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Development (Cambridge, England) Jul 2019Retinoic acid (RA), a metabolite of retinol (vitamin A), functions as a ligand for nuclear RA receptors (RARs) that regulate development of chordate animals. RA-RARs can... (Review)
Review
Retinoic acid (RA), a metabolite of retinol (vitamin A), functions as a ligand for nuclear RA receptors (RARs) that regulate development of chordate animals. RA-RARs can activate or repress transcription of key developmental genes. Genetic studies in mouse and zebrafish embryos that are deficient in RA-generating enzymes or RARs have been instrumental in identifying RA functions, revealing that RA signaling regulates development of many organs and tissues, including the body axis, spinal cord, forelimbs, heart, eye and reproductive tract. An understanding of the normal functions of RA signaling during development will guide efforts for use of RA as a therapeutic agent to improve human health. Here, we provide an overview of RA signaling and highlight its key functions during development.
Topics: Animals; Embryo, Mammalian; Embryo, Nonmammalian; Gene Expression Regulation, Developmental; Genes, Developmental; Humans; Mice; Receptors, Retinoic Acid; Signal Transduction; Transcription Factors; Tretinoin; Zebrafish
PubMed: 31273085
DOI: 10.1242/dev.167502 -
Cells Dec 2020The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological... (Review)
Review
The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological functions in multiple organ systems, are essential for normal immune competence, and are involved in the regulation of cell growth and differentiation. Vitamin A derivatives have held promise in cancer treatment and ATRA is used in differentiation therapy of acute promyelocytic leukemia (APL). ATRA and other retinoids have also been successfully applied in a variety of dermatological conditions such as skin cancer, psoriasis, acne, and ichthyosis. Moreover, modulation of retinoic acid receptors and retinoid X (or rexinoid) receptors function may affect dermal cells. The studies using complex genetic models with various combinations of retinoic acid receptors (RARs) and retinoid X (or rexinoid) receptors (RXRs) indicate that retinoic acid and its derivatives have therapeutic potential for a variety of serious dermatological disorders including some malignant conditions. Here, we provide a synopsis of the main advances in understanding the role of ATRA and its receptors in dermatology.
Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoid X Receptors; Signal Transduction; Skin; Skin Neoplasms; Tretinoin
PubMed: 33322246
DOI: 10.3390/cells9122660 -
Cellular and Molecular Life Sciences :... Apr 2015The identification of neurological symptoms caused by vitamin A deficiency pointed to a critical, early developmental role of vitamin A and its metabolite, retinoic acid... (Review)
Review
The identification of neurological symptoms caused by vitamin A deficiency pointed to a critical, early developmental role of vitamin A and its metabolite, retinoic acid (RA). The ability of RA to induce post-mitotic, neural phenotypes in various stem cells, in vitro, served as early evidence that RA is involved in the switch between proliferation and differentiation. In vivo studies have expanded this "opposing signal" model, and the number of primary neurons an embryo develops is now known to depend critically on the levels and spatial distribution of RA. The proneural and neurogenic transcription factors that control the exit of neural progenitors from the cell cycle and allow primary neurons to develop are partly elucidated, but the downstream effectors of RA receptor (RAR) signaling (many of which are putative cell cycle regulators) remain largely unidentified. The molecular mechanisms underlying RA-induced primary neurogenesis in anamniote embryos are starting to be revealed; however, these data have been not been extended to amniote embryos. There is growing evidence that bona fide RARs are found in some mollusks and other invertebrates, but little is known about their necessity or functions in neurogenesis. One normal function of RA is to regulate the cell cycle to halt proliferation, and loss of RA signaling is associated with dedifferentiation and the development of cancer. Identifying the genes and pathways that mediate cell cycle exit downstream of RA will be critical for our understanding of how to target tumor differentiation. Overall, elucidating the molecular details of RAR-regulated neurogenesis will be decisive for developing and understanding neural proliferation-differentiation switches throughout development.
Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Cell Cycle Proteins; Humans; Neoplasms; Neurogenesis; Neurons; Receptors, Retinoic Acid; Signal Transduction; Tretinoin
PubMed: 25558812
DOI: 10.1007/s00018-014-1815-9 -
Journal of Lipid Research Nov 2002Over the last quarter century, more than 532 genes have been put forward as regulatory targets of retinoic acid. In some cases this control is direct, driven by a... (Review)
Review
Over the last quarter century, more than 532 genes have been put forward as regulatory targets of retinoic acid. In some cases this control is direct, driven by a liganded heterodimer of retinoid receptors bound to a DNA response element; in others, it is indirect, reflecting the actions of intermediate transcription factors, non-classical associations of receptors with other proteins, or even more distant mechanisms. Given the broad range of scientific questions continually under investigation, researchers do not always have occasion to classify target genes along these lines. However, our understanding of the genetic role of retinoids will be enhanced if such a distinction can be made for each regulated gene. We have therefore evaluated published data from 1,191 papers covering 532 genes and have classified these genes into four categories according to the degree to which an hypothesis of direct versus indirect control is supported overall. We found 27 genes that are unquestionably direct targets of the classical pathway in permissive cellular contexts (Category 3 genes), plus 105 genes that appear to be candidates, pending the results of specific additional experiments (Category 2). Data on another 267 targets are not evocative of direct or indirect regulation either way, although control by retinoic acid through some mechanism is clear (Category 1). Most of the remaining 133 targets seem to be regulated indirectly, usually through a transcriptional intermediary, in the contexts studied so far (Category 0).
Topics: Animals; Databases, Factual; Down-Regulation; Gene Expression Regulation; Genes; Tretinoin; Up-Regulation
PubMed: 12401878
DOI: 10.1194/jlr.r100015-jlr200 -
Cells Mar 2023One of the most fundamental discoveries in human biology was that of the existence of essential micronutrients that the body cannot synthesize but nonetheless requires...
One of the most fundamental discoveries in human biology was that of the existence of essential micronutrients that the body cannot synthesize but nonetheless requires for proper functioning [...].
Topics: Humans; Tretinoin; Retinoid X Receptors; Receptors, Retinoic Acid
PubMed: 36980205
DOI: 10.3390/cells12060864 -
Clinical Cancer Research : An Official... Apr 2023Myeloid-derived suppressor cells (MDSC) are associated with resistance to anti-PD-1 therapies. All-trans retinoic acid (ATRA) may induce maturation of MDSCs and alter...
Myeloid-derived suppressor cells (MDSC) are associated with resistance to anti-PD-1 therapies. All-trans retinoic acid (ATRA) may induce maturation of MDSCs and alter their immunosuppressive effects. Adding ATRA to pembrolizumab may target this resistance mechanism to enhance the overall impact of anti-PD-1-based immunotherapy. See related article by Tobin et al., p. 1209.
Topics: Humans; Myeloid-Derived Suppressor Cells; Melanoma; Tretinoin; Cell Differentiation
PubMed: 36656164
DOI: 10.1158/1078-0432.CCR-22-3652 -
AAPS PharmSciTech Jun 2011The aim of this work is to prepare tretinoin/dimethyl-beta-cyclodextrin complexes and fully characterize them through various analytical techniques. According to the... (Comparative Study)
Comparative Study
The aim of this work is to prepare tretinoin/dimethyl-beta-cyclodextrin complexes and fully characterize them through various analytical techniques. According to the phase solubility studies performed, the equilibrium for maximum complexation is reached in about 8 days presenting an A(L)-type diagram (soluble complexes) corresponding mainly to 1:1 stoichiometry (K(s) = 13,600 M(-1)), although the possibility of the presence of 1:2 complexes was mathematically proven. Differential scanning calorimetry, X-ray diffraction and all the other analytical techniques have proven the presence of true complex formation in all the preparation methods tested. H-NMR and FTIR spectra allowed the selection of the best complexation method. The comparison between Raman spectra revealed that the more relevant feature is the band at 1,573 cm(-1), which corresponds to the entire delocalization of the superconjugated system, and after inclusion is observed as a positive frequency shift. Based on these results and the data obtained by molecular modelling calculations, it is proposed that the structure of the drug included into the cyclodextrin corresponds to the side chain including the functional group COOH. The complex was also analysed by atomic force microscopy to determine its size distribution which was heterogeneous and polymodal. However, it could be observed that they all have the same phase constitution.
Topics: Chemistry, Pharmaceutical; Magnetic Resonance Spectroscopy; Protein Structure, Secondary; Spectroscopy, Fourier Transform Infrared; Tretinoin; X-Ray Diffraction; beta-Cyclodextrins
PubMed: 21533999
DOI: 10.1208/s12249-011-9612-3 -
Nutrients Apr 2022This review addresses the fasting vs. re-feeding effects of retinoic acid (RA) biosynthesis and functions, and sexually dimorphic RA actions. It also discusses other... (Review)
Review
This review addresses the fasting vs. re-feeding effects of retinoic acid (RA) biosynthesis and functions, and sexually dimorphic RA actions. It also discusses other understudied topics essential for understanding RA activities-especially interactions with energy-balance-regulating hormones, including insulin and glucagon, and sex hormones. This report will introduce RA homeostasis and hormesis to provide context. Essential context also will encompass RA effects on adiposity, muscle function and pancreatic islet development and maintenance. These comments provide background for explaining interactions among insulin, glucagon and cortisol with RA homeostasis and function. One aim would clarify the often apparent RA contradictions related to pancreagenesis vs. pancreas hormone functions. The discussion also will explore the adverse effects of RA on estrogen action, in contrast to the enhancing effects of estrogen on RA action, the adverse effects of androgens on RA receptors, and the RA induction of androgen biosynthesis.
Topics: Estrogens; Glucagon; Insulin; Receptors, Retinoic Acid; Tretinoin
PubMed: 35458115
DOI: 10.3390/nu14081553 -
Nutrients Apr 2022The vitamin A metabolite all-trans retinoic acid (RA) plays a key role in tissue homeostasis and mucosal immunity. RA is produced by gut-associated dendritic cells,... (Review)
Review
The vitamin A metabolite all-trans retinoic acid (RA) plays a key role in tissue homeostasis and mucosal immunity. RA is produced by gut-associated dendritic cells, which are among the first cells encountered by HIV. Acute HIV infection results in rapid reduction of RA levels and dysregulation of immune cell populations whose identities and function are largely controlled by RA. Here, we discuss the potential link between the roles played by RA in shaping intestinal immune responses and the manifestations and pathogenesis of HIV-associated enteropathy and similar conditions observed in SIV-infected non-human primate models. We also present data demonstrating the ability of RA to enhance the activation of replication-competent viral reservoirs from subjects on suppressive anti-retroviral therapy. The data suggest that retinoid supplementation may be a useful adjuvant for countering the pathologic condition of the gastro-intestinal tract associated with HIV infection and as part of a strategy for reactivating viral reservoirs as a means of depleting latent viral infection.
Topics: Animals; HIV Infections; Humans; Immunity, Mucosal; Tretinoin; Virus Replication; Vitamin A
PubMed: 35458172
DOI: 10.3390/nu14081611 -
Scientific Reports Nov 2023Acne vulgaris, a prevalent skin disorder among teenagers and young adults, can have numerous psychological consequences. Topical treatment of acne would be advantageous...
Acne vulgaris, a prevalent skin disorder among teenagers and young adults, can have numerous psychological consequences. Topical treatment of acne would be advantageous by reducing the risk of systemic adverse drug reactions. However, the major challenge would be skin penetration through the stratum corneum. Therefore, during this study, tretinoin (TRT) and bicalutamide (BCT) loaded niosomes with follicular targeting potential were fabricated through the thin film hydration technique. Formulation optimization was performed using the Design-Expert software and optimum formulation was characterized in terms of particle size, zeta potential, transmission electron microscopy, drug loading, and differential scanning calorimetry. In vivo follicular targeting was assessed using rhodamine B-loaded niosomes to follow the skin penetration pathways. The results showed that, the optimum formulation was spherical in shape and had an average diameter of 319.20 ± 18.50 nm and a zeta potential of - 29.70 ± 0.36 mV. Furthermore, entrapment efficiencies were 94.63 ± 0.50% and > 99% and loading capacities were 1.40 ± 0.01% and 1.48 ± 0.00% for BCT and TRT, respectively. According to the animal study results, the prepared niosomes with an average diameter of about 300 nm showed significant accumulation in hair follicles. It seems that the designed niosomal BCT-TRT co-delivery system would be promising in acne management with follicular targeting potential.
Topics: Animals; Liposomes; Skin Absorption; Tretinoin; Acne Vulgaris; Particle Size
PubMed: 37973805
DOI: 10.1038/s41598-023-47302-6