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Hweixian Leong Penny, Tyler R Prestwood, Nupur Bhattacharya, Fionna Sun, Justin A Kenkel, Matthew G Davidson, Lei Shen, Luis A Zuniga, E Scott Seeley, Reetesh Pai, Okmi Choi, Lorna Tolentino, Jinshan Wang, Joseph L Napoli, Edgar G Engleman
Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APC(Min/+) mice, a model that recapitulates FAP in most respects...
September 16, 2016: Cancer Immunology Research
Anaïs Boglino, Marian Ponce, Xavier Cousin, Enric Gisbert, Manuel Manchado
The aim of this study was the characterization of transcriptional regulatory pathways mediated by retinoic acid (RA) in Senegalese sole larvae. For this purpose, pre-metamorphic larvae were treated with a low concentration of DEAB, an inhibitor of RALDH enzyme, until the end of metamorphosis. No differences in growth, eye migration or survival were observed. Nevertheless, gene expression analysis revealed a total of 20 transcripts differentially expressed during larval development and only six related with DEAB treatments directly involved in RA metabolism and actions (rdh10a, aldh1a2, crbp1, igf2r, rarg and cyp26a1) to adapt to a low-RA environment...
September 10, 2016: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
Nupur Bhattacharya, Robert Yuan, Tyler R Prestwood, Hweixian Leong Penny, Michael A DiMaio, Nathan E Reticker-Flynn, Charles R Krois, Justin A Kenkel, Tho D Pham, Yaron Carmi, Lorna Tolentino, Okmi Choi, Reyna Hulett, Jinshan Wang, Daniel A Winer, Joseph L Napoli, Edgar G Engleman
Although all-trans-retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-associated CRC, and sporadic CRC specimens have similar alterations in atRA metabolic enzymes, consistent with reduced colonic atRA. Inhibition of atRA signaling promoted tumorigenesis, whereas atRA supplementation reduced tumor burden...
September 20, 2016: Immunity
O Nilsson, N Isoherranen, M H Guo, J C Lui, Y H Jee, I Guttmann-Bauman, C Acerini, W Lee, R Allikmets, J A Yanovski, A Dauber, J Baron
Nutritional excess of vitamin A, a precursor for retinoic acid (RA), causes premature epiphyseal fusion, craniosynostosis, and light-dependent retinopathy. Similarly, homozygous loss-of-function mutations in CYP26B1, one of the major RA-metabolizing enzymes, cause advanced bone age, premature epiphyseal fusion, and craniosynostosis. In this paper, a patient with markedly accelerated skeletal and dental development, retinal scarring, and autism-spectrum disease is presented and the role of retinoic acid in longitudinal bone growth and skeletal maturation is reviewed...
September 2, 2016: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
V R Kasimanickam
Mammalian spermatogenesis involves highly regulated temporal and spatial dynamics, carefully controlled by several signalling processes. Retinoic acid (RA) signalling could have a critical role in spermatogenesis by promoting spermatogonia differentiation, adhesion of germ cells to Sertoli cells, and release of mature spermatids. An optimal testicular RA concentration is maintained by retinaldehyde dehydrogenases (ALDHs), which oxidize RA precursors to produce RA, whereas the CYP26 class of enzymes catabolizes (oxidize) RA into inactive metabolites...
August 28, 2016: Reproduction in Domestic Animals, Zuchthygiene
Robert S Foti, Philippe Diaz, Dominique Douguet
The CYP26s are responsible for metabolizing retinoic acid and play an important role in maintaining homeostatic levels of retinoic acid. Given the ability of CYP2C8 to metabolize retinoic acid, we evaluated the potential for CYP2C8 inhibitors to also inhibit CYP26. In vitro assays were used to evaluate the inhibition potencies of CYP2C8 inhibitors against CYP26A1 and CYP26B1. Using tazarotenic acid as a substrate for CYP26, IC50 values for 17 inhibitors of CYP2C8 were determined for CYP26A1 and CYP26B1, ranging from ∼20 nM to 100 μM, with a positive correlation observed between IC50s for CYP2C8 and CYP26A1...
July 17, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Richard W Naylor, Lauren Brilli Skvarca, Christine Thisse, Bernard Thisse, Neil A Hukriede, Alan J Davidson
Despite the fundamental importance of patterning along the dorsal-ventral (DV) and anterior-posterior (AP) axes during embryogenesis, uncertainty exists in the orientation of these axes for the mesoderm. Here we examine the origin and formation of the zebrafish kidney, a ventrolateral mesoderm derivative, and show that AP patterning of the non-axial mesoderm occurs across the classic gastrula stage DV axis while DV patterning aligns along the animal-vegetal pole. We find that BMP signalling acts early to establish broad anterior and posterior territories in the non-axial mesoderm while retinoic acid (RA) functions later, but also across the classic DV axis...
2016: Nature Communications
A García-Sánchez, E Marcos-Vadillo, C Sanz, L Hernández-Hernández, G Cerutti-Müller, F Marqués-García, F Lorente, M Isidoro-García, I Dávila
BACKGROUND AND OBJECTIVE: Vitamin A has been linked to the development of allergic diseases although its role is not fully understood, Retinoic acid (RA), a metabolite of Vitamin A, has been previously associated with the prostaglandin pathway, and PTGDR, a receptor of PGD2, has been proposed as a candidate gene in allergy and asthma. Considering the role of PTGDR in allergy, the goal of this study was to analyze the effect of RA on the activation of the promoter region of the PTGDR gene...
2016: Journal of Investigational Allergology & Clinical Immunology
Shu-Ting Pan, Danfeng Xue, Zhi-Ling Li, Zhi-Wei Zhou, Zhi-Xu He, Yinxue Yang, Tianxin Yang, Jia-Xuan Qiu, Shu-Feng Zhou
The human cytochrome P450 (CYP) superfamily consisting of 57 functional genes is the most important group of Phase I drug metabolizing enzymes that oxidize a large number of xenobiotics and endogenous compounds, including therapeutic drugs and environmental toxicants. The CYP superfamily has been shown to expand itself through gene duplication, and some of them become pseudogenes due to gene mutations. Orthologs and paralogs are homologous genes resulting from speciation or duplication, respectively. To explore the evolutionary and functional relationships of human CYPs, we conducted this bioinformatic study to identify their corresponding paralogs, homologs, and orthologs...
2016: International Journal of Molecular Sciences
Lei Hu, Jin-Feng Lv, Wei Zhuo, Cong-Min Zhang, Hong-Hao Zhou, Lan Fan
OBJECTIVES: All-trans-retinoic acid (ATRA), a naturally occurring metabolite of vitamin A, has been shown to have great potential as an antitumorigenic drug to treat acute leukaemia by promoting cancer cell differentiation. Cytochrome P450 oxidoreductase (POR) is the only obligate electron donor for all of the microsomal cytochrome P450 enzymes including CYP26A1 which is highly specific for ATRA metabolism and efficacy in human myeloid leukaemia cells. In this study, we aimed to investigate the effect of POR on ATRA efficacy and CYP26A1 expression in human myeloid leukaemia HL-60 cells...
September 2016: Journal of Pharmacy and Pharmacology
Jiaojiao Jing, Cristian Pattaro, Anselm Hoppmann, Yukinori Okada, Caroline S Fox, Anna Köttgen
Genomewide association studies have identified numerous chronic kidney disease-associated genetic variants, but often do not pinpoint causal genes. This limitation was addressed by combining Mouse Genome Informatics with human genomewide association studies of kidney function. Genes for which mouse models showed abnormal renal physiology, morphology, glomerular filtration rate (GFR), or urinary albumin-to-creatinine ratio were identified from Mouse Genome Informatics. The corresponding human orthologs were then evaluated for GFR-associated single-nucleotide polymorphisms in 133,814 individuals and urinary albumin-to-creatinine ratio-associated SNPs in 54,451 individuals in genome-wide association studies meta-analysis of the CKDGen Consortium...
October 2016: Kidney International
Mildred V Duprey-Díaz, Jonathan M Blagburn, Rosa E Blanco
Retinoic acid (RA) is important during development, in neuronal plasticity, and also in peripheral nervous system regeneration. Here we use the frog visual system as a model to investigate the changes in RA signaling that take place after axonal injury to the central nervous system. Immunocytochemistry was used to localize different components of RA signaling within sections of the retina and optic tectum, namely, the synthetic enzyme retinaldehyde dehydrogenase (RALDH), the RA binding proteins CRABPI and II, the retinoic acid receptors RARα, β and (, and finally the catabolic enzyme CYP26A1...
May 27, 2016: Journal of Chemical Neuroanatomy
Yang Zeng, Yoshika Kurokawa, Tin-Tin Win-Shwe, Qin Zeng, Seishiro Hirano, Zhenya Zhang, Hideko Sone
Polyamidoamine (PAMAM) dendrimers have potential for biological applications as delivery systems for genes, drugs, and imaging agents into the brain, but their developmental neurotoxicity remains unknown. We investigated the effects of PAMAM dendrimers with various surface functional groups and multiple generations on neuronal differentiation using human neural progenitor cells at an equal mass concentration. Only PAMAM dendrimers containing amine (NH2) surface groups at concentrations of 10 μg/mL significantly reduced cell viability and neuronal differentiation, compared with non-amine-terminated dendrimers...
2016: Journal of Toxicological Sciences
Myrto Dimopoulou, Aart Verhoef, Bennard van Ravenzwaay, Ivonne M C M Rietjens, Aldert H Piersma
Embryotoxic responses are critically dependent on the timing of exposure during embryo development. Here, we examined the time- dependent developmental effects in rat embryos exposed to flusilazole (FLU), and their link to retinoic acid (RA) mediated pathways. To this end, we assessed the effects of 4h exposure of rat embryos in vitro to 300μM FLU during four developmental time windows (0-4, 4-8, 24-28 and 44-48h), evaluating morphological parameters, expression and localization of five genes directly or indirectly linked with the RA pathway...
September 2016: Reproductive Toxicology
Mohamed K A Awadalla, Thamir M Alshammari, Leif A Eriksson, Patricia Saenz-Méndez
A new CYP26A1 homology model was built based on the crystal structure of cyanobacterial CYP120A1. The model quality was examined for stereochemical accuracy, folding reliability, and absolute quality using a variety of different bioinformatics tools. Furthermore, the docking capabilities of the model were assessed by docking of the natural substrate all-trans-retinoic acid (atRA), and a group of known azole- and tetralone-based CYP26A1 inhibitors. The preferred binding pose of atRA suggests the (4S)-OH-atRA metabolite production, in agreement with recently available experimental data...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Chunhong Chen, Aline Stedman, Emmanuelle Havis, Isabelle Anselme, Daria Onichtchouk, François Giudicelli, Sylvie Schneider-Maunoury
Early patterning of the vertebrate neural plate involves a complex hierarchy of inductive interactions orchestrated by signalling molecules and their antagonists. The morphogen retinoic acid, together with the Cyp26 enzymes which degrade it, play a central role in this process. The cyp26a1 gene expressed in the anterior neural plate thus contributes to the fine modulation of the rostrocaudal retinoic acid gradient. Despite this important role of cyp26a1 in early brain formation, the mechanisms that control its expression in the anterior neural plate are totally unknown...
2016: PloS One
Robert S Foti, Nina Isoherranen, Alex Zelter, Leslie J Dickmann, Brian R Buttrick, Philippe Diaz, Dominique Douguet
Cytochrome P450 (CYP) 26A1 and 26B1 are heme-containing enzymes responsible for metabolizing all-trans retinoic acid (at-RA). No crystal structures have been solved, and therefore homology models that provide structural information are extremely valuable for the development of inhibitors of cytochrome P450 family 26 (CYP26). The objectives of this study were to use homology models of CYP26A1 and CYP26B1 to characterize substrate binding characteristics, to compare structural aspects of their active sites, and to support the role of CYP26 in the metabolism of xenobiotics...
May 2016: Journal of Pharmacology and Experimental Therapeutics
Philippe Diaz, Weize Huang, Charles M Keyari, Brian Buttrick, Lauren Price, Nicolas Guilloteau, Sasmita Tripathy, Vanessa G Sperandio, Frank R Fronczek, Fanny Astruc-Diaz, Nina Isoherranen
Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the existing atRA metabolism inhibitors toward CYP26A1 and CYP26B1 is unknown, and no selective CYP26A1 or CYP26B1 inhibitors have been developed. Here the synthesis and potent inhibitory activity of the first CYP26A1 selective inhibitors is reported. A series of nonazole CYP26A1 selective inhibitors was identified with low nM potency...
March 24, 2016: Journal of Medicinal Chemistry
Jessie Chang, Isaac Skromne, Robert K Ho
The sub-division of the posterior-most territory of the neural plate results in the formation of two distinct neural structures, the hindbrain and the spinal cord. Although many of the molecular signals regulating the development of these individual structures have been elucidated, the mechanisms involved in delineating the boundary between the hindbrain and spinal cord remain elusive. Two molecules, retinoic acid (RA) and the Cdx4 transcription factor have been previously implicated as important regulators of hindbrain and spinal cord development, respectively...
February 15, 2016: Developmental Biology
Minghui Li, Ruijuan Feng, He Ma, Ranran Dong, Zhilong Liu, Wentao Jiang, Wenjing Tao, Deshou Wang
Existing studies demonstrated that retinoic acid (RA) regulates meiotic initiation via stra8-independent pathway in teleosts which lack stra8 in their genomes. However, stra8 was recently identified from several fish species including Southern catfish (Silurus meridionalis). To explore the existence of stra8-dependent pathway in RA mediated meiotic initiation in fishes, in the present study, the genes encoding RA synthase aldh1a2 and catabolic enzyme cyp26a1 and cyp26b1 were cloned from the Southern catfish...
June 1, 2016: General and Comparative Endocrinology
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