Vitamin A and retinoids: from nutrition to pharmacotherapy in dermatology and oncology.
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Chemical Phenomena↗
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Induction of erythrophagocytic activity in cultured mouse trophoblast cells by phorbol myristate acetate and all-trans-retinal.
Phorbol myristate acetate (PMA) and all-trans-retinal (retinal) were evaluated as possible phagocytic stimulators of cultured, post implantation, trophoblast cells. Ectoplacental cones dissected from 7.5 day-old mouse embryos provided the source of trophoblastic cells. Co-cultures were performed using stimulated and non-stimulated trophoblast cells and erythrocytes under standard conditions. Phagocytic activity was expressed as the total number of phagocytic cells per ectoplacental cone, and as phagosomic vacuoles per trophoblast giant cell, either in the presence or absence of the stimulators. Both chemical agents had similar effects, less than 12 h after stimulation, statistically significant numbers of erythrophagosomes appear in the trophoblast giant cells (TGC). These findings demonstrate that TGC, like neutrophils and macrophages, can be activated to phagocytosis by exogenous factors. This enhanced activity may result from the generation and release of reactive oxygen species. In conclusion, our data suggest that, because stimulation was provided, the remarkable in vivo phagocytic activity of the trophoblast can be maintained under in vitro conditions, allowing study of the pathways and regulatory steps involved in this process.
Animals↗
Pituitary adenylate cyclase-activating polypeptide (PACAP38) modulates lymphocyte and macrophage functions: stimulation of adherence and opposite effect on mobility.
The effects of pituitary adenylate cyclase-activating polypeptide (PACAP38) in a concentration range from 10(-13) to 10(-6) M were studied, in vitro, on two functions of peritoneal rat lymphocytes and macrophages: adherence and mobility (spontaneous and chemotaxis). The results show that PACAP38 raised the adherence of the two cell types, increased the mobility of macrophages and decreased the mobility of lymphocytes. The maximal effects were observed at 10(-10) M in macrophages and at 10(-9) M in lymphocytes. Moreover, incubation with increasing concentrations of phorbol myristate acetate (PMA), a protein kinase C (PKC) activator, resulted in a progressive enhancement of adherence and chemotaxis of both macrophages and lymphocytes. In contrast, retinal, a PKC inhibitor, significantly decreased these capacities. Incubation of macrophages with both PMA and PACAP38 did not have a synergistic effect on chemotaxis and adherence whereas, with lymphocytes, adherence was increased and chemotaxis was partially decreased. On the other hand, incubation with forskolin (an enhancer of intracellular cyclic AMP [cAMP] levels) caused inhibition and stimulation of chemotaxis and adherence, respectively, in both cell types. PACAP38 prevented the inhibitory effect of forskolin on chemotaxis of macrophages but not of lymphocytes, whereas the simultaneous presence of PACAP38 and forskolin was synergistic for adherence of both peritoneal cells. In addition, PACAP38 was chemoattractant for macrophages but not for lymphocytes. Furthermore, a VIP receptor antagonist was able to partially reverse the modulatory effects of PACAP38 on lymphocytes, but not on macrophages. These data suggest that PACAP38 exerts its action through the binding to type I PACAP receptors and PKC activation in macrophages and through the elevation of intracellular cAMP levels by binding to type II PACAP receptors in lymphocytes. The present work reveals an additional link between neuropeptides and the immune system and suggests that the peptide PACAP modulates the immunological function of macrophages and lymphocytes.
Animals↗
Regulation of VIP production and secretion by murine lymphocytes.
Vasoactive intestinal peptide (VIP) is a neuropeptide present in the lymphoid microenvironment with a multiplicity of actions. Two sources for VIP have been described in the immune system, the terminals present in central and peripheral lymphoid organs and the immune cells. Although VIP is synthesized by lymphocytes, there is no evidence demonstrating that VIP is released, and which stimuli are able to induce VIP production and secretion. In this study, we demonstrated for the first time, that agents that mediate important immune functions, such as proliferation and antigenic stimulation (Con A, LPS, and anti-TCR antibody), inflammation (LPS, TNFalpha, IL-6 and IL-1beta) or apoptosis (dexamethasone) induce the production and release of VIP to the lymphoid microenvironment. We conclude that VIP is produced and secreted by lymphocytes and propose that during an immune response, the timely release of VIP within the lymphoid organs and peritoneum should influence the differentiation and/or downregulation of the ongoing response.
Animals↗
Vitamin A-related compounds, all-trans retinal and retinoic acids, selectively inhibit activities of mammalian replicative DNA polymerases.
Retinoic acids, vitamin A-related compounds, are known to be inhibitors of telomerase. We found that fucoxanthin from the sea alga Petalonia bingamiae is a potent inhibitor of mammalian replicative DNA polymerases (i.e., pol alpha, delta and epsilon). Since fucoxanthin is a carotenoid (provitamin A-related) compound, we characterized the biochemical modes of vitamin A-related compounds including vitamin A and provitamin A in this report. Subsequently, we found that fucoxanthin, all-trans retinal (RAL, vitamin A aldehyde) and all-trans retinoic acid (RA, vitamin A acid) inhibited the activities of replicative DNA polymerases with IC(50) values of 18-190, 14-17 and 8-30 microM, respectively. On the other hand, all-trans retinol (vitamin A) did not influence any of the DNA polymerase activities. RA inhibited not only the activities of pol alpha, delta and epsilon with IC(50) values of 30, 28 and 8 microM, respectively, but of pol beta with an IC(50) value of 27 microM. The tested vitamin A-related compounds did not influence the activities of DNA polymerases from a higher plant, cauliflower, prokaryotic DNA polymerases, or DNA metabolic enzymes such as human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. RAL and RA should be called selective inhibitors of mammalian DNA polymerases including telomerase, and RAL was a specific inhibitor of mammalian replicative DNA polymerases. As expected from these results in vitro, some of them could prevent the growth of NUGC-3 human gastric cancer cells, and especially RAL was a potent antineoplastic agent with an LD(50) value of 19 microM. The cells were halted at G1 phase in the cell cycle by RAL.
Antineoplastic Agents↗
Kinetic analysis of mouse retinal dehydrogenase type-2 (RALDH2) for retinal substrates.
Retinal dehydrogenase (RALDH) isozymes catalyze the terminal oxidation of retinol into retinoic acid (RA) that is essential for embryogenesis and tissue differentiation. To understand the role of mouse type 2 RALDH in synthesizing the ligands (all-trans and 9-cis RA) needed to bind and activate nuclear RA receptors, we determined the detailed kinetic properties of RALDH2 for various retinal substrates. Purified recombinant RALDH2 showed a pH optimum of 9.0 for all-trans retinal oxidation. The activity of the enzyme was lower at 37 degrees C compared to 25 degrees C. The efficiency of conversion of all-trans retinal to RA was 2- and 5-fold higher than 13-cis and 9-cis retinal, respectively. The K(m) for all-trans and 13-cis retinal were similar (0.66 and 0.62 microM, respectively). However, the K(m) of RALDH2 for 9-cis retinal substrate (2.25 microM) was 3-fold higher compared to all-trans and 13-cis retinal substrates. Among several reagents tested for their ability to either inhibit or activate RALDH2, citral and para-hydroxymercuribenzoic acid (p-HMB) inhibited and MgCl(2) activated the reaction. Comparison of the kinetic properties of RALDH2 for retinal substrates and its activity towards various reagents with those of previously reported rat kidney RALDH1 and human liver aldehyde dehydrogenase-1 showed distinct differences. Since RALDH2 has low K(m) and high catalytic efficiency for all-trans retinal, it may likely be involved in the production of all-trans RA in vivo.
Aldehyde Oxidoreductases↗
Purification and characterization of a novel cytosolic NADP(H)-dependent retinol oxidoreductase from rabbit liver.
Rabbit liver cytosol exhibits very high retinol dehydrogenase activity. At least two retinol dehydrogenases were demonstrated to exist in rabbit liver cytosol, and the major one, a cytosolic NADP(H)-dependent retinol dehydrogenase (systematic name: retinol oxidoreductase) was purified about 1795-fold to electrophoretic and column chromatographic homogeneity by a procedure involving column chromatography on AF-Red Toyopearl twice and then hydroxyapatite. Its molecular mass was estimated to be 34 kDa by SDS-PAGE, and 144 kDa by HPLC gel filtration, suggesting that it is a homo-tetramer. The enzyme uses free retinol and retinal, and their complexes with CRBP as substrates in vitro. The optimum pH values for retinol oxidation of free retinol and CRBP-retinol were 8.8-9.2 and 8.0-9.0, respectively, and those for retinal reduction of free retinal and retinal-CRBP were the same, 7.0-7.6. Km for free retinol and Vmax for retinal formation were 2.8 microM and 2893 nmol/min per mg protein at 37 degrees C (pH 9.0) and the corresponding values with retinol-CRBP as a substrate were 2.5 microM and 2428 nmol/min per mg protein at 37 degrees C (pH 8.6); Km for free retinal and Vmax for retinol formation were 6.5 microM and 4108 nmol/min per mg protein, and the corresponding values with retinal-CRBP as a substrate were 5.1 microM and 3067 nmol/min per mg protein at 37 degrees C, pH 7.4. NAD(H) was not effective as a cofactor. 4-Methylpyrazole was a weak inhibitor (IC50 = 28 mM) of the enzyme, and ethanol was neither a substrate nor an inhibitor of the enzyme. This enzyme exhibits relatively broad aldehyde reductase activity and some ketone reductase activity, the activity for aromatic substitutive aldehydes being especially high and effective. Whereas, except in the case of retinol, oxidative activity toward the corresponding alcohols was not detected. This novel cytosolic enzyme may play an important role in vivo in maintaining the homeostasis of retinal, the substrate of retinoic acid synthesis, at least in rabbit liver, since a high concentration of retinol in liver and the lower Km of the enzyme for retinol force the oxidative reaction, while higher activity of retinal reductase at physiological pH forces the reductive reaction.
Alcohol Oxidoreductases↗
Effect of retinoids on the growth of squamous cell carcinoma of the palate in rats.
The in vivo effects of retinoids on head and neck tumors were studied using Fisher 344 rats with squamous cell carcinoma implanted in the palate. Retinoids were given orally to rats, starting 2 weeks after tumor implantation. The animals were killed at 4 weeks, and the tumor volumes and body weights were measured. The animals had a greater response to all-trans-retinoic acid (58 per cent) and 13-cis-retinoic acid (60 per cent) than to all-trans-retinol (20 per cent) and 13-cis-retinal (30 per cent). Comparison of both tumor volumes and body weights among the retinoid-treated groups revealed that the body weights increased while the tumor volumes decreased. Retinoids seem to inhibit local tumor growth through their effects on host cellular and humoral immunity and through the inhibition of tumor cell keratinization.
Animals↗
Effects of beta-carotene, retinal, riboflavin, alpha-tocopherol and vitamins C and K1 on sister-chromatid exchanges induced by 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and cyclophosphamide in human lymphocyte cultures.
The vitamins and related compounds cited in the title were investigated for their abilities to modulate sister-chromatid exchanges (SCEs) induced by Trp-P-2 or cyclophosphamide (CP) in human peripheral lymphocyte cultures in the presence of an exogenous metabolizing system from rat liver. When inducer and test substances were given simultaneously, beta-carotene, retinal and alpha-tocopherol caused a dose-dependent decrease of SCE frequencies induced by Trp-P-2 and CP. Vitamin K1, however, brought about an identical effect with Trp-P-2 only, while with CP an initial decrease of SCEs was followed by a statistically significant re-increase at higher concentrations. Vitamin C was ineffective against Trp-P-2, but caused an overall increase of SCEs induced by CP. When blood cultures were preincubated with vitamins before the addition of CP or Trp-P-2, basically identical effects were observed with beta-carotene, retinal, alpha-tocopherol, vitamin K1 and vitamin C. Riboflavin decreased SCEs induced by Trp-P-2 in all treatment schedules, although statistically confirmed minima were observed in the dose-response curves, except in post-treatment experiments. On the other hand, riboflavin only reduced SCEs induced by CP when it was preincubated with lymphocytes. When vitamins were applied in a post-treatment schedule after removal of Trp-P-2 or CP, again, basically identical results against both genotoxins were observed with beta-carotene, retinal and alpha-tocopherol with vitamin K1, however, only with respect to Trp-P-2, and with vitamin C only with respect to CP. In the post-treatment schedule, vitamin K1 caused a decrease of SCE frequencies induced by CP, and vitamin C a decrease of SCEs induced by Trp-P-2.
Animals↗
Conformational change in bacterio-opsin on binding to retinal.
The detailed mechanism of retinal binding to bacterio-opsin is important to understanding retinal pigment formation as well as to the process of membrane protein folding. We have measured the temperature dependence of bacteriorhodopsin formation from bacterio-opsin and all-trans retinal. An Arrhenius plot of the apparent second-order rate constants gives an activation energy of 11.6 +/- 0.7 kcal/mol and an activation entropy of -4 +/- 2 cal/mol deg. Comparison of the activation entropy to model compound reactions suggests that chromophore formation in bacteriorhodopsin involves a substantial protein conformational change. Cleavage of the polypeptide chain between residues 71 and 72 has little effect on the activation energy or entropy, indicating that the connecting loop between helices B and C is not involved in this conformational change.
Bacteriorhodopsins↗
Why is the human visual system sensitive only to light of wavelengths from approximately 760 to 380 nm? An answer from thermochemistry and chemical kinetics.
The range of visible light has been explained by the knowledge available of gas-phase thermochemistry and chemical kinetics. The C, C-pi bond dissociation energy at the 11 and 12 positions of the rhodopsin complex is estimated to be approximately 37.4+/-1.5 kcal/mol. This energy is just equivalent to wavelength of the red limit of the visible light. The photons of the violet limit (approx. 75.2 kcal/mol) can break the weakest C-C and H-C bonds in important species involved in the photo-induced cis-trans isomerization cycle and can stop the visual cycle.
Humans↗
Positive, accurate animal identification.
Positive, accurate identification of animals and their products would be very helpful in livestock commerce, prevention of theft and fraud and in tracing animals and products to origin. Food safety, animal health, and prevention of epidemics, would be enhanced by combining identification with location. Identification may be by electronic chips, iris or retinal scans, antibody or DNA analysis. A cross listing of one or more means in a central repository would facilitate tracing origin of animals and build confidence in transactions of all kinds.
Animal Identification Systems↗
Simultaneous quantification of retinol, retinal, and retinoic acid isomers by high-performance liquid chromatography with a simple gradiation.
A new method of high-performance liquid chromatography (HPLC) analysis to quantify isomers of retinol, retinal and retinoic acid simultaneously was established. The HPLC system consisted of a silica gel absorption column and a linear gradient with two kinds of solvents containing n-Hexane, 2-propanol, and glacial acetic acid in different ratios. It separated six retinoic acid isomers (13-cis, 9-cis, all-trans, all-trans-4-oxo, 9-cis-4-oxo, 13-cis-4-oxo), three retinal isomers (13-cis-, 9-cis-, and all-trans) and two retinol isomers (13-cis- and all-trans). Human serum samples were subjected to this HPLC analysis and at least, all-trans retinol, 13-cis retinol, and all-trans retinoic acid were detectable. This HPLC system is useful for evaluating retinoic acid formation from retinol via a two-step oxidation pathway. Moreover, it could be applied to monitoring the concentrations of various retinoids, including all-trans retinoic acid in human sera.
Chromatography, High Pressure Liquid↗
Phototrophic growth of halobacteria and its use for isolation of photosynthetically-deficient mutants.
Phototrophic growth conditions for halobacteria in complex and synthetic media have been established, demonstrating the photosynthetic capacity of this class of archaebacteria. Mutagenesis, 5-bromo-2'-deoxyuridine selection and screening techniques are described which are useful tools in the elucidation of the structure-function relationship of retinal proteins in halobacteria.
Anaerobiosis↗
Retinal and non-retinal inputs upon retinopetal RMA neurons in the lamprey: a light and electron microscopic study combining HRP axonal tracing and GABA immunocytochemistry.
A light and electron microscopic study, combining HRP axonal tracing or degeneration and GABA immunocytochemistry, was performed in the lamprey Lampetra fluviatilis in order to analyze retinal and non-retinal inputs upon the retinopetal neurons localized in the reticular mesencephalic area (RMA). The iontophoretic deposit of HRP onto the central stump of the cut optic nerve produced a dense anterograde labeling in the retino-recipient strata marginale and cellular externum of the optic tectum as well as the retrograde labeling of retinopetal neurons in the mesencephalic tegmentum. The large ascending proximal dendrites of the retinopetal neurons constituted a distinct bundle coursing first dorso-laterally in the dorsal mesencephalic tegmentum, and then dorso-medially in the strata fibrosum centrale and cellulare et fibrosum internum of the optic tectum before their distal portions penetrated the retino-recipient tectal layers. The distribution of GABA immunoreactivity was also investigated in the tectal layers and dorsal mesencephalic tegmentum with both pre- and post-embedding methods. The retinal terminals, identified either following HRP iontophoresis in the optic nerve or in early phases of degeneration after short-term survivals following retinal lesion, contained rounded-shaped synaptic vesicles and were always GABA immunonegative. They established asymmetrical synaptic contacts on the distal dendrites of RMA neurons and represented 11.4% of all terminals contacting such neurons (15% of these neurons were GABA immunopositive). The dense extra-retinal input upon the retinopetal RMA neurons was composed of five types of axon terminal profiles, either GABA-immunopositive or -immunonegative. Considering the different cytochemical types of axon terminals contacting RMA neurons, as well as the characteristics of the retinal targets of these neurons, we suggest that, globally, the effects of RMA neurons upon the retina are mainly inhibitory.
Afferent Pathways↗
Role of noncovalent binding of 11-cis-retinal to opsin in dark adaptation of rod and cone photoreceptors.
Regeneration of visual pigments of vertebrate rod and cone photoreceptors occurs by the initial noncovalent binding of 11-cis-retinal to opsin, followed by the formation of a covalent bond between the ligand and the protein. Here, we show that the noncovalent interaction between 11-cis-retinal and opsin affects the rate of dark adaptation. In rods, 11-cis-retinal produces a transient activation of the phototransduction cascade that precedes sensitivity recovery, thus slowing dark adaptation. In cones, 11-cis-retinal immediately deactivates phototransduction. Thus, the initial binding of the same ligand to two very similar G protein receptors, the rod and cone opsins, activates one and deactivates the other, contributing to the remarkable difference in the rates of rod and cone dark adaptation.
3',5'-Cyclic-GMP Phosphodiesterases↗
Multiple phosphorylation of rhodopsin and the in vivo chemistry underlying rod photoreceptor dark adaptation.
Dark adaptation requires timely deactivation of phototransduction and efficient regeneration of visual pigment. No previous study has directly compared the kinetics of dark adaptation with rates of the various chemical reactions that influence it. To accomplish this, we developed a novel rapid-quench/mass spectrometry-based method to establish the initial kinetics and site specificity of light-stimulated rhodopsin phosphorylation in mouse retinas. We also measured phosphorylation and dephosphorylation, regeneration of rhodopsin, and reduction of all-trans retinal all under identical in vivo conditions. Dark adaptation was monitored by electroretinography. We found that rhodopsin is multiply phosphorylated and then dephosphorylated in an ordered fashion following exposure to light. Initially during dark adaptation, transduction activity wanes as multiple phosphates accumulate. Thereafter, full recovery of photosensitivity coincides with regeneration and dephosphorylation of rhodopsin.
Adaptation, Ocular↗
Selective photostimulation of genetically chARGed neurons.
To permit direct functional analyses of neural circuits, we have developed a method for stimulating groups of genetically designated neurons optically. Coexpression of the Drosophila photoreceptor genes encoding arrestin-2, rhodopsin (formed by liganding opsin with retinal), and the alpha subunit of the cognate heterotrimeric G protein--an explosive combination we term "chARGe"--sensitizes generalist vertebrate neurons to light. Illumination of a mixed population of neurons elicits action potentials selectively and cell-autonomously in its genetically chARGed members. In contrast to bath-applied photostimulants or caged neurotransmitters, which act indiscriminately throughout the illuminated volume, chARGe localizes the responsiveness to light. Distributed activity may thus be fed directly into a circumscribed population of neurons in intact tissue, irrespective of the spatial arrangement of its elements.
Action Potentials↗