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| Retinoic acid (simplified nomenclature for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-trans-retinoic acid is required for chordate animal development, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. In adult tissues, the activity of endogenous retinoic acid appears limited to immune function and male fertility.
All-trans-retinoic acid is the major occurring retinoic acid, while isomers like 13-cis- and 9-cis-retinoic acid are also present in much lower levels.
The key role of all-trans-retinoic acid in embryonic development mediates the high teratogenicity of retinoid pharmaceuticals, such as isotretinoin (13-cis-retinoic acid) used for treatment of acne or retinol used for skin disorders. High oral doses of preformed vitamin A (retinyl palmitate), and all-trans-retinoic acid itself, also have teratogenic potential by this same mechanism. |
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Read full article at Wikipedia
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InChI=1S/C20H28O2/c1- 15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14+ |
| SHGAZHPCJJPHSC-YCNIQYBTSA-N |
| CC(\C=C\C1=C(C)CCCC1(C)C)=C/C=C/C(C)=C/C(O)=O |
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Homo sapiens
(NCBI:txid9606)
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Found in
blood
(UBERON:0000178).
See:
Geigy Scientific Tables, 8th Rev edition, pp. 165-177. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp., Basel, Switzerland c1981-1992.
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antioxidant
A substance that opposes oxidation or inhibits reactions brought about by dioxygen or peroxides.
Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
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signalling molecule
A molecular messenger in which the molecule is specifically involved in transmitting information between cells. Such molecules are released from the cell sending the signal, cross over the gap between cells by diffusion, and interact with specific receptors in another cell, triggering a response in that cell by activating a series of enzyme controlled reactions which lead to changes inside the cell.
retinoid X receptor agonist
An agonist that selectively binds to and activates a retinoid X receptor.
AP-1 antagonist
An antogonist that interferes with the action of activator protein 1 (AP-1).
retinoic acid receptor agonist
An agonist that selectively binds to and activates a retinoic acid receptor.
human metabolite
Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens).
(via retinoic acid )
metabolite
Any intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
(via vitamin A )
fat-soluble vitamin (role)
Any vitamin that dissolves in fats and are stored in body tissues. Unlike the water-soluble vitamins, they are stored in the body for long periods of time and generally pose a greater risk for toxicity when consumed in excess.
(via vitamin A )
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antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
keratolytic drug
A drug that softens, separates, and causes desquamation of the cornified epithelium or horny layer of skin. Keratolytic drugs are used to expose mycelia of infecting fungi or to treat corns, warts, and certain other skin diseases.
anti-inflammatory agent
Any compound that has anti-inflammatory effects.
retinoic acid receptor agonist
An agonist that selectively binds to and activates a retinoic acid receptor.
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View more via ChEBI Ontology
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(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid
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tretinoin
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WHO MedNet
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tretinoína
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WHO MedNet
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trétinoïne
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WHO MedNet
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tretinoinum
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WHO MedNet
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(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-2,4,6,8-tetraenoic acid
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ChEBI
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(all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid
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KEGG COMPOUND
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3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexene-1-yl)-2,4,6,8-nonatetraenoic acid
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KEGG COMPOUND
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3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-all-trans-tetraenoic acid
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ChemIDplus
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3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2E,4E,6E,8E-tetraenoic acid
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LIPID MAPS
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Acide retinoique (French)
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KEGG COMPOUND
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AGN 100335
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KEGG COMPOUND
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all-(E)-retinoic acid
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KEGG COMPOUND
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all-trans retinoic acid
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ChemIDplus
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all-trans-beta-Retinoic acid
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KEGG COMPOUND
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all-trans-retinoic acid
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KEGG COMPOUND
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all-trans-tretinoin
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KEGG COMPOUND
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all-trans-vitamin A acid
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KEGG COMPOUND
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all-trans-vitamin A1 acid
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KEGG COMPOUND
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beta-Retinoic acid
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KEGG COMPOUND
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retinoic acid
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KEGG COMPOUND
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Ro 1-5488
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KEGG COMPOUND
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trans-retinoic acid
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KEGG COMPOUND
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Tretin M
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KEGG COMPOUND
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vitamin A acid
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KEGG COMPOUND
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Altreno
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DrugBank
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Atralin
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ChemIDplus
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Avita
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ChemIDplus
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Betarretin
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ChemIDplus
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Biacna
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DrugBank
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Cordes vas
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ChemIDplus
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Dermairol
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ChemIDplus
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Refissa
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ChemIDplus
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Renova
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DrugBank
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Retin-A
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DrugBank
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Retisol-A
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DrugBank
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Stieva-A
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DrugBank
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Tri-luma
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DrugBank
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Veltin
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DrugBank
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Vesanoid
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DrugBank
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Vitinoin
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DrugBank
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2722
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DrugCentral
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C00777
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KEGG COMPOUND
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D00094
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KEGG DRUG
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DB00755
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DrugBank
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FDB022710
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FooDB
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HMDB0001852
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HMDB
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LMPR01090019
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LIPID MAPS
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REA
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PDBeChem
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Retinoic_acid
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Wikipedia
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Tretinoin
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Wikipedia
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| View more database links |
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2057223
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Reaxys Registry Number
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Reaxys
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302-79-4
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CAS Registry Number
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KEGG COMPOUND
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302-79-4
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CAS Registry Number
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ChemIDplus
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Cuomo F, Ceglie S, Miguel M, Lindman B, Lopez F (2021)
Oral delivery of all-trans retinoic acid mediated by liposome carriers.
Colloids and surfaces. B, Biointerfaces 201, 111655 [PubMed:33662750]
[show Abstract]
All-trans retinoic acid (ATRA) is a molecule that finds wide applications in medicine. Connection between cancer cell proliferation and ATRA is a well-established item. Driven by the potential applications of liposomes in stabilizing and protecting therapeutic compounds thus enabling effective delivery of encapsulated compounds, recent research efforts have been directed to understanding mechanisms of oral delivery through the gastrointestinal tract. The surface charge of the liposome bilayers can modify the interactions between the aggregates and the gastrointestinal fluids. Here, we investigated the ability of cationic and anionic liposomes to encapsulate, protect and deliver ATRA in an in-vitro digestion process as a different oral administration route. Stability and encapsulation efficiency of ATRA in negatively and positively charged liposomes enriched with α-tocopherol were investigated by means of UV-vis spectroscopy, dynamic light scattering and ζ-potential. The applicability of the carriers was tested by means of an in-vitro digestion procedure allowing for the measurement of the bioavailability of ATRA. From this study evidence was provided that the water insoluble molecules, ATRA and α-tocopherol are intercalated in liposome membranes regardless of the surface charge of the vesicle bilayers. Comparisons between cationic and anionic liposomes incorporating retinoic acid show differences in bioavailability. The cationic vesicles are preferable for a larger amount of ATRA bioavailability, which can be understood from electrostatic interactions. Thus ATRA is ionized in a wide range of pHs but protonated in anionic vesicles. | Ul Hassan I, Chowdhary A, Kidambi A (2021)
A rare case of all-trans retinoic acid induced myocarditis.
European heart journal. Cardiovascular Imaging 22, e131 [PubMed:34050360] | Guo Y, Zhang H, Chen X, Liu Y (2021)
All-trans retinoic acid reduces mammalian target of rapamycin via a Sirtuin1-dependent mechanism in neurons.
Neuroreport 32, 975-982 [PubMed:34050114]
[show Abstract]
Neuroinflammation has emerged as a key contributor in the pathogenesis of Alzheimer's disease (AD). Mammalian target of rapamycin (mTOR) is a key regulator of metabolism, cell growth and protein synthesis. And an elevated mTOR activity has been detected in AD-affected brain areas. Previous studies have suggested that all-trans retinoic acid (atRA) and rapamycin (RAPA), an mTOR inhibitor, protect lipopolysaccharide (LPS)-induced neuronal inflammation through inhibiting nuclear import of NFκB. The aim of this study was to test the effects of atRA on mTOR expression. Here we discovered that mTOR and p-mTOR expression are elevated in LPS-treated mice or primary rat neurons, while atRA blocks the mTOR gene upregulation via a SIRT1-dependent mechanism. The results of this study demonstrated that atRA may protect LPS-induced neuronal inflammation through suppressing mTOR signaling. | Hanna GJ, ONeill A, Cutler JM, Flynn M, Vijaykumar T, Clark JR, Wirth LJ, Lorch JH, Park JC, Mito JK, Lohr JG, Kaufman J, Burr NS, Zon LI, Haddad RI (2021)
A phase II trial of all-trans retinoic acid (ATRA) in advanced adenoid cystic carcinoma.
Oral oncology 119, 105366 [PubMed:34091189]
[show Abstract]
BackgroundEffective therapies are lacking for recurrent, metastatic adenoid cystic carcinoma (R/M ACC) and preclinical models suggest retinoic acid agonists inhibit ACC growth. This phase II trial evaluated all-trans retinoic acid (ATRA) as a novel therapy for ACC.MethodsPatients with R/M ACC (any site) with clinical and/or radiographic progression ≤12 months prior to study entry were eligible. Cohort 1 (CH1) received ATRA 45 mg/m2 split oral daily dosing on days 1-14 of a 28-day cycle; Cohort 2 (CH2) received the same dosing continuously. Primary endpoint was best overall response rate (CR + PR) (RECIST v1.1). Secondary endpoints: safety and progression-free survival (PFS). Exploratory analyses: ATRA impact on MYB expression and genomic predictors of response.ResultsEighteen patients enrolled. There were no responses, but 61% (11/18) had stable disease (SD) and 28% (5/18) progression as best response; 11% (2/18) unevaluable. Median duration of stability: 3.7 months (95%CI, 1.9-3.9). One patient (CH1) remains on drug with SD approaching 1 year. Half of those who received prior VEGFR therapy achieved SD (4/8). At median follow up of 7.9 months, median PFS was 3.2 months (95%CI, 1.8-3.9). N = 1 required dose adjustment; N = 1 came off drug for toxicity. There were no grade 3-4 adverse events. NOTCH1 and PI3K pathway alterations were most frequent. Low MYB protein expression was associated with longer duration of stability on ATRA (P < 0.01).Conclusion(s)While the trial did not meet its prespecified response endpoint, ATRA alone or in combination may be a low toxicity treatment for disease growth stabilization in R/M ACC. | Zhong Z, Li HY, Zhong H, Lin W, Lin S, Zhou T (2021)
All-trans retinoic acid regulating angiopoietins-1 and alleviating extracellular matrix accumulation in interstitial fibrosis rats.
Renal failure 43, 658-663 [PubMed:33820492]
[show Abstract]
All-trans retinoic acid (ATRA) is one of essentially active metabolite of vitamin A, and plays an important role in diverse physiological processes, such as cellular growth and function. Renal interstitial fibrosis (RIF) is a common pathological characteristic of chronic renal disease causing end-stage renal disease currently lacking effective treatment. Low level of Angiopoietins-1 (Angpt-1) is associated with extracellular matrix accumulation and fibrosis diseases. This study was performed to assess the association of ATRA with Angpt-1 in RIF disease. Rats were divided into three groups: group of sham (SHO group), group of unilateral ureteral obstruction group (UUO group), UUO mice administrated daily at the dose of ATRA (ATRA group). Masson-staining was used to detect the histologic lesion. Immunohistochemistry and Western-blot were applied to determine the targeted proteins. RIF score was significantly increased in UUO rats when compared with that of SHO group, and the fibrosis score was notably reduced in ATRA group. Transforming growth factor-β1 (TGF-β1), collagen IV (Col-IV) and fibronectin (FN) expressions in UUO group were significantly up-regulated, whereas Angpt-1 expression was significantly down-regulated compared with the SHO group. ATRA treatment reduced TGF-β1, Col-IV and FN expressions and improved Angpt-1 expression compared with the UUO group. The protein expression of Angpt-1 in kidney tissue of UUO group was negatively correlated with RIF index and protein expressions of Col-IV, FN and TGF-β1. In conclusion, low expression of Angpt-1 was associated with the RIF disease and ATRA treatment can increase the Angpt-1 and alleviate the RIF lesion in UUO rats. | Handberg-Thorsager M, Gutierrez-Mazariegos J, Arold ST, Kumar Nadendla E, Bertucci PY, Germain P, Tomançak P, Pierzchalski K, Jones JW, Albalat R, Kane MA, Bourguet W, Laudet V, Arendt D, Schubert M (2018)
The ancestral retinoic acid receptor was a low-affinity sensor triggering neuronal differentiation.
Science advances 4, eaao1261 [PubMed:29492455]
[show Abstract]
Retinoic acid (RA) is an important intercellular signaling molecule in vertebrate development, with a well-established role in the regulation of hox genes during hindbrain patterning and in neurogenesis. However, the evolutionary origin of the RA signaling pathway remains elusive. To elucidate the evolution of the RA signaling system, we characterized RA metabolism and signaling in the marine annelid Platynereis dumerilii, a powerful model for evolution, development, and neurobiology. Binding assays and crystal structure analyses show that the annelid retinoic acid receptor (RAR) binds RA and activates transcription just as vertebrate RARs, yet with a different ligand-binding pocket and lower binding affinity, suggesting a permissive rather than instructive role of RA signaling. RAR knockdown and RA treatment of swimming annelid larvae further reveal that the RA signal is locally received in the medial neuroectoderm, where it controls neurogenesis and axon outgrowth, whereas the spatial colinear hox gene expression in the neuroectoderm remains unaffected. These findings suggest that one early role of the new RAR in bilaterian evolution was to control the spatially restricted onset of motor and interneuron differentiation in the developing ventral nerve cord and to indicate that the regulation of hox-controlled anterior-posterior patterning arose only at the base of the chordates, concomitant with a high-affinity RAR needed for the interpretation of a complex RA gradient. | Moretti A, Li J, Donini S, Sobol RW, Rizzi M, Garavaglia S (2016)
Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid.
Scientific reports 6, 35710 [PubMed:27759097]
[show Abstract]
The aldehyde dehydrogenase family 1 member A3 (ALDH1A3) catalyzes the oxidation of retinal to the pleiotropic factor retinoic acid using NAD+. The level of ALDHs enzymatic activity has been used as a cancer stem cell marker and seems to correlate with tumour aggressiveness. Elevated ALDH1A3 expression in mesenchymal glioma stem cells highlights the potential of this isozyme as a prognosis marker and drug target. Here we report the first crystal structure of human ALDH1A3 complexed with NAD+ and the product all-trans retinoic acid (REA). The tetrameric ALDH1A3 folds into a three domain-based architecture highly conserved along the ALDHs family. The structural analysis revealed two different and coupled conformations for NAD+ and REA that we propose to represent two snapshots along the catalytic cycle. Indeed, the isoprenic moiety of REA points either toward the active site cysteine, or moves away adopting the product release conformation. Although ALDH1A3 shares high sequence identity with other members of the ALDH1A family, our structural analysis revealed few peculiar residues in the 1A3 isozyme active site. Our data provide information into the ALDH1As catalytic process and can be used for the structure-based design of selective inhibitors of potential medical interest. | Daşkın D, Gündüz U (2013)
Preparation and evaluation of polymer based microcarriers for all-trans-retinoic acid.
Pharmaceutical development and technology 18, 1017-1025 [PubMed:22428994]
[show Abstract]
Polymeric biomaterials are being investigated for the last several years because of their controllable properties. In this study, it was aimed to prepare and evaluate the atRA carrying system using Poly(lactide-co-glycolide) (PLGA). Microparticles were characterized in terms of morphology and encapsulation efficiency. Release studies were performed for the evaluation of drug release rates. Cytotoxicity tests were implemented on MCF-7 Human breast cancer cell line for the investigation of drug and polymer toxicity. The microparticles were found smooth and spherical in shape. However, as the loaded drug amount increased, the sizes of microparticles also increased and the size distribution became less uniform. The sizes of atRA-loaded microparticles ranged between 1-10 µm. The encapsulation efficiency of atRetinoic acid (all-trans-Retinoic acid) was achieved approximately %90. Approximately, 45% of atRA was released from atRA-loaded microparticles by the end of 4-5 days. Cell growth inhibition was observed after 4 days of incubation of cells with PLGA microparticles. | Miura T, Takada A, Ooe M (2012)
Tretinoin cyclodextrin complex (RA/CyD) causes less irritation with an equal antiwrinkle effect compared with conventional tretinoin: clinical and histologic studies of photoaged skin.
Aesthetic plastic surgery 36, 971-981 [PubMed:22538278]
[show Abstract]
BackgroundTopical tretinoin [all-trans-retinoic acid (RA)] currently is widely used to treat photoaged skin. However, undesirable side effects such as erythema, irritation, and scaling are unavoidable and limit the use of tretinoin. To address these issues, the authors developed the tretinoin cyclodextrin complex (RA/CyD), which is tretinoin encapsulated by cyclodextrin. Cyclodextrins are cyclic oligosaccharides commonly used in food additives and fabric fresheners. This study aimed to evaluate the antiwrinkle effect of RA/CyD and alleviation of the side effects compared with RA treatment alone.MethodsIn this study, 12 photoaged patients completed an 8 week study using RA and RA/CyD in a double-blind manner. Before and after the treatment, the patients' evaluations, wrinkle scores, skin elasticity, and wrinkle area measurement using skin replica were evaluated. Three men were recruited for histologic analysis.ResultsThe patients reported that undesirable irritant reactions were more moderate with RA/CyD than with RA. In the assessment of wrinkle scores, skin elasticity, and wrinkle area measurement, RA/CyD demonstrated an antiwrinkle effect statistically equal to that of RA. In histology, both RA/CyD and RA demonstrated epidermal hyperplasia. In immunohistochemistry, inflammation induced by RA/CyD was more moderate than that induced by RA.ConclusionThe findings show that RA and RA/CyD result in the equivalent clinical improvement for patients with photoaging. The use of RA/CyD overcomes the drawbacks of RA while possessing equal effect. It is expected that CyD will broaden tretinoin treatment.Level of evidence iiiThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. | Ohno M, Ikenaka Y, Ishizuka M (2012)
All-trans retinoic acid inhibits the recruitment of ARNT to DNA, resulting in the decrease of CYP1A1 mRNA expression in HepG2 cells.
Biochemical and biophysical research communications 417, 484-489 [PubMed:22177959]
[show Abstract]
Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) are well-conserved transcription factors among species. However, there are a very limited number of reports on the physiological function of AHR, particularly on the regulation of AHR by endogenous compounds. We hence investigated the effects of all-trans retinoic acid (atRA) on cytochrome P450 (CYP) 1A1 gene transcription as a model of AHR-regulated transcription mechanisms in HepG2 cells, a human hepatoma cell line. Treatment with atRA significantly reduced transactivation and expression of CYP1A1 mRNA to less than half of its control value, and this inhibitory effect was mediated by RARα. The result of chromatin immunoprecipitation assay indicated that treatment with atRA at 1-100 nM drastically inhibited the recruitment of ARNT to DNA regions containing xenobiotic responsive elements. In conclusion, atRA at physiological concentrations could reduce AHR-mediated gene transcription via the inhibition of recruitment of ARNT to relevant DNA regions. | Sun DF, Gao ZH, Liu HP, Yuan Y, Qu XJ (2012)
Sphingosine 1-phosphate antagonizes the effect of all-trans retinoic acid (ATRA) in a human colon cancer cell line by modulation of RARβ expression.
Cancer letters 319, 182-189 [PubMed:22261335]
[show Abstract]
All-trans retinoic acid (ATRA) is a promising therapeutic agent, but exhibits low efficacy against human cancers. We investigated the effect of sphingosine-1-phosphate (S1P) on ATRA activity in human colon cancer HT-29 cells. S1P antagonized ATRA activity on HT-29 cell proliferation and retinoic acid receptor beta (RARβ) expression. S1P treatment or transient co-transfection with SphK2 expression vector antagonized ATRA-induced RARβ promoter activity. Proteasome inhibition prevented S1P-induced modulation of ATRA activity. Overall, S1P antagonized ATRA's inhibitory effects by down-regulating RARβ expression, likely via the proteasome-dependent pathway. Decreasing S1P production or inhibiting SphK2 activity could enhance the efficacy of retinoids in cancer treatments. | Zhou RJ, Yang XQ, Wang D, Zhou Q, Xia L, Li MX, Zeng LL, Wang G, Yang ZZ (2012)
Anti-tumor effects of all-trans retinoic acid are enhanced by genistein.
Cell biochemistry and biophysics 62, 177-184 [PubMed:21898109]
[show Abstract]
The effects of all-trans retinoic acid (ATRA) on cancer are complex. ATRA has anti-cancer effects as it promotes cancer cell differentiation. However, ATRA also up-regulates expression of vascular endothelial growth factor (VEGF) in cancer cells, which leads to angiogenesis and can, thus, facilitate cancer growth. Genistein, a crucial non-nutrient component in soybean, exhibits anti-cancer effects by inhibiting protein tyrosine kinase that is involved in up-regulation of VEGF. We hypothesized that genistein, applied simultaneously with ATRA, would counter its undesired angiogenic effects and, thus, enhance the anti-cancer effects of ATRA. The purpose of this study was to document potential synergistic effects of genistein and ATRA in A549 lung adenocarcinoma cells. We further explored the role of genistein on countering the ATRA-induced VEGF expression. We demonstrate that genistein enhances the ATRA-induced growth inhibition of A549 cells by promoting apoptosis. Further, the combined use of ATRA and genistein leads to cancer cell arrest in G0/G1 and G2/M cell cycle phases. Finally, expression of VEGF (both mRNA and protein) was diminished in A549 cells exposed to both ATRA and genistein. In conclusion, our results demonstrate that genistein effectively enhances anti-cancer effects of ATRA, particularly, by countering the ATRA-induced up-regulation of VEGF. Our study provides an experimental basis for combined use of ATRA and genistein in the treatment of lung cancer. | Ridolfi DM, Marcato PD, Justo GZ, Cordi L, Machado D, Durán N (2012)
Chitosan-solid lipid nanoparticles as carriers for topical delivery of tretinoin.
Colloids and surfaces. B, Biointerfaces 93, 36-40 [PubMed:22244299]
[show Abstract]
Tretinoin (TRE) or all-trans retinoic acid is employed in the topical treatment of various skin diseases including acne and psoriasis. However, its use is strongly limited by side effects and high chemical instability. TRE encapsulation in nanostructured systems reduces these problems. Chitosan is a biopolymer that exhibits a number of interesting properties such as bioadhesion and antibacterial activity. The aim of this work was to prepare and characterize solid lipid nanoparticles (SLN) containing TRE, with and without addition of chitosan, to assess their in vitro cytotoxicity in keratinocytes and to evaluate their antibacterial activity against bacteria related to acne. SLN without (SLN-TRE) and with (SLN-chitosan-TRE) chitosan were prepared by hot high pressure homogenization. The hydrodynamic mean diameter and zeta potential were 162.7±1.4 nm and -31.9±2.0 mV for SLN-TRE, and 284.8±15.0 nm and 55.9±3.1 mV for SLN-chitosan-TRE. The SLN-chitosan-TRE exhibited high encapsulation efficiency, high physical stability in the tested period (one year), were not cytotoxic to keratinocytes and showed high antibacterial activity against P. acnes and S. aureus. Therefore chitosan-SLN can be good candidates to encapsulate TRE and to increase its therapeutic efficacy in the topical treatment of acne. | Margheri M, Pacini N, Tani A, Nosi D, Squecco R, Dama A, Masala E, Francini F, Zecchi-Orlandini S, Formigli L (2012)
Combined effects of melatonin and all-trans retinoic acid and somatostatin on breast cancer cell proliferation and death: molecular basis for the anticancer effect of these molecules.
European journal of pharmacology 681, 34-43 [PubMed:22532966]
[show Abstract]
Melatonin has been shown to inhibit breast cancer cell growth in numerous studies. However, our understanding of the therapeutic effects of this hormone is still marginal and there is little information concerning its combination with other antitumor agents to achieve additional potential benefits. All-trans retinoic acids or somatostatin have been used in combination with melatonin in several pre-clinical and clinical trials, but they have never been combined altogether as an anti-breast cancer treatment. In the present study, we investigated whether the association of melatonin, all-trans retinoic acid and somatostatin leads to an enhanced anticancer activity in MCF-7 breast cancer cells. In such conditions, MCF-7 cells were investigated for cell growth/viability and proliferation, as well as for the expression of cyclin A, and components of the Notch and EGFR pathways, by Western blotting and confocal immunofluorescence. Electrophysiological, morphological, and biochemical analysis were also performed to reveal signs of cell damage and death. We found that melatonin in combination with all-trans retinoic acid and somatostatin potentiated the effects of melatonin alone on MCF-7 cell viability and growth inhibition; this phenomenon was associated with altered conductance through Ca²⁺ and voltage-activated K⁺ (BK) channels, and with substantial impairments of Notch-1 and epidermal growth factor (EGF)-mediated signaling. The combined treatment also caused a marked reduction in mitochondrial membrane potential and intracellular ATP production as well as induction of necrotic cell death. Taken together our results indicate that co-administration of melatonin with all-trans retinoic acid and somatostatin may be of significant therapeutic benefit in breast cancer. | Iland H, Bradstock K, Seymour J, Hertzberg M, Grigg A, Taylor K, Catalano J, Cannell P, Horvath N, Deveridge S, Browett P, Brighton T, Chong L, Springall F, Ayling J, Catalano A, Supple S, Collins M, Di Iulio J, Reynolds J, Australasian Leukaemia and Lymphoma Group (2012)
Results of the APML3 trial incorporating all-trans-retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia.
Haematologica 97, 227-234 [PubMed:21993673]
[show Abstract]
BackgroundInitial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols.Design and methodsIn an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine.ResultsEight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001).ConclusionsThe combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459). | Fernández-Calotti PX, Lopez-Guerra M, Colomer D, Pastor-Anglada M (2012)
Enhancement of fludarabine sensitivity by all-trans-retinoic acid in chronic lymphocytic leukemia cells.
Haematologica 97, 943-951 [PubMed:22180426]
[show Abstract]
BackgroundA subset of patients with fludarabine-resistant chronic lymphocytic leukemia has previously been shown to express elevated intracellular levels of the concentrative high-affinity fludarabine transporter hCNT3, without any detectable related activity. We have recently shown that all-trans-retinoic acid is capable of inducing hCNT3 trafficking to plasma membrane in the MEC1 cell line. We, therefore, evaluated the effect of all-trans-retinoic acid on hCNT3 in primary chronic lymphocytic leukemia cells as a suitable mechanism to improve fludarabine-based therapy of chronic lymphocytic leukemia.Design and methodsCells from 23 chronic lymphocytic leukemia patients wild-type for P53 were analyzed for ex vivo sensitivity to fludarabine. hCNT3 activity in chronic lymphocytic leukemia cell samples was evaluated by measuring the uptake of [8-(3)H]-fludarabine. The amounts of transforming growth factor-β1 and hCNT3 messenger RNA were analyzed by real-time polymerase chain reaction. The effect of all-trans-retinoic acid on hCNT3 subcellular localization was analyzed by confocal microscopy and its effect on fludarabine-induced apoptosis was evaluated by flow cytometry analysis using annexin V staining.ResultsChronic lymphocytic leukemia cases showing higher ex vivo basal sensitivity to fludarabine also had a greater basal hCNT3-associated fludarabine uptake capacity compared to the subset of patients showing ex vivo resistance to the drug. hCNT3 transporter activity in chronic lymphocytic leukemia cells from the latter patients was either negligible or absent. Treatment of the fludarabine-resistant subset of chronic lymphocytic leukemia cells with all-trans-retinoic acid induced increased fludarabine transport via hCNT3 which was associated with a significant increase in fludarabine sensitivity.ConclusionsImprovement of ex vivo fludarabine sensitivity in chronic lymphocytic leukemia cells is associated with increased hCNT3 activity after all-trans-retinoic acid treatment. | Chen S, Fang Y, Ma L, Liu S, Li X (2012)
Realgar-induced apoptosis and differentiation in all-trans retinoic acid (ATRA)-sensitive NB4 and ATRA-resistant MR2 cells.
International journal of oncology 40, 1089-1096 [PubMed:22134377]
[show Abstract]
Realgar has been used in Western medicine and Chinese traditional medicine since ancient times, and its promising anticancer activity has attracted much attention in recent years, especially for acute promyelocytic leukemia (APL). However, the therapeutic action of realgar treatment for APL remains to be fully elucidated. Cellular cytotoxicity, proliferation, apoptosis and differentiation were comprehensively investigated in realgar-treated cell lines derived from PML-RARα+ APL patient, including the all-trans retinoic acid (ATRA)-sensitive NB4 and ATRA-resistant MR2 cell lines. For analysis of key regulators of apoptosis and differentiation, gene expression profiles were performed in NB4 cells. Realgar was found to induce apoptosis and differentiation in both cell lines, and these effects were exerted simultaneously. Gene expression profiles indicated that genes influenced by realgar treatment were involved in the modulation of signal transduction, translation, transcription, metabolism and the immune response. Given its low toxicity, realgar is a promising alternative reagent for the therapy of APL. Our data contribute to an understanding of the underlying mechanism responsible for the therapeutic effects of realgar in the clinical treatment of APL. | Huang H, Qin Y, Xu R, You X, Teng R, Yang L, Xu M, Liu H (2012)
Combination therapy with arsenic trioxide, all-trans retinoic acid, and chemotherapy in acute promyelocytic leukemia patients with various relapse risks.
Leukemia research 36, 841-845 [PubMed:22534100]
[show Abstract]
To improve the recovery rate of high-risk patients with acute promyelocytic leukemia (APL), we used all-trans retinoic acid (ATRA)/arsenic trioxide (ATO)/daunorubicin combination in remission induction, daunorubicin and cytarabine in consolidation, and ATRA/ATO/methotrexate ± 6-mercaptopurine in maintenance treatment of APL patients with various risks for relapse. Our results showed a high complete remission rate of 95.3%. Excluding the cases of early-death, no significant differences in event-free survival were observed between the intermediate-risk and high-risk group (p = 0.393) and the low-risk and high-risk group (p = 0.162). In addition, there were no significant differences between the groups in cumulative incidence of central nervous system relapse. In conclusion, our results suggest that APL patients benefit from combination ATO/ATRA/chemotherapy, and that this regimen is especially beneficial for patients with high-risk prognostic factors. | Simon AM, Jagadeeshan S, Abraham E, Akhilandeshwaran A, Pillai JJ, Kumar NA, Sivakumari AN, Kumar GS (2012)
Poly (D,L-lactic-co-glycolide) nanoparticles for the improved therapeutic efficacy of all-trans-retinoic acid: a study of acute myeloid leukemia (AML) cell differentiation in vitro.
Medicinal chemistry (Shariqah (United Arab Emirates)) 8, 805-810 [PubMed:22741806]
[show Abstract]
All-trans-retinoic acid reverses malignant cell growth and induces cell differentiation and apoptosis. Poor aqueous solubility and uncertain bioavailability are the limiting factors for using all-trans-retinoic acid for tumor therapy. The objective of present study was to encapsulate the hydrophobic drug all-trans-retinoic acid in the polymer poly (lactide-coglycolide). The encapsulation was expected to improve the bioavailability and solubility of the drug. Oil in water single emulsion solvent evaporation technique used for the preparation efficiently encapsulated about 60% of the drug. The drug release profile showed a biphasic pattern with 70% of the drug being released in first 48 hrs and the residual drug showing a slow controlled release reaching up to 8 days. The particle size of 150-200 nm as determined with TEM was ideal for tumor targeting. All-trans-retinoic acid loaded nanoparticles were efficient to induce differentiation and blocked the proliferation of HL-60 cells invitro. These studies also revealed that the dosage of drug required for the therapeutic effects have been reduced efficiently. Our studies thereby demonstrate that Poly (lactide-co-glycolide) based nanoparticles may be efficient for parenteral administration of the drug. | Malehmir M, Haghpanah V, Larijani B, Ahmadian S, Alimoghaddam K, Heshmat R, Ghavamzadeh A, Adabi K, Ghaffari SH (2012)
Multifaceted suppression of aggressive behavior of thyroid carcinoma by all-trans retinoic acid induced re-differentiation.
Molecular and cellular endocrinology 348, 260-269 [PubMed:21924320]
[show Abstract]
Since all-trans retinoic acid (ATRA) has shown promising results in differentiation therapy, the present study was designed to investigate the effects of ATRA on thyroid carcinoma and to evaluate the effectiveness of ATRA in redifferentiation induction of thyroid carcinoma. Therefore, we investigated cell growth rate, morphological and nuclear: cytoplasmic ratio, adherent-dependent growth, response to chemotherapy drug following differentiation, T3 and T4 measurement, and critical genes expression pattern. Papillary cell line showed more growth inhibition by ATRA, in addition, mesenchymal and spindle-shape of 8305C cells changed to polygonal. Additionally, high nuclear: cytoplasmic ratio of anaplastic decreased significantly. Redifferentiation significantly suppressed the anchorage-dependent growth in the both cell lines in a dose-dependent manner, potentiated the arsenic trioxide (ATO) effects in anaplastic and papillary cell lines. Furthermore, reduction in the expression of stemness, and invasion related genes was observed in the both cell lines. Altogether, ATRA treatment could hold the aggressive behavior of thyroid carcinoma in restraint and/or potentiate the effect of chemotherapy drug ATO. | Kelsey L, Katoch P, Johnson KE, Batra SK, Mehta PP (2012)
Retinoids regulate the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells.
PloS one 7, e32846 [PubMed:22514600]
[show Abstract]
The retinoids, the natural or synthetic derivatives of Vitamin A (retinol), are essential for the normal development of prostate and have been shown to modulate prostate cancer progression in vivo as well as to modulate growth of several prostate cancer cell lines. 9-cis-retinoic acid and all-trans-retinoic acid are the two most important metabolites of retinol. Gap junctions, formed of proteins called connexins, are ensembles of intercellular channels that permit the exchange of small growth regulatory molecules between adjoining cells. Gap junctional communication is instrumental in the control of cell growth. We examined the effect of 9-cis-retinoic acid and all-trans retinoic acid on the formation and degradation of gap junctions as well as on junctional communication in an androgen-responsive prostate cancer cell line, LNCaP, which expressed retrovirally introduced connexin32, a connexin expressed by the luminal cells and well-differentiated cells of prostate tumors. Our results showed that 9-cis-retinoic acid and all-trans retinoic acid enhanced the assembly of connexin32 into gap junctions. Our results further showed that 9-cis-retinoic acid and all-trans-retinoic acid prevented androgen-regulated degradation of gap junctions, post-translationally, independent of androgen receptor mediated signaling. Finally, our findings showed that formation of gap junctions sensitized connexin32-expressing LNCaP cells to the growth modifying effects of 9-cis-retinoic acid, all-trans-retinoic acid and androgens. Thus, the effects of retinoids and androgens on growth and the formation and degradation of gap junctions and their function might be related to their ability to modulate prostate growth and cancer. | Cione E, Pingitore A, Perri M, Genchi G (2009)
Influence of all-trans-retinoic acid on oxoglutarate carrier via retinoylation reaction.
Biochimica et biophysica acta 1791, 3-7 [PubMed:18977311]
[show Abstract]
All-trans-retinoic acid (atRA), an activated metabolite of vitamin A, is incorporated covalently into proteins both invivo and invitro. AtRA reduced the transport activity of the oxoglutarate carrier (OGC) isolated from testes mitochondria to 58% of control via retinoylation reaction. Labeling of testes mitochondrial proteins with (3)HatRA demonstrated the binding of atRA to a 31.5 KDa protein. This protein was identified as OGC due to the competition for the labeling reaction with 2-oxoglutarate, the specific OGC substrate. The role of retinoylated proteins is currently being explored and here we have the first evidence that retinoic acids bind directly to OGC and inhibit its activity in rat testes mitochondria via retinoylation reaction. This study indicates the evidence of a specific interaction between atRA and OGC and establishes a novel mechanism for atRA action, which could influence the physiological biosynthesis of testosterone in situations such as retinoic acid treatment. | Li H, Clagett-Dame M (2009)
Vitamin A deficiency blocks the initiation of meiosis of germ cells in the developing rat ovary in vivo.
Biology of reproduction 81, 996-1001 [PubMed:19587328]
[show Abstract]
Vitamin A (retinol) is required for male and female reproduction as well as to support many developmental processes. In the male, meiotic entry of germ cells occurs after birth and throughout adulthood, whereas in the female, the entry into meiosis I occurs during embryonic development. Evidence from cultured embryonic ovaries suggests that the vitamin A metabolite, all-trans retinoic acid (atRA), initiates this process. However, in vivo evidence to support a normal role for atRA in meiotic entry is lacking. The present study demonstrates that although germ cell number is normal in ovaries from both vitamin A-sufficient (VAS) embryos and those that are deficient in atRA, the majority of germ cells in the most severely atRA-deficient group fail to enter meiosis and remain in an undifferentiated state. In contrast, in a group that is only moderately deficient in atRA, a small number of ovarian germ cells enter meiosis (30%) compared with 75% of cells in the VAS control group. The expression of the atRA-responsive gene, Stra8, is reduced by approximately 90% and 50% in the severely and moderately atRA-deficient ovaries, respectively, compared with the VAS controls. These results provide the first in vivo evidence that vitamin A regulates the entry of germ cells into meiosis in the developing ovary. | Cvekl A, Wang WL (2009)
Retinoic acid signaling in mammalian eye development.
Experimental eye research 89, 280-291 [PubMed:19427305]
[show Abstract]
Retinoic acid (RA) is a biologically active metabolite of vitamin A (retinol) that serves as a signaling molecule during a number of developmental and physiological processes. RA signaling plays multiple roles during embryonic eye development. RA signaling is initially required for reciprocal interactions between the optic vesicle and invaginating lens placode. RA signaling promotes normal development of the ventral retina and optic nerve through its activities in the neural crest cell-derived periocular mesenchyme. RA coordinates these processes by regulating biological activities of a family of non-steroid hormone receptors, RARalpha/beta/gamma, and RXRalpha/beta/gamma. These DNA-binding transcription factors recognize DNA as RAR/RXR heterodimers and recruit multiprotein transcriptional co-repressor complexes. RA-binding to RAR receptors induces a conformational change in the receptor, followed by the replacement of co-repressor with co-activator complexes. Inactivation of RARalpha/beta/gamma receptors in the periocular mesenchyme abrogates anterior eye segment formation. This review summarizes recent genetic studies of RA signaling and progress in understanding the molecular mechanism of transcriptional co-activators that function with RAR/RXR. | Tippmann F, Hundt J, Schneider A, Endres K, Fahrenholz F (2009)
Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23, 1643-1654 [PubMed:19144697]
[show Abstract]
Late-onset Alzheimer's disease is often connected with nutritional misbalance, such as enhanced cholesterol intake, deficiency in polyunsaturated fatty acids, or hypovitaminosis. The alpha-secretase ADAM10 has been found to be regulated by retinoic acid, the bioreactive metabolite of vitamin A. Here we show that retinoids induce gene expression of ADAM10 and alpha-secretase activity by nonpermissive retinoid acid receptor/retinoid X receptor (RAR/RXR) heterodimers, whereby alpha- and beta-isotypes of RAR play a major role. However, ligands of other RXR binding partners, such as the vitamin D receptor, do not stimulate alpha-secretase activity. On the basis of these findings, we examined the effect of synthetic retinoids and found a strong enhancement of nonamyloidogenic processing of the amyloid precursor protein by the vitamin A analog acitretin: it stimulated ADAM10 promoter activity with an EC(50) of 1.5 microM and led to an increase of mature ADAM10 protein that resulted in a two- to three-fold increase of the ratio between alpha- and beta-secretase activity in neuroblastoma cells. The alpha-secretase stimulation by acitretin was completely inhibited by the ADAM10-specific inhibitor GI254023X. Intracerebral injection of acitretin in APP/PS1-21 transgenic mice led to a reduction of Abeta(40) and Abeta(42). The results of this study may have clinical relevance because acitretin has been approved for the treatment of psoriasis since 1997 and found generally safe for long-term use in humans. | Watson DS, Huang Z, Szoka FC (2009)
All-trans retinoic acid potentiates the antibody response in mice to a lipopeptide antigen adjuvanted with liposomal lipid A.
Immunology and cell biology 87, 630-633 [PubMed:19597529]
[show Abstract]
Retinoic acid (RA), the bioactive metabolite of retinol, is essential for robust humoral immunity in animals and humans. Recent interest in RA as a vaccine adjuvant has been encouraged by reports showing cooperative enhancement of antibody responses to tetanus toxin in rodents by all-trans RA (ATRA) and a Toll-like receptor-3 agonist. We hypothesized that RA would augment the antibody response to a co-delivered lipopeptide immunogen derived from the membrane proximal region (MPR) of HIV-1 gp41. The MPR is weakly immunogenic and could benefit from potent new humoral adjuvants. When co-formulated in liposomes and administered to BALB/C mice, ATRA alone did not elicit serum anti-peptide antibodies to an MPR-derived lipopeptide. However, addition of ATRA, but not 13-cis RA, to a liposomal formulation containing the Toll-like receptor-4 agonist monophosphoryl lipid A resulted in a fourfold enhancement of serum anti-peptide IgG titers as compared with a formulation containing lipid A alone (P=0.00039). The difference did not arise from biophysical changes in the liposome formulation, including vesicle size, vesicle charge and liposome association of antigen. Thus, ATRA warrants further study as a vaccine adjuvant. | Molenaar R, Greuter M, van der Marel AP, Roozendaal R, Martin SF, Edele F, Huehn J, Förster R, O'Toole T, Jansen W, Eestermans IL, Kraal G, Mebius RE (2009)
Lymph node stromal cells support dendritic cell-induced gut-homing of T cells.
Journal of immunology (Baltimore, Md. : 1950) 183, 6395-6402 [PubMed:19841174]
[show Abstract]
T cells are imprinted to express tissue-specific homing receptors upon activation in tissue-draining lymph nodes, resulting in their migration to the site of Ag entry. Expression of gut-homing molecules alpha(4)beta(7) and CCR9 is induced by retinoic acid, a vitamin A metabolite produced by retinal dehydrogenases, which are specifically expressed in dendritic cells as well as stromal cells in mucosa-draining lymph nodes. In this study, we demonstrate that mesenteric lymph node stromal cell-derived retinoic acid can directly induce the expression of gut-homing molecules on proliferating T cells, a process strongly enhanced by bone marrow-derived dendritic cells in vitro. Therefore, cooperation of sessile lymph node stromal cells with mobile dendritic cells warrants the imprinting of tissue specific homing receptors on activated T cells. | Engedal N, Auberger P, Blomhoff HK (2009)
Retinoic acid regulates Fas-induced apoptosis in Jurkat T cells: reversal of mitogen-mediated repression of Fas DISC assembly.
Journal of leukocyte biology 85, 469-480 [PubMed:19112091]
[show Abstract]
The effect of the immune regulator vitamin A on T cell death has been poorly characterized. In the present study, we demonstrate that an active metabolite of vitamin A, retinoic acid (RA), promotes cell death in Jurkat leukemic T cells by counteracting mitogen-mediated repression of Fas-induced apoptosis. The effect of RA was dose-dependent, and at the optimal concentration of 1 muM, repression of Fas-induced cell death by the mitogens 12-O-tetradecanoylphorbol 13-acetate (TPA) or Con A was reversed by approximately 50% and 30%, respectively. RA promoted apoptosis rather than necrosis, as judged by analysis of cell morphology, mitochondrial membrane depolarization, and DNA fragmentation. TPA-mediated protection from Fas-induced apoptosis is dependent on ERK and NF-kappaB. However, analyses of ERK and NF-kappaB activities and expression of target genes indicated that RA-mediated counteraction of the protective effect of TPA did not involve negative crosstalk with ERK or NF-kappaB survival pathways. RA-induced cell death was accompanied by enhanced cleavage of procaspase-3, -6, and -8, as well as enhanced cleavage of DNA fragmentation factor 45. Interestingly, RA-mediated cleavage of procaspase-8 occurred very early and before any effect of RA could be detected on procaspase-3 cleavage, suggesting that RA might act at the level of the Fas death-inducing signaling complex (DISC). Indeed, DISC immunoprecipitation studies revealed that RA treatment reversed the inhibitory effect of TPA on CH11-induced recruitment and processing of procaspase-8 at the DISC. In conclusion, we have identified a role of RA in abrogating mitogen-mediated repression of Fas DISC assembly, thus enhancing Fas-induced apoptosis in leukemic T cells. | Ross AC, Chen Q, Ma Y (2009)
Augmentation of antibody responses by retinoic acid and costimulatory molecules.
Seminars in immunology 21, 42-50 [PubMed:18819820]
[show Abstract]
Antibody production is crucial for a successful vaccine response. Beyond the ability of vitamin A (VA) and its active metabolite, all-trans-retinoic acid (RA) to restore growth in VA-deficient animals, supplementation with VA and/or treatment with RA can augment antibody responses in both VA-deficient and VA-adequate animals. RA alone, and in combination with stimuli that are ligands for the Toll-like receptor family, can augment the adaptive immune response leading to a heightened primary antibody response, and a stronger recall response upon restimulation. Mechanisms may include regulation of cell populations, type 1/type 2 cytokines, and B cell-related transcription factors, leading to accelerated B cell maturation. | Cui C, Zhang Y, Wang L, Liu H, Cui G (2009)
Enhanced anticancer activity of glutamate prodrugs of all-trans retinoic acid.
The Journal of pharmacy and pharmacology 61, 1353-1358 [PubMed:19814868]
[show Abstract]
ObjectivesAll-trans retinoic acid (ATRA), an active metabolite of vitamin A, is widely used in the treatment of acute promyelocytic leukaemia and myelodysplastic syndrome. However, its high lipophilicity is thought to be responsible for the slow dissolution and low bioavailability following oral administration. In order to obtain compounds with better solubility characteristics to improve the transportation and bioavailability of ATRA, derivatives of ATRA containing glutamic acid or its sodium salt were synthesised.MethodsThe ATRA derivatives synthesised - all-trans retinoyl glutamate (RAE) and all-trans retinoyl sodium glutamate (RAENa(2)) - were characterised in terms of melting point, optical rotation, mass spectrometry, NMR and partition coefficient. A liposomal preparation formed from RAE was characterised by particle size and zeta potential. The anti-tumour activity of RAE and RAENa(2) was compared with that of ATRA in mice bearing S(180) tumours and their effects on the cell cycle were determined in human pro-myelocytic leukaemia HL-60 cells.Key findingsRAE and RAENa(2) were more active than ATRA against tumour growth. Flow cytometry indicated that RAE and RAENa(2) induced HL-60 cell cycle arrest, similar to ATRA. DNA fragmentation studies suggested that apoptosis may be one of the mechanisms responsible for the anti-tumour activities.ConclusionsThe two derivatives of ATRA, RAE and RAENa(2), exhibited improved aqueous solubility and were more effective in mice bearing S(180) tumours. | Vaezeslami S, Jia X, Vasileiou C, Borhan B, Geiger JH (2008)
Structural analysis of site-directed mutants of cellular retinoic acid-binding protein II addresses the relationship between structural integrity and ligand binding.
Acta crystallographica. Section D, Biological crystallography 64, 1228-1239 [PubMed:19018099]
[show Abstract]
The structural integrity of cellular retinoic acid-binding protein II (CRABPII) has been investigated using the crystal structures of CRABPII mutants. The overall fold was well maintained by these CRABPII mutants, each of which carried multiple different mutations. A water-mediated network is found to be present across the large binding cavity, extending from Arg111 deep inside the cavity to the alpha2 helix at its entrance. This chain of interactions acts as a ;pillar' that maintains the integrity of the protein. The disruption of the water network upon loss of Arg111 leads to decreased structural integrity of the protein. A water-mediated network can be re-established by introducing the hydrophilic Glu121 inside the cavity, which results in a rigid protein with the alpha2 helix adopting an altered conformation compared with wild-type CRABPII. | Wang K, Chen S, Xie W, Wan YJ (2008)
Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway.
Biochemical pharmacology 75, 2204-2213 [PubMed:18400206]
[show Abstract]
A panel of retinoids and carotenoids was screened as potential inducers of CYP3A4 through the RXR/VDR-mediated signaling pathway. Transient transfection assays revealed that 3 out of 12 retinoids screened transactivated RXRalpha/VDR and induced CYP3A4 reporter activity. These three retinoids are the active metabolites of retinoids, 9-cis-retinal, 9-cis-retinoic acid (9-cis-RA), and all-trans-retinoic acid (all-trans-RA). 9-cis-RA and all-trans-RA preferentially transactivated the RXR/VDR heterodimers and RXR homodimers. Retinoids and VDR agonist 1alpha, 25-dihydroxyvitamin D(3), but not PXR or CAR activator, could induce Cyp3a11 mRNA level in hepatocytes derived from PXR/CAR-double null mouse. Moreover, retinoids induced CYP3A4 enzyme activity in HepG2 human hepatoma and Caco-2 human colorectal adenocarcinoma cells. A direct role of retinoid-mediated CYP3A4 induction through RXRalpha/VDR was proved by the results that 9-cis-retinal, 9-cis-RA, and all-trans-RA recruited RXRalpha and VDR to CYP3A4 regulatory region pER6 (proximal everted repeat with a 6-nucleotide spacer) and dXREM (distal xenobiotic-responsive enhancer module). Thus, using various approaches, we have unequivocally demonstrated that retinoids transactivate RXR/VDR heterodimers and RXR homodimers and induce CYP3A expression at mRNA as well as enzyme activity levels in both liver and intestinal cells. It is possible that retinoids might alter endobiotic metabolism through CYP3A4 induction in vivo. | Zhou Q, Nie R, Li Y, Friel P, Mitchell D, Hess RA, Small C, Griswold MD (2008)
Expression of stimulated by retinoic acid gene 8 (Stra8) in spermatogenic cells induced by retinoic acid: an in vivo study in vitamin A-sufficient postnatal murine testes.
Biology of reproduction 79, 35-42 [PubMed:18322276]
[show Abstract]
Vitamin A is required for male fertility and normal spermatogenesis. Retinoic acid (RA), an active metabolite of vitamin A, is necessary for spermatogonial maturation and proper entry of germ cells into meiotic prophase in the postnatal testes. The expression of Stra8, which is essential for successful meiosis in both male and female gonads and normal spermatogenesis, is directly related to the availability of RA. This study examined the developmental expression pattern of Stra8 transcript in both male and female gonads, provided specific cellular localization of STRA8 protein in the postnatal and adult testis, and investigated RA actions in adult germ cells in a vitamin A-sufficient condition. The peak of Stra8 mRNA expression coincided with the onset of meiosis in postnatal testes. STRA8 protein was detected in gonocytes as early as 5 days postpartum. The expression of STRA8 protein in the neonatal testes was not uniform among spermatogonia, perhaps heralding the asynchronous beginning of spermatogenesis. In adult testes, the highest level of Stra8 mRNA and protein was found in seminiferous epithelial stages VI-VIII. STRA8 protein was localized to some type A and B spermatogonia, preleptotene spermatocytes, and early leptotene spermatocytes. In the vitamin A-sufficient adult testes, RA but not retinol acetate stimulated Stra8 mRNA expression. STRA8 protein expression in adult spermatogonia was induced by RA stimulation, suggesting its role in spermatogonial differentiation. Retinoic acid also increased the number of preleptotene spermatocytes exhibiting 5-bromo-2-deoxyuridine incorporation, indicating a more synchronized premeiotic DNA replication. | Kiss I, Rühl R, Szegezdi E, Fritzsche B, Tóth B, Pongrácz J, Perlmann T, Fésüs L, Szondy Z (2008)
Retinoid receptor-activating ligands are produced within the mouse thymus during postnatal development.
European journal of immunology 38, 147-155 [PubMed:18085670]
[show Abstract]
Vitamin A deficiency is known to be accompanied with immune deficiency and susceptibility to a wide range of infectious diseases. Experimental evidence suggests that the active metabolites of vitamin A that mediate its effects on the immune system are the retinoic acids (RA), which are ligands for the nuclear RA receptor (RAR) family. RA were previously shown both to promote proliferation and to regulate apoptosis of thymocytes. In this study we detected the age-dependent mRNA expression of retinaldehyde dehydrogenases (RALDH1 and 2), cellular RA binding protein-II and CYP26A, proteins responsible for the synthesis, nuclear transport and degradation of RA in the postnatally developing thymus. RALDH1 was located in thymic epithelial cells. However, the amount of all-trans RA in thymic homogenates was close to the detection limit, suggesting that in this tissue all-trans RA is not the main RAR-regulating product of retinol metabolism. At the same time, by measuring the induction of a RAR-responsive transgene in two independent transgenic mouse strains, we demonstrated the production of an RAR-activating ligand, which was age and RALDH dependent. Our data provide evidence for the existence of endogenous retinoid synthesis in the thymus and suggest that retinoids similar to glucocorticoids might indeed be involved in the regulation of thymic proliferation and selection processes by being present in the thymus in functionally effective amounts. | Ryan RO (2008)
Nanodisks: hydrophobic drug delivery vehicles.
Expert opinion on drug delivery 5, 343-351 [PubMed:18318655]
[show Abstract]
Members of the class of exchangeable apolipoproteins possess the unique capacity to transform phospholipid vesicle substrates into nanoscale disk-shaped bilayers. This reaction can proceed in the presence of exogenous hydrophobic biomolecules, resulting in the formation of novel transport vehicles termed nanodisks (NDs). The objective of this study is to describe the structural organization of NDs and evaluate the utility of these complexes as hydrophobic biomolecule transport vehicles. The topics presented focus on two distinct water insoluble drugs, amphotericin B (AMB) and all trans retinoic acid (ATRA). In vitro and in vivo studies reveal that AMB-ND display potent anti-fungal and anti-protozoal activity, while ATRA-ND show promise in the treatment of cancer. The versatility conferred by the presence of a polypeptide component provides opportunities for targeted delivery of ND to cells. | Chao EY, Caravella JA, Watson MA, Campobasso N, Ghisletti S, Billin AN, Galardi C, Wang P, Laffitte BA, Iannone MA, Goodwin BJ, Nichols JA, Parks DJ, Stewart E, Wiethe RW, Williams SP, Smallwood A, Pearce KH, Glass CK, Willson TM, Zuercher WJ, Collins JL (2008)
Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity.
Journal of medicinal chemistry 51, 5758-5765 [PubMed:18800767]
[show Abstract]
A cocrystal structure of T1317 (3) bound to hLXRbeta was utilized in the design of a series of substituted N-phenyl tertiary amines. Profiling in binding and functional assays led to the identification of LXR modulator GSK9772 ( 20) as a high-affinity LXRbeta ligand (IC 50 = 30 nM) that shows separation of anti-inflammatory and lipogenic activities in human macrophage and liver cell lines, respectively. A cocrystal structure of the structurally related analog 19 bound to LXRbeta reveals regions within the receptor that can affect receptor modulation through ligand modification. Mechanistic studies demonstrate that 20 is greater than 10-fold selective for LXR-mediated transrepression of proinflammatory gene expression versus transactivation of lipogenic signaling pathways, thus providing an opportunity for the identification of LXR modulators with improved therapeutic indexes. | Kim B, Lee JH, Yang MS, Jou I, Joe EH (2008)
Retinoic acid enhances prostaglandin E2 production through increased expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in rat brain microglia.
Journal of neuroscience research 86, 1353-1360 [PubMed:18183617]
[show Abstract]
Retinoic acid (RA) is a well-known antiinflammatory agent. In this study, we show that RA has a dual effect on cyclooxygenase-2 (COX-2) expression in inflammatory activated microglia, the resident brain macrophages. After treatment of microglia with LPS or thrombin, COX-2 expression was induced in two phases, specifically, an initial increase at about 12 hr after stimulation followed by a decrease, and another increase at about 48-72 hr. However, PGE(2) and 15d-PGJ(2) were detected at about 12 hr, and the levels continuously increased thereafter. Interestingly, all-trans retinoic acid (ATRA) suppressed the expression of early-phase COX-2 but augmented late-phase COX-2 and inhibited iNOS in the whole time sequence. ATRA enhanced PGE(2) production but had little effect on 15d-PGJ(2). Moreover, ATRA selectively up-regulated the expression of a PGE(2) synthase, mPGES-1, but had little effect on the PGD(2) synthase, H-PGDS. The results collectively suggest that ATRA modulates microglial responses to inflammatory stimulators, particularly at the late phase, via enhancement of COX-2 expression and PGE(2) production. | Jiang SJ, Campbell LA, Berry MW, Rosenfeld ME, Kuo CC (2008)
Retinoic acid prevents Chlamydia pneumoniae-induced foam cell development in a mouse model of atherosclerosis.
Microbes and infection 10, 1393-1397 [PubMed:18678272]
[show Abstract]
Chlamydia pneumoniae, a common respiratory pathogen, has been associated with cardiovascular disease. C. pneumoniae infection accelerates atherosclerotic lesion development in hyperlipidemic animals. Retinoic acid, an anti-oxidant, inhibits infection of endothelial cells by C. pneumoniae. The present study demonstrated that retinoic acid suppresses the acceleration of foam cell lesion development induced by C. pneumoniae in hyperlipidemic C57BL/6J mice. Retinoic acid treatment had no effect on foam cell lesion development in uninfected animals. Lung infection and duration was decreased in treated mice, suggesting one mechanism by which retinoic acid reduces C. pneumoniae-accelerated foam cell lesion formation in hyperlipidemic mice. | Puolakkainen M, Lee A, Nosaka T, Fukushi H, Kuo CC, Campbell LA (2008)
Retinoic acid inhibits the infectivity and growth of Chlamydia pneumoniae in epithelial and endothelial cells through different receptors.
Microbial pathogenesis 44, 410-416 [PubMed:18162363]
[show Abstract]
Chlamydia pneumoniae is a human respiratory pathogen that has also been associated with cardiovascular disease. C. pneumoniae infection accelerates atherosclerotic plaque development in hyperlipidemic animals and promotes oxidation of low density lipoprotein in vitro. All-trans-retinoic acid (ATRA), an antioxidant, has been shown to inhibit C. pneumoniae infectivity for endothelial cells by preventing binding of the organism to the M6P/IGF2 receptor on the cell surface. This current study investigates whether ATRA similarly affects C. pneumoniae infectivity of epithelial cells, which are the primary site of infection in the respiratory tract, and the effects on intracellular growth in both endothelial and epithelial cells. Because ATRA binds to both the nuclear retinoid acid receptor (RAR) and the M6P/IGF2 receptor, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB), an ATRA analog, which binds to the RAR but not the M6P/IGF2 receptor was used to differentiate the receptor mediating the effects of ATRA. The results of this study showed two separate effects of ATRA. The first effect is through interaction with the M6P/IGF2 receptor on the cell surface preventing attachment of the organism (inhibition by ATRA but not TTNPB) in endothelial cells and the second is through the nuclear receptor (inhibition by both ATRA and TTNPB) which inhibits growth in both epithelial and endothelial cells. | Pasquali MA, Gelain DP, Zanotto-Filho A, de Souza LF, de Oliveira RB, Klamt F, Moreira JC (2008)
Retinol and retinoic acid modulate catalase activity in Sertoli cells by distinct and gene expression-independent mechanisms.
Toxicology in vitro : an international journal published in association with BIBRA 22, 1177-1183 [PubMed:18440196]
[show Abstract]
Vitamin A (retinol) exerts a major role in several biological functions. However, it was observed that retinol induces oxidative stress on different cellular types. Catalase (EC 1.11.1.6; CAT) is a hydrogen peroxide metabolizing enzyme, and its activity and expression is widely used as an index to measure oxidative stress and perturbations in the cellular redox state. The aim of this study was to investigate the effects of retinol and its major biologically active metabolite, all-trans retinoic acid (RA), on CAT regulation. For this purpose, cultured Sertoli cells (a physiological target of vitamin A) were treated with retinol or RA. Retinol (7 microM, 14 microM) and RA (100 nM, 1 microM) enhanced intracellular reactive species production and increased CAT activity after 24 h of treatment. Retinol increased CAT immunocontent but did not alter CAT mRNA expression, while the increase in CAT activity by RA was not related to alterations in immunocontent or mRNA expression. In vitro incubation of purified CAT with retinol or RA did not alter enzyme activity. | Pai T, Chen Q, Zhang Y, Zolfaghari R, Ross AC (2007)
Galactomutarotase and other galactose-related genes are rapidly induced by retinoic acid in human myeloid cells.
Biochemistry 46, 15198-15207 [PubMed:18052213]
[show Abstract]
Aldose-1-epimerase (mutarotase) catalyzes the interconversion of alpha and beta hexoses, which is essential for normal carbohydrate metabolism and the production of complex oligosaccharides. Galactose mutarotase (GALM) has been well characterized at the protein level, but information is lacking on the regulation of GALM gene expression. We report herein that all-trans-retinoic acid (RA), an active metabolite of vitamin A that is known to induce myeloid lineage cell differentiation into macrophage-like cells, induces a rapid and robust regulation of GALM mRNA expression in human myeloid cells. all-trans-RA at a physiological concentration (20 nM), or Am580, a ligand selective for the nuclear retinoid receptor RARalpha, increased GALM mRNA in THP-1 cells, with significantly increased expression in 2 h, increasing further to an approximately 8-fold elevation after 6-40 h (P < 0.005). In contrast, tumor necrosis factor-alpha did not increase GALM mRNA expression, although it is capable of inducing cell differentiation. RA also increased GALM mRNA in U937 and HL-60 cells. The increase in GALM mRNA by RA was blocked by pretreating THP-1 cells with actinomycin D but not by cycloheximide. GALM protein and mutarotase activity were also increased time dependently in RA-treated THP-1 cells. In addition to GALM, several other genes in the biosynthetic pathway of galactosyl-containing complex oligosaccharides were more highly expressed in RA-treated THP-1 cells, including B4GALT5, ST3GAL3, ST6GALNAC5, and GALNAC4S-6ST. Thus, the results of this study identify RA as a significant regulator of GALM and other galactose-related genes in myeloid-monocytic cells, which could affect energy utilization and synthesis of cell-surface glycoproteins or glycolipids involved in cell motility, adhesion, and/or functional properties. | Alique M, Herrero JF, Lucio-Cazana FJ (2007)
All-trans retinoic acid induces COX-2 and prostaglandin E2 synthesis in SH-SY5Y human neuroblastoma cells: involvement of retinoic acid receptors and extracellular-regulated kinase 1/2.
Journal of neuroinflammation 4, 1 [PubMed:17204142]
[show Abstract]
BackgroundOur recent results show that all-trans retinoic acid (ATRA), an active metabolite of vitamin A, induces COX-dependent hyperalgesia and allodynia in rats. This effect was mediated by retinoic acid receptors (RARs) and was associated with increased COX-2 expression in the spinal cord. Since ATRA also up-regulated COX-2 expression in SH-SY5Y human neuroblastoma cells, the current study was undertaken to analyze in these cells the mechanism through which ATRA increases COX activity.MethodsCultured SH-SY5Y neuroblastoma cells were treated with ATRA. COX expression and kinase activity were analyzed by western blot. Transcriptional mechanisms were analyzed by RT-PCR and promoter assays. Pharmacological inhibitors of kinase activity and pan-antagonists of RAR or RXR were used to assess the relevance of these signaling pathways. Production of prostaglandin E2 (PGE2) was quantified by enzyme immunoabsorbent assay. Statistical significance between individual groups was tested using the non-parametric unpaired Mann-Whitney U test.ResultsATRA induced a significant increase of COX-2 expression in a dose- and time-dependent manner in SH-SY5Y human neuroblastoma cells, while COX-1 expression remained unchanged. Morphological features of differentiation were not observed in ATRA-treated cells. Up-regulation of COX-2 protein expression was followed by increased production of PGE2. ATRA also up-regulated COX-2 mRNA expression and increased the activity of a human COX-2 promoter construct. We next explored the participation of RARs and mitogen-activated peptide kinases (MAPK). Pre-incubation of SH-SY5Y human neuroblastoma cells with either RAR-pan-antagonist LE540 or MAP kinase kinase 1 (MEK-1) inhibitor PD98059 resulted in the abolition of ATRA-induced COX-2 promoter activity, COX-2 protein expression and PGE2 production whereas the retinoid X receptor pan-antagonist HX531, the p38 MAPK inhibitor SB203580 or the c-Jun kinase inhibitor SP600125 did not have any effect. The increase in RAR-beta expression and extracellular-regulated kinase 1/2(ERK1/2) phosphorylation in ATRA-incubated cells suggested that RARs and ERK1/2 were in fact activated by ATRA in SH-SY5Y human neuroblastoma cells.ConclusionThese results highlight the importance of RAR-dependent and kinase-dependent mechanisms for ATRA-induced COX-2 expression and activity. | Vasileiou C, Vaezeslami S, Crist RM, Rabago-Smith M, Geiger JH, Borhan B (2007)
Protein design: reengineering cellular retinoic acid binding protein II into a rhodopsin protein mimic.
Journal of the American Chemical Society 129, 6140-6148 [PubMed:17447762]
[show Abstract]
Rational redesign of the binding pocket of Cellular Retinoic Acid Binding Protein II (CRABPII) has provided a mutant that can bind retinal as a protonated Schiff base, mimicking the binding observed in rhodopsin. The reengineering was accomplished through a series of choreographed manipulations to ultimately orient the reactive species (the epsilon-amino group of Lys132 and the carbonyl of retinal) in the proper geometry for imine formation. The guiding principle was to achieve the appropriate Bürgi-Dunitz trajectory for the reaction to ensue. Through crystallographic analysis of protein mutants incapable of forming the requisite Schiff base, a highly ordered water molecule was identified as a key culprit in orienting retinal in a nonconstructive manner. Removal of the ordered water, along with placing reinforcing mutations to favor the desired orientation of retinal, led to a triple mutant CRABPII protein capable of nanomolar binding of retinal as a protonated Schiff base. The high-resolution crystal structure of all-trans-retinal bound to the CRABPII triple mutant (1.2 A resolution) unequivocally illustrates the imine formed between retinal and the protein. | Romero-Sandoval EA, Molina C, Alique M, Moreno-Manzano V, Lucio FJ, Herrero JF (2006)
Vitamin A active metabolite, all-trans retinoic acid, induces spinal cord sensitization. I. Effects after oral administration.
British journal of pharmacology 149, 56-64 [PubMed:16847436]
[show Abstract]
Background and purposeRetinoic acid is an active metabolite of vitamin A involved in the modulation of the inflammatory and nociceptive responses. The aim of the present study was to analyze the properties of spinal cord neuronal responses of male Wistar rats treated with all-trans retinoic acid (ATRA) p.o. in the normal situation and under carrageenan-induced inflammation. We also studied the expression and distribution of cyclooxygenases (COX) in the spinal cord.Experimental approachProperties of spinal cord neurons were studied by means of the single motor unit technique. The expression of COX enzymes in the spinal cord was assessed by Western blot analysis and immunohistochemistry.Key resultsIntensity thresholds for mechanical and electrical stimulation (C-fibers) were significantly lower in animals treated with ATRA than vehicle, either in normal rats or in rats with inflammation. The size of cutaneous receptive fields was also larger in animals treated with ATRA in the normal and inflammatory conditions. The expression of COX-2 enzyme, but not COX-1, was significantly higher in animals treated with ATRA. COX-2 labeling was observed in dorsal horn cells and in ventral horn motoneurons.Conclusions and implicationsIn conclusion, the oral treatment with ATRA in rats induces a sensitization-like effect on spinal cord neuronal responses similar to that observed in animals with inflammation and might explain the enhancement of allodynia and hyperalgesia observed in previously published behavioral experiments. The mechanism of action involves an over-expression of COX-2, but not COX-1, in dorsal and ventral horn areas of the lumbar spinal cord. | Buletic Z, Soprano KJ, Soprano DR (2006)
Retinoid targets for the treatment of cancer.
Critical reviews in eukaryotic gene expression 16, 193-210 [PubMed:17073551]
[show Abstract]
Retinoic acid (RA), the most potent natural retinoid, is essential for normal cell growth and differentiation. The RA signaling pathway is multistep, involving the precise regulation of retinoid levels and the control of RA-dependent gene expression in target cells. Within this complex scheme, there are many different aberrations in the RA signaling pathway of tumor cells that have been found to be associated with abnormal cell growth and tumorigenesis. This article reviews the normal pathways of RA signaling, followed by a discussion of the various sites that have been implicated in tumorigenesis and targeted for drug development. Currently, there are several retinoids and one rexinoid approved for the treatment of specific cancers. Future experimentation in drug discovery will continue to explore the efficacy of retinoids/rexinoids, either alone or in combination with other chemotherapeutic agents and/or chromatin remodeling agents, and the development of agents to modulate RA metabolism within cells. It is likely that different drug treatments will be developed that are specifically tailored to the unique point(s) in the RA signaling pathways that are aberrant in specific types of tumor cells. | Sakakura M, Nishii K, Usui E, Monma F, Tsukada T, Shiku H (2006)
Bilateral osteonecrosis of the head of the femur during treatment with retinoic acid in a young patient with acute promyelocytic leukemia.
International journal of hematology 83, 252-253 [PubMed:16720557]
[show Abstract]
All-trans retinoic acid (ATRA) is the drug of choice for the treatment of acute promyelocytic leukemia (APL). In general, ATRA is well tolerated, but it does have side effects, the most severe of which is ATRA syndrome. We report the case of a young patient with APL treated with ATRA for induction and maintenance therapy who then developed avascular necrosis of both femoral heads. We also review cases of APL patients with osteonecrosis of the femoral head after ATRA therapy. | Engedal N, Gjevik T, Blomhoff R, Blomhoff HK (2006)
All-trans retinoic acid stimulates IL-2-mediated proliferation of human T lymphocytes: early induction of cyclin D3.
Journal of immunology (Baltimore, Md. : 1950) 177, 2851-2861 [PubMed:16920920]
[show Abstract]
Vitamin A is established as an important immune regulator, but the mechanisms whereby vitamin A regulates T cell biology are poorly defined. In this study, we show that an active metabolite of vitamin A, all-trans retinoic acid (RA), potently stimulates T cell proliferation by modulating IL-2-mediated signaling downstream of IL-2R and independent of the induction of IL-2. Thus, at concentrations as low as 0.1 nM, RA enhanced the division of normal human T lymphocytes that were simultaneously stimulated with anti-CD3 mAbs and saturating concentrations of IL-2. At the optimal concentration of RA (50 nM), a 3-fold increase in T cell proliferation was observed. The induced proliferation was preceded by increased phosphorylation of the retinoblastoma protein and enhanced G1- to S-phase progression. Interestingly, the promitogenic effect of RA was found to be particularly directed toward increased expression of cyclin D3 at both the mRNA and protein level. Furthermore, the stimulatory effect of RA on cyclin D3 expression as well as on cell proliferation was completely abolished in the presence of the JAK inhibitor AG-490 or blocking IL-2R alpha mAbs, and RA also enhanced cyclin D3 expression and T cell proliferation in the presence of IL-2 alone. Finally, we showed that the proliferative effect of RA was mimicked by agonists of the retinoic acid receptor (RAR) and completely inhibited by a RAR-selective antagonist. In conclusion, our results indicate that RA, via RAR, stimulates IL-2-induced signaling in a JAK-dependent manner to enhance cyclin D3 expression and thereby promote T cell proliferation. | Ross AC, Ambalavanan N, Zolfaghari R, Li NQ (2006)
Vitamin A combined with retinoic acid increases retinol uptake and lung retinyl ester formation in a synergistic manner in neonatal rats.
Journal of lipid research 47, 1844-1851 [PubMed:16685080]
[show Abstract]
Vitamin A (VA) is stored in tissues predominantly as retinyl esters (REs), which provide substrate for the production of bioactive retinoids. Retinoic acid (RA), a principal metabolite, has been shown to induce postnatal lung development. To better understand lung RE storage, we compared VA (given as retinyl palmitate), RA, and a nutrient-metabolite combination, VARA, given orally on postnatal days 5-7, for their ability to increase lung RE in neonatal rats. VARA increased lung RE significantly [ approximately 14, 2.4, 2.1, and <1 nmol/g for VARA, VA, RA, and control (C), respectively; P < 0.001]; the increase by VARA was more than additive compared with the effects of VA and RA alone. Lung histology and morphometry were unchanged. In a 6 h metabolic study, providing [(3)H]retinol with VARA, compared with VA or C, increased the uptake of newly absorbed (3)H by 3-fold, indicating that VARA stimulated the uptake of [(3)H]retinol and its retention as [(3)H]RE in neonatal lungs. After cessation of VARA, lung RE remained increased for 9 d afterward, through the period of alveolar development. In conclusion, VARA, a 10:1 nutrient-metabolite combination, increased lung RE significantly compared with VA alone and could be a promising therapeutic option for enhancing the delivery of VA to the lungs. | Clagett-Dame M, McNeill EM, Muley PD (2006)
Role of all-trans retinoic acid in neurite outgrowth and axonal elongation.
Journal of neurobiology 66, 739-756 [PubMed:16688769]
[show Abstract]
The vitamin A metabolite, all-trans retinoic acid (atRA) plays essential roles in nervous system development, including neuronal patterning, survival, and neurite outgrowth. Our understanding of how the vitamin A acid functions in neurite outgrowth comes largely from cultured embryonic neurons and model neuronal cell systems including human neuroblastoma cells. Specifically, atRA has been shown to increase neurite outgrowth from embryonic DRG, sympathetic, spinal cord, and olfactory receptor neurons, as well as dissociated cerebra and retina explants. A role for atRA in axonal elongation is also supported by a limited number of studies in vivo, in which a deficiency in retinoid signaling produced either by dietary or genetic means has been shown to alter neurite outgrowth from the spinal cord and hindbrain regions. Human neuroblastoma cells also show enhanced numbers of neurites and longer processes in response to atRA. The mechanism whereby retinoids regulate neurite outgrowth includes, but is not limited to, the regulation of the transcription of neurotrophin receptors. More recent evidence supports a role for atRA in regulating components of other signaling pathways or candidate neurite-regulating factors. Some of these effects, such as that on neuron navigator 2 (NAV2), may be direct, whereas others may be secondary to other atRA-induced changes in the cell. This review focuses on what is currently known about neurite initiation and growth, with emphasis on the manner in which atRA may influence these events. | Saidi SA, Holland CM, Charnock-Jones DS, Smith SK (2006)
In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.
Molecular cancer 5, 13 [PubMed:16569247]
[show Abstract]
UnlabelledFenofibrate, an agonist of PPAR-alpha, in doses above 25 microM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell cycle gene expression. Expression of PPAR-alpha mRNA was reduced by >75% using RNA-interference but this resulted in only minor changes in biological effects. A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth.ConclusionThe combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro. | Fukasawa H, Kagechika H, Shudo K (2006)
[Retinoid therapy for autoimmune diseases].
Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 29, 114-126 [PubMed:16819260]
[show Abstract]
Retinoid is a collective term for compounds which bind to and activate retinoic acid receptors (RARalpha, beta, gamma and RXRalpha, beta, gamma), members of nuclear hormone receptor superfamily. The most important endogeneous retinoid is all-trans-retinoic acid (ATRA) which is an RARalpha, beta and gamma ligand. ATRA and its mimics have been in clinical use for treatment of acute promyelocytic leukemia (APL) and some skin diseases. Many synthetic retinoids have been developed and attempts to improve their medicinal properties have been made. Among them, tamibarotene (Am80) is an RARalpha- and RARbeta-specific (but RARgamma- and RXRs-nonbinding) synthetic retinoid that is effective in the treatment of psoriasis patients and relapsed APL. Experimentally, this compound is also active in animal models of rheumatoid arthritis and experimental autoimmune encephalomyelitis. On this background, possible application of retinoids for the treatment of autoimmune diseases was discussed. In particular, Th1 dominant autoimmune diseases may be the targets of the retinoids. | Fujishita K, Koizumi S, Inoue K (2006)
Upregulation of P2Y2 receptors by retinoids in normal human epidermal keratinocytes.
Purinergic signalling 2, 491-498 [PubMed:18404486]
[show Abstract]
Retinoids, vitamin A derivatives, are important regulators of the growth and differentiation of skin cells. Although retinoids are therapeutically used for several skin ailments, little is known about their effects on P2 receptors, known to be involved in various functions in the skin. DNA array analysis showed that treatment of normal human epidermal keratinocytes (NHEKs) with all-trans-retinoic acid (ATRA), an agonist to RAR (retinoic acid receptor), enhanced the expression of mRNA for the P2Y2 receptor, a metabotropic P2 receptor that is known to be involved in the proliferation of the epidermis. The expression of other P2 receptors in NHEKs was not affected by ATRA. ATRA increased the mRNA for the P2Y2 receptor in a concentration-dependent fashion (1 nM to 1 muM). Am80, a synthesized agonist to RAR, showed a similar enhancement, whereas 9-cis-retinoic acid (9-cisRA), an agonist to RXR (retinoid X receptor), enhanced P2Y2 gene expression to a lesser extent. Ca(2+) imaging analysis showed that ATRA also increased the function of P2Y2 receptors in NHEKs. Retinoids are known to enhance the turnover of the epidermis by increasing both proliferation and terminal differentiation. The DNA microarray analysis also revealed that ATRA upregulates various genes involved in the differentiation of NHEKs. Our present results suggest that retinoids, at least in part, exert their proliferative effects by upregulating P2Y2 receptors in NHEKs. This effect of retinoids may be closely related to their therapeutic effect against various ailments or aging events in skins such as over-keratinization, pigmentation and re-modeling. | Chivot M (2005)
Retinoid therapy for acne. A comparative review.
American journal of clinical dermatology 6, 13-19 [PubMed:15675886]
[show Abstract]
Retinoids play a vital role in the treatment of acne because they act on the primary lesion, the microcomedo. They are synthetic derivatives of vitamin A (retinol), and are selected for their effectiveness. Several compounds are used for acne, either in topical or systemic form.We describe and compare the different topical retinoids, tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), adapalene (derived from naphthoic acid), and tazarotene (acetylenic retinoid). They act mainly as comedolytics, but anti-inflammatory actions have also been discovered recently. The retinoids have great beneficial effects, but also some adverse effects, the main one being teratogenicity. It is preferable not to use them in topical form for pregnant women, although a pregnancy test is only compulsory for tazarotene. Only isotretinoin is used in systemic form. It acts on all the factors of acne and offers long remissions, and sometimes complete cures. Precautions must be taken for women of childbearing age due to its teratogenicity. It is also important to be aware of its other adverse effects, explain them to the patient and, if possible, deal with them in advance. | Wang L, Mear JP, Kuan CY, Colbert MC (2005)
Retinoic acid induces CDK inhibitors and growth arrest specific (Gas) genes in neural crest cells.
Development, growth & differentiation 47, 119-130 [PubMed:15839997]
[show Abstract]
Retinoic acid (RA), the active metabolite of vitamin A, regulates cellular growth and differentiation during embryonic development. In excess, this vitamin is also highly teratogenic to animals and humans. The neural crest is particularly sensitive to RA, and high levels adversely affect migration, proliferation and cell death. We investigated potential gene targets of RA associated with neural crest proliferation by determining RA-mediated changes in gene expression over time, using microarrays. Statistical analysis of the top ranked RA-regulated genes identified modest changes in multiple genes previously associated with cell cycle control and proliferation including the cyclin-dependent kinase inhibitors Cdkn1a (p21), Cdkn2b (p15(INK4b)), and Gas3/PMP22. The expression of p21 and p15(INK4b) contribute to decreased proliferation by blocking cell cycle progression at G1-S. This checkpoint is pivotal to decisions regulating proliferation, apoptosis, or differentiation. We have also confirmed the overexpression of Gas3/PMP22 in RA-treated neural crests, which is associated with cytoskeletal changes and increased apoptosis. Our results suggest that increases in multiple components of diverse regulatory pathways have an overall cumulative effect on cellular decisions. This heterogeneity contributes to the pleiotropic effects of RA, specifically those affecting proliferation and cell death. | Stefanaki C, Stratigos A, Katsambas A (2005)
Topical retinoids in the treatment of photoaging.
Journal of cosmetic dermatology 4, 130-134 [PubMed:17166212]
[show Abstract]
A large number of different substances comprise the family of retinoids, which are traditionally described as vitamin A derivatives. By exerting their action through nuclear and cytoplasmic receptors they may improve photoaging. Tretinoin is the best studied retinoid in the treatment of photoaging. Others such as isotretinoin, retinaldehyde, and tazarotene, although less well studied, have given promising results. | Yu Z, Lin J, Xiao Y, Han J, Zhang X, Jia H, Tang Y, Li Y (2005)
Induction of cell-cycle arrest by all-trans retinoic acid in mouse embryonic palatal mesenchymal (MEPM) cells.
Toxicological sciences : an official journal of the Society of Toxicology 83, 349-354 [PubMed:15537748]
[show Abstract]
all-trans retinoic acid (atRA), the oxidative metabolite of vitamin A, is essential for normal embryonic development. Also, high levels of atRA are teratogenic in many species and can effectively induce cleft palate in the mouse. Most cleft palate resulted from the failed fusion of secondary palate shelves, and maintenance of the normal cell proliferation is important in this process of shelf growth. To clarify the mechanism by which atRA causes cleft palate, we investigated the effect of atRA on proliferation activity and cell cycle distribution in mouse embryonic palatal mesenchymal (MEPM) cells. atRA inhibited the growth of MEPM cells by inducing apoptosis in a dose-dependent manner. atRA also caused a G1 block in the cell cycle with an increase in the proportion of cells in G0/G1 and a decrease in the proportion of cells in S phase, as determined by flow cytometry. We next investigated the effects of atRA on molecules that regulate the G1 to S phase transition. These studies demonstrated that atRA inhibited expression of cyclins D and E at the protein level. Furthermore, atRA treatment reduced phosphorylated Rb and decreased cdk2 and cdk4 kinase activity. These data suggest that atRA had antiproliferative activity by modulating G1/S cell cycle regulators and by inhibition of Rb phosphorylation in MEPM cells, which might account for the pathogenesis of cleft palate induced by retinoic acid. | Merrill RA, Ahrens JM, Kaiser ME, Federhart KS, Poon VY, Clagett-Dame M (2004)
All-trans retinoic acid-responsive genes identified in the human SH-SY5Y neuroblastoma cell line and their regulated expression in the nervous system of early embryos.
Biological chemistry 385, 605-614 [PubMed:15318809]
[show Abstract]
The vitamin A metabolite, all-trans retinoic acid (atRA), is required for embryonic development. atRA binds to the nuclear retinoic acid receptors and regulates the transcription of specific target genes. In order to identify atRA-induced genes that play a role in neural development, a subtractive library was created from SH-SY5Y neuroblastoma cells, a human cell line that exhibits changes in cell adhesion and neurite outgrowth after exposure to the vitamin A acid. We report here the identification of 14 genes that are rapidly induced by atRA (retinoic acid induced in neuroblastoma or RAINB), eight of which were previously not known to be atRA responsive (BTBD11, calmin, cyclin M2, ephrin B2, HOXD10, NEDD9, RAINB6 and tenascin R). mRNA regulation by atRA was confirmed in SH-SY5Y cells by Northern blotting, and gene regulation was studied in additional human cell lines using the quantitative polymerase chain reaction. The majority of the atRA-responsive clones revealed in this screen are highly expressed in the nervous system of developing rat embryos. Further, the expression of several of these genes is perturbed in developing rat embryos exposed to excess atRA or conversely, deprived of sufficient retinoid during early development. We propose that a subset of these genes lie downstream of atRA and its receptors in the regulation of neurite outgrowth and cell adhesion in both neural and non-neural tissues within the developing embryo. | Merrill RA, See AW, Wertheim ML, Clagett-Dame M (2004)
Crk-associated substrate (Cas) family member, NEDD9, is regulated in human neuroblastoma cells and in the embryonic hindbrain by all-trans retinoic acid.
Developmental dynamics : an official publication of the American Association of Anatomists 231, 564-575 [PubMed:15376324]
[show Abstract]
The vitamin A metabolite, all-trans retinoic acid (atRA), plays an essential role in vertebrate embryogenesis, including development of the nervous system. In the human neuroblastoma cell line, SH-SY5Y, atRA rapidly induces (within 4 hr) the expression of the Crk-associated substrate (Cas) family member, neural precursor cell-expressed, developmentally down-regulated gene 9 (NEDD9) also called the human enhancer of filamentation (HEF1). NEDD9 is expressed in the developing hindbrain (5-somite stage) in the presumptive rhombomeres 2, 3, and 5 before the onset of overt segmentation. Exposure of rat embryos to excess atRA at times ranging from E9.25 to E12 leads to altered NEDD9 expression in the developing hindbrain within 6 hr. NEDD9 expression is also perturbed in vitamin A-deficient embryos. A putative retinoic acid response element in the 5' region of the NEDD9 promoter binds specifically to a RXR/RAR heterodimer and forms a higher molecular weight complex upon addition of a retinoic acid receptor-specific antibody. Regulation of NEDD9 may be an important means whereby atRA promotes cell spreading and neurite outgrowth in SH-SY5Y human neuroblastoma cells, and NEDD9 represents a new downstream target of atRA and its receptors in the developing hindbrain. | Chen Q, Ross AC (2004)
Retinoic acid regulates cell cycle progression and cell differentiation in human monocytic THP-1 cells.
Experimental cell research 297, 68-81 [PubMed:15194426]
[show Abstract]
All-trans-retinoic acid (RA), a natural metabolite of retinol, carries out most of the biological activities of vitamin A and is required for normal growth, cell differentiation, and immune functions. In the present studies, THP-1 human monocytes were used to investigate the mechanisms by which RA may regulate progression through the G1/S phase of the cell cycle. Physiological concentrations of all-trans-RA reduced the levels of cyclin E mRNA by 6 h and reduced cyclin E protein in a dose- and time-dependent manner. Similar reductions were observed for the retinoic acid receptor RARalpha and RXRalpha proteins. Concomitantly, RA increased the level of the cyclin-dependent kinase inhibitor p27 (Kip-1). The levels of retinoblastoma mRNA and protein (pRb) were also increased, while the proportion of hyperphosphorylated (phosphoserine 807/811) pRb was markedly reduced. Overall, RA increased the functionality of pRb as an inhibitor of cell cycle progression. Furthermore, RA reduced the binding activity of the transcription factor E2F to its core DNA element. Retinoic acid-induced changes in cell cycle-related proteins occurred in 4-6 h, including reduced cyclin E expression in bromodeoxyuridine (BrdU)-labeled cells, before the onset of cell differentiation as indicated by an increase in the percentage of G1 phase cells and a reduction in S phase cells at 24 h. The expression of CD11b, a cell surface marker of macrophage-like differentiation was increased by RA, as was phagocytic activity. The multiple effects of RA on cell cycle progression may help to explain its well-documented ability to induce the differentiation of THP-1 cells, and thereby to enhance macrophage-like immune functions. | Engedal N, Ertesvag A, Blomhoff HK (2004)
Survival of activated human T lymphocytes is promoted by retinoic acid via induction of IL-2.
International immunology 16, 443-453 [PubMed:14978018]
[show Abstract]
At the end of an immune response, most activated T cells spontaneously undergo programmed cell death (apoptosis). In the present study we show that all-trans retinoic acid (atRA), a major vitamin A metabolite, can inhibit the spontaneous apoptosis of activated human T lymphocytes in vitro. Isolated peripheral blood T lymphocytes were activated by 12-O-tetradecanoyl phorbol 13-acetate and cultured for up to 11 days without any further stimuli. With time, a gradual increase in cell death was observed. This spontaneous death of activated T cells was apoptotic, as demonstrated by cell shrinkage, DNA fragmentation and depolarization of the mitochondrial membrane. In the presence of physiological concentrations of atRA, the percentage of T cells exhibiting these apoptotic features was significantly reduced. After 5 days of stimulation, the percentage of TUNEL+ T cells decreased from 28 to 12% in the presence of atRA. The anti-apoptotic effect of atRA was mimicked by the retinoic acid receptor (RAR)-selective agonists 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid and AM-580, and totally abrogated by the RAR-selective antagonist Ro 41-5253. Cytokines of the IL-2 family have been shown to improve the survival of activated T cells. Strikingly, we found that the ability of atRA to inhibit apoptosis was significantly correlated with its ability to increase the production of IL-2. Furthermore, a blocking anti-IL-2 receptor antibody completely abrogated the anti-apoptotic effect of atRA. Together, these results suggest that retinoic acid inhibits spontaneous apoptosis of activated T lymphocytes through a RAR-dependent increase in IL-2 production. | Miloso M, Villa D, Crimi M, Galbiati S, Donzelli E, Nicolini G, Tredici G (2004)
Retinoic acid-induced neuritogenesis of human neuroblastoma SH-SY5Y cells is ERK independent and PKC dependent.
Journal of neuroscience research 75, 241-252 [PubMed:14705145]
[show Abstract]
Retinoic acid (RA), an active metabolite of vitamin A, is a natural morphogen involved in development and differentiation of the nervous system. To elucidate signaling mechanisms involved in RA-induced neuritogenesis, we used human neuroblastoma SH-SY5Y cells, an established in vitro model for studying RA action, to examine the role of extracellular signal-regulated kinase (ERK) 1 and 2 in RA-induced neuritogenesis and cell survival. From immunoblotting experiments, we observed that RA induced delayed but persistent ERK1 and ERK2 phosphorylation (until 96 hr) that was reduced significantly by the specific mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor U0126. For the subsequent studies we chose 24 hr as the reference time. Inhibition of ERK activation did not affect RA-induced neuritogenesis (percentage of neurite-bearing cells and neurite length) but significantly reduced cell survival. In addition, we analyzed the signaling pathway that mediates ERK activation. Our results suggest that RA-induced ERK phosphorylation does not follow the classic Raf kinase-dependent pathway. Protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI 3-K) are possible alternative kinases involved in the ERK signaling pathway. In fact, in the presence of the specific PKC inhibitor GF 109203X, or the specific PI 3-K inhibitor wortmannin, we observed a significant dose-dependent reduction in ERK phosphorylation. RA-induced neuritogenesis and cell survival were reduced by GF 109203X in a concentration-dependent manner. These results suggest that rather than ERK1 and ERK2, it is PKC that plays an important role during early phases of RA-induced neuritogenesis. | Pérez de Lema G, Lucio-Cazaña FJ, Molina A, Luckow B, Schmid H, de Wit C, Moreno-Manzano V, Banas B, Mampaso F, Schlöndorff D (2004)
Retinoic acid treatment protects MRL/lpr lupus mice from the development of glomerular disease.
Kidney international 66, 1018-1028 [PubMed:15327395]
[show Abstract]
BackgroundRetinoic acid (tRA) is an active metabolite of vitamin A with potent anti-inflammatory properties. We analyzed the effects of tRA on the development of lupus nephritis in MRL/lpr mice.MethodsMRL/lpr mice received chow supplemented with vehicle or tRA (daily 10 mg/kg) from 8 to 14 weeks until their sacrifice. MRL/wt mice served as an additional control.ResultstRA-treated MRL/lpr mice showed reduced lymphoadenopathy and splenomegaly as compared to vehicle-treated controls. Treatment reduced proteinuria to almost basal levels. Plasma IgG and anti-DNA antibodies increased comparably in both vehicle and tRA-treated mice. Vehicle-treated mice showed characteristic renal lesions. In contrast tRA-treated mice showed almost normal glomerular histology with a pronounced reduction in endocapillary cell proliferation. T-cell and macrophage infiltrates were reduced after tRA treatment within glomeruli and interstitium as compared to vehicle-treated animals. In spite of this, immune complex and complement deposition were comparable in both groups. Adoptively transferred T cells from vehicle-treated to tRA-treated MRL/lpr mice did not induce renal lesions or proteinuria. These beneficial effects of tRA treatment were associated with reduced renal expression of chemokines and inflammatory cytokines. Surprisingly, renal transforming growth factor-beta (TGF-beta) mRNA levels of tRA-treated mice were elevated, possibly indicating that TGF-beta acts as an anti-inflammatory signal in this lupus model.ConclusiontRA treatment reduces lymphoproliferation and glomerulonephritis in MRL/lpr mice. This occurs in spite of unaltered anti-DNA titers and glomerular immune complex deposition, and cannot be overcome by T-cell transfer from nephritic MRL/lpr mice. | Niles RM (2004)
Signaling pathways in retinoid chemoprevention and treatment of cancer.
Mutation research 555, 81-96 [PubMed:15476854]
[show Abstract]
The Vitamin A metabolite, retinoic acid, has been shown to have chemopreventive and therapeutic activity for certain cancers such as head and neck, cervical, neuroblastoma and promyelocytic leukemia. Retinoic acid achieves these activities by inducing differentiation and/or growth arrest. A large number of studies have investigated the mechanism(s) by which retinoic acid alters the behavior of premalignant and tumor cells. Although much important data has been obtained, the exact signaling pathways required for retinoic acid to exert its biological effects remains elusive. In this review, we outline the role and function of retinoid nuclear receptors, followed by a discussion of how major signaling pathways are affected in different tumor types by retinoids. We conclude by examining the effect of retinoic acid on G1 cell cycle regulatory proteins in various tumors. | Ross AC, Zolfaghari R (2004)
Regulation of hepatic retinol metabolism: perspectives from studies on vitamin A status.
The Journal of nutrition 134, 269S-275S [PubMed:14704332]
[show Abstract]
Liver vitamin A (retinol) is obtained from several sources and is subject to multiple fates. Lecithin:retinol acyltransferase (LRAT), a microsomal enzyme present in liver and several other retinol-metabolizing tissues, esterifies retinol that is associated with a cellular retinol-binding protein, CRBP or CRBP-II. Recent research has shown that LRAT mRNA expression and enzyme activity are regulated in a tissue-specific manner. In vitamin A-deficient liver, both LRAT mRNA and activity are significantly down-regulated as well as rapidly induced after the administration of vitamin A or its principal hormonal metabolite, retinoic acid (RA). In long-term feeding studies and the metabolic steady state, liver LRAT is expressed dose-dependently across a wide range of dietary vitamin A. Additionally, an RA-inducible cytochrome P450, P450RAI or CYP26, is down-regulated in liver during vitamin A deficiency and up-regulated dose-dependently by dietary vitamin A and exogenous RA. Based on these results, we propose that LRAT and CYP26 serve as two molecular mechanisms, coordinately regulated by all-trans-RA, to control the availability of retinol and RA, respectively. The LRAT reaction, besides providing a readily retrievable storage form of vitamin A, may regulate the availability of retinol to other pathways, while the CYP26 reaction may serve to prevent a detrimental "overshoot" of RA concentration. Moreover, retinoid metabolism in the liver is likely to be closely integrated with that in peripheral tissues through the rapid interorgan transfer and recycling of retinoids, affecting the whole-body economy of vitamin A. | Mey J, McCaffery P (2004)
Retinoic acid signaling in the nervous system of adult vertebrates.
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 10, 409-421 [PubMed:15359008]
[show Abstract]
The majority of the functions of vitamin A are carried out by its metabolite, retinoic acid (RA), a potent transcriptional activator acting through members of the nuclear receptor family of transcription factors. In the CNS, RA was first recognized to be essential for the control of patterning and differentiation in the developing embryo. It has recently come to light, however, that many of the same functions that RA directs in the embryo are involved in the regulation of plasticity and regeneration in the adult brain. The same intricate metabolic control system of synthetic and catabolic enzymes, combined with cytoplasmic binding proteins, is used in both embryo and adult to create regions of high and low RA to modulate gene transcription. This review summarizes some of the discoveries in the new field of retinoid neurobiology including its functions in neural plasticity and LTP in the hippocampus; its possible role in motor disorders such as Parkinson's disease, motoneuron disease, and Huntington's disease; its role in regeneration after sciatic nerve and spinal cord injury; and its possible involvement in psychiatric diseases such as depression. | Vélez C, Aránega AE, Marchal JA, Prados J, Melguizo C, Carrillo E, Boulaiz H, Madeddu R, Sánchez-Montesinos I, Aránega A (2003)
Contractile regulatory proteins tropomyosin and troponin-T as indicators of the modulatory role of retinoic acid.
Cells, tissues, organs 175, 25-33 [PubMed:14605492]
[show Abstract]
Retinoic acid (RA), the active metabolite of vitamin A, plays a significant role in regulating cardiac form and function throughout the life of the organism. Both cardiac morphogenesis and myocardial differentiation are affected by alterations in RA homeostasis. In order to test the effect of all-trans RA and 13-cis RA on cardiomyocyte differentiation, we studied the level and the subcellular compartmentalization of alpha-tropomyosin and troponin-T proteins in cultures of chick embryo cardiomyocytes obtained from Hamburger and Hamilton's (HH) stage 22, 32 and 40 embryos. The retinoids increased the levels of alpha-tropomyosin and troponin-T in the cytoplasmic and cytoskeletal fractions of cells at all three stages of development. The greatest increases in alpha-tropomyosin occurred in the cytoplasmic fraction in HH22 cells cultured for 24 h with all-trans RA or 13-cis RA, whereas the greatest increases in troponin-T were found in the cytoplasmic fraction of HH32 cells exposed to retinoids for 24 h. In cultures treated for 48 h with retinoids, the levels of alpha-tropomyosin and troponin-T showed significant increases in the cytoplasmic compartment of cells treated in HH32-with respect to the control values. These findings are further evidence that RA plays a modulating role in the formation and reorganization of sarcomeric proteins during the process of cardiomyocyte maturation. | De Lorenzo MS, Yamaguchi K, Subbaramaiah K, Dannenberg AJ (2003)
Bryostatin-1 stimulates the transcription of cyclooxygenase-2: evidence for an activator protein-1-dependent mechanism.
Clinical cancer research : an official journal of the American Association for Cancer Research 9, 5036-5043 [PubMed:14581379]
[show Abstract]
Bryostatin-1 (bryostatin) is a macrocyclic lactone derived from Bugula neritina, a marine bryozoan. On the basis of the strength of in vitro and animal studies, bryostatin is being investigated as a possible treatment for a variety of human malignancies. Severe myalgias are a common dose-limiting side effect. Because cyclooxygenase-2 (COX-2)-derived prostaglandins can cause pain, we investigated whether bryostatin induced COX-2. Bryostatin (1-10 nM) induced COX-2 mRNA, COX-2 protein, and prostaglandin biosynthesis. These effects were observed in macrophages as well as in a series of human cancer cell lines. Transient transfections localized the stimulatory effects of bryostatin to the cyclic AMP response element of the COX-2 promoter. Electrophoretic mobility shift assays and supershift experiments revealed a marked increase in the binding of activator protein-1 (AP-1)(c-Jun/c-Fos) to the cyclic AMP response element of the COX-2 promoter. Pharmacological and transient transfection studies indicated that bryostatin stimulated COX-2 transcription via the protein kinase C-->mitogen-activated protein kinase-->AP-1 pathway. All-trans-retinoic acid, a prototypic AP-1 antagonist, blocked bryostatin-mediated induction of COX-2. Taken together, these results suggest that bryostatin-mediated induction of COX-2 can help to explain the myalgias that are commonly associated with treatment. Moreover, it will be worthwhile to evaluate whether the addition of a selective COX-2 inhibitor can increase the antitumor activity of bryostatin. | Lai L, Bohnsack BL, Niederreither K, Hirschi KK (2003)
Retinoic acid regulates endothelial cell proliferation during vasculogenesis.
Development (Cambridge, England) 130, 6465-6474 [PubMed:14627725]
[show Abstract]
A dietary deficiency of vitamin A is associated with cardiovascular abnormalities in avian and murine systems. Retinoic acid (RA) is the active metabolite of vitamin A and whether it directly regulates mammalian blood vessel formation has not been determined and is investigated herein. We used mice rendered RA-deficient via targeted deletion of retinaldehyde dehydrogenase 2 (Raldh2(-/-)), the enzyme required to produce active RA in the embryo. Histological examination at E8.0-8.5, prior to cardiac function and systemic blood circulation, revealed that capillary plexi formed in Raldh2(-/-) yolk sacs and embryos, but were dilated, and not appropriately remodeled or patterned. Raldh2(-/-) endothelial cells exhibited significantly increased expression of phosphohistone 3 and decreased expression of p21 and p27, suggesting that RA is required to control endothelial cell cycle progression during early vascular development. Uncontrolled endothelial cell growth, in Raldh2(-/-) mutants, was associated with decreased endothelial cell maturation, disrupted vascular plexus remodeling and lack of later stages of vessel assembly, including mural cell differentiation. Maternally administrated RA restored endothelial cell cycle control and vascular patterning. Thus, these data indicate that RA plays a crucial role in mammalian vascular development; it is required to control endothelial cell proliferation and vascular remodeling during vasculogenesis. | Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R (2003)
All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta.
Nature structural biology 10, 820-825 [PubMed:12958591]
[show Abstract]
Retinoids regulate gene expression through binding to the nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). In contrast, no ligands for the retinoic acid receptor-related orphan receptors beta and gamma (ROR beta and gamma) have been identified, yet structural data and structure-function analyses indicate that ROR beta is a ligand-regulated nuclear receptor. Using nondenaturing mass spectrometry and scintillation proximity assays we found that all-trans retinoic acid (ATRA) and several retinoids bind to the ROR beta ligand-binding domain (LBD). The crystal structures of the complex with ATRA and with the synthetic analog ALRT 1550 reveal the binding modes of these ligands. ATRA and related retinoids inhibit ROR beta but not ROR alpha transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR beta target genes. Our results identify ROR beta as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action. | Merrill RA, Plum LA, Kaiser ME, Clagett-Dame M (2002)
A mammalian homolog of unc-53 is regulated by all-trans retinoic acid in neuroblastoma cells and embryos.
Proceedings of the National Academy of Sciences of the United States of America 99, 3422-3427 [PubMed:11904404]
[show Abstract]
The vitamin A metabolite, all-trans retinoic acid (atRA), plays an important role in neuronal development, including neurite outgrowth. However, the genes that lie downstream of atRA and its receptors in neuronal cells are largely unknown. By using the human neuroblastoma cell line, SH-SY5Y, we have identified an atRA-responsive gene (RAINB1: retinoic acid inducible in neuroblastoma cells) that is induced within 4 h after exposure of SH-SY5Y cells to atRA. RAINB1 mRNA is highly expressed in the nervous system (10.5- to 11-kb transcript) in both developing embryos and adults. Its expression is perturbed in developing rat embryos exposed to excess or insufficient atRA. RAINB1 is present on chromosome 11 and is spread over 38 exons, resulting in a putative ORF of 2,429 amino acids. The RAINB1 protein shows high similarity to a gene in Caenorhabditis elegans, unc-53, that is required for axonal elongation of mechanosensory neurons, suggesting that these proteins are orthologs. Thus, RAINB1 may represent a critical downstream gene in atRA-mediated neurite outgrowth. | Arnhold T, Elmazar MM, Nau H (2002)
Prevention of vitamin A teratogenesis by phytol or phytanic acid results from reduced metabolism of retinol to the teratogenic metabolite, all-trans-retinoic acid.
Toxicological sciences : an official journal of the Society of Toxicology 66, 274-282 [PubMed:11896294]
[show Abstract]
Previous studies in our laboratory showed a synergistic interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in regard to teratogenic effects produced in mice (M. M. Elmazar et al., 2001, TOXICOL: Appl. Pharmacol. 170, 2-9). In the present study the influence of phytol and phytanic acid (a RXR-selective ligand) on the teratogenicity of retinol and the RAR-selective ligand all-trans-retinoic acid was investigated by coadministration experiments on day 8.25 of gestation in NMRI mice. Phytol and phytanic acid, noneffective when administered alone, did not potentiate the teratogenicity induced by retinol or all-trans-retinoic acid. On the contrary, phytol and phytanic acid greatly reduced retinol-induced teratogenic effects (ear anotia, tail defects, exencephaly). The effect of phytol on all-trans-retinoic acid teratogenesis was limited (only resorptions and tail defects were reduced). Pharmacokinetic studies in nonpregnant animals revealed that phytol coadministration with retinol reduced plasma levels of retinol and retinyl esters, and drastically reduced the levels of the teratogenic retinol metabolite, all-trans-retinoic acid. Phytanic acid also reduced the oxidative metabolism and teratogenic effects of retinol. These results indicate that phytol and phytanic acid did not synergize with retinol and all-trans-retinoic acid in our mouse teratogenesis model. Instead, phytol and phytanic acid effectively blocked the teratogenic effects of retinol by drastically reducing the metabolic production of all-trans-retinoic acid. Phytol and phytanic acid may be useful for the prevention of vitamin A teratogenicity. | Werner EA, DeLuca HF (2001)
Metabolism of a physiological amount of all-trans-retinol in the vitamin A-deficient rat.
Archives of biochemistry and biophysics 393, 262-270 [PubMed:11556813]
[show Abstract]
Because only retinol and not all-trans-retinoic acid (atRA) can satisfy all of the functions of vitamin A, we have investigated the retinol metabolites in tissues of vitamin A-deficient (VAD) rats responding to a radioactive dose of [20-(3)H]all-trans-retinol. As expected, atRA is the major vitamin A metabolite present in the target tissues of VAD rats given a physiological dose (1 microg) of [20-(3)H]all-trans-retinol (atROL). Both atROL and atRA were detected by high-performance liquid chromatographic (HPLC) analysis of the radioactivity extracted from the liver, kidney, small intestine, lung, spleen, bone, skin, or testis of these animals. Novel retinol metabolites were observed in the aqueous extracts from the testis, lung, and skin. However, these metabolites were detected in very small amounts and were not characterized further. Importantly, neither 9-cis-retinoic acid (9cRA), 9-cis-retinol (9cROL), nor 13-cis-retinoic acid (13cRA) was present in detectable amounts. The amounts of atRA varied in each tissue, ranging from 0.29 +/- 0.05 fmol of RA/g of tissue in the femurs to 12.9 +/- 4.3 fmol of RA/g of tissue in the kidneys. The absence of 9cRA in vivo was not due to degradation of this retinoid during the extraction procedure or HPLC analysis of the extracted radioactivity. As atROL completely fulfills all of the physiological roles of vitamin A, and 9cRA is not detected in any of the tissues analyzed, these results suggest that 9cRA may have no physiological relevance in the rat. | Ben-Dor A, Nahum A, Danilenko M, Giat Y, Stahl W, Martin HD, Emmerich T, Noy N, Levy J, Sharoni Y (2001)
Effects of acyclo-retinoic acid and lycopene on activation of the retinoic acid receptor and proliferation of mammary cancer cells.
Archives of biochemistry and biophysics 391, 295-302 [PubMed:11437362]
[show Abstract]
The biochemical mechanisms underlying the inhibitory effects of lycopene, the main tomato carotenoid, on the growth of cancer cells are largely unknown. It has been hypothesized that lycopene derivatives may act as ligands for a nuclear receptor in analogy to retinoic acid, the hormone derived from beta-carotene. The inhibition of human mammary cancer (MCF-7) cell growth and the transactivation of the retinoic acid receptor (RAR) reporter gene by synthetic acyclo-retinoic acid, the open chain analog of retinoic acid, was compared to the effects of lycopene and retinoic acid in the same systems. Acyclo-retinoic acid activated the DR-5 retinoic acid response element with a approximately 100-fold lower potency than retinoic acid. This effect was independent of cotransfection with the RARalpha receptor. Lycopene exhibited only very modest activity in this system. In contrast to the results from the transactivation studies, acyclo-retinoic acid, retinoic acid, and lycopene inhibited cell growth with a similar potency. Preincubation with each of the three compounds slowed down cell cycle progression from G1 to S phase. In summary, acyclo-retinoic acid inhibited cancer cell growth and interacted with RAR. However, it exhibited low affinity for RAR and a correspondingly low efficacy in activating this receptor, indicating that RAR does not mediate the growth inhibitory effect of the compound. In addition, the concentrations of acyclo-retinoic acid and of lycopene required for inducing inhibition of cell growth were similar, suggesting that acyclo-retinoic acid is unlikely to be the active metabolite of lycopene. | DeCicco KL, Youngdahl JD, Ross AC (2001)
All-trans-retinoic acid and polyriboinosinic : polyribocytidylic acid in combination potentiate specific antibody production and cell-mediated immunity.
Immunology 104, 341-348 [PubMed:11722649]
[show Abstract]
Retinoic acid (RA), an active metabolite of vitamin A, may synergize with interferons (IFN) to evoke a heightened immune response, suggesting combination therapy as a promising treatment for various cancers. Recently, we demonstrated a strong synergism between RA and polyriboinosinic : polyribocytidylic acid (PIC), an inducer of IFN, on antibody production in immunocompromised vitamin A-deficient animals. In the present study, we examined whether this combination could potentiate T-cell-dependent antibody production in non-immunocompromised rats. Forty male Lewis rats were treated with 100 microg all-trans-RA, 20 microg PIC, or the combination in either an 11-d study to evaluate antibody production, changes in lymphocyte populations, and cell proliferation, or a 21-hr study to evaluate early changes in lymphocyte populations and gene expression. The combination of RA + PIC significantly potentiated anti-tetanus IgG levels (P < 0.002). Similarly, this combination also increased the numbers of B cells and major histocompatibility complex (MHC) class II+ cells in spleen and lymph nodes, and natural killer (NK) cells in spleen and blood (P < 0.05). RA + PIC-treated rats had significantly higher levels of interleukin (IL)-10, IL-12, and signal transducer and activator of transcription-1 (STAT-1) mRNA (P < 0.05), and STAT-1 protein (P < 0.02). Treatments administered in vivo significantly modulated T-cell proliferation to anti-CD3/phorbol myristyl acetate + IFN-alpha ex vivo. These changes in antibody production, cell distribution, cytokine gene expression, and T-cell proliferation suggest that the combination of RA + PIC stimulates humoral and cell-mediated immunity, and deserves further testing in models of cancer chemoprevention in vivo. | Grosjean S, Devaux Y, Seguin C, Meistelman C, Zannad F, Mertes PM, Kelly RA, Ungureanu-Longrois D (2001)
Retinoic acid attenuates inducible nitric oxide synthase (NOS2) activation in cultured rat cardiac myocytes and microvascular endothelial cells.
Journal of molecular and cellular cardiology 33, 933-945 [PubMed:11343416]
[show Abstract]
S. Grosjean, Y. Devaux, C. Seguin, C. Meistelman, F. Zannad, P.-M. Mertes, R. A. Kelly and D. Ungureanu-Longrois. Retinoic Acid Attenuates Inducible Nitric Oxide Synthase (NOS2) Activation in Cultured Rat Cardiac Myocytes and Microvascular Endothelial Cells. Journal of Molecular and Cellular Cardiology (2001) 33, 933-945. The inducible NO synthase (NOS2) in cardiac tissue contributes to myocardial and coronary inflammation and dysfunction. Several natural (endogenous) hormones such as retinoic acid, the active metabolite of vitamin A, have the ability to attenuate NOS2 activation in inflammatory cells. The aim of this study was to investigate the effect of RA on NOS2 activation in cultured cardiac microvascular endothelial cells (CMEC) and adult rat ventricular myocytes (ARVM). CMEC were stimulated either with a combination of 10 microg/ml lipopolysaccharide (LPS) and 50 IU/ml interferon- gamma (IFN- gamma) or with a combination of 1 ng/ml interleukin-1 beta (IL-1 beta)+IFN- gamma whereas ARVM were stimulated with 1 ng/ml IL-1 beta and 50 IU/ml IFN- gamma in the absence or presence of all-trans retinoic acid (atRA). Activation of the NOS2 pathway was estimated by measurement of mRNA (Northern blot) and protein (Western blot) expression, enzyme activity by conversion of [(3)H]L -arginine to [(3)H]L -citrulline, and nitrite accumulation. NOS2 mRNA half-life was studied in CMEC and ARVM in the presence of actinomycin D. In CMEC and ARVM stimulated with a combination of LPS and/or cytokines, atRA (10(-6), 10(-5)M) significantly (P<0.05) attenuated NOS2 mRNA and protein expression, enzymatic activity and reduced supernatant nitrite concentration. Upon stimulation with LPS/IFN- gamma, atRA significantly decreased NOS2 mRNA half-life. This was not seen after stimulation with IL-1 beta/IFN- gamma. These results document for the first time an effect of RA on NOS2 activation in cardiac cells. They may contribute to the characterization of the immunomodulatory effects of retinoids in myocardial and coronary inflammatory disorders. | Ballock RT, Zhou X, Mink LM, Chen DH, Mita BC (2001)
Both retinoic acid and 1,25(OH)2 vitamin D3 inhibit thyroid hormone-induced terminal differentiaton of growth plate chondrocytes.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society 19, 43-49 [PubMed:11332619]
[show Abstract]
Thyroid hormone has been known for over 50 years to be a potent regulator of skeletal maturation at the growth plate. The receptor for thyroid hormone has been discovered to be a member of the nuclear hormone receptor superfamily. Retinoic acid and 1,25(OH)2 vitamin D3, whose receptors also belong to this nuclear hormone receptor family, have been implicated in the control of chondrocyte proliferation and differentiation at the growth plate. Recent studies demonstrate that the receptors for thyroid hormone, retinoic acid, and vitamin D bind to a similar DNA response element in the promoter region of target genes and may form heterodimers to regulate gene transcription in target cells. These observations led us to hypothesize that the retinoic acid and/or vitamin D signaling pathways may interact with thyroid hormone signaling at the molecular level to modulate growth plate chondrocyte differentiation. Using a chemically defined, serum-free model of growth plate chondrocyte maturation, both all-trans retinoic acid and 1,25(OH)2 vitamin D3 markedly inhibited thyroid hormone-induced terminal differentiation in a dose-dependent manner. In the absence of thyroid hormone, retinoic acid stimulated alkaline phosphatase activity modestly at the highest dose used, however neither retinoic acid nor 1,25(OH)2 vitamin D3 induced expression of type X collagen mRNA. We conclude that retinoic acid and vitamin D are likely to be antagonists of thyroid hormone signaling in the growth plate. | Gampe RT, Montana VG, Lambert MH, Wisely GB, Milburn MV, Xu HE (2000)
Structural basis for autorepression of retinoid X receptor by tetramer formation and the AF-2 helix.
Genes & development 14, 2229-2241 [PubMed:10970886]
[show Abstract]
The 9-cis-retinoic acid receptors (RXRalpha, RXRbeta, and RXRgamma) are nuclear receptors that play key roles in multiple hormone-signaling pathways. Biochemical data indicate that, in the absence of ligand, RXR can exist as an inactive tetramer and that its dissociation, induced by ligand, is important for receptor activation. In this article we report the inactivated tetramer structures of the RXRalpha ligand-binding domain (LBD), either in the absence of or in the presence of a nonactivating ligand. These structures reveal that the RXR LBD tetramer forms a compact, disc-shaped complex, consisting of two symmetric dimers that are packed along helices 3 and 11. In each monomer, the AF-2 helix protrudes away from the core domain and spans into the coactivator binding site in the adjacent monomer of the symmetric dimer. In this configuration, the AF-2 helix physically excludes the binding of coactivators and suggests an autorepression mechanism that is mediated by the AF-2 helix within the tetramer. The RXR-tetramer interface is assembled from amino acids that are conserved across several closely related receptors, including the HNF4s and COUP transcription factors, and may therefore provide a model for understanding structure and regulation of this subfamily of nuclear receptors. | Nonnecke BJ, Horst RL, Hammell DC, Franklin ST (2000)
Effects of supplemental vitamin A on retinoic acid concentrations in the plasma of preruminant calves.
International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition 70, 278-286 [PubMed:11214352]
[show Abstract]
Neonatal calves are fed frequently milk replacers with vitamin A concentrations exceeding those recommended by the National Research Council. The vitamin A metabolite, retinoic acid (RA), affects profoundly cellular differentiation and homeostasis. For this reason, effects of dietary vitamin A on plasma concentrations of RA isomers in milk replacer-fed calves were examined. Male, Holstein calves (n = 24) were fed colostrum within 12 hours after birth and, thereafter, a custom-formulated low vitamin A milk replacer providing 0, 1700 [National Research Council (NRC) daily requirement for young growing calves] (controls), 34,000 (industry standard in the United States) or 68,000 IU of vitamin A daily. Concentrations of retinol and RA isomers in plasma samples collected from birth to 27 days of age were determined by HPLC. Retinol was affected by dietary vitamin A with higher concentrations occurring in calves supplemented with > or = 34,000 IU of vitamin A/day than in control (1700 IU of vitamin daily) and unsupplemented calves. Relative to controls, concentrations of all isomers of RA were higher in calves supplemented with > or = 34,000 of vitamin A daily during the experimental period. The predominant isomer in all calves was 9,13-dicis-RA. In control calves, 9,13-dicis-RA and 9-cis-RA were maximal at 1 to 6 days of age and then decreased progressively. In calves fed > or = 34,000 IU of vitamin A daily, concentrations of these isomers were markedly higher at 6 days of age, relative to controls, and remained elevated for the duration of the study. In all calves, retinol was correlated positively with 9,13-dicis- and 9-cis-RA from 9 to 27 days of age. 9,13-cis-Retinoic acid was correlated positively with 9-cis- and 13-cis-RA from 13 to 27 days of age. It is concluded that supplementing milk replacer-fed calves with vitamin A at levels exceeding current NRC recommendations by > or = 20-fold causes an elevation in plasma concentrations of retinol and retinoic acids. 9,13-dicis- and 9-cis-Retinoic acids were most affected by supplemental vitamin A. Physiologic consequences of increased plasma RA concentrations induced by high dietary levels of vitamin A warrant investigation. | Kobayashi M, Yu RT, Yasuda K, Umesono K (2000)
Cell-type-specific regulation of the retinoic acid receptor mediated by the orphan nuclear receptor TLX.
Molecular and cellular biology 20, 8731-8739 [PubMed:11073974]
[show Abstract]
Malformations in the eye can be caused by either an excess or deficiency of retinoids. An early target gene of the retinoid metabolite, retinoic acid (RA), is that encoding one of its own receptors, the retinoic acid receptor beta (RARbeta). To better understand the mechanisms underlying this autologous regulation, we characterized the chick RARbeta2 promoter. The region surrounding the transcription start site of the avian RARbeta2 promoter is over 90% conserved with the corresponding region in mammals and confers strong RA-dependent transactivation in primary cultured embryonic retina cells. This response is selective for RAR but not retinoid X receptor-specific agonists, demonstrating a principal role for RAR(s) in retina cells. Retina cells exhibit a far higher sensitivity to RA than do fibroblasts or osteoblasts, a property we found likely due to expression of the orphan nuclear receptor TLX. Ectopic expression of TLX in fibroblasts resulted in increased sensitivity to RA induction, an effect that is conserved between chick and mammals. We have identified a cis element, the silencing element relieved by TLX (SET), within the RARbeta2 promoter region which confers TLX- and RA-dependent transactivation. These results indicate an important role for TLX in autologous regulation of the RARbeta gene in the eye. | Malik MA, Blusztajn JK, Greenwood CE (2000)
Nutrients as trophic factors in neurons and the central nervous system: role of retinoic acid.
The Journal of nutritional biochemistry 11, 2-13 [PubMed:15539337]
[show Abstract]
In multicellular organisms, death, survival, proliferation, and differentiation of a given cell depend on signals produced by neighboring and/or distant cells, resulting in the coordinated development and function of the various tissues. In the nervous system, control of cell survival and differentiation is achieved through the action of a distinct group of polypeptides collectively known as neurotrophic factors. Recent findings support the view that trophic factors also are involved in the response of the nervous system to acute injury. By contrast, nutrients are not traditionally viewed as potential trophic factors; however, there is increasing evidence that at least some influence neuronal differentiation. During development the brain is responsive to variations in nutrient supply, and this increased sensitivity or vulnerability of the brain to nutrient supply may reappear during neuronal repair, a period during which a rapid membrane resynthesis and reestablishment of synthetic pathways occur. To further evaluate the potential of specific nutrients to act as pharmacologic agents in the repair of injured neurons, the effects of retinoic acid, an active metabolite of vitamin A, and its role as a trophic factor are discussed. This literature review is intended to provide background information regarding the effect of retinoic acid on the cholinergic phenotype and the differentiation of these neurons and to explain how it may promote neuronal repair and survival following injury. | Lee HY, Sueoka N, Hong WK, Mangelsdorf DJ, Claret FX, Kurie JM (1999)
All-trans-retinoic acid inhibits Jun N-terminal kinase by increasing dual-specificity phosphatase activity.
Molecular and cellular biology 19, 1973-1980 [PubMed:10022884]
[show Abstract]
Jun N-terminal kinases (JNKs) are serine-threonine kinases that play a critical role in the regulation of cell growth and differentiation. We previously observed that JNK activity is suppressed by all-trans-retinoic acid (t-RA), a ligand for retinoic acid nuclear receptors (RARs), in normal human bronchial epithelial cells, which are growth inhibited by t-RA. In this study, we investigated the mechanism by which t-RA inhibits JNK and the possibility that this signaling event is blocked in non-small cell lung cancer (NSCLC) cells. Virtually all NSCLC cell lines are resistant to the growth-inhibitory effects of t-RA, and a subset of them have a transcriptional defect specific to retinoid nuclear receptors. We found that in NSCLC cells expressing functional retinoid receptors, serum-induced JNK phosphorylation and activity were inhibited by t-RA in a bimodal pattern, transiently within 30 min and in a sustained fashion beginning at 12 h. Retinoid receptor transcriptional activation was required for the late, but not the early, suppression of JNK activity. t-RA inhibited serum-induced JNK activity by blocking mitogen-activated protein (MAP) kinase kinase 4-induced signaling events. This effect of t-RA was phosphatase dependent and involved an increase in the expression of the dual-specificity MAP kinase phosphatase 1 (MKP-1). t-RA did not activate MKP-1 expression or inhibit JNK activity in a NSCLC cell line with retinoid receptors that are refractory to ligand-induced transcriptional activation. These findings provide the first evidence that t-RA suppresses JNK activity by inhibiting JNK phosphorylation. Retinoid receptor transcriptional activation was necessary for the sustained inhibition of JNK activity by t-RA, and this signaling event was disrupted in NSCLC cells with retinoid receptors that are refractory to ligand-induced transcriptional activation. | Renaud JP, Rochel N, Ruff M, Vivat V, Chambon P, Gronemeyer H, Moras D (1995)
Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid.
Nature 378, 681-689 [PubMed:7501014]
[show Abstract]
The 2.0-A crystal structure of the ligand-binding domain (LBD) of the human retinoic acid receptor (RAR)-gamma bound to all-trans retinoic acid reveals the ligand-binding interactions and suggests an electrostatic guidance mechanism. The overall fold is similar to that of the human RXR-alpha apo-LBD, except for the carboxy-terminal part which folds back towards the LBD core, contributing to the hydrophobic ligand pocket and 'sealing' its entry site. We propose a 'mouse trap' mechanism whereby a ligand-induced conformational transition repositions the amphipathic alpha-helix of the AF-2 activating domain and forms a transcriptionally active receptor. | Kleywegt GJ, Bergfors T, Senn H, Le Motte P, Gsell B, Shudo K, Jones TA (1994)
Crystal structures of cellular retinoic acid binding proteins I and II in complex with all-trans-retinoic acid and a synthetic retinoid.
Structure (London, England : 1993) 2, 1241-1258 [PubMed:7704533]
[show Abstract]
BackgroundRetinoic acid (RA) plays a fundamental role in diverse cellular activities. Cellular RA binding proteins (CRABPs) are thought to act by modulating the amount of RA available to nuclear RA receptors. CRABPs and cellular retinol-binding proteins (CRBPs) share a unique fold of two orthogonal beta-sheets that encapsulate their ligands. It has been suggested that a trio of residues are the prime determinants defining the high specificity of CRBPs and CRABPs for their physiological ligands.ResultsBovine/murine CRABP I and human CRABP II have been crystallized in complex with their natural ligand, all-trans-RA. Human CRABP II has also been crystallized in complex with a synthetic retinoid, 'compound 19'. Their structures have been determined and refined at resolutions of 2.9 A, 1.8 A and 2.2 A, respectively.ConclusionsThe retinoid-binding site in CRABPs differs significantly from that observed in CRBP. Structural changes in three juxtaposed areas of the protein create a new, displaced binding site for RA. The carboxylate of the ligand interacts with the expected trio of residues (Arg132, Tyr134 and Arg111; CRABP II numbering). The RA ligand is almost flat with the beta-ionone ring showing a significant deviation (-33 degrees) from a cis conformation relative to the isoprene tail. The edge atoms of the beta-ionone ring are accessible to solvent in a suitable orientation for presentation to metabolizing enzymes. The bulkier synthetic retinoid causes small conformational changes in the protein structure. | Zanotti G, Marcello M, Malpeli G, Folli C, Sartori G, Berni R (1994)
Crystallographic studies on complexes between retinoids and plasma retinol-binding protein.
The Journal of biological chemistry 269, 29613-29620 [PubMed:7961949]
[show Abstract]
The three-dimensional structures of complexes between bovine plasma retinol-binding protein (RBP) and three retinol analogs with different end groups (fenretinide, all-trans retinoic acid, and axerophthene) have been determined to 1.8-1.9-A resolution. Their models are very similar to that of the bovine retinol.RBP complex: the root mean square deviations between equivalent alpha-carbons in the two proteins range from 0.17 to 0.24 A. The retinoid molecules fit in the beta-barrel cavity assuming the same conformation of the vitamin, and the substitutions have no consequences on the overall protein structure. While confirming that an intact hydroxyl end group is not an absolute requirement for a correct retinoid binding to RBP, this study has shown the occurrence of conformational changes, although limited, in the rather flexible loop region at the entrance of the beta-barrel upon fenretinide and retinoic acid binding. These changes are suitable for accommodating the end groups of the above retinoids. Instead, no such changes have been revealed in RBP complexed with axerophthene, a retinol analog bearing a hydrogen atom in place of the hydroxyl end group. The protein conformational changes in the above loop region, the steric hindrance of bulky end groups of bound retinoids, and the lack of the retinol hydroxyl group appear to be responsible for the possible reduced affinity of retinoids for RBP relative to retinol and, at the same time, for the abolished or reduced affinity of retinoid.RBP complexes for transthyretin relative to retinol-RBP. |
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