Specific Antagonist of Retinoid Toxicity in Mice

Standeven, Andrew M.; Johnson, A. T. Charlie; Escobar, Maria; Chandraratna, Roshantha A.S.

doi:10.1006/taap.1996.0110

Cited by 38 publications

(23 citation statements)

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“…The RAR antagonist AGN194301, a specific and highly effective antagonist of RAR␣ (26), completely blocked the all-trans-RA-induced SCD mRNA expression. Because RARs are believed to act generally as heterodimers with RXRs (41,42), the regulation of SCD by RA is most likely mediated through the preferred RAR-RXR heterodimer.…”

Section: Discussionmentioning

confidence: 97%

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Regulation of Stearoyl Coenzyme A Desaturase Expression in Human Retinal Pigment Epithelial Cells by Retinoic Acid

Samuel¹,

Kutty²,

Nagineni³

et al. 2001

Journal of Biological Chemistry

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Stearoyl-CoA desaturase (SCD) is a regulatory enzyme involved in the synthesis of the monounsaturated fatty acids palmitoleate and oleate. The regulation of SCD is of physiological importance because the ratio of saturated fatty acids to unsaturated fatty acids is thought to modulate membrane fluidity. Differential display analysis of retinal pigment epithelial (ARPE-19) cells identified SCD as a gene regulated by retinoic acid. Two SCD transcripts of 3.9 and 5.2 kilobases in size were found to be expressed in these cells by Northern blot analysis. All-trans-retinoic acid (all-trans-RA) increased SCD mRNA expression in a dose-and time-dependent manner; a ϳ7-fold increase was observed with 1 M all-trans-RA at 48 h. SCD mRNA expression was also increased by 9-cis-retinoic acid (9-cis-RA) as well as 4-(E-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TT-NPB), a retinoic acid receptor (RAR)-specific agonist. AGN194301, a RAR␣-specific antagonist, suppressed the SCD expression induced by all-trans-RA, TTNPB, and 9-cis-RA. These results indicate the involvement of RAR␣ in the induction of SCD expression by retinoic acid. However, AGN194204, a RXR (retinoid X receptor) pan agonist, also increased SCD mRNA expression. This increase was not blocked by AGN194301, suggesting that an RARindependent mechanism may also be involved. Thus, SCD expression in retinal pigment epithelial cells is regulated by retinoic acid, and the regulation appears to be mediated through RAR and RXR.Stearoyl-CoA desaturase (SCD, EC 1.14.99.5), 1 a microsomal enzyme, catalyzes the initial desaturation of long chain saturated fatty acids into monounsaturated fatty acids. Palmitate and stearate are the preferred substrates for this enzyme. They are converted to palmitoleate and oleate, respectively (1, 2). This oxidative reaction also requires the participation of 0 2 , NADPH, cytochrome b 5 , and cytochrome b 5 reductase. Two SCD genes, SCD1 and SCD2, characterized from both rat and mouse, encode functionally active proteins that share Ͼ80% sequence homology (3, 4). SCD1 and SCD2 show different tissue-specific expression patterns, possibly because of marked differences in the promoter sequences of their genes (5). There are also two loci for SCD genes in the human genome, one on chromosome 10 and another on chromosome 17 (6). However, the gene on chromosome 17 appears to be a transcriptionally inactive pseudogene. The gene on chromosome 10 encodes the functionally active 359-amino acid SCD protein. This gene yields two transcripts, 5.2 and 3.9 kb in size, which differ in the length of the 3Ј-untranslated region.The regulation of SCD by dietary factors, hormones, and peroxisomal proliferators has been studied in mouse and rat (7-12). The regulation of SCD is of physiological importance because changes in this enzyme activity could lead to changes in cell membrane phospholipid composition (8). Palmitoleic and oleic acids are the predominant unsaturated fatty acids present in fat depots and membrane phospholipids (9...

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Section: Discussionmentioning

confidence: 97%

“…All-trans-RA is known to mediate its response through RAR (24), and TTNPB, a synthetic retinoid analog, acts as a selective RAR agonist (25). Both the all-trans-RA-and TTNPB-mediated increases in SCD mRNA expression were effectively blocked by AGN194301, a RAR␣-specific antagonist (26).…”

Section: Identification Of Scd As a Differentially Expressed Gene In mentioning

confidence: 99%

Regulation of Stearoyl Coenzyme A Desaturase Expression in Human Retinal Pigment Epithelial Cells by Retinoic Acid

Samuel¹,

Kutty²,

Nagineni³

et al. 2001

Journal of Biological Chemistry

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“…Furthermore, three of the drugs identified (Entinostat, TTNPB, and Exemestane) showed direct overlap between the CN-AML patients and A9M-L2 model of which two (Entinostat and TTNPB) demonstrated statistically robust perturbation scores of 1. One of the compounds (TTNPB) had previously been shown to have in vivo toxicity in mouse models [35] and, therefore, Entinostat, a HDACi shown to be welltolerated in vivo [33,34], was selected for further analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Two drugs, namely; TTNPB (tetrahydro-tetramethylnaphthalenyl-propenyl benzoic acid) and Entinostat had a strong biological connection and perturbation score of 1.0 for both signatures. TTNPB is a retinoic acid agonist shown previously to exhibit in vivo toxicity in mouse [35]. Entinostat, a well-tolerated HDACi [33,34], was therefore selected as a candidate drug for further analysis.…”

Section: Leukemia Gene Signature Sscmap Analysismentioning

confidence: 99%

Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia

et al. 2013

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The incidence of refractory acute myeloid leukemia (AML) is on the increase due in part to an aging population that fails to respond to traditional therapies. High throughput genomic analysis promises better diagnosis, prognosis, and therapeutic intervention based on improved patient stratification. Relevant preclinical models are urgently required to advance drug development in this area. The collaborating oncogenes, HOXA9 and MEIS1, are frequently co-overexpressed in cytogenetically normal AML (CN-AML), and a conditional transplantation mouse model was developed that demonstrated oncogene dependency and expression levels comparable to CN-AML patients. Integration of gene signatures obtained from the mouse model and a cohort of CN-AML patients using statistically significant connectivity map analysis identified Entinostat as a drug with the potential to alter the leukemic condition toward the normal state. Ex vivo treatment of leukemic cells, but not age-matched normal bone marrow controls, with Entinostat validated the gene signature and resulted in reduced viability in liquid culture, impaired colony formation, and loss of the leukemia initiating cell. Furthermore, in vivo treatment with Entinostat resulted in prolonged survival of leukemic mice. This study demonstrates that the HDAC inhibitor Entinostat inhibits disease maintenance and prolongs survival in a clinically relevant murine model of cytogenetically normal

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“…40) However, ATRA has been reported to have severe side effects; some of them, such as teratogenicity, weight loss, and skin disorder, have been shown to arise via RAR stimulation. 10,41) On the other hand, it was reported that stimulation to PPARβ/δ suppressed inflammation-induced body weight loss. 42) In this study, no significant weight change was observed by treatment with PPARβ/δ selective agonist, GW0742.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Administration of GW0742, a High-Affinity Peroxisome Proliferator-Activated Receptor Agonist, Repairs Collapsed Alveoli in an Elastase-Induced Mouse Model of Emphysema

Ozawa

Horiguchi

Akita

et al. 2016

Biological & Pharmaceutical Bulletin

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Pulmonary emphysema is a disease in which lung alveoli are irreversibly damaged, thus compromising lung function. Our previous study revealed that all-trans-retinoic acid (ATRA) induces the differentiation of human lung alveolar epithelial type 2 progenitor cells and repairs the alveoli of emphysema model mice. ATRA also reportedly has the ability to activate peroxisome proliferator-activated receptor (PPAR) β/δ. A selective PPARβ/δ ligand has been reported to induce the differentiation of human keratinocytes during wound repair. Here, we demonstrate that treatment using a high-affinity PPARβ/δ agonist, GW0742, reverses the lung tissue damage induced by elastase in emphysema-model mice and improves respiratory function. Mice treated with elastase, which collapsed their alveoli, were then treated with either 10% dimethyl sulfoxide (DMSO) in saline (control group) or GW0742 (1.0 mg/kg twice a week) by pulmonary administration. Treatment with GW0742 for 2 weeks increased the in vivo expression of surfactant proteins A and D, which are known alveolar type II epithelial cell markers. GW0742 treatment also shortened the average distance between alveolar walls in the lungs of emphysema model mice, compared with a control group treated with 10% DMSO in saline. Treatment with GW0742 for 3 weeks also improved tissue elastance (cm H 2 O/mL), as well as the ratio of the forced expiratory volume in the first 0.05 s to the forced vital capacity (FEV 0.05/ FVC). In each of these experiments, GW0742 treatment reversed the damage caused by elastase. In conclusion, PPARβ/δ agonists are potential therapeutic agents for pulmonary emphysema.

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Specific Antagonist of Retinoid Toxicity in Mice

Cited by 38 publications

References 0 publications

Regulation of Stearoyl Coenzyme A Desaturase Expression in Human Retinal Pigment Epithelial Cells by Retinoic Acid

Regulation of Stearoyl Coenzyme A Desaturase Expression in Human Retinal Pigment Epithelial Cells by Retinoic Acid

Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia

Pulmonary Administration of GW0742, a High-Affinity Peroxisome Proliferator-Activated Receptor Agonist, Repairs Collapsed Alveoli in an Elastase-Induced Mouse Model of Emphysema

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