Targeted therapy of atherosclerosis by pH-sensitive hyaluronic acid nanoparticles co-delivering all-trans retinal and rapamycin.

Atherosclerosis, the leading cause of death in the elderly worldwide, is typically characterized by elevated reactive oxygen species (ROS) levels and a chronic inflammatory state at the arterial plaques. Herein, pH-sensitive nanoparticles (HRRAP NPs) co-delivering all-trans retinal (ATR), an antioxidant linked to hyaluronic acid (HA) through a pH-sensitive hydrazone bond, and rapamycin (RAP), an anti-atherosclerotic drug loaded into the nanoparticle core, are developed for targeted combination therapy of atherosclerosis. In this way, HRRAP NPs might simultaneously reduce ROS levels via ATR antioxidant activity and reduce inflammation via the anti-inflammatory effect of RAP. In response to mildly acidic conditions mimicking the lesional inflammation in vitro, HRRAP NPs dissociated and both ATR and RAP were effectively released. The developed HRRAP NPs effectively inhibited pro-inflammatory macrophage proliferation, and displayed dose- and time-dependent specific internalization by different cellular models of atherosclerosis. Also, HRRAP NP combination therapy showed an efficient synergetic anti-atherosclerotic effect in vitro by effectively inhibiting the inflammatory response and oxidative stress in inflammatory cells. More importantly, HR NPs specifically accumulated in the atherosclerotic plaques of apolipoprotein E-deficient (ApoE-/-) mice, by active interaction with HA receptors overexpressed by different cells of the plaque. The treatment with HRRAP NPs remarkably inhibited the progression of atherosclerosis in ApoE-/- mice which resulted in stable plaques with considerably smaller necrotic cores, lower matrix metalloproteinase-9, and decreased proliferation of macrophages and smooth muscle cells (SMCs). Furthermore, HRRAP NPs attenuated RAP adverse effects and exhibited a good safety profile after long-term treatment in mice. Consequently, the developed pH-sensitive HRRAP NP represent a promising nanoplatform for atherosclerosis combination therapy.

Properties and Therapeutic Implications of an Enigmatic D477G RPE65 Variant Associated with Autosomal Dominant Retinitis Pigmentosa.

RPE65 isomerase, expressed in the retinal pigmented epithelium (RPE), is an enzymatic component of the retinoid cycle, converting all-trans retinyl ester into 11-cis retinol, and it is essential for vision, because it replenishes the photon capturing 11-cis retinal. To date, almost 200 loss-of-function mutations have been identified within the RPE65 gene causing inherited retinal dystrophies, most notably Leber congenital amaurosis (LCA) and autosomal recessive retinitis pigmentosa (arRP), which are both severe and early onset disease entities. We previously reported a mutation, D477G, co-segregating with the disease in a late-onset form of autosomal dominant RP (adRP) with choroidal involvement; uniquely, it is the only RPE65 variant to be described with a dominant component. Families or individuals with this variant have been encountered in five countries, and a number of subsequent studies have been reported in which the molecular biological and physiological properties of the variant have been studied in further detail, including observations of possible novel functions in addition to reduced RPE65 enzymatic activity. With regard to the latter, a human phase 1b proof-of-concept study has recently been reported in which aspects of remaining vision were improved for up to one year in four of five patients with advanced disease receiving a single one-week oral dose of 9-cis retinaldehyde, which is the first report showing efficacy and safety of an oral therapy for a dominant form of RP. Here, we review data accrued from published studies investigating molecular mechanisms of this unique variant and include hitherto unpublished material on the clinical spectrum of disease encountered in patients with the D477G variant, which, in many cases bears striking similarities to choroideremia.

Misfolded rhodopsin mutants display variable aggregation properties.

The largest class of rhodopsin mutations causing autosomal dominant retinitis pigmentosa (adRP) is mutations that lead to misfolding and aggregation of the receptor. The misfolding mutants have been characterized biochemically, and categorized as either partial or complete misfolding mutants. This classification is incomplete and does not provide sufficient information to fully understand the disease pathogenesis and evaluate therapeutic strategies. A Förster resonance energy transfer (FRET) method was utilized to directly assess the aggregation properties of misfolding rhodopsin mutants within the cell. Partial (P23H and P267L) and complete (G188R, H211P, and P267R) misfolding mutants were characterized to reveal variability in aggregation properties. The complete misfolding mutants all behaved similarly, forming aggregates when expressed alone, minimally interacting with the wild-type receptor when coexpressed, and were unresponsive to treatment with the pharmacological chaperone 9-cis retinal. In contrast, variability was observed between the partial misfolding mutants. In the opsin form, the P23H mutant behaved similarly as the complete misfolding mutants. In contrast, the opsin form of the P267L mutant existed as both aggregates and oligomers when expressed alone and formed mostly oligomers with the wild-type receptor when coexpressed. The partial misfolding mutants both reacted similarly to the pharmacological chaperone 9-cis retinal, displaying improved folding and oligomerization when expressed alone but aggregating with wild-type receptor when coexpressed. The observed differences in aggregation properties and effect of 9-cis retinal predict different outcomes in disease pathophysiology and suggest that retinoid-based chaperones will be ineffective or even detrimental.

A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration.

Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead to autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently is untreatable. Using a cell-based high-throughput screen (HTS) to identify small molecules that can stabilize the P23H-opsin mutant, which causes most cases of adRP, we identified a novel pharmacological chaperone of rod photoreceptor opsin, YC-001. As a non-retinoid molecule, YC-001 demonstrates micromolar potency and efficacy greater than 9-cis-retinal with lower cytotoxicity. YC-001 binds to bovine rod opsin with an EC50 similar to 9-cis-retinal. The chaperone activity of YC-001 is evidenced by its ability to rescue the transport of multiple rod opsin mutants in mammalian cells. YC-001 is also an inverse agonist that non-competitively antagonizes rod opsin signaling. Significantly, a single dose of YC-001 protects Abca4 -/- Rdh8 -/- mice from bright light-induced retinal degeneration, suggesting its broad therapeutic potential.

Efficacy and safety of retinaldehyde 0.1% and 0.05% creams used to treat photoaged skin: A randomized double-blind controlled trial.

BACKGROUND: Although topical retinoic acid effectively restores photoaged skin, the associated irritation limits the utility of the material. Retinaldehyde (RAL) is the natural precursor of retinoic acid and can also be used to treat photoaged skin; the safety profile is good. AIMS: To evaluate the efficacy and safety of new anti-aging creams containing RAL at 0.1% and 0.05% used to treat photoaged skin. PATIENTS AND METHODS: We enrolled 40 female Korean volunteers who applied RAL 0.1% or RAL 0.05% creams twice daily for 3 months. Wrinkles on, and the textures of, both crow's feet were quantitatively assessed using the Antera 3D® system. Transepidermal water loss (TEWL), skin hydration, the melanin index, and skin brightness were also evaluated. Overall improvement was assessed using a five-point scale by both the patients and the dermatologists. RESULTS: The 3-month application improved overall photoaging in both RAL 0.1% (95%) and RAL 0.05% groups (95%). Both RAL 0.1% and RAL 0.05% afforded significant textural improvements (13.7% and 12.6%, respectively), reduced the TEWL (14.5%, 17.9%), and increased hydration (10.2%, 6.0%); however, no statistical differences were observed between two groups. Only RAL 0.1% significantly improved the melanin index (by 6.5%). CONCLUSIONS: Both RAL 0.1% and RAL 0.05% creams were well tolerated and improved skin hydration and texture. However, only RAL 0.1% cream improved the melanin index.

Retinal-conjugated pH-sensitive micelles induce tumor senescence for boosting breast cancer chemotherapy.

Evoking tumor cellular senescence, an irreversible status of cell growth quiescence, has been recently proposed as a potential strategy to improve the efficacy of cancer treatment. In the current study, all-trans retinal, the precursor of all-trans retinoic acid, was conjugated to dextran via hydrazone bond to generate amphiphilic dextran-retinal (DR) conjugates, which self-assembled into pH-sensitive DR micelles. Our results showed that DR micelles moderately inhibited MCF-7 breast cancer cell growth through inducing p21-associated cellular senescence, which relied on retinoic acid receptors (RARs) and was accompanied by significant G0/G1 cell cycle arrest. Moreover, DR micelles were capable of encapsulating doxorubicin (DOX) to generate DOX-loaded DD micelles, facilitating the uptake and release of DOX in cancer cells. Compared with free DOX, DD micelles more effectively suppressed tumor growth and prolonged survival time of mouse xenograft model through inducing tumor apoptosis and cellular senescence. However, blocking cellular senescence diminished DD-caused apoptosis in MCF-7 cells by 40-50%. Therefore, pH-sensitive DR micelles not only served as a potent platform for DOX delivery, but also enhanced the anti-tumor effect of DOX by inducing tumor cellular senescence. These data reveal a great potential of evoking tumor senescence with retinal-conjugated micelles for boosting breast cancer chemotherapy.

Targeting the Proteostasis Network in Rhodopsin Retinitis Pigmentosa.

Mutations in rhodopsin are one of the most common causes of retinitis pigmentosa (RP). Misfolding of rhodopsin can result in disruptions in cellular protein homeostasis, or proteostasis. There is currently no available treatment for RP. In this review, we discuss the different approaches currently being investigated for treatment of rhodopsin RP, focusing on the potential of manipulation of the proteostasis network as a therapeutic approach to combat retinal degeneration.

Clinical and instrumental evaluation of the efficacy of a new depigmenting agent containing a combination of a retinoid, a phenolic agent and an antioxidant for the treatment of solar lentigines.

BACKGROUND: Solar lentigines are common benign macular hyperpigmented lesions localized on sun-exposed areas. OBJECTIVE: To evaluate the efficacy and safety of a new depigmenting agent containing a retinoid (retinaldehyde), a new phenolic agent (4-(1-phenylethyl)-resorcinol) and a reducing agent (δ-tocopheryl-ß-D-glucopyranoside) in the topical treatment of solar lentigines. PATIENTS AND METHODS: Twenty patients with solar lentigines of the face and hands applied the depigmenting agent on each lentigo once daily for 12 weeks. The outcome was evaluated at 45 days (T1) and 3 months (T2) after the end of treatment compared to baseline (T0) by means of clinical evaluation, Mexameter® and Visioface devices for digital and ultraviolet computerized image analysis of skin color as well as in vivo reflectance confocal microscopy. RESULTS: Image analysis and confocal laser reflectance microscopy showed that hyperpigmentation was significantly reduced at T2 compared to baseline and to controls. CONCLUSION: The study treatment was well tolerated and showed significant improvement in the depigmentation of solar lentigines.

Reversal of skin aging with topical retinoids.

Topical skin care and its place in plastic surgery today are often overlooked by clinicians formulating a plan for facial rejuvenation. Not only is it important to consider topical skin care as part of comprehensive care, but clinicians should also be educated with the data available in today's literature. This review aims to familiarize the reader with the biological processes of skin aging and evidence-based clinical outcomes afforded by various topical therapies. Furthermore, this review will focus on solar damage, the value of retinoids, and how they can be used in conjunction with forms of treatment such as chemical peel, dermabrasion, and lasers. Finally, guidelines will be provided to help the physician administer appropriate skin care based on the data presented.

Lipid emulsion administered intravenously or orally attenuates triglyceride accumulation and expression of inflammatory markers in the liver of nonobese mice fed parenteral nutrition formula.

The accumulation of hepatic TG and development of hepatic steatosis (HS) is a serious complication of the use of parenteral nutrition (PN) formulas containing a high percentage of dextrose. But whether fat emulsions or other nutrients can ameliorate the induction of HS by high-carbohydrate diets is still uncertain. We hypothesized that administration of a lipid emulsion (LE; Intralipid) and/or the vitamin A metabolite retinal (RAL) will reduce hepatic TG accumulation and attenuate indicators of inflammation. C57BL/6 male mice were fed PN formula as their only source of hydration and nutrition for 4-5 wk. In Expt. 1, mice were fed PN only or PN plus treatment with RAL (1 µg/g orally), LE (200 µL i.v.), or both LE and RAL. In Expt. 2, LE was orally administered at 4 and 13.5% of energy to PN-fed mice. All PN mice developed HS compared with mice fed normal chow (NC) and HS was reduced by LE. The liver TG mass was lower in the PN+LE and PN+RAL+LE groups compared with the PN and PN+RAL groups (P < 0.01) and in the 4% and 13.5% PN+LE groups compared with PN alone. Hepatic total retinol was higher in the RAL-fed mice (P < 0.0001), but RAL did not alter TG mass. mRNA transcripts for fatty acid synthase (Fasn) and sterol regulatory element-binding protein-1c (Srebpf1) were higher in the PN compared with the NC mice, but FAS protein and Srebpf1 mRNA were lower in the PN+LE groups compared with PN alone. The inflammation marker serum amyloid P component was also reduced. In summary, LE given either i.v. or orally may be sufficient to reduce the steatotic potential of orally fed high-dextrose formulas and may suppress the early development of HS during PN therapy.

Primary amines protect against retinal degeneration in mouse models of retinopathies.

Vertebrate vision is initiated by photoisomerization of the visual pigment chromophore 11-cis-retinal and is maintained by continuous regeneration of this retinoid through a series of reactions termed the retinoid cycle. However, toxic side reaction products, especially those involving reactive aldehyde groups of the photoisomerized product, all-trans-retinal, can cause severe retinal pathology. Here we lowered peak concentrations of free all-trans-retinal with primary amine-containing Food and Drug Administration (FDA)-approved drugs that did not inhibit chromophore regeneration in mouse models of retinal degeneration. Schiff base adducts between all-trans-retinal and these amines were identified by MS. Adducts were observed in mouse eyes only when an experimental drug protected the retina from degeneration in both short-term and long-term treatment experiments. This study demonstrates a molecular basis of all-trans-retinal-induced retinal pathology and identifies an assemblage of FDA-approved compounds with protective effects against this pathology in a mouse model that shows features of Stargardt's disease and age-related retinal degeneration.

Retinaldehyde/hyaluronic acid fragments: a synergistic association for the management of skin aging.

BACKGROUND: Retinaldehyde (RAL) was proven effective in treating photodamaged skin. Topical treatments with specific intermediate-size hyaluronate fragments (HAFi, 50-400 kDa) have been shown to stimulate keratinocytes proliferation and epidermal hyperplasia. The aim of this open, multicentric, international study was to assess the efficacy of the combination RAL-HAFi in the correction of skin photoaging. PATIENTS/METHODS: Either RAL 0.05%-HAFi 0.5% (Eluage® cream; group 1) or RAL 0.05%-HAFi 1% (Eluage® antiwrinkle concentrate; group 2) or both products (group 3) were applied daily to the 1462 subjects during 90 days. Overall photoaging severity was evaluated in the three groups by the dermatologists at D0, D30, and D90 based on the Larnier's scale. Wrinkles and/or furrows and clinical signs of aging were evaluated using a 4-point scale. The skin microrelief of the crow's feet, evaluated by optical profilometry, was performed in subjects from group 3. RESULTS: The 3-month application significantly improved overall photoaging through decrease of the Larnier's score in the three groups (P<0.001). At D90, significant improvement of wrinkles was shown in groups 2 and 3 [forehead wrinkles (-19% and -10%, respectively, P<0.001), nasolabial folds (-20% and -16%, P<0.001), crow's feet (-27% in the two groups, P<0.001), and perioral wrinkles (-34% and -23%, P<0.001)]. Clinical signs of photoaging on the entire face improved significantly in groups 1 and 3 [elasticity (-32% and -33%, respectively, P<0.001), hyperpigmentation (-34% and -31%, P<0.001), and ptosis (-18% and -22%; P<0.001)]. Results were confirmed using an optical profilometry technique. Products were very well tolerated. CONCLUSION: This clinical study showed the efficacy and value of the RAL-HAFi combination in the management of aging skin in a large cohort of patients.

Temozolomide and 13-cis retinoic acid in patients with anaplastic gliomas: a prospective single-arm monocentric phase-II study (RNOP-05).

The objective of this prospective, monocentric phase-II pilot study was to evaluate toxicity and efficacy of neoadjuvant temozolomide (TMZ) and 13-cis retinoic acid (13-cRA) treatment in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection. The primary endpoint of the study was median progression-free survival (PFS). Secondary endpoints were toxicity and PFS rates at 6, 12 and 24 months. Thirty-two adult patients were included in the study and treated with a median number of 10 TMZ and 13-cRA cycles (range 1-26). The majority of patients had favorable prognostic factors characterized by young age, complete resection, oligodendroglial histology, 1p/19q co-deletion, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation and isocitrate dehydrogenase 1 (IDH1) mutation. Grade 3/4 myelotoxicity occurred in 5/32 patients, and about 90% of patients suffered from grade 2/3 adverse events attributable to 13-cRA. The median PFS was 37.8 months (95% CI 22.2-53.4). The 6-, 12- and 24-month PFS rates were 84.4, 75 and 42.4%. The extent of tumor resection was the only prognostic factor associated with better PFS. TMZ and 13-cRA treatment did not improve PFS when retrospectively compared to the TMZ-treated group within the randomized NOA-04 phase-III trial. In conclusion, 13-cRA addition to TMZ in a neoadjuvant setting showed acceptable toxicity, but did not yield an advantage in PFS in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection.

Light prevents exogenous 11-cis retinal from maintaining cone photoreceptors in chromophore-deficient mice.

PURPOSE: To determine the effect of light/dark cycles on the cones of 11-cis retinal-treated RPE65/rhodopsin double knockout (Rpe65(-/-)Rho(-/-)) mice. Studies have shown that cones degenerate in chromophore-deficient mouse models for Leber Congenital Amaurosis (LCA), but exogenous supplementation of the native 11-cis retinal chromophore can inhibit this degeneration, suggesting that 11-cis retinal could be used as a therapeutic agent for preserving functional cones in patients with LCA. However, these treated mice were maintained in the dark. METHODS: 11-cis Retinal was introduced into Rpe65(-/-)Rho(-/-) mice at postnatal day 10 as a single subcutaneous injection mixed with a basement membrane matrix. The mice were maintained in either normal light/dark cycles or constant dark conditions. Fluorescence microscopy was used to assess retinal morphology. Cone cell survival was determined by counting cone opsin-containing cells on flat-mounted P30 retinas. Cross-sections of P21 mouse retina were used to assess cone cell integrity by visualizing opsin localization. Cone function was determined by electroretinography (ERG). RESULTS: Previous studies have shown that 11-cis retinal-treated mice lacking RPE65 and raised in constant dark have higher cone photoreceptor cell number, improved cone opsin localization, and enhanced cone ERG signals when compared with untreated mice. However, in this study the authors show that 11-cis retinal-treated Rpe65(-/-)Rho(-/-) mice raised in cyclic light did not show the improvements seen with the dark-reared mice. CONCLUSIONS: Thus, 11-cis retinal by itself, as well as other agents that form photosensitive pigments, will not be good therapeutic candidates for preserving cones in LCA.

Acne rosacea: effectiveness of 532 nm laser on the cosmetic appearance of the skin.

OBJECTIVE: The aim of the study was to perform a prospective blinded trial to compare the improvement of midface acne rosacea using 532 nm laser therapy with and without a retinaldehyde-based topical application. SETTING: A private clinic and surgicentre specializing in facial plastic surgery. DESIGN: A prospective randomized blinded clinical trial. METHODS: Fourteen patients with type 1 erythematotelangiectatic acne rosacea were enrolled in the study. The side of the face to be treated was chosen randomly. The opposite side of the face served as the control. Patients underwent six treatments with the 532 nm laser, with four sets of photodocumentation over a period of 3 months. Following each treatment, patients were asked to rate their degree of improvement based on a 5-point improvement scale. A final assessment was performed by five separate blinded evaluators. MAIN OUTCOME MEASURES: Final photographic evaluation to assess (1) reduction in overall redness, (2) reduction in visible telangiectasia, (3) difference between left and right sides of the face, and (4) degree of overall skin texture improvement. RESULTS: Three men and eight women completed the study. Six right hemifaces and five left hemifaces were treated. One hundred percent of patients noted a mild to moderate improvement in all signs of type 1 acne rosacea, including overall redness of the face, telangiectasia, and skin texture. The blinded evaluators were able to note a difference between the treated and untreated sides 47% of the time. CONCLUSION: The 532 nm laser combined with the topical retinaldehyde improved overall redness, telangiectasia, and skin texture in acne rosacea patients. The degree of improvement was greater when compared to using the laser alone as the sole treatment modality.

Cosmeceuticals: the evidence behind the retinoids.

A wide range of cosmeceutical products are available on the market currently, but evidence to support their use is often lacking in the literature. Specifically, there is a substantial amount of evidence supporting the efficacy of tretinoin in photoaging, but the evidence supporting retinoid-based cosmeceuticals remains sparse. The authors review the current data in the literature related to vitamin A-derived cosmeceutical products and conclude that cosmeceuticals containing retinaldehyde have been shown in large randomized, controlled trials to have the most beneficial effect on aging skin.

Interest of the association retinaldehyde/glycolic acid in adult acne.

BACKGROUND: Topical retinoids have been successfully used in the treatment of acne vulgaris but may induce irritation when used twice daily. The association of retinaldehyde (RAL) with glycolic acid (GA) have complementary activities, which could be of interest for adult women with acne because of a better tolerance/efficacy ratio. The aim of this study was to evaluate the tolerance and the efficiency of RAL (0.1%)/GA (6%) in adult women with acne when used alone or in combination with their usual acne products except retinoids. METHODS: Three hundred ninety-seven women with acne (aged between 30 and 40 years old) were included in this open multicentric study. They had to apply cream containing RAL/GA for 90 days without stopping their previous acne treatment (except topical retinoids). The tolerance was the main criteria and the second one is the efficacy, which was assessed by counting inflammatory and retentional lesions after 30 and 90 days of treatment. RESULTS: Used alone or in association with other anti-acne treatments, RAL/GA was considered to be highly tolerated. A significant decrease in both inflammatory and retentional lesions between day 0 and day 90 indicates that RAL/GA can be used as monotherapy for mild acne or could potentate the efficiency of other anti-acne products used at the same time by patients suffering from moderate acne. Complaints about side-effects were rare. The subjective evaluation of the preparation's efficacy by investigators and patients was strongly favourable. CONCLUSION: These data show that a combination of RAL 0.1% and GA 6% may be used in association with other topical anti-acne treatments with an excellent tolerance.

Upregulation of thioredoxin system via Nrf2-antioxidant responsive element pathway in adaptive-retinal neuroprotection in vivo and in vitro.

We tested the hypothesis that stress responses mediated by the Nrf2-antioxidant responsive element (ARE) pathway are involved in the initiation of retinal neuroprotection provided by bright-cyclic-light rearing. Albino rats born and raised in dim (5 lux) or bright (400 lux) cyclic light were exposed to damaging light (3000 lux, 6 h). After exposure, the outer nuclear layer thickness and area and the electroretinogram a- and b-wave amplitudes were significantly reduced in the dim-light-reared rats compared to the bright-light-reared rats, demonstrating a light adaptation neuroprotection phenomenon. In bright-cyclic-light-reared rats, the retinal levels of thioredoxin (Trx) (2.4-fold), Trx reductase (TrxR) (2.9-fold), and proteins modified by 4-hydroxynonenal (4-HNE) (1.5-fold) were upregulated by Western blot analyses, and the nuclear translocation of Nrf2 (2.2-fold) and the DNA binding activity of Nrf2, small Maf, and cJun to the ARE were increased as determined by electrophoretic mobility shift assays. In mouse photoreceptor-derived 661W cells, pretreatment with a sublethal dose of 4-HNE protected against H(2)O(2)-induced cell damage. Treatment with 4-HNE upregulated cellular Trx, TrxR, and heme oxygenase-1 (HO-1) levels in addition to DNA binding activity of Nrf2, small Maf, and cJun to the ARE. Downregulation of Nrf2 using RNA interference technology diminished 4-HNE-mediated upregulation of Trx and Trx reductase but did not affect the upregulation of HO-1 by 4-HNE. Cytoprotection by 4-HNE pretreatment against H(2)O(2)-induced cell damage was not observed in 661W cells with a silenced Nrf2 gene. The results suggest that upregulation of the Trx system by 4-HNE via the Nrf2-ARE pathway may be involved in the molecular mechanism of the retinal neuroprotection phenomenon.

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.

Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety.

Aging of skin is an intricate biological process consisting of two types. While intrinsic or chronological aging is an inevitable process, photoaging involves the premature aging of skin occurring due to cumulative exposure to ultraviolet radiation. Chronological and photoaging both have clinically differentiable manifestations. Various natural and synthetic retinoids have been explored for the treatment of aging and many of them have shown histological and clinical improvement, but most of the studies have been carried out in patients presenting with photoaged skin. Amongst the retinoids, tretinoin possibly is the most potent and certainly the most widely investigated retinoid for photoaging therapy. Although retinoids show promise in the treatment of skin aging, irritant reactions such as burning, scaling or dermatitis associated with retinoid therapy limit their acceptance by patients. This problem is more prominent with tretinoin and tazarotene whereas other retinoids mainly represented by retinaldehyde and retinol are considerably less irritating. In order to minimize these side effects, various novel drug delivery systems have been developed. In particular, nanoparticles have shown a good potential in improving the stability, tolerability and efficacy ofretinoids like tretinoin and retinol. However, more elaborate clinical studies are required to confirm their advantage in the delivery of topical retinoids.