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PubMed2006

Improvement in rod and cone function in mouse model of Fundus albipunctatus after pharmacologic treatment with 9-cis-retinal.

PURPOSE: To assess changes in rod and cone visual functions in a mouse model of Fundus albipunctatus with disrupted 11-cis-retinol dehydrogenase (RDH) genes after pharmacologic treatment with an artificial retinal chromophore. METHODS: Retinoid levels and photoreceptor functions of Rdh5-/-Rdh11-/- mice at a variety of light intensities were analyzed with normal-phase HPLC and ERG techniques. Production of 11-cis-retinal, the visual pigment chromophore, was suppressed with a potent inhibitor of the retinoid cycle, all-trans-retinylamine (Ret-NH2). The chromophore was replaced by a functional geometric isomer, 9-cis-retinal, delivered by oral gavage. RESULTS: Aberrant cone responses were detected in 12-month-old Rdh5-/-Rdh11-/- mice raised in a 12-hour light/12-hour dark cycle. This cone defect was exacerbated in conditions of low levels of 11-cis-retinal. Administration of 9-cis-retinal increased the rate of dark adaptation and improved cone function in Rdh5-/-Rdh11-/- mice. CONCLUSIONS: Disruption of 11-cis-RDHs causes a slowly developing cone dystrophy caused by inefficient cone pigment regeneration. Rod and cone visual function improved significantly in the mouse model of F. albipunctatus after treatment with 9-cis-retinal, suggesting a potential approach to slow the progression of cone dystrophy in affected humans.

Animals↗
PubMed2002

4-(N,N-dipropylamino)benzaldehyde inhibits the oxidation of all-trans retinal to all-trans retinoic acid by ALDH1A1, but not the differentiation of HL-60 promyelocytic leukemia cells exposed to all-trans retinal.

BACKGROUND: The signal transduction pathways mediated by retinoic acid play a critical role in the regulation of cell growth and differentiation during embryogenesis and hematopoiesis as well as in a variety of tumor cell lines in culture. Following the reports that two members of the superfamily of aldehyde dehydrogenase (ALDH) enzymes, ALDH1A1 and ALDH1A2, were capable of catalyzing the oxidation of all-trans retinal to all-trans retinoic acid with submicromolar Km values, we initiated an investigation of the ability of 4-(N,N-dipropylamino)benzaldehyde (DPAB) to inhibit the oxidation of retinal by purified mouse and human ALDH1A1. RESULTS: Our results show that DPAB potently inhibits retinal oxidation, with IC50 values of 0.11 and 0.13 microM for purified mouse and human ALDH1A1, respectively. Since the HL-60 human myeloid leukemic cell line has been used extensively to study the retinoic acid induced differentiation of HL-60 cells to granulocytes, and ALDH1A1 activity had previously been reported in HL-60 cells, we investigated the ability of DPAB to block differentiation of HL-60 promyelocytic leukemia cells exposed to retinal in culture. In HL-60 cells coincubated with 1 microM retinal and 50 microM DPAB for 144 hours, cell differentiation was inhibited only 30%. Furthermore, the NAD-dependent oxidation of propanal or retinal was less than 0.05 nmoles NADH formed/min-10(7) cells in spectrophotometric assays using HL-60 cell extracts. CONCLUSION: Although ALDH1A1 may be the major catalytic activity for retinal oxidation in some retinoid-dependent mouse and Xenopus embryonic tissues and in adult human and mouse hematopoietic stem cells, another catalytic activity appears to synthesize the retinoic acid ligand necessary to stimulate the differentiation of HL-60 cells to end stage granulocytes.

Aldehyde Dehydrogenase↗
PubMed2002

Cloning of monkey RALDH1 and characterization of retinoid metabolism in monkey kidney proximal tubule cells.

All-trans and 9-cis retinoic acids function as ligands for retinoic acid receptors (RARs and RXRs), which are ligand-dependent transcription factors and play important roles in development and cellular differentiation. Several retinal dehydrogenases are likely to contribute to the production of all-trans and 9-cis RAs in vivo, but their respective roles in different tissues are still poorly characterized. We have previously characterized and cloned from kidney tissues the rat retinal dehydrogenase type 1 (RALDH1), which oxidizes all-trans and 9-cis retinal with high efficiency but is inactive with 13-cis retinal. Here we have characterized the retinal-oxidizing activity in monkey JTC12 cells, which are derived from kidney proximal tubules. In vitro assay of cell lysates revealed the presence of a NAD+-dependent dehydrogenase that catalyzed the oxidation of all-trans, 9-cis, and 13-cis retinal. Northern blot analysis of JTC12 RNAs and cloning by reverse transcription-polymerase chain reaction demonstrated expression of a monkey homolog of RALDH1. Bacterially expressed JTC12 RALDH1 catalyzed conversion of all three retinal isomers, with a higher catalytic efficiency for 9-cis retinal than for all-trans and 13-cis retinal. Accordingly, live JTC12 produced 9-cis retinoic acid more efficiently than all-trans retinoic acid from their respective retinal precursors. Only metabolites corresponding to the same steric conformation were formed from 9-cis or all-trans retinal, indicating a lack of detectable isomerizing activity in JTC12 cells.

Aldehyde Oxidoreductases↗
PubMed1999

Subcellular accumulation of beta-carotene and retinoids in growth-inhibited NCI-H69 small cell lung cancer cells.

Delivery of beta-carotene in tetrahydrofuran slowed the growth of NCI-H69 small cell lung cancer cells. Analysis of cells and cellular fractions revealed that beta-carotene-treated cells accumulated beta-carotene as well as some polar metabolites, primarily in the crude nuclei. Cells were grown at 1 x 10(5) cells/ml and treated with 20 microM beta-carotene. Growth monitoring up to 15 days indicated an inverse relationship between the duration of beta-carotene treatment and the rate of cell growth. Reverse-phase high-performance liquid chromatography analysis of treated cells showed the presence of beta-carotene, retinoic acid, retinol, and retinal, with beta-carotene accounting for the major material recovered. When cellular fractions were analyzed for beta-carotene, it was found to be located primarily in the crude nuclei. These results demonstrate that treatment of small cell lung cancer cells with beta-carotene results in a reduced growth of the cells. Further investigation is required to show a direct effect of beta-carotene or its intracellular polar metabolites on these cells. Accumulation of beta-carotene in the nucleus suggests a need for evaluating the nuclear role for beta-carotene.

Antioxidants↗
PubMed1987

Dynamic actions of arachidonic acid and protein kinase C in pituitary stimulation by gonadotropin-releasing hormone.

The relative contributions of arachidonic acid (AA)- and protein kinase C-dependent pathways during the immediate LH response to short term stimulation by GnRH were analyzed in perifused anterior pituitary cells cultured on Cytodex beads. The LH response to a 2-min pulse of 10 nM GnRH was biphasic, with a rapid increase to an initial peak, followed by a second peak or shoulder before the gradual return to baseline release. Retinal, which inhibits activation of protein kinase C, reduced the total LH response to GnRH by 35-40% and advanced the termination of the response, but did not alter the height, position, or rate of onset of the initial LH peak. In contrast, pretreatment with the lipoxygenase inhibitor nordihydroguaiaretic acid decreased the total LH response to GnRH by 60%, reduced the magnitude and latency of the first LH peak, and shortened the duration of the response. Pretreatment with both retinal and nordihydroguaiaretic acid abolished the GnRH-induced LH release. Addition of 2-min pulses of AA induced LH responses of short duration that coincided with the first phase of GnRH-stimulated LH release. Application of 2-min pulses of either tetradecanoyl phorbol 13-acetate (TPA) or dioctanoyl glycerol generated LH responses with delayed onsets that corresponded to the second phase of the GnRH-induced response. The LH response to the combined action of AA and TPA approximated that induced by GnRH. These results suggest that mobilization and metabolism of AA are important in the rapid initial phase of the LH response to GnRH, and that activation of protein kinase C-dependent mechanisms participates in the maintenance of the LH response. During continuous perifusion with 10 nM GnRH, addition of 2-min pulses of 100 nM GnRH and 100 microM AA, but not 100 nM TPA, stimulated further increases in LH release. This suggests that during prolonged GnRH action, LH release is primarily maintained by protein kinase C-dependent mechanisms. The results of this study indicate that GnRH stimulation of LH release requires the coordinated actions of at least two major interrelated mechanisms, namely those activated by AA and/or its metabolites and those maintained by protein kinase C-dependent pathways.

Animals↗
PubMed1989

Gonadotropin-releasing hormone-stimulated luteinizing hormone (LH) release from ovine gonadotrophs in culture is separate from phorbol ester-stimulated LH release.

The proposed involvement of protein kinase-C (PKC) as a mediator of GnRH action in pituitary cells was investigated. Treatment of dispersed ovine pituitary cells with the PKC activator phorbol 12-myristate-13-acetate (PMA) for 6 h at a dose of 10 nM stimulated the release of 5- to 10-fold more LH than did GnRH at the same dose. Analogs of PMA also stimulated LH release, but at levels parallel to their reported abilities to activate PKC. Treatment with GnRH plus PMA stimulated more LH release than either one alone in a strictly additive manner at all dose combinations from 10 pM to 100 nM. The PKC-activating diacylglycerol sn-1,2-dioctanoylglycerol also stimulated LH release that was additive with GnRH-stimulated LH release. Furthermore, retinal, an inhibitor of PKC, inhibited only PMA-stimulated LH release and not GnRH-stimulated LH release. These results do not support the theory that PKC activation is a necessary part of the mechanism of GnRH-stimulated LH release. The theory that calcium mobilization is also part of the mechanism of GnRH-stimulated LH release was, however, supported by the finding that GnRH did not stimulate LH release from ovine pituitary cells incubated in calcium-free medium. This demonstrates the absolute requirement for calcium in GnRH action, as proposed by others. In addition, the calcium ionophores A23187 and ionomycin were able to trigger LH release by themselves as well as augment GnRH- and PMA-stimulated LH release. This further strengthens the hypothesis that calcium mobilization is important in LH secretion.

Animals↗
PubMed2000

Sertoli cell prostaglandin D2 synthetase is a multifunctional molecule: its expression and regulation.

PGD2 synthetase (PGD-S; PGH2 D-isomerase; EC 5.3.99.2) is a bifunctional protein first identified in the mammalian brain. It acts as a PGD2-producing enzyme and a retinoid transporter. PGD-S is present in the testis, where its protein and messenger RNA levels are similar to those in the brain. In view of its diversified regulatory functions, we investigated its regulation using primary cultures of Sertoli cells in vitro to assess its role in the testis. When Sertoli cells were cultured in serum-free medium to allow the formation of specialized junctions, it was found that PGD-S expression increased steadily with time, coinciding with the formation of inter-Sertoli junctions in vitro. However, neither germ cells (using a Sertoli/germ cell ratio between 1:1 and 1:30 when Sertoli cells were cultured at a density of 5x10(4) cells/cm2) nor germ cell-conditioned medium affected the expression of Sertoli cell PGD-S in vitro. These results thus unequivocally demonstrated that germ cells do not play a role in regulating testicular PGD-S expression. Although FSH, dihydrotestosterone, and testosterone had no apparent effect on Sertoli cell PGD-S expression, the addition of progesterone(1x10(-11) to 1x10(-9) M) and T3 (1x10(-11) to 1x10(-9) M) to Sertoli cell cultures elicited a significant increase in PGD-S expression by as much as 4.5- and 2.5 fold, respectively. As PGD-S is a known retinoid transporter, the effects of all-trans-retinoic acid and all-trans-retinal on Sertoli cell PGD-S expression were also assessed. Both compounds were found to induce Sertoli cell PGD-S expression. In summary, PGD-S is a putative Sertoli cell product whose expression is regulated by progesterone, metabolites of vitamin A, and T3. In view of its dual biological properties, a study of its regulation and physiology will yield new insights into understanding its role in the testis.

Aging↗
PubMed2006

A novel cytochrome P450, zebrafish Cyp26D1, is involved in metabolism of all-trans retinoic acid.

Retinoid signaling is essential for development of vertebrate embryos, and its action is mainly through retinoic acid (RA) binding to its RA receptors and retinoid-X receptors, while the critical concentration and localization of RA in embryos are determined by the presence and activity of retinal dehydrogenases (for RA synthesis) and cytochrome P450 RAs (Cyp26s) (for degradation of RA). Previously, we identified a novel cyp26 gene (cyp26d1) in zebrafish that is expressed in hindbrain during early development. Using reverse-phase HPLC analyses, we show here that zebrafish Cyp26D1 expressed in 293T cells could metabolize all-trans RA, 9-cis RA, and 13-cis RA, but could not metabolize retinol or retinal. The metabolites of all-trans RA produced by Cyp26D1 were the same as that produced by Cyp26A1, which are mainly 4-hydroxy-all-trans-RA and 4-oxo-all-trans-RA. Performing mRNA microinjection into zebrafish embryos, we demonstrated that overexpression of Cyp26D1 in embryos not only caused the distance between rhombomere 5 and the first somite of the injected embryos to be shorter than control embryos but also resulted in left-right asymmetry of somitogenesis in the injected embryos. These alterations were similar to those caused by the overexpression of cyp26a1 in zebrafish embryos and to that which resulted from treating embryos with 1 microm 4-diethylamino-benzaldehyde (retinal dehydrogenase inhibitor), implying that cyp26d1 can antagonize RA activity in vivo. Together, our in vitro and in vivo results provided direct evidence that zebrafish Cyp26D1 is involved in RA metabolism.

Amino Acid Sequence↗
PubMed2003

Provitamin A conversion to retinal via the beta,beta-carotene-15,15'-oxygenase (bcox) is essential for pattern formation and differentiation during zebrafish embryogenesis.

The egg yolk of vertebrates contains carotenoids, which account for its characteristic yellow color in some species. Such plant-derived compounds, e.g. beta-carotene, serve as the natural precursors (provitamins) of vitamin A, which is indispensable for chordate development. As egg yolk also contains stored vitamin A, carotenoids have so far been solely discussed as pigments for the coloration of the offspring. Based on our recent molecular identification of the enzyme catalyzing provitamin A conversion to vitamin A, we address a possible role of provitamin A during zebrafish (Danio rerio) development. We cloned the zebrafish gene encoding the vitamin A-forming enzyme, a beta,beta-carotene-15,15'-oxygenase. Analysis of its mRNA expression revealed that it is under complex spatial and temporal control during development. Targeted gene knockdown using the morpholino antisense oligonucleotide technique indicated a vital role of the provitamin A-converting enzyme. Morpholino-injected embryos developed a morphological phenotype that included severe malformation of the eyes, the craniofacial skeleton and pectoral fins, as well as reduced pigmentation. Analyses of gene expression changes in the morphants revealed that distinct retinoic acid-dependent developmental processes are impaired, such as patterning of the hindbrain and differentiation of hindbrain neurons, differentiation of neural crest derivatives (including the craniofacial skeleton), and the establishment of the ventral retina. Our data provide strong evidence that, for several developmental processes, retinoic acid generation depends on local de novo formation of retinal from provitamin A via the carotene oxygenase, revealing an unexpected, essential role for carotenoids in embryonic development.

Acyclic Monoterpenes↗
PubMed1988

Characterization of retinoid metabolism in the developing chick limb bud.

Retinoids (vitamin A derivatives) have been shown to have striking effects on developing and regenerating vertebrate limbs. In the developing chick limb, retinoic acid is a candidate morphogen that may coordinate the pattern of cellular differentiation along the anteroposterior limb axis. We describe a series of investigations of the metabolic pathway of retinoids in the chick limb bud system. To study retinoid metabolism in the bud, all-trans-[3H]retinol, all-trans-[3H]retinal and all-trans-[3H]retinoic acid were released into the posterior region of the limb anlage, the area that contains the zone of polarizing activity, a tissue possibly involved in limb pattern formation. We found that the locally applied [3H]retinol is primarily converted to [3H]retinal, [3H]retinoic acid and a yet unidentified metabolite. When [3H]retinal is locally applied, it is either oxidized to [3H]retinoic acid or reduced to [3H]retinol. In contrast, local delivery of retinoic acid to the bud yields neither retinal nor retinol nor the unknown metabolite. This flow of metabolites agrees with the biochemical pathway of retinoids that has previously been elucidated in a number of other animal systems. To find out whether metabolism takes place directly in the treated limb bud, we have compared the amount of [3H]retinoid present in each of the four limb anlagen following local treatment of the right wing bud. The data suggest that retinoid metabolism takes place mostly in the treated limb bud. This local metabolism could provide a simple mechanism to generate in a controlled fashion the biologically active all-trans-retinoic acid from its abundant biosynthetic precursor retinol. In addition, local metabolism supports the hypothesis that retinoids are local chemical mediators involved in pattern formation.

Animals↗
PubMed2002

The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation.

Mutations in the photopigment rhodopsin are the major cause of autosomal dominant retinitis pigmentosa. The majority of mutations in rhodopsin lead to misfolding of the protein. Through the detailed examination of P23H and K296E mutant opsin processing in COS-7 cells, we have shown that the mutant protein does not accumulate in the Golgi, as previously thought, instead it forms aggregates that have many of the characteristic features of an aggresome. The aggregates form close to the centrosome and lead to the dispersal of the Golgi apparatus. Furthermore, these aggregates are ubiquitinated, recruit cellular chaperones and disrupt the intermediate filament network. Mutant opsin expression can disrupt the processing of normal opsin, as co-transfection revealed that the wild-type protein is recruited to mutant opsin aggregates. The degradation of mutant opsin is dependent on the proteasome machinery. Unlike the situation with DeltaF508-CFTR, proteasome inhibition does not lead to a marked increase in aggresome formation but increases the retention of the protein within the ER, suggesting that the proteasome is required for the efficient retrotranslocation of the mutant protein. Inhibition of N-linked glycosylation with tunicamycin leads to the selective retention of the mutant protein within the ER and increases the steady state level of mutant opsin. Glycosylation, however, has no influence on the biogenesis and targeting of wild-type opsin in cultured cells. This demonstrates that N-linked glycosylation is required for ER-associated degradation of the mutant protein but is not essential for the quality control of opsin folding. The addition of 9-cis-retinal to the media increased the amount of P23H, but not K296E, that was soluble and reached the plasma membrane. These data show that rhodopsin autosomal dominant retinitis pigmentosa is similar to many other neurodegenerative diseases in which the formation of intracellular protein aggregates is central to disease pathogenesis, and they suggest a mechanism for disease dominance.

Animals↗
PubMed1993

Retinals and retinols induced by estrogen in the blood plasma of Xenopus laevis.

Injection of estrogen into male Xenopus laevis induced the appearance of retinals (retinal and 3-dehydroretinal) and a considerable increase in the amount of retinols (retinol and 3-dehydroretinol) in the blood plasma. These retinoids were mainly in the all-trans form. Without estrogen injection, retinols were normally found in the blood plasma of both males and females, but only trace amounts of retinals were detected and these were restricted to the plasma of females. The proteins in the blood plasma of estrogen-injected males were separated into two fractions. One fraction included vitellogenin, the precursor of egg yolk proteins, and the other contained some plasma proteins other than vitellogenin. Retinals were detected in the former and retinols in the latter. It is suggested that retinals are bound to vitellogenin and are taken up into oocytes in the process of vitellogenesis.

Animals↗
PubMed2000

[Studies on organofluorine compounds: an overview of our 30 years].

This review article covers our research activities over 30 years in organofluorine chemistry. The followings are briefly summarized researches in this memorandum: (1) Trifluoromethylation of organic halides with trifluoromethyl copper complex and its application to trifluoromethylated nucleosides, (2) a systematic study on reactivity of aromatic trifluoromethyl compounds, (3) valence bond isomers of aromatic compounds stabilized by the trifluoromethyl groups, and (4) synthesis of fluorinated bioactive compounds which involve vitamin D3, arachidonic acid and its metabolites, and retinal.

Chemistry, Organic↗
PubMed2006

Letter: radical ion and protonated molecule formation with retinal in electrospray and nanospray.

This paper reports a preliminary study of the nanospray ionisation mass spectrometry analyses of retinoic acid and retinal. The results are compared and contrasted to the results normally observed with electrospray ionisation. A significant difference in behaviour was observed for the balance between radical ion formation and protonated molecule formation for retinal. The results suggest that the influence of the very different ionisation conditions present in nanospray is very important in determining how ionisation is achieved and has potentially wide ranging applications in the fields of mass spectral analysis of biological and medical extracts.

Chromatography, High Pressure Liquid↗
PubMed2006

Heterogeneity in regeneration of bacteriorhodopsin from bacterio-opsin and all-trans retinal at high temperatures: implications for dynamic structural fluctuations.

Measurements of regeneration kinetics were performed in order to investigate the regeneration mechanisms of bacteriorhodopsin (bR) from thermally unfolded bacterio-opsin (bO) and all-trans retinal. Regeneration kinetics data were successfully fitted to a single exponential function when regeneration was performed at 25 degrees C after incubation at high temperatures. Conversely, the process of regeneration after the addition of retinal to bO at high temperatures occurred at two different rate constants. These findings strongly suggest that the slower regeneration of bR at high temperatures occurs as a result of dynamic structural fluctuation of bO, whereas the faster process corresponds to regeneration from bO, which retains a native structure capable of retinal binding.

Bacteriorhodopsins↗
PubMed2005

Regeneration of bacteriorhodopsin from thermally unfolded bacterio-opsin and all-trans retinal at high temperatures.

The temperature dependence of regeneration of bacteriorhodopsin (bR) from its apoprotein, bacterio-opsin (bO), and all-trans retinal was investigated using two different procedures to probe the structural properties of bO at high temperatures. Regeneration experiments performed at 25 degrees C after incubation of bO within the temperature range of 35-75 degrees C indicate that irreversible thermal unfolding begins at 50 degrees C. When bO is incubated for one hour and mixed with retinal at the same elevated temperatures, however, a greater extent of regeneration to bR occurs, even at temperatures ranging from 50 to 65 degrees C. These experimental results indicate that regeneration of bR occurs from thermally unfolded bO and suggest dynamic structural fluctuation of bO in the unfolded state.

Bacteriorhodopsins↗