Retinoic Acid Receptors (retinoic + acid_receptor)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Ethanol Impairs Activation of Retinoic Acid Receptors in Cerebellar Granule Cells in a Rodent Model of Fetal Alcohol Spectrum Disorders

ALCOHOLISM, Issue 5 2010
Ambrish Kumar
Background:, Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations. In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells. Methods:, The cerebellum of ethanol unexposed and exposed pups was used to study the expression of retinoic acid receptors (RARs or RXRs) by immunohistochemistry and by Western blot analysis. We also studied the effect of ethanol on expression of RA receptors in the cerebellar granule cells. Activation of RA receptors (DNA-binding activities) in response to high-dose ethanol was determined by electrophoretic mobility shift and supershift assays. Results:, Findings from these studies demonstrated that ethanol exposure reduced the expression of RAR,/, while it increased the expression of RXR,/, in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure. Conclusion:, For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells. Taken together, these findings could provide insight into the treatment options for brain defects caused by excessive ethanol exposure, such as in Fetal Alcohol Spectrum Disorders. [source]


Expression of retinoic acid receptor , in dermatofibrosarcoma protuberans

JOURNAL OF CUTANEOUS PATHOLOGY, Issue 11 2009
Zhou Xiaoli
Background:, Retinoic acid receptor , (RAR ,) has been shown to act as a tumor suppressor in many solid human tumors. To investigate the putative role of RAR , in dermatofibrosarcoma protuberans (DFSP), we examined the expression of RAR , in DFSPs and analyzed the correlation of expression patterns between RAR , and cyclooxygenase (COX)-2 as well as clinicopathological variables. Methods:, Using tissue microarray and immunohistochemistry, we evaluated nuclear RAR , staining and cytoplasm COX-2 staining in 53 DFSPs. Results:, 48 DFSPs (90.58%) were immunopositive for RAR ,, while 32 DFSPs (60.38%) were immunopositive for COX-2. RAR , staining was significantly inversely correlated with COX-2 staining (p < 0.001; r =,0.668). Conclusions:, Our data indicated that RAR , expressed in DFSPs and correlated with COX-2 expression. RAR , may be a potential therapeutic target for unresectable DFSP cases. [source]


Retinoic acid signalling induces the differentiation of mouse fetal liver-derived hepatic progenitor cells

LIVER INTERNATIONAL, Issue 10 2009
Jiayi Huang
Abstract Background: Hepatic progenitor cells (HPCs) can be isolated from fetal liver and extrahepatic tissues. Retinoic acid (RA) signalling plays an important role in development, although the role of RA signalling in liver-specific progenitors is poorly understood. Aims: We sought to determine the role of RA in regulating hepatic differentiation. Methods: RNA was isolated from liver tissues of various developmental stages. Liver marker expression was assessed by reverse transcriptase-polymerase chain reaction and immunofluorescence staining. Reversibly immortalized HPCs derived from mouse embryonic day 14.5 (E14.5) liver (aka, HP14.5) were established. Albumin promoter-driven reporter (Alb-GLuc) was used to monitor hepatic differentiation. Glycogen synthesis was assayed as a marker for terminal hepatic differentiation. Results: Retinoic acid receptor (RAR)-,, retinoid X receptor (RXR)-, and RXR-, expressed in E12.5 to postnatal day 28 liver samples. Expression of RAR-, and RXR-, was low perinatally, whereas RAR-, was undetectable in prenatal tissues and increased postnatally. Retinal dehydrogenase 1 and 2 (Raldh1 and Raldh2) were expressed in all tissues, while Raldh3 was weakly expressed in prenatal samples but was readily detected postnatally. Nuclear receptor corepressors were highly expressed in all tissues, while expression of nuclear co-activators decreased in perinatal tissues and increased after birth. HP14.5 cells expressed high levels of early liver stem cell markers. Expression of RA signalling components and coregulators was readily detected in HP14.5. RA was shown to induce Alb-GLuc activity and late hepatocyte markers. RA was further shown to induce glycogen synthesis in HP14.5 cells, an important function of mature hepatocytes. Conclusions: Our results strongly suggest that RA signalling may play an important role in regulating hepatic differentiation. [source]


Effects of retinoids and thiazolidinediones on proliferation, insulin release, insulin mRNA, GLUT 2 transporter protein and mRNA of INS-1 cells

CELL BIOCHEMISTRY AND FUNCTION, Issue 3 2001
J. Blumentrath
Abstract Both 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (ATRA) are active metabolites of vitamin A (retinol). There exists an interaction between retinoid receptors and peroxisome proliferator-activated receptors (PPAR,). To define their functions in an insulin secreting system the effects of ATRA, 9cRA and the PPAR, agonist rosiglitazone on cell proliferation, insulin release and glucose transporter (GLUT) 2 of INS-1 cells were tested. Retinoic acid receptor (RAR-, and -,) and retinoid X receptor (RXR-, and -,) proteins are present (immunoblots). Both 9cRA and ATRA inhibit INS-1 cell proliferation ([3H]-thymidine assay) in a concentration dependent manner. Both 9cRA and ATRA increased insulin release, but only ATRA ralsed the GLUT 2 mRNA in a bell-shaped concentration response curve after 48,h. The insulinotropic effect of one compound is not significantly superimposed by the other indicating that the same binding sites are used by 9cRA and ATRA. The acute and chronic effects of the PPAR, agonist rosiglitazone on insulin release were additionally determined since glitazones act as transcription factors together with RXR agonists. At high concentrations (100,,m) rosiglitazone inhibited glucose (8.3,mm) stimulated insulin secretion (acute experiment over 60,min). Insulin secretion, however, was increased during a 24,h treatment at a concentration of 10,,m and again inhibited at 100,,m. Changes in preproinsulin mRNA expression were not observed. Rosiglitazone (100,,m) increased GLUT 2 mRNA paralleled by an increase of GLUT 2 protein, but only after 24,h of treatment. This data indicate that RAR and RXR mediate insulin release. The changes in GLUT 2 have no direct impact on insulin release; the inhibition seen at high concentrations of either compound is possibly the result of the observed inhibition of cell proliferation. Effects of rosiglitazone on preproinsulin mRNA and GLUT 2 (mRNA and protein) do not play a role in modulating insulin secretion. With the presence of an RXR receptor agonist the effect of rosiglitazone on insulin release becomes stimulatory. Thus the effects of RAR-, RXR agonists and rosiglitazone depend on their concentrations, the duration of their presence and are due to specific interactions. Copyright © 2001 John Wiley & Sons, Ltd. [source]


Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid Receptors

CHEMBIOCHEM, Issue 7 2009
José García
Abstract RAR and RXR agonists: A collection of pyrazine-based RAR/RXR ligands were prepared by a series of palladium catalyzed cross-coupling reactions and characterized. Structure,activity relationships were elucidated. Retinoic acid receptor (RAR) ,/,-subtype-selective and retinoid X receptor (RXR) inverse agonist activities are described for pyrazine acrylic acid arotinoid, 14,d. Heterocyclic arotinoids derived from central-region dihalogenated pyrazine scaffolds have been synthesized by consecutive halogen and/or position-selective palladium-catalyzed cross-coupling reactions. Pyrazines were further functionalized as alkyl ethers or methylamines prior to the last Pd-catalyzed reactions. Transient transactivation studies with the retinoic acid receptor (RAR) ,, ,, and , subtypes and with retinoid X receptor (RXR) , revealed distinct agonist, antagonist, and inverse agonist activities for these compounds. Of interest are the RAR,,,-selective inverse agonists with pyrazine acrylic acid structures, in particular 14,c, which is RAR,-selective, and 14,d, a pan-RAR/RXR inverse agonist with more affinity for the RAR subtypes that enhance the interaction of RAR with cognate corepressors. [source]


Functional retinoid receptors in budding ascidians

DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 1 2000
Mika Kamimura
A homolog of retinoid X receptors (RXR), named PmRXR, was cloned from the budding ascidian, Polyandrocarpa misakiensis. Gel-shift assays revealed that PmRXR and a previously identified P. misakiensis retinoic acid receptor (PmRAR) formed a complex to bind vertebrate-type retinoic acid response element (RARE). Transfection assays were carried out using a reporter gene containing a RARE upstream of lacZ. Two chimeric effector genes were constructed by placing PmRXR and PmRAR cDNA fragments (containing the DNA-binding, ligand-binding and ligand-dependent transactivation domains) downstream of the human RXR, and RAR, cDNA (covering the N-terminal coding region), respectively. Each chimeric cDNA was ligated to a notochord-specific enhancer. In case the embryos were transfected with all three transgenes and treated with retinoic acid (RA), the reporter gene was activated in the notochord cells. The result suggests that the PmRXR/PmRAR complex functions as an RA-dependent transcriptional activator. The PmRXR mRNA was detected in a mesenchymal cell type, called glomerulocyte, in the developing Polyandrocarpa bud. As this cell type has been shown to express PmRAR mRNA, it seems possible that the PmRXR/PmRAR complex mediates RA signaling in this cell type to induce the expression of genes involved in the morphogenesis of the developing bud. [source]


Retinoic acid controls expression of tissue remodeling genes Hmgn1 and Fgf18 at the digit,interdigit junction

DEVELOPMENTAL DYNAMICS, Issue 2 2010
Xianling Zhao
Abstract Previous studies on retinoic acid receptor (RAR) mutants suggested that retinoic acid (RA) is required for loss of interdigital mesenchyme during digit formation. Here, we report that the RA-generating enzyme retinaldehyde dehydrogenase-2 (Raldh2) is expressed in the interdigital mesenchyme whereas Cyp26b1, controlling RA degradation, is expressed in digits, limiting autopodal RA action to the interdigital zones. Embryonic day 13.5 Raldh2,/, mouse embryos lose expression of the RARE-lacZ RA-reporter transgene and matrix metalloproteinase-11 (Mmp11) throughout the interdigital mesenchyme, while expression of RARb, Fgf18, and high mobility group N1 (Hmgn1) is lost at the digit,interdigit junction. Raldh2,/, autopods exhibit reduced interdigital apoptosis associated with loss of Bmp7 expression, but Bmp2, Bmp4, Msx2, and Fgf8 were unaffected. Although interdigital expression of Hmgn1 was greatly down-regulated in Raldh2,/, autopods, complementary expression of Sox9 in digit cartilage was unaffected. Regulation of Hmgn1 and Fgf18 at the digit,interdigit junction suggests RA controls tissue remodeling as well as apoptosis. Developmental Dynamics 239:665,671, 2010. © 2009 Wiley-Liss, Inc. [source]


Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers

INTERNATIONAL JOURNAL OF CANCER, Issue 4 2003
Sabine Zöchbauer-Müller
Abstract An important method for silencing tumor suppressor genes in cancers is by aberrant methylation (referred to as methylation) of CpG islands in gene promoter regions. In lung cancer, methylation of the genes retinoic acid receptor ,-2 (RAR,- 2), CDH13 (H-cadherin), p16INK4a (p16), RASSF1A (RAS association domain family I) is frequent. Thus, we investigated methylation of these genes in 4 different types of specimens (oropharyngeal brushes, sputum samples, bronchial brushes and bronchioloalveolar lavage [BAL] samples) of the upper aerodigestive tract epithelium from heavy smokers without evidence of cancer but with morphometric evidence of sputum atypia and compared the frequencies of methylation in the different types of specimens. In addition, we also analyzed sputum samples from 30 never smokers for methylation of these genes. Our major findings are: (i) At least one gene was methylated in one or more specimens from 48% of the smokers. However, methylation was statistically significant less frequently in never smokers compared to smokers. (ii) In general, methylation occurred more frequently in samples from the central airways (sputum, bronchial brushes) compared to the peripheral airways (BAL) and only occasionally in the oropharynx. (iii) RAR,- 2 was the most frequently methylated gene, whereas the frequency of methylation for the other genes was lower. (iv) Data from sputum samples and bronchial brushes were comparable. Our findings suggest that detection of methylation should be investigated as an intermediate marker for lung cancer risk assessment and response to chemopreventive regimens. © 2003 Wiley-Liss, Inc. [source]


Expression of retinoic acid receptor , in dermatofibrosarcoma protuberans

JOURNAL OF CUTANEOUS PATHOLOGY, Issue 11 2009
Zhou Xiaoli
Background:, Retinoic acid receptor , (RAR ,) has been shown to act as a tumor suppressor in many solid human tumors. To investigate the putative role of RAR , in dermatofibrosarcoma protuberans (DFSP), we examined the expression of RAR , in DFSPs and analyzed the correlation of expression patterns between RAR , and cyclooxygenase (COX)-2 as well as clinicopathological variables. Methods:, Using tissue microarray and immunohistochemistry, we evaluated nuclear RAR , staining and cytoplasm COX-2 staining in 53 DFSPs. Results:, 48 DFSPs (90.58%) were immunopositive for RAR ,, while 32 DFSPs (60.38%) were immunopositive for COX-2. RAR , staining was significantly inversely correlated with COX-2 staining (p < 0.001; r =,0.668). Conclusions:, Our data indicated that RAR , expressed in DFSPs and correlated with COX-2 expression. RAR , may be a potential therapeutic target for unresectable DFSP cases. [source]


Retinoids and retinoic acid receptors regulate growth arrest and apoptosis in human mammary epithelial cells and modulate expression of CBP/p300

MICROSCOPY RESEARCH AND TECHNIQUE, Issue 1 2002
Eric C. Dietze
Abstract Retinoids and retinoic acid receptors (RARs) are important mediators of normal epithelial cell homeostasis. To assess the role of retinoids and RARs in regulating growth arrest and apoptosis in benign and malignant mammary epithelial cells, two model systems were developed: 1) RAR function was suppressed in retinoid-sensitive normal human mammary epithelial cells (HMECs) by the dominant-negative retinoic acid receptor, RAR,403 (DNRAR), and 2) retinoid-resistant MCF-7 breast cancer cells were transduced with a functional RAR,2. Inhibition of RAR function by the DNRAR in HMECs resulted in retinoid-resistance, increased proliferation, and dysregulated growth when cells were cultured in reconstituted extracellular matrix (rECM). Expression of RAR,2 in MCF-7 cells resulted in sensitivity to retinoid-induced growth arrest and apoptosis. The CREB-binding protein (CBP) and the homologous protein p300 are tightly regulated, rate-limiting integrators of diverse signaling pathways and are recruited during retinoid-mediated transcriptional activation. The relationship between retinoid receptor expression, growth regulation, and transcriptional regulation of CBP/p300 is poorly understood. Inhibition of RAR function in HMECs by DNRAR suppressed expression of CBP/p300 and expression of RAR,2 in MCF-7 cells promoted induction of CBP/p300 when cells were treated with 1.0 ,M all- trans -retinoic acid (ATRA). These results suggest that ATRA and RARs regulate growth arrest of HMECs and modulate CBP/p300 protein expression. Since CBP and p300 are normally present in limiting amounts, their regulation by ATRA and RARs may be an important element in the control of transcriptional activation of genes regulating growth arrest and apoptosis. Microsc. Res. Tech. 59:23,40, 2002. © 2002 Wiley-Liss, Inc. [source]


In vivo imaging of retinoic acid receptor ,2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells

THE PROSTATE, Issue 1 2005
David Z. Qian
Abstract BACKGROUND In retinoid resistant epithelial tumors, the lack of retinoic acid receptor ,2 (RAR,2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RAR,2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RAR,2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RAR,2 re-activation with anti-tumor activity. METHODS We selected the RAR,2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RAR,2 promoter (pGL2-RAR,2-PC3). Then, we used the bioluminescence technology to monitor the reporter gene expression in real time both in vitro and in vivo following combination treatment with the histone deacetylase inhibitor MS-275 and 13- cis retinoic acid (CRA). Based on the effective dose for the RAR,2 re-activation, we tested the anti-tumor activity of this drug combination. RESULTS Following combination treatment with MS-275 and CRA, we observed endogenous RAR,2 re-expression, acetylation at the RAR,2 promoter level, and synergistic activation of the luciferase reporter gene by real time imaging both in vitro and in vivo. Combination treatment with MS-275 and CRA restored retinoid sensitivity in human prostate carcinoma cell lines, and had a greater inhibitory effect on tumor cell growth than single agents in vitro and in vivo. CONCLUSIONS This study provides evidence that HDAC inhibitors restore retinoid sensitivity in prostate cancer cells, and in vivo real time imaging of RAR,2 activation may represent a useful tool to study the pharmacodynamics of combination therapy with HDAC inhibitors and retinoids. © 2005 Wiley-Liss, Inc. [source]


Ligands for retinoic acid receptors are elevated in osteoarthritis and may contribute to pathologic processes in the osteoarthritic joint

ARTHRITIS & RHEUMATISM, Issue 6 2009
Mark R. Davies
Objective Vitamin A derivatives, including all- trans -retinoic acid (ATRA), have a well-established role during skeletal development and limb formation and have been shown to have profound effects on chondrocyte phenotype. The aim of this study was to elucidate the effects of retinoids and components of the retinoid metabolic pathway on chondrocyte phenotype in the tibiofemoral joints of patients with osteoarthritis (OA), to show that the retinoids can have multiple effects relevant to the OA disease process. Methods Human explant tissue and a chondrocyte-like cell line were treated with ATRA, and the responses of 4 key markers of chondrocyte phenotype were analyzed. In addition, the effects of ATRA on a number of novel genes associated with OA were assessed using a low-density microarray containing 80 disease marker genes. Results Vitamin A metabolite levels were elevated in synovial fluid, serum, and cartilage from patients with OA. Expression profiling of a retinoic acid receptor , coactivator protein, P/CAF, demonstrated elevated expression in patients with OA, suggesting the potential for increased signaling via the retinoid receptors in the disease. ATRA increased the levels of matrix metalloproteinase 13 and aggrecanase activity in human cartilage explants and in a human chondrocyte cell line. Furthermore, ATRA altered the expression of a wide range of relevant genes, including the types I, II, IX, and XI collagen genes, toward a nonchondrogenic and OA-like phenotype. Conclusion These results suggest that retinoid signaling could have a central role in OA, and that components of the pathway may provide potential disease biomarkers or targets for therapeutic intervention. [source]


Functional characterization of hypertrophy in chondrogenesis of human mesenchymal stem cells

ARTHRITIS & RHEUMATISM, Issue 5 2008
Michael B. Mueller
Objective Mesenchymal stem cells (MSCs) are promising candidate cells for cartilage tissue engineering. Expression of cartilage hypertrophy markers (e.g., type X collagen) by MSCs undergoing chondrogenesis raises concern for a tissue engineering application for MSCs, because hypertrophy would result in apoptosis and ossification. To analyze the biologic basis of MSC hypertrophy, we examined the response of chondrifying MSCs to culture conditions known to influence chondrocyte hypertrophy, using an array of hypertrophy-associated markers. Methods Human MSC pellet cultures were predifferentiated for 2 weeks in a chondrogenic medium, and hypertrophy was induced by withdrawing transforming growth factor , (TGF,), reducing the concentration of dexamethasone, and adding thyroid hormone (T3). Cultures were characterized by histologic, immunohistochemical, and biochemical methods, and gene expression was assessed using quantitative reverse transcription,polymerase chain reaction. Results The combination of TGF, withdrawal, a reduction in the level of dexamethasone, and the addition of T3 was essential for hypertrophy induction. Cytomorphologic changes were accompanied by increased alkaline phosphatase activity, matrix mineralization, and changes in various markers of hypertrophy, including type X collagen, fibroblast growth factor receptors 1,3, parathyroid hormone,related protein receptor, retinoic acid receptor ,, matrix metalloproteinase 13, Indian hedgehog, osteocalcin, and the proapoptotic gene p53. However, hypertrophy was not induced uniformly throughout the pellet culture, and distinct regions of dedifferentiation were observed. Conclusion Chondrogenically differentiating MSCs behave in a manner functionally similar to that of growth plate chondrocytes, expressing a very similar hypertrophic phenotype. Under the in vitro culture conditions used here, MSC-derived chondrocytes underwent a differentiation program analogous to that observed during endochondral embryonic skeletal development, with the potential for terminal differentiation. This culture system is applicable for the screening of hypertrophy-inhibitory conditions and agents that may be useful to enhance MSC performance in cartilage tissue engineering. [source]


Carotenoids and retinoids as suppressors on adipocyte differentiation via nuclear receptors

BIOFACTORS, Issue 1-4 2000
Teruo Kawada
Abstract The adipocyte differentiation program is regulated by the sequential expression of transcriptional activators, mainly peroxisome proliferator activated receptor (PPAR) families. In the present study, we have decided to systematically examine the effects of vitamin A and its precursors, carotenoids and retinoids, on terminal differentiation from preadipocytes to adipocytes on the cellular and molecular aspects. The effects of active form of vitamin A, retinoic acid (RA), are believed to be mediated by specific nuclear receptor proteins [retinoic acid receptor (RAR)] which are members of the steroid and thyroid/retinoid receptor superfamily of ligand dependent transcriptional regulators. RAR,, RAR,, RXR,, and RXR, mRNA were abundant in adipose tissue and 3T3-L1 adipose cells. The autoregulated amplification of RAR, mRNA was observed by these own ligands in 3T3-L1 cells. And, RA inhibited PPAR,2 expression more effectively and caused concomitantly a greater inhibition of adipocyte differentiation. These results suggest that the inhibitory action of adipocyte differentiation by carotenoids and retinoids are exhibited through the RAR up-regulation and the suppression of PPAR,2. The nature of the cross talk of vitamin A actions between the RARs, RXRs and PPARs via co-activator in adipose tissue will likely prove to be important for understanding the process of adipogenesis. [source]


Modulation of lung molecular biomarkers by ,-carotene in the Physicians' Health Study,

CANCER, Issue 5 2009
Chun Liu MD
Abstract BACKGROUND: ,-Carotene supplementation showed neither benefit nor harm among apparently healthy physicians (all men) in the Physicians' Health Study (PHS) trial. The objective of the current investigation was to evaluate how long-term ,-carotene supplementation affects molecular markers of lung carcinogenesis in the PHS. METHODS: The protein levels of total p53, cyclin D1, proliferating cellular nuclear antigen (PCNA), retinoic acid receptor , (RAR,), and cytochrome p450 enzyme 1A1 (CYP1A1) were measured using the immunohistochemical method in 40 available archival lung tissue samples from patients who were diagnosed with lung cancer in the PHS. The protein levels of these markers were compared by category of ,-carotene treatment assignment and other characteristics using unconditional logistic regression models. RESULTS: The positivity for total p53, RAR,, cyclin D1, and PCNA was nonsignificantly lower among lung cancer patients who were assigned to receive ,-carotene than those who were assigned to receive ,-carotene placebo. There was a borderline significant difference in CYP1A1 positivity with an OR of 0.2 (95% confidence interval, 0.2-1.1; P = .06) in a comparison of men who received ,-carotene and men who received ,-carotene placebo. CONCLUSIONS: The 50-mg ,-carotene supplementation on alternate days had no significant influence on molecular markers of lung carcinogenesis that were evaluated in the PHS. This finding provides mechanistic support for the main PHS trial results of ,-carotene, which demonstrated no benefit or harm to the risk of developing lung cancer. Cancer 2009. © 2009 American Cancer Society. [source]


Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid Receptors

CHEMBIOCHEM, Issue 7 2009
José García
Abstract RAR and RXR agonists: A collection of pyrazine-based RAR/RXR ligands were prepared by a series of palladium catalyzed cross-coupling reactions and characterized. Structure,activity relationships were elucidated. Retinoic acid receptor (RAR) ,/,-subtype-selective and retinoid X receptor (RXR) inverse agonist activities are described for pyrazine acrylic acid arotinoid, 14,d. Heterocyclic arotinoids derived from central-region dihalogenated pyrazine scaffolds have been synthesized by consecutive halogen and/or position-selective palladium-catalyzed cross-coupling reactions. Pyrazines were further functionalized as alkyl ethers or methylamines prior to the last Pd-catalyzed reactions. Transient transactivation studies with the retinoic acid receptor (RAR) ,, ,, and , subtypes and with retinoid X receptor (RXR) , revealed distinct agonist, antagonist, and inverse agonist activities for these compounds. Of interest are the RAR,,,-selective inverse agonists with pyrazine acrylic acid structures, in particular 14,c, which is RAR,-selective, and 14,d, a pan-RAR/RXR inverse agonist with more affinity for the RAR subtypes that enhance the interaction of RAR with cognate corepressors. [source]


Highly Potent Naphthofuran-Based Retinoic Acid Receptor Agonists

CHEMMEDCHEM, Issue 5 2009
Efrén, Pérez Santín Dr.
Abstract A series of arotinoids with a central benzofuran or naphthofuran ring structure were synthesized by an efficient three-step process. Most of these 3-substituted naphthofuran arotinoids are potent agonists of the retinoic acid receptor (RAR) subtypes, with activities in the nanomolar range. A collection of arotinoids with a central benzofuran or naphthofuran ring structure was efficiently synthesized by a three-step process that comprises a Sonogashira coupling, an iodine-induced 5- endo -dig cyclization of the o -methoxyphenyl- or naphthyl-ethynyl benzoates, and finally a Suzuki/Sonogashira coupling of the corresponding 3-iodobenzo- or naphthofurans. Most of these 3-substituted naphthofuran arotinoids (but not the 5,7-di- tert -butylbenzofurans with the same substitution pattern at the C2 and C3 positions) are potent agonists of the retinoic acid receptor (RAR) subtypes, with activities in the nanomolar range. [source]


Retinoic acid signaling is required for proper morphogenesis of mammary gland

DEVELOPMENTAL DYNAMICS, Issue 4 2005
Y. Alan Wang
Abstract Retinoic acid (RA), a bioactive chemical compound synthesized from dietary derived vitamin A, has been successfully used as a chemopreventive and chemotherapeutic agent through the regulation of cell proliferation, differentiation, and apoptosis acting via the retinoic acid receptors. Despite two decades of research on the function of retinoic acid, the physiological role of RA in mammary gland development is still not well characterized. In this report, we demonstrate that RA is required for proper morphogenesis of mouse mammary gland in a novel transgenic mouse model system. It was found that inhibition of RA signaling in vivo leads to excessive mammary ductal morphogenesis through upregulation of cyclin D1 and MMP-3 expression. Furthermore, we show that the transgene-induced excessive branching morphogenesis could be reversed by treatment with RA, demonstrating the direct physiological effect of RA signaling in vivo. In addition, we demonstrate that excessive branching morphogenesis in the transgenic mammary gland are cell-autonomous and do not require stromal signals within the transgenic mammary gland. Finally, we provide evidence suggesting that retinoic acid signaling is required for appropriate mammary gland differentiation. Collectively, our data indicate for the first time that retinoic acid signaling is required to maintain the homeostasis of mammary gland morphogenesis. Developmental Dynamics 234:892,899, 2005. © 2005 Wiley-Liss, Inc. [source]


Retinoic acid, a regeneration-inducing molecule

DEVELOPMENTAL DYNAMICS, Issue 2 2003
Malcolm Maden
Abstract Retinoic acid (RA) is the biologically active metabolite of vitamin A. It is a low molecular weight, lipophilic molecule that acts on the nucleus to induce gene transcription. In amphibians and mammals, it induces the regeneration of several tissues and organs and these examples are reviewed here. RA induces the "super-regeneration" of organs that can already regenerate such as the urodele amphibian limb by respecifying positional information in the limb. In organs that cannot normally regenerate such as the adult mammalian lung, RA induces the complete regeneration of alveoli that have been destroyed by various noxious treatments. In the mammalian central nervous system (CNS), which is another tissue that cannot regenerate, RA does not induce neurite outgrowth as it does in the embryonic CNS, because one of the retinoic acid receptors, RAR,2, is not up-regulated. When RAR,2 is transfected into the adult spinal cord in vitro, then neurite outgrowth is stimulated. In all these cases, RA is required for the development of the organ, in the first place suggesting that the same gene pathways are likely to be used for both development and regeneration. This suggestion, therefore, might serve as a strategy for identifying potential tissue or organ targets that have the capacity to be stimulated to regenerate. Developmental Dynamics 226:237,244, 2003.© 2003 Wiley-Liss, Inc. [source]


Macrophages and neurons are targets of retinoic acid signaling after spinal cord contusion injury

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2006
Kirsten Schrage
Abstract The physiological reactions after spinal cord injury are accompanied by local synthesis of the transcriptional activator retinoic acid (RA). RA exerts its effects by binding to retinoic acid receptors (RAR) which heterodimerize with retinoid X receptors (RXR) and then act as ligand-activated transcription factors. To identify possible cellular targets of RA we investigated protein levels and cellular distribution of retinoid receptors in the rat spinal cord at 4, 7, 14 and 21 days after a contusion injury. In the nonlesioned spinal cord, immunoreactivity for RAR,, RXR,, RXR, and RXR, was localized in the cytosol of neurons, that of RXR, and RXR, in astrocytes and that of RAR,, RXR, and RXR, in some oligodendrocytes. After contusion injury RAR, and all RXRs appeared in the cell nuclei of reactive microglia and macrophages. This nuclear staining began at 4 days, was most prominent at 7 and 14 days and had decreased at 21 days after injury. A similar nuclear translocation was also observed for the RAR,, RXR, and RXR, staining in neurons situated around the border of the contusion. These observations suggest that RA participates as a signal for the physiological responses of microglia and neurons after CNS injury. [source]


Comparative distribution of the mammalian mediator subunit thyroid hormone receptor-associated protein (TRAP220) mRNA in developing and adult rodent brain

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2002
Anastasia Galeeva
Abstract TRAP220 (thyroid hormone receptor-associated protein) is a recently cloned nuclear receptor coactivator, which interacts with several nuclear receptors in a ligand-dependent manner and stimulates transcription by recruiting the TRAP mediator complex to hormone responsive promoter regions. TRAP220 has been shown to interact with thyroid hormone receptors, vitamin D receptors, peroxisome proliferator-activated receptors, retinoic acid receptors and oestrogen receptors. Thyroid hormone and retinoic acid play very important roles in brain development and they also influence adult brain. Using in situ hybridization we have examined expression of TRAP220 mRNA in the central nervous system during development and in adult rat and mouse brain. Expression of TRAP220 was seen already during early embryonic development in the epithelium of neural tube at E9 in mouse and at E12 in rat. At later stages of development the strongest signal was seen in different layers of cerebral neocortex, external germinal layer of cerebellum, differentiating fields of hippocampus and neuroepithelium, and a moderate signal was detected in basal ganglia, different areas of diencephalon and midbrain. In adult rat brain the signal was more restricted than during development. TRAP220 expression occurred mostly in the granular layer of cerebellar cortex, piriform cortex and hippocampal formation. The signal was found predominantly in neurons. Our work supports the assumption that TRAP220 plays an important role in growth and differentiation of central nervous system and may have a function in certain areas of adult brain. [source]


Expression of PPAR, RXR isoforms and fatty acid transporting proteins in the rat and human gastrointestinal tracts

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2005
Q. Wang
Abstract Dietary fatty acid (FA) absorption across the gastrointestinal (GI) tract is of critical importance for sustenance, however, excessive FA absorption has also been linked to metabolic syndrome and associated disorders. The expression of isoforms that regulate the dietary FA absorption are not as well characterized in the GI tract as they are elsewhere. Peroxisome proliferator-activated receptors (PPAR,, ,, and ,) and 9- cis -retinoic acid receptors (RXR,, ,, and ,) are nuclear hormone transcription factors that control FA homeostasis, in part through the regulation of expression of membrane-bound FA transporting proteins. The present study was designed to elucidate the expression of PPAR and RXR isoforms and FA transporting proteins (FABPpm and FAT/CD36) in the rat and human GI tracts using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemical staining. The results revealed rat GI expression of all the PPAR and RXR isoforms, FABPpm and FAT/CD36. PPAR,, PPAR,, PPAR,, RXR,, FABPpm, and FAT/CD36 isoforms exhibited ubiquitous expression in human GI tract, whereas RXR, was not detected. RXR, was observed in a majority of the human GI samples. These results provide a physiological foundation for rational drug design and drug delivery for the mitigation of metabolic syndrome and associated disorders to normalize intestinal FA absorption. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:363,372, 2005 [source]


Ethanol Impairs Activation of Retinoic Acid Receptors in Cerebellar Granule Cells in a Rodent Model of Fetal Alcohol Spectrum Disorders

ALCOHOLISM, Issue 5 2010
Ambrish Kumar
Background:, Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations. In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells. Methods:, The cerebellum of ethanol unexposed and exposed pups was used to study the expression of retinoic acid receptors (RARs or RXRs) by immunohistochemistry and by Western blot analysis. We also studied the effect of ethanol on expression of RA receptors in the cerebellar granule cells. Activation of RA receptors (DNA-binding activities) in response to high-dose ethanol was determined by electrophoretic mobility shift and supershift assays. Results:, Findings from these studies demonstrated that ethanol exposure reduced the expression of RAR,/, while it increased the expression of RXR,/, in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure. Conclusion:, For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells. Taken together, these findings could provide insight into the treatment options for brain defects caused by excessive ethanol exposure, such as in Fetal Alcohol Spectrum Disorders. [source]


Retinoids and retinoic acid receptors regulate growth arrest and apoptosis in human mammary epithelial cells and modulate expression of CBP/p300

MICROSCOPY RESEARCH AND TECHNIQUE, Issue 1 2002
Eric C. Dietze
Abstract Retinoids and retinoic acid receptors (RARs) are important mediators of normal epithelial cell homeostasis. To assess the role of retinoids and RARs in regulating growth arrest and apoptosis in benign and malignant mammary epithelial cells, two model systems were developed: 1) RAR function was suppressed in retinoid-sensitive normal human mammary epithelial cells (HMECs) by the dominant-negative retinoic acid receptor, RAR,403 (DNRAR), and 2) retinoid-resistant MCF-7 breast cancer cells were transduced with a functional RAR,2. Inhibition of RAR function by the DNRAR in HMECs resulted in retinoid-resistance, increased proliferation, and dysregulated growth when cells were cultured in reconstituted extracellular matrix (rECM). Expression of RAR,2 in MCF-7 cells resulted in sensitivity to retinoid-induced growth arrest and apoptosis. The CREB-binding protein (CBP) and the homologous protein p300 are tightly regulated, rate-limiting integrators of diverse signaling pathways and are recruited during retinoid-mediated transcriptional activation. The relationship between retinoid receptor expression, growth regulation, and transcriptional regulation of CBP/p300 is poorly understood. Inhibition of RAR function in HMECs by DNRAR suppressed expression of CBP/p300 and expression of RAR,2 in MCF-7 cells promoted induction of CBP/p300 when cells were treated with 1.0 ,M all- trans -retinoic acid (ATRA). These results suggest that ATRA and RARs regulate growth arrest of HMECs and modulate CBP/p300 protein expression. Since CBP and p300 are normally present in limiting amounts, their regulation by ATRA and RARs may be an important element in the control of transcriptional activation of genes regulating growth arrest and apoptosis. Microsc. Res. Tech. 59:23,40, 2002. © 2002 Wiley-Liss, Inc. [source]


Differentiation, proliferation and retinoid receptor status of papillary carcinoma of the thyroid

PATHOLOGY INTERNATIONAL, Issue 4 2003
Weihua Tang
Messenger RNA expression of retinoic acid receptors (RAR,, RAR, and RAR,) and retinoid X receptors (RXR,, RXR, and RXR,) was examined using reverse transcription-polymerase chain reaction in 42 papillary thyroid carcinomas (PTCs). A loss of mRNA expression was observed in 18 cases of the 42 PTCs, including three cases for RAR,, 14 cases for RAR,, six cases for RXR, and five cases for RXR,. The expressions of RAR, and RXR, were found in all 42 PTCs. Based on Ki 67/MIB1 labeling index (LI), the 42 PTCs were classified into Group A (20 cases; LI = 0,2%), Group B (17 cases; LI = 2,5%) and Group C (5 cases; LI > 5%). The PTCs of groups B and C showed solid, trabecular or scirrhous arrangements, infiltrative growth, loss of cellular polarity and cohesiveness more frequently, but capsulated growth pattern less frequently, when compared with PTCs of Group A. They also showed more frequent extrathyroidal extension than Group A. However, no significant differences were identified in sex, age, nodal status and tumor size. Loss of expression for one or more retinoid receptors frequently occurred in groups B and C. These results suggest that the loss of retinoid receptors might occur during the loss of differentiation and tumor progression of PTC. [source]


Metabolism of a sulfur-containing heteroarotionoid antitumor agent, SHetA2, using liquid chromatography/tandem mass spectrometry

RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 21 2008
Zhongfa Liu
SHetA2 {[(4-nitrophenyl)amino][2,2,4,4-tetramethylthiochroman-6-yl)amino]methanethione], NSC 726189}, a sulfur-containing heteroarotinoid, selectively inhibits cancer cell growth and induces apoptosis without activation of nuclear retinoic acid receptors (RARs). The objective of this study was to investigate its in vitro metabolism in rat and human liver microsomes and in vivo metabolism in the mouse and rat using liquid chromatography-ultraviolet/multi-stage mass spectrometry (LC-UV/MSn) on an ion-trap mass spectrometer coupled with a photo-diode array (PDA) detector. In vitro, in the absence of glutathione (GSH), oxidation of the four aliphatic methyl groups of SHetA2 yielded one mono-, two di-, and one tri-hydroxylated SHetA2 metabolites, which were identified based on their UV and multi-stage mass spectra. In the presence of GSH, in addition to these primary oxidative metabolites, four GSH adducts of SHetA2 and a novel rare form thioether GSH adduct was detected and characterized. In vivo, the monohydroxylated SHetA2 metabolites were also detected in mouse and rat plasma and two GSH adducts were detected in rat liver following intravenous (i.v.) bolus administration of SHetA2 at 40,mg/kg. Copyright © 2008 John Wiley & Sons, Ltd. [source]


Retinoid ameliorates experimental autoimmune myositis, with modulation of Th cell differentiation and antibody production in vivo

ARTHRITIS & RHEUMATISM, Issue 10 2009
Naho Ohyanagi
Objective Polymyositis and dermatomyositis are chronic inflammatory muscle diseases. Retinoids are compounds that bind to the retinoic acid binding site of retinoic acid receptors and have biologic activities similar to those of vitamin A. Recent studies indicate that retinoids promote Th2 differentiation and suppress Th1 and Th17 differentiation in vitro. The present study was undertaken to examine the effects of a synthetic retinoid, Am80, on experimental autoimmune myositis as well as on Th phenotype development and antibody production. Methods Experimental autoimmune myositis was induced in SJL/J mice by immunization with rabbit myosin. Am80 was administered orally once daily. Its effects were evaluated by measurement of the numbers of infiltrating inflammatory cells, production of inflammatory cytokines in muscle, production of Th-specific cytokines by myosin-stimulated splenic T cells, and production of antimyosin antibodies in serum. Results In mice with experimental autoimmune myositis, orally administered Am80 significantly reduced the number of infiltrating inflammatory cells and the expression of tumor necrosis factor , and interleukin-1, (IL-1,) in muscle. Moreover, Am80 increased production of interferon-,, IL-4, and IL-10, but not IL-17, by myosin-stimulated splenic T cells of mice with experimental autoimmune myositis, suggesting that it could enhance differentiation into Th1 and Th2, but not Th17, in vivo. Am80 also decreased serum levels of IgG2a and IgG2b antimyosin antibodies, but did not affect levels of IgG1 antimyosin antibodies. In addition, it suppressed chemokine expression and activator protein 1 activity in myoblasts in vitro. Conclusion The synthetic retinoid Am80 has an inhibitory effect on experimental autoimmune myositis. It might regulate the development of Th phenotype and antibody production in vivo, in addition to its effects on cytokine and chemokine production. [source]


Ligands for retinoic acid receptors are elevated in osteoarthritis and may contribute to pathologic processes in the osteoarthritic joint

ARTHRITIS & RHEUMATISM, Issue 6 2009
Mark R. Davies
Objective Vitamin A derivatives, including all- trans -retinoic acid (ATRA), have a well-established role during skeletal development and limb formation and have been shown to have profound effects on chondrocyte phenotype. The aim of this study was to elucidate the effects of retinoids and components of the retinoid metabolic pathway on chondrocyte phenotype in the tibiofemoral joints of patients with osteoarthritis (OA), to show that the retinoids can have multiple effects relevant to the OA disease process. Methods Human explant tissue and a chondrocyte-like cell line were treated with ATRA, and the responses of 4 key markers of chondrocyte phenotype were analyzed. In addition, the effects of ATRA on a number of novel genes associated with OA were assessed using a low-density microarray containing 80 disease marker genes. Results Vitamin A metabolite levels were elevated in synovial fluid, serum, and cartilage from patients with OA. Expression profiling of a retinoic acid receptor , coactivator protein, P/CAF, demonstrated elevated expression in patients with OA, suggesting the potential for increased signaling via the retinoid receptors in the disease. ATRA increased the levels of matrix metalloproteinase 13 and aggrecanase activity in human cartilage explants and in a human chondrocyte cell line. Furthermore, ATRA altered the expression of a wide range of relevant genes, including the types I, II, IX, and XI collagen genes, toward a nonchondrogenic and OA-like phenotype. Conclusion These results suggest that retinoid signaling could have a central role in OA, and that components of the pathway may provide potential disease biomarkers or targets for therapeutic intervention. [source]


Topical adapalene gel 0·1% vs. isotretinoin gel 0·05% in the treatment of acne vulgaris: a randomized open-label clinical trial

BRITISH JOURNAL OF DERMATOLOGY, Issue 3 2002
D. Ioannides
Summary Background Topical application of isotretinoin and adapalene has proved effective in treating acne vulgaris. Both drugs demonstrate therapeutic advantages and less irritancy over tretinoin, the most widely used treatment for acne. They both act as retinoid agonists, but differ in their affinity profile for nuclear and cytosolic retinoic acid receptors. Objectives To compare the efficacy and tolerability of adapalene gel 0·1% and isotretinoin gel 0·05% in the treatment of acne vulgaris of the face, in a randomized open-label clinical trial. Methods Eighty patients were enrolled and were instructed to apply adapalene gel 0·1% or isotretinoin gel 0·05% once daily over a 12-week treatment period. Efficacy determination included noninflammatory and inflammatory lesion counts by the investigator and global evaluation of improvement. Cutaneous tolerance was assessed by determining erythema, scaling and burning with pruritus. Results Adapalene and isotretinoin gels were highly effective in treating facial acne. Adapalene gel produced greater reductions in noninflammatory and inflammatory lesion counts than did isotretinoin gel, but differences between treatments were not statistically significant. Adapalene gel was significantly better tolerated than isotretinoin gel during the whole treatment period. Conclusions The two gels studied demonstrated comparable efficacy. When adapalene and isotretinoin were compared, significantly lower skin irritation was noted with adapalene, indicating that adapalene may begin a new era of treatment with low-irritant retinoids. [source]


Strategy and mechanism for the prevention of hepatocellular carcinoma: Phosphorylated retinoid X receptor , is a critical target for hepatocellular carcinoma chemoprevention

CANCER SCIENCE, Issue 3 2009
Masahito Shimizu
Hepatocellular carcinoma (HCC) is a major health care problem worldwide. The prognosis of patients with HCC is poor because even in the early stages when surgical treatment might be expected to be curative, the incidence of recurrence in patients with underlying cirrhosis is very high due to multicentric carcinogenesis. Therefore, strategies to prevent recurrence and second primary HCC are required to improve the prognosis. One of the most practical approaches to prevent the multicentric development of HCC is ,clonal deletion' therapy, which is defined as the removal of latent (i.e. invisible) (pre)malignant clones from the liver in a hypercarcinogenic state. Retinoids, a group of structural and functional analogs of vitamin A, exert their biological function primarily through two distinct nuclear receptors, retinoic acid receptors and retinoid X receptors (RXR), and abnormalities in the expression and function of these receptors are highly associated with the development of various cancers, including HCC. In particular, a malfunction of RXR, due to phosphorylation by the Ras,mitogen-activated protein kinase signaling pathway is profoundly associated with the development of HCC and thus may be a critical target for HCC chemoprevention. Acyclic retinoid, which has been clinically shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit Ras activity and phosphorylation of the extracellular signal-regulated kinase and RXR, proteins. In conclusion, the inhibition of RXR, phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective strategy for HCC chemoprevention and clonal deletion. Acyclic retinoid, which targets phosphorylated RXR,, may thus play a critical role in preventing the development of multicentric HCC. (Cancer Sci 2009; 100: 369,374) [source]