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https://www.readbyqxmd.com/read/28446509/inhibition-of-the-all-trans-retinoic-acid-hydroxylases-cyp26a1-and-cyp26b1-results-in-dynamic-tissue-specific-changes-in-endogenous-atra-signaling
#1
Faith Stevison, Cathryn Hogarth, Sasmita Tripathy, Travis Kent, Nina Isoherranen
all-trans-retinoic acid (atRA), the active metabolite of vitamin A, is a ligand for several nuclear receptors and acts as a critical regulator of many physiological processes. The cytochrome P450 family 26 (CYP26) enzymes are responsible for atRA clearance, and are potential drug targets to increase concentrations of endogenous atRA in a tissue-specific manner. Talarozole is a potent inhibitor of CYP26A1 and CYP26B1, and has shown some success in clinical trials. Yet, it is not known what magnitude of change is needed in tissue atRA concentrations to promote atRA signaling changes...
April 26, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28436029/wnt4-acts-downstream-of-bmp2-to-mediate-the-regulation-of-atra-signaling-on-runx1-expression-implications-for-terminal-differentiation-of-antler-chondrocytes
#2
Hong-Liang Zhang, Zhan-Qing Yang, Cui-Cui Duan, Shuang Geng, Kai Wang, Hai-Fan Yu, Zhan-Peng Yue, Bin Guo
Although ATRA is involved in regulating the proliferation and differentiation of chondrocytes, its underlying mechanism remains unknown. Here we showed that ATRA could stimulate the proliferation of antler chondrocytes and expression of COL X and MMP13 which were two well-known markers for hypertrophic chondrocytes. Silencing of CRABP2 prevented the induction of ATRA on chondrocyte terminal differentiation, while overexpression of CRABP2 exhibited the opposite effects. CYP26A1 and CYP26B1 weakened the sensitivity of antler chondrocytes to ATRA...
April 24, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28422378/cellular-retinoic-acid-bioavailability-in-various-pathologies-and-its-therapeutic-implication
#3
REVIEW
Makoto Osanai
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...
April 19, 2017: Pathology International
https://www.readbyqxmd.com/read/28361034/combinatorial-ranking-of-gene-sets-to-predict-disease-relapse-the-retinoic-acid-pathway-in-early-prostate-cancer
#4
Hieu T Nim, Milena B Furtado, Mirana Ramialison, Sarah E Boyd
BACKGROUND: Quantitative high-throughput data deposited in consortia such as International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) present opportunities and challenges for computational analyses. METHODS: We present a computational strategy to systematically rank and investigate a large number (2(10)-2(20)) of clinically testable gene sets, using combinatorial gene subset generation and disease-free survival (DFS) analyses. This approach integrates protein-protein interaction networks, gene expression, DNA methylation, and copy number data, in association with DFS profiles from patient clinical records...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28339981/transcriptome-analysis-of-comb-and-testis-from-rose-comb-silky-chicken-r1-r1-and-beijing-fatty-wild-type-chicken-r-r
#5
Y Wang, J Li, C Feng, Y Zhao, X Hu, N Li
Rose-comb was one of the chicken comb-variants first used by Bateson and Punnet in 1902 to demonstrate Mendelian inheritance in animals. Rose-comb is a monogenic trait that has been widely described in chickens. It is caused by a large structural rearrangement that leads to mis-expression of transcription factor MNR2 on chromosome 7. Rose-comb has pleiotropic effects in homozygous roosters, which is associated with poor sperm mobility. It was postulated that this is caused by the disruption of the CCDC108 gene located at the distal inversion breakpoint...
March 2, 2017: Poultry Science
https://www.readbyqxmd.com/read/28275201/physiologically-based-pharmacokinetic-model-of-all-trans-retinoic-acid-with-application-to-cancer-populations-and-drug-interactions
#6
Jing Jing, Cara Nelson, Jisun Paik, Yoshiyuki Shirasaka, John K Amory, Nina Isoherranen
All-trans retinoic acid (atRA) is a front-line treatment of acute promyelocytic leukemia (APL). Due to its activity in regulating the cell cycle, it has also been evaluated for the treatment of other cancers. However, the efficacy of atRA has been limited by atRA inducing its own metabolism during therapy, resulting in a decrease of atRA exposure during continuous dosing. Frequent relapse occurs in patients receiving atRA monotherapy. In an attempt to combat therapy resistance, inhibitors of atRA metabolism have been developed...
May 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28253328/reprogramming-of-the-retinoic-acid-pathway-in-decidualizing-human-endometrial-stromal-cells
#7
Rie Ozaki, Keiji Kuroda, Yuko Ikemoto, Asako Ochiai, Akemi Matsumoto, Jun Kumakiri, Mari Kitade, Atsuo Itakura, Joanne Muter, Jan J Brosens, Satoru Takeda
Upon breaching of the endometrial surface epithelium, the implanting embryo embeds in the decidualizing stroma. Retinoic acid (RA), a metabolite of vitamin A, is an important morphogen during embryonic and fetal development, although the role of the RA pathway in the surrounding decidual cells is not understood. Here we show that decidual transformation of human endometrial stromal cells (HESCs) results in profound reprogramming of the RA signaling and metabolism pathways. Differentiating HESCs downregulate the intracellular carrier proteins CRABP2 and FABP5, responsible for transfer and binding of RA to the nuclear receptors RAR and PPARβ/δ, respectively...
2017: PloS One
https://www.readbyqxmd.com/read/28238841/vitamin-a-status-affects-the-plasma-parameters-and-regulation-of-hepatic-genes-in-streptozotocin-induced-diabetic-rats
#8
Yang Li, Yang Liu, Guoxun Chen
Vitamin A (VA) status regulates metabolism in rats. Whether VA status and availability of retinoic acid (RA) contribute to the insulin-regulated hepatic gene expression remains to be determined. Zucker lean rats with VA sufficient (VAS) or VA deficient (VAD) status were treated with streptozotocin (STZ) to induce insulin-dependent diabetes. They were treated with saline (STZ-VAS-C or STZ-VAD-C), RA (STZ-VAS-RA or STZ-VAD-RA), insulin (STZ-VAS-INS or STZ-VAD-INS), or insulin + RA (STZ-VAS-INS+RA or STZ-VAD-INS+RA) for 3 hours...
February 23, 2017: Biochimie
https://www.readbyqxmd.com/read/28213303/diethylstilbestrol-flutamide-and-their-combination-impaired-the-spermatogenesis-of-male-adult-zebrafish-through-disrupting-hpg-axis-meiosis-and-apoptosis
#9
Pan Yin, Ying-Wen Li, Qi-Liang Chen, Zhi-Hao Liu
Both diethylstilbestrol (DES, an environmental estrogen) and flutamide (FLU, an anti-androgen) are found to impair spermatogenesis by disrupting hypothalamic-pituitary-gonadal (HPG) axis and altering androgen levels through different mechanisms/modes of action in fish with poorly understood underlying mechanisms. Furthermore, it is not known whether and how a combined exposure of DES and FLU has a stronger effect than the compounds alone. In this study, male zebrafish adults were exposed to DES, FLU and their combination (DES+FLU) for 30days, and their effects on histological structure and sperm count in testis, androgen level in plasma, as well as the mRNA levels of genes involved in HPG axis, meiotic regulation and apoptosis were analyzed...
April 2017: Aquatic Toxicology
https://www.readbyqxmd.com/read/28187790/retinoic-acid-and-tgf-%C3%AE-signalling-cooperate-to-overcome-mycn-induced-retinoid-resistance
#10
David J Duffy, Aleksandar Krstic, Melinda Halasz, Thomas Schwarzl, Anja Konietzny, Kristiina Iljin, Desmond G Higgins, Walter Kolch
BACKGROUND: Retinoid therapy is widely employed in clinical oncology to differentiate malignant cells into their more benign counterparts. However, certain high-risk cohorts, such as patients with MYCN-amplified neuroblastoma, are innately resistant to retinoid therapy. Therefore, we employed a precision medicine approach to globally profile the retinoid signalling response and to determine how an excess of cellular MYCN antagonises these signalling events to prevent differentiation and confer resistance...
February 10, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28103795/lineage-specific-duplication-of-amphioxus-retinoic-acid-degrading-enzymes-cyp26-resulted-in-sub-functionalization-of-patterning-and-homeostatic-roles
#11
João E Carvalho, Maria Theodosiou, Jie Chen, Pascale Chevret, Susana Alvarez, Angel R De Lera, Vincent Laudet, Jenifer C Croce, Michael Schubert
BACKGROUND: During embryogenesis, tight regulation of retinoic acid (RA) availability is fundamental for normal development. In parallel to RA synthesis, a negative feedback loop controlled by RA catabolizing enzymes of the cytochrome P450 subfamily 26 (CYP26) is crucial. In vertebrates, the functions of the three CYP26 enzymes (CYP26A1, CYP26B1, and CYP26C1) have been well characterized. By contrast, outside vertebrates, little is known about CYP26 complements and their biological roles...
January 19, 2017: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/28087752/deficient-retinoid-driven-angiogenesis-may-contribute-to-failure-of-adult-human-lung-regeneration-in-emphysema
#12
John-Poul Ng-Blichfeldt, Joana Alçada, M Angeles Montero, Charlotte H Dean, Uta Griesenbach, Mark J Griffiths, Matthew Hind
BACKGROUND: Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease. OBJECTIVES: To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema...
January 13, 2017: Thorax
https://www.readbyqxmd.com/read/28087565/perturbation-of-retinoid-homeostasis-increases-malformation-risk-in-embryos-exposed-to-pregestational-diabetes
#13
Leo M Y Lee, Maran B W Leung, Rachel C Y Kwok, Yun Chung Leung, Chi Chiu Wang, Peter J McCaffery, Andrew J Copp, Alisa S W Shum
Pregestational diabetes is highly associated with an increased risk of birth defects. However, factors that can increase or reduce the expressivity and penetrance of malformations in pregnancies in women with diabetes remain poorly identified. All-trans retinoic acid (RA) plays crucial roles in embryogenesis. Here, we find that Cyp26a1, which encodes a key enzyme for catabolic inactivation of RA required for tight control of local RA concentrations, is significantly downregulated in embryos of diabetic mice...
April 2017: Diabetes
https://www.readbyqxmd.com/read/28067449/13cra-regulates-the-differentiation-of-antler-chondrocytes-through-targeting-runx3
#14
Hong-Liang Zhang, Hang Cao, Zhan-Qing Yang, Shuang Geng, Kai Wang, Hai-Fan Yu, Bin Guo, Zhan-Peng Yue
Although 13cRA is involved in the regulation of cellular proliferation and differentiation, its physiological roles in chondrocyte proliferation and differentiation still remain unknown. Here, we showed that 13cRA could induce the proliferation of sika deer antler chondrocytes and expression of Ccnd3 and Cdk6. Administration of 13cRA to antler chondrocytes resulted in an obvious increase in the expression of chondrocyte marker Col II and hypertrophic chondrocyte marker Col X. Silencing of Crabp2 expression by specific siRNA could prevent the 13cRA-induced up-regulation of Col X, whereas overexpression of Crabp2 showed the opposite effects...
March 2017: Cell Biology International
https://www.readbyqxmd.com/read/27904043/role-of-the-drug-metabolizing-enzyme-cyp-during-mouse-liver-development
#15
Wataru Ochiai, Akiyo Hirose, Taisuke Kawamura, Kyoko Komachi, Yuka Yamamoto, Satoshi Kitaoka, Jo Hatogai, Yoshiki Kusunoki, Risako Kon, Nobutomo Ikarashi, Kiyoshi Sugiyama
The drug-metabolizing enzyme CYP is mainly involved in the metabolism of various substances in the liver, such as drugs, endogenous substances, and carcinogens. Recent reports have also revealed that CYP1B1 plays a major role in the developmental process. Because the level of CYP expression is markedly high in the liver, we hypothesize that CYP plays a role in the developmental process of the liver. To verify this hypothesis, we analyzed the expression patterns of various CYP molecular species and their functions during the differentiation of embryonic stem cells (ES cells) into hepatocytes and the developmental process in mice...
2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27904037/analysis-of-cyp2r1-and-cyp26a1-expression-patterns-in-regeneration-in-mice-with-liver-injury
#16
Akiyo Hirose, Wataru Ochiai, Yuka Yamamoto, Masashi Fukaya, Hiroshi Iwasaki, Nozomi Wakui, Ayumi Takahashi, Yusuke Takahashi, Satoshi Kitaoka, Jo Hatogai, Nobutomo Ikarashi, Kiyoshi Sugiyama
Cytochrome P450 enzymes (CYPs) are involved in the metabolism of various substances in the liver and small intestine and show markedly higher expression levels in the liver compared to other organs. The liver exhibits a remarkable capacity to regenerate. After excision of 70% of the liver, the organ can regenerate to its original size in approximately 1 week. Unlike the normal liver, in the injured liver, hepatic stem cells known as oval cells are considered to play an important role in regeneration. However, the role of CYPs in liver regeneration remains unclear...
2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27893754/cyp26-enzymes-facilitate-second-heart-field-progenitor-addition-and-maintenance-of-ventricular-integrity
#17
Ariel B Rydeen, Joshua S Waxman
Although retinoic acid (RA) teratogenicity has been investigated for decades, the mechanisms underlying RA-induced outflow tract (OFT) malformations are not understood. Here, we show zebrafish embryos deficient for Cyp26a1 and Cyp26c1 enzymes, which promote RA degradation, have OFT defects resulting from two mechanisms: first, a failure of second heart field (SHF) progenitors to join the OFT, instead contributing to the pharyngeal arch arteries (PAAs), and second, a loss of first heart field (FHF) ventricular cardiomyocytes due to disrupted cell polarity and extrusion from the heart tube...
November 2016: PLoS Biology
https://www.readbyqxmd.com/read/27865410/comparative-analysis-of-testis-transcriptomes-associated-with-male-infertility-in-cattleyak
#18
Xin Cai, Shumin Yu, TserangDonko Mipam, Fang Yang, Wangsheng Zhao, Wenjing Liu, SuiZhong Cao, Liuhong Shen, Fangfang Zhao, Lei Sun, Chuanfei Xu, Shixin Wu
Cattleyak exhibit equivalent adaptability to harsh environment as yak and much higher performances than yak. However, male infertility of cattleyak due to spermatogenic arrest greatly restricts their effective utilization in yak breeding. Although much work has been done to investigate the mechanisms of spermatogenic arrest, there is little information available in regard to the differences in transcriptomic profiling between cattleyak and yak testes. In this work, histologic observation indicated that spermatogonia were the main type of germ cells present in cattleyak testis, whereas all types of germ cells in differentiation were present in yak testis...
January 15, 2017: Theriogenology
https://www.readbyqxmd.com/read/27860312/cytochrome-p450-26a1-modulates-natural-killer-cells-in-mouse-early-pregnancy
#19
Chao-Yang Meng, Zhong-Yin Li, Wen-Ning Fang, Zhi-Hui Song, Dan-Dan Yang, Dan-Dan Li, Ying Yang, Jing-Pian Peng
Cytochrome P450 26A1 (CYP26A1) has a spatiotemporal expression pattern in the uterus, with a significant increase in mRNA and protein levels during peri-implantation. Inhibiting the function or expression of CYP26A1 can cause pregnancy failure, suggesting an important regulatory role of CYP26A1 in the maintenance of pregnancy. However, little is known about the exact mechanism involved. In this study, using a pCR3.1-cyp26a1 plasmid immunization mouse model and a Cyp26a1-MO (Cyp26a1-specific antisense oligos) knockdown mouse model, we report that the number of Dolichos biflorus agglutinin (DBA) lectin-positive uterine natural killer (uNK) cells was reduced in pCR3...
April 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/27638841/restoring-retinoic-acid-attenuates-intestinal-inflammation-and-tumorigenesis-in-apcmin-mice
#20
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...
November 2016: Cancer Immunology Research
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