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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 -
Progress in Retinal and Eye Research Mar 2023The eye is an ideal organ for imaging by a multi-photon excitation approach, because ocular tissues such as the sclera, cornea, lens and neurosensory retina, are highly... (Review)
Review
The eye is an ideal organ for imaging by a multi-photon excitation approach, because ocular tissues such as the sclera, cornea, lens and neurosensory retina, are highly transparent to infrared (IR) light. The interface between the retina and the retinal pigment epithelium (RPE) is especially informative, because it reflects the health of the visual (retinoid) cycle and its changes in response to external stress, genetic manipulations, and drug treatments. Vitamin A-derived retinoids, like retinyl esters, are natural fluorophores that respond to multi-photon excitation with near IR light, bypassing the filter-like properties of the cornea, lens, and macular pigments. Also, during natural aging some retinoids form bisretinoids, like diretinoid-pyridiniumethanolamine (A2E), that are highly fluorescent. These bisretinoids appear to be elevated concurrently with aging. Vitamin A-derived retinoids and bisretinoidss are detected by two-photon ophthalmoscopy (2PO), using a new class of light sources with adjustable spatial, temporal, and spectral properties. Furthermore, the two-photon (2P) absorption of IR light by the visual pigments in rod and cone photoreceptors can initiate visual transduction by cis-trans isomerization of retinal, enabling parallel functional studies. Recently we overcame concerns about safety, data interpretation and complexity of the 2P-based instrumentation, the major roadblocks toward advancing this modality to the clinic. These imaging and retina-function assessment advancements have enabled us to conduct the first 2P studies with humans.
Topics: Humans; Mice; Animals; Vision, Ocular; Vitamin A; Retina; Retinoids; Retinal Pigment Epithelium
PubMed: 36787681
DOI: 10.1016/j.preteyeres.2023.101170 -
The Journal of Physical Chemistry. B Oct 2017Antioxidant efficiency of all-trans-retinol has been studied on the basis of characteristic thermochemical properties using density functional theory. The influence of...
Antioxidant efficiency of all-trans-retinol has been studied on the basis of characteristic thermochemical properties using density functional theory. The influence of the solvent polarity has also been evaluated. It is found that retinol may act in parallel as an effective antioxidant via H atom donating as well as a pro-oxidant in yielding reactive hydroxyl radical. In fact, the lowest values of bond dissociation enthalpy were found at the C18-H and C18-OH positions. Retinol was also determined to be a good electron donor but bad acceptor in the single electron transfer (ET) reaction with hydroperoxyl (HOO) radical. In addition, potential energy surfaces of H atom transfer (HAT) and radical adduct formation (RAF) reactions between retinol and HOO radical were also investigated in the gas phase and in the solvent. The results demonstrated that the RAF mechanism was generally more predominant than ET and HAT ones. The most favored radical addition position was found at the C2═C3 double bond in the cyclohexenyl ring. Moreover, the radical scavenging reactivity via RAF reactions was strongly exergonic and thermodynamically feasible while the ET one was endergonic. Natural bond orbital analysis showed that the lone pairs of electrons on the oxygen atom of the HOO radical were donated to the unoccupied antibonding orbital of transferred H atom in HAT reactions. In contrast, in the case of RAF reactions, strong interactions between 2p orbitals on oxygen atoms of the radical and the π orbital of the double bond on the retinol molecule were recognized. The results obtained in this work were in agreement with previous experimental observations.
Topics: Electrons; Free Radical Scavengers; Hydroxyl Radical; Models, Chemical; Molecular Structure; Protons; Reactive Oxygen Species; Thermodynamics; Vitamin A
PubMed: 28937764
DOI: 10.1021/acs.jpcb.7b07065 -
Molecules (Basel, Switzerland) Mar 2021Vitamin A is a fat-soluble micronutrient essential for growth, immunity, and good vision. The preformed retinol is commonly found in food of animal origin whereas... (Review)
Review
Vitamin A is a fat-soluble micronutrient essential for growth, immunity, and good vision. The preformed retinol is commonly found in food of animal origin whereas provitamin A is derived from food of plant origin. This review summarises the current evidence from animal, human and cell-culture studies on the effects of vitamin A towards bone health. Animal studies showed that the negative effects of retinol on the skeleton were observed at higher concentrations, especially on the cortical bone. In humans, the direct relationship between vitamin A and poor bone health was more pronounced in individuals with obesity or vitamin D deficiency. Mechanistically, vitamin A differentially influenced the stages of osteogenesis by enhancing early osteoblastic differentiation and inhibiting bone mineralisation via retinoic acid receptor (RAR) signalling and modulation of osteocyte/osteoblast-related bone peptides. However, adequate vitamin A intake through food or supplements was shown to maintain healthy bones. Meanwhile, provitamin A (carotene and β-cryptoxanthin) may also protect bone. In vitro evidence showed that carotene and β-cryptoxanthin may serve as precursors for retinoids, specifically all-trans-retinoic acid, which serve as ligand for RARs to promote osteogenesis and suppressed nuclear factor-kappa B activation to inhibit the differentiation and maturation of osteoclasts. In conclusion, we suggest that both vitamin A and provitamin A may be potential bone-protecting agents, and more studies are warranted to support this hypothesis.
Topics: Animals; Bone and Bones; Humans; Obesity; Osteogenesis; Receptors, Retinoic Acid; Vitamin A; Vitamin D Deficiency
PubMed: 33801011
DOI: 10.3390/molecules26061757 -
Journal of Molecular Endocrinology Oct 2022Vitamin A (retinol) is an essential, fat-soluble vitamin that plays critical roles in embryonic development, vision, immunity, and reproduction. Severe vitamin A... (Review)
Review
Vitamin A (retinol) is an essential, fat-soluble vitamin that plays critical roles in embryonic development, vision, immunity, and reproduction. Severe vitamin A deficiency results in profound embryonic dysgenesis, blindness, and infertility. The roles of bioactive vitamin A metabolites in regulating cell proliferation, cellular differentiation, and immune cell function form the basis of their clinical use in the treatment of dermatologic conditions and hematologic malignancies. Increasingly, vitamin A also has been recognized to play important roles in cardiometabolic health, including the regulation of adipogenesis, energy partitioning, and lipoprotein metabolism. While these roles are strongly supported by animal and in vitro studies, they remain poorly understood in human physiology and disease. This review briefly introduces vitamin A biology and presents the key preclinical data that have generated interest in vitamin A as a mediator of cardiometabolic health. The review also summarizes clinical studies performed to date, highlighting the limitations of many of these studies and the ongoing controversies in the field. Finally, additional perspectives are suggested that may help position vitamin A metabolism within a broader biological context and thereby contribute to enhanced understanding of vitamin A's complex roles in clinical cardiometabolic disease.
Topics: Adipogenesis; Animals; Cardiovascular Diseases; Female; Homeostasis; Humans; Pregnancy; Vitamin A; Vitamin A Deficiency
PubMed: 35900842
DOI: 10.1530/JME-22-0078 -
Nutrients May 2023β-cryptoxanthin is a dietary carotenoid for which there have been few studies on the safety and pharmacokinetics following daily oral supplementation. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
β-cryptoxanthin is a dietary carotenoid for which there have been few studies on the safety and pharmacokinetics following daily oral supplementation.
METHODS
90 healthy Asian women between 21 and 35 years were randomized into three groups: 3 and 6 mg/day oral β-cryptoxanthin, and placebo. At 2, 4, and 8 weeks of supplementation, plasma carotenoid levels were measured. The effects of β-cryptoxanthin on blood retinoid-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition were investigated.
RESULTS
β-cryptoxanthin supplementation for 8 weeks (3 and 6 mg/day) was found to be safe and well tolerated. Plasma β-cryptoxanthin concentration was significantly higher in the 6 mg/day group (9.0 ± 4.1 µmol/L) compared to 3 mg/day group (6.0 ± 2.6 µmol/L) ( < 0.03), and placebo (0.4 ± 0.1 µmol/L) ( < 0.001) after 8 weeks. Plasma all-trans retinol, α-cryptoxanthin, α-carotene, β-carotene, lycopene, lutein, and zeaxanthin levels were not significantly changed. No effects were found on blood retinol-dependent gene expression, mood, physical activity and sleep, metabolic parameters, and fecal microbial composition.
CONCLUSIONS
Oral β-cryptoxanthin supplementation over 8 weeks lead to high plasma concentrations of β-cryptoxanthin, with no impact on other carotenoids, and was well tolerated in healthy women.
Topics: Humans; Female; Vitamin A; Beta-Cryptoxanthin; Carotenoids; beta Carotene; Lutein; Zeaxanthins; Dietary Supplements
PubMed: 37242207
DOI: 10.3390/nu15102325 -
The Journal of Biological Chemistry Nov 2017Interphotoreceptor retinoid-binding protein (IRBP) is a specialized lipophilic carrier that binds the all- and 11- isomers of retinal and retinol, and this facilitates...
Interphotoreceptor retinoid-binding protein (IRBP) is a specialized lipophilic carrier that binds the all- and 11- isomers of retinal and retinol, and this facilitates their transport between photoreceptors and cells in the retina. One of these retinoids, all-retinal, is released in the rod outer segment by photoactivated rhodopsin after light excitation. Following its release, all-retinal is reduced by the retinol dehydrogenase RDH8 to all-retinol in an NADPH-dependent reaction. However, all-retinal can also react with outer segment components, sometimes forming lipofuscin precursors, which after conversion to lipofuscin accumulate in the lysosomes of the retinal pigment epithelium and display cytotoxic effects. Here, we have imaged the fluorescence of all-retinol, all-retinal, and lipofuscin precursors in real time in single isolated mouse rod photoreceptors. We found that IRBP removes all-retinol from individual rod photoreceptors in a concentration-dependent manner. The rate constant for retinol removal increased linearly with IRBP concentration with a slope of 0.012 min μm IRBP also removed all-retinal, but with much less efficacy, indicating that the reduction of retinal to retinol promotes faster clearance of the photoisomerized rhodopsin chromophore. The presence of physiological IRBP concentrations in the extracellular medium resulted in lower levels of all-retinal and retinol in rod outer segments following light exposure. It also prevented light-induced lipofuscin precursor formation, but it did not remove precursors that were already present. These findings reveal an important and previously unappreciated role of IRBP in protecting the photoreceptor cells against the cytotoxic effects of accumulated all-retinal.
Topics: Animals; Cattle; Eye Proteins; Light; Lipofuscin; Mice; Mice, Knockout; Retinaldehyde; Retinol-Binding Proteins; Rod Cell Outer Segment; Vitamin A
PubMed: 28972139
DOI: 10.1074/jbc.M117.795187 -
International Journal of Molecular... Jun 2024All- retinoic acid (ATRA), the major active metabolite of all- retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread... (Review)
Review
All- retinoic acid (ATRA), the major active metabolite of all- retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.
Topics: Humans; Retinoic Acid Receptor gamma; Receptors, Retinoic Acid; Animals; Tretinoin; Protein Binding; Leukemia, Promyelocytic, Acute; Antineoplastic Agents
PubMed: 38928275
DOI: 10.3390/ijms25126568 -
Methods in Enzymology 2020All-trans-retinoic acid (RA) is a bioactive lipid that influences many processes in embryonic and adult tissues. Given its bioactive nature, cellular concentrations of...
All-trans-retinoic acid (RA) is a bioactive lipid that influences many processes in embryonic and adult tissues. Given its bioactive nature, cellular concentrations of this molecule are highly regulated. The oxidation of all-trans-retinol to all-trans-retinaldehyde represents the first and rate-limiting step of the RA synthesis pathway. As such, it is the target of mechanisms that fine-tune RA levels within the cell. RDH10 is one enzyme responsible for the oxidation of all-trans-retinol to all-trans-retinaldehyde, and together with the all-trans-retinaldehyde reductase DHRS3 forms an oligomeric protein complex. The resulting retinoid oxidoreductase complex (ROC) is bifunctional and has the capacity to regulate steady-state levels of the direct precursor of RA, all-trans-retinaldehyde. As ROC represents a major regulatory element within the RA synthesis pathway, it is essential that methods are in place that allow for the study of this complex. Here we describe the production and isolation of recombinant ROC using a baculovirus expression system. Recombinant proteins retain enzymatic activities in intact microsomes and can be affinity purified for analysis. These methods can be used to assist in the assessment of ROC properties and the regulation of this protein complex's functional attributes.
Topics: Alcohol Oxidoreductases; Oxidoreductases; Retinaldehyde; Retinoids; Tretinoin
PubMed: 32359661
DOI: 10.1016/bs.mie.2020.02.005 -
Nutrients Dec 2016Embryonic development is orchestrated by a small number of signaling pathways, one of which is the retinoic acid (RA) signaling pathway. Vitamin A is essential for... (Review)
Review
Embryonic development is orchestrated by a small number of signaling pathways, one of which is the retinoic acid (RA) signaling pathway. Vitamin A is essential for vertebrate embryonic development because it is the molecular precursor of the essential signaling molecule RA. The level and distribution of RA signaling within a developing embryo must be tightly regulated; too much, or too little, or abnormal distribution, all disrupt embryonic development. Precise regulation of RA signaling during embryogenesis is achieved by proteins involved in vitamin A metabolism, retinoid transport, nuclear signaling, and RA catabolism. The reversible first step in conversion of the precursor vitamin A to the active retinoid RA is mediated by retinol dehydrogenase 10 (RDH10) and dehydrogenase/reductase (SDR family) member 3 (DHRS3), two related membrane-bound proteins that functionally activate each other to mediate the interconversion of retinol and retinal. Alcohol dehydrogenase (ADH) enzymes do not contribute to RA production under normal conditions during embryogenesis. Genes involved in vitamin A metabolism and RA catabolism are expressed in tissue-specific patterns and are subject to feedback regulation. Mutations in genes encoding these proteins disrupt morphogenesis of many systems in a developing embryo. Together these observations demonstrate the importance of vitamin A metabolism in regulating RA signaling during embryonic development in vertebrates.
Topics: Alcohol Oxidoreductases; Animals; Embryonic Development; Humans; Signal Transduction; Tretinoin; Vertebrates; Vitamin A
PubMed: 27983671
DOI: 10.3390/nu8120812