-
Scientific Reports Jul 2023Topically applied all-trans-retinoic acid (RA) is a gold-standard anti-aging molecule used in dermatology. As its cosmetic counterpart used in anti-aging, Retinol...
Topically applied all-trans-retinoic acid (RA) is a gold-standard anti-aging molecule used in dermatology. As its cosmetic counterpart used in anti-aging, Retinol (ROL) is also a known metabolic precursor of RA. Despite this metabolic link, they haven't been compared exhaustively in vivo at a mechanistic level. Therefore, to highlight the effect of a topical application of both molecules on in vivo skin, we undertook a longitudinal 1-year study and performed an untargeted proteomic analysis to get a more holistic view on the underlying biological mechanisms of action. The generation of the temporal proteomics signatures of retinol and all-trans-retinoic acid reveals the impact of these molecules on biological functions related to the aging of skin. New biological functions impacted by retinoids were discovered: glycan metabolism and protein biosynthesis. In addition, the temporal analysis reveals highest modulations at early time points while the physical measures, such as epidermal thickening, was mostly observed at the latest time point, demonstrating a strong time lapse between molecular and morphological impacts. Finally, these global temporal signatures could be used to identify new cosmetic compounds of interest.
Topics: Humans; Vitamin A; Proteome; Longitudinal Studies; Proteomics; Tretinoin
PubMed: 37433822
DOI: 10.1038/s41598-023-37750-5 -
Journal of Zhejiang University....The present study was designed to analyze the metabolites of all-trans-retinal (atRal) and compare the cytotoxicity of atRal versus its derivative all-trans-retinoic...
The present study was designed to analyze the metabolites of all-trans-retinal (atRal) and compare the cytotoxicity of atRal versus its derivative all-trans-retinoic acid (atRA) in human retinal pigment epithelial (RPE) cells. We confirmed that atRA was produced in normal pig neural retina and RPE. The amount of all-trans-retinol (atROL) converted from atRal was about 2.7 times that of atRal-derived atRA after incubating RPE cells with 10 μmol/L atRal for 24 h, whereas atRA in medium supernatant is more plentiful (91 vs. 29 pmol/mL), suggesting that atRA conversion facilitates elimination of excess atRal in the retina. Moreover, we found that mRNA expression of retinoic acid-specific hydroxylase CYP26b1 was dose-dependently up-regulated by atRal exposure in RPE cells, indicating that atRA inactivation may be also initiated in atRal-accumulated RPE cells. Our data show that atRA-caused viability inhibition was evidently reduced compared with the equal concentration of its precursor atRal. Excess accumulation of atRal provoked intracellular reactive oxygen species (ROS) overproduction, heme oxygenase-1 (HO-1) expression, and increased cleaved poly(ADP-ribose) polymerase 1 (PARP1) expression in RPE cells. In contrast, comparable dosage of atRA-induced oxidative stress was much weaker, and it could not activate apoptosis in RPE cells. These results suggest that atRA generation is an antidotal metabolism pathway for atRal in the retina. Moreover, we found that in the eyes of ABCA4RDH8 mice, a mouse model with atRal accumulation in the retina, the atRA content was almost the same as that in the wild type. It is possible that atRal accumulation simultaneously and equally promotes atRA synthesis and clearance in eyes of ABCA4RDH8 mice, thus inhibiting the further increase of atRA in the retina. Our present study provides further insights into atRal clearance in the retina.
Topics: ATP-Binding Cassette Transporters; Alcohol Oxidoreductases; Animals; Cell Survival; Cells, Cultured; Humans; Inactivation, Metabolic; Mice; Retina; Retinal Pigment Epithelium; Swine; Tretinoin
PubMed: 31749343
DOI: 10.1631/jzus.B1900271 -
Investigative Ophthalmology & Visual... Jan 2017Two-photon excited fluorescence (TPEF) imaging has potential as a functional tool for tracking visual pigment regeneration in the living eye. Previous studies have shown...
PURPOSE
Two-photon excited fluorescence (TPEF) imaging has potential as a functional tool for tracking visual pigment regeneration in the living eye. Previous studies have shown that all-trans-retinol is likely the chief source of time-varying TPEF from photoreceptors. Endogenous TPEF from retinol could provide the specificity desired for tracking the visual cycle. However, in vivo characterization of native retinol kinetics is complicated by visual stimulation from the imaging beam. We have developed an imaging scheme for overcoming these challenges and monitored the formation and clearance of retinol.
METHODS
Three macaques were imaged by using an in vivo two-photon ophthalmoscope. Endogenous TPEF was excited at 730 nm and recorded through the eye's pupil for more than 90 seconds. Two-photon excited fluorescence increased with onset of light and plateaued within 40 seconds, at which point, brief incremental stimuli were delivered at 561 nm. The responses of rods to stimulation were analyzed by using first-order kinetics.
RESULTS
Two-photon excited fluorescence resulting from retinol production corresponded to the fraction of rhodopsin bleached. The photosensitivity of rhodopsin was estimated to be 6.88 ± 5.50 log scotopic troland. The rate of retinol clearance depended on intensity of incremental stimulation. Clearance was faster for stronger stimuli and time constants ranged from 50 to 300 seconds.
CONCLUSIONS
This study demonstrates a method for rapidly measuring the rate of clearance of retinol in vivo. Moreover, TPEF generated due to retinol can be used as a measure of rhodopsin depletion, similar to densitometry. This enhances the utility of two-photon ophthalmoscopy as a technique for evaluating the visual cycle in the living eye.
Topics: Animals; Dark Adaptation; Female; Macaca fascicularis; Male; Models, Animal; Ophthalmoscopy; Optical Imaging; Retinal Pigments; Retinal Rod Photoreceptor Cells; Retinol-Binding Proteins; Rhodopsin; Vitamin A
PubMed: 28129424
DOI: 10.1167/iovs.16-20061 -
Journal of Molecular Endocrinology Nov 2022The landmark 1987 discovery of the retinoic acid receptor (RAR) came as a surprise, uncovering a genomic kinship between the fields of vitamin A biology and steroid... (Review)
Review
The landmark 1987 discovery of the retinoic acid receptor (RAR) came as a surprise, uncovering a genomic kinship between the fields of vitamin A biology and steroid receptors. This stunning breakthrough triggered a cascade of studies to deconstruct the roles played by the RAR and its natural and synthetic ligands in embryonic development, skin, growth, physiology, vision, and disease as well as providing a template to elucidate the molecular mechanisms by which nuclear receptors regulate gene expression. In this review, written from historic and personal perspectives, we highlight the milestones that led to the discovery of the RAR and the subsequent studies that enriched our knowledge of the molecular mechanisms by which a low-abundant dietary compound could be so essential to the generation and maintenance of life itself.
Topics: Ligands; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Tretinoin; Vitamin A
PubMed: 35900848
DOI: 10.1530/JME-22-0117 -
Scientific Reports Jun 2022There is limited research about the impacts of new nematicides, including fluazaindolizine, fluopyram, and fluensulfone, on the plant-parasitic nematode Meloidogyne...
There is limited research about the impacts of new nematicides, including fluazaindolizine, fluopyram, and fluensulfone, on the plant-parasitic nematode Meloidogyne incognita, despite it being a pervasive agricultural pest. In this study, M. incognita second-stage juveniles were exposed for 24-h to fluensulfone, fluazaindolizine, fluopyram, and oxamyl and total RNA was extracted and sequenced using next-generation sequencing to determine gene expression. The effects of nematicide exposure on cellular detoxification pathways, common differentially expressed (DE) genes, and fatty acid and retinol-binding genes were examined. Fluopyram and oxamyl had the smallest impacts on the M. incognita transcriptome with 48 and 151 genes that were DE, respectively. These compounds also elicited a weak response in the cellular detoxification pathway and fatty acid and retinol-binding (FAR) genes. Fluensulfone and fluazaindolizine produced robust transcriptional responses with 1208 and 2611 DE genes, respectively. These compounds had strong impacts on cellular detoxification, causing differential regulation of transcription factors and genes in the detox pathway. These compounds strongly down-regulated FAR genes between 52-85%. Having a greater understanding of how these compounds function at a molecular level will help to promote proper stewardship, aid with nematicide discovery, and help to stay a step ahead of nematicide resistance.
Topics: Animals; Antinematodal Agents; Fatty Acids; Tylenchoidea; Vitamin A
PubMed: 35697824
DOI: 10.1038/s41598-022-13815-9 -
The British Journal of Nutrition Dec 2021SARS-CoV2 infects respiratory epithelial cells via its cellular receptor angiotensin-converting enzyme 2, causing a viral pneumonia with pronounced inflammation... (Review)
Review
SARS-CoV2 infects respiratory epithelial cells via its cellular receptor angiotensin-converting enzyme 2, causing a viral pneumonia with pronounced inflammation resulting in significant damage to the lungs and other organ systems, including the kidneys, though symptoms and disease severity are quite variable depending on the intensity of exposure and presence of underlying conditions that may affect the immune response. The resulting disease, coronavirus disease 2019 (COVID-19), can cause multi-organ system dysfunction in patients requiring hospitalisation and intensive care treatment. Serious infections like COVID-19 often negatively affect nutritional status, and the resulting nutritional deficiencies may increase disease severity and impair recovery. One example is the viral infection measles, where associated vitamin A (VA) deficiency increases disease severity and appropriately timed supplementation during recovery reduces mortality and hastens recovery. VA may play a similar role in COVID-19. First, VA is important in maintaining innate and adaptive immunity to promote clearance of a primary infection as well as minimise risks from secondary infections. Second, VA plays a unique role in the respiratory tract, minimising damaging inflammation, supporting repair of respiratory epithelium and preventing fibrosis. Third, VA deficiency may develop during COVID-19 due to specific effects on lung and liver stores caused by inflammation and impaired kidney function, suggesting that supplements may be needed to restore adequate status. Fourth, VA supplementation may counteract adverse effects of SARS-CoV2 on the angiotensin system as well as minimises adverse effects of some COVID-19 therapies. Evaluating interactions of SARS-CoV2 infection with VA metabolism may thus provide improved COVID-19 therapy.
Topics: Adaptive Immunity; COVID-19; Humans; Immunity, Innate; Inflammation; RNA, Viral; Vitamin A
PubMed: 33468263
DOI: 10.1017/S0007114521000246 -
Developmental Dynamics : An Official... Aug 2021Retinol binding protein 1 (Rbp1) acts as an intracellular regulator of vitamin A metabolism and retinoid transport. In mice, Rbp1 deficiency decreases the capacity of...
BACKGROUND
Retinol binding protein 1 (Rbp1) acts as an intracellular regulator of vitamin A metabolism and retinoid transport. In mice, Rbp1 deficiency decreases the capacity of hepatic stellate cells to take up all-trans retinol and sustain retinyl ester stores. Furthermore, Rbp1 is crucial for visual capacity. Although the function of Rbp1 has been studied in the mature eye, its role during early anterior neural development has not yet been investigated in detail.
RESULTS
We showed that rbp1 is expressed in the eye, anterior neural crest cells (NCCs) and prosencephalon of the South African clawed frog Xenopus laevis. Rbp1 knockdown led to defects in eye formation, including microphthalmia and disorganized retinal lamination, and to disturbed induction and differentiation of the eye field, as shown by decreased rax and pax6 expression. Furthermore, it resulted in reduced rax expression in the prosencephalon and affected cranial cartilage. Rbp1 inhibition also interfered with neural crest induction and migration, as shown by twist and slug. Moreover, it led to a significant reduction of the all-trans retinoic acid target gene pitx2 in NCC-derived periocular mesenchyme. The Rbp1 knockdown phenotypes were rescued by pitx2 RNA co-injection.
CONCLUSION
Rbp1 is crucial for the development of the anterior neural tissue.
Topics: Animals; Embryonic Development; Eye Proteins; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Neural Crest; PAX6 Transcription Factor; Prosencephalon; Retinol-Binding Proteins, Cellular; Signal Transduction; Tretinoin; Xenopus Proteins; Xenopus laevis
PubMed: 33570783
DOI: 10.1002/dvdy.313 -
Nutrients Dec 2019Vitamin A (all--retinol), its active derivatives retinal and retinoic acid, and their synthetic analogues constitute the group of retinoids. It is obtained from diet... (Review)
Review
Vitamin A (all--retinol), its active derivatives retinal and retinoic acid, and their synthetic analogues constitute the group of retinoids. It is obtained from diet either as preformed vitamin A or as carotenoids. Retinal plays a biological role in vision, but most of the effects of vitamin A are exerted by retinoic acid, which binds to nuclear receptors and regulates gene transcription. Vitamin A deficiency is an important nutritional problem, particularly in the developing world. Retinol and carotenoids from diet during pregnancy and lactation influence their concentration in breast milk, which is important in the long term, not only for the offspring, but also for maternal health. In this study, we review the role of vitamin A in mammary gland metabolism, where retinoid signaling is required not only for morphogenesis and development of the gland and for adequate milk production, but also during the weaning process, when epithelial cell death is coupled with tissue remodeling.
Topics: Animals; Carotenoids; Diet; Female; Humans; Lactation; Mammary Glands, Animal; Mammary Glands, Human; Milk, Human; Nutritional Requirements; Pregnancy; Vitamin A; Vitamin A Deficiency; Weaning
PubMed: 31892157
DOI: 10.3390/nu12010080 -
Yakugaku Zasshi : Journal of the... 2021"Retinoid" is the general term for vitamin A derivatives and chemical compounds that act like vitamin A. Vitamin A are composed of four isoprene units and are named... (Review)
Review
"Retinoid" is the general term for vitamin A derivatives and chemical compounds that act like vitamin A. Vitamin A are composed of four isoprene units and are named according to their terminal functional group, such as retinol (OH, 1), retinal (CHO, 2), and retinoic acid (COH, 3). Vitamin A usually refers to retinol. In the past few decades, major advances in research on vitamin A have improved our understanding of its fundamental roles and physiological significance in living cells. In this review, three types of chemical biology studies using vitamin A analogs are described: (1) conformational studies of the chromophore in retinal proteins (rhodopsin, phoborhodopsin, and retinochrome), especially the conformation around the cyclohexene ring; (2) structure-activity relationship studies of retinoic acid analogs to create new signaling molecules for activating nuclear receptors; and (3) development of a new channelrhodopsin with an absorption maximum at longer wavelength to overcome the various demerits of channelrhodopsins used in optogenetics, as well as the stereoselective synthesis of retinoid isomers and their analogs using a diene-tricarbonyliron complex or a palladium-catalyzed cross-coupling reaction between vinyl triflates and stannyl olefins.
Topics: Alkenes; Catalysis; Channelrhodopsins; Cyclohexenes; Eye Proteins; Isomerism; Mesylates; Molecular Conformation; Nuclear Reactors; Palladium; Retinoids; Stereoisomerism; Structure-Activity Relationship; Vinyl Compounds; Vitamin A
PubMed: 33790122
DOI: 10.1248/yakushi.20-00230 -
MBio Aug 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the global pandemic and life-threatening coronavirus disease 2019 (COVID-19)....
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the global pandemic and life-threatening coronavirus disease 2019 (COVID-19). Although vaccines and therapeutic antibodies are available, their efficacy is continuously undermined by rapidly emerging SARS-CoV-2 variants. Here, we found that all- retinoic acid (ATRA), a vitamin A (retinol) derivative, showed potent antiviral activity against all SARS-CoV-2 variants in both human cell lines and human organoids of the lower respiratory tract. Mechanistically, ATRA directly binds in a deep hydrophobic pocket of the receptor binding domain (RBD) located on the top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation. In summary, our results reveal the pharmacological biotargets and structural mechanism of ATRA and other retinoids in SARS-CoV-2 infection and suggest that ATRA and its derivatives could be potential hit compounds against a broad spectrum of coronaviruses. Retinoids, a group of compounds including vitamin A and its active metabolite all- retinoic acid (ATRA), regulate serial physiological activity in multiple organ systems, such as cell growth, differentiation, and apoptosis. The ATRA analogues reported to date include more than 4,000 natural and synthetic molecules that are structurally and/or functionally related to ATRA. Here, we found that ATRA showed potent antiviral activity against all SARS-CoV-2 variants by directly binding in a deep hydrophobic pocket of the receptor binding domain (RBD) located on top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation, suggesting the pharmacological feasibility of using ATRA or its derivatives as a remedy for and prevention of COVID-19 disease.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; Humans; Peptidyl-Dipeptidase A; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Tretinoin; Vitamin A; COVID-19 Drug Treatment
PubMed: 35862773
DOI: 10.1128/mbio.01485-22