The vitamin A analogues: 13-cis retinoic acid, 9-cis retinoic acid, and Ro 13-6307 inhibit neuroblastoma tumour growth in vivo

2001 ◽  
Vol 36 (1) ◽  
pp. 127-131 ◽  
Author(s):  
Frida Ponthan ◽  
Per Borgstr�m ◽  
Moustapha Hassan ◽  
Erik Wassberg ◽  
Christopher P.F. Redfern ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Tumour Growth

scholarly journals Efficiency of a few retinoids and carotenoids in vivo in controlling benzo[a]pyrene-induced forestomach tumour in female Swiss mice

2005 ◽  
Vol 94 (4) ◽  
pp. 540-543 ◽  
Author(s):  
Umesh C. Goswami ◽  
Namita Sharma
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Tumour Growth ◽  
Control Group ◽  
Daily Consumption ◽  
Tumour Incidence ◽  
Swiss Mice ◽  
Animal Growth ◽  
Β Carotene

The anticarcinogenic effect of vitamin A2 (dehydroretinol and 3-hydroxyretinol) compounds was studied and compared with that of vitamin A1 (retinoic acid, retinol and retinal) and carotenoids (lutein and β-carotene) in the benzo[a]pyrene (B(a)P)-induced forestomach tumour model of female Swiss mice in vivo. Tumour growth and gross tumour incidence observed after the administration of B(a)P (eight doses of 1 mg, twice weekly for 4 weeks) and retinoids/carotenoids (2·5 and 4·7 μm per animal per d, 2 weeks before, during and 2 weeks after B(a)P) showed that the groups supplemented with lutein and 3-hydroxyretinol produced the best results in inhibiting tumour growth and had low tumour incidence compared with the control group given B(a)P only (P<0·05). Weights recorded after the different treatments showed that the β-carotene-supplemented group exhibited maximum weight gain, followed by retinal, retinol, retinoic acid, lutein, dehydroretinol and 3-hydroxyretinol. These results indicate that the anticarcinogenicity of the compounds is not related to the vitamin A biopotencies. Vitamin A2 compounds having half the biopotency of the vitamin A1 compounds were seen to be anticarcinogenic. Again, among the carotenoids, lutein, having 50 % less biopotency, showed more significant results than β-carotene. Thus it is imperative to conclude that the low animal growth achieved with these compounds has a correlation with the highest suppression of tumour occurrence in the present experiment. Therefore, the daily consumption of foods having high content of lutein and vitamin A2 should be given due importance and weight in further studies.

Complex regulation of TGF beta expression by retinoic acid in the vitamin A-deficient rat

Development ◽  
1991 ◽  
Vol 111 (4) ◽  
pp. 1081-1086 ◽  
Author(s):  
A.B. Glick ◽  
B.K. McCune ◽  
N. Abdulkarem ◽  
K.C. Flanders ◽  
J.A. Lumadue ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Vitamin A Deficiency ◽  
Alveolar Epithelium ◽  
Tgf Beta ◽  
Basal Expression ◽  
Beta 2 ◽  
Complex Regulation ◽  
First Time

We report the results of a histochemical study, using polyclonal antipeptide antibodies to the different TGF beta isoforms, which demonstrates that retinoic acid regulates the expression of TGF beta 2 in the vitamin A-deficient rat. Basal expression of TGF beta 2 diminished under conditions of vitamin A deficiency. Treatment with retinoic acid caused a rapid and transient induction of TGF beta 2 and TGF beta 3 in the epidermis, tracheobronchial and alveolar epithelium, and intestinal mucosa. Induction of TGF beta 1 expression was also observed in the epidermis. In contrast to these epithelia, expression of the three TGF beta isoforms increased in vaginal epithelium during vitamin A deficiency, and decreased following systemic administration of retinoic acid. Our results show for the first time the widespread regulation of TGF beta expression by retinoic acid in vivo, and suggest a possible mechanism by which retinoics regulate the functions of both normal and pre-neoplastic epithelia.

Vitamin A alters the internal viscosity of fragments of limb-bud mesenchyme

Development ◽  
1980 ◽  
Vol 59 (1) ◽  
pp. 325-339
Author(s):  
T. E. Kwasigroch ◽  
D. M. Kochhar
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Mesenchymal Cells ◽  
Limb Bud ◽  
Mouse Limb ◽  
Vitamin A Acid ◽  
Internal Viscosity ◽  
Fusion Experiments

Two techniques were used to examine the effect of vitamin A compounds (vitamin A acid = retinoic acid and vitamin A acetate) upon the relative strengths of adhesion among mouse limb-bud mesenchymal cells. Treatment with retinoic acid in vivo and with vitamin A acetate in vitro reduced the rate at which the fragments of mesenchyme rounded-up when cultured on a non-adhesive substratum, but these compounds did not alter the behavior of tissues tested in fragment-fusion experiments. These conflicting results indicate that the two tests measure different activities of cells and suggest that treatment with vitamin A alters the property(ies) of cells which regulate the internal viscosity of tissues.

Hepatic lecithin: Retinol acyltransferase activity is induced in vivo by retinoic acid, but not by triiodothyronine, in vitamin A-deficient, hypothyroid rats

1997 ◽  
Vol 8 (8) ◽  
pp. 456-460 ◽  
Author(s):  
A.Catharine Ross ◽  
Diana T. Foulke ◽  
Tomokazu Matsuura ◽  
Maria Tresini ◽  
Joseph J. Breen ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Acyltransferase Activity

scholarly journals Vitamin A5/X, a new food to lipid hormone concept for a nutritional ligand to control RXR-mediated signaling

2020 ◽  
Author(s):  
Wojciech Krezel ◽  
Aurea Rivas ◽  
Monika Szklenar ◽  
Marion Ciancia ◽  
Rosana Alvarez ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Retinoic Acid Receptors ◽  
Organic Chemical ◽  
New Class ◽  
Human Food Chain ◽  
Mouse Study ◽  
Β Carotene

Abstract Background: Vitamin A is a family of derivatives synthesized from carotenoids acquired from the diet and can be converted in animals to bioactive forms essential for life. The vitamin A1 (all-trans-retinol / ATROL) and provitamin A1 (all-trans-β,β-carotene / ATBC) are precursors of all-trans-retinoic acid acting as a ligand for the retinoic acid receptors. The contribution of ATROL and ATBC to formation of 9-cis-13,14-dihydroretinoic acid (9CDHRA), the only endogenous retinoid acting as retinoid X receptor ligand remains unknown. Methods: Novel and well know retinoids and carotenoids were synthesized via organic chemical synthesis. Further, novel and well know retinoids / carotenoids were administered to in vitro oligodendrocyte cell culture and to in vivo oral supplemented mice with following HPLC-MS / UV-Vis based metabolomic evaluation of these administered retinoids / carotenoids. In addition, working memory analyses were performed in a mouse study. Results: In this study, we show that ATROL and ATBC are at best only weak and non-selective precursors of 9CDHRA. Instead, we identify 9-cis-13,14-dihydroretinol (9CDHROL) and 9-cis-13,14-dihydro-β,β-carotene (9CDHBC) as novel direct nutritional precursors of 9CDHRA, which are present endogenously in humans and the human food chain matrix. We also propose that the endogenous carotenoid 9-cis-β,β-carotene (9CBC) can also act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA.Conclusion: In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes as a new class of vitamin or a new independent member of the vitamin A family, named “Vitamin A5/X”.

Vitamin A deficiency in mice causes a systemic expansion of myeloid cells

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3349-3356 ◽  
Author(s):  
Takeshi Kuwata ◽  
I-Ming Wang ◽  
Tomohiko Tamura ◽  
Roshini M. Ponnamperuma ◽  
Rachel Levine ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Cell Population ◽  
Vitamin A Deficiency ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Direct Result ◽  
Essentially Normal ◽  
Deficient Mice

Abstract To examine the role of retinoids in hematopoietic cell growth in vivo, we studied female SENCAR mice made vitamin A deficient by dietary restriction. Deficient mice exhibited a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. The abnormal expansion of myeloid cells was detected from an early stage of vitamin A deficiency and contrasted with essentially normal profiles of T and B lymphocytes. This abnormality was reversed on addition of retinoic acid to the vitamin A–deficient diet, indicating that the myeloid cell expansion is a direct result of retinoic acid deficiency. TUNEL analysis indicated that spontaneous apoptosis, a normal process in the life cycle of myeloid cells, was impaired in vitamin A–deficient mice, which may play a role in the increased myeloid cell population. Quantitative reverse transcriptase-polymerase chain reaction analysis of purified granulocytes showed that expression of not only RAR, but RXRs, 2 nuclear receptors that mediate biologic activities of retinoids, was significantly reduced in cells of deficient mice. This work shows that retinoids critically control the homeostasis of myeloid cell population in vivo and suggests that deficiency in this signaling pathway may contribute to various myeloproliferative disorders.

Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants

Development ◽  
1994 ◽  
Vol 120 (10) ◽  
pp. 2723-2748 ◽  
Author(s):  
D. Lohnes ◽  
M. Mark ◽  
C. Mendelsohn ◽  
P. Dolle ◽  
A. Dierich ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Congenital Malformations ◽  
Double Mutant ◽  
Congenital Abnormalities ◽  
Retinoic Acid Receptor ◽  
Retinoic Acid Receptors ◽  
Acid Receptor ◽  
Null Mutants

Numerous congenital malformations have been observed in fetuses of vitamin A-deficient (VAD) dams [Wilson, J. G., Roth, C. B., Warkany, J., (1953), Am. J. Anat. 92, 189–217]. Previous studies of retinoic acid receptor (RAR) mutant mice have not revealed any of these malformations [Li, E., Sucov, H. M., Lee, K.-F., Evans, R. M., Jaenisch, R. (1993) Proc. Natl. Acad. Sci. USA 90, 1590–1594; Lohnes, D., Kastner, P., Dierich, A., Mark, M., LeMeur, M., Chambon, P. (1993) Cell 73, 643–658; Lufkin, T., Lohnes, D., Mark, M., Dierich, A., Gorry, P., Gaub, M. P., Lemeur, M., Chambon, P. (1993) Proc. Natl. Acad. Sci. USA 90, 7225–7229; Mendelsohn, C., Mark, M., Dolle, P., Dierich, A., Gaub, M.P., Krust, A., Lampron, C., Chambon, P. (1994a) Dev. Biol. in press], suggesting either that there is a considerable functional redundancy among members of the RAR family during ontogenesis or that the RARs are not essential transducers of the retinoid signal in vivo. In order to discriminate between these possibilities, we have generated a series of RAR compound null mutants. These RAR double mutants invariably died either in utero or shortly after birth and presented a number of congenital abnormalities, which are reported in this and in the accompanying study. We describe here multiple eye abnormalities which are found in various RAR double mutant fetuses and are similar to those previously seen in VAD fetuses. Interestingly, we found further abnormalities not previously reported in VAD fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathways of Retinoid Synthesis in Mouse Bone Marrow-Derived Macrophages and Hematopoietic Progenitors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1009-1009
Author(s):  
Haixia Niu ◽  
Gayla Hadwiger ◽  
Hideji Fujiwara ◽  
John S. Welch
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Real Time Pcr ◽  
Hematopoietic Cells ◽  
Dominant Negative ◽  
Gfp Reporter ◽  
Enzymatic Pathways

Abstract Introduction: Retinoid receptors are nuclear hormone receptors which are dynamically regulated during terminal myeloid maturation. Retinoic acid receptor α (RARA) is the target of at least ten fusion proteins that lead to acute promyelocytic leukemia (APL). All trans-retinoic acid (ATRA) has been thought to be the principle natural ligand for RARs and it has been used for the treatment of patients with APL. However, the enzymatic pathways that regulate natural retinoids metabolism in hematopoietic cells have not been well defined. ATRA is synthesized from vitamin A through two sequential steps. Vitamin A is oxidized by an alcohol dehydrogenase to yield retinal, which is then irreversibly oxidized by an aldehyde dehydrogenase (ALDH) to generate retinoic acid (RA). At least 19 different human ALDHs have been identified. Among them, ALDH1A1, ALDH1A2 and ALDH1A3 have been shown to oxidize all trans-retinal to ATRA with high affinity, which can be inhibited by diethylaminobenzaldehyde (DEAB). Whether other ALDHs participate in RA metabolism is unknown. Our study identified two distinct retinoid metabolism pathways that are active in bone marrow (BM) progenitors and in macrophages (Mφ). Methods: Gal4-UAS reporter system was used to detect natural RARA ligands in mouse primary hematopoietic cells. We transduced UAS-GFP mouse BM cells with retrovirus that expresses a fusion protein containing the DNA binding domain of Gal4 (which recognizes the UAS promoter) and the ligand binding domain of RARA. An IRES mCherry cassette was included for normalization purposes. Transduced cells were cultured in vitro, or transplanted into lethally irradiated recipient mice. Cells with intracellular RARA ligands activate GFP expression. GFP and mCherry expression were evaluated by flow cytometry. Real-time PCR and Affymetrix array were used to quantify ALDH expression. We identified RARA ligands by mass spectrometry (MS). Results: In vitro, we found that both mouse BM Kit+ cells (Kit+ progenitors) and BM-derived macrophages (BMMφ) could synthesize active RARA ligands via different pathways, but only when the cell culture media was supplemented with vitamin A. Kit+ progenitors utilize DEAB-sensitive ALDH pathways, whereas BMMφ use DEAB-insensitive pathways. By real-time PCR we found Kit+ progenitors have high expression of Aldh1a1, Aldh1a2 and Aldh1a3, whereas BMMφ have no detectable expression of these enzymes. We compared gene expression in Kit+ progenitors and BMMφ by Affymetrix profiling and found that Aldh3b1 was overexpressed in BMMφ. Ectopic expression of Aldh3b1 in 293T cells resulted activation of the same GFP reporter, which could be abrogated by two different antagonist, Ro41-5253 and BMS493, suggesting that Aldh3b1 generated an RARA specific ligand, which we subsequently identified as ATRA via MS. Reciprocally, we found that siRNA knock down of Aldh3b1 in BMMφ reduced the transactivation of the RARA-dependent GFP reporter. The X-RARA fusions have been proposed to act via dominant-negative mechanisms, decreasing retinoid-dependent transcription and myeloid maturation. Surprisingly, in vivo, only rare GFPdim cells were observed in BM cells and no GFP positive cells in peritoneal Mφ of UAS-GFP/Gal4-RARA transplant mice. As positive control, we treated mice with ATRA and observed a dose-dependent GFP increase in both cell types, suggesting that the in vivo reporter can respond to ATRA, but ATRA is not synthesized during adult hematopoiesis, and that dominant-negative inhibition of ATRA-dependent transcription may not be the predominant pathogenic effect of the X-RARA fusion oncoproteins. Conclusion: We have found that at least two distinct enzymatic pathways may be utilized in primary hematopoietic cells to synthesize active RARA ligands from vitamin A. Mouse BM Kit+ progenitors predominantly employ a set of DEAB-sensitive enzymes (Aldh1a1, Aldh1a2 and Aldh1a3), whereas Mφ utilize DEAB-insensitive pathways. We identified Aldh3b1 as a likely candidate and shown that it is capable of ATRA synthesis in vitro. Although these enzymes are expressed in primary BM cells, we found that this does not result in active intracellular RARA ligands in monocytes or Mφ in vivo, suggesting that the rate-limiting step in retinoid synthesis in vivo is likely to involve additional enzymes required for intracellular transport of protein-bound, serum-available vitamin A. Disclosures No relevant conflicts of interest to declare.

Vitamin A deficiency in mice causes a systemic expansion of myeloid cells

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3349-3356 ◽  
Author(s):  
Takeshi Kuwata ◽  
I-Ming Wang ◽  
Tomohiko Tamura ◽  
Roshini M. Ponnamperuma ◽  
Rachel Levine ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Cell Population ◽  
Vitamin A Deficiency ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Direct Result ◽  
Essentially Normal ◽  
Deficient Mice

To examine the role of retinoids in hematopoietic cell growth in vivo, we studied female SENCAR mice made vitamin A deficient by dietary restriction. Deficient mice exhibited a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. The abnormal expansion of myeloid cells was detected from an early stage of vitamin A deficiency and contrasted with essentially normal profiles of T and B lymphocytes. This abnormality was reversed on addition of retinoic acid to the vitamin A–deficient diet, indicating that the myeloid cell expansion is a direct result of retinoic acid deficiency. TUNEL analysis indicated that spontaneous apoptosis, a normal process in the life cycle of myeloid cells, was impaired in vitamin A–deficient mice, which may play a role in the increased myeloid cell population. Quantitative reverse transcriptase-polymerase chain reaction analysis of purified granulocytes showed that expression of not only RAR, but RXRs, 2 nuclear receptors that mediate biologic activities of retinoids, was significantly reduced in cells of deficient mice. This work shows that retinoids critically control the homeostasis of myeloid cell population in vivo and suggests that deficiency in this signaling pathway may contribute to various myeloproliferative disorders.

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