scholarly journals Chemical synthesis of all-trans-[11-3H]retinoyl β-glucuronide and its metabolism in rats in vivo

1989 ◽  
Vol 263 (2) ◽  
pp. 403-409 ◽  
Author(s):  
A B Barua ◽  
J A Olson
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Chemical Synthesis ◽  
Significant Role ◽  
Intraperitoneal Injection ◽  
Single Step ◽  
Polar Metabolites

All-trans-[11-3H]retinoyl beta-glucuronide (RAG) was synthesized in a single step from all-trans-[11-3H]retinoyl fluoride, with a 24% yield. After its intraperitoneal injection into rats, RAG was detected in the blood, liver, intestine and kidney during the following 24 h period. Although the concentration of radiolabelled metabolites decreased with time, RAG predominated at nearly all times in nearly all tissues. Small amounts of retinoic acid (RA) were also universally present, together with unidentified polar metabolites and small amounts of non-polar esters of RA. The major excretion products of RAG in faeces and urine were RA and polar metabolites. Thus RAG, although converted in part to RA in vivo, persists as a major component in blood and tissues for at least 24 h. These observations support the concept that the retinoid beta-glucuronides might serve a physiologically significant role in the function of vitamin A.

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.

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

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 All-trans-retinoyl β-glucuronide: new procedure for chemical synthesis and its metabolism in vitamin A-deficient rats

1996 ◽  
Vol 314 (1) ◽  
pp. 249-252 ◽  
Author(s):  
Bruno BECKER ◽  
Arun B. BARUA ◽  
James A. OLSON
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Chemical Synthesis ◽  
Glucuronic Acid ◽  
Major Metabolite ◽  
Triazole Derivative ◽  
Tetrabutylammonium Salt ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
High Yields

All-trans-retinoyl β-glucuronide (RAG) was chemically synthesized in high yields (up to 79%) by a new procedure involving the reaction of the tetrabutylammonium salt of glucuronic acid with all-trans-retinoic acid (RA) via the imidazole or triazole derivative. When RAG was fed orally to vitamin A-deficient rats, RA was identified as the major metabolite in the serum within hours of administration of RAG. Very little or no RAG was detected in the serum. Thus RAG, which was not appreciably hydrolysed to RA in vitamin A-sufficient rats [Barua and Olson (1987) Biochem J. 263, 403–409], was rapidly converted into RA in vitamin A-deficient rats.

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.

scholarly journals Transition out of HSC Dormancy By a Continuous Upregulation of Metabolism Is Controlled Via Dietary Vitamin A/ Retinoic Acid Signaling

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. LBA-4-LBA-4
Author(s):  
Nina Cabezas-Wallscheid ◽  
Florian Buettner ◽  
Daniel Klimmeck ◽  
Pia Sommerkamp ◽  
Luisa Ladel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Single Cell ◽  
Critical Role ◽  
Dietary Vitamin ◽  
Self Renewal

Abstract Long-term quiescence or dormancy preserves the genomic integrity as well as the long-term self-renewal and functional capacities of hematopoietic stem cells (HSCs) during homeostasis. In response to infections, inflammatory or chemotherapy induced stress, dormant HSCs (dHSCs) become reversibly activated and are critical for the re-establishment of homeostasis. In our previous work, we defined the molecular landscape of HSCs and its immediate progenitors by determining their DNA-methylome, RNA- transcriptome and their proteome (Cabezas-Wallscheid et al., Cell Stem Cell 2014). This revealed the vitamin A/retinoic acid (RA) signaling pathway to be molecularly predominantly enriched in HSCs. However, the functional relevance of dietary vitamin A for maintenance of HSCs remains uncertain. Moreover, the molecular identity of very rare dHSCs as well as the mechanism regulating their maintenance or the transition out and back into dormancy remains unknown. We now show by single-cell RNA-seq analysis of >300 dHSCs and active HSCs (aHSCs) that the molecular transition from the most inactive dHSCs cluster to the most active HSCs can be best described as a continuous stream-like process linked to a steadily increasing metabolic activation. These single cell derived data are not consistent with a binary switch model, but instead suggest that activation/ differentiation downstream of dHSCs occurs in a continuum without the generation of discrete progenitor cell types. During this process,protein synthesis is increased first, followed by the increase of cell cycle related components. We then measured the time to first division starting from either a dHSC or an aHSC for 285 SiCs by single cell live cell imaging. We found that aHSCs showed an average of 29.5±0.7 hours to enter mitosis, while dHSCs needed 40.8±1.3 hours. This pronounced difference (11.3 hours) between two initially non-cycling populations suggests that dHSCs reside in a deeper level of quiescence, namely dormancy, which is also consistent with the molecular data mentioned above. The association of delayed cell cycle entry with the extremely low biosynthetic activity defines the status of dormancy and distinguishes it from quiescence. Furthermore, based on the acquired expression signatures, we describe the first marker-based, non-label retaining mouse model to specify dHSCs (Gpr-EGFP). We show molecularly and functionally that HSC-Gpr-pos cells resemble dHSCs demonstrating that the Gpr-EGFP mouse line can now be used as a simple alternative approach to track dHSCs and thus circumvent time-consuming label-retaining assays. The Gpr-EGFP model now allows to closely follow cell cycle dynamics within the dHSC compartment. Importantly, the mechanism regulating maintenance and the transition out of dormancy remains unknown. Our data focusing specifically on the most primitive HSCs revealed a critical role for vitamin A/RA signaling in controlling the cell cycle plasticity of dHSCs. We now show by in vitro and in vivo experiments, that treatment with the RA agonist all-trans retinoic-acid (ATRA) preserves dHSCs and maintains critical properties of HSCs. This includes maintenance of long-term self-renewal, low proliferation associated with decreased levels of Cdk6, expression of key transcription factors (Hoxb4), reduced protein synthesis and low levels of reactive oxygen species (ROS) as well as low Myc protein levels. Indeed, in response to activation signals, the presence of ATRA prevents up-regulation of c-Myc protein in HSCs and the effects of ATRA or drug induced Myc inhibition result in similar consequences on HSCs. Moreover, ATRA not only represses ROS production, but also prevents HSCs from entering the cell cycle upon diverse stress stimuli (pIC, LPS, 5-FU) in vivo. Most of the studies on vitamin A deficit-associated immunodeficiency are dedicated to the impaired function of lymphocytes. Thus, we analyzed the consequences of a vitamin A deficient diet for dormant HSCs. Strikingly, we found that HSCs are progressively lost over time and dHSCs did not recover after pIC-mediated activation in the absence of vitamin A. Collectively, these data uncover a critical role of vitamin A/RA signaling for the re-establishment of the dormant HSC population after stress-mediated activation. Together, our results highlight a so far unrecognized impact of dietary vitamin A on the regulation of cell cycle mediated stem cell plasticity. Disclosures No relevant conflicts of interest to declare.

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)

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