Developmental role of endogenous retinoids in the determination of morphallactic field in budding tunicates

We have extracted retinoids from the budding tunicate Polyandrocarpa misakiensis and, using HPLC, identified some major peaks as cis-retinal, all-trans-retinal and all-trans-retinoic acid, of which cis-retinal was most abundant (~2 micromolar). In developing buds, the amount of cis-retinal was about one-fifth that of the adult animals. In those buds, aldehyde dehydrogenase, which could metabolize retinal in vitro, was expressed in epithelial cells and then in mesenchymal cells at the proximal extremity, that is, the future developmental field of the bud. Exogenous retinoic acid comparable to the endogenous level could induce an additional field at the distal end of the bud, resulting in a double monster. The induction always accompanied an ectopic expression of aldehyde dehydrogenase. The results of this work suggest that retinoic acid or related molecule(s) act as an endogenous trigger of morphallactic development of Polyandrocarpa buds.

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All-trans Retinoic Acid Counteracts Diarrhea and Inhibition of Downregulated in Adenoma Expression in Gut Inflammation

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz249 ◽

2019 ◽

Vol 26 (4) ◽

pp. 534-545 ◽

Cited By ~ 1

Author(s):

Shubha Priyamvada ◽

Arivarasu N Anbazhagan ◽

Anoop Kumar ◽

Ishita Chatterjee ◽

Alip Borthakur ◽

...

Keyword(s):

Retinoic Acid ◽

Intestinal Epithelial ◽

Gut Inflammation ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Function Expression ◽

Ifn Γ

Abstract Background Intestinal epithelial apical membrane Cl-/HCO3- exchanger DRA (downregulated in adenoma, SLC26A3) has emerged as an important therapeutic target for diarrhea, emphasizing the potential therapeutic role of agents that upregulate DRA. All-trans retinoic acid (ATRA), a key vitamin A metabolite, was earlier shown by us to stimulate DRA expression in intestinal epithelial cells. However, its role in modulating DRA in gut inflammation has not been investigated. Aims Our aim was to analyze the efficacy of ATRA in counteracting inflammation-induced decrease in DRA in vitro and in vivo. Methods Interferon-γ (IFN-γ)-treated Caco-2 cells and dextran sulfate sodium (DSS)-treated C57BL/6J mice served as in vitro and in vivo models of gut inflammation, respectively. The effect of ATRA on IFN-γ-mediated inhibition of DRA function, expression, and promoter activity were elucidated. In the DSS colitis model, diarrheal phenotype, cytokine response, in vivo imaging, myeloperoxidase activity, and DRA expression were measured in the distal colon. Results All-trans retinoic acid (10 μM, 24 h) abrogated IFN-γ (30 ng/mL, 24 h)-induced decrease in DRA function, expression, and promoter activity in Caco-2 cells. All-trans retinoic acid altered IFN-γ signaling via blocking IFN-γ-induced tyrosine phosphorylation of STAT-1. All-trans retinoic acid cotreatment (1 mg/kg BW, i.p. daily) of DSS-treated mice (3% in drinking water for 7 days) alleviated colitis-associated weight loss, diarrheal phenotype, and induction of IL-1β and CXCL1 and a decrease in DRA mRNA and protein levels in the colon. Conclusion Our data showing upregulation of DRA under normal and inflammatory conditions by ATRA demonstrate a novel role of this micronutrient in alleviating IBD-associated diarrhea.

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Defective lens fiber differentiation and pancreatic tumorigenesis caused by ectopic expression of the cellular retinoic acid-binding protein I

Development ◽

10.1242/dev.119.2.363 ◽

1993 ◽

Vol 119 (2) ◽

pp. 363-375

Author(s):

A.V. Perez-Castro ◽

V.T. Tran ◽

M.C. Nguyen-Huu

Keyword(s):

Retinoic Acid ◽

Binding Proteins ◽

Binding Protein ◽

Ectopic Expression ◽

Retinoic Acid Receptors ◽

Acid Binding Protein ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Retinoic Acid Binding Proteins

All-trans retinoic acid, a metabolite of retinol, is a possible morphogen in vertebrate development. Two classes of cellular proteins, which specifically bind all-trans retinoic acid, are thought to mediate its action: the nuclear retinoic acid receptors (RAR alpha, beta, gamma), and the cytoplasmic binding proteins known as cellular retinoic acid-binding proteins I and II (CRABP I and II). The function of the retinoic acid receptors is to regulate gene transcription by binding to DNA in conjunction with the nuclear retinoid X receptors (RXR alpha, beta, gamma), which in turn have 9-cis retinoic acid as a ligand. Several lines of evidence suggest that the role of the cellular retinoic acid-binding proteins is to control the concentration of free retinoic acid reaching the nucleus in a given cell. Here, we have addressed the role of the cellular retinoic acid-binding protein I in development by ectopically expressing it in the mouse lens, under the control of the alpha A-crystallin promoter. We show that this ectopic expression interferes with the development of the lens and with the differentiation of the secondary lens fiber cells, causing cataract formation. These results suggest that correct regulation of intracellular retinoic acid concentration is required for normal eye development. In addition, the generated transgenic mice also present expression of the transgene in the pancreas and develop pancreatic carcinomas, suggesting that overexpression of the cellular retinoic acid-binding protein is the cause of the tumors. These results taken together provide evidence for a role of the cellular retinoic acid-binding protein in development and cell differentiation. The relevance of these findings to the possible role of the cellular retinoic acid-binding proteins in the transduction of the retinoic acid signal is discussed.

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Pim2 cooperates with PML-RARα to induce acute myeloid leukemia in a bone marrow transplantation model

Blood ◽

10.1182/blood-2009-03-210070 ◽

2010 ◽

Vol 115 (22) ◽

pp. 4507-4516 ◽

Cited By ~ 8

Author(s):

Shuchi Agrawal-Singh ◽

Steffen Koschmieder ◽

Sandra Gelsing ◽

Carol Stocking ◽

Martin Stehling ◽

...

Keyword(s):

Retinoic Acid ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Immature Myeloid Cells ◽

Retinoic Acid Receptor Α ◽

Transplantation Model

Abstract Although the potential role of Pim2 as a cooperative oncogene has been well described in lymphoma, its role in leukemia has remained largely unexplored. Here we show that high expression of Pim2 is observed in patients with acute promyelocytic leukemia (APL). To further characterize the cooperative role of Pim2 with promyelocytic leukemia/retinoic acid receptor α (PML/RARα), we used a well-established PML-RARα (PRα) mouse model. Pim2 coexpression in PRα-positive hematopoietic progenitor cells (HPCs) induces leukemia in recipient mice after a short latency. Pim2-PRα cells were able to repopulate mice in serial transplantations and to induce disease in all recipients. Neither Pim2 nor PRα alone was sufficient to induce leukemia upon transplantation in this model. The disease induced by Pim2 overexpression in PRα cells contained a slightly higher fraction of immature myeloid cells, compared with the previously described APL disease induced by PRα. However, it also clearly resembled an APL-like phenotype and showed signs of differentiation upon all-trans retinoic acid (ATRA) treatment in vitro. These results support the hypothesis that Pim2, which is also a known target of Flt3-ITD (another gene that cooperates with PML-RARα), cooperates with PRα to induce APL-like disease.

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Sustained response to recombinant human erythropoietin and intermittent all-trans retinoic acid in patients with myelodysplastic syndromes

Blood ◽

10.1182/blood.v99.5.1578 ◽

2002 ◽

Vol 99 (5) ◽

pp. 1578-1584 ◽

Cited By ~ 39

Author(s):

Roberto Stasi ◽

Maurizio Brunetti ◽

Edmondo Terzoli ◽

Sergio Amadori

Keyword(s):

Retinoic Acid ◽

Intermediate Risk ◽

Erythroid Response ◽

Human Erythropoietin ◽

Continuation Therapy ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Clinically Significant

In vitro studies suggest that all-trans retinoic acid (ATRA) synergizes with erythropoietin (EPO) for the stimulation of hematopoiesis in patients with myelodysplastic syndrome (MDS). A clinical trial was performed to evaluate whether a combination of these agents was effective in relieving the cytopenias associated with MDS. Twenty-seven patients with low- or intermediate-risk MDS were enrolled in a 12-week study. ATRA was administered orally at the dose of 80 mg/m2 per day in 2 divided doses for 7 consecutive days every other week. Recombinant human EPO was given subcutaneously 3 times a week. The EPO dose was initiated at 150 U/kg and was increased to 300 U/kg if after 6 weeks there was no or there was suboptimal erythroid response. Patients who responded to therapy were continued on ATRA and EPO at the same doses for 6 additional months (extension phase). Further treatment was given to patients with a continued response. Clinically significant erythroid responses with increases of hemoglobin levels of at least 1 g/dL or reduction of transfusion needs were seen in 13 (48%) patients, with 4 showing improved responses after dose escalation of EPO. Ten (37%) patients displayed continued responses during 6 months of extended treatment, and 7 (26%) are still responsive after a follow-up period of 13 months. Neutrophil responses were observed in 5 of 12 patients with neutropenia, and platelet responses were observed in 6 of 9 patients with thrombocytopenia. Three patients displayed trilineage responses that were sustained during continuation therapy. Side effects were observed in all patients but were of mild entity and did not require discontinuation of therapy. It is concluded that the combination ATRA + EPO is an effective and well-tolerated treatment for patients with low- and intermediate-risk MDS. The optimal ATRA and EPO schedule and the role of maintenance treatment remain to be determined and warrant further investigation.

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High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling

Cell Death and Disease ◽

10.1038/s41419-018-0903-4 ◽

2018 ◽

Vol 9 (9) ◽

Cited By ~ 32

Author(s):

Donghyeok Kim ◽

Bo-hyun Choi ◽

In-geun Ryoo ◽

Mi-Kyoung Kwak

Keyword(s):

Ovarian Cancer ◽

Stem Cell ◽

Retinoic Acid ◽

Cancer Stem Cell ◽

Cancer Cells ◽

Aldehyde Dehydrogenase ◽

Ovarian Cancer Cells ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Response of Aldehyde Dehydrogenase (ALDH) after Cisplatin and All-Trans Retinoic Acid (ATRA) treatment of Spheroid-derived Cells (SDCs) from cervical cancer cell lines

10.1055/s-0038-1671355 ◽

2018 ◽

Cited By ~ 1

Author(s):

J Xu ◽

J Sehouli ◽

AM Kaufmann

Keyword(s):

Cervical Cancer ◽

Retinoic Acid ◽

Cell Lines ◽

Cancer Cell ◽

Aldehyde Dehydrogenase ◽

Cancer Cell Lines ◽

Cervical Cancer Cell ◽

Atra Treatment ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Enhanced Oral Absorption of All-trans Retinoic Acid upon Encapsulation in Solid Lipid Nanoparticles

Pharmaceutical Nanotechnology ◽

10.2174/2211738508999201027220825 ◽

2020 ◽

Vol 8 (6) ◽

pp. 495-510

Author(s):

Manoj Kumar ◽

Garima Sharma ◽

Dinesh Singla ◽

Sukhjeet Singh ◽

Vandita Kakkar ◽

...

Keyword(s):

Retinoic Acid ◽

Side Effects ◽

Solid Lipid Nanoparticles ◽

In Vitro Release ◽

Lipid Nanoparticles ◽

Solid Lipid ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Vitro Release

Background:: All-trans retinoic acid (ATRA) is widely employed in the treatment of various proliferative and inflammatory diseases. However, its therapeutic efficacy is imperiled due to its poor solubility and stability. Latter was surmounted by its incorporation into a solid matrix of lipidic nanoparticles (SLNs). Methods:: ATRA loaded SLNs (ATRA-SLNs) were prepared using a novel microemulsification technique (USPTO 9907758) and an optimal composition and were characterized in terms of morphology, differential scanning calorimetry (DSC), and powder X-ray diffraction studies (PXRD). In vitro release, oral plasma pharmacokinetics (in rats) and stability studies were also done. Results:: Rod-shaped ATRA-SLNs could successfully incorporate 3.7 mg/mL of ATRA, increasing its solubility (from 4.7 μg/mL) by 787 times, having an average particle size of 131.30 ± 5.0 nm and polydispersibility of 0.283. PXRD, DSC, and FTIR studies confirmed the formation of SLNs. Assay/total drug content and entrapment efficiency of ATRA-SLNs was 92.50 ± 2.10% and 84.60 ± 3.20% (n=6), respectively, which was maintained even on storage for one year under refrigerated conditions as an aqueous dispersion. In vitro release in 0.01 M phosphate buffer (pH 7.4) with 3% tween 80 was extended 12 times from 2h for free ATRA to 24 h for ATRA-SLNs depicting Korsmeyer Peppas release. Oral administration in rats showed 35.03 times enhanced bioavailability for ATRA-SLNs. Conclusion:: Present work reports preparation and evaluation of bioenhanced ATRA-SLNs containing a high concentration of ATRA (>15 times than that reported by others). Latter is attributed to the novel preparation process and intelligent selection of components. Lay Summary: All-trans retinoic acid (ATRA) shows an array of pharmacological activities but its efficacy is limited due to poor solubility, stability and side effects. In present study its solubility and efficacy is improved by 787 and 35.5 times, respectively upon incorporation into solid lipid nanoparticles (ATRA-SLNs). Latter extended its release by 12 times and provided stability for at least a year under refrigeration. A controlled and sustained release will reduce dose related side effects. ATRA-SLNs reported presently can thus be used in treatment /prophylaxis of disorders like cancers, tuberculosis, age related macular degeneration and acne and as an immune-booster.

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All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission

Cells ◽

10.3390/cells10051202 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1202

Author(s):

Bojjibabu Chidipi ◽

Syed Islamuddin Shah ◽

Michelle Reiser ◽

Manasa Kanithi ◽

Amanda Garces ◽

...

Keyword(s):

Retinoic Acid ◽

Mitochondrial Fission ◽

Normal Function ◽

Mitochondrial Network ◽

Protein Levels ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Area And Perimeter

In the heart, mitochondrial homeostasis is critical for sustaining normal function and optimal responses to metabolic and environmental stressors. Mitochondrial fusion and fission are thought to be necessary for maintaining a robust population of mitochondria, and disruptions in mitochondrial fission and/or fusion can lead to cellular dysfunction. The dynamin-related protein (DRP1) is an important mediator of mitochondrial fission. In this study, we investigated the direct effects of the micronutrient retinoid all-trans retinoic acid (ATRA) on the mitochondrial structure in vivo and in vitro using Western blot, confocal, and transmission electron microscopy, as well as mitochondrial network quantification using stochastic modeling. Our results showed that ATRA increases DRP1 protein levels, increases the localization of DRP1 to mitochondria in isolated mitochondrial preparations. Our results also suggested that ATRA remodels the mitochondrial ultrastructure where the mitochondrial area and perimeter were decreased and the circularity was increased. Microscopically, mitochondrial network remodeling is driven by an increased rate of fission over fusion events in ATRA, as suggested by our numerical modeling. In conclusion, ATRA results in a pharmacologically mediated increase in the DRP1 protein. It also results in the modulation of cardiac mitochondria by promoting fission events, altering the mitochondrial network, and modifying the ultrastructure of mitochondria in the heart.

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