protein levels. Thus, RAMA can be a potent therapeutic agent for the treatment of colon tumours.

  15. Retinoic acid-independent expression of Meis2 during autopod patterning in the developing bat and mouse limb.

    Science.gov (United States)

    Mason, Mandy K; Hockman, Dorit; Curry, Lyle; Cunningham, Thomas J; Duester, Gregg; Logan, Malcolm; Jacobs, David S; Illing, Nicola

    2015-01-01

    The bat has strikingly divergent forelimbs (long digits supporting wing membranes) and hindlimbs (short, typically free digits) due to the distinct requirements of both aerial and terrestrial locomotion. During embryonic development, the morphology of the bat forelimb deviates dramatically from the mouse and chick, offering an alternative paradigm for identifying genes that play an important role in limb patterning. Using transcriptome analysis of developing Natal long-fingered bat (Miniopterus natalensis) fore- and hindlimbs, we demonstrate that the transcription factor Meis2 has a significantly higher expression in bat forelimb autopods compared to hindlimbs. Validation by reverse transcriptase and quantitative polymerase chain reaction (RT-qPCR) and whole mount in situ hybridisation shows that Meis2, conventionally known as a marker of the early proximal limb bud, is upregulated in the bat forelimb autopod from CS16. Meis2 expression is localised to the expanding interdigital webbing and the membranes linking the wing to the hindlimb and tail. In mice, Meis2 is also expressed in the interdigital region prior to tissue regression. This interdigital Meis2 expression is not activated by retinoic acid (RA) signalling as it is present in the retained interdigital tissue of Rdh10 (trex/trex) mice, which lack RA. Additionally, genes encoding RA-synthesising enzymes, Rdh10 and Aldh1a2, and the RA nuclear receptor Rarβ are robustly expressed in bat fore- and hindlimb interdigital tissues indicating that the mechanism that retains interdigital tissue in bats also occurs independently of RA signalling. Mammalian interdigital Meis2 expression, and upregulation in the interdigital webbing of bat wings, suggests an important role for Meis2 in autopod development. Interdigital Meis2 expression is RA-independent, and retention of interdigital webbing in bat wings is not due to the suppression of RA-induced cell death. Rather, RA signalling may play a role in the thinning

  16. All-trans retinoic acid protects against arsenic-induced uterine toxicity in female Sprague-Dawley rats

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, A.; Chatterji, U., E-mail: urmichatterji@gmail.com

    2011-12-15

    Background and purpose: Arsenic exposure frequently leads to reproductive failures by disrupting the rat uterine histology, hormonal integrity and estrogen signaling components of the rat uterus, possibly by generating reactive oxygen species. All-trans retinoic acid (ATRA) was assessed as a prospective therapeutic agent for reversing reproductive disorders. Experimental approach: Rats exposed to arsenic for 28 days were allowed to either recover naturally or were treated simultaneously with ATRA for 28 days or treatment continued up to 56 days. Hematoxylin-eosin double staining was used to evaluate changes in the uterine histology. Serum gonadotropins and estradiol were assayed by ELISA. Expression of the estrogen receptor (ER{alpha}), an estrogen responsive gene vascular endothelial growth factor (VEGF), and cell cycle regulatory proteins, cyclin D1 and CDK4, was assessed by RT-PCR, immunohistochemistry and western blot analysis. Key results: ATRA ameliorated sodium arsenite-induced decrease in circulating estradiol and gonadotropin levels in a dose- and time-dependent manner, along with recovery of luminal epithelial cells and endometrial glands. Concomitant up regulation of ER{alpha}, VEGF, cyclin D1, CDK4 and Ki-67 was also observed to be more prominent for ATRA-treated rats as compared to the rats that were allowed to recover naturally for 56 days. Conclusions and implications: Collectively, the results reveal that ATRA reverses arsenic-induced disruption of the circulating levels of gonadotropins and estradiol, and degeneration of luminal epithelial cells and endometrial glands of the rat uterus, indicating resumption of their functional status. Since structural and functional maintenance of the pubertal uterus is under the influence of estradiol, ATRA consequently up regulated the estrogen receptor and resumed cellular proliferation, possibly by an antioxidant therapeutic approach against arsenic toxicity. Highlights: Black-Right-Pointing-Pointer Arsenic

  17. Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

    International Nuclear Information System (INIS)

    Kojima, Hiroyuki; Takeda, Yukimasa; Muromoto, Ryuta; Takahashi, Miki; Hirao, Toru; Takeuchi, Shinji; Jetten, Anton M.; Matsuda, Tadashi

    2015-01-01

    Highlights: • Nuclear receptors, RORα and RORγ, are key regulators of Th17 cell differentiation. • Isoflavones have RORα/γ agonistic activities. • Isoflavones enhance the interaction of RORα/γ with co-activator. • These compounds enhance the expression of Il17a mRNA in mouse EL4 cells. • Dietary isoflavones can act as modulators of Il17a expression via RORα/γ. - Abstract: The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. In this study, we investigated the effects of isoflavones on RORα/γ activity and the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In doxycycline-inducible CHO stable cell lines, we found that four isoflavones, biochanin A (BA), genistein, formononetin, and daidzein, enhanced RORα- or RORγ-mediated transcriptional activity in a dose-dependent manner. In an activation assay of the Il17a promoter using Jurkat cells, these compounds enhanced the RORα- or RORγ-mediated activation of the Il17a promoter at concentrations of 1 × 10 −6 M to 1 × 10 −5 M. In mammalian two-hybrid assays, the four isoflavones enhanced the interaction between the RORα- or RORγ-ligand binding domain and the co-activator LXXLL peptide in a dose-dependent manner. In addition, these isoflavones potently enhanced Il17a mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin, but showed slight enhancement of Il17a gene expression in RORα/γ-knockdown EL4 cells. Immunoprecipitation and immunoblotting assays also revealed that BA enhanced the interaction between RORγt and SRC-1, which is a co-activator for nuclear receptors. Taken together, these results suggest that the isoflavones have the ability to enhance IL-17 gene expression by stabilizing the interactions between RORα/γ and co-activators. This also

  18. Exogenous retinoic acid induces digit reduction in opossums (Monodelphis domestica) by disrupting cell death and proliferation, and apical ectodermal ridge and zone of polarizing activity function.

    Science.gov (United States)

    Molineaux, Anna C; Maier, Jennifer A; Schecker, Teresa; Sears, Karen E

    2015-03-01

    Retinoic acid (RA) is a vitamin A derivative. Exposure to exogenous RA generates congenital limb malformations (CLMs) in species from frogs to humans. These CLMs include but are not limited to oligodactyly and long-bone hypoplasia. The processes by which exogenous RA induces CLMs in mammals have been best studied in mouse, but as of yet remain unresolved. We investigated the impact of exogenous RA on the cellular and molecular development of the limbs of a nonrodent model mammal, the opossum Monodelphis domestica. Opossums exposed to exogenous retinoic acid display CLMs including oligodactly, and results are consistent with opossum development being more susceptible to RA-induced disruptions than mouse development. Exposure of developing opossums to exogenous RA leads to an increase in cell death in the limb mesenchyme that is most pronounced in the zone of polarizing activity, and a reduction in cell proliferation throughout the limb mesenchyme. Exogenous RA also disrupts the expression of Shh in the zone of polarizing activity, and Fgf8 in the apical ectodermal ridge, and other genes with roles in the regulation of limb development and cell death. Results are consistent with RA inducing CLMs in opossum limbs by disrupting the functions of the apical ectodermal ridge and zone of polarizing activity, and driving an increase in cell death and reduction of cell proliferation in the mesenchyme of the developing limb. © 2015 Wiley Periodicals, Inc.

  19. Nanosecond pulsed electric field suppresses development of eyes and germ cells through blocking synthesis of retinoic acid in Medaka (Oryzias latipes.

    Directory of Open Access Journals (Sweden)

    Eri Shiraishi

    Full Text Available Application of nanosecond pulsed electric fields (nsPEFs has attracted rising attention in various scientific fields including medical, pharmacological, and biological sciences, although its effects and molecular mechanisms leading to the effects remain poorly understood. Here, we show that a single, high-intensity (10-30 kV/cm, 60-ns PEF exposure affects gene expression and impairs development of eyes and germ cells in medaka (Oryzias latipes. Exposure of early blastula stage embryos to nsPEF down-regulated the expression of several transcription factors which are essential for eye development, causing abnormal eye formation. Moreover, the majority of the exposed genetic female embryos showed a fewer number of germ cells similar to that of the control (unexposed genetic male at 9 days post-fertilization (dpf. However, all-trans retinoic acid (atRA treatment following the exposure rescued proliferation of germ cells and resumption of normal eye development, suggesting that the phenotypes induced by nsPEF are caused by a decrease of retinoic acid levels. These results confirm that nsPEFs induce novel effects during embryogenesis in medaka.

  20. A new module in neural differentiation control: two microRNAs upregulated by retinoic acid, miR-9 and -103, target the differentiation inhibitor ID2.

    Directory of Open Access Journals (Sweden)

    Daniela Annibali

    Full Text Available The transcription factor ID2 is an important repressor of neural differentiation strongly implicated in nervous system cancers. MicroRNAs (miRNAs are increasingly involved in differentiation control and cancer development. Here we show that two miRNAs upregulated on differentiation of neuroblastoma cells--miR-9 and miR-103--restrain ID2 expression by directly targeting the coding sequence and 3' untranslated region of the ID2 encoding messenger RNA, respectively. Notably, the two miRNAs show an inverse correlation with ID2 during neuroblastoma cell differentiation induced by retinoic acid. Overexpression of miR-9 and miR-103 in neuroblastoma cells reduces proliferation and promotes differentiation, as it was shown to occur upon ID2 inhibition. Conversely, an ID2 mutant that cannot be targeted by either miRNA prevents retinoic acid-induced differentiation more efficient than wild-type ID2. These findings reveal a new regulatory module involving two microRNAs upregulated during neural differentiation that directly target expression of the key differentiation inhibitor ID2, suggesting that its alteration may be involved in neural cancer development.

  1. Urocanic acid isomers are good hydroxyl radical scavengers: a comparative study with structural analogues and with uric acid

    NARCIS (Netherlands)

    Kammeyer, A.; Eggelte, T. A.; Bos, J. D.; Teunissen, M. B.

    1999-01-01

    UV-exposure of the epidermis leads to the isomerisation of trans-UCA into cis-UCA as well as to the generation of hydroxyl radicals. This study shows by means of the deoxyribose degradation test that UCA isomers are more powerful hydroxyl radical scavengers than the other 4-(5-)substituted imidazole

  2. Hif1α down-regulation is associated with transposition of great arteries in mice treated with a retinoic acid antagonist

    Directory of Open Access Journals (Sweden)

    Amati Francesca

    2010-09-01

    Full Text Available Abstract Background Congenital heart defect (CHD account for 25% of all human congenital abnormalities. However, very few CHD-causing genes have been identified so far. A promising approach for the identification of essential cardiac regulators whose mutations may be linked to human CHD, is the molecular and genetic analysis of heart development. With the use of a triple retinoic acid competitive antagonist (BMS189453 we previously developed a mouse model of congenital heart defects (81%, thymic abnormalities (98% and neural tube defects (20%. D-TGA (D-transposition of great arteries was the most prevalent cardiac defect observed (61%. Recently we were able to partially rescue this abnormal phenotype (CHD were reduced to 64.8%, p = 0.05, by oral administration of folic acid (FA. Now we have performed a microarray analysis in our mouse models to discover genes/transcripts potentially implicated in the pathogenesis of this CHD. Results We analysed mouse embryos (8.5 dpc treated with BMS189453 alone and with BMS189453 plus folic acid (FA by microarray and qRT-PCR. By selecting a fold change (FC ≥ ± 1.5, we detected 447 genes that were differentially expressed in BMS-treated embryos vs. untreated control embryos, while 239 genes were differentially expressed in BMS-treated embryos whose mothers had also received FA supplementation vs. BMS-treated embryos. On the basis of microarray and qRT-PCR results, we further analysed the Hif1α gene. In fact Hif1α is down-regulated in BMS-treated embryos vs. untreated controls (FCmicro = -1.79; FCqRT-PCR = -1.76; p = 0.005 and its expression level is increased in BMS+FA-treated embryos compared to BMS-treated embryos (FCmicro = +1.17; FCqRT-PCR = +1.28: p = 0.005. Immunofluorescence experiments confirmed the under-expression of Hif1α protein in BMS-treated embryos compared to untreated and BMS+FA-treated embryos and, moreover, we demonstrated that at 8.5 dpc, Hif1α is mainly expressed in the embryo heart

  3. Frying stability of high oleic sunflower oils as affected by composition of tocopherol isomers and linoleic acid content.

    Science.gov (United States)

    Aladedunye, Felix; Przybylski, Roman

    2013-12-01

    The influence of linoleic acid content and tocopherol isomeric composition on the frying performance of high oleic sunflower oil was evaluated during a 14-day restaurant style frying operation. At equal linoleic acid content, no significant difference was observed between high oleic sunflower oil containing only α-tocopherol and the sample containing a mixture of α-, γ-, and δ-isomers as measured by the amount of total polar components, oligomers, anisidine value, and free fatty acids. On the contrary, at similar tocopherol isomeric composition, high oleic sunflower oil containing lower amount of linoleic acid showed superior frying stability compared to the sample with a higher content of linoleic acid, suggesting that the frying performance of high oleic sunflower oil is dictated primarily by the level of linoleic acid, with the tocopherol isomeric composition of the oil having no significant influence. In all oil samples, the loss of γ-tocopherol was higher than the corresponding loss of α-tocopherol. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Dose-dependent stimulation of hepatic retinoic acid hydroxylation/oxidation and glucuronidation in brook trout, Salvelinus fontinalis, after exposure to 3,3{prime}, 4,4{prime}-tetrachlorobiphenyl

    Energy Technology Data Exchange (ETDEWEB)

    Boyer, P.M.; Ndayibagira, A.; Spear, P.A.

    2000-03-01

    Extremely low stores of vitamin A have been reported in fish and birds inhabiting regions contaminated by coplanar polychlorinated biphenyls (PCBs) and other organochlorines, suggesting many possible effects on retinoid biochemical pathways. Metabolic imbalances associated with biologically active retinoids (e.g., retinoic acid) could be associated with tetratogenesis, edema, growth inhibition, reproductive impairment, immunosuppression, and susceptibility to cancer. Sexually mature brook trout were injected imtraperitoneally with the coplanar PCB 3,3{prime}, 4,4{prime}-tetrachlorobiphenyl (TCBP) and again 4 weeks later. At 8 weeks, retinoic acid metabolism was measured in liver microsomes. To the authors' knowledge, retinoic acid conjugation by UDP-glucuronyltransferase is described here for the first time in fish. A substantial rate of glucuronidation was detected in the microsomes from control brook trout, which tended to increase over the dose range of TCBP. Glucuronidation was significantly greater in fish receiving the 10 {micro}g/g body weight dose level. Metabolism through the cytochrome P450 system was also dose-dependent, resulting in significantly greater production of 4-hydroxyretinoic acid at the 10 {micro}g/g dose level. In contrast, subsequent oxidation to 4-oxo-retinoic acid was greatest at the 1 {micro}g/g dose level and did not increase further at higher doses. Liver stores of dehydroretinyl palmitate/oleate were significantly decreased at the 5 and 10 {micro}g/g dose levels.

  5. Structural analysis of site-directed mutants of cellular retinoic acid-binding protein II addresses the relationship between structural integrity and ligand binding

    International Nuclear Information System (INIS)

    Vaezeslami, Soheila; Jia, Xiaofei; Vasileiou, Chrysoula; Borhan, Babak; Geiger, James H.

    2008-01-01

    A water network stabilizes the structure of cellular retionic acid binding protein II. The structural integrity of cellular retinoic acid-binding protein II (CRABPII) has been investigated using the crystal structures of CRABPII mutants. The overall fold was well maintained by these CRABPII mutants, each of which carried multiple different mutations. A water-mediated network is found to be present across the large binding cavity, extending from Arg111 deep inside the cavity to the α2 helix at its entrance. This chain of interactions acts as a ‘pillar’ that maintains the integrity of the protein. The disruption of the water network upon loss of Arg111 leads to decreased structural integrity of the protein. A water-mediated network can be re-established by introducing the hydrophilic Glu121 inside the cavity, which results in a rigid protein with the α2 helix adopting an altered conformation compared with wild-type CRABPII

  6. Apoptosis- and differentiation-inducing activities of jacaric acid, a conjugated linolenic acid isomer, on human eosinophilic leukemia EoL-1 cells.

    Science.gov (United States)

    Liu, Wai-Nam; Leung, Kwok-Nam

    2014-11-01

    Conjugated linolenic acids (CLNAs) are a group of naturally occurring positional and geometrical isomers of the C18 polyunsaturated essential fatty acid, linolenic acid (LNA), with three conjugated double bonds (C18:3). Although previous research has demonstrated the growth-inhibitory effects of CLNA on a wide variety of cancer cell lines in vitro, their action mechanisms and therapeutic potential on human myeloid leukemia cells remain poorly understood. In the present study, we found that jacaric acid (8Z,10E,12Z-octadecatrienoic acid), a CLNA isomer which is present in jacaranda seed oil, inhibited the in vitro growth of human eosinophilic leukemia EoL-1 cells in a time- and concentration-dependent manner. Mechanistic studies showed that jacaric acid triggered cell cycle arrest of EoL-1 cells at the G0/G1 phase and induced apoptosis of the EoL-1 cells, as measured by the Cell Death Detection ELISAPLUS kit, Annexin V assay and JC-1 dye staining. Notably, the jacaric acid-treated EoL-1 cells also underwent differentiation as revealed by morphological and phenotypic analysis. Collectively, our results demonstrated the capability of jacaric acid to inhibit the growth of EoL-1 cells in vitro through triggering cell cycle arrest and by inducing apoptosis and differentiation of the leukemia cells. Therefore, jacaric acid might be developed as a potential candidate for the treatment of certain forms of myeloid leukemia with minimal toxicity and few side effects.

  7. DNA vaccination with all-trans retinoic acid treatment induces long-term survival and elicits specific immune responses requiring CD4+ and CD8+ T-cell activation in an acute promyelocytic leukemia mouse model

    Czech Academy of Sciences Publication Activity Database

    Furugaki, K.; Pokorná, Kateřina; le Pogam, C.; Aoki, M.; Reboul, M.; Bajzik, V.; Krief, P.; Janin, A.; Noguera, M.-E.; West, R.; Charron, D.; Chomienne, C.; Pla, M.; Moins-Teisserenc, H.; Padua, R.A.

    2010-01-01

    Roč. 115, č. 3 (2010), s. 653-656 ISSN 0006-4971 Grant - others:GA UK(CZ) 94308 Institutional research plan: CEZ:AV0Z50520514 Keywords : all-trans retinoic acid * DNA vaccination * protective immunity Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 10.558, year: 2010

  8. Retinoic Acid for High-risk Neuroblastoma Patients after Autologous Stem Cell Transplantation - Cochrane Review Retinsäure nach erfolgter autologer Stammzelltransplantation bei Hochrisiko-Patienten mit Neuroblastom - Cochrane Review

    NARCIS (Netherlands)

    Peinemann, F.; van Dalen, E. C.; Berthold, F.

    2016-01-01

    Neuroblastoma is a rare malignant disease and patients with high-risk neuroblastoma have a poor prognosis. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome. The objective was to evaluate effects of

  9. Preparation of New 2,3-Diphenylpropenoic Acid Esters – Good Yields Even for the More Hindered Z Isomers

    Directory of Open Access Journals (Sweden)

    István Pálinkó

    2004-03-01

    Full Text Available The potassium salt of E- and Z-2,3-diphenylpropenoic acids prepared in situ could be esterified efficiently in DMSO with the appropriate alkyl halides at room temperature. In this way 10 previously undescribed esters of these acids were synthesised and characterised. Excellent yields were observed for most of the E isomers and the more hindered Z esters were also obtained in good yields, far better than those obtained applying the classical acid-catalysed esterification reaction.

  10. Ex vivo culture of human fetal gonads: manipulation of meiosis signalling by retinoic acid treatment disrupts testis development.

    Science.gov (United States)

    Jørgensen, A; Nielsen, J E; Perlman, S; Lundvall, L; Mitchell, R T; Juul, A; Rajpert-De Meyts, E

    2015-10-01

    What are the effects of experimentally manipulating meiosis signalling by addition of retinoic acid (RA) in cultured human fetal gonads? RA-treatment accelerated meiotic entry in cultured fetal ovary samples, while addition of RA resulted in a dysgenetic gonadal phenotype in fetal testis cultures. One of the first manifestations of sex differentiation is the initiation of meiosis in fetal ovaries. In contrast, meiotic entry is actively prevented in the fetal testis at this developmental time-point. It has previously been shown that RA-treatment mediates initiation of meiosis in human fetal ovary ex vivo. This was a controlled ex vivo study of human fetal gonads treated with RA in 'hanging-drop' tissue cultures. The applied experimental set-up preserves germ cell-somatic niche interactions and the investigated outcomes included tissue integrity and morphology, cell proliferation and survival and the expression of markers of meiosis and sex differentiation. Tissue from 24 first trimester human fetuses was included in this study, all from elective terminations at gestational week (GW) 7-12. Gonads were cultured for 2 weeks with and without addition of 1 µM RA. Samples were subsequently formalin-fixed and investigated by immunohistochemistry and cell counting. Proteins investigated and quantified included; octamer-binding transcription factor 4 (OCT4), transcription factor AP-2 gamma (AP2γ) (embryonic germ cell markers), SRY (sex determining region Y)-box 9 (SOX9), anti-Müllerian hormone (AMH) (immature Sertoli cell markers), COUP transcription factor 2 (COUP-TFII) (marker of interstitial cells), forkhead box L2 (FOXL2) (granulosa cell marker), H2A histone family, member X (γH2AX) (meiosis marker), doublesex and mab-3 related transcription factor 1 (DMRT1) (meiosis regulator), cleaved poly ADP ribose polymerase (PARP), cleaved Caspase 3 (apoptosis markers) and Ki-67 antigen (Ki-67) (proliferation marker). Also, proliferation was determined using a 5'-bromo-2

  11. Effect of all-trans retinoic acid combined with trichostatin A on the nude mice bearing human follicular thyroid carcinoma

    International Nuclear Information System (INIS)

    Yu Libo; Yuan Gengbiao

    2011-01-01

    Objective: To study the changes of iodine uptake of the follicular thyroid carcinoma cell line (FTC-133) and nude mice bearing human follicular thyroid carcinoma after the induction with all-trans retinoic acid (ATRA), trichostatin A (TSA) or ATRA combined with TSA. Methods: After the induction with ATRA, TSA, or ATRA combined with TSA in different concentrations for 96 h, the iodine uptake of FTC-133 cells was observed. The concentrations for different groups were as follows: ATRA 1.0 ×10 -6 mol/L(A low group), ATRA 1.0 × 10 -4 mol/L (A high group), TSA 1.65 ×10 -7 mol/L (T group), A low + T group, A high + T group and ethanol (control group). Cell quantities and morphology were observed by HE staining. FTC-133 cells were subcutaneously injected into nude mice. Twelve nude mice were randomly divided into 4 groups after tumor formation: ATRA group (2 mg/kg, intragastric administration), TSA group (10 mg/kg, intraperitoneal injection), combined therapy group (ATRA + TSA, the same doses as above) and saline control group (10 ml/kg, intragastric and intraperitoneal administration, respectively). Drugs were administered to the tumor-bearing mice according to the mouse body mass daily. At the 22nd day, the tumor-bearing mice were injected with 37 MBq 131 I intraperitoneally. The biodistribution of 131 I and gamma imaging were performed at 4, 6, 12 and 24 h after the injection respectively. Histopathological examinations of the tumor samples were taken after imaging completion. The results were analyzed by analysis of variance (ANOVA) with SPSS 13.0. Results: The cellular iodine uptake were (23 885 ± 616.0) and (13 849 ±728.2) counts · min -1 · 10 -6 cells in the A low + T group and A high + T group respectively, and the data were (985 ± 84.2) - (17 600 ± 782.7) counts · min -1 · 10 -6 in the other groups (F=600.879, P<0.001). The % ID/g of tumor at 6 h was 6.17 ±0.46 in the combined group and it increased to 9.34 ±0.61 at 12 h and 11.19 ± 0.98 at 24 h. The

  12. A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene.

    Science.gov (United States)

    Lee, M O; Liu, Y; Zhang, X K

    1995-08-01

    The lactoferrin gene is highly expressed in many different tissues, and its expression is controlled by different regulators. In this report, we have defined a retinoic acid response element (RARE) in the 5'-flanking region of the lactoferrin gene promoter. The lactoferrin-RARE is composed of two AGGTCA-like motifs arranged as a direct repeat with 1-bp spacing (DR-1). A gel retardation assay demonstrated that it bound strongly with retinoid X receptor (RXR) homodimers and RXR-retinoic acid receptor (RAR) heterodimers as well as chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan receptor. In CV-1 cells, the lactoferrin-RARE linked with a heterologous thymidine kinase promoter was strongly activated by RXR homodimers in response to 9-cis-retinoic acid (9-cis-RA) but not to all-trans-RA. When the COUP-TF orphan receptor was cotransfected, the 9-cis-RA-induced RXR homodimer activity was strongly repressed. A unique feature of the lactoferrin-RARE is that it has an AGGTCA-like motif in common with an estrogen-responsive element (ERE). The composite RARE/ERE contributes to the functional interaction between retinoid receptors and the estrogen receptor (ER) and their ligands. In CV-1 cells, cotransfection of the retinoid and estrogen receptors led to mutual inhibition of the other's activity, while an RA-dependent inhibition of ER activity was observed in breast cancer cells. Furthermore, the lactoferrin-RARE/ERE showed differential transactivation activity in different cell types. RAs could activate the lactoferrin-RARE/ERE in human leukemia HL-60 cells and U937 cells but not in human breast cancer cells. By gel retardation analyses, we demonstrated that strong binding of the endogenous COUP-TF in breast cancer cells to the composite element contributed to diminished RA response in these cells. Thus, the lactoferrin-RARE/ERE functions as a signaling switch module that mediates multihormonal responsiveness in the regulation of lactoferrin gene

  13. Effects of cis-9, trans-11 and trans-10, cis-12 conjugated linoleic acid (CLA) isomers on immune function in healthy men

    NARCIS (Netherlands)

    Albers, R.; Wielen, R.P.J. van der; Brink, E.J.; Hendriks, H.F.J.; Dorovska-Taran, V.N.; Mohede, I.C.M.

    2003-01-01

    Objectives: To study the effects of two different mixtures of the main conjugated linoleic acid (CLA) isomers cis-9, trans-11 CLA and trans-10, cis-12 CLA on human immune function. Design: Double-blind, randomized, parallel, reference-controlled intervention study. Subjects and intervention:

  14. Structural Elucidation of Z- and E- Isomers of 5-Alkyl-4-ethoxycarbonyl-5-(4`-chlorophenyl-3-oxa-4-pentenoic Acids

    Directory of Open Access Journals (Sweden)

    H. M. F. Madkour

    2000-05-01

    Full Text Available Z- and E-isomers of 5-alkyl-4-ethoxycarbonyl-5-(4`-chlorophenyl-3-oxa-4-pentenoic acids were prepared via the condensation of p-chloroacetophenone and/or pchloropropiophenone with diethyl-2,2`-oxydiacetate in the presence of sodium hydride as a basic catalyst. The Z-isomers of 2a and 2b were found to be predominant. The behaviour of the corresponding anhydrides towards the action of hydrazine, phenylhydrazine, primary aromatic amines, hydrocarbons and ethanolysis has also been investigated. The structures and configurations of the products have been elucidated by chemical and spectroscopic means.

  15. Eosinophils from Murine Lamina Propria Induce Differentiation of Naïve T Cells into Regulatory T Cells via TGF-β1 and Retinoic Acid.

    Directory of Open Access Journals (Sweden)

    Hong-Hu Chen

    Full Text Available Treg cells play a crucial role in immune tolerance, but mechanisms that induce Treg cells are poorly understood. We here have described eosinophils in lamina propria (LP that displayed high aldehyde dehydrogenase (ALDH activity, a rate-limiting step during all-trans retinoic acid (ATRA synthesis, and expressed TGF-β1 mRNA and high levels of ATRA. Co-incubation assay confirmed that LP eosinophils induced the differentiation of naïve T cells into Treg cells. Differentiation promoted by LP eosinophils were inhibited by blocked either TGF-β1 or ATRA. Peripheral blood (PB eosinophils did not produce ATRA and could not induce Treg differentiation. These data identifies LP eosinophils as effective inducers of Treg cell differentiation through a mechanism dependent on TGF-β1 and ATRA.

  16. Morphogenetic and neuronal characterization of human neuroblastoma multicellular spheroids cultured under undifferentiated and all-trans-retinoic acid-differentiated conditions

    Directory of Open Access Journals (Sweden)

    Gwon-Soo Jung

    2013-05-01

    Full Text Available In this study, we aimed to compare the morphogenetic andneuronal characteristics between monolayer cells andspheroids. For this purpose, we established spheroid formationby growing SH-SY5Y cells on the hydrophobic surfaces ofthermally-collapsed elastin-like polypeptide. After 4 days ofculture, the relative proliferation of the cells within spheroidswas approximately 92% of the values for monolayer cultures.As measured by quantitative assays for mRNA and proteinexpressions, the production of synaptophysin and neuronspecificenolase (NSE as well as the contents of cell adhesionmolecules (CAMs and extracellular matrix (ECM proteins aremuch higher in spheroids than in monolayer cells. Under theall-trans-retinoic acid (RA-induced differentiation condition,spheroids extended neurites and further up-regulated theexpression of synaptophysin, NSE, CAMs, and ECM proteins.Our data indicate that RA-differentiated SH-SY5Y neurospheroidsare functionally matured neuronal architectures. [BMBReports 2013; 46(5: 276-281

  17. Nicotine-mediated suppression of the retinoic acid metabolizing enzyme CYP26A1 limits the oncogenic potential of breast cancer.

    Science.gov (United States)

    Osanai, Makoto; Lee, Gang-Hong

    2011-06-01

    Tobacco smoke influences cancer development in tissues that are not directly exposed, and epidemiological studies have indicated that smoking women might experience decreased risk of breast cancer as a result of antiestrogenic effects. However, it remains to be clarified whether nicotine, one of the major addictive and best-investigated constituents of tobacco smoke, has any effect on breast cancer. Our recent work demonstrated that the retinoic acid metabolizing enzyme CYP26A1 enhances oncogenic and cell survival properties of breast carcinoma cells, implying a role as an oncogene. Here, we present evidence that nicotine significantly suppresses constitutive expression of CYP26A1, and that cells treated with nicotine exhibit enhanced sensitivity to apoptosis. In addition, nicotine may inhibit anchorage independent growth, cellular invasiveness and motility. These data show that nicotine can limit CYP26A1-mediated oncogenic characteristics, and suggest mechanisms by which nicotine might inhibit breast cancer development. © 2011 Japanese Cancer Association.

  18. Retinoic acid signalling is required for the efficient differentiation of CD4+ T cells into pathogenic effector cells during the development of intestinal inflammation

    DEFF Research Database (Denmark)

    Rivollier, Aymeric Marie Christian; Pool, Lieneke; Frising, Ulrika

    Epidemiological studies of vitamin A-deficient populations have illustrated the importance of the vitamin A metabolite retinoic acid (RA) in mucosal immune responses. However, RA seems to be a double-edge sword in CD4+ T cell biology. While it sustains the development of foxp3+ regulatory T cells......, it was also very recently reported to be essential for the stability of the Th1 lineage and to prevent transition to a Th17 program. Here we explored the role of RA signalling in CD4+ T cells during the development of intestinal inflammation in the T cell transfer colitis model. We found that RA signalling......-deficient CD4+ T cells are less potent at inducing intestinal inflammation compared to their RA signalling-competent counterparts and exhibit a differentiation skewing towards more IFNγ- IL-17+, IL-17+IFNγ+ and foxp3+ cells, while their capacity to differentiate into IL-17-IFNγ+ Th1 cells is compromised...

  19. Gas chromatography and silver-ion high-performance liquid chromatography analysis of conjugated linoleic acid isomers in free fatty acid form using sulphuric acid in methanol as catalyst.

    Science.gov (United States)

    Luna, Pilar; Juárez, Manuela; de la Fuente, Miguel Angel

    2008-09-12

    This study used GC and silver-ion HPLC to examine the effects of temperature and time on methylation of individual and mixtures of conjugated linoleic acid (CLA) isomers in free fatty acid form using sulphuric acid as catalyst. In the conditions tested (temperatures between 20 and 50 degrees C and times between 10 and 60 min) methylation was complete while avoiding isomerization of conjugated dienes and the formation of artefacts that could interfere with chromatographic determinations. An analytical method using solvent extraction of the lipids followed by selective elution of the free fatty acids from aminopropyl bonded phase columns and methylation with H(2)SO(4) in mild conditions was then applied to determine the CLA isomers in free fatty acid form in rumen fluid, and the results were evaluated.

  20. A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signaling pathway and causes Lenz microphthalmia syndrome

    Science.gov (United States)

    Esmailpour, Taraneh; Riazifar, Hamidreza; Liu, Linan; Donkervoort, Sandra; Huang, Vincent H; Madaan, Shreshtha; Shoucri, Bassem M; Busch, Anke; Wu, Jie; Towbin, Alexander; Chadwick, Robert B; Sequeira, Adolfo; Vawter, Marquis P; Sun, Guoli; Johnston, Jennifer J; Biesecker, Leslie G; Kawaguchi, Riki; Sun, Hui; Kimonis, Virginia; Huang, Taosheng

    2014-01-01

    Introduction Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. Methods and results Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. Conclusions We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway. PMID:24431331

  1. Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders.

    Science.gov (United States)

    Niewiadomska-Cimicka, Anna; Krzyżosiak, Agnieszka; Ye, Tao; Podleśny-Drabiniok, Anna; Dembélé, Doulaye; Dollé, Pascal; Krężel, Wojciech

    2017-07-01

    Retinoic acid (RA) signaling through retinoic acid receptors (RARs), known for its multiple developmental functions, emerged more recently as an important regulator of adult brain physiology. How RAR-mediated regulation is achieved is poorly known, partly due to the paucity of information on critical target genes in the brain. Also, it is not clear how reduced RA signaling may contribute to pathophysiology of diverse neuropsychiatric disorders. We report the first genome-wide analysis of RAR transcriptional targets in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing and transcriptomic analysis of RARβ-null mutant mice, we identified genomic targets of RARβ in the striatum. Characterization of RARβ transcriptional targets in the mouse striatum points to mechanisms through which RAR may control brain functions and display neuroprotective activity. Namely, our data indicate with statistical significance (FDR 0.1) a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein coupled receptor (p = 5.0e -5 ), cAMP (p = 4.5e -4 ), and calcium signaling (p = 3.4e -3 ). Many identified RARβ target genes related to these pathways have been implicated in Alzheimer's, Parkinson's, and Huntington's disease (HD), raising the possibility that compromised RA signaling in the striatum may be a mechanistic link explaining the similar affective and cognitive symptoms in these diseases. The RARβ transcriptional targets were particularly enriched for transcripts affected in HD. Using the R6/2 transgenic mouse model of HD, we show that partial sequestration of RARβ in huntingtin protein aggregates may account for reduced RA signaling reported in HD.

  2. Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis.

    Science.gov (United States)

    Wieser, Friedrich; Wu, Juanjuan; Shen, Zhaoju; Taylor, Robert N; Sidell, Neil

    2012-06-01

    To determine the effects of all-trans-retinoic acid (RA) on establishment and growth of endometrial lesions, peritoneal interleukin-6 (IL-6) and macrophage chemotactic factor-1 (MCP-1) concentrations, and CD38, CD11b, and F4/80 expression on peritoneal macrophages in an immunocompetent mouse model of endometriosis. Experimental transplantation study using mice. Academic medical center. C57BL/6 recipient mice and syngeneic green fluorescent protein transgenic (GFP+) mice. Recipient mice were inoculated with GFP+ minced uterine tissue to induce endometriosis and treated with RA (400 nmol/day) or vehicle for 17 days (3 days before to 14 days after tissue injection). Total number of GFP+ implants in recipient mice, number of implants showing visible blood vessels, total volume of established lesions per mouse, concentrations of IL-6 and MCP-1 in peritoneal fluid, and expression of CD11b, F4/80, and CD38 on peritoneal macrophages. Retinoic acid treatment for 17 days reduced the number of implants versus controls and decreased the frequency of lesions with vessels. Peritoneal washings in RA-treated animals had lower concentrations of IL-6 and MCP-1 than controls 3 days after endometrial inoculation and lower levels of IL-6 on day 14 after inoculation. Concomitant with these effects on day 14, CD38, CD11b, and F4/80 were higher on macrophages from RA-treated mice versus controls. The development of endometriotic implants is inhibited by RA. This effect may be caused, at least in part, by reduced IL-6 and MCP-1 production and enhanced differentiation of peritoneal macrophages. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  3. Enhanced apoptosis and radiosensitization by combined 13-CIS-retinoic acid and interferon-α2a; role of RAR-β gene

    International Nuclear Information System (INIS)

    Ryu, Samuel; Stein, Joseph P.; Chung, Chung T.; Lee, Yong J.; Kim, Jae Ho

    2001-01-01

    Purpose: Combined use of 13-cis-retinoic acid (cRA) and interferon-α2a (IFNα) induced significant radiosensitization in human cervical cancer ME-180 cell line, whereas it failed to achieve similar radiation enhancement in HeLa cells. The differential radiosensitization could be from the difference of retinoic acid receptor (RAR) expression because RAR-β was highly expressed in ME-180 cells in contrast to the HeLa cells where RAR-β was not detectable. We examined the role of this gene in mediating radiosensitization by cRA and IFNα, and explored the mechanism of radiation-induced cell killing. Methods and Materials: Human cervical cancer cell lines, ME-180 and HeLa, were treated with cRA and IFNα followed by radiation. Apoptosis and radiosensitization were quantitated by TUNEL assay (in situ DNA nick end labeling) and colony-forming ability of surviving cells. The cells were transfected with bcl-2 gene and RAR-β gene to test the role of these genes in mediating radiosensitization and apoptosis. Results: Synergistic radiosensitization and apoptosis was observed by combined use of cRA and IFNα with radiation in ME-180 cells which express high level of RAR-β mRNA, whereas these were not seen in HeLa cells where RAR-β mRNA is not detectable. Both radiosensitization and apoptosis were abolished by bcl-2 gene in ME-180 cells. RAR-β gene transfection induced similar radiation enhancement and apoptosis in HeLa cells. Conclusion: Apoptosis and radiation response were enhanced in the cells with high level of RAR-β mRNA expression. The RAR-β gene appears to mediate the radiation-induced apoptosis by cRA and IFNα. These findings indicate that presence of RAR-β in the cancer cells could be exploited for patient selection in using these drugs for apoptosis and radiosensitization

  4. The Effects of Sertoli Cells Condition Medium and Retinoic Acid on the Number of Colonies of Bone Marrow Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Maryam Salem

    2017-04-01

    Full Text Available Background & objectives: According to importance of bone marrow mesenchymal stem cells in production of different cell lines, transplantation of these cells are used for treatment of many different diseases during cell therapy. Viability and proliferation of these cells after transplantation are very important. Since infertility is as public health problem in men and women, the scientists attempt to produce germ cells from differentiation of stem cells. It is supposed to use these cells for treatment of different illnesses especially for men with lack of germ cells in testes in future. However, in using stem cells for cell therapy the culture medium should be designed to increase the number of cells and efficiency of transplantation and to guarantee the health of the cells in terms of DNA damage. This study designed a suitable culture medium in order to increase the number of colonies and decrease the cell injuries. Methods: In this study mesenchymal stem cells isolated from bone marrow of mice and exposed to retinoic acid (RA with concentration of 10-6 M and Sertoli cells condition medium. Since mesenchymal stem cells (MSCs produce fibroblastic colonies so the number of colonies was counted every 3 days after culture (days of 2, 5, 8, 11, and 15 under inverted microscope. The staining of ethidium bromide-acridine orange was also done for determination of apoptotic nucleus in days of 10 and 15 after culture. Results: The results showed that the effects of retinoic acid on grow and viability of MSCs is related to the time. It seems that RA increased the proliferation of the cells and the number of colonies increased in low time but the apoptotic cells elevated with increasing the time of culture. Condition medium of Sertoli cells also increased the proliferation of bone marrow stem cells. Conclusion: According to proliferative properties of condition medium, it seems that using condition medium together with RA is better than RA alone for

  5. Transcriptional changes in organoculture of full-thickness human skin following topical application of all-trans retinoic acid

    Science.gov (United States)

    Gillbro, J M; Al-Bader, T; Westman, M; Olsson, M J; Mavon, A

    2014-01-01

    Synopsis Objective Retinoids are used as therapeutic agents for numerous skin diseases, for example, psoriasis, acne and keratinization disorders. The same substances have also been recognized in the treatment for hyperpigmentation disorders such as melasma. Other studies on photo-damaged skin have shown that retinoids reduce wrinkles, surface roughness, mottled pigmentation, and visual skin appearance as a whole. We tested the hypothesis that an organoculture of full-thickness human skin could be used as a preclinical model to investigate the retinoid transcriptional profile in human skin in vitro. Methods Full-thickness skin explants were exposed to topically applied all-trans retinoic acid (RA) for 24 h. The gene expression profile was analysed using oligonucleotide microarrays, and data were validated with real-time (RT) PCR. Results We showed that the expression of 93 genes was significantly altered more than twofold. Several of the altered genes, for example, KRT4, CYP26 and LCN2, have previously been shown to be affected by RA in keratinocyte monocultures, reconstructed epidermis and skin biopsies from patients treated topically or orally with RA. In addition, genes, such as SCEL, NRIP1, DGAT2, RDH12 EfnB2, MAPK14, SAMD9 and CEACAM6 not previously reported to be affected by RA in human skin, were identified for the first time in this study. Conclusion The results in the present study show that full-thickness human explants represent a valuable pre-clinical model for studying the effects of retinoids in skin. Résumé Objectif Les rétinoïdes sont utilisés comme agents thérapeutiques pour de nombreuses maladies de la peau, p.ex. le psoriasis, l'acné et les troubles de la kératinisation. Les mêmes substances ont également été reconnues dans le traitement des troubles de l' hyperpigmentation tels que le melasma. D'autres études sur la peau photo-endommagée ont montré que les rétinoïdes réduisent les rides, la rugosité de la surface, la

  6. An irresolute linker: separation, and structural and spectroscopic characterization of the two linkage isomers of a Ru(ii)-(2-(2'-pyridyl)pyrimidine-4-carboxylic acid) complex.

    Science.gov (United States)

    Iengo, E; Demitri, N; Balducci, G; Alessio, E

    2014-08-28

    For the first time the two linkage isomers of a Ru(ii) complex with 2-(2'-pyridyl)pyrimidine-4-carboxylic acid (cppH) - that form in comparable amounts - have been fully characterized individually. The X-ray structure of each isomer is related to its NMR spectrum in solution.

  7. Oscillatory behaviour of isomers of hydroxybenzoic acid with and without catalyst

    Energy Technology Data Exchange (ETDEWEB)

    Nath, Masood A.; Rastogi, R.P.; Peerzada, G.M. [University of Kashmir, Srinagar (India). Dept. of Chemistry]. E-mail: nath_masood@yahoo.co.in

    2009-07-01

    The present work establishes and compares the oscillatory behaviour of mono-, di- and trihydroxybenzoic acids as organic substrates in acidic bromate (1.0 mol L{sup -1} H{sub 2}SO{sub 4}) without catalyst and in the presence of Mn{sup 2+} ion as the main catalyst. The oscillations are also affected by other catalyst such as Fe{sup 2+} ion. Further, the oscillations start diminishing in mixed catalyst systems. The experimental parameters were obtained potentiometrically and the results have been interpreted on the basis of FKN mechanism. (author)

  8. Synthesis and pharmacological characterization at glutamate receptors of the four enantiopure isomers of tricholomic acid

    DEFF Research Database (Denmark)

    Pinto, Andrea; Conti, Paola; De Amici, Marco

    2008-01-01

    of the studied amino acids reflect the relationship between the activity/selectivity and the stereochemistry of the two stereogenic centers: while the (2 S,5' S) stereoisomer is an agonist at the AMPA and KA receptors, its (2 R,5' R) enantiomer interacts selectively with the NMDA receptors; the (2 S,5' R...

  9. The effects of platelet activating factor and retinoic acid on the expression of ELAM-1 and ICAM-1 and the functions of neutrophils

    Directory of Open Access Journals (Sweden)

    Si-Feng Chen

    1995-01-01

    Full Text Available Preincubation of pulmonary microvascular endothelial cells (PMVECs with platelet-activating factor (PAF for 3.5 h increased the adhesion rate of polymorphonuclear leukocytes (PMNs to PMVECs from 57.3% to 72.8% (p < 0.01. Preincubation of PMNs with PAF also increased PMN-PMVEC adhesion rate. All-trans retinoic acid (RA blocked the adherence of untreated PMNs to PAF-pretreated PMVECs but not the adherence of PAF-pretreated PMNs to untreated PMVECs. PAF increased the expression of intercellular adhesion molecule-1 (ICAM-1 and E-selection (ELAM-1 on PMVECs, PMN chemotaxis to zymosan-activated serum and histamine, and PMN aggregation and the release of acid phosphatase from PMNs. Co-incubation of RA inhibited PAF-induced PMN aggregation, the release of acid phosphatase from PMNs, and PMN chemotaxis to zymosan-activated serum and histamine while the expression of ICAM-1 and ELAM-1 did not change. Our results suggest that RA can be used to ameliorate PMN-mediated inflammation.

  10. Identification of a dicaffeoylquinic acid isomer from Arctium lappa with a potent anti-ulcer activity.

    Science.gov (United States)

    Carlotto, Juliane; da Silva, Luisa M; Dartora, Nessana; Maria-Ferreira, Daniele; Sabry, Diego de A; Filho, Arquimedes P S; de Paula Werner, Maria F; Sassaki, Guilherme L; Gorin, Philip A J; Iacomini, Marcello; Cipriani, Thales R; de Souza, Lauro M

    2015-04-01

    Leaves of Arctium lappa contain several mono- and dicaffeoylquinic acids, as evaluated by liquid chromatography-mass spectrometry. In order to investigate the protection on gastric mucosa against ulcers, rats were treated with fractions from leaf extract prior to ethanol-induced ulcers. The original fraction obtained as ethanol soluble fraction from hot aqueous extract was able to protect de gastric mucosa, and this effect was retained in the ethyl acetate fraction, obtained from liquid/liquid fractionation. The main compound in this fraction was isolated and chemically characterized by nuclear magnetic resonance and mass spectrometry, assisted by isopropylidene derivatization which gave rise a mass increment of 40 units. Therefore, the underivatized compound that had m/z 515.119 [M-H](-) was shifted to m/z 555.151, being confirmed as 1,3-O-dicaffeoylquinic acid, which presented an ED50 of 57 µg kg(-1) on gastric protection, lesser than the therapeutic concentration of omeprazole (40 mg kg(-1)). Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders.

    Science.gov (United States)

    Moreno-Ramos, Oscar A; Olivares, Ana María; Haider, Neena B; de Autismo, Liga Colombiana; Lattig, María Claudia

    2015-01-01

    Autism spectrum disorders (ASDs) are a range of complex neurodevelopmental conditions principally characterized by dysfunctions linked to mental development. Previous studies have shown that there are more than 1000 genes likely involved in ASD, expressed mainly in brain and highly interconnected among them. We applied whole exome sequencing in Colombian-South American trios. Two missense novel SNVs were found in the same child: ALDH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)). Gene expression studies reveal that Aldh1a3 and Foxn1 are expressed in ~E13.5 mouse embryonic brain, as well as in adult piriform cortex (PC; ~P30). Conserved Retinoic Acid Response Elements (RAREs) upstream of human ALDH1A3 and FOXN1 and in mouse Aldh1a3 and Foxn1 genes were revealed using bioinformatic approximation. Chromatin immunoprecipitation (ChIP) assay using Retinoid Acid Receptor B (Rarb) as the immunoprecipitation target suggests RA regulation of Aldh1a3 and Foxn1 in mice. Our results frame a possible link of RA regulation in brain to ASD etiology, and a feasible non-additive effect of two apparently unrelated variants in ALDH1A3 and FOXN1 recognizing that every result given by next generation sequencing should be cautiously analyzed, as it might be an incidental finding.

  12. All-trans retinoic acid increases the expression of oxidative myosin heavy chain through the PPARδ pathway in bovine muscle cells derived from satellite cells.

    Science.gov (United States)

    Kim, Jongkyoo; Wellmann, Kimberly B; Smith, Zachary K; Johnson, Bradley J

    2018-04-24

    All-trans retinoic acid (ATRA) has been associated with various physiological phenomenon in mammalian adipose tissue and skeletal muscle. We hypothesized that ATRA may affect skeletal muscle fiber type in bovine satellite cell culture through various transcriptional processes. Bovine primary satellite cell (BSC) culture experiments were conducted to determine dose effects of ATRA on expression of genes and protein levels related to skeletal muscle fiber type and metabolism. The semimembranosus from crossbred steers (n = 2 steers), aged approximately 24 months, were used to isolate BSC for 3 separate assays. Myogenic differentiation was induced using 3% horse serum upon cultured BSC with increasing doses (0, 1, 10, 100, 1000 nM) of ATRA. After 96 h of incubation, cells were harvested and used to measure the gene expression of protein kinase B (Akt), AMP-activated protein kinase alpha (AMPK), glucose transporter 4 (GLUT4), myogenin, lipoprotein lipase (LPL), myosin heavy chain (MHC) I, MHC IIA,MHC IIX, insulin like growth factor -1 (IGF-1), Peroxisome proliferator activated receptor gamma (PPARγ), PPARδ, and Smad transcription factor 3 (SMAD3) mRNA relative to ribosomal protein subunit 9 (RPS9). The mRNA expression of LPL was increased (P < 0.05) with 100 and 1000nM of ATRA. Expression of GLUT4 was altered (P < 0.05) by ATRA. The treatment of ATRA (1000nM) also increased (P < 0.05) mRNA gene expression of SMAD3. The gene expression of both PPARδ and PPARγ were increased (P < 0.05) with 1000nM of ATRA. Protein level of PPARδ was also affected (P < 0.05) by 1000nM of ATRA and resulted in a greater (P < 0.05) protein level of PPARδ compared to CON. All-trans retinoic acid (10nM) increased gene expression of MHC I (P < 0.05) compared to CON. Expression of MHC IIA was also influenced (P < 0.05) by ATRA. The mRNA expression of MHC IIX was decreased (P < 0.05) with 100 and 1000nM of ATRA.In muscle cells, ATRA may cause muscle fibers to transition towards the MHC

  13. Critical determinant of intestinal permeability and oral bioavailability of pegylated all trans-retinoic acid prodrug-based nanomicelles: Chain length of poly (ethylene glycol) corona.

    Science.gov (United States)

    Li, Zhenbao; Han, Xiaopeng; Zhai, Yinglei; Lian, He; Zhang, Dong; Zhang, Wenjuan; Wang, Yongjun; He, Zhonggui; Liu, Zheng; Sun, Jin

    2015-06-01

    Pegylation method is widely used to prolong the blood circulation time of proteins and nanoparticles after intravenous administration, but the effect of surface poly (ethylene glycol) (PEG) chain length on oral absorption of the pegylated nanoparticles is poorly reported. The aim of our study was to investigate the influence of PEG corona chain length on membrane permeability and oral bioavailability of the amphiphilic pegylated prodrug-based nanomicelles, taking all trans-retinoic acid (ATRA) as a model drug. The amphiphilic ATRA-PEG conjugates were synthesized by esterification reaction between all trans-retinoic acid and mPEGs (mPEG500, mPEG1000, mPEG2000, and mPEG5000). The conjugates could self-assemble in aqueous medium to form nanomicelles by emulsion-solvent evaporation method. The resultant nanomicelles were in spherical shape with an average diameter of 13-20 nm. The drug loading efficiency of ATRA-PEG500, ATRA-PEG1000, ATRA-PEG2000, and ATRA-PEG5000 was about 38.4, 26.6, 13.1, and 5.68 wt%, respectively. With PEG chain length ranging from 500 to 5000, ATRA-PEG nanomicelles exhibited a bell shape of chemical stability in different pH buffers, intestinal homogenate and plasma. More importantly, they were all rapidly hydrolyzed into the parent drug in hepatic homogenate, with the half-time values being 0.3-0.4h. In comparison to ATRA solution and ATRA prodrug-based nanomicelles, ATRA-PEG1000 showed the highest intestinal permeability. After oral administration, ATRA-PEG2000 and ATRA-PEG5000 nanomicelles were not nearly absorbed, while the oral bioavailability of ATRA-PEG500 and ATRA-PEG1000 demonstrated about 1.2- and 2.0-fold higher than ATRA solution. Our results indicated that PEG1000 chain length of ATRA-PEG prodrug nanomicelles has the optimal oral bioavailability probably due to improved stability and balanced mucus penetration capability and cell binding, and that the PEG chain length on a surface of nanoparticles cannot exceed a key threshold with

  14. In vitro radiosensitization of human cervical carcinoma cells by combined use of 13-cis-retinoic acid and interferon-α2a

    International Nuclear Information System (INIS)

    Ryu, Samuel; Kim, Ok Bae; Kim, Sang-Hie; He, Shao Quin; Kim, Jae Ho

    1998-01-01

    Background: Significant antitumor activity has been reported with the combined use of 13-cis-retinoic acid (cRA) and interferon-α2a (IFN-α) in the treatment of advanced-stage cervical cancers and skin cancers. Since IFN-α has been shown to be a modest radiation enhancer for selected malignant tumor cells and the cytotoxic activity is more enhanced by combining cRA and IFN-α, we hypothesized that the exposure of selected human carcinoma cells to combined cRA and IFN-α would render the cells highly radiosensitive. Methods and Materials: Two human cervical carcinoma cell lines, ME-180 and HeLa-S3, were chosen for the present study because of the different characteristics of the retinoic acid receptor status of the cell lines. To demonstrate the effects of combined cRA and IFN-α treatment on radiation response, we exposed the cells to cRA, IFN-α, or a combination of the drugs for 72 h before radiation. Experiments were carried out at minimally cytotoxic concentrations of the drug for radiation studies. End points of the study were cell growth inhibition and clonogenic ability of the single-plated cells. Effects of cRA and IFN-α on radiation response were quantitatively analyzed by constructing the radiation cell survival curves of ME-180 and HeLa cells. Results: ME-180 cells exhibited varying degrees of cytotoxicity with cRA and IFN-α, while HeLa cells showed no toxic effects with the same treatment. Combined treatment of cRA and IFN-α produced an additive cytotoxic effect in ME-180 cells. Radiosensitization was minimal when ME-180 cells were treated with either cRA or IFN-α before radiation. When ME-180 cells were exposed to 10 μM cRA for 48 h and 1000 U/ml IFN-α for 24 h prior to radiation, there was a significant enhancement in radiation-induced cell killing; the dose modification factor was 2.1 ± 0.9 at the 1% cell-survival level. On the other hand, HeLa-S3 cells exhibited no increased cytotoxicity or radiation enhancement under the same experimental

  15. Phase 2 Randomized Controlled Trial of Radiation Therapy Plus Concurrent Interferon-Alpha and Retinoic Acid Versus Cisplatin for Stage III Cervical Carcinoma

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    Basu, Partha, E-mail: BasuP@iarc.fr [Screening Group, Early Detection and Prevention Section, International Agency for Research on Cancer, Lyon (France); Jenson, Alfred Bennett [James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky (United States); Majhi, Tapas; Choudhury, Prabir [Department of Radiation Oncology, Chittaranjan National Cancer Institute, Kolkata (India); Mandal, Ranajit; Banerjee, Dipanwita [Department of Gynecological Oncology, Chittaranjan National Cancer Institute, Kolkata (India); Biswas, Jaydip [Department of Surgical Oncology, Chittaranjan National Cancer Institute, Kolkata (India); Pan, Jianmin; Rai, Shesh Nath; Ghim, Shin je; Miller, Donald [James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky (United States)

    2016-01-01

    Purpose: Because a combination of retinoic acid, interferon-alpha, and radiation therapy demonstrated synergistic action and effectiveness to treat advanced cervical cancers in earlier studies, we designed this randomized phase 2 open-label trial to assess efficacy and safety of interferon alpha-2b (IFN) and 13-cis-retinoic acid (RA) administered concomitantly with radiation therapy (IFN-RA-radiation) to treat stage III cervical cancer. Methods and Materials: Stage III cervical cancer patients were randomized to study and control groups in a 1:1 ratio. All patients were treated with radiation therapy; study arm patients received IFN (3 × 10{sup 6} IU subcutaneously) 3 times a week for 4 weeks and daily RA (40 mg orally) for 30 days starting on day 1 of radiation, whereas control arm patients received weekly cisplatinum (40 mg/m{sup 2}) for 5 weeks during radiation. Patients were followed for 3 years. The primary endpoint was overall survival at 3 years. Results: Patients in the study (n=104) and control (n=105) groups were comparable for clinicopathological characteristics, radiation therapy–related variables and treatment response. Proportions of disease-free patients in the study and control groups were 38.5% and 44.8%, respectively, after median follow-up of 29.2 months. Hazard ratios were 0.67 (95% confidence interval [CI]: 0.44-1.01) and 0.69 (95% CI: 0.44-1.06) for overall and disease-fee survival, respectively, comparing the study group to control, and demonstrated an inferior outcome with RA-IFN-radiation, although differences were statistically nonsignificant. Kaplan-Meier curves of disease-free and overall survival probabilities also showed inferior survival in the study group compared to those in the control. Acute toxicities of chemoradiation were significantly higher with 2 acute toxicity-related deaths. Conclusions: Treatment with RA-IFN-radiation did not demonstrate survival advantage over chemoradiation despite being less toxic. The

  16. High-dose dexamethasone or all-trans-retinoic acid restores the balance of macrophages towards M2 in immune thrombocytopenia.

    Science.gov (United States)

    Feng, Q; Xu, M; Yu, Y Y; Hou, Y; Mi, X; Sun, Y X; Ma, S; Zuo, X Y; Shao, L L; Hou, M; Zhang, X H; Peng, J

    2017-09-01

    Essentials M1/M2 imbalance is involved in many autoimmune diseases, and could be restored. The expressions and functions of M1 and M2 were investigated in an in vitro culture system. A preferred M1 polarization is involved in the pathogenesis of immune thrombocytopenia (ITP). High-dose dexamethasone or all-trans-retinoic acid restores M1/M2 balance in ITP patients. Background Immune thrombocytopenia (ITP) is an autoimmune disorder. Deficiency of immune tolerance in antigen-presenting cells and cross-communication between antigen-presenting cells and T cells are involved in the pathogenesis of ITP. Macrophages can polarize into proinflammatory M1 or anti-inflammatory M2 phenotypes in response to different environmental stimuli, and have diverse immunologic functions. Objectives To investigate the M1/M2 imbalance in ITP and whether high-dose dexamethasone (HD-DXM) or all-trans-retinoic acid (ATRA) could restore this imbalance. Methods The numbers of M1 and M2 macrophages in the spleens of ITP patients and patients with traumatic spleen rupture were analyzed by immunofluorescence. Monocyte-derived macrophages were cultured and induced with cytokines and drugs. The expression of M1 and M2 markers and functions of M1 and M2 macrophages before and after modulation by HD-DXM or ATRA were evaluated with flow cytometry and ELISA. Results There was preferred M1 polarization in ITP spleens as compared with healthy controls. Monocyte-derived macrophages from ITP patients had increased expression of M1 markers and impaired immunosuppressive functions. Either HD-DXM or ATRA corrected this imbalance by decreasing the expression of M1 markers and increasing the expression of M2 markers. Moreover, HD-DXM-modulated or ATRA-modulated macrophages suppressed both CD4 + and CD8 + T-cell proliferation and expanded CD4 + CD49 + LAG3 + type 1 T-regulatory cells. HD-DXM or ATRA modulated macrophages to shift the T-cell cytokine profile towards Th2. Treating patients with HD-DXM or ATRA

  17. Vaccenic acid and trans fatty acid isomers from partially hydrogenated oil both adversely affect LDL cholesterol: a double-blind, randomized controlled trial.

    Science.gov (United States)

    Gebauer, Sarah K; Destaillats, Frédéric; Dionisi, Fabiola; Krauss, Ronald M; Baer, David J

    2015-12-01

    Adverse effects of industrially produced trans fatty acids (iTFAs) on the risk of coronary artery disease are well documented in the scientific literature; however, effects of naturally occurring trans fatty acids (TFAs) from ruminant animals (rTFA), such as vaccenic acid (VA) and cis-9,trans-11 conjugated linoleic acid (c9,t11-CLA), are less clear. Although animal and cell studies suggest that VA and c9,t11-CLA may be hypocholesterolemic and antiatherogenic, epidemiologic data comparing rTFAs and iTFAs are inconsistent, and human intervention studies have been limited, underpowered, and not well controlled. We determined the effects of VA, c9,t11-CLA, and iTFA, in the context of highly controlled diets (24 d each), on lipoprotein risk factors compared with a control diet. We conducted a double-blind, randomized, crossover feeding trial in 106 healthy adults [mean ± SD age: 47 ± 10.8 y; body mass index (in kg/m(2)): 28.5 ± 4.0; low-density lipoprotein (LDL) cholesterol: 3.24 ± 0.63 mmol/L]. Diets were designed to have stearic acid replaced with the following TFA isomers (percentage of energy): 0.1% mixed isomers of TFA (control), ∼3% VA, ∼3% iTFA, or 1% c9,t11-CLA. Total dietary fat (34% of energy) and other macronutrients were matched. Total cholesterol (TC), LDL cholesterol, triacylglycerol, lipoprotein(a), and apolipoprotein B were higher after VA than after iTFA; high-density lipoprotein (HDL) cholesterol and apolipoprotein AI also were higher after VA. Compared with control, VA and iTFA both increased TC, LDL cholesterol, ratio of TC to HDL cholesterol, and apolipoprotein B (2-6% change; P cholesterol, apolipoprotein AI, apolipoprotein B, and lipoprotein(a) (2-6% change; P < 0.05), whereas iTFA did not. c9,t11-CLA lowered triacylglycerol (P ≤ 0.01) and had no effect on other lipoprotein risk factors. With respect to risk of cardiovascular disease, these results are consistent with current nutrition labeling guidelines, with the requirement of VA, but

  18. Regulating Chondrogenesis of Human Mesenchymal Stromal Cells with a Retinoic Acid Receptor-Beta Inhibitor: Differential Sensitivity of Chondral Versus Osteochondral Development

    Directory of Open Access Journals (Sweden)

    Solvig Diederichs

    2014-05-01

    Full Text Available Aim: Main objective was to investigate whether the synthetic retinoic acid receptor (RAR-β antagonist LE135 is able to drive in vitro chondrogenesis of human mesenchymal stromal cells (MSCs or improve differentiation by suppressing hypertrophic chondrocyte development. Methods: Chondrogenesis of human bone marrow and adipose tissue-derived MSCs was induced in micromass pellet culture for six weeks. Effects of LE135 alone and in combinatorial treatment with TGF-β on deposition of cartilaginous matrix including collagen type II and glycosaminoglycans, on deposition of non-hyaline cartilage collagens type I and X, and on hypertrophy markers including alkaline phosphatase (ALP, indian hedghehog (IHH and matrix metalloproteinase (MMP-13 were assessed. Results: LE135 was no inducer of chondrogenesis and failed to stimulate deposition of collagen type II and glycosaminoglycans. Moreover, addition of LE135 to TGF-β-treated pellets inhibited cartilaginous matrix deposition and gene expression of COL2A1. In contrast, non-hyaline cartilage collagens were less sensitive to LE135 and hypertrophy markers remained unaffected. Conclusion: This demonstrates a differential sensitivity of chondral versus endochondral differentiation pathways to RARβ signaling; however, opposite to the desired direction. The relevance of trans-activating versus trans-repressing RAR signaling, including effects on activator protein (AP-1 is discussed and implications for overcoming current limits of hMSC chondrogenesis are considered.

  19. Bradycardia during Induction Therapy with All-trans Retinoic Acid in Patients with Acute Promyelocytic Leukemia: Case Report and Literature Review

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    Pin-Zi Chen

    2018-01-01

    Full Text Available A 41-year-old man with newly diagnosed acute promyelocytic leukemia (APL received induction chemotherapy, containing all-trans retinoic acid (ATRA, idarubicin, and arsenic trioxide. On the 11th day of therapy, he experienced complete atrioventricular (AV block; therefore, ATRA and arsenic trioxide were immediately postponed. His heart rate partially recovered, and ATRA was rechallenged with a half dose. However, complete AV block as well as differentiation syndrome recurred on the next day. ATRA was immediately discontinued, and a temporary pacemaker was inserted. Two days after discontinuing ATRA, AV block gradually improved, and ATRA was uneventfully rechallenged again. The Naranjo adverse drug reaction probability scale was 7 for ATRA, suggesting it was the probable cause of arrhythmia. A literature search identified 6 other cases of bradycardia during ATRA therapy, and all of them occurred during APL induction therapy, with onset ranging from 4 days to 25 days. Therefore, monitoring vital signs and performing electrocardiogram are highly recommended during the first month of induction therapy with ATRA. ATRA should be discontinued if complete AV block occurs. Rechallenging with ATRA can be considered in fully recovered and clinically stable patients.

  20. Regulating chondrogenesis of human mesenchymal stromal cells with a retinoic Acid receptor-Beta inhibitor: differential sensitivity of chondral versus osteochondral development.

    Science.gov (United States)

    Diederichs, Solvig; Zachert, Kerstin; Raiss, Patric; Richter, Wiltrud

    2014-01-01

    Main objective was to investigate whether the synthetic retinoic acid receptor (RAR)-β antagonist LE135 is able to drive in vitro chondrogenesis of human mesenchymal stromal cells (MSCs) or improve differentiation by suppressing hypertrophic chondrocyte development. Chondrogenesis of human bone marrow and adipose tissue-derived MSCs was induced in micromass pellet culture for six weeks. Effects of LE135 alone and in combinatorial treatment with TGF-β on deposition of cartilaginous matrix including collagen type II and glycosaminoglycans, on deposition of non-hyaline cartilage collagens type I and X, and on hypertrophy markers including alkaline phosphatase (ALP), indian hedghehog (IHH) and matrix metalloproteinase (MMP)-13 were assessed. LE135 was no inducer of chondrogenesis and failed to stimulate deposition of collagen type II and glycosaminoglycans. Moreover, addition of LE135 to TGF-β-treated pellets inhibited cartilaginous matrix deposition and gene expression of COL2A1. In contrast, non-hyaline cartilage collagens were less sensitive to LE135 and hypertrophy markers remained unaffected. This demonstrates a differential sensitivity of chondral versus endochondral differentiation pathways to RARβ signaling; however, opposite to the desired direction. The relevance of trans-activating versus trans-repressing RAR signaling, including effects on activator protein (AP)-1 is discussed and implications for overcoming current limits of hMSC chondrogenesis are considered. © 2014 S. Karger AG, Basel.

  1. Retinoic Acid Modulates Interferon-γ Production by Hepatic Natural Killer T Cells via Phosphatase 2A and the Extracellular Signal-Regulated Kinase Pathway

    Science.gov (United States)

    Chang, Heng-Kwei

    2015-01-01

    Retinoic acid (RA), an active metabolite converted from vitamin A, plays an active role in immune function, such as defending against infections and immune regulation. Although RA affects various types of immune cells, including antigen-presenting cells, B lymphocytes, and T lymphocytes, whether it affects natural killer T (NKT) cells remain unknown. In this study, we found that RA decreased interferon (IFN)-γ production by activated NKT cells through T-cell receptor (TCR) and CD28. We also found that RA reduced extracellular signal-regulated kinase (ERK) phosphorylation, but increased phosphatase 2A (PP2A) activity in TCR/CD28-stimulated NKT cells. The increased PP2A activity, at least partly, contributed to the reduction of ERK phosphorylation. Since inhibition of ERK activation decreases IFN-γ production by TCR/CD28-stimulated NKT cells, RA may downregulate IFN-γ production by TCR/CD28-stimulated NKT cells through the PP2A-ERK pathway. Our results demonstrated a novel function of RA in modulating the IFN-γ expression by activated NKT cells. PMID:25343668

  2. Retinoic acid induction of CD1d expression primes chronic lymphocytic leukemia B cells for killing by CD8+ invariant natural killer T cells.

    Science.gov (United States)

    Ghnewa, Yasmeen G; O'Reilly, Vincent P; Vandenberghe, Elisabeth; Browne, Paul V; McElligott, Anthony M; Doherty, Derek G

    2017-10-01

    Invariant natural killer T (iNKT) cells are cytotoxic T cells that respond to glycolipid antigens presented by CD1d. Therapeutic activation of iNKT cells with α-galactosylceramide (α-GalCer) can prevent and reverse tumor growth in mice and clinical trials involving α-GalCer-stimulated iNKT cells are ongoing in humans. B cells express CD1d, however, we show that CD1d expression is reduced on B cells from patients with chronic lymphocytic leukemia (CLL). B cells from CLL patients pulsed with α-GalCer failed to stimulate cytolytic degranulation by iNKT cell lines, but could present the more potent glycolipid analogue, 7DW8-5. Retinoic acid receptor-α (RAR-α) agonists induced CD1d expression by CLL B cells, restoring their ability to present α-GalCer to CD8α + iNKT cells, resulting in cytolytic degranulation. Thus, RAR-α agonists can augment the anti-tumor activities of iNKT cells against CLL cells in vitro. Their inclusion in iNKT cell-based therapies may benefit patients with CLL. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Tissue transglutaminase contributes to the all-trans-retinoic acid-induced differentiation syndrome phenotype in the NB4 model of acute promyelocytic leukemia.

    Science.gov (United States)

    Csomós, Krisztián; Német, István; Fésüs, László; Balajthy, Zoltán

    2010-11-11

    Treatment of acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA) results in terminal differentiation of leukemic cells toward neutrophil granulocytes. Administration of ATRA leads to massive changes in gene expression, including down-regulation of cell proliferation-related genes and induction of genes involved in immune function. One of the most induced genes in APL NB4 cells is transglutaminase 2 (TG2). RNA interference-mediated stable silencing of TG2 in NB4 cells (TG2-KD NB4) coupled with whole genome microarray analysis revealed that TG2 is involved in the expression of a large number of ATRA-regulated genes. The affected genes participate in granulocyte functions, and their silencing lead to reduced adhesive, migratory, and phagocytic capacity of neutrophils and less superoxide production. The expression of genes related to cell-cycle control also changed, suggesting that TG2 regulates myeloid cell differentiation. CC chemokines CCL2, CCL3, CCL22, CCL24, and cytokines IL1B and IL8 involved in the development of differentiation syndrome are expressed at significantly lower level in TG2-KD NB4 than in wild-type NB4 cells upon ATRA treatment. Based on our results, we propose that reduced expression of TG2 in differentiating APL cells may suppress effector functions of neutrophil granulocytes and attenuate the ATRA-induced inflammatory phenotype of differentiation syndrome.

  4. The role of retinoic acid receptors and their cognate ligands in reproduction in a context of triorganotin based endocrine disrupting chemicals

    Directory of Open Access Journals (Sweden)

    Macejova Dana

    2016-07-01

    Full Text Available Retinoic acid (RA, an active form of vitamin A, regulates the embryonic development, male and female reproduction and induces important effects on the cell development, proliferation, and differentiation. These effects are mediated by the retinoid (RAR and rexinoid nuclear receptors (RXR, which are considered to be a ligand-activated, DNA-binding, trans-acting, and transcription-modulating proteins, involved in a general molecular mechanism responsible for the transcriptional responses in target genes. Organotin compounds are typical environmental contaminants and suspected endocrine disrupting substances. They may affect processes of reproductive system in mammals, predominantly via nuclear receptor signaling pathways. Triorganotins, such as tributyltin chloride (TBTCl and triphenyltin chloride (TPTCl, are capable to bind to RXR molecules, and thus represent potent agonists of RXR subtypes of nuclear receptors not sharing any structural characteristics with endogenous ligands of nuclear receptors. Th is article summarizes selected effects of biologically active retinoids and rexinoids on both male and female reproduction and also deals with the effects of organotin compounds evoking endocrine disrupting actions in reproduction.

  5. Studies on Multifunctional Effect of All-Trans Retinoic Acid (ATRA on Matrix Metalloproteinase-2 (MMP-2 and Its Regulatory Molecules in Human Breast Cancer Cells (MCF-7

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    Anindita Dutta

    2009-01-01

    Full Text Available Background. Vitamin A derivative all-trans retinoic acid (ATRA is considered as a potent chemotherapeutic drug for its capability of regulating cell growth and differentiation. We studied the effect of ATRA on MMP-2 in MCF-7, human breast cancer cells, and the probable signaling pathways which are affected by ATRA on regulating pro-MMP-2 activity and expression. Methods. Gelatin zymography, RT-PCR, ELISA, Western blot, Immunoprecipitation, and Cell adhesion assay are used. Results. Gelatin zymography showed that ATRA caused a dose-dependent inhibition of pro-MMP-2 activity. ATRA treatment downregulates the expression of MT1-MMP, EMMPRIN, FAK, NF-kB, and p-ERK. However, expression of E-cadherin, RAR, and CRABP increased upon ATRA treatment. Binding of cells to extra cellular matrix (ECM protein fibronectin reduced significantly after ATRA treatment. Conclusions. The experimental findings clearly showed the inhibition of MMP-2 activity upon ATRA treatment. This inhibitory effect of ATRA on MMP-2 activity in human breast cancer cells (MCF-7 may result due to its inhibitory effect on MT1-MMP, EMMPRIN, and upregulation of TIMP-2. This study is focused on the effect of ATRA on MMP, MMP-integrin-E-cadherin interrelationship, and also the effect of the drug on different signaling molecules which may involve in the progression of malignant tumor development.

  6. In vitro induction and differentiation of umbilical cord mesenchymal stem cells into neuron-like cells by all-trans retinoic acid

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    Wei Jin

    2015-04-01

    Full Text Available AIM: To determine the optimal concentration for inducing the differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs into neuron-like cells, although it is understood that all-trans retinoic acid (ATRA regulates cell proliferation in the nervous system by modulating the balance between mitosis and apoptosis. METHODS: The abilities of ATRA to promote apoptosis as well as neural differentiation were assessed in cultured hUC-MSCs by morphological observation, MTT assay, annexin V-FITC/PI flow cytometry and immunocytochemistry. RESULTS: The data showed that low concentrations of ATRA (0.5 µmol, 0.25 µmol had no effect on the number of cells. However, treatment with 1.0 µmol or 2.0 µmol ATRA induced a 24.16% and 52.67% reduction in cell number, respectively, compared with vehicle-treated cultures. Further, 4.0 µmol ATRA had a potent effect on cell number, with almost no adherent cells recovered after 24h. We further showed that 0.5 µmol ATRA caused these cells to express characteristic markers of neuronal progenitor cells. CONCLUSION: Taken together, we conclude that ATRA has a dose-dependent influence on the neural differentiation and apoptosis of hUC-MSCs. These findings have implications on the use of ATRA-differentiated hUC-MSCs for the study of neural degeneration diseases.

  7. Retinoic acid-induced differentiation increases the rate of oxygen consumption and enhances the spare respiratory capacity of mitochondria in SH-SY5Y cells.

    Science.gov (United States)

    Xun, Zhiyin; Lee, Do-Yup; Lim, James; Canaria, Christie A; Barnebey, Adam; Yanonne, Steven M; McMurray, Cynthia T

    2012-04-01

    Retinoic acid (RA) is used in differentiation therapy to treat a variety of cancers including neuroblastoma. The contributing factors for its therapeutic efficacy are poorly understood. However, mitochondria (MT) have been implicated as key effectors in RA-mediated differentiation process. Here we utilize the SH-SY5Y human neuroblastoma cell line as a model to examine how RA influences MT during the differentiation process. We find that RA confers an approximately sixfold increase in the oxygen consumption rate while the rate of glycolysis modestly increases. RA treatment does not increase the number of MT or cause measurable changes in the composition of the electron transport chain. Rather, RA treatment significantly increases the mitochondrial spare respiratory capacity. We propose a competition model for the therapeutic effects of RA. Specifically, the high metabolic rate in differentiated cells limits the availability of metabolic nutrients for use by the undifferentiated cells and suppresses their growth. Thus, RA treatment provides a selective advantage for the differentiated state. Published by Elsevier Ireland Ltd.

  8. Effects of all-trans-retinoic acid on human SH-SY5Y neuroblastoma as in vitro model in neurotoxicity research.

    Science.gov (United States)

    Cheung, Yuen-Ting; Lau, Way Kwok-Wai; Yu, Man-Shan; Lai, Cora Sau-Wan; Yeung, Sze-Chun; So, Kwok-Fai; Chang, Raymond Chuen-Chung

    2009-01-01

    Human neuroblastoma SH-SY5Y is a dopaminergic neuronal cell line which has been used as an in vitro model for neurotoxicity experiments. Although the neuroblastoma is usually differentiated by all-trans-retinoic acid (RA), both RA-differentiated and undifferentiated SH-SY5Y cells have been used in neuroscience research. However, the changes in neuronal properties triggered by RA as well as the subsequent responsiveness to neurotoxins have not been comprehensively studied. Therefore, we aim to re-evaluate the differentiation property of RA on this cell line. We hypothesize that modulation of signaling pathways and neuronal properties during RA-mediated differentiation in SH-SY5Y cells can affect their susceptibility to neurotoxins. The differentiation property of RA was confirmed by showing an extensive outgrowth of neurites, increased expressions of neuronal nuclei, neuron specific enolase, synaptophysin and synaptic associated protein-97, and decreased expression of inhibitor of differentiation-1. While undifferentiated SH-SY5Y cells were susceptible to 6-OHDA and MPP+, RA-differentiation conferred SH-SY5Y cells higher tolerance, potentially by up-regulating survival signaling, including Akt pathway as inhibition of Akt removed RA-induced neuroprotection against 6-OHDA. As a result, the real toxicity cannot be revealed in RA-differentiated cells. Therefore, undifferentiated SH-SY5Y is more appropriate for studying neurotoxicity or neuroprotection in experimental Parkinson's disease research.

  9. A phase II study of concurrent temozolomide and cis-retinoic acid with radiation for adult patients with newly diagnosed supratentorial glioblastoma

    International Nuclear Information System (INIS)

    Butowski, Nicholas; Prados, Michael D.; Lamborn, Kathleen R.; Larson, David A.; Sneed, Patricia K.; Wara, William M.; Malec, Mary; Rabbitt, Jane; Page, Margaretta; Chang, Susan M.

    2005-01-01

    Purpose: This Phase II study was designed to determine the median survival time of adults with supratentorial glioblastoma treated with a combination of temozolomide (TMZ) and 13-cis-retinoic acid (cRA) given daily with conventional radiation therapy (XRT). Methods and Materials: This was a single arm, open-labeled, Phase II study. Patients were treated with XRT in conjunction with cRA and TMZ. Both drugs were administered starting on Day 1 of XRT, and chemotherapy cycles continued after the completion of XRT to a maximum of 1 year. Results: Sixty-one patients were enrolled in the study. Time to progression was known for 55 patients and 6 were censored. The estimated 6-month progression-free survival was 38% and the estimated 1-year progression-free survival was 15%. Median time to progression was estimated as 21 weeks. The estimated 1-year survival was 57%. The median survival was 57 weeks. Conclusions: The combined therapy was relatively well tolerated, but there was no survival advantage compared with historical studies using XRT either with adjuvant nitrosourea chemotherapy, with TMZ alone, or with the combination of TMZ and thalidomide. Based on this study, cRA does not seem to add a significant synergistic effect to TMZ and XRT

  10. Urinary retinoic acid receptor-β2 gene promoter methylation and hyaluronidase activity as noninvasive tests for diagnosis of bladder cancer.

    Science.gov (United States)

    Eissa, Sanaa; Zohny, Samir F; Shehata, Hanan Hussien; Hegazy, Marwa G A; Salem, Ahmed M; Esmat, Mohamed

    2012-04-01

    We evaluated the significance of urinary retinoic acid receptor-β2 (RAR-β2) gene promoter methylation and hyaluronidase activity in comparison with voided urine cytology (VUC) in diagnosis of bladder cancer. This study included 100 patients diagnosed with bladder cancer, 65 patients with benign urological disorders and 51 healthy volunteers. Urine supernatant was used for determining hyaluronidase activity by zymography while urine sediment was used for cytology and detection of methylated RAR-β2 gene promoter by methylation specific nested PCR. The sensitivity and specificity were 53% and 90.5% for VUC, 65% and 89.7% for percent methylation fraction of RAR-β2 gene promoter, and 89% and 90.5% for hyaluronidase activity; combination of the three parameters increased sensitivity to 95%. A significant association was observed between investigated markers and advanced grade tumor. Combined use of RAR-β2 gene promoter methylation, hyaluronidase activity and VUC is promising non-invasive tool for bladder cancer detection. Copyright © 2012. Published by Elsevier Inc.

  11. Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro.

    Science.gov (United States)

    Yoshino, Hironori; Iwabuchi, Miyu; Kazama, Yuka; Furukawa, Maho; Kashiwakura, Ikuo

    2018-04-01

    Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are pattern-recognition receptors that recognize pathogen-associated molecular patterns and induce antiviral immune responses. Recent studies have demonstrated that RLR activation induces antitumor immunity and cytotoxicity against different types of cancer, including lung cancer. However a previous report has demonstrated that ionizing radiation exerts a limited effect on RLR in human monocytic cell-derived macrophages, suggesting that RLR agonists may be used as effective immunostimulants during radiation therapy. However, it is unclear whether ionizing radiation affects the cytotoxicity of RLR agonists against cancer cells. Therefore, in the present study the effects of cotreatment with ionizing radiation and RLR agonists on cytotoxicity against human non-small cell lung cancer cells A549 and H1299 was investigated. Treatment with RLR agonist poly(I:C)/LyoVec™ [poly(I:C)] exerted cytotoxic effects against human non-small cell lung cancer. The cytotoxic effects of poly(I:C) were enhanced by cotreatment with ionizing radiation, and poly(I:C) pretreatment resulted in the radiosensitization of non-small cell lung cancer. Furthermore, cotreatment of A549 and H1299 cells with poly(I:C) and ionizing radiation effectively induced apoptosis in a caspase-dependent manner compared with treatment with poly(I:C) or ionizing radiation alone. These results indicate that RLR agonists and ionizing radiation cotreatment effectively exert cytotoxic effects against human non-small cell lung cancer through caspase-mediated apoptosis.

  12. The mucosal adjuvant cholera toxin B instructs non-mucosal dendritic cells to promote IgA production via retinoic acid and TGF-β.

    Directory of Open Access Journals (Sweden)

    Anouk K Gloudemans

    Full Text Available It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA, and how T cell-dependent (TD or -independent (TI pathways might be involved. Mucosal dendritic cells (DCs are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL, B cell activating factor (BAFF, Retinoic Acid (RA, TGF-β or nitric oxide (NO. We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-β signaling inhibitor or neutralizing anti-TGF-β was added, demonstrating the involvement of RA and TGF-β in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant.

  13. The mucosal adjuvant cholera toxin B instructs non-mucosal dendritic cells to promote IgA production via retinoic acid and TGF-β.

    Science.gov (United States)

    Gloudemans, Anouk K; Plantinga, Maud; Guilliams, Martin; Willart, Monique A; Ozir-Fazalalikhan, Arifa; van der Ham, Alwin; Boon, Louis; Harris, Nicola L; Hammad, Hamida; Hoogsteden, Henk C; Yazdanbakhsh, Maria; Hendriks, Rudi W; Lambrecht, Bart N; Smits, Hermelijn H

    2013-01-01

    It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA), and how T cell-dependent (TD) or -independent (TI) pathways might be involved. Mucosal dendritic cells (DCs) are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL), B cell activating factor (BAFF), Retinoic Acid (RA), TGF-β or nitric oxide (NO). We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB) could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR) ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-β signaling inhibitor or neutralizing anti-TGF-β was added, demonstrating the involvement of RA and TGF-β in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant.

  14. Effects of early gestational all-trans retinoic acid treatment on motor skills: a longitudinal study in the offspring of Sprague-Dawley rats.

    Science.gov (United States)

    Coluccia, Addolorata; Borracci, Pietro; Belfiore, Domenico; Renna, Giuseppe; Giustino, Arcangela; Carratù, Maria Rosaria

    2008-11-01

    The purpose of the present study was to investigate the behavioral outcomes of all-trans retinoic acid (RA) treatment in the period spanning gestational day (GD) 8-10. A sublethal dose (2.5mg/kg b.w.) compatible with high neonatal survival, sufficient to supply male offspring for later behavioral testing, was used. Indeed, the mortality rate at birth was 7.8%. Reproduction parameters (body weight gain of dams during gestation, number of dams giving birth, pregnancy length, litter size at birth), offspring body weight gain and the development of their somatic characteristics (ear unfolding, auditory conduit opening, eyes opening, hair growth) were not altered by RA. Instead, the onset of righting reflex and negative geotaxis were delayed by 2 days, suggesting vestibular involvement and abnormal functioning of the cerebellum. Then, the performance of RA-treated rats on open field and rotarod/accelerod tasks was assessed from postnatal day (PND) 21 to 90. Similar to the previously investigated GD 11-13 RA treatment, the GD 8-10 RA treatment impaired the open field activity and rotarod/accelerod performance in young adult rats, thus suggesting a task-specific rather than a stage-specific effect of low-dose retinoids during brain development. The delayed appearance of these outcomes underlines the relevance of longitudinal studies to sort out specific RA-targeted neurochemical-behavioral pathways that could be labelled as having no phenotype based on standard examination at birth.

  15. Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF-A pathways downstream of retinoic acid from the meninges.

    Science.gov (United States)

    Mishra, Swati; Choe, Youngshik; Pleasure, Samuel J; Siegenthaler, Julie A

    2016-12-01

    Growth and maturation of the cerebrovasculature is a vital event in neocortical development however mechanisms that control cerebrovascular development remain poorly understood. Mutations in or deletions that include the FOXC1 gene are associated with congenital cerebrovascular anomalies and increased stroke risk in patients. Foxc1 mutant mice display severe cerebrovascular hemorrhage at late gestational ages. While these data demonstrate Foxc1 is required for cerebrovascular development, its broad expression in the brain vasculature combined with Foxc1 mutant's complex developmental defects have made it difficult to pinpoint its function(s). Using global and conditional Foxc1 mutants, we find 1) significant cerebrovascular growth defects precede cerebral hemorrhage and 2) expression of Foxc1 in neural crest-derived meninges and brain pericytes, though not endothelial cells, is required for normal cerebrovascular development. We provide evidence that reduced levels of meninges-derived retinoic acid (RA), caused by defects in meninges formation in Foxc1 mutants, is a major contributing factor to the cerebrovascular growth defects in Foxc1 mutants. We provide data that suggests that meninges-derived RA ensures adequate growth of the neocortical vasculature via regulating expression of WNT pathway proteins and neural progenitor derived-VEGF-A. Our findings offer the first evidence for a role of the meninges in brain vascular development and provide new insight into potential causes of cerebrovascular defects in patients with FOXC1 mutations. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Premature Epiphyseal Closure of the Lower Extremities Contributing to Short Stature after cis-Retinoic Acid Therapy in Medulloblastoma: A Case Report.

    Science.gov (United States)

    Noyes, Jessica J; Levine, Michael A; Belasco, Jean B; Mostoufi-Moab, Sogol

    2016-01-01

    Prolonged cis-retinoic acid (RA) exposure contributes to premature epiphyseal closure. cis-RA is administered in various treatment regimens for pediatric cancers, thus increasing the risk for bone deformities and compromised growth. We present a case of premature epiphyseal closure in a 9-year-old female with a history of medulloblastoma and treatment with a multimodal regimen including cis-RA. She was subsequently diagnosed with radiation-induced endocrine late effects including hypothyroidism and growth hormone deficiency (GHD). Seven months after initiation of GH therapy, an increased prominence of the wrists and knees combined with a deceleration in growth velocity prompted further evaluation; radiographs revealed bilateral premature closure of the distal femur and proximal tibia growth plates despite normal left wrist bone age. High doses of vitamin A and its analogs are linked to premature closure of the lower-extremity growth plates in animals and children. Pediatric brain tumor patients are at increased risk of growth failure due to concurrent radiation-induced GHD, damage to the spinal bones, and cis-RA-associated premature closure of the lower-extremity growth plates, with significant reduction in adult stature. A better appreciation of the detrimental effect of cis-RA on the growing skeleton is needed to monitor at-risk patients and to provide timely interventions. © 2015 S. Karger AG, Basel.

  17. Pro-apoptotic signaling induced by Retinoic acid and dsRNA is under the control of Interferon Regulatory Factor-3 in breast cancer cells.

    Science.gov (United States)

    Bernardo, Ana R; Cosgaya, José M; Aranda, Ana; Jiménez-Lara, Ana M

    2017-07-01

    Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.

  18. Direct nuclear magnetic resonance identification and quantification of geometric isomers of conjugated linoleic acid in milk lipid fraction without derivatization steps: Overcoming sensitivity and resolution barriers

    International Nuclear Information System (INIS)

    Tsiafoulis, Constantinos G.; Skarlas, Theodore; Tzamaloukas, Ouranios; Miltiadou, Despoina; Gerothanassis, Ioannis P.

    2014-01-01

    Highlights: • The first NMR quantification of four geometric 18:2 CLA isomers has been achieved. • Sensitivity and resolution NMR barriers have been overcome. • Selective suppression and reduced 13 C spectral width have been utilized. • The method is applied in the milk lipid fraction without derivatization steps. • The method is selective, sensitive with very good analytical characteristics. - Abstract: We report the first successful direct and unequivocal identification and quantification of four minor geometric (9-cis, 11-trans) 18:2, (9-trans, 11-cis) 18:2, (9-cis, 11-cis) 18:2 and (9-trans, 11-trans) 18:2 conjugated linoleic acid (CLA) isomers in lipid fractions of lyophilized milk samples with the combined use of 1D 1 H-NMR, 2D 1 H- 1 H TOCSY and 2D 1 H- 13 C HSQC NMR. The significant sensitivity barrier has been successfully overcome under selective suppression of the major resonances, with over 10 4 greater equilibrium magnetization of the -(CH 2 ) n - 1 H spins compared to that of the 1 H spins of the conjugated bonds of the CLA isomers. The resolution barrier has been significantly increased using reduced 13 C spectral width in the 2D 1 H- 13 C HSQC experiment. The assignment was confirmed with spiking experiments with CLA standard compounds and the method does not require any derivatization steps for the lipid fraction. The proposed method is selective, sensitive and compares favorably with the GS-MS method of analysis

  19. Histidine, lysine, and arginine radical cations: isomer control via the choice of auxiliary ligand (L) in the dissociation of [CuII(L)amino acid]*2+ complexes.

    Science.gov (United States)

    Ke, Yuyong; Zhao, Junfang; Verkerk, Udo H; Hopkinson, Alan C; Siu, K W Michael

    2007-12-27

    Histidine, lysine, and arginine radical cations have been generated through collision-induced dissociation (CID) of complexes [CuII(auxiliary ligand)namino acid]*2+, using tri-, bi-, as well as monodentate auxiliary ligands. On the basis of the observed CID products, the existence of two isomeric amino-acid populations is postulated. The Type 1 radical cations of histidine and lysine, stable on the mass spectrometer time scale, were found to lose water, followed by the loss of carbon monoxide under more energetic CID conditions. The arginine Type 1 radical cation behaved differently, losing dehydroalanine. The Type 2 radical cations were metastable and easily fragmented by the loss of carbon dioxide, effectively preventing direct observation. Type 1 radical cations are proposed to result from neutral (canonical) amino-acid coordination, whereas Type 2 radical cations are from zwitterionic amino-acid coordination to copper in the complex. The ratio of Type 1/Type 2 ions was found to be dependent on the auxiliary ligand, providing a method of controlling which radical cation would be formed primarily. Density functional calculations at B3LYP/6-311++G(d,p) have been used to determine the relative energies of five His*+ isomers. Barriers against interconversion between the isomers and against fragmentation have been calculated, giving insight as to why the Type 1 ions are stable, while only fragmentation products of the Type 2 ions are observable under CID conditions.

  20. Development of the optical sensor for discriminating isomers of fatty acids based on emissive network polymers composed of polyhedral oligomeric silsesquioxane.

    Science.gov (United States)

    Narikiyo, Hayato; Kakuta, Takahiro; Matsuyama, Hiroki; Gon, Masayuki; Tanaka, Kazuo; Chujo, Yoshiki

    2017-07-01

    It was shown that water-soluble network polymers composed of polyhedral oligomeric silsesquioxane (POSS) had hydrophobic spaces inside the network because of strong hydrophobicity of the cubic silica cage. In this study, the water-soluble POSS network polymers connected with triphenylamine derivatives (TPA-POSS) were synthesized, and their functions as a sensor for discriminating the geometric isomers of fatty acids were investigated. Accordingly, in the photoluminescence spectra, different time-courses of intensity and peak wavelengths of the emission bands were detected from the TPA-POSS-containing solution in the presence of cis- or trans-fatty acids during incubation. Furthermore, variable time-dependent changes were obtained by changing coexisting ratios between two geometric isomers. From the mechanistic investigation, it was implied that these changes could be originated from the difference in the degree of interaction between the POSS networks and each fatty acid. Our data could be applicable for constructing a sensing material for generation and proportion of trans-fatty acids in the oil. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. On-line monitoring of in-vitro oral bioaccessibility tests as front-end to liquid chromatography for determination of chlorogenic acid isomers in dietary supplements.

    Science.gov (United States)

    Kremr, Daniel; Cocovi-Solberg, David J; Bajerová, Petra; Ventura, Karel; Miró, Manuel

    2017-05-01

    A novel fully automated in-vitro oral dissolution test assay as a front-end to liquid chromatography has been developed and validated for on-line chemical profiling and monitoring of temporal release profiles of three caffeoylquinic acid (CQA) isomers, namely, 3-CQA,4-CQA and 5-CQA, known as chlorogenic acids, in dietary supplements. Tangential-flow filtration is harnessed as a sample processing approach for on-line handling of CQA containing extracts of hard gelatin capsules and introduction of protein-free samples into the liquid chromatograph. Oral bioaccessibility/dissolution test assays were performed at 37.0±0.5°C as per US Pharmacopeia recommendations using pepsin with activity of ca. 749,000 USP units/L in 0.1mol/L HCl as the extraction medium and a paddle apparatus stirred at 50rpm. CQA release rates and steady-state dissolution conditions were determined accurately by fitting the chromatographic datasets, namely, the average cumulative concentrations of bioaccessible pools of every individual isomer monitored during 200min, with temporal resolutions of ≥10min, to a first-order dissolution kinetic model. Distinct solid-to-liquid phase ratios in the mimicry of physiological extraction conditions were assessed. Relative standard deviations for intra-day repeatability and inter-day intermediate precision of 5-CQA within the 5-40µg/mL concentration range were <3.4% and <5.5%, respectively. Trueness of the automatic flow method for determination of 5-CQA released from dietary supplements in gastric fluid surrogate was demonstrated by spike recoveries, spanning from 91.5-104.0%, upon completion of the dissolution process. The proposed hyphenated setup was resorted for evaluating potential differences in dissolution profiles and content of the three most abundant chlorogenic acid isomers in dietary supplements from varied manufacturers. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. A 2-week pretreatment with 13-cis-retinoic acid + interferon-α-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers

    International Nuclear Information System (INIS)

    Dunst, J.; Haensgen, G.; Becker, A.; Krause, U.; Fuechsel, G.; Koehler, U.

    1998-01-01

    Background: We have evaluated the tumor tissue pO 2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-α-2a prior to and during radiotherapy. Patients and methods: From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-α-2a (IFN-α-2a) as part of a phase-II protocol. cRA/IFN-α-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6x10 6 IU IFN-α-2a subcutaneously daily). After this indicution period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy, cRA/IFN-α-2a-treatment was continued with 50% of the daily doses. Tumor tissue pO 2 -measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO 2 -histograph. Results: In 11 out of the 22 patients, pO 2 -measurements were performed prior to the cRA/IFN-induction therapy. The median pO 2 of these untreated tumors was 17.7±16.3 mm Hg. The relative frequency of hypoxic readings with pO 2 -values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3±21.0%). After the 2-week induction period with cRA/IFN, the median pO 2 had increased from 17.7pm16.3 mm Hg to 27.6±19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO 2 of 10 mm Hg or less), the median pO 2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO 2 increased from 6.3±2.7 mm Hg to 27.0±5.6 mm Hg (p=0.004, t-test for paired samples). The frequency of hypoxic readings (pO 2 -values 2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission. Conclusions: Pretreatment with cRA/IFN improves oxygenation of

  3. Radiotherapy plus cis-retinoic acid/interferon-α in cervical cancers: response and impact of cRA/IFN on tumor tissue oxygenation

    International Nuclear Information System (INIS)

    Haensgen, Gabriele; Koehler, Uwe; Dunst, Juergen

    1997-01-01

    Background: We have evaluated the impact of 13-cis-retinoic acid plus interferon in combination with radiotherapy on response and on tumor oxygenation in a phase II-study. Materials and methods: From June 1995 through April 1996, thirty-four patients with squamous cell carcinoma FIGO IIB (N=8) and IIIB (N=26) of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-α-2a (IFN-α-2a) as part of a phase-II-protocol at the Universities of Halle-Wittenberg (N=25), Leipzig (N=7) and Dresden (N=2). cRA/IFN-α-2a started 14 days prior to radiotherapy (1 mg per kilogramm body weight cRA orally daily plus 6x10 6 I.U. IFN-α-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 45Gy in 25 fractions of 1.8Gy plus HDR-brachytherapy with 5x7Gy). During radiotherapy, cRA/IFN-α-2a-treatment was continued with 50% of the daily doses. In 14 patients treated at the University of Halle-Wittenberg, tumor tissue pO 2 -measurements were performed prior to radiotherapy, at 20Gy, and at the end of radiotherapy with an Eppendorf-pO 2 -histograph. The oxygenation data of these patients were compared to 14 patients who had also pO 2 -measurements but had refused to participate in the cRA/IFN-α-2a-protocol and received radiotherapy alone during the same period. Results: All 8 patients with FIGO IIB tumors had a complete clinical remission 3 months after radiotherapy. In FIGO IIIB cancers, (19(26)) (73%) achieved a cCR, 5 (19%) had a PR and 2 died within six months after treatment due to intercurrent disease. The toxicity of cRA/IFN-α-2a was only mild to moderate (fever 43%, skin toxicity 36%, diarrhea 20%, elevation of liver enzymes 20%) with no grade (3(4)) toxicity. The 14 patients with cRA/IFN-α-2a-pretreatment prior to radiotherapy had significant higher median pO 2 -values in their tumors at the

  4. Potential predictive assay using RAR-β for radiosensitization by 13-cis-retinoic acid and interferonα2a in human carcinoma cells

    International Nuclear Information System (INIS)

    Ryu, Samuel; Nevaldine, Barbara H.; Unguraneau, Carmen; Chung, Chung T.; King, Gerald A.; Stein, Joseph P.

    1997-01-01

    Purpose: Cell culture studies have shown increased cytotoxicity and inhibition of cell proliferation by combined use of 13-cis-retinoic acid (CRA) and interferon-α2a (IFN). Clinically, a direct antitumor activity has been observed by combined use of CRA and IFN in patients with cancer of the cervix and skin. Since IFN is known to enhance radiation response in selected human carcinoma cell lines, we carried out a series of experiments in an effort to improve the efficacy of radiation therapy by CRA and IFN in combination. Materials and Methods: Human cervical carcinoma ME-180 and HeLa cell lines were exposed to 10 μM CRA and 1000 unit/ml IFN in combination for 48 hours prior to radiation. Endpoint of radiosensitization study was colony-forming ability of single cells. Retinoic acid receptors (RAR and RXR) were detected by RNAse protection assay. Apoptosis was quantitated by using immunohistochemical staining method (Apop Tag). The cells were also transfected with bcl-2 or RAR-β gene to explore the mechanism of radiation-induced cell killing. Results: A substantial radiosensitization was observed by the combined use of CRA and IFN in human cervical carcinoma ME-180 cells in culture. The radiation enhancement ratio was 2.0 at 1% cell survival level. The principal mode of radiation-induced cell killing was apoptosis since more than 90% of the ME-180 cells showed evidence of apoptosis by combined treatment of CRA, IFN, and radiation. Both apoptosis and radiosensitization were blocked by transfecting bcl-2 gene into ME-180 cells. In contrast to these results with ME-180 cells, no radiosensitization was observed in HeLa cells by CRA and IFN under the same experimental conditions. Both cell lines express various RXR and RAR mRNAs. However, the RAR-β was undetectable in HeLa cells but present at high levels in ME-180 cells, as determined by RNAse protection assay. Because of this differential expression of RAR-β mRNA, we hypothesized that RAR-β may mediate the

  5. Effect of all-trans retinoic acid treatment on prohibitin and renin-angiotensin-aldosterone system expression in hypoxia-induced renal tubular epithelial cell injury.

    Science.gov (United States)

    Zhou, Tian-Biao; Ou, Chao; Rong, Liang; Drummen, Gregor P C

    2014-09-01

    All-trans retinoic acid (ATRA) exerts various effects on physiological processes such as cell growth, differentiation, apoptosis and inflammation. Prohibitins (PHB), including prohibitin 1 (PHB1) and prohibitin 2 (PHB2), are evolutionary conserved and pleiotropic proteins implicated in various cellular functions, including proliferation, tumor suppression, apoptosis, transcription, and mitochondrial protein folding. The renin-angiotensin-aldosterone system plays a pivotal role in the regulation of blood pressure and volume homeostasis. All these factors and systems have been implicated in renal interstitial fibrosis. Therefore, the objective of this study was to investigate the effect of ATRA treatment on the renin-angiotensin-aldosterone system and expression of prohibitins to further understand its role in the processes leading to renal interstitial fibrosis. The hypoxic and oxidative stress conditions in obstructive renal disease were simulated in a hypoxia/reoxygenation model with renal tubular epithelial cells (RTEC) as a model system. Subsequently, the effect of ATRA on mRNA and protein expression levels was determined and correlations were established between factors involved in the renin-angiotensin-aldosterone system, the prohibitins, cellular redox status, renal interstitial fibrosis and ATRA treatment. Correlation analysis showed that both PHB1 and PHB2 protein levels were negatively correlated with angiotensin I, ACE1, angiotensin II, TGF-β1, Col-IV, FN, ROS, and MDA (PHB1: r = -0.792, -0.834, -0.805, -0.795, -0.778, -0.798, -0.751, -0.682; PHB2: r = -0.872, -0.799, -0.838, -0.773, -0.769, -0.841, -0.794, -0.826; each p system under hypoxia/reoxygenation conditions. © The Author(s) 2014.

  6. Resveratrol strongly enhances the retinoic acid-induced superoxide generating activity via up-regulation of gp91-phox gene expression in U937 cells.

    Science.gov (United States)

    Kikuchi, Hidehiko; Mimuro, Hitomi; Kuribayashi, Futoshi

    2018-01-01

    The membrane bound cytochrome b 558 composed of gp91-phox and p22-phox proteins, and cytosolic proteins p40-, p47-and p67-phox are important components of superoxide (O 2 - )-generating system in phagocytes. Here, we describe that resveratrol, a pleiotropic phytochemical belonging to the stilbenoids, dramatically activates the O 2 - -generating system during retinoic acid (RA)-induced differentiation of human monoblastic leukemia U937 cells to macrophage-like cells. When U937 cells were cultured in the presence of RA and resveratrol, the O 2 - -generating activity increased more than 5-fold compared with that in the absence of the latter. Semiquantitative RT-PCR showed that co-treatment with RA and resveratrol strongly enhanced transcription of the gp91-phox compared with those of the RA-treatment only. On the other hand, immunoblot analysis revealed that co-treatment with RA and resveratrol caused remarkable accumulation of protein levels of gp91-phox (to 4-fold), p22-phox (to 5-fold) and p47-phox (to 4-fold) compared with those of the RA-treatment alone. In addition, ChIP assay suggested that resveratrol participates in enhancing the gene expression of gp91-phox via promoting acetylation of Lys-9 residues and Lys-14 residues of histone H3 within chromatin around the promoter regions of the gene. These results suggested that resveratrol strongly enhances the RA-induced O 2 - -generating activity via up-regulation of gp91-phox gene expression in U937 cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. All Trans Retinoic Acid, Transforming Growth Factor β and Prostaglandin E2 in Mouse Plasma Synergize with Basophil-Secreted Interleukin-4 to M2 Polarize Murine Macrophages.

    Directory of Open Access Journals (Sweden)

    Victor W Ho

    Full Text Available In previous studies we found that macrophages (MФs from SH2-containing inositol-5'-phosphatase (SHIP deficient mice are M2 polarized while their wild type (WT counterparts are M1 polarized and that this difference in MФ phenotype can be recapitulated during in vitro derivation from bone marrow if mouse plasma (MP, but not fetal calf serum, is added to standard M-CSF-containing cultures. In the current study we investigated the mechanism by which MP skews SHIP-/- but not +/+ MФs to an M2 phenotype. Our results suggest that SHIP-/- basophils constitutively secrete higher levels of IL-4 than SHIP+/+ basophils and this higher level of IL-4 is sufficient to skew both SHIP+/+ and SHIP-/- MФs to an M2 phenotype, but only when MP is present to increase the sensitivity of the MФs to this level of IL-4. MP increases the IL-4 sensitivity of both SHIP+/+ and -/- MФs not by increasing cell surface IL-4 or CD36 receptor levels, but by triggering the activation of Erk and Akt and the production of ROS, all of which play a critical role in sensitizing MФs to IL-4-induced M2 skewing. Studies to identify the factor(s in MP responsible for promoting IL-4-induced M2 skewing suggests that all-trans retinoic acid (ATRA, TGFβ and prostaglandin E2 (PGE2 all play a role. Taken together, these results indicate that basophil-secreted IL-4 plays an essential role in M2 skewing and that ATRA, TGFβ and PGE2 within MP collaborate to dramatically promote M2 skewing by acting directly on MФs to increase their sensitivity to IL-4.

  8. Retinoic acid induces signal transducer and activator of transcription (STAT) 1, STAT2, and p48 expression in myeloid leukemia cells and enhances their responsiveness to interferons.

    Science.gov (United States)

    Matikainen, S; Ronni, T; Lehtonen, A; Sareneva, T; Melén, K; Nordling, S; Levy, D E; Julkunen, I

    1997-06-01

    IFNs are antiproliferative cytokines that have growth-inhibitory effects on various normal and malignant cells. Therefore, they have been used in the treatment of certain forms of cancer, such as chronic myelogenous leukemia and hairy cell leukemia. However, there is little evidence that IFNs would be effective in the treatment of acute myelogenous leukemia, and molecular mechanisms underlying IFN unresponsiveness have not been clarified. Here we have studied the activation and induction of IFN-specific transcription factors signal transducer and activator of transcription (STAT) 1, STAT2, and p48 in all-trans-retinoic acid (ATRA)-differentiated myeloid leukemia cells using promyelocytic NB4, myeloblastic HL-60, and monoblastic U937 cells as model systems. These cells respond to ATRA by growth inhibition and differentiation. We show that in undifferentiated NB4 cells, 2',5'-oligoadenylate synthetase and MxB gene expression is not activated by IFN-alpha, possibly due to a relative lack of signaling molecules, especially p48 protein. However, during ATRA-induced differentiation, steady-state STAT1, STAT2, and especially p48 mRNA and corresponding protein levels were elevated both in NB4 and U937 cells, apparently correlating to an enhanced responsiveness of these cells to IFNs. ATRA treatment of NB4 cells sensitized them to IFN action as seen by increased IFN-gamma activation site DNA-binding activity or by efficient formation of IFN-alpha-specific ISGF3 complex and subsequent oligoadenylate synthetase and MxB gene expression. Lack of p48 expression could be one of the mechanisms of promyelocytic leukemia cell escape from growth-inhibitory effects of IFN-alpha.

  9. Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yadong; Dong, Shiyi; Wang, Weicai; Wang, Jianning [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Wang, Miao [Department of Oral and Maxillofacial Surgery, Kiang Wu Hospital, Macao (China); Chen, Mu [Department of Stomatology, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen (China); Hou, Jinsong [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Huang, Hongzhang, E-mail: drhuang52@163.com [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China)

    2016-08-26

    Administration of all-trans retinoic acid (atRA) on E12.0 (embryonic day 12.0) leads to failure of medial edge epithelium (MEE) disappearance and cleft palate. However, the molecular mechanism underlying the relationship between atRA and MEE remains to be identified. In this study, atRA (200 mg/kg) administered by gavage induced a 75% incidence of cleft palate in C57BL/6 mice. Notch1 was up-regulated in MEE cells in the atRA-treated group compared with the controls at E15.0, together with reduced apoptosis and elevated proliferation. Next, we investigated the mechanisms underlying atRA, Notch1 and MEE degradation in palate organ culture. Our results revealed that down-regulation of Notch1 partially rescued the inhibition of atRA-induced palate fusion. Molecular analysis indicated that atRA increased the expression of Notch1 and Rbpj and decreased the expression of P21. In addition, depletion of Notch1 expression decreased the expression of Rbpj and increased the expression of P21. Moreover, inhibition of Rbpj expression partially reversed atRA-induced MEE persistence and increased P21 expression. These findings demonstrate that atRA inhibits MEE degradation, which in turn induces a cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway. - Highlights: • atRA exposure on E12.0 induced MEE persistence and cleft palate. • Notch1 was up-regulated in MEE cells in the atRA-treated embryos. • atRA inhibits MEE degradation, which in turn induces cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway.

  10. Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Jingzhou Hu

    Full Text Available The retinoic-acid-inducible gene (RIG-like receptor (RLR family proteins are major pathogen reorganization receptors (PRR responsible for detection of viral RNA, which initiates antiviral response. Here, we evaluated the functional role of one RLR family member, RIG-I, in human head and neck squamous cell carcinoma (HNSCC. RIG-I is abundantly expressed both in poorly-differentiated primary cancer and lymph node metastasis, but not in normal adjacent tissues. Activation of RIG-I by transfection with low dose of 5'-triphosphate RNA (3p-RNA induces low levels of interferon and proinflammatory cytokines and promotes NF-κB- and Akt-dependent cell proliferation, migration and invasion. In contrast, activation of RIG-I by a high dose of 3p-RNA induces robust mitochondria-derived apoptosis accompanied by decreased activation of Akt, which is independent of the interferon and TNFα receptor, but can be rescued by over-expression of constitutively active Akt. Furthermore, co-immunoprecipitation experiments indicate that the CARD domain of RIG-I is essential for inducing apoptosis by interacting with caspase-9. Together, our results reveal a dual role of RIG-I in HNSCC through regulating activation of Akt, in which RIG-I activation by low-dose viral dsRNA increases host cell survival, whereas higher level of RIG-I activation leads to apoptosis. These findings highlight the therapeutic potential of dsRNA mediated RIG-I activation in the treatment of HNSCC.

  11. Teratogenicity Induced By 13-Cis-Retinoic Acid and/or Gamma Irradiation on Bone of Fetuses and Placenta of Pregnant Albino Rats

    International Nuclear Information System (INIS)

    Ramadan, F.L.; Ismail, N.H.

    2011-01-01

    Isotretinoin (13-cis retinoic acid) has revolutionized the management of severe treatment-resistant acne and it has been widely used for a range of dermatological conditions. During pregnancy, high incidence of developmental anomalies were occurred in pregnant rats given isotretinion and/or exposed to gamma irradiation on specific days during organogenesis. The objective of this study was to evaluate the side effects of isotretinoin administration and/or exposure to gamma radiation on the placenta of pregnant rats, vertebrae and neural spine of their fetuses. Isotretinoin at the dose level 70 mg/kg was daily administered via an oral stomach tube to pregnant adult albino rats from the 11th to 15th days of pregnancy while mothers were subjected to gamma radiation 1.5 Gy as fractionated dose (0.5 Gy/3 times) on the 11th, 12th and 13th day of gestation. The experimental investigations carried out one day prior to parturition (the 20 th day of gestation) have demonstrated that isotretinoin intake from the 11th-15th days of gestation induced embryological, biochemical, histochemical and histopathological disorders in irradiated mothers and their fetuses. The data obtained revealed that isotretinoin administration and/or gamma irradiation caused significant elevation in alkaline phosphatase accompanied by a decline in total protein and DNA in the placenta tissues and vertebrae bone. In addition, histopathological results showed different distortions in the placenta which varied from necrotic nuclei of giant cells, haemorrhage and pyknotic nuclei in trophoblast. Moreover, ill-shaped vertebrae with degenerated osteogenic layers and reduced number of chondrocytes together with severe damage in spine neural arch were viewed. In conclusion, isotretinoin is a serious and powerful drug and should be used with great caution, therefore, it is recommended that radiation workers especially females have to be careful toward isotretinoin intake during pregnancy.

  12. All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo.

    Science.gov (United States)

    Ma, Hayley S; Greenblatt, Sarah M; Shirley, Courtney M; Duffield, Amy S; Bruner, J Kyle; Li, Li; Nguyen, Bao; Jung, Eric; Aplan, Peter D; Ghiaur, Gabriel; Jones, Richard J; Small, Donald

    2016-06-09

    FMS-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia (AML) portends a poor prognosis, and ineffective targeting of the leukemic stem cell (LSC) population remains one of several obstacles in treating this disease. All-trans retinoic acid (ATRA) has been used in several clinical trials for the treatment of nonpromyelocytic AML with limited clinical activity observed. FLT3 tyrosine kinase inhibitors (TKIs) used as monotherapy also achieve limited clinical responses and are thus far unable to affect cure rates in AML patients. We explored the efficacy of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication (ITD)(+) LSCs. Our studies reveal highly synergistic drug activity, preferentially inducing apoptosis in FLT3/ITD(+) cell lines and patient samples. Colony-forming unit assays further demonstrate decreased clonogenicity of FLT3/ITD(+) cells upon treatment with ATRA and TKI. Most importantly, the drug combination depletes FLT3/ITD(+) LSCs in a genetic mouse model of AML, and prolongs survival of leukemic mice. Furthermore, engraftment of primary FLT3/ITD(+) patient samples is reduced in mice following treatment with FLT3 TKI and ATRA in combination, with evidence of cellular differentiation occurring in vivo. Mechanistically, we provide evidence that the synergism of ATRA and FLT3 TKIs is at least in part due to the observation that FLT3 TKI treatment upregulates the antiapoptotic protein Bcl6, limiting the drug's apoptotic effect. However, cotreatment with ATRA reduces Bcl6 expression to baseline levels through suppression of interleukin-6 receptor signaling. These studies provide evidence of the potential of this drug combination to eliminate FLT3/ITD(+) LSCs and reduce the rate of relapse in AML patients with FLT3 mutations.

  13. Effect of All-Trans Retinoic Acid (ATRA against expression of Matrix Metalloproteinase-2 (MMP-2 in model mice (Rattus norvegicus periodontitis

    Directory of Open Access Journals (Sweden)

    Ilma Soraya

    2017-08-01

    Full Text Available Introduction: Periodontitis is a condition of inflammation of the tooth supporting tissues generally caused by bacteria Phorphyromonas gingivalis (Pg. and is usually characterized by the occurrence of the alveolar bone resorption. Matrix metalloproteinase-2 (MMP-2 is an enzyme that plays an important role in inflammatory conditions. All-trans retinoic acid (ATRA is a metabolite of vitamin A which plays a role in healing the inflamed tissue and maintain the immune system. The purpose of this study was to determine the effect of ATRA on the expression of MMP-2 in mouse models Rattus norvegicus of periodontitis. Methods: Experimental laboratory by using post test only with control group design. This study used 25 male Wistar mice (Rattus norvegicus that divided into 5 groups. Group 1 (G1 is a group of healthy mice, group 2 (G2 is a group of sick mice as induced periodontitis without treatment, group 3 (G3 is a group of periodontitis mice treated with 5 mg/kg dose of ATRA, group 4 (G4 is a group of periodontitis mice treated with 10 mg/kg dose of ATRA, group 5 (G5 is a group of periodontitis mice treated with 20 mg/kg dose of ATRA. Periodontitis induction was induced by Pg. bacteria every 3 days for 28 days and followed by administration of ATRA for 7 days. Expression of MMP-2 from gingival tissues and periodontal ligament was obtained by immunohistochemical methods. Results were analyzed using the Shapiro-Wilk Test and Mann-Whitney Test. Results: The results showed there were significant differences in the positive area of MMP-2 and MMP-2 color intensity (p < 0.05 between groups. Conclusion: ATRA dose of 20 mg/kg is the most effective dose in inhibiting the expression of MMP-2 in mice models of periodontitis when compared with the dose on other groups.

  14. Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I.

    Directory of Open Access Journals (Sweden)

    Seung Bum Park

    Full Text Available Hepatitis C virus (HCV actively evades host interferon (IFN responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP and poly(IC. The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in the full-length HCV sequence (JFH1 genotype 2a strain were made to introduce premature termination codons in the -2/+1 reading frame coding for F/ARFP while preserving the original reading frame, which enhanced IFNα and IFNβ induction by HCV. The potentiation of IFN response by the F/ARFP mutations was diminished in Huh7.5 cells, which already have a defective RIG-I, and by decreasing RIG-I expression in Huh7 cells. Furthermore, adding F/ARFP back via trans-complementation suppressed IFN induction in the F/ARFP mutant. The F/ARFP mutants, on the other hand, were not resistant to exogenous IFNα. Finally, HCV-infected human liver samples showed significant F/ARFP antibody reactivity, compared to HCV-uninfected control livers. Therefore, HCV F/ARFP likely cooperates with other viral factors to suppress type I and III IFN induction occurring through the RIG-I signaling pathway. This study identifies a novel mechanism of pattern recognition receptor modulation by HCV and suggests a biological function of the HCV alternate reading frame in the modulation of host innate immunity.

  15. All-trans-retinoic Acid Modulates the Plasticity and Inhibits the Motility of Breast Cancer Cells: ROLE OF NOTCH1 AND TRANSFORMING GROWTH FACTOR (TGFβ).

    Science.gov (United States)

    Zanetti, Adriana; Affatato, Roberta; Centritto, Floriana; Fratelli, Maddalena; Kurosaki, Mami; Barzago, Maria Monica; Bolis, Marco; Terao, Mineko; Garattini, Enrico; Paroni, Gabriela

    2015-07-17

    All-trans-retinoic acid (ATRA) is a natural compound proposed for the treatment/chemoprevention of breast cancer. Increasing evidence indicates that aberrant regulation of epithelial-to-mesenchymal transition (EMT) is a determinant of the cancer cell invasive and metastatic behavior. The effects of ATRA on EMT are largely unknown. In HER2-positive SKBR3 and UACC812 cells, showing co-amplification of the ERBB2 and RARA genes, ATRA activates a RARα-dependent epithelial differentiation program. In SKBR3 cells, this causes the formation/reorganization of adherens and tight junctions. Epithelial differentiation and augmented cell-cell contacts underlie the anti-migratory action exerted by the retinoid in cells exposed to the EMT-inducing factors EGF and heregulin-β1. Down-regulation of NOTCH1, an emerging EMT modulator, is involved in the inhibition of motility by ATRA. Indeed, the retinoid blocks NOTCH1 up-regulation by EGF and/or heregulin-β1. Pharmacological inhibition of γ-secretase and NOTCH1 processing also abrogates SKBR3 cell migration. Stimulation of TGFβ contributes to the anti-migratory effect of ATRA. The retinoid switches TGFβ from an EMT-inducing and pro-migratory determinant to an anti-migratory mediator. Inhibition of the NOTCH1 pathway not only plays a role in the anti-migratory action of ATRA; it is relevant also for the anti-proliferative activity of the retinoid in HCC1599 breast cancer cells, which are addicted to NOTCH1 for growth/viability. This effect is enhanced by the combination of ATRA and the γ-secretase inhibitor N-(N-(3,5-difluorophenacetyl)-l-alanyl)-S-phenylglycine t-butyl ester, supporting the concept that the two compounds act at the transcriptional and post-translational levels along the NOTCH1 pathway. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Retinoic acid-pretreated Wharton's jelly mesenchymal stem cells in combination with triiodothyronine improve expression of neurotrophic factors in the subventricular zone of the rat ischemic brain injury.

    Science.gov (United States)

    Sabbaghziarani, Fatemeh; Mortezaee, Keywan; Akbari, Mohammad; Kashani, Iraj Ragerdi; Soleimani, Mansooreh; Moini, Ashraf; Ataeinejad, Nahid; Zendedel, Adib; Hassanzadeh, Gholamreza

    2017-02-01

    Stroke is the consequence of limited blood flow to the brain with no established treatment to reduce the neurological deficits. Focusing on therapeutic protocols in targeting subventricular zone (SVZ) neurogenesis has been investigated recently. This study was designed to evaluate the effects of retinoic acid (RA)-pretreated Wharton's jelly mesenchymal stem cells (WJ-MSCs) in combination with triiodothyronine (T3) in the ischemia stroke model. Male Wistar rats were used to induce focal cerebral ischemia by middle cerebral artery occlusion (MCAO). There were seven groups of six animals: Sham, Ischemic, WJ-MSCs, RA-pretreated WJ-MSCs, T3, WJ-MSCs +T3, and RA-pretreated WJ-MSCs + T3. The treatment was performed at 24 h after ischemia, and animals were sacrificed one week later for assessments of retinoid X receptor β (RXRβ), brain-derived neurotrophic factor (BDNF), Sox2 and nestin in the SVZ. Pro-inflammatory cytokines in sera were measured at days four and seven after ischemia. RXRβ, BDNF, Sox2 and nestin had the significant expressions in gene and protein levels in the treatment groups, compared with the ischemic group, which were more vivid in the RA-pretreated WJ-MSCs + T3 (p ≤ 0.05). The same trend was also resulted for the levels of TNF-α and IL-6 at four days after ischemia (p ≤ 0.05). In conclusion, application of RA-pretreated WJ-MSCs + T3 could be beneficial in exerting better neurotrophic function probably via modulation of pro-inflammatory cytokines.

  17. Regulatory CD8{sup +} T cells induced by exposure to all-trans retinoic acid and TGF-{beta} suppress autoimmune diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Kishi, Minoru [Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Yasuda, Hisafumi, E-mail: yasuda@med.kobe-u.ac.jp [Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan); Abe, Yasuhisa; Sasaki, Hirotomo; Shimizu, Mami; Arai, Takashi; Okumachi, Yasuyo; Moriyama, Hiroaki; Hara, Kenta; Yokono, Koichi; Nagata, Masao [Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017 (Japan)

    2010-03-26

    Antigen-specific regulatory CD4{sup +} T cells have been described but there are few reports on regulatory CD8{sup +} T cells. We generated islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific regulatory CD8{sup +} T cells from 8.3-NOD transgenic mice. CD8{sup +} T cells from 8.3-NOD splenocytes were cultured with IGRP, splenic dendritic cells (SpDCs), TGF-{beta}, and all-trans retinoic acid (ATRA) for 5 days. CD8{sup +} T cells cultured with either IGRP alone or IGRP and SpDCs in the absence of TGF-{beta} and ATRA had low Foxp3{sup +} expression (1.7 {+-} 0.9% and 3.2 {+-} 4.5%, respectively). In contrast, CD8{sup +} T cells induced by exposure to IGRP, SpDCs, TGF-{beta}, and ATRA showed the highest expression of Foxp3{sup +} in IGRP-reactive CD8{sup +} T cells (36.1 {+-} 10.6%), which was approximately 40-fold increase compared with that before induction culture. CD25 expression on CD8{sup +} T cells cultured with IGRP, SpDCs, TGF-{beta}, and ATRA was only 7.42%, whereas CD103 expression was greater than 90%. These CD8{sup +} T cells suppressed the proliferation of diabetogenic CD8{sup +} T cells from 8.3-NOD splenocytes in vitro and completely prevented diabetes onset in NOD-scid mice in cotransfer experiments with diabetogenic splenocytes from NOD mice in vivo. Here we show that exposure to ATRA and TGF-{beta} induces CD8{sup +}Foxp3{sup +} T cells ex vivo, which suppress diabetogenic T cells in vitro and in vivo.

  18. Outcome of high-risk stage 3 neuroblastoma with myeloablative therapy and 13-cis-retinoic acid: a report from the Children's Oncology Group.

    Science.gov (United States)

    Park, Julie R; Villablanca, Judith G; London, Wendy B; Gerbing, Robert B; Haas-Kogan, Daphne; Adkins, E Stanton; Attiyeh, Edward F; Maris, John M; Seeger, Robert C; Reynolds, C Patrick; Matthay, Katherine K

    2009-01-01

    The components of therapy required for patients with INSS Stage 3 neuroblastoma and high-risk features remain controversial. A retrospective cohort design was used to determine if intensive chemoradiotherapy with purged autologous bone marrow rescue (ABMT) and/or 13-cis-retinoic acid (13-cis-RA) improved outcome for patients with high-risk neuroblastoma that was not metastatic to distant sites. We identified 72 patients with INSS Stage 3 neuroblastoma enrolled between 1991 and 1996 on the Phase 3 CCG-3891 randomized trial. Patients were analyzed on an intent-to-treat basis using a log-rank test. The 5-year event-free survival (EFS) and overall survival (OS) rates for patients with Stage 3 neuroblastoma were 55 +/- 6% and 59 +/- 6%, respectively (n = 72). Patients randomized to ABMT (n = 20) had 5-year EFS of 65 +/- 11% and OS of 65 +/- 11% compared to 41 +/- 11 (P = 0.21) and 46 +/- 11% (P = 0.23) for patients randomized to CC (n = 23), respectively. Patients randomized to 13-cis-RA (n = 23) had 5-year EFS of 70 +/- 10% and OS of 78 +/- 9% compared to 63 +/- 12% (P = 0.67) and 67 +/- 12% (P = 0.55) for those receiving no further therapy (n = 16), respectively. Patients randomized to both ABMT and 13-cis-RA (n = 6) had a 5-year EFS of 80 +/- 11% and OS of 100%. Patients with high-risk Stage 3 neuroblastoma have an overall poor prognosis despite aggressive chemoradiotherapy. Further studies are warranted to determine if myeloablative consolidation followed by 13-cis-RA maintenance therapy statistically significantly improves outcome.

  19. Outcome of High-Risk Stage 3 Neuroblastoma with Myeloablative Therapy and 13-cis-Retinoic Acid: A Report from the Children’s Oncology Group

    Science.gov (United States)

    Park, Julie R.; Villablanca, Judith G.; London, Wendy B.; Gerbing, Robert B.; Haas-Kogan, Daphne; Stanton Adkins, E.; Attiyeh, Edward F.; Maris, John M.; Seeger, Robert C.; Patrick Reynolds, C.; Matthay, Katherine K.

    2009-01-01

    Background The components of therapy required for patients with INSS Stage 3 neuroblastoma and high risk features remain controversial. Procedure A retrospective cohort design was used to determine if intensive chemoradiotherapy with purged autologous bone marrow rescue (ABMT) and/or 13-cis-retinoic acid (13-cis-RA) improved outcome for patients with high-risk neuroblastoma that was not metastatic to distant sites. We identified 72 patients with INSS Stage 3 neuroblastoma enrolled between 1991 and 1996 on the Phase III CCG 3891 randomized trial. Patients were analyzed on an intent-to-treat basis using a log-rank test. Results The 5-year event-free survival (EFS) and overall survival (OS) rates for patients with Stage 3 neuroblastoma were 55 +/- 6% and 59% +/- 6%, respectively (n=72). Patients randomized to ABMT (n=20) had 5-year EFS of 65% +/- 11% and OS of 65% +/- 11% compared to 41% +/- 11 (p=0.21) and 46% +/- 11% (p=0.23) for patients randomized to CC (n=23), respectively. Patients randomized to 13-cis-RA (n=23) had 5-year EFS of 70% +/- 10% and OS of 78% +/- 9% compared to 63% +/- 12% (p=0.67) and 67% +/- 12% (p=0.55) for those receiving no further therapy (n=16), respectively. Patients randomized to both ABMT and 13-cis-RA (n=6) had a 5-year EFS of 80% ± 11% and OS of 100%. Conclusion Patients with high-risk Stage 3 neuroblastoma have an overall poor prognosis despite aggressive chemoradiotherapy. Further studies are warranted to determine if myeloablative consolidation followed by 13-cis-RA maintenance therapy statistically significantly improves outcome. PMID:18937318

  20. Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice

    International Nuclear Information System (INIS)

    Zhang, Yadong; Dong, Shiyi; Wang, Weicai; Wang, Jianning; Wang, Miao; Chen, Mu; Hou, Jinsong; Huang, Hongzhang

    2016-01-01

    Administration of all-trans retinoic acid (atRA) on E12.0 (embryonic day 12.0) leads to failure of medial edge epithelium (MEE) disappearance and cleft palate. However, the molecular mechanism underlying the relationship between atRA and MEE remains to be identified. In this study, atRA (200 mg/kg) administered by gavage induced a 75% incidence of cleft palate in C57BL/6 mice. Notch1 was up-regulated in MEE cells in the atRA-treated group compared with the controls at E15.0, together with reduced apoptosis and elevated proliferation. Next, we investigated the mechanisms underlying atRA, Notch1 and MEE degradation in palate organ culture. Our results revealed that down-regulation of Notch1 partially rescued the inhibition of atRA-induced palate fusion. Molecular analysis indicated that atRA increased the expression of Notch1 and Rbpj and decreased the expression of P21. In addition, depletion of Notch1 expression decreased the expression of Rbpj and increased the expression of P21. Moreover, inhibition of Rbpj expression partially reversed atRA-induced MEE persistence and increased P21 expression. These findings demonstrate that atRA inhibits MEE degradation, which in turn induces a cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway. - Highlights: • atRA exposure on E12.0 induced MEE persistence and cleft palate. • Notch1 was up-regulated in MEE cells in the atRA-treated embryos. • atRA inhibits MEE degradation, which in turn induces cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway.

  1. All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07-04 study.

    Science.gov (United States)

    Schlenk, Richard F; Lübbert, Michael; Benner, Axel; Lamparter, Alexander; Krauter, Jürgen; Herr, Wolfgang; Martin, Hans; Salih, Helmut R; Kündgen, Andrea; Horst, Heinz-A; Brossart, Peter; Götze, Katharina; Nachbaur, David; Wattad, Mohammed; Köhne, Claus-Henning; Fiedler, Walter; Bentz, Martin; Wulf, Gerald; Held, Gerhard; Hertenstein, Bernd; Salwender, Hans; Gaidzik, Verena I; Schlegelberger, Brigitte; Weber, Daniela; Döhner, Konstanze; Ganser, Arnold; Döhner, Hartmut

    2016-12-01

    The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m 2 , days 6-8; 15 mg/m 2 , days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95).

  2. Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

    Science.gov (United States)

    Kojima, Hiroyuki; Muromoto, Ryuta; Takahashi, Miki; Takeuchi, Shinji; Takeda, Yukimasa; Jetten, Anton M.; Matsuda, Tadashi

    2013-01-01

    The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. However, it remains unclear whether environmental chemicals, including pesticides, have agonistic and/or antagonistic activity against RORα/γ. In this study, we investigated the RORα/γ activity of several azole-type fungicides, and the effects of these fungicides on the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In the ROR-reporter gene assays, five azole-type fungicides (imibenconazole, triflumizole, hexaconazole, tetraconazole and imazalil) suppressed RORα- and/or RORγ-mediated transcriptional activity as did benzenesulphonamide T0901317, a ROR inverse agonist and a liver X receptor (LXR) agonist. In particular, imibenconazole, triflumizole and hexaconazole showed RORγ inverse agonistic activity at concentrations of 10−6 M. However, unlike T0901317, these fungicides failed to show any LXRα/β agonistic activity. Next, five azole-type fungicides, showing ROR inverse agonist activity, were tested on IL-17 mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin. The quantitative RT-PCR analysis revealed that these fungicides suppressed the expression of IL-17 mRNA without effecting RORα and RORγ mRNA levels. In addition, the inhibitory effect of imibenconazole as well as that of T0901317 was absorbed in RORα/γ-knocked down EL4 cells. Taken together, these results suggest that some azole-type fungicides inhibit IL-17 production via RORα/γ. This also provides the first evidence that environmental chemicals can act as modulators of IL-17 expression in immune cells. PMID:22289359

  3. Sensitivity of MLL-rearranged AML cells to all-trans retinoic acid is associated with the level of H3K4me2 in the RARα promoter region

    International Nuclear Information System (INIS)

    Sakamoto, K; Imamura, T; Yano, M; Yoshida, H; Fujiki, A; Hirashima, Y; Hosoi, H

    2014-01-01

    All-trans retinoic acid (ATRA) is well established as differentiation therapy for acute promyelocytic leukemia (APL) in which the PML–RARα (promyelocytic leukemia-retinoic acid receptor α) fusion protein causes blockade of the retinoic acid (RA) pathway; however, in types of acute myeloid leukemia (AML) other than APL, the mechanism of RA pathway inactivation is not fully understood. This study revealed the potential mechanism of high ATRA sensitivity of mixed-lineage leukemia (MLL)-AF9-positive AML compared with MLL-AF4/5q31-positive AML. Treatment with ATRA induced significant myeloid differentiation accompanied by upregulation of RARα, C/EBPα, C/EBPε and PU.1 in MLL-AF9-positive but not in MLL-AF4/5q31-positive cells. Combining ATRA with cytarabine had a synergistic antileukemic effect in MLL-AF9-positive cells in vitro. The level of dimethyl histone H3 lysine 4 (H3K4me2) in the RARα gene-promoter region, PU.1 upstream regulatory region (URE) and RUNX1+24/+25 intronic enhancer was higher in MLL-AF9-positive cells than in MLL-AF4-positive cells, and inhibiting lysine-specific demethylase 1, which acts as a histone demethylase inhibitor, reactivated ATRA sensitivity in MLL-AF4-positive cells. These findings suggest that the level of H3K4me2 in the RARα gene-promoter region, PU.1 URE and RUNX1 intronic enhancer is determined by the MLL-fusion partner. Our findings provide insight into the mechanisms of ATRA sensitivity in AML and novel treatment strategies for ATRA-resistant AML

  4. Effect of weaning status on lipids of Galician Blond veal: total fatty acids and 18:1 cis and trans isomers.

    Science.gov (United States)

    Bispo, Esperanza; Moreno, Teresa; Latorre, Alicia; González, Laura; Herradón, Pedro G; Franco, Daniel; Monserrat, Lorenzo

    2010-10-01

    The effect of weaning at different ages (NW=not weaned, W5=5.5 months and W2=2 months) on fatty acids (FA) of the Longissimus thoracis (LT) muscle was studied in 36 Galician Blond (GB) calves. Total FA (TFA) were determined by gas chromatography (GC) and 18:1 isomers by a combination of reversed-phase high performance liquid chromatography (HPLC) and GC. NW group showed higher (Pconjugated linoleic acid (CLA) and 18:1 trans-11 compared to LT from W5 and W2 calves. W2 calves showed the highest levels of n-6 PUFA (P<0.01), 18:1 trans-10 and 18:1 trans-6/7/8 (P<0.001). Generally, W5 calves had intermediate values for TFA and 18:1 isomers. As the suckling period was longer, GB milk and veal FA profiles became more similar, it seems that muscle FA were partially transmitted by the milk FA intake due to the persistence of the reticular grove closing reflex. Copyright (c) 2010 The American Meat Science Association. Published by Elsevier Ltd.. All rights reserved.

  5. The p85α regulatory subunit of PI3K mediates cAMP-PKA and retinoic acid biological effects on MCF7 cell growth and migration.

    Science.gov (United States)

    Donini, Caterina F; Di Zazzo, Erika; Zuchegna, Candida; Di Domenico, Marina; D'Inzeo, Sonia; Nicolussi, Arianna; Avvedimento, Enrico V; Coppa, Anna; Porcellini, Antonio

    2012-05-01

    Phosphoinositide-3-OH kinase (PI3K) signalling regulates various cellular processes, including cell survival, growth, proliferation and motility, and is among the most frequently mutated pathways in cancer. Although the involvement of p85αPI3K SH2 domain in signal transduction has been extensively studied, the function of the SH3 domain at the N-terminus remains elusive. A serine (at codon 83) adjacent to the N-terminal SH3 domain in the PI3K regulatory subunit p85αPI3K that is phosphorylated by protein kinase A (PKA) in vivo and in vitro has been identified. Virtually all receptors binding p85αPI3K can cooperate with cAMP-PKA signals via phosphorylation of p85αPI3KSer83. To analyse the role of p85αPI3KSer83 in retinoic acid (RA) and cAMP signalling, in MCF7 cells, we used p85αPI3K mutated forms, in which Ser83 has been substituted with alanine (p85A) to prevent phosphorylation or with aspartic acid (p85D) to mimic the phosphorylated residue. We demonstrated that p85αPI3KSer83 is crucial for the synergistic enhancement of RARα/p85αPI3K binding induced by cAMP/RA co-treatment in MCF7 cells. Growth curves, colorimetric MTT assay and cell cycle analysis demonstrated that phosphorylation of p85αPI3KSer83 plays an important role in the control of MCF7 cell proliferation and in RA-induced inhibition of proliferation. Wound healing and transwell experiments demonstrated that p85αPI3KSer83 was also essential both for the control of migratory behaviour and for the reduction of motility induced by RA. This study points to p85αPI3KSer83 as the physical link between different pathways (cAMP-PKA, RA and FAK), and as an important regulator of MCF7 cell proliferation and migration.

  6. Inhibition of fat cell differentiation in 3T3-L1 pre-adipocytes by all-trans retinoic acid: Integrative analysis of transcriptomic and phenotypic data

    Directory of Open Access Journals (Sweden)

    Katharina Stoecker

    2017-03-01

    Full Text Available The process of adipogenesis is controlled in a highly orchestrated manner, including transcriptional and post-transcriptional events. In developing 3T3-L1 pre-adipocytes, this program can be interrupted by all-trans retinoic acid (ATRA. To examine this inhibiting impact by ATRA, we generated large-scale transcriptomic data on the microRNA and mRNA level. Non-coding RNAs such as microRNAs represent a field in RNA turnover, which is very important for understanding the regulation of mRNA gene expression. High throughput mRNA and microRNA expression profiling was performed using mRNA hybridisation microarray technology and multiplexed expression assay for microRNA quantification. After quantitative measurements we merged expression data sets, integrated the results and analysed the molecular regulation of in vitro adipogenesis. For this purpose, we applied local enrichment analysis on the integrative microRNA-mRNA network determined by a linear regression approach. This approach includes the target predictions of TargetScan Mouse 5.2 and 23 pre-selected, significantly regulated microRNAs as well as Affymetrix microarray mRNA data. We found that the cellular lipid metabolism is negatively affected by ATRA. Furthermore, we were able to show that microRNA 27a and/or microRNA 96 are important regulators of gap junction signalling, the rearrangement of the actin cytoskeleton as well as the citric acid cycle, which represent the most affected pathways with regard to inhibitory effects of ATRA in 3T3-L1 preadipocytes. In conclusion, the experimental workflow and the integrative microRNA–mRNA data analysis shown in this study represent a possibility for illustrating interactions in highly orchestrated biological processes. Further the applied global microRNA–mRNA interaction network may also be used for the pre-selection of potential new biomarkers with regard to obesity or for the identification of new pharmaceutical targets.

  7. Synthesis of Phosphatidylcholine Containing Highly Unsaturated Fatty Acid by Phospholipase A2 and Effect on Retinoic Acid Induced Differentiation of HL-60 Cells

    OpenAIRE

    細川, 雅史; 大島, 宏哲; 甲野, 裕之; 高橋, 是太郎; 羽田野, 六男; 小田島, 粛夫

    1993-01-01

    Phosphatidylcholine containing highly unsaturated fatty acid (HUFA-PC) was prepared by porcine pancreatic phospholipase A2, which catalyzed esterification between lysophosphatidylcholine (LPC) and highly unsaturated fatty acid (HUFA), under a scaled-up reaction system. Fatty acid mixture prepared from sardine oil, purified eicosapentaenoic acid (EPA), and purified docosahexaenoic acid (DHA) were used as the substrates of HUFA. The yield of HUFA-PC was 17.0-19.9%. Synthesized phosphatidylcholi...

  8. Dysregulated microRNA clusters in response to retinoic acid and CYP26B1 inhibitor induced testicular function in dogs.

    Directory of Open Access Journals (Sweden)

    Vanmathy R Kasimanickam

    Full Text Available Spermatogenesis is a multistep synchronized process. Diploid spermatogonia differentiate into haploid spermatozoa following mitosis, meiosis and spermiogenesis. Division and differentiation of male germ cells is achieved through the sequential expression of several genes. Numerous mRNAs in the differentiating germ cells undergo post-transcriptional and translational regulation. MiRNAs are powerful negative regulators of mRNA transcription, stability, and translation and recognize their mRNA targets through base-pairing. Retinoic acid (RA signaling is essential for spermatogenesis and testicular function. Testicular RA level is critical for RA signal transduction. This study investigated the miRNAs modulation in an RA- induced testicular environment following the administration of all-trans RA (2 µM and CYP26B1- inhibitor (1 µM compared to control. Eighty four canine mature miRNAs were analyzed and their expression signatures were distinguished using real-time PCR based array technology. Of the miRNAs analyzed, miRNA families such as miR-200 (cfa-miR-200a, cfa-miR-200b and cfa-miR-200c, Mirlet-7 (cfa-let-7a, cfa-let-7b, cfa-let-7c, cfa-let-7g and cfa-let-7f, miR-125 (cfa-miR-125a and cfa-miR-125b, miR-146 (cfa-miR-146a and cfa-miR-146b, miR-34 (cfa-miR-34a, cfa-miR-34b and cfa-miR-34c, miR-23 (cfa-miR-23a and cfa-miR-23b, cfa-miR-184, cfa-miR-214 and cfa-miR-141 were significantly up-regulated with testicular RA intervention via administration of CYP26B1 inhibitor and all-trans-RA and species of miRNA such as cfa-miR-19a, cfa-miR-29b, cfa-miR-29c, cfa-miR-101 and cfa-miR-137 were significantly down-regulated. This study explored information regarding chromosome distribution, human orthologous sequences and the interaction of target genes of miRNA families significantly distinguished in this study using prediction algorithms. This study importantly identified dysregulated miRNA species resulting from RA-induced spermatogenesis. The present

  9. Chmp 1A is a mediator of the anti-proliferative effects of All-trans Retinoic Acid in human pancreatic cancer cells

    Directory of Open Access Journals (Sweden)

    Nguyen Hanh

    2009-02-01

    Full Text Available Abstract Background We recently have shown that Charged multivesicular protein/Chromatin modifying protein1A (Chmp1A functions as a tumor suppressor in human pancreatic tumor cells. Pancreatic cancer has the worst prognosis of all cancers with a dismal 5-year survival rate. Preclinical studies using ATRA for treating human pancreatic cancer suggest this compound might be useful for treatment of pancreatic cancer patients. However, the molecular mechanism by which ATRA inhibits growth of pancreatic cancer cells is not clear. The objective of our study was to investigate whether Chmp1A is involved in ATRA-mediated growth inhibition of human pancreatic tumor cells. Results We performed microarray studies using HEK 293T cells and discovered that Chmp1A positively regulated Cellular retinol-binding protein 1 (CRBP-1. CRBP-1 is a key regulator of All-trans retinoic acid (ATRA through ATRA metabolism and nuclear localization. Since our microarray data indicates a potential involvement of Chmp1A in ATRA signaling, we tested this hypothesis by treating pancreatic tumor cells with ATRA in vitro. In the ATRA-responsive cell lines, ATRA significantly increased the protein expression of Chmp1A, CRBP-1, P53 and phospho-P53 at serine 15 and 37 position. We found that knockdown of Chmp1A via shRNA abolished the ATRA-mediated growth inhibition of PanC-1 cells. Also, Chmp1A silencing diminished the increase of Chmp1A, P53 and phospho-P53 protein expression induced by ATRA. In the ATRA non-responsive cells, ATRA did not have any effect on the protein level of Chmp1A and P53. Chmp1A over-expression, however, induced growth inhibition of ATRA non-responsive cells, which was accompanied by an increase of Chmp1A, P53 and phospho-P53. Interestingly, in ATRA responsive cells Chmp1A is localized to the nucleus, which became robust upon ATRA treatment. In the ATRA-non-responsive cells, Chmp1A was mainly translocated to the plasma membrane upon ATRA treatment. Conclusion

  10. Protective effects of TRH and its analogues against various cytotoxic agents in retinoic acid (RA)-differentiated human neuroblastoma SH-SY5Y cells.

    Science.gov (United States)

    Jaworska-Feil, L; Jantas, D; Leskiewicz, M; Budziszewska, B; Kubera, M; Basta-Kaim, A; Lipkowski, A W; Lason, W

    2010-12-01

    TRH (thyroliberin) and its analogues were reported to possess neuroprotective effects in cellular and animal experimental models of acute and chronic neurodegenerative diseases. In the present study we evaluated effects of TRH and its three stable analogues, montirelin (CG-3703), RGH-2202 and Z-TRH (N-(carbobenzyloxy)-pGlutamyl-Histydyl-Proline) on the neuronally differentiated human neuroblastoma SH-SY5Y cell line, which is widely accepted for studying potential neuroprotectants. We found that TRH and all the tested analogues at concentrations 0.1-50 μM attenuated cell damage induced by MPP(+) (2 mM), 3-nitropropionate (10 mM), hydrogen peroxide (0.5 mM), homocysteine (250 μM) and beta-amyloid (20μM) in retinoic acid differentiated SH-SY5Y cells. Furthermore, we demonstrated that TRH and its analogues decreased the staurosporine (0.5 μM)-induced LDH release, caspase-3 activity and DNA fragmentation, which indicate the anti-apoptotic proprieties of these peptides. The neuroprotective effects of TRH (10 μM) and RGH-2202 (10 μM) on St-induced cell death was attenuated by inhibitors of PI3-K pathway (wortmannin and LY294002), but not MAPK/ERK1/2 (PD98059 and U0126). Moreover, TRH and its analogues at neuroprotective concentrations (1 and 10 μM) increased expression of Bcl-2 protein, as confirmed by Western blot analysis. All in all, these results extend data on neuroprotective properties of TRH and its analogues and provide evidence that mechanism of anti-apoptotic effects of these peptides in SH-SY5Y cell line involves induction of PI3K/Akt pathway and Bcl-2. Furthermore, the data obtained on human cell line with a dopaminergic phenotype suggest potential utility of TRH and its analogues in the treatment of some neurodegenerative diseases including Parkinson's disease. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. All-trans retinoic acid promotes TGF-β-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus.

    Directory of Open Access Journals (Sweden)

    Ling Lu

    Full Text Available It has been documented all-trans retinoic acid (atRA promotes the development of TGF-β-induced CD4(+Foxp3(+ regulatory T cells (iTreg that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs.Addition of atRA to naïve CD4(+CD25(- cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3(+ iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4(+ cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4(+ cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4(+ cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4(+ cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered.We have identified the cellular and molecular mechanism(s by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.

  12. A randomized phase II chemoprevention trial of 13-CIS retinoic acid with or without alpha tocopherol or observation in subjects at high risk for lung cancer.

    Science.gov (United States)

    Kelly, Karen; Kittelson, John; Franklin, Wilbur A; Kennedy, Timothy C; Klein, Catherine E; Keith, Robert L; Dempsey, Edward C; Lewis, Marina; Jackson, Mary K; Hirsch, Fred R; Bunn, Paul A; Miller, York E

    2009-05-01

    No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without alpha tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus alpha tocopherol (13-cis RA/alpha toco) or observation for 12 months. Outcome measures are derived from histologic evaluation of bronchial biopsy specimens obtained by bronchoscopy at baseline and follow-up. The primary outcome measure is treatment "failure" defined as histologic progression (any increase in the maximum histologic score) or failure to return for follow-up bronchoscopy. Seventy-five subjects were randomized (27/22/26 to observations/13-cis RA/13-cis RA/alpha toco); 59 completed the trial; 55 had both baseline and follow-up bronchoscopy. The risk of treatment failure was 55.6% (15 of 27) and 50% (24 of 48) in the observation and combined (13 cis RA plus 13 cis RA/alpha toco) treatment arms, respectively (odds ratio adjusted for baseline histology, 0.97; 95% confidence interval, 0.36-2.66; P = 0.95). Among subjects with complete histology data, maximum histology score in the observation arm increased by 0.37 units and by 0.03 units in the treated arms (difference adjusted for baseline, -0.18; 95% confidence interval, -1.16 to 0.81; P = 0.72). Similar (nonsignificant) results were observed for treatment effects on endobronchial proliferation as assessed by Ki-67 immunolabeling. Twelve-month treatment with 13-cis RA produced nonsignificant changes in bronchial histology, consistent with results in other trials. Agents advancing to phase III randomized trials should produce greater histologic changes. The

  13. A Randomized Phase II Chemoprevention Trial of 13-CIS Retinoic Acid with Or without α Tocopherol or Observation in Subjects at High Risk for Lung Cancer

    Science.gov (United States)

    Kelly, Karen; Kittelson, John; Franklin, Wilbur A.; Kennedy, Timothy C.; Klein, Catherine E.; Keith, Robert L.; Dempsey, Edward C.; Lewis, Marina; Jackson, Mary K.; Hirsch, Fred R.; Bunn, Paul A.; Miller, York E.

    2011-01-01

    No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without α tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus α tocopherol (13-cis RA/α toco) or observation for 12 months. Outcome measures are derived from histologic evaluation of bronchial biopsy specimens obtained by bronchoscopy at baseline and follow-up. The primary outcome measure is treatment “failure” defined as histologic progression (any increase in the maximum histologic score) or failure to return for follow-up bronchoscopy. Seventy-five subjects were randomized (27/22/26 to obervations/13-cis RA/13-cis RA/α toco); 59 completed the trial; 55 had both baseline and follow-up bronchoscopy. The risk of treatment failure was 55.6% (15 of 27) and 50% (24 of 48) in the observation and combined (13 cis RA plus 13 cis RA/α toco) treatment arms, respectively (odds ratio adjusted for baseline histology, 0.97; 95% confidence interval, 0.36–2.66; P = 0.95). Among subjects with complete histology data, maximum histology score in the observation arm increased by 0.37 units and by 0.03 units in the treated arms (difference adjusted for baseline, −0.18; 95% confidence interval, −1.16 to 0.81; P = 0.72). Similar (nonsignificant) results were observed for treatment effects on endobronchial proliferation as assessed by Ki-67 immunolabeling. Twelve-month treatment with 13-cis RA produced nonsignificant changes in bronchial histology, consistent with results in other trials. Agents advancing to phase III randomized trials should produce greater histologic changes. The addition of

  14. Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

    Energy Technology Data Exchange (ETDEWEB)

    Kojima, Hiroyuki, E-mail: kojima@iph.pref.hokkaido.jp [Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819 (Japan); Muromoto, Ryuta; Takahashi, Miki [Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan); Takeuchi, Shinji [Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819 (Japan); Takeda, Yukimasa; Jetten, Anton M. [National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709 (United States); Matsuda, Tadashi [Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812 (Japan)

    2012-03-15

    The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. However, it remains unclear whether environmental chemicals, including pesticides, have agonistic and/or antagonistic activity against RORα/γ. In this study, we investigated the RORα/γ activity of several azole-type fungicides, and the effects of these fungicides on the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In the ROR-reporter gene assays, five azole-type fungicides (imibenconazole, triflumizole, hexaconazole, tetraconazole and imazalil) suppressed RORα- and/or RORγ-mediated transcriptional activity as did benzenesulphonamide T0901317, a ROR inverse agonist and a liver X receptor (LXR) agonist. In particular, imibenconazole, triflumizole and hexaconazole showed RORγ inverse agonistic activity at concentrations of 10{sup −6} M. However, unlike T0901317, these fungicides failed to show any LXRα/β agonistic activity. Next, five azole-type fungicides, showing ROR inverse agonist activity, were tested on IL-17 mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin. The quantitative RT-PCR analysis revealed that these fungicides suppressed the expression of IL-17 mRNA without effecting RORα and RORγ mRNA levels. In addition, the inhibitory effect of imibenconazole as well as that of T0901317 was absorbed in RORα/γ-knocked down EL4 cells. Taken together, these results suggest that some azole-type fungicides inhibit IL-17 production via RORα/γ. This also provides the first evidence that environmental chemicals can act as modulators of IL-17 expression in immune cells. -- Highlights: ► Nuclear receptors, RORα and RORγ, are key regulators of Th17 cell differentiation. ► Five azole-type fungicides act as RORα/γ inverse agonists. ► These fungicides

  15. Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

    International Nuclear Information System (INIS)

    Kojima, Hiroyuki; Muromoto, Ryuta; Takahashi, Miki; Takeuchi, Shinji; Takeda, Yukimasa; Jetten, Anton M.; Matsuda, Tadashi

    2012-01-01

    The retinoic acid receptor-related orphan receptors α and γ (RORα and RORγ), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. However, it remains unclear whether environmental chemicals, including pesticides, have agonistic and/or antagonistic activity against RORα/γ. In this study, we investigated the RORα/γ activity of several azole-type fungicides, and the effects of these fungicides on the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In the ROR-reporter gene assays, five azole-type fungicides (imibenconazole, triflumizole, hexaconazole, tetraconazole and imazalil) suppressed RORα- and/or RORγ-mediated transcriptional activity as did benzenesulphonamide T0901317, a ROR inverse agonist and a liver X receptor (LXR) agonist. In particular, imibenconazole, triflumizole and hexaconazole showed RORγ inverse agonistic activity at concentrations of 10 −6 M. However, unlike T0901317, these fungicides failed to show any LXRα/β agonistic activity. Next, five azole-type fungicides, showing ROR inverse agonist activity, were tested on IL-17 mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin. The quantitative RT-PCR analysis revealed that these fungicides suppressed the expression of IL-17 mRNA without effecting RORα and RORγ mRNA levels. In addition, the inhibitory effect of imibenconazole as well as that of T0901317 was absorbed in RORα/γ-knocked down EL4 cells. Taken together, these results suggest that some azole-type fungicides inhibit IL-17 production via RORα/γ. This also provides the first evidence that environmental chemicals can act as modulators of IL-17 expression in immune cells. -- Highlights: ► Nuclear receptors, RORα and RORγ, are key regulators of Th17 cell differentiation. ► Five azole-type fungicides act as RORα/γ inverse agonists. ► These fungicides suppress

  16. All-trans retinoic acid inhibits the recruitment of ARNT to DNA, resulting in the decrease of CYP1A1 mRNA expression in HepG2 cells

    International Nuclear Information System (INIS)

    Ohno, Marumi; Ikenaka, Yoshinori; Ishizuka, Mayumi

    2012-01-01

    Highlights: ► AHR and ARNT transcriptionally regulate genes related to metabolisms such as CYP1A1. ► We investigated the effect of retinoic acid (RA) on the function of AHR/ARNT. ► RA inhibited the recruitment of ARNT, not AHR, to the regulatory region of CYP1A1. ► It resulted in a reduction of constitutive expression of CYP1A1 to less than half. -- Abstract: Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) are well-conserved transcription factors among species. However, there are a very limited number of reports on the physiological function of AHR, particularly on the regulation of AHR by endogenous compounds. We hence investigated the effects of all-trans retinoic acid (atRA) on cytochrome P450 (CYP) 1A1 gene transcription as a model of AHR-regulated transcription mechanisms in HepG2 cells, a human hepatoma cell line. Treatment with atRA significantly reduced transactivation and expression of CYP1A1 mRNA to less than half of its control value, and this inhibitory effect was mediated by RARα. The result of chromatin immunoprecipitation assay indicated that treatment with atRA at 1–100 nM drastically inhibited the recruitment of ARNT to DNA regions containing xenobiotic responsive elements. In conclusion, atRA at physiological concentrations could reduce AHR-mediated gene transcription via the inhibition of recruitment of ARNT to relevant DNA regions.

  17. Influence of vaginal bacteria and D- and L-lactic acid isomers on vaginal extracellular matrix metalloproteinase inducer: implications for protection against upper genital tract infections.

    Science.gov (United States)

    Witkin, Steven S; Mendes-Soares, Helena; Linhares, Iara M; Jayaram, Aswathi; Ledger, William J; Forney, Larry J

    2013-08-06

    We evaluated levels of vaginal extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP-8) in vaginal secretions in relation to the composition of vaginal bacterial communities and D- and L-lactic acid levels. The composition of vaginal bacterial communities in 46 women was determined by pyrosequencing the V1 to V3 region of 16S rRNA genes. Lactobacilli were dominant in 71.3% of the women, followed by Gardnerella (17.4%), Streptococcus (8.7%), and Enterococcus (2.2%). Of the lactobacillus-dominated communities, 51.5% were dominated by Lactobacillus crispatus, 36.4% by Lactobacillus iners, and 6.1% each by Lactobacillus gasseri and Lactobacillus jensenii. Concentrations of L-lactic acid were slightly higher in lactobacillus-dominated vaginal samples, but most differences were not statistically significant. D-Lactic acid levels were higher in samples containing L. crispatus than in those with L. iners (Pvaginal communities dominated by species of lactobacilli was in concordance with the proportions found in axenic cultures of the various species grown in vitro. Levels of L-lactic acid (Pvaginal concentrations of EMMPRIN and MMP-8 levels were highly correlated (Pinfections. A large proportion of preterm births (>50%) result from infections caused by bacteria originating in the vagina, which requires that they traverse the cervix. Factors that influence susceptibility to these infections are not well understood; however, there is evidence that matrix metalloproteinase (MMP-8) is known to alter the integrity of the cervix. In this work, we show that concentrations of vaginal extracellular matrix metalloproteinase inducer (EMMPRIN) are influenced by members of the vaginal microbial community and concentrations of D- or L-lactic acid isomers in vaginal secretions. Elevated levels of D-lactic acid and the ratio of D- to L-lactic acid influence EMMPRIN concentrations as well as MMP-8 levels. Thus, isomers of lactic acid may function as

  18. Comparative aerobic soil metabolism of fenvalerate isomers

    International Nuclear Information System (INIS)

    Lee, P.W.; Powell, W.R.; Stearns, S.M.; McConnell, O.J.

    1987-01-01

    An aerobic soil metabolism study was conducted to determine the degradation rate of individual isomer of fenvalerate and to assess the potential influence of the RS, SR, and RR isomers to the metabolism of the most insecticidally active SS isomer. Individual [phenoxyphenyl- 14 C]fenvalerate isomers degraded at different rates. The calculated half-lives for the SR, RS, SS, and RR isomers in fenvalerate (racemic mixture) were 155, 89, 108, and 178 days, respectively. The resolved SS isomer degraded at a faster rate with a calculated half-life of 74 days. Racemization of the resolved SS isomer did not occur. A qualitative difference in the chemical nature of soil metabolites between fenvalerate and the resolved SS isomer was not observed. Soil degradation products, phenoxybenzoic acid, 3-(4-hydroxyphenoxy)benzoic acid, and 4'-OH- and CONH 2 -fenvalerate, each accounted for less than 2% of the applied radioactivity. Extensive degradation of these soil metabolites was evident since approximately 50% of the applied radioactivity was recovered as 14 C 2 and as unextractable bound residues

  19. Effect of silage type and concentrate level on conjugated linoleic acids, trans-C18 : 1 isomers and fat content in milk from dairy cows

    DEFF Research Database (Denmark)

    Nielsen, Torben Skov; Straarup, Ellen Marie; Jungersen, Mogens Vestergaard

    2006-01-01

    to one of four diets in a 2 x 2 factorial arrangement of treatments and a six week experimental period. Treatments were total mixed rations with maize (M) or grass (G) silage differing in polyunsaturated fatty acid (PUFA) profile and starch content, combined with a high (H) or a low (L) level......:1 and reduced cis9, trans11-CLA and trans11-C18:1 when maize but not grass silage was provided. The results suggest that high levels of concentrate (grain) do not significantly alter the pattern of PUFA biohydrogenation in the rumen, the concentration of CLA and trans-C18:1 isomers in milk or cause milk fat...

  20. Rhenium(V) oxo complexes relevant to technetium renal imaging agents derived from mercaptoacetylglycylglycylaminobenzoic acid isomers. Structural and molecular mechanics studies

    International Nuclear Information System (INIS)

    Hansen, L.; Taylor, A. Jr; Marzilli, L.G.; Cini, R.

    1992-01-01

    The synthesis and characterization of three rhenium(V) oxo complexes derived from isomers of mercaptoacetylglycylglycylaminobenzoic acid (MAG 2 -ABAH 5 ) are reported. The isomers were synthesized from o-, m- and p-aminobenzoic acid and differed in the position of the terminal carboxyl group. The anions of 8-10, [ReO(MAG 2 -*ABAH)] - (* = para (8), meta (9), ortho (10)), contained the tetraanionic form of the ligands with the carboxyl group protonated. Compounds 8,9, and 10 were synthesized by exchange reactions of ReOCl 3 (Me 2 SO)(Ph 3 P) under moderate conditions and were isolated as [Ph 4 P] + , [Bu 4 N] + , and [Ph 4 P] + salts, respectively. The structures of 8 and 10 were determined by X-ray diffraction methods; except for the location of the carboxyl group, the structures are similar. The coordination geometry is pseudo square pyramidal, with nitrogen and sulfur donor atoms forming a square base and the oxo ligand at the apex. The orientation of the carboxyl group in 10 is anti to the Re double-bond O group. Since the carboxyl groups are protonated in 8 and 10 and in other relevant structures from this class of radiopharmaceuticals including [Ph 4 As][TcO(MAG 3 H)] (MAG 3 H = tetraanionic form of mercaptoacetyltriglycine), the authors developed molecular mechanics parameters that allowed them to calculate the structures of 8, 10, and [TcO(MAG 3 H)] - . They then extended the calculations to all three isomeric complexes in their deprotonated forms and to [TcO(MAG 3 )] 2- in order to approximate their solution phase structures. They conclude that the [TcO(MAG 3 )] 2- species is conformationally flexible, and they have made an initial assessment of structures vs renal clearance

  1. Development and Optimization of an UPLC-QTOF-MS/MS Method Based on an In-Source Collision Induced Dissociation Approach for Comprehensive Discrimination of Chlorogenic Acids Isomers from Momordica Plant Species

    Directory of Open Access Journals (Sweden)

    N. E. Madala

    2014-01-01

    Full Text Available Chlorogenic acids (CGA have been profiled in the leaves of Momordica balsamina, Momordica charantia, and Momordica foetida. All three species were found to contain the trans and cis isomers of 4-acyl para-coumaroylquinic acid (pCoQA, caffeoylquinic acid (CQA, and feruloylquinic acid (FQA. To the best of our knowledge, this is the first report of pCoQA and FQA and their cis isomers in these Momordica species. These profiles were obtained by a newly developed UPLC-qTOF-MS method based on the in-source collision induced dissociation (ISCID method optimized to mimic the MS2 and MS3 fragmentation of an ion trap-based MS. The presence of the cis isomers is believed to be due to high UV exposure of these plants. Furthermore, the absence of the 3-acyl and 5-acyl CGA molecules points to a metabolic mark that is unusual and represents a very interesting biochemical phenotype of these species. Our optimized ISCID method was also shown to be able to distinguish between the geometrical isomers of all three forms of CGA, a phenomenon previously deemed impossible with other common mass spectrometry systems used for CGA analyses.

  2. Teratogenic effect of retinoic acid in swiss mice Efeito teratogênico do ácido retinóico em camundongo swiss

    Directory of Open Access Journals (Sweden)

    Paulo Roberto Veiga Quemelo

    2007-12-01

    Full Text Available PURPOSE: To identify the types of malformations resulting from the administration of retinoic acid (RA to Swiss mice on different days of pregnancy. METHODS: Twenty-four pregnant Swiss mice were divided into 4 groups of 6 animals each. The experimental groups received a single intraperitoneal injection of RA (70 mg/kg on gestational days 7, 8 and 9 (D7, D8 and D9, while control animals (C received only saline solution. RESULTS: Were obtained: exencephaly (C:0; D7:16.1%; D8:25.4%; D9:0, myelomeningocele (C:0; D7:25.8%, D8:30.9%, D9:0, spina bifida occulta (C:0, D7:29%, D8:41.8%, D90, gastroschisis (C:0, D7:6.4% D8:5.4%, D9:0, omphalocele (C:0, D7:6.4%, D8:14.5%, D9:0, lower limb alterations (C:0, D7:74.1%, D8:80%, D9:0, imperforated anus (C:0, D7:100%, D8:100%, D9:100%, and tail agenesis/alteration (C: D7:100%, D8:100%, D9:100%. CONCLUSION: The experimental model using Swiss mice proved to be efficient in the induction of the different types of defects, with the eighth gestational day being the one that most favored the induction of neural tube defect, omphalocele, gastroschisis, lower limb defects, imperforated anus and tail agenesis/alteration. On this basis, this is a useful model for future investigation of neural development and of the formation of the appendicular skeleton.OBJETIVO: Identificar os tipos de malformação resultantes da administração do ácido retinóico (AR a camundongos Swiss em diferentes dias gestacionais. MÉTODOS: Foram utilizados 24 camundongos fêmeas, linhagem Swiss, prenhes, divididos em 4 grupos com 6 animais cada. Os grupos experimentais receberam uma única injeção intraperitoneal de AR (70mg/Kg nos dias gestacionais 7, 8 e 9 (D7, D8 e D9, enquanto que os animais do grupo controle (C receberam apenas solução salina. RESULTADOS: Foram encontrados: exencefalia (C:0; D7:16.1%; D8:25.4%; D9:0; mielomeningocele (C:0; D7:25.8%; D8:30.9%; D9:0; Espina Bífida Oculta (C:0; D7:29%; D8:41.8%; D90; gastrosquise (C:0

  3. Effect of the cryopreservation method used, the embryonic stage and the use of conjugated linoleic acid isomers on the cryotolerance of in vitro-produced bovine embryos

    Directory of Open Access Journals (Sweden)

    Luciana Simões Rafagnin Marinho

    2015-12-01

    Full Text Available Conjugated linoleic acid (CLA might be able to improve the cryotolerance of in vitro-produced (IVP embryos. The effect of two CLA isomers on the cryotolerance of bovine IVP embryos, as well as that of the stage of embryonic development and the method used for cryopreservation was evaluated by three experiments. In Experiment 1, oocytes (n = 3,917 were fertilized in vitro and cultured with 0, 50, 100, or 200 ?M trans-10, cis-12 (t10, c12 CLA. In Experiment 2, fertilized oocytes (n = 2,131 were cultured with 100 ?M t10, c12 or cis-9, trans-11 (c9, t11 CLA, or a combination of both isomers. The embryos were vitrified at the blastocyst (BL or the expanded blastocyst (EB stage. In Experiment 3, oocytes (n = 1,720 were fertilized and cultured with or without 100 ?M t10, c12 CLA, and the blastocysts were vitrified or frozen. Blastocyst development rate as well as the rates of re-expansion and hatching after thawing was recorded. Moreover, the mean cell number and mRNA expression of acetyl-CoA carboxylase (ACC1 and stearoyl-CoA desaturase (SCD1 as well as fatty acid synthase (FASN multienzyme complex were determined. In Experiment 1, the highest concentration of t10, c12 CLA that did not reduce blastocyst development rate was 100 ?M. In Experiment 2, the rates of re-expansion and hatching among the EBs obtained through IVP after supplementation with t10, c12 CLA (73.1% and 57.7%, with c9, t11 CLA (80.0% and 68.6%, with the combination (78.3% and 52.2%, and with the control group (85.4% and 58.3% were similar. At the BL stage, the rates of re-expansion and hatching were lower than those at the EB stage, and CLA combination allowed a hatching rate (8.0% lower than that observed in the control group (40.0%. In Experiment 3, the hatching rates for vitrified EBs (vitrified control; 67.4% and vitrified CLA EBs (65.8% were higher than those obtained for frozen EBs, exposed (13.3% or not exposed (28.6% to CLA. In addition, in Experiment 3, the hatching rate was

  4. Preferential alkali metal adduct formation by cis geometrical isomers of dicaffeoylquinic acids allows for efficient discrimination from their trans isomers during ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry

    CSIR Research Space (South Africa)

    Makola, MM

    2016-03-01

    Full Text Available distinguish between various isomers of flavonoid glycosides, but were able to obtain structural information such as the site of glycosylation on the flavonoid. The metal binding of catechol-containing molecules has also been known for a long time... with serious biological and chemical implications.[34] In mass spectrometry studies, the metal binding/chelation by catechol-containing flavonoids has been noted and used to discriminate between closely related molecules.[35] In the current study...

  5. Acute Coronary Syndrome Manifesting as an Adverse Effect of All-trans-Retinoic Acid in Acute Promyelocytic Leukemia: A Case Report with Review of the Literature and a Spotlight on Management

    Directory of Open Access Journals (Sweden)

    K. Govind Babu

    2016-01-01

    Full Text Available Background. Acute promyelocytic leukemia is characterized by t(15;17. This leads to the formation of PML/RARα which blocks the differentiation of blasts at the stage of promyelocytes. This is reversed by all-trans-retinoic acid (ATRA, a vitamin A derivative. Acute myocardial ischemia is a rare side effect of ATRA. Case Report. We report a case of acute coronary syndrome manifesting as an adverse effect of ATRA in a lady with APL who had no other risk factors for cardiovascular disease. Conclusions. We emphasize the need for high index of suspicion for the diagnosis of this entity. In the light of this case, the rare instances of ATRA associated acute myocardial ischemia recorded in the literature and the options available for treatment of acute promyelocytic leukemia sans ATRA have been reviewed.

  6. Usefulness of {sup 131}I-SPECT/CT and {sup 18}F-FDG PET/CT in evaluating successful {sup 131}I and retinoic acid combined therapy in a patient with metastatics struma ovarii

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Hyo Jung; Lee, In Ki; Kang, Keon Wook; Lee, Dong Soo; Chung, June Key [Dept. of Nuclear Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul (Korea, Republic of); Ryu, Young Hoon [Dept. of Nuclear Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Min, Hye Sook [Dept. of Pathology, Seoul National University Hospital, Seoul (Korea, Republic of); Lee, Dae Hee [Dept. of Oncology, GSAM Hosptial, Gunpo (Korea, Republic of)

    2015-03-15

    Metastatic struma ovarii is an extremely rare disease, and the treatment of choice has not been established. Here, we introduce the case of a 36-year-old female pregnant patient with metastatic struma ovarii. Initial treatment was an exploratory laparotomy to remove multiple peritoneal masses. After delivery, a total thyroidectomy was done for the further {sup 131}I-therapy. {sup 131}I-SPECT/CT and {sup 18}F-FDG PET/CT showed multiple hepatic metastases and extensive peritoneal seeding nodules. Multiple {sup 131}I and retinoic acid combination therapies were performed, resulting in marked improvement. {sup 131}I-SPECT/CT and {sup 18}F-FDG PET/CT were quite useful for evaluating the biologic characteristics of the metastase.

  7. Expression analysis of some genes regulated by retinoic acid in controls and triadimefon-exposed embryos: is the amphibian Xenopus laevis a suitable model for gene-based comparative teratology?

    Science.gov (United States)

    Di Renzo, Francesca; Rossi, Federica; Bacchetta, Renato; Prati, Mariangela; Giavini, Erminio; Menegola, Elena

    2011-06-01

    The use of nonmammal models in teratological studies is a matter of debate and seems to be justified if the embryotoxic mechanism involves conserved processes. Published data on mammals and Xenopus laevis suggest that azoles are teratogenic by altering the endogenous concentration of retinoic acid (RA). The expression of some genes (Shh, Ptch-1, Gsc, and Msx2) controlled by retinoic acid is downregulated in rat embryos exposed at the phylotypic stage to the triazole triadimefon (FON). In order to propose X. laevis as a model for gene-based comparative teratology, this work evaluates the expression of Shh, Ptch-1, Gsc, and Msx2 in FON-exposed X. laevis embryos. Embryos, exposed to a high concentration level (500 µM) of FON from stage 13 till 17, were examined at stages 17, 27, and 47. Stage 17 and 27 embryos were processed to perform quantitative RT-PCR. The developmental rate was never affected by FON at any considered stage. FON-exposed stage 47 larvae showed the typical craniofacial malformations. A significant downregulation of Gsc was observed in FON-exposed stage 17 embryos. Shh, Ptch-1, Msx2 showed a high fluctuation of expression both in control and in FON-exposed samples both at stages 17 and 27. The downregulation of Gsc mimics the effects of FON on rat embryos, showing for this gene a common effect of FON in the two vertebrate classes. The high fluctuation observed in the gene expression of the other genes, however, suggests that X. laevis at this stage has limited utility for gene-based comparative teratology. © 2011 Wiley-Liss, Inc.

  8. All-trans retinoic acid inhibits the recruitment of ARNT to DNA, resulting in the decrease of CYP1A1 mRNA expression in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Ohno, Marumi; Ikenaka, Yoshinori [Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Kita-ku, Sapporo 060-0818 (Japan); Ishizuka, Mayumi, E-mail: ishizum@vetmed.hokudai.ac.jp [Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Kita-ku, Sapporo 060-0818 (Japan)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer AHR and ARNT transcriptionally regulate genes related to metabolisms such as CYP1A1. Black-Right-Pointing-Pointer We investigated the effect of retinoic acid (RA) on the function of AHR/ARNT. Black-Right-Pointing-Pointer RA inhibited the recruitment of ARNT, not AHR, to the regulatory region of CYP1A1. Black-Right-Pointing-Pointer It resulted in a reduction of constitutive expression of CYP1A1 to less than half. -- Abstract: Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) are well-conserved transcription factors among species. However, there are a very limited number of reports on the physiological function of AHR, particularly on the regulation of AHR by endogenous compounds. We hence investigated the effects of all-trans retinoic acid (atRA) on cytochrome P450 (CYP) 1A1 gene transcription as a model of AHR-regulated transcription mechanisms in HepG2 cells, a human hepatoma cell line. Treatment with atRA significantly reduced transactivation and expression of CYP1A1 mRNA to less than half of its control value, and this inhibitory effect was mediated by RAR{alpha}. The result of chromatin immunoprecipitation assay indicated that treatment with atRA at 1-100 nM drastically inhibited the recruitment of ARNT to DNA regions containing xenobiotic responsive elements. In conclusion, atRA at physiological concentrations could reduce AHR-mediated gene transcription via the inhibition of recruitment of ARNT to relevant DNA regions.

  9. Enhancing cytotoxic and apoptotic effect in OVCAR-3 and MDAH-2774 cells with all-trans retinoic acid and zoledronic acid: a paradigm of synergistic molecular targeting treatment for ovarian cancer

    Directory of Open Access Journals (Sweden)

    Kısım Aslı

    2010-07-01

    Full Text Available Abstract Background Ovarian cancer is the most fatal gynecologic malignancies in the world. Although, platinum based treatments are widely used, the disease becomes treatment refractory within two years, and novel treatment options should be searched. All- trans retinoic acid (ATRA induces growth arrest, differentiation and cell death in some types of cancer cells and its combination with various anticancer agents results in enhanced cytotoxicity. Zoledronic acid is a common bisphosphonate known for its anticancer effects beyond its current use in the treatment of cancer-induced bone disease. We aimed to investigate the possible additive/synergistic effect of both agents in OVCAR-3 and MDAH-2774 ovarian cancer cell lines, since both agents show superiority to conventional cytotoxics in terms of adverse events. Methods XTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3/7 activity measurement were used. OligoGeArray® which consists of 112 apoptosis related genes was used to elucidate the genetic changes within cancer cells. To validate our oligoarray results, quantitative real-time PCR was performed on four selected genes that were maximally effected by the combination treatment: lymphotoxin beta receptor (LTBR, myeloid cell leukemia-1 (MCL-1, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A, TNFRSF1A-associated death domain protein (TRADD. Results We demonstrated that a novel combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in both ovarian cancer cells. While the combination therapy significantly induced proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF, TRADD and caspase 4, some of the antiapoptotic genes such as members of MCL-1, LTBR, BAG3 and Bcl-2 family members were inhibited. Conclusions These are the preliminary molecular results of a novel combination treatment of

  10. Conjugated linoleic acid (CLA. Cis 9, trans 11 and trans 10, cis 12 isomer detection in crude and refined corn oils by capillary GC

    Directory of Open Access Journals (Sweden)

    Özlem Tokuşoğlu

    2008-06-01

    Full Text Available Conjugated linoleic acids (CLAs exhibit protective effects against various types of cancer and heart diseases. With the newly developed capillary gas chromatographic method (GC, cis9, trans11 and trans10, cis12 octadecadienoic acid isomers of CLA (C18:2 were determined in crude and refined corn oils as qualitative and quantitative measurements. Cis 9, trans11 C18:2 (c9, t11 CLA was the major CLA isomer in both oils. It was found that c9, t11 CLA was 0.62% of the total lipid in crude oil and 1.24% of the total lipid in refined oil. Using the refining process, the total CLA was 1.38% whereas that of crude corn oil was 0.62%. An approximate 2.2 fold increase in the total CLA was found in refined oil (n = 9 (p y = 2.782x + 0.046 (R2 = 0.9999] were performed (p El ácido linoleico conjugado (CLA parece exhibir efecto protector frente a enfermedades cardiovasculares y varios tipos de cáncer. En este trabajo, se establece un mátodo analítico mediante cromatografía de gases con columna capilar para la determinación cualitativa y cuantitativa de los isómeros cis 9,trans 11 y trans 10, cis 12 en aceites de maiz crudo y refinado. El isómero cis 9, trans11 C18:2 fue el mayoritario encontrándose en concentraciones de 0.62% en el aceite cru,do y de 1.24 % en el aceite refinado. La cantidad total de CLA encontrada en el aceite refinado (n = 9 (p 2 = 0.9999 y de recuperación [y = 2.782x+0.046 (R2 = 0.9999]. El método cromatográfico propuesto podría ser usado para el control de calidad de los aceites vegetales.

  11. Evaluation of the influence of different heat-treatment methods on fatty acids content particulary trans isomers in french fries

    OpenAIRE

    Mojska, H.; Malecka, K.; Gielecinska, I.; Sitek, A.; Pawlicka, M.

    2009-01-01

    The aim of our study was to evaluate the influence of different heat treatment methods on trans fatty acids content in French fries. French fries were heat-treated by using a deep fryer, a frying pan, an oven and a microwave. The fatty acids content was analyzed by high-resolution capillary gas chromatography using MS detector (GC/MS). The highest increase in fat was determined in French fries prepared in deep fryer in comparison to raw French fries, whereas the lowest by using oven and micro...

  12. Determination of 15 isomers of chlorobenzoic acid in soil samples using accelerated sample extraction followed by liquid chromatography

    Czech Academy of Sciences Publication Activity Database

    Křesinová, Zdena; Muzikář, Milan; Olšovská, Jana; Cajthaml, Tomáš

    2011-01-01

    Roč. 84, č. 4 (2011), s. 1141-1147 ISSN 0039-9140 R&D Projects: GA MŠk 2B06156; GA ČR GA525/09/1058 Institutional research plan: CEZ:AV0Z50200510 Keywords : Chlorobenzoic acid * hplc * Accelerated solvent extraction Subject RIV: EE - Microbiology, Virology Impact factor: 3.794, year: 2011

  13. Analogues of arginine vasopressin modified in the N-terminal part of the molecule with pipecolic acid isomers

    Czech Academy of Sciences Publication Activity Database

    Sobolewski, D.; Prahl, A.; Slaninová, Jiřina; Lammek, B.

    2009-01-01

    Roč. 611, - (2009), s. 501-502 ISSN 0065-2598. [American Peptide Society Symposium /20./. 26.06.2007-30.06.2007, Montreal] Institutional research plan: CEZ:AV0Z40550506 Keywords : vasopressin * pipecolic acid * biological activity Subject RIV: CC - Organic Chemistry

  14. The content of conjugated linoleic acid (CLA) isomer groups in milk of two Polish sheep breeds determined by silver ion liquid chromatography (Ag(+)-HPLC).

    Science.gov (United States)

    Rozbicka-Wieczorek, Agnieszka; Radzik-Rant, Aurelia; Rant, Witold; Czauderna, Marian

    2013-01-01

    Sheep milk is rich in CLA isomers which are biologically active components influencing human health. There are four geometric CLA isomer pairs: cis, trans; trans, cis; trans, trans and cis, cis. The aim of the present study was the analysis of CLA isomer groups content by Ag+-HPLC in milk fat of Zelazneńska (ZS) and Wrzosówka (WS) sheep breeds. The ewes of both breeds were kept under the same environmental and nutritional conditions. Milk samples were collected from 60 suckling ewes (30 from each breed), at the age of 3-4 years and in their 4th week of lactation. A higher total amount of all CLA isomer groups was obtained in milk of ZS ewes, however, this result was statistically insignificant. The percentage of the main c9, t11 isomer in total CLA was higher in Wrzosówka milk (68% vs. 74%). The content of the trans, trans isomer group in milk fat of the studied breeds was similar. The percentage of this group in total CLA in milk of WS and ZS constitutes 7.2% and 7.7%, respectively. The amount of cis,cis isomers in milk fat of ZS was higher thanWS (P < or = 0.01).

  15. Efeito do ácido trans-retinóico na inibição de colesteatoma em cobaias Effect of trans-retinoic acid in the inhibition of cholesteatoma in guinea pigs

    Directory of Open Access Journals (Sweden)

    Marcos Luiz Antunes

    2008-02-01

    Full Text Available O colesteatoma de orelha média atingia mais de 5 milhões de pessoas até a década de 80. Vários modelos animais já foram utilizados para alternativas de tratamento do colesteatoma sem sucesso. OBJETIVO: Estudar os efeitos do ácido trans-retinóico, uso tópico na orelha externa em cobaias, na inibição da formação do colesteatoma de orelha média induzido pelo propilenoglicol. Estudo experimental prospectivo. MATERIAL E MÉTODOS: 25 cobaias foram submetidas à aplicação de propilenoglicol a 100% na bula timpânica bilateralmente e uma solução de ácido trans-retinóico foi aplicada topicamente (total de 5 aplicações na orelha externa, região justa-timpânica, na orelha direita, enquanto na orelha esquerda aplicou-se solução fisiológica (orelha controle. As cobaias foram sacrificadas após 6 semanas do procedimento inicial e os ossos temporais foram separados, fixados e descalcificados, para análise macroscópica e histológica. RESULTADOS: Os achados macroscópicos evidenciaram a presença e suspeita de colesteatoma em 25% das orelhas direitas e 85% das orelhas esquerdas (P=0,0003*. Os achados histológicos dos 40 ossos temporais evidenciaram a presença de colesteatoma em 30% das orelhas direitas e 75% das orelhas esquerdas (P=0,0104*. CONCLUSÃO: O uso tópico do ácido trans-retinóico é efetivo na inibição da formação de colesteatoma induzido pelo propilenoglicol em cobaias.Middle ear cholesteatoma affected more than 5 million people until the 80`s. Many animal models were used, unsuccessfully, to study an alternative therapy to cholesteatoma. AIM: observe the effect of the trans-retinoic acid in the inhibition of middle ear cholesteatomas induced by propylene glycol. STUDY DESIGN: Clinical and Experimental. METHODS: 25 guinea pigs were submitted to the application of a 100% propylene glycol solution in their bulla bilaterally and a solution of trans-retinoic acid was applied locally in the external right ear, while

  16. CLA isomer t10,c12 induce oxidation and apoptosis in 3t3 adipocyte cells in a similar effect as omega-3 linolenic acid and DHA.

    Directory of Open Access Journals (Sweden)

    Jon Meadus

    2017-02-01

    Full Text Available Background: Commercial conjugated linoleic acid (CLA dietary supplements contain an equal mixture of the C18:2 isomers, cis-9trans-11 and trans-10cis-12. Predominantly, CLA-c9t11 occurs naturally in meat and dairy products at ~ 0.5% of total fat , whereas CLA-t10c12 occurs at >0.1%. Recent studies show that CLA-c9t11 generally promotes lipid accumulation but CLA-t10c12 may inhibit lipid accumulation and may also promote inflammation. The omega-3 fatty acids α-linolenic acid (C18:3n-3 and docosahexaenoic acid (DHA have also been observed to inhibit lipid accumulation and effect inflammation; therefore we examined the effects of the two main isomersof CLA and omega -3 fatty acids C18:3n-3 and DHA at the molecular levelto determine if they are causing similar oxidative stresses.Methods:Purified CLA-c9t11 and CLA-t10c12 were added to 3T3 cells induced into mature adipocyte cultures at 100uM concentrations and compared with 100uM C18:3n-3(α-linolenic acid and 50uM docosahexaenoic acid (DHA to observe their effect on growth, gene transcription and general oxidation. The results of multiple separate trials were averaged and compared for significance at levels of P< 0.05, using one way ANOVA and Student’s t-test.Results:C18:3n-3, DHA and CLA-t10c12inhibited 3T3 adipose cell growth and caused a significant increase in lipid hydro peroxide activity. CLA-t10c12 and c9t11 increased AFABP, FAS and ACOX1 mRNA gene expression but DHA and C18:3n-3decreased the same mRNAs. CLA-c9t11 but not the t10c12 stimulated adipoQ expression even though; CLA-c9t11 had only a slightly greater affinity for PPARγ than CLA-t10c12, according to TR-FRET assays. The expression of the xenobiotic metabolism genes, aldo-keto reduct as 1c1 (akr1c1, superoxide dismutase (SODand inflammation chemokine secretions of eotaxin (CCL11, Rantes (CCL5, MIG (CCL9 and MCP-1 were increased by DHA, C18:3n-3and CLA-t10c12 but not CLA-c9t11. This correlated with an increase in apoptosis factors

  17. Grass Carp Laboratory of Genetics and Physiology 2 Serves As a Negative Regulator in Retinoic Acid-Inducible Gene I- and Melanoma Differentiation-Associated Gene 5-Mediated Antiviral Signaling in Resting State and Early Stage of Grass Carp Reovirus Infection

    OpenAIRE

    Rao, Youliang; Wan, Quanyuan; Yang, Chunrong; Su, Jianguo

    2017-01-01

    Laboratory of genetics and physiology 2 (LGP2) is a key component of RIG-I-like receptors (RLRs). However, the lack of the caspase recruitment domains (CARDs) results in its controversial functional performance as a negative or positive regulator in antiviral responses. Especially, no sufficient evidence uncovers the functional mechanisms of LGP2 in RLR signaling pathways in teleost. Here, negative regulation mechanism of LGP2 in certain situations in retinoic acid-inducible gene I (RIG-I) an...

  18. Contents of conjugated linoleic acid isomers cis9,trans11 and trans10,cis12 in ruminant and non-ruminant meats available in the Italian market

    Directory of Open Access Journals (Sweden)

    Francesca M. Cicognini

    2014-04-01

    Full Text Available Conjugated linoleic acid (CLA isomers are considered healthy factors due to their anticarcinogenic, anti-atherosclerotic and lipolytic effect. A recommended daily intake from 0.8 to 3 g CLA/day/person has been proposed to obtain biological effects in humans. The aim of this work was to provide data on cis9,trans11 (c9,t11 CLA and trans10,cis12 (t10,c12 CLA contents in meats collected from Italian largescale retail trade and completing a food CLA database. In a first trial, beef loin meats were characterised for label information available for consumers: origin (i.e., Ireland, France- Italy, Piedmont and sex of animals. No differences were observed for c9,t11 and t10,c12 CLA contents (mg/g fat of loin meat from male or female. Piedmontese meat showed lower (P<0.05 c9,t11 CLA level (mg/g fat than Irish and French-Italian meats, whereas similar t10,c12 CLA contents were measured in Piedmontese, Irish and French-Italian meats. Successively, meat samples from different animal species (male and female beef, veal, suckling lamb, belly beef, canned beef meat, pork and horse were characterised for their contents in c9,t11 and t10,c12 CLA. Lamb meat had the highest (P<0.05 c9,t11 CLA content (mg/g fat. The c9,t11 CLA was lower than 2 mg/g fat in veal, pork and horse meats. Low t10,c12 CLA amounts were found in all analysed meat samples. These data provided information to estimate the average daily intake of CLA from meats in an Italian cohort, which can be used in epidemiological studies.

  19. Atlas of Nuclear Isomers

    International Nuclear Information System (INIS)

    Jain, Ashok Kumar; Maheshwari, Bhoomika; Garg, Swati; Patial, Monika; Singh, Balraj

    2015-01-01

    We present an atlas of nuclear isomers containing the experimental data for the isomers with a half-life ≥ 10 ns together with their various properties such as excitation-energy, half-life, decay mode(s), spin-parity, energies and multipolarities of emitted gamma transitions, etc. The ENSDF database complemented by the XUNDL database has been extensively used in extracting the relevant data. Recent literature from primary nuclear physics journals, and the NSR bibliographic database have been searched to ensure that the compiled data Table is as complete and current as possible. The data from NUBASE-12 have also been checked for completeness, but as far as possible original references have been cited. Many interesting systematic features of nuclear isomers emerge, some of them new; these are discussed and presented in various graphs and figures. The cutoff date for the extraction of data from the literature is August 15, 2015

  20. Atlas of Nuclear Isomers

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Ashok Kumar, E-mail: ajainfph@iitr.ac.in [Department of Physics, Indian Institute of Technology, Roorkee-247667 (India); Maheshwari, Bhoomika; Garg, Swati; Patial, Monika [Department of Physics, Indian Institute of Technology, Roorkee-247667 (India); Singh, Balraj [Department of Physics and Astronomy, McMaster University, Hamilton, Ontario-L8S 4M1 (Canada)

    2015-09-15

    We present an atlas of nuclear isomers containing the experimental data for the isomers with a half-life ≥ 10 ns together with their various properties such as excitation-energy, half-life, decay mode(s), spin-parity, energies and multipolarities of emitted gamma transitions, etc. The ENSDF database complemented by the XUNDL database has been extensively used in extracting the relevant data. Recent literature from primary nuclear physics journals, and the NSR bibliographic database have been searched to ensure that the compiled data Table is as complete and current as possible. The data from NUBASE-12 have also been checked for completeness, but as far as possible original references have been cited. Many interesting systematic features of nuclear isomers emerge, some of them new; these are discussed and presented in various graphs and figures. The cutoff date for the extraction of data from the literature is August 15, 2015.

  1. Seniority isomers in nuclei

    International Nuclear Information System (INIS)

    Van Isacker, P

    2011-01-01

    Seniority isomers are nuclear states with an electromagnetic decay that is hindered by selection rules related to the seniority quantum number. A simple analysis is presented of their possible formation with reference to the nickel isotopes 70–76 Ni and the N = 50 isotones from molybdenum to cadmium. It is shown that the existence of seniority isomers in a j = 9/2 shell is predominantly governed by the quadrupole pairing matrix element of the nucleon-nucleon interaction. The analysis is generalized to shells with larger j.

  2. Validation of a Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry Method for Determination of All-Trans Retinoic Acid in Human Plasma and Its Application to a Bioequivalence Study

    Directory of Open Access Journals (Sweden)

    Jing-Bo Peng

    2014-01-01

    Full Text Available A sensitive, reliable and specific LC-MS-MS method was developed and validated for the identification and quantitation of all-trans retinoic acid (ATRA in human plasma. Acitretin was used as the internal standard (IS. After liquid-liquid extraction of 500 μL plasma with methyl tert-butyl ether (MTBE, ATRA and the IS were chromatographed on a HyPURITY C18 column (150 mm × 2.1 mm, 5 μm with the column temperature set at 40 °C. The mobile phase was consisted of 40% phase A (MTBE–methanol–acetic acid, 50:50:0.5, v/v and 60% phase B (water–methanol–acetic acid, 50:50:0.5, v/v with a flow rate of 0.3 mL/min. The API 4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring (MRM mode via the positive electrospray ionization interface using the transition m/z 301.4 → 123.1 for ATRA and m/z 326.9 → 177.1 for IS, respectively. The calibration curve was linear over the range of 0.45–217.00 ng/mL (r ≥ 0.999 with a lower limit of quantitation (LLOQ of 0.45 ng/mL. The intra- and inter-day precisions values were below 8% relative standard deviation and the accuracy was from 98.98% to 106.19% in terms of relative error. The validated method was successfully applied in a bioequivalence study of ATRA in Chinese healthy volunteers.

  3. Role of retinoic receptors in lung carcinogenesis

    Directory of Open Access Journals (Sweden)

    Renyi-Vamos Ferenc

    2008-07-01

    Full Text Available Abstract Several in vitro and in vivo studies have examined the positive and negative effects of retinoids (vitamin A analogs in premalignant and malignant lesions. Retinoids have been used as chemopreventive and anticancer agents because of their pleiotropic regulator function in cell differentiation, growth, proliferation and apoptosis through interaction with two types of nuclear receptors: retinoic acid receptors and retinoid X receptors. Recent investigations have gradually elucidated the function of retinoids and their signaling pathways and may explain the failure of earlier chemopreventive studies. In this review we have compiled basic and recent knowledge regarding the role of retinoid receptors in lung carcinogenesis. Sensitive and appropriate biological tools are necessary for screening the risk population and monitoring the efficacy of chemoprevention. Investigation of retinoid receptors is important and may contribute to the establishment of new strategies in chemoprevention for high-risk patients and in the treatment of lung cancer.

  4. Effects of all-trans retinoic acid on tumor recurrence and metastasis Efecto del ácido trans-retinoico sobre la recidiva tumoral y el desarrollo metastásico

    Directory of Open Access Journals (Sweden)

    I. García-Alonso

    2005-04-01

    Full Text Available Objective: all-trans-retinoic acid (ATRA promotes cell differentiation. We have studied its effect on the local recurrence and metastatic spreading of an experimental rhabdomyosarcoma in rats. Design: syngenic rhabdomyosarcoma cells (S4MH were inoculated s.c. in male WAG/RijCrl rats. After 25 days tumors were excised and a 40% hepatectomy was performed for all animals. Ten days later the rats were sacrificed and a thorough necropsy was performed. The animals were randomly allocated to receive daily doses of ATRA (5 mg/kg, i.p. or its solvent (Clinoleic®/ethanol 90/10, starting three days before surgery until the end of the experiment. Results: ATRA reduced the incidence of local recurrence from 70 to 33% (p Objetivo: el ácido trans-retinoico (ATRA, "all-trans retinoic acid" es un agente inductor de la diferenciación celular. Se estudia su efecto sobre la recidiva local y la diseminación metastásica de los tumores sólidos. Diseño experimental: mediante inoculación subcutánea de células de rabdomiosarcoma (S4MH se ha inducido un tumor en ratas WAG/RijCrl. Tras 25 días, se practicó una tumorectomía y simultáneamente hepatectomía del 40%. Los animales se sacrificaron el día 35, y fueron sometidos a estudio necrópsico. La mitad de los animales fueron tratados con ATRA (5 mg/kg, i.p. desde el día 22 al 35, mientras que los controles recibieron el excipiente (Clinoleico®/etanol 90/10. Resultados: el tratamiento redujo la tasa de recidiva local del 70 al 33% (p < 0,05, aunque no afectó a su tamaño (1,8 vs. 2,0 cc. El volumen medio de las metástasis inguinales se redujo a la sexta parte (0,2 vs. 1,2 cc; p < 0,05, si bien su frecuencia aumentó con el ATRA (86 vs. 29%; p < 0,05. La extensión retroperitoneal del rabdomisoarcoma también se redujo (0,7 vs. 5,1 cc; p < 0,05, aunque no hubo variación en la incidencia (71 vs. 67%. La incidencia de afectación pulmonar (100% en controles se redujo hasta el 33% (p < 0,05, a la vez que el

  5. All-trans retinoic acid inhibits KIT activity and induces apoptosis in gastrointestinal stromal tumor GIST-T1 cell line by affecting on the expression of survivin and Bax protein

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    Taguchi Takahiro

    2010-12-01

    Full Text Available Abstract Background Imatinib, a selective tyrosine kinase inhibitor, has been used as a standard first-line therapy for irresectable and metastasized gastrointestinal stromal tumor (GIST patients. Unfortunately, most patients responding to imatinib will eventually exhibit imatinib-resistance, the cause of which is not fully understood. The serious clinical problem of imatinib-resistance demands alternative therapeutic strategy. This study was conducted to investigate the effect of all-trans retinoic acid (ATRA on GIST cell lines. Methods Cell proliferation was determined by trypan blue dye exclusion test. Western blot analysis was performed to test the expression of activated KIT, its downstream proteins, and apoptosis associated proteins. The cytotoxic interactions of imatinib with ATRA were evaluated using the isobologram of Steel and Peckham. Results and conclusion In this work, for the first time we have demonstrated that ATRA affected on cell proliferation of GIST-T1 and GIST-882 cell line through inhibition of cell growth in a dose dependent manner and induced apoptosis. High dose of ATRA induced morphologic change in GIST-T1 cells, rounded-up cells, and activated the caspase-3 protein. In further examination, we found that the ATRA-induced apoptosis in GIST-T1 cells was accompanied by the down-regulated expression of survivin and up-regulated expression of Bax protein. Moreover, ATRA suppressed the activity of KIT protein in GIST-T1 cells and its downstream signal, AKT activity, but not MAPK activity. We also have demonstrated that combination of ATRA with imatinib showed additive effect by isobologram, suggesting that the combination of ATRA and imatinib may be a novel potential therapeutic option for GIST treatment. Furthermore, the scracht assay result suggested that ATRA was a potential reagent to prevent the invasion or metastasis of GIST cells.

  6. The colocalization potential of HIV-specific CD8+ and CD4+ T-cells is mediated by integrin β7 but not CCR6 and regulated by retinoic acid.

    Directory of Open Access Journals (Sweden)

    Vanessa Sue Wacleche

    Full Text Available CD4(+ T-cells from gut-associated lymphoid tissues (GALT are major targets for HIV-1 infection. Recruitment of excess effector CD8(+ T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8(+ and CD4(+ T-cells into the GALT and explored the role of retinoic acid (RA in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin β7, CCR6, and CXCR3 was identified as a "signature" for HIV-specific but not CMV-specific CD4(+ T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8(+ T-cells also expressed high levels of integrin β7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4(+ versus CD8(+ T-cells. All trans RA (ATRA upregulated the expression of integrin β7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8(+ T-cells may colocalize in excess with CD4(+ T-cells into the GALT via integrin β7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6(+CD4(+ T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8(+ T-cells to migrate in the vicinity of CCR6(+CD4(+ T-cells may facilitate HIV replication and dissemination at mucosal sites.

  7. The retinoic acid-induced up-regulation of insulin-like growth factor 1 and 2 is associated with prolidase-dependent collagen synthesis in UVA-irradiated human dermal equivalents.

    Science.gov (United States)

    Shim, Joong Hyun; Shin, Dong Wook; Lee, Tae Ryong; Kang, Hak Hee; Jin, Sun Hee; Noh, Minsoo

    2012-04-01

    Ultraviolet (UV) A irradiation causes the degeneration of extracellular matrix in the skin dermis, mainly due to disrupted collagen homeostasis, resulting in the photo-aging of human skin. All-trans retinoic acid (ATRA) improves photo-aged human skin in vivo. Although the effects of ATRA on collagen synthesis and MMP regulation are well known, the effects of ATRA on other collagen homeostasis-associated genes have not been elucidated. This study was aimed to study the factors that are pharmacologically associated with the effect of ATRA on collagen homeostasis. The gene transcription profile of collagen homeostasis-associated genes was systematically evaluated in three-dimensional human dermal equivalents (HDEs) following UVA-irradiation and/or ATRA treatment. In addition to the expected changes in MMPs and collagen synthesis in HDEs in response to ATRA, prolidase, an important enzyme in the recycling of proline and hydroxyproline from degraded collagen molecules, was significantly decreased by UVA irradiation, and its down-regulation was antagonized by ATRA. Transfection with a prolidase-specific siRNA led to a significant decrease in procollagen synthesis in human fibroblasts. ATRA inhibited the UVA irradiation-induced decrease in prolidase activity through an insulin-like growth factor (IGF) receptor signaling pathway in HDEs. ARTA increased IGF1 and IGF2 production in HDEs, and neutralizing IGFs with anti-IGF antibodies abolished the effect of ATRA on proliase activity. These data demonstrate that ATRA regulates prolidase activity in HDEs via IGF receptor signaling, suggesting one of the pharmacological mechanisms by which improves photo-aged human skin. Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  8. Mass spectrometric differentiation of linear peptides composed of L-amino acids from isomers containing one D-amino acid residue.

    Science.gov (United States)

    Serafin, Scott V; Maranan, Rhonda; Zhang, Kangling; Morton, Thomas Hellman

    2005-09-01

    MS/MS of electrosprayed ions is shown to have the capacity to discriminate between peptides that differ by configuration about their alpha-carbons. It is not necessary for the peptides to possess tertiary structures that are affected by stereochemistry, since five epimers of the pentapeptide, H2N-Gly-Leu-Ser-Phe-Ala-OH (GLSFA) all display different collisionally activated dissociation (CAD) patterns of their protonated parent ions. The figure of merit, r, is a ratio of ratios of fragment ion abundances between stereoisomers, where r = 1 corresponds to no stereochemical effect. Values of r as high as 3.8 are seen for diastereomer pairs. Stereochemical effects are also seen for the diprotonated dodecapeptide H2N-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-OH (LVFFAEDVGSNK), a tryptic fragment from the amyloid beta-protein. Triply charged complexes of the protonated dodecapeptide with cobalt(II) ions undergo CAD at lower collision energies than do doubly protonated LVFFAEDVGSNK ions. Statistically significant (p < 0.01) differences between the all-L-dodecapeptide and the ones containing a d-serine or a D-aspartic acid are observed.

  9. Effects of exogenous retinol and retinoic acid on the biosynthesis of 14C-mannose labelled glycolipids and glycoproteins in rat liver

    International Nuclear Information System (INIS)

    Sato, Mayumi; DeLuca, L.M.; Muto, Yasutoshi

    1978-01-01

    The in vivo and in vitro effects of retinol and retionic acid was investigated on the synthesis of mannolipids and mannopeptides in rat liver. Weanling male, Wister-strain rats (Japan Clea Inc., Tokyo), weighing 35 to 40g are housed in hanging wire bottom cages and maintained on a vitamin A-deficient diet. The incorporation of 14 C-mannose into glycolipids and glycoproteins showed a decrease in vitamin A-depleted rats as compared with vitamin A-fed rats. The mannose-containing lipids were separated into retinyl phosphate (MRP, R sub(f) 0.2) and dolichyl mannosyl phosphate (DMP, R sub(f) 0.4), respectively, by DEAE-cellulose, silicic acid and thin-layer chromatography. A rapid increase in the synthesis of labelled MPR was observed, exhibiting a peak between 25 and 60 minutes after intraperitoneal administration of retinol to vitamin A-depleted rats. Similarly, administration of retionic acid brought about elevation of 14 C-mannolipid (R sub(f) 0.2) synthesis with a peak at 60 minutes after injection. On the other hand, the incorporation of 14 C-mannose into DMP (R sub(f) 0.4) remained unchanged by such treatment. These results suggest that not only retinol but also retionic acid plays an important biological role in manosyl transfer reaction in rat liver. However, the molecular participation of a metabolite of retionic acid in the formation of manolipid and the structure of such a metabolite remain to be established. (Iwakiri, K.)

  10. Destruction of C2H4O2 isomers in ice-phase by X-rays: Implication on the abundance of acetic acid and methyl formate in the interstellar medium

    Science.gov (United States)

    Rachid, Marina G.; Faquine, Karla; Pilling, S.

    2017-12-01

    The C2H4O2 isomers methyl formate (HCOOCH3), acetic acid (CH3COOH) and glycoaldehyde (HOCH2CHO) have been detected in molecular clouds in the interstellar medium, as well as, hot cores, hot corinos and around protostellar objects. However, their abundances are very different, being methyl formate more abundant than the other two isomers. This fact may be related to the different destruction by ionizing radiation of these molecules. The goal of this work is experimentally study the photodissociation processes of methyl formate and acetic acid ices when exposed to broadband soft X-ray from 6 up to 2000 eV. The experiments were performed coupled to the SGM beamline in the Brazilian Synchrotron Light Source (LNLS/CNPEM) at Campinas, Brazil. The simulated astrophysical ices (12 K) were monitored throughout the experiment using infrared vibrational spectroscopy (FTIR). The analysis of processed ices allowed the determination of the effective destruction cross sections of the parent molecules as well as the effective formation cross section of daughter molecular species such as CO, CO2, H2O, CH4 and H2CO (only for methyl formate) and the hydrocarbons C2H6 and C5H10 (only for acetic acid). The half-lives of molecules at ices toward young stellar objects (YSOs) and inside molecular clouds (e.g. Sgr B2 and W51) due to the presence of incoming soft X-rays were estimated. We determined the effective formation rate and the branching ratios for assigned daughter species after the establishment of a chemical equilibrium. The main product from photodissociation of both methyl formate and acetic acid is CO, that can be formed by recombination of ions, formed during the photodissociation, in the ice surface. The relative abundance between methyl formate and acetic acid (NCH3COOH/NHCOOCH3) in different astronomical scenarios and their column density evolution in the presence of X-rays were calculated. Our results suggest that such radiation field can be one of the factors that

  11. Diagnostic fragment-ion-based and extension strategy coupled to DFIs intensity analysis for identification of chlorogenic acids isomers in Flos Lonicerae Japonicae by HPLC-ESI-MS(n).

    Science.gov (United States)

    Zhang, Jia-Yu; Zhang, Qian; Li, Ning; Wang, Zi-Jian; Lu, Jian-Qiu; Qiao, Yan-Jiang

    2013-01-30

    A method of modified diagnostic fragment-ion-based extension strategy (DFIBES) coupled to DFIs (diagnostic fragmentation ions) intensity analysis was successfully established to simultaneously screen and identify the chlorogenic acids (CGAs) in Flos Lonicerae Japonicae (FLJ) by HPLC-ESI-MS(n). DFIs, such as m/z 191 [quinic acid-H](-), m/z 179 [caffeic acid-H](-) and m/z 173 [quinic acid-H-H2O](-) were determined or proposed from the fragmentation patterns analysis of corresponding reference substances for every chemical family of CGAs. A "structure extension" method was then proposed based on the well-demonstrated fragmentation patterns and was successively applied into the rapid screening of CGAs in FLJ. Considering that substitution isomerism is a common phenomenon, a full ESI-MS(n) fragmentation analysis according to the intensity of DFIs has been performed to identify the CGA isomers. Based on the DFIs and intensity analysis, 41 peaks attributed to CGAs including 4 caffeoylquinic acids (CQA), 7 CQA glycosides, 6 dicaffeoylquinic acids (DiCQA), 10 DiCQA glycosides, 1 tricaffeoylquinic acids (TriCQA), 4p-coumaroylquinic acids (pCoQA), 3 feruloylquinic acids (FQA) and 6 caffeoylferuloylquinic acids (CFQA) were identified preliminarily in a 65-min chromatographic run. It was the first time to systematically report the presence of CGAs in FLJ, especially for CQA glycosides, DiCQA glycosides, TriCQA, pCoQA and CFQA. All the results indicated that the method of developed DFIBES coupled to DFIs analysis was feasible, reliable and universal for screening and identifying the constituents with the same carbon skeletons especially the isomeric compounds from the complex extract of TCMs. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Retinoic acid-induced granulocytic differentiation of HL60 human promyelocytic leukemia cells is preceded by downregulation of autonomous generation of inositol lipid-derived second messengers

    International Nuclear Information System (INIS)

    Porfiri, E.; Hoffbrand, A.V.; Wickremasinghe, R.G.

    1991-01-01

    Inositol phosphates (InsPs) and diacyglycerol (DAG) are second messengers derived via the breakdown of inositol phospholipids, and which play important signalling roles in the regulation of proliferation of some cell types. The authors have studied the operation of this pathway during the early stages of retionic acid (RA)-induced granulocytic differentiation of HL60 myeloid leukemia cells. The autonomous breakdown of inositol lipids that occurred in HL60 cells labeled with [3H] inositol was completely abolished following 48 hours of RA treatment. The rate of influx of 45Ca2+ was also significantly decreased at 48 hours, consistent with the role of inositol lipid-derived second messengers in regulating Ca2+ entry into cells. The downregulation of inositol lipid metabolism clearly preceded the onset of reduced proliferation induced by RA treatment, and was therefore not a consequence of decreased cell growth. The generation of InsPs in RA-treated cells was reactivated by the fluoroaluminate ion, a direct activator of guanine nucleotide-binding protein(s) (G proteins) that regulate the inositol lipid signalling pathway. Subtle alterations to a regulatory mechanism may therefore mediate the RA-induced downregulation of this pathway. The data are consistent with the hypothesis that the autonomous generation of inositol lipid-derived second messengers may contribute to the continuous proliferation of HL60 cells, and that the RA-induced downregulation of this pathway may, in turn, play a role in signalling the cessation of proliferation that preceedes granulocytic differentiation

  13. Osteotoxicity after chronic dietary administration of 13-CIS-retinoic acid, retinyl palmitate or selenium in mice exposed to tumor initiation and promotion

    International Nuclear Information System (INIS)

    Forsyth, K.S.; Gensler, H.L.; Watson, R.R.

    1989-01-01

    In view of the clinical trials of retinoids as therapeutic agents for premalignant skin lesions, a radiographic study was undertaken to measure skeletal toxicities after chronic dietary administration of retinoids in mice exposed to tumor initiation and promotion. CD-1 mice were initiated with 0.15 moles of 7,12-dimethylbenz[a]anthracene and promoted twice daily with 8 nmoles of 12-O-tetradecanoylphorbol-13-acetate for 23 weeks. Diets were supplemented with 60 IU, 200 IU, or 700 IU or retinyl palmitate (RP) per g diet. After 5 weeks, the 700 IU of RP/g diet was lowered to 350 IU/g diet. Administration of these diets to mice during the 23 weeks of tumor promotion results in a 0-fold, 2-fold, or 10-fold increase in bone fractures, respectively. Osteoporotic bone lesions identified on radiographs rose 0-fold, 0-fold, and 10-fold at the respective doses, whereas metaphyseal flares increased O-fold, 1.4-fold, and 3.6-fold. Bone deformities was augmented O-fold, 1.8-fold and 2.9-fold at the respective doses. Addition of selenium did not alter the bone toxicity of RP. 13-cis-retionic acid (CRA) was less toxic at 700 IU/g diet than was RP at that dose, as evidence by the death of 12 of 70 mice by the 6th week of dietary RP and no deaths in the 35 mice fed 700 IU CRA/g diet for 23 weeks. CRA at 700 IU/g diet resulted in 3/4 as many osteoporotic bones, 1/3 as many bone fractures, 4/5 as many metaphyseal flares, and a similar number of bone deformities as mice fed 700/350 IU/g diet. At the dose of 200 IU/g food, osterotoxicities were similar in the mice fed diets supplemented with RP and CRA

  14. Development of a validated UPLC method for simultaneous estimation of both free and entrapped (in solid lipid nanoparticles) all-trans retinoic acid and cholecalciferol (vitamin D3) and its pharmacokinetic applicability in rats.

    Science.gov (United States)

    Kumar, Manoj; Sharma, Gaurav; Singla, Dinesh; Singh, Sukhjeet; Sahwney, Sudhir; Chauhan, Anurag S; Singh, Gagandeep; Kaur, Indu Pal

    2014-03-01

    A sensitive ultra-performance liquid chromatography (UPLC) method was developed for simultaneous estimation of all-trans retinoic acid (ATRA) and cholecalciferol (vitamin D3) in rat plasma. The method was validated over the linear range of 1.0-5000ng/ml (r(2)=0.999) for both vitamins with a limit of detection of 0.5ng/ml. Chromatographic separation was achieved using liquid-liquid extraction (LLE) on an Acquity BEH RP 18 column (2.1mm×50mm, I.D. 1.7μm), with mobile phase comprising of acetonitrile:methanol:water (90:8:2, v/v/v), at a flow rate of 0.20ml/min and a total run time of 5min. Intra and inter-day variability (RSD) was ≤3.1%, and the accuracy varied between 95.4-99.9% and 95.3-101.1% respectively, for ATRA and 98.5-100.8% and 99.3-101.7%, respectively for vitamin D3. High recovery of ≥96.0% for ATRA and ≥87.80% for vitamin D3 was achieved. ATRA and vitamin D3 were stable in plasma under different storage and processing conditions. The method was applied to estimate the total drug content and entrapment efficiency of ATRA and vitamin D3 loaded solid lipid nanoparticles (SLNs). Concentration of these two agents was determined in rat plasma after simultaneous subcutaneous administration in free form or when loaded into SLNs thus establishing pharmacokinetic application of the developed procedure. Results indicated an improvement in AUC0-∞ by 5.4 times and 29.4 times for ATRA and vitamin D3, respectively, upon their incorporation into SLNs. Simultaneous administration of these two vitamins and their improved and prolonged bioavailability has scope for their use in treatment and control of tuberculosis. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Bio-based phenolic-branched-chain fatty acid isomers synthesized from vegetable oils and natural monophenols using modified h+-ferrierite zeolite

    Science.gov (United States)

    A new group of phenolic branched-chain fatty acids (n-PBC-FA), hybrid molecules of natural monophenols (i.e., thymol, carvacrol and creosote) and mixed fatty acid (i.e., derived from soybean and safflower oils), were efficiently produced through a process known as arylation. The reaction involves a...

  16. Progressive loss of sensitivity to growth control by retinoic acid and transforming growth factor-beta at late stages of human papillomavirus type 16-initiated transformation of human keratinocytes.

    Science.gov (United States)

    Creek, K E; Geslani, G; Batova, A; Pirisi, L

    1995-01-01

    Retinoids (vitamin A and its natural and synthetic derivatives) have shown potential as chemopreventive agents, and diets poor in vitamin A and/or its precursor beta-carotene have been linked to an increased risk of cancer at several sites including the cervix. Human papillomavirus (HPV) plays an important role in the etiology of cervical cancer. We have developed an in vitro model of cancer progression using human keratinocytes (HKc) immortalized by HPV16 DNA (HKc/HPV16). Although immortal, early passage HKc/HPV16, like normal HKc, require epidermal growth factor (EGF) and bovine pituitary extract (BPE) for proliferation and undergo terminal differentiation in response to serum and calcium. However, following prolonged culture, growth factor independent HKc/HPV16 lines that no longer require EGF and BPE can be selected (HKc/GFI). Further selection of HKc/GFI produces lines that are resistant to serum- and calcium- induced terminal differentiation (HKc/DR). HKc/DR, but not early passage HKc/HPV16, are susceptible to malignant conversion following transfection with viral Harvey ras or Herpes simplex virus type II DNA. We have investigated the sensitivity of low to high passage HKc/HPV16 and HKc/GFI to growth control by all-trans-retinoic acid (RA, an active metabolite of vitamin A). Early passage HKc/HPV16 are very sensitive to growth inhibition by RA, and in these cells RA decreases the expression of the HPV16 oncogenes E6 and E7. However, as the cells progress in culture they lose their sensitivity to RA. Growth inhibition by RA may be mediated through the cytokine transforming growth factor-beta (TGF-beta), a potent inhibitor of epithelial cell proliferation. RA treatment of HKc/HPV16 and HKc/GFI results in a dose-and time-dependent induction (maximal of 3-fold) in secreted levels of TGF-beta. Also, Northern blot analysis of mRNA isolated from HKc/HPV16 demonstrated that RA treatment induced TGF-beta 1 and TGF-beta 2 expression about 3- and 50-fold, respectively

  17. Sensitive GC/MS determination of 15 isomers of chlorobenzoic acids in accelerated solvent extracts of soils historically contaminated with PCBs and validation of the entire method

    Czech Academy of Sciences Publication Activity Database

    Křesinová, Zdena; Hostačná, Lucie; Medková, Jaroslava; Čvančarová, Monika; Stella, Tatiana; Cajthaml, Tomáš

    2014-01-01

    Roč. 94, č. 8 (2014), s. 822-836 ISSN 0306-7319 R&D Projects: GA ČR(CZ) 13-28283S; GA TA ČR TE01020218 Institutional support: RVO:61388971 Keywords : chlorobenzoic acid * GC/MS * separation * PCB * contamination Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 1.295, year: 2014

  18. Differential expression of lactic acid isomers, extracellular matrix metalloproteinase inducer, and matrix metalloproteinase-8 in vaginal fluid from women with vaginal disorders.

    Science.gov (United States)

    Beghini, J; Linhares, I M; Giraldo, P C; Ledger, W J; Witkin, S S

    2015-11-01

    Do metabolites in vaginal samples vary between women with different vaginal disorders. Cross-sectional study. Campinas, Brazil. Seventy-seven women (39.9%) with no vaginal disorder, 52 women (26.9%) with vulvovaginal candidiasis (VVC), 43 women (22.3%) with bacterial vaginosis (BV), and 21 women (10.9%) with cytolytic vaginosis (CTV). Concentrations of D- and L-lactic acid, extracellular matrix metalloproteinase inducer (EMMPRIN), and matrix metalloproteinase-8 (MMP-8), and the influence of Candida albicans on EMMPRIN production by cultured vaginal epithelial cells, were determined by enzyme-linked immunosorbent assay (ELISA). Associations were determined by the Mann-Whitney U-test and by Spearman's rank correlation test. Metabolite levels and their correlation with diagnoses. Vaginal concentrations of D- and L-lactic acid were reduced from control levels in BV (P vaginal epithelial cells. Vaginal secretions from women with BV are deficient in D- and L-lactic acid, women with VVC have elevated EMMPRIN and MMP-8 levels, and women with CTV have elevated L-lactic acid levels. These deviations may contribute to the clinical signs, symptoms, and sequelae that are characteristic of these disorders. © 2014 Royal College of Obstetricians and Gynaecologists.

  19. Comparative evaluation of the cytotoxicity of 5.25% sodium hypochlorite, 2% chlorhexidine and mixture of a tetracycline isomer, an acid and a detergent on human red blood corpuscles: An in-vitro study

    Directory of Open Access Journals (Sweden)

    Krishna Prasad Shetty

    2014-01-01

    Full Text Available Aim: The aim of this study was to analyze the cytotoxicity of various volumes of 5.25% of sodium hypochlorite, 2% of chlorhexidine gluconate and mixture of a tetracycline isomer, an acid and a detergent (MTAD by checking for hemolysis of human red blood corpuscles. Materials and Methods: A total volume of 100 μl of diluted red blood corpuscles obtained through centrifugation was added to three irrigating solutions (5.25% of sodium hypochlorite, 2% of chlorhexidine and MTAD of six test tubes each. Individual irrigants per group were added in increasing volume starting from the second test tube keeping the first one as the control. After incubation for 3 min hemoglobin content was measured using an automated hemoanalyzer data was analyzed using one sample t-test. Results: Sodium hypochlorite is the most cytotoxic solution followed by MTAD and chlorhexidine. Conclusions: This study suggests that the three irrigating solutions do cause detrimental effects on the diluted red blood corpuscles. A great deal of care should therefore be exercised when using 5.25% sodium hypochlorite during endodontic irrigation.

  20. Chemical and physiological aspects of isomers of conjugated fatty acids Aspectos químicos e fisiológicos de isômeros conjugados de ácidos graxos

    Directory of Open Access Journals (Sweden)

    Eliane Bonifácio Teixeira de Carvalho

    2010-06-01

    Full Text Available Conjugated fatty acid (CFA is the general term to describe the positional and geometric isomers of polyunsaturated fatty acids with conjugated double bonds. The CFAs of linoleic acid (CLAs are found naturally in foods derived from ruminant animals, meat, or dairy products. The CFAs of α-linolenic acid (CLNAs are found exclusively in various types of seed oils of plants. There are many investigations to assess the effects to health from CFAs consumption, which have been associated with physiological processes that are involved with non transmissible chronic diseases such as cancer, atherosclerosis, inflammation, and obesity. Conclusive studies about the CFAs effects in the body are still scarce and further research about their participation in physiological processes are necessary. This review aimed to discuss the influence of conjugated fatty acids on physiological processes in animal organism.Ácido graxo conjugado (AGC é o termo geral usado para descrever os isômeros posicionais e geométricos dos ácidos graxos poliinsaturados com duplas ligações conjugadas. Os AGCs do ácido linoléico (ALCs são encontrados naturalmente em alimentos derivados de animais ruminantes, carnes e produtos lácteos. Os AGCs do ácido α-linolênico (ALNCs são encontrados exclusivamente em óleos de sementes de vários tipos de plantas. Desenvolvem-se muitas investigações com o objetivo de avaliar os efeitos do consumo de AGCs para a saúde, já que estes têm sido associados a processos fisiológicos relacionados com doenças crônicas não transmissíveis como câncer, aterosclerose, inflamação e obesidade. Estudos conclusivos sobre os efeitos dos AGCs no organismo humano ainda são raros e mais pesquisas sobre sua atuação em processos fisiológicos são necessárias. O objetivo desta revisão é discutir a influência dos ácidos graxos conjugados sobre os processos fisiológicos.

  1. Can voltammetry distinguish glycan isomers?

    Czech Academy of Sciences Publication Activity Database

    Trefulka, Mojmír; Paleček, Emil

    2015-01-01

    Roč. 69, č. 1 (2015), s. 241-244 ISSN 0366-6352 R&D Projects: GA ČR(CZ) GAP301/11/2055 Institutional support: RVO:68081707 Keywords : oligosaccharide isomers * Os(VI) complexes * chemical modification Subject RIV: BO - Biophysics Impact factor: 1.326, year: 2015

  2. Development of high-spin isomer beams

    International Nuclear Information System (INIS)

    Zhou Xiaohong

    2000-01-01

    The physical motivations with high-spin isomer beams were introduced. Taking HSIB of RIKEN as an example, the methods to produce, separate, transport and purity high-spin isomer beams were described briefly, and the detection of γ rays emitted from the reactions induced by the high-spin isomer beams was presented. Finally, the progress to develop the high-spin isomers in the N = 83 isotones as second beams was stressed

  3. The effect of chronic low-dose UVB radiation on Langerhans cells, sunburn cells, urocanic acid isomers, contact hypersensitivity and serum immunoglobulins in mice

    International Nuclear Information System (INIS)

    El-Ghorr, A.A.; Norval, M.; Lappin, M.B.

    1995-01-01

    C3H mice were irradiated three times a week for up to 6 weeks with either 500 J/m 2 or 1000 J/m 2 broadband UVB (270-350 nm) or 3000 J/m 2 narrowband UVB (311-312 nm; TL01 source). Each dose was suberythemal to the mouse strain used. The number of Langerhans cells (LC) in the epidermis was reduced by over 50% after 2 weeks of irradiation with the UVB source and by 20% following TL01 irradiation. Continued irradiation for up to 6 weeks resulted in no further decrease in LC numbers in the case of the UVB source but a steady decline to 40% in the case of the TL01 source. Sunburn cells were detected following irradiation with both sources but the numbers were very low in comparison with acute exposure. Ultraviolet-B exposure resulted in doubling of the thickness of the epidermis throughout the 6 weeks of irradiation while TL01 exposure did not alter epidermal thickness. Conversion of trans- to cis-urocanic acid (UCA) was observed with both UVB and TL01 sources. The percentage of cis-UCA started to return to normal after 4 weeks of TL01 exposure despite continued irradiation. As observed following a single exposure, the contact hypersensitivity (CH) response was significantly reduced following 6 weeks of UVB irradiation but was unaffected by TL01 exposure, indicating no correlation between cis-UCA levels and CH response. (author)

  4. Isomer-specific regulation of metabolism and PPARgamma signaling by CLA in human preadipocytes

    DEFF Research Database (Denmark)

    Brown, J Mark; Boysen, Maria Sandberg; Jensen, Søren Skov

    2003-01-01

    Trans-10,cis-12 conjugated linoleic acid (CLA) has previously been shown to be the CLA isomer responsible for CLA-induced reductions in body fat in animal models, and we have shown that this isomer, but not the cis-9,trans-11 CLA isomer, specifically decreased triglyceride (TG) accumulation...... transporter 4 gene expression. Furthermore, trans-10,cis-12 CLA reduced oleic acid uptake and oxidation when compared with all other treatments. In parallel to CLA's effects on metabolism, trans-10,cis-12 CLA decreased, whereas cis-9,trans-11 CLA increased, the expression of peroxisome proliferator...

  5. Treatment of isomers in nucleosynthesis codes

    Science.gov (United States)

    Reifarth, René; Fiebiger, Stefan; Göbel, Kathrin; Heftrich, Tanja; Kausch, Tanja; Köppchen, Christoph; Kurtulgil, Deniz; Langer, Christoph; Thomas, Benedikt; Weigand, Mario

    2018-03-01

    The decay properties of long-lived excited states (isomers) can have a significant impact on the destruction channels of isotopes under stellar conditions. In sufficiently hot environments, the population of isomers can be altered via thermal excitation or de-excitation. If the corresponding lifetimes are of the same order of magnitude as the typical time scales of the environment, the isomers have to be treated explicitly. We present a general approach to the treatment of isomers in stellar nucleosynthesis codes and discuss a few illustrative examples. The corresponding code is available online at http://exp-astro.de/isomers/.

  6. Calorimetric study of bromoacetophenone isomers

    International Nuclear Information System (INIS)

    Amaral, Luísa M.P.F.; Ribeiro da Silva, Manuel A.V.

    2014-01-01

    Highlights: • A calorimetric study of bromoacetophenone isomers was performed. • Enthalpies of formation were derived by rotating-bomb combustion calorimetry. • Enthalpies of phase transition were determined by Calvet microcalorimetry. • Cox scheme was applied for the estimation of Δ f H m o (g) for the compounds. • The values of Δ f H m o (g) were compared with literature values for similar compounds. - Abstract: The standard (p o = 0.1 MPa) molar enthalpies of formation of 2-, 2′-, 3′- and 4′-bromoacetophenones were derived from the standard molar energies of combustion in oxygen, to yield CO 2 (g) and HBr·600H 2 O (l) at T = 298.15 K, measured by rotating bomb combustion calorimetry. The standard molar enthalpies associated with phase transitions of the isomers studied at T = 298.15 K, were obtained by high temperature Calvet microcalorimetry. The standard (p o = 0.1 MPa) molar enthalpies of formation of all the bromoacetophenone isomers in the gaseous phase at T = 298.15 K were derived from the experimental results. The gas-phase enthalpies of formation were also estimated by the empirical scheme developed by Cox and the values obtained were compared with the experimental ones. The results are interpreted in terms of the energetic increments for the introduction of the substituents in the benzene ring

  7. Isomers chart; Table des isomeres

    Energy Technology Data Exchange (ETDEWEB)

    Dupont-Gautier, P; Chantelot, S; Moisson, N [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

    1967-07-01

    The nuclear isomers are nuclides offering the same mass number and the same atomic number, but different energy levels. In the following chart the zero energy ground states are omitted and the metastable isomers, i.e. of non-zero energy, known and of measurable lifetime, are listed. The lower limit of this lifetime was set here to 0.1 x 10{sup -6} s. The various isomers were classified in increasing lifetimes. (authors) [French] Les isomeres nucleaires sont des nucleides presentant le meme nombre de masse et le meme numero atomique, mais des niveaux energetiques differents. Dans la table suivante, on a neglige les etats fondamentaux d'energie nulle et on a recense les isomeres metastables, c'est-a-dire d'energie non nulle, connus et de periode mesurable. La limite inferieure de cette periode a ete fixee ici a 0,1 x 10{sup -6} s. Les differents isomeres ont ete classes par periodes croissantes. (auteurs)

  8. Isomers chart; Table des isomeres

    Energy Technology Data Exchange (ETDEWEB)

    Dupont-Gautier, P.; Chantelot, S.; Moisson, N. [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

    1967-07-01

    The nuclear isomers are nuclides offering the same mass number and the same atomic number, but different energy levels. In the following chart the zero energy ground states are omitted and the metastable isomers, i.e. of non-zero energy, known and of measurable lifetime, are listed. The lower limit of this lifetime was set here to 0.1 x 10{sup -6} s. The various isomers were classified in increasing lifetimes. (authors) [French] Les isomeres nucleaires sont des nucleides presentant le meme nombre de masse et le meme numero atomique, mais des niveaux energetiques differents. Dans la table suivante, on a neglige les etats fondamentaux d'energie nulle et on a recense les isomeres metastables, c'est-a-dire d'energie non nulle, connus et de periode mesurable. La limite inferieure de cette periode a ete fixee ici a 0,1 x 10{sup -6} s. Les differents isomeres ont ete classes par periodes croissantes. (auteurs)

  9. Effectiveness of Iron Ethylenediamine-N,N′-bis(hydroxyphenylacetic) Acid (o,o-EDDHA/Fe3+) Formulations with Different Ratios of Meso and d,l-Racemic Isomers as Iron Fertilizers

    OpenAIRE

    Alcañiz Lucas, Sara; Jordá Guijarro, Juana Dolores; Cerdán, Mar

    2017-01-01

    Two o,o-EDDHA/Fe3+ formulations (meso, 93.5% w/w of meso isomer; and d,l-racemic, 91.3% w/w of d,l-racemic mixture) were prepared, and their efficacy to avoid or to relieve iron deficiency in Fe-sufficient and Fe-deficient tomato plants grown on hydroponic solution was compared with that of the current o,o-EDDHA/Fe3+ formulations (50% of meso and d,l-racemic isomers). The effectiveness of the three o,o-EDDHA/Fe3+ formulations was different depending on the iron nutritional status of plants. T...

  10. DECIDER: prospective randomized multicenter phase II trial of low-dose decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients >60 years with acute myeloid leukemia who are ineligible for induction chemotherapy

    International Nuclear Information System (INIS)

    Grishina, Olga; Schmoor, Claudia; Döhner, Konstanze; Hackanson, Björn; Lubrich, Beate; May, Annette M.; Cieslik, Caroline; Müller, Michael J.; Lübbert, Michael

    2015-01-01

    Acute myeloid leukemia (AML) is predominantly a disease of older patients with a poor long-term survival. Approval of decitabine (DAC) in the European Union (EU) in 2012 for the treatment of patients with AML ≥65 years marks the potential for hypomethylating agents in elderly AML. Nevertheless the situation is dissatisfactory and the quest for novel treatment approaches, including combination epigenetic therapy is actively ongoing. The given randomized trial should be helpful in investigating the question whether combinations of DAC with the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and/or all-trans retinoic acid (ATRA), which in vitro show a very promising synergism, are superior to the DAC monotherapy. The accompanying translational research project will contribute to find surrogate molecular end points for drug efficacy and better tailor epigenetic therapy. An additional aim of the study is to investigate the prognostic value of geriatric assessments for elderly AML patients treated non-intensively. DECIDER is a prospective, randomized, observer blind, parallel group, multicenter, Phase II study with a 2x2 factorial design. The primary endpoint is objective best overall response (complete remission (CR) and partial remission (PR)). The target population is AML patients aged 60 years or older and unfit for standard induction chemotherapy. Patients are randomized to one of the four treatment groups: DAC alone or in combination with VPA or ATRA or with both add-on drugs. One interim safety analysis was planned and carried out with the objective to stop early one or more of the treatment arms in case of an unacceptable death rate. This analysis showed that in all treatment arms the critical stopping rule was not reached. No important safety issues were observed. The Data Monitoring Committee (DMC) recommended continuing the study as planned. The first patient was included in December 2011. A total of 189 out of 200 planned patients were randomized

  11. Atlas of nuclear isomers and their systematics

    International Nuclear Information System (INIS)

    Jain, Ashok Kumar; Maheshwari, Bhoomika

    2015-01-01

    Isomers can be viewed as a separate class of nuclei and offer interesting possibilities to study the behavior of nuclei under varied conditions of excitation energy, spin, life-time and particle configuration. We have completed a horizontal evaluation of nuclear isomers and the resulting data set contains a wealth of information which offers new insights in the nuclear structure of a wide range of configurations, nuclei approaching the drip lines etc. We now have reliable data on approximately 2460 isomers having a half-life ≥ 10 ns. A few of the systematics of the properties of nuclear isomers like excitation energy, half-life, spin, abundance etc. will be presented. The data set of semi-magic isomers strongly supports the existence of seniority isomers originating from the higher spin orbitals. (author)

  12. High spin isomer beam line at RIKEN

    Energy Technology Data Exchange (ETDEWEB)

    Kishida, T.; Ideguchi, E.; Wu, H.Y. [Institute of Physical and Chemical Research, Saitama (Japan)] [and others

    1996-12-31

    Nuclear high spin states have been the subject of extensive experimental and theoretical studies. For the production of high spin states, fusion reactions are usually used. The orbital angular momentum brought in the reaction is changed into the nuclear spin of the compound nucleus. However, the maximum induced angular momentum is limited in this mechanism by the maximum impact parameter of the fusion reaction and by the competition with fission reactions. It is, therefore, difficult to populate very high spin states, and as a result, large {gamma}-detector arrays have been developed in order to detect subtle signals from such very high spin states. The use of high spin isomers in the fusion reactions can break this limitation because the high spin isomers have their intrinsic angular momentum, which can bring the additional angular momentum without increasing the excitation energy. There are two methods to use the high spin isomers for secondary reactions: the use of the high spin isomers as a target and that as a beam. A high spin isomer target has already been developed and used for several experiments. But this method has an inevitable shortcoming that only {open_quotes}long-lived{close_quotes} isomers can be used for a target: {sup 178}Hf{sup m2} (16{sup +}) with a half-life of 31 years in the present case. By developing a high spin isomer beam, the authors can utilize various short-lived isomers with a short half-life around 1 {mu}s. The high spin isomer beam line of RIKEN Accelerator Facility is a unique apparatus in the world which provides a high spin isomer as a secondary beam. The combination of fusion-evaporation reaction and inverse kinematics are used to produce high spin isomer beams; in particular, the adoption of `inverse kinematics` is essential to use short-lived isomers as a beam.

  13. Optical absorption spectra of Ag-11 isomers

    DEFF Research Database (Denmark)

    Martinez, Jose Ignacio; Fernandez, E. M.

    2009-01-01

    The optical absorption spectra of the three most; stable structural isomers of the Ag-11 cluster were calculated using the time-dependent, density functional theory within the Casida formalism. The slightly different, spectra, of the isomers may permit the identification of the ground-stale confi......The optical absorption spectra of the three most; stable structural isomers of the Ag-11 cluster were calculated using the time-dependent, density functional theory within the Casida formalism. The slightly different, spectra, of the isomers may permit the identification of the ground...

  14. Alpha and gamma spectroscopy of fission isomers

    International Nuclear Information System (INIS)

    Makarenko, V.E.

    1988-01-01

    The attempts to discover in the experiment decay of fission isomers of heavy nuclei in the U-Am range by emitting α particles or γ quanta are considered. Some facilities for searching αdecay of spontaneously fissile isomers are given in brief. The first experimental results are discussed

  15. Evidence for an isomer in 76Ni

    International Nuclear Information System (INIS)

    Sawicka, M.; Pfuetzner, M.; Grzywacz, R.; Daugas, J.M.; Belier, G.; Sauvestre, J.E.; Matea, I.; Lewitowicz, M.; Georgiev, G.; Grawe, H.; Mayet, P.; Becker, F.; Bingham, C.; Borcea, R.; Hammache, F.; Ibrahim, F.; Bouchez, E.; Buta, A.; Dragulescu, E.; Giovinazzo, J.; Meot, V.; Negoita, F.; De Oliveira Santos, F.; Perru, O.; Roig, O.; Rykaczewski, K.P.; Saint-Laurent, M.G.; Sorlin, O.; Stanoiu, M.; Stefan, I.; Stodel, C.; Theisen, C.; Verney, D.

    2004-01-01

    In the experiment performed at the LISE2000 spectrometer at GANIL neutron-rich nickel isotopes were studied by microsecond isomer spectroscopy. Evidence for an isomer in 76 Ni is found, consistently with the shell model prediction of an 8 + state of ν(g 9/2 ) 2 structure. (orig.)

  16. Effectiveness of Iron Ethylenediamine-N,N'-bis(hydroxyphenylacetic) Acid (o,o-EDDHA/Fe3+) Formulations with Different Ratios of Meso and d,l-Racemic Isomers as Iron Fertilizers.

    Science.gov (United States)

    Alcañiz, Sara; Jordá, Juana D; Cerdán, Mar

    2017-01-18

    Two o,o-EDDHA/Fe 3+ formulations (meso, 93.5% w/w of meso isomer; and d,l-racemic, 91.3% w/w of d,l-racemic mixture) were prepared, and their efficacy to avoid or to relieve iron deficiency in Fe-sufficient and Fe-deficient tomato plants grown on hydroponic solution was compared with that of the current o,o-EDDHA/Fe 3+ formulations (50% of meso and d,l-racemic isomers). The effectiveness of the three o,o-EDDHA/Fe 3+ formulations was different depending on the iron nutritional status of plants. The three o,o-EDDHA/Fe 3+ formulations tested were effective in preventing iron chlorosis in healthy plants. However, the higher the meso concentration in the formulations, the higher the effectiveness in the recovery of iron chlorotic plants from iron deficiency. Accordingly, o,o-EDDHA/Fe 3+ formulations rich in meso isomer are recommended in hydroponic systems.

  17. Study on Separation of Structural Isomer with Magneto-Archimedes method

    Science.gov (United States)

    Kobayashi, T.; Mori, T.; Akiyama, Y.; Mishima, F.; Nishijima, S.

    2017-09-01

    Organic compounds are refined by separating their structural isomers, however each separation method has some problems. For example, distillation consumes large energy. In order to solve these problems, new separation method is needed. Considering organic compounds are diamagnetic, we focused on magneto-Archimedes method. With this method, particle mixture dispersed in a paramagnetic medium can be separated in a magnetic field due to the difference of the density and magnetic susceptibility of the particles. In this study, we succeeded in separating isomers of phthalic acid as an example of structural isomer using MnCl2 solution as the paramagnetic medium. In order to use magneto-Archimedes method for separating materials for food or medicine, we proposed harmless medium using oxygen and fluorocarbon instead of MnCl2 aqueous solution. As a result, the possibility of separating every structural isomer was shown.

  18. Roles of the tyrosine isomers meta-tyrosine and ortho-tyrosine in oxidative stress.

    Science.gov (United States)

    Ipson, Brett R; Fisher, Alfred L

    2016-05-01

    The damage to cellular components by reactive oxygen species, termed oxidative stress, both increases with age and likely contributes to age-related diseases including Alzheimer's disease, atherosclerosis, diabetes, and cataract formation. In the setting of oxidative stress, hydroxyl radicals can oxidize the benzyl ring of the amino acid phenylalanine, which then produces the abnormal tyrosine isomers meta-tyrosine or ortho-tyrosine. While elevations in m-tyrosine and o-tyrosine concentrations have been used as a biological marker of oxidative stress, there is emerging evidence from bacterial, plant, and mammalian studies demonstrating that these isomers, particularly m-tyrosine, directly produce adverse effects to cells and tissues. These new findings suggest that the abnormal tyrosine isomers could in fact represent mediators of the effects of oxidative stress. Consequently the accumulation of m- and o-tyrosine may disrupt cellular homeostasis and contribute to disease pathogenesis, and as result, effective defenses against oxidative stress can encompass not only the elimination of reactive oxygen species but also the metabolism and ultimately the removal of the abnormal tyrosine isomers from the cellular amino acid pool. Future research in this area is needed to clarify the biologic mechanisms by which the tyrosine isomers damage cells and disrupt the function of tissues and organs and to identify the metabolic pathways involved in removing the accumulated isomers after exposure to oxidative stress. Published by Elsevier B.V.

  19. Activation of Retinoid X Receptors by Phytanic Acid and Docohexaenoic Acid: Role in the Prevention and Therapy of Prostate Cancer

    National Research Council Canada - National Science Library

    Tang, Xiao-Han

    2005-01-01

    .... Meanwhile, both phytanic acid and DHA inhibited the growth of Pc-3 and LNCaP cells. Phytanic acid and retinoic acid synergistically inhibited the growth of both of these prostate cancer cell lines...