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PubMed2006

Distinct distal regulatory elements control tyrosinase expression in melanocytes and the retinal pigment epithelium.

Pigment cells of mammals are characterized by two different developmental origins: cells of the retinal pigment epithelium (RPE) originate from the optic cup of the developing forebrain, whereas melanocytes arise from the neural crest. The pigmentation gene tyrosinase is expressed in all pigment cells but differentially regulated in melanocytes and RPE. The tyrosinase promoter does not confer strong expression in pigment cells in vivo, while inclusion of a distal regulatory element at position -15 kb is necessary and sufficient to provide strong expression in melanocytes. Nevertheless, the regulatory elements responsible for correct spatial and temporal tyrosinase expression in the RPE remained unidentified so far. In this report, we show that a 186 kb BAC containing the tyrosinase gene provides transgene expression in both RPE and melanocytes indicating the presence of regulatory sequences required for expression in the RPE. A deletion analysis of the BAC was performed demonstrating that a RPE-regulatory element resides between -17 and -75 kb. Using multi-species comparative genomic analysis we identified three conserved sequences within this region. When tested in transgenic mice one of these sequences located at -47 kb targeted expression to the RPE. In addition, deletion of this regulatory element within a tyrosinase::lacZ BAC provided evidence that this sequence is not only sufficient but also required for correct spatial and temporal expression in the RPE. The identification of this novel element demonstrates that tyrosinase gene expression is controlled by separate distal regulatory sequences in melanocytes and RPE.

Albinism, Oculocutaneous↗
PubMed2000

Inhibition of experimental choroidal neovascularization by overexpression of tissue inhibitor of metalloproteinases-3 in retinal pigment epithelium cells.

PURPOSE: To evaluate the feasibility of introducing exogenous tissue inhibitor of metalloproteinases-3 gene into the rat retinal pigment epithelium using hemagglutinating virus of Japan liposomes and to assess the effect of tissue inhibitor of metalloproteinases-3 overexpression in retinal pigment epithelium cells on the formation of experimental choroidal neovascularization. METHODS: Hemagglutinating virus of Japan liposomes containing hemagglutin epitope-tagged tissue inhibitor of metalloproteinases-3 gene were injected into the subretinal space in rat eyes. Localization of oligonucleotides was evaluated by fluorescence microscopy. Exogenous tissue inhibitor of metalloproteinases-3 mRNA expression was assessed by reverse transcribed polymerase chain reaction. Exogenous tissue inhibitor of metalloproteinases-3 protein expression was visualized by immunostaining with monoclonal antibody 12CA5 against the hemagglutin epitope. Three days after transfection of tissue inhibitor of metalloproteinases-3 gene into retinal pigment epithelium cells, intense laser photocoagulation was performed and the incidence of choroidal neovascularization was assessed by fluorescein fundus angiography. RESULTS: Exogenous tissue inhibitor of metalloproteinases-3 mRNA expression in the choroid and retina was detected on day 3. The efficiency of tissue inhibitor of metalloproteinases-3 gene transfection into retinal pigment epithelium cells was greatest on day 7 and decreased gradually thereafter. The incidence of choroidal neovascularization in tissue inhibitor of metalloproteinases-3 gene-transfected eyes was markedly decreased compared with controls. CONCLUSIONS: This study shows that tissue inhibitor of metalloproteinases-3 gene can be transferred into rat retinal pigment epithelium using the hemagglutinating virus of Japan-liposome method and that tissue inhibitor of metalloproteinases-3 gene overexpression can inhibit development of experimental choroidal neovascularization. This method may represent a future treatment modality for human macular degeneration associated with choroidal neovascularization.

Animals↗
PubMed2001

Limited macular translocation for the management of subfoveal retinal pigment epithelial loss after submacular surgery.

PURPOSE: To report a case of subfoveal retinal pigment epithelial (retinal pigment epithelium) loss after submacular surgery managed successfully by limited macular translocation. METHODS: Case report. RESULTS: A 28-year-old woman presented with a visual acuity of 20/100 caused by subfoveal choroidal neovas-cularization secondary to ocular histoplasmosis syndrome. Submacular resection of the choroidal neovascularization was complicated by inadvertent retinal pigment epithelium loss from beneath the foveal center. She underwent limited macular translocation 5 days after the initial surgery and had successful displacement of the fovea to an area inferior to the retinal pigment epithelium defect. Her visual acuity was 20/60 4 months postoperatively. CONCLUSION: This report demonstrates the feasibility of using limited macular translocation for the management of eyes with central retinal pigment epithelium defect after submacular surgery and extends the clinical indications for limited macular translocation.

Adult↗
PubMed2002

Retinal pigment epithelial changes after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling.

PURPOSE: To report the results of macular hole surgery using indocyanine green to improve visualization and facilitate peeling of the internal limiting membrane. METHODS: A retrospective noncomparative review of a consecutive series of 22 patients (22 eyes) who underwent macular hole repair using indocyanine green to facilitate visualization of the internal limiting membrane was performed. One patient was excluded because of a history of a rhegmatogenous retinal detachment. All patients underwent a three-port pars plana vitrectomy with internal limiting membrane peeling. Indocyanine green (0.1% solution) was used to assist in the visualization of the internal limiting membrane. The main outcome measures were postoperative visual acuity, macular hole status, and postoperative retinal pigment epithelial changes. RESULTS: In 21 eyes, the median preoperative best-corrected visual acuity was 20/200 (range, 20/60 to counting fingers at 5 feet). The median postoperative visual acuity was 20/400 (range, 20/60-1/200) with an average follow-up of 13 weeks. The macular hole was closed in 18 eyes (86%) at the most recent follow-up. Ten eyes were found to have atrophic retinal pigment epithelium changes in the area of the previous macular hole. CONCLUSIONS: Indocyanine green assists in visualization of the internal limiting membrane in macular hole surgery. In our series, 10 eyes had unusual atrophic changes in the retinal pigment epithelium at the site of the previous macular hole, or in the area where the indocyanine green solution would have had direct access to the bare retinal pigment epithelium cells. Although the use of indocyanine green improves visualization and assists with peeling of the internal limiting membrane, the safety and potential toxicity of indocyanine green to the retinal pigment epithelium require further investigation.

Aged↗
PubMed2002

Recurring transitory blindness caused by primary marginal pigment epithelial iris cysts.

PURPOSE: To report four cases of primary pupillary pigment epithelial iris cysts, all members of one family, in which two of the patients had recurring transitory visual impairment. METHODS: Observational case series. History was taken, the patients were examined with slit-lamp and ultrasound biomicroscopy, and surgically removed cyst tissue was examined with transmission electron microscopy. RESULTS: Pupillary pigment epithelial cysts of the iris generally show an autosomal dominant heredity pattern, with occasional lack of penetrance. In two of our cases, the size and location of the cysts caused visual symptoms, necessitating surgical removal. The cyst wall consists entirely of pigment epithelial cells. CONCLUSION: The origin of pupillary pigment epithelial cysts is unclear, and a hereditary background is very likely. Their clinical significance is in their similarity to pigmented tumors of the iris. They may also be indicative of coexisting systemic disease. In symptomatic cases, treatment is indicated.

Adolescent↗
PubMed2003

Autologous retinal pigment epithelium and choroid translocation in patients with exudative age-related macular degeneration: short-term follow-up.

PURPOSE: To evaluate the feasibilty of translocating autologous retinal pigment epithelium cells and choroid after the removal of a subfoveal choroidal neovascular membrane in patients with exudative age-related macular degeneration. DESIGN: Interventional case series. METHODS: This was a prospective evaluation of six patients with a follow-up of 7 to 13 months. All patients had large (> 1 disk diameter) subfoveal choroidal membranes, five with subretinal hemorrhage. Preoperative visual acuity ranged from 20/400 to 20/200. After the extraction of the neovascular complex, an autologous peripheral full-thickness patch of retinal pigment epithelium, Bruch membrane, choriocapillary, and choroid was cut out from the midperiphery and repositioned under the macula. Functional tests included Early Treatment Diabetic Retinopathy Study vision testing, fixation testing on a optical coherence tomography monitor, fluorescein and indocyanine green angiography, and scanning laser ophthalmoscopy autofluorescence. RESULTS: The retinal pigment epithelium patch appeared flat and had a brown furry aspect in four patients. Fixation was on the patch in these four patients. Postoperative vision ranged from 20/200 to 20/64, with a 2-line increase in three patients. Revascularization was visible on fluorescein and indocyanide angiography in three patients examined in this manner. Normal retinal pigment epithelium autofluorescence was present over the patch in four patients. CONCLUSIONS: The translocation of a full-thickness patch with autologous peripheral retinal pigment epithelium to the macula after choroidal neovascular membrane extraction was feasible and may result in a surviving and functioning graft for more than 1 year. Longer follow-up to evaluate its long-term benefit is necessary, as well as refinement of the surgery.

Aged↗
PubMed1994

Anterior chamber depth and pigment dispersion syndrome.

Pigment dispersion syndrome is thought to be the result of iris pigment abrasion by zonular packets. This condition primarily affects young males with myopia, perhaps because of deeper anterior chambers that make such pigment abrasion more likely. Males have been described to have larger eyes and deeper anterior chambers. This constellation, however, does not explain conclusively the predominance of males who have pigment dispersion syndrome. We, therefore, studied whether anterior chambers in males are deeper than those in females, not only in absolute measures but also relative to the axial length. Our results of 60 patients disclosed that men had not only significantly deeper mean absolute anterior chambers (men, 3.22 +/- 0.42 mm; women, 2.88 +/- 0.38 mm; P = .002) but also deeper mean relative anterior chambers (men, 13.54% +/- 1.66%; women, 12.45% +/- 1.2%; P = .013). No significant differences existed between genders with regard to lens thickness, extent of ametropia, and visual acuity. Thus, normal developmental differences between genders may predispose males for deeper anterior chambers and, consequently, for pigment dispersion syndrome.

Adult↗
PubMed1993

Giant retinal pigment epithelial tears in acute retinal necrosis.

We observed large peripheral tears of the retinal pigment epithelium in two patients, a 59-year-old man and a 15-year-old girl, who had acute retinal necrosis. These tears ranged from 90 to 180 degrees of the circumference of the peripheral retinal pigment epithelium and occurred in areas of previous retinal viral infection. Both patients had curled folds of tissue at the posterior edge of the retinal pigment epithelial tear. During vitrectomy at the time of fluid-air exchange, we noted the edge of these tears to sag posteriorly. Because of the area that was denuded of retinal pigment epithelium by the tears, we selected a more posterior location for argon laser endophotocoagulation in both patients. These large retinal pigment epithelial tears did not appear to have an adverse effect on the outcome of surgical treatment of the retinal detachments.

Acyclovir↗
PubMed2001

Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium.

Choroidal neovascularization in age-related macular degeneration is a frequent and poorly treatable cause of vision loss in elderly Caucasians. This choroidal neovascularization has been associated with the expression of vascular endothelial growth factor (VEGF). In current animal models choroidal neovascularization is induced by subretinal injection of growth factors or vectors encoding growth factors such as VEGF, or by disruption of the Bruch's membrane/retinal pigment epithelium complex with laser treatment. We wished to establish a transgenic murine model of age-related macular degeneration, in which the overexpression of VEGF by the retinal pigment epithelium induces choroidal neovascularization. A construct consisting of a tissue-specific murine retinal pigment epithelium promoter (RPE(65) promoter) coupled to murine VEGF(164) cDNA with a rabbit beta-globin-3' UTR was introduced into the genome of albino mice. Transgene mRNA was expressed in the retinal pigment epithelium at all ages peaking at 4 months. The expression of VEGF protein was increased in both the retinal pigment epithelium and choroid. An increase of intravascular adherent leukocytes and vessel leakage was observed. Histopathology revealed intrachoroidal neovascularization that did not penetrate through an intact Bruch's membrane. These results support the hypothesis that additional insults to the integrity of Bruch's membrane are required to induce growth of choroidal vessels into the subretinal space as seen in age-related macular degeneration. This model may be useful to screen for inhibitors of choroidal vessel growth.

Age Factors↗
PubMed2003

Reconstituted 3-dimensional human skin of various ethnic origins as an in vitro model for studies of pigmentation.

Reconstituted 3-dimensional human skin equivalents containing melanocytes and keratinocytes on an artificial dermal substitute are gaining popularity for studies of skin metabolism because they exhibit morphological and growth characteristics similar to human epidermis. In this study, we show that such a pigmented epidermis model can be used to assess the regulation of pigmentation by known melanogenic compounds. In monolayers or in melanocyte-keratinocyte co-cultures, melanocyte-keratinocyte interactions are missing or are spatially limited. The commercial skin equivalents used in this study were derived from epidermal cells obtained from donors of three different ethnic origins (African- American, Asian, and Caucasian), and they reflect those distinct skin phenotypes. We used these pigmented human epidermis models to test compounds for potential effects on pigmentation in a more physiologically relevant context, which allows further characterization and validation of interesting melanogenic factors. We used known melanogenic stimulators (alpha-melanocyte-stimulating hormone and 3,4-dihydroxyphenylalanine) and inhibitors (hydroquinone, arbutin, kojic acid, and niacinamide) and examined their effects on the production of melanin and its distribution in upper layers of the skin. Our studies indicate that commercial skin equivalents provide a convenient and cost-effective alternative to animal testing for evaluating the regulation of mammalian pigmentation by melanogenic factors and for elucidating their mechanisms of action.

Asian People↗
PubMed1989

Photolysis intermediates of the artificial visual pigment cis-5,6-dihydro-isorhodopsin.

The photolysis intermediates of an artificial bovine rhodopsin pigment, cis-5,6-dihydro-isorhodopsin (cis-5,6,-diH-ISORHO, lambda max 461 nm), which contains a cis-5,6-dihydro-9-cis-retinal chromophore, are investigated by room temperature, nanosecond laser photolysis, and low temperature irradiation studies. The observations are discussed both in terms of low temperature experiments of Yoshizawa and co-workers on trans-5,6-diH-ISORHO (Yoshizawa, T., Y. Shichida, and S. Matuoka. 1984. Vision Res. 24: 1455-1463), and in relation to the photolysis intermediates of native bovine rhodopsin (RHO). It is suggested that in 5,6-diH-ISORHO, a primary bathorhodopsin intermediate analogous to the bathorhodopsin intermediate (BATHO) of the native pigment, rapidly converts to a blue-shifted intermediate (BSI, lambda max 430 nm) which is not observed after photolysis of native rhodopsin. The analogs from lumirhodopsin (LUMI) to meta-II rhodopsin (META-II) are generated subsequent to BSI, similar to their generation from BATHO in the native pigment. It is proposed that the retinal chromophore in the bathorhodopsin stage of 5,6-diH-ISORHO is relieved of strain induced by the primary cis to trans isomerization by undergoing a geometrical rearrangement of the retinal. Such a rearrangement, which leads to BSI, would not take place so rapidly in the native pigment due to ring-protein interactions. In the native pigment, the strain in BATHO would be relieved only on a longer time scale, via a process with a rate determined by protein relaxation.

Isomerism↗
PubMed1989

Wavelength regulation in iodopsin, a cone pigment.

The opsin shift, the difference in wavenumber between the absorption peak of a visual pigment and the protonated Schiff base of the chromophore, represents the influence of the opsin binding site on the chromophore. The opsin shift for the chicken cone pigment iodopsin is much larger than that for rhodopsin. To understand the origin of this opsin shift and the mechanism of wavelength regulation in iodopsin, a series of synthetic 9-cis and 11-cis dehydro- and dihydro-retinals was used to regenerate iodopsin-based pigments. The opsin shifts of these pigments are quite similar to those found in bacteriorhodopsin-based artificial pigments. On the basis of these studies, a tentative model of wavelength regulation in iodopsin is proposed.

Animals↗
PubMed1996

Spectral broadening of interacting pigments: polarized absorption by photosynthetic proteins.

Excitonic interaction between pigment molecules is largely responsible for the static and dynamic spectroscopic properties of photosynthetic pigment-proteins. This paper provides a new description of its effect on polarized absorption spectroscopy, in particular on circular dichroism (CD). We investigate excitonic spectra of finite width and use "spectral moments" to compare 1) inhomogeneously broadened excitonic spectra, 2) spectra that are (homogeneously broadened by vibrations or electron-phonon interaction, and 3) spectra that are simulated by applying convolution after the interaction has been evaluated. Two cases are distinguished. If the excitonic splitting is smaller than the width of the interacting absorption bands, the broadening of the excitonic spectrum can be approximated by a convolution approach, although a correction is necessary for CD spectra. If the excitonic splitting exceeds the bandwidth, the well-known exchange narrowing occurs. We demonstrate that this is accompanied by redistribution of dipole strength and spectral shifts. The magnitude of a CD spectrum is conveniently expressed by its first spectral moment. As will be shown, this is independent of spectral broadening as well as dispersive shifts induced by pigment-protein interactions. Consequently, it provides a simple tool to relate the experimental CD spectrum of a pigment complex to the excitonic interactions from which it originates. To illustrate the potential of the presented framework, the spectroscopy of the LH2 pigment-protein complex from purple bacteria is analyzed and compared for dimer-like and ring-like structures. Furthermore, it is demonstrated that the variability of the CD of chlorosomes from green bacteria can be explained by small changes in the structure of their cylindrical bacteriochlorophyll c subunits.

Absorption↗
PubMed1995

Monocyte-induced cytokine expression in cultured human retinal pigment epithelial cells.

Monocytes and retinal pigment epithelial cells are intimately associated in membranes of eyes with proliferative vitreoretinopathy and in certain types of uveitis. The goal of this study was to determine whether monocytes modulate cytokine expression in retinal pigment epithelial cells, and if so, to identify the monocyte products responsible for this effect. Cultured human retinal pigment epithelial cells were exposed to varying concentrations of monocyte-conditioned medium from unstimulated human monocytes for 1-48 hr, or from monocytes prestimulated with lipopolysaccharide. mRNA expression of interleukin-1 beta, interleukin-6, interleukin-8, melanoma growth stimulating activity/gro alpha and gamma, macrophage colony stimulating factor, transforming growth factor-beta 2, basic fibroblast growth factor and activin beta A chain was determined by reverse transcription polymerase chain reaction. Protein secretion of selected cytokines, interleukin-1 beta, interleukin-6, interleukin-8, macrophage colony stimulating factor and transforming growth factor-beta 2 was measured in RPE-conditioned medium by ELISA. Retinal pigment epithelial cells constitutively expressed mRNA for interleukin-6, macrophage colony stimulating factor, transforming growth factor-beta 2, basic fibroblast growth factor and activin beta A chain. Interleukin-1 beta, melanoma growth stimulating activity/gro alpha and gamma and interleukin-8 were not expressed under basal conditions. Stimulated monocyte-conditioned medium markedly induced mRNA of all cytokines except basic fibroblast growth factor and transforming growth factor-beta 2 in a dose- and time-dependent manner. Unstimulated monocyte-conditioned medium was a less potent inducing agent, but still enhanced mRNA expression of interleukin-6, interleukin-8 and melanoma growth stimulating activity/gro alpha. Stimulated monocyte-conditioned medium also induced a time-dependent increase in interleukin-6, Interleukin-8, macrophage colony stimulation factor and transforming growth factor-beta 2, but not interleukin-1 beta protein secretion (p < 0.05 for all time points). Neutralizing antibodies to interleukin-1 beta, or tumour necrosis factor alpha, but not interleukin-1 alpha, significantly reduced cytokine mRNA expression induced by stimulated monocyte-conditioned medium. The combination of all three neutralizing antibodies almost entirely eliminated monocyte-induced mRNA expression and protein production of all cytokines studied. Activated monocytes secrete a heterogeneous mixture of products that together strongly induce expression of multiple cytokines in human retinal pigment epithelial cells. Most if not all of the inducing effect can be accounted for by interleukin-1 beta and tumour necrosis factor alpha. Because cytokines have been implicated in proliferative vitreoretinopathy and uveitis, monocyte-mediated cytokine expression by RPE cells may serve to initiate and perpetuate these diseases.

Antibodies↗
PubMed1988

Diurnal rhythm in the electroretinogram of the Royal College of Surgeons (RCS) pigmented rat.

RCS pigmented rats, born and raised in cyclic light for 22-23 days and then placed in darkness for up to 24 hr, showed a diurnal rhythm in the rod electroretinogram (ERG) that was comparable with that seen in normal pigmented rats. a-Wave and b-wave sensitivities were 21- and 34% lower, respectively, 1.5 hr after expected light onset compared with those at other times of day. In contrast to findings in normal rats, however, these sensitivity decreases in the RCS rats were not associated with an increase in the frequency of large phagosomes in the pigment epithelium; phagosome frequency was subnormal and relatively constant over the day. These findings suggest that depressed ERG sensitivities 1.5 hr after expected light onset in both normal and RCS pigmented rats reflect altered rod photoreceptor function associated with the process of outer-segment disc shedding and not with engulfment of shed discs into phagosomes by the pigment epithelium.

Animals↗
PubMedDate not supplied

Number and variations of the red and green visual pigment genes in Japanese men with normal color vision.

PURPOSE: We analyzed the red/green visual pigment genes in color-normal Japanese men to understand the relationship between color anomalies and genetic defects. METHODS: DNA from 120 color-normal Japanese men was subjected to polymerase chain reaction (PCR)-amplification for exons 2-5 of the red/green visual pigment genes and the PCR products were sequenced. The red:green gene ratios were estimated from the sequencing electropherograms of exon 5 and also from MvaI-restriction fragment analysis of the same exon. The first gene and the downstream genes in the pigment gene array were separately analyzed by PCR, direct sequencing, and/or single-strand conformation polymorphisms. RESULTS: The red:green gene ratios estimated from the ratios of peak heights of nucleotides on the sequencing electropherograms coincided with those estimated from the MvaI-restriction fragment analysis. Among the subjects analyzed, they were 1:1 in 43% (n = 52), 1:2 in 41% (n = 49), 1:3 in 6% (n = 7), and 1:>3 in 9% (n = 11). The first gene in the pigment gene arrays was red in all subjects. Only 1 subject (N22) had a green-red hybrid gene. Exons 2 and 4 had 2 haplotypes each, but exon 3 was highly polymorphic. Exon 5 of the green genes had one polymorphism at codon 283 with a frequency of 32%. CONCLUSIONS: The features of visual pigment genes in color-normal Japanese men were revealed. The data and establishing techniques may be useful for analyzing these genes in color-deficient subjects in the Japanese population.

Color Perception↗
PubMed2000

Colour pigments of Trichoderma harzianum. Preliminary investigations with thin-layer chromatography-Fourier transform infrared spectroscopy and high-performance liquid chromatography with diode array and mass spectrometric detection.

The colour pigments of Trichoderma harzianum fermentation broth were separated and the main fractions were tentatively identified by reversed-phase thin-layer chromatography-Fourier transform infrared spectroscopy (RP-TLC-FT-IR), RP-HPLC-diode array detection and RP-HPLC-MS. It was established that the multistep gradient elution developed for RP-TLC separation of pigments can be successfully used as a pilot method for the rational design of gradient elution in RP-HPLC for the separation of the same pigments. FT-IR and MS measurements were unable to identify the exact chemical structures of the main pigment fractions, the presence of OH, =CH and C=O (RP-TLC-FT-IR) and OH and NH, substructures (RP-HPLC-MS) was confirmed. It was assumed that the main pigment fractions are oxidation polymers originating from monomer molecules containing polar substructures and double bonds in the alkyl chain which are liable for oxidation during the aerobic fermentation process.

Chromatography, High Pressure Liquid↗
PubMed2001

Application of high-performance liquid chromatography to the characterization of the betalain pigments in prickly pear fruits.

The qualitative and quantitative betalain pigment content of two cultivars of prickly pear (Opuntia ficus-indica) fruits grown in southeastern Spain was evaluated. After methanolic extraction of crushed fruits, reversed-phase high-performance liquid chromatography and photodiode array detection were applied simultaneously for the separation, identification and quantification of these pigments. Two main pigments were obtained, which were identified as indicaxanthin (lambda(max) 484 nm) and betanin (lambda(max) 535 nm). Spectrophotometric evaluation of both pigments showed a yield of around 20-30 mg per 100 g of fresh pulp. When the influence of temperature (25 to 90 degrees C) on betacyanin pigment stability was investigated, the results revealed a substantial degree of thermodegradation at temperatures higher than 70 degrees C.

Betalains↗