scholarly journals Vitamin A5/X, a New Food to Lipid Hormone Concept for a Nutritional Ligand to Control RXR-Mediated Signaling

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 925
Author(s):  
Wojciech Krężel ◽  
Aurea Rivas ◽  
Monika Szklenar ◽  
Marion Ciancia ◽  
Rosana Alvarez ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
High Performance ◽  
New Class ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Human Food Chain ◽  
Β Carotene

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. 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 (RXR) ligand, remains unknown. To address this point novel and already known retinoids and carotenoids were stereoselectively synthesized and administered in vitro to oligodendrocyte cell culture and supplemented in vivo (orally) to mice with a following high-performance liquid chromatography-mass spectrometry (HPLC-MS)/UV-Vis based metabolic profiling. 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. Furthermore, 9CDHROL displayed RXR-dependent promnemonic activity in working memory test similar to that reported for 9CDHRA. We also propose that the endogenous carotenoid 9-cis-β,β-carotene (9CBC) can act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA. In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes a new class of vitamin or a new independent member of the vitamin A family, named “Vitamin A5/X”.

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”.

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

Cells ◽  
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.

scholarly journals Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo

Oncotarget ◽  
2016 ◽  
Vol 7 (29) ◽  
pp. 46028-46041 ◽  
Author(s):  
Farzaneh Atashrazm ◽  
Ray M. Lowenthal ◽  
Joanne L. Dickinson ◽  
Adele F. Holloway ◽  
Gregory M. Woods
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Therapeutic Potential ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy

2015 ◽  
Vol 26 (7) ◽  
pp. 763-773
Author(s):  
Muhammad N. Aslam ◽  
Shannon McClintock ◽  
Shazli P. Khan ◽  
Patricia Perone ◽  
Ronald Allen ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Cell Growth ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Acid Therapy ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Myeloid Leukemia Cell

scholarly journals Simultaneous Determination of all-trans-Retinoic Acid, β-Carotene, and Vitamin A in Galenic Preparations by Liquid Chromatography

2001 ◽  
Vol 84 (2) ◽  
pp. 354-360
Author(s):  
Vincenzo Pucci ◽  
Francesca Bugamelli ◽  
Roberto Mandrioli ◽  
Maria A Raggi
Keyword(s):  
Liquid Chromatography ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Degradation Products ◽  
Extraction Procedure ◽  
Uv Detector ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Β Carotene

Abstract The concentrations of vitamin A, β-carotene, and all-trans-retinoic acid in oral preparations were determined in a single analysis by a method based on isocratic, reversed-phase liquid chromatography (LC). The LC system consisted of a C18 column, a mobile phase of acetonitrile, dichloromethane, methanol, and water and a UV detector set at 330 nm. The linearity ranges were 25–250 ng/mL for trans-retinoic acid and vitamin A, and 100–1000 ng/mL for β-carotene. This LC method for the determination of retinoids is simple, precise, and accurate. No extraction procedure is required before the chromatographic analysis; only a suitable dilution is necessary. The method proved to be reliable, fast, and economical. Furthermore, this method is indicative of stability, because it allows for the determination of degradation products such as 13-cis-retinoic acid.

Chemokine Induction by All-Trans Retinoic Acid in Acute Promyelocytic Leukemia - Triggering the Retinoic Acid Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2980-2980
Author(s):  
Maaike Luesink ◽  
Jeroen Pennings ◽  
Willemijn Wissink ◽  
Peter Linssen ◽  
Petra Muus ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Plasma Levels ◽  
Promyelocytic Leukemia ◽  
Inflammatory Cascade ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Cc Chemokines ◽  
Retinoic Acid Syndrome

Abstract The most important complication of all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) is the retinoic acid syndrome (RAS), a life-threatening hyper-inflammatory reaction with a distinct capillary leak syndrome and multi-organ failure. Once established, the syndrome has proven very difficult to manage. Early recognition in combination with prompt corticosteroid treatment significantly reduces the mortality rate of patients with this syndrome. Nonetheless, still 15% of the induction deaths in APL is caused by RAS. The pathogenic mechanism of the hyper-inflammatory cascade in RAS is not fully understood yet. Infiltration of differentiating APL cells in the lung is important in the development of RAS. In addition, differentiation of APL cells by ATRA is associated with increased expression and release of pro-inflammatory cytokines, chemokines and adhesion molecules in vitro and it has been hypothesized that this is important for the triggering of the hyper-inflammatory cascade in RAS. We investigated the effect of ATRA on the expression and secretion of chemokines in APL cells in vitro and in vivo. Using microarray, quantitative PCR and ELISA we demonstrated significant induction (up to 16000-fold) of 8 CC-chemokines (CCLs) in the NB4 APL cell line after differentiation induction with ATRA in vitro. To demonstrate the significance of chemokine induction by ATRA in vivo, we measured plasma levels of CCLs in 3 APL patients, treated with a combination of ATRA, idarubicine and prednisone according to the AIDA-2000/P protocol. One of these patients developed an obvious retinoic acid syndrome. During therapy we observed increased plasma levels of 3 CCLs in all three patients. Induction of 5 other CCLs (CCL3, CCL4, CCL7, CCL8, CL11) was only observed during RAS, suggesting that upregulation of these 5 CC-chemokines is specific for RAS. To investigate whether the plasma levels of CC-chemokines are functionally relevant, we measured chemo-attraction of peripheral blood leukocytes towards plasma of an APL patient who developed RAS using a transwell system. Plasma from this patient during RAS showed significant more chemo-attraction than plasma from the same patient before treatment with ATRA, idarubicine and prednisone. Subsequently we investigated whether the therapeutic effect of dexamethasone in RAS can be ascribed to downregulation of chemokine expression in APL cells. Despite dexamethasone, the induction of chemokine expression in NB4 cells by ATRA sustained. We conclude that ATRA causes massive secretion of chemokines by APL cells, which might trigger the hyper-inflammatory cascade in RAS by continuous attraction of APL cells and other inflammatory cells towards tissues like the lung. Dexamethasone does not abrogate the production of CC-chemokines by APL cells, but rather seems to inhibit the hyper-inflammatory cascade at the level of the effector cells and target tissues like the lung. This might explain why dexamethasone is not able to sufficiently reverse a retinoic acid syndrome once it has been established. The application of neutralizing CC-chemokine receptor antibodies or other antagonists might be an alternative route to treat an established retinoic acid syndrome.

LncRNA H19-mediated mouse cleft palate induced by all-trans retinoic acid

2016 ◽  
Vol 36 (4) ◽  
pp. 395-401 ◽  
Author(s):  
L Gao ◽  
Y Liu ◽  
Y Wen ◽  
W Wu
Keyword(s):  
Retinoic Acid ◽  
Cleft Palate ◽  
Target Gene ◽  
Functional Roles ◽  
New Class ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Age Related ◽  
And Control

Long noncoding RNAs (lncRNAs) are the new class of transcripts and pervasively transcribed in the genome, which have been found to play important functional roles in many tissues and organs. LncRNAs can interact with target gene to exert their functions. However, the function and mechanism of lncRNA in cleft palate (CP) development remain elusive. Here, we investigated the role of lncRNA H19 and its target gene insulin-like growth factor 2 (IGF2) in CP of mice. All-trans retinoic acid (atRA) is a well-known teratogenic effecter of CP. After establishment of the CP mouse model using atRA in vivo, we found that the rate of CP in mice was 100%. The tail lengths of fetuses in atRA-treated mice were shorter than those of control mice from embryonic day (E)12 to E17. The expression of lncRNA H19 and IGF2 were embryo age-related differences between atRNA-treated and control mice. In addition, the the relationship between lncRNA H19 and IGF2 were negative correlation in the critical period of developmental palate. These findings suggest that lncRNA H19 mediate atRA-induced CP in mice.

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

2019 ◽  
Vol 26 (4) ◽  
pp. 534-545 ◽  
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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