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Topical and systemic retinoids are often used long-term in the treatment of ichthyoses and other disorders of cornification. The Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group was formed to address the numerous clinical concerns with use of these medications in children and adolescents and to establish best practices regarding the use of retinoids. Consensus was achieved using the Delphi process with recommendations based on the best available evidence and expert opinion. An executive summary of the results is presented herein.

Skin development and patterning is dependent on factors that regulate the stepwise differentiation of dermal fibroblasts concomitant with dermal-epidermal reciprocal signaling, two processes that are poorly understood. Here we show that dermal EZH2, the methyltransferase enzyme of the epigenetic Polycomb Repressive Complex 2 (PRC2), is a new coordinator of both these processes. Dermal EZH2 activity is present during dermal fibroblast differentiation and is required for spatially restricting Wnt/β-catenin signaling to reinforce dermal fibroblast cell fate. Later in development, dermal EZH2 regulates the expression of reticular dermal markers and initiation of secondary hair follicles. Embryos lacking dermal Ezh2 have elevated epidermal proliferation and differentiation that can be rescued by small molecule inhibition of retinoic acid (RA) signaling. Together, our study reveals that dermal EZH2 is acting like a rheostat to control the levels of Wnt/β-catenin and RA signaling to impact fibroblast differentiation cell autonomously and epidermal keratinocyte development non-cell autonomously, respectively.

Background Mycosis fungoides (MF) is a cutaneous lymphoma; most patients present with early, skin-limited disease and are managed by dermatologists. Objective The purpose of this study was to systematically review and assess the evidence on topical treatments for early-stage (IA, IB, IIA) MF. Methods We performed a literature search via MEDLINE, Embase, Web of Science, and Cochrane databases. Grading Recommendations Assessment, Development and Evaluation (GRADE) criteria were used to assess the certainty of the data. Results Two searches yielded 1252 references; 26 met the inclusion criteria and included literature on nitrogen mustard, retinoids, corticosteroids, carmustine, fluorouracil, methotrexate-laurocapram, hexadecylphosphocholine, peldesine, ingenol mebutate, topical methotrexate with oxygen flow-assisted LP3 carrier, and resiquimod. Most studies were single intervention, observational series. Nitrogen mustard, with the most published reports, was effective with 12%-82% early-stage MF patients (total n > 1000) achieving complete remission (CR) (low certainty evidence). Clinical CR was achieved among 10%-60% treated with topical retinoids (low certainty evidence). Two moderate-sized retrospective case series on topical steroids had 18%-63% CR (low certainty evidence). Only single studies were available for the other therapies. Conclusions For most outcomes of interest, the GRADE certainty for topical therapies for early-stage MF was low. Further randomized controlled trials and inclusion of quality of life indicators are needed.

Retinoid-related orphan receptor α (RORα) is a transcription factor expressed in a variety of tissues throughout the body. Knockout of RORα leads to various impairments, including defects in cerebellar development, circadian rhythm, lipid metabolism, immune function, and bone development. Previous studies have shown significant reduction of RORα expression in Purkinje cells (PCs) of spinocerebellar ataxia (SCA) type 1 and type 3/MJD (Machado-Joseph disease) model mice. However, it remains unclear to what extent the RORα reduction in PCs is involved in the disease pathology. Here, RORα expression was downregulated specifically in mature mouse PCs by intravenous infusion of blood-brain barrier-permeable adeno-associated virus (AAV), expressing a microRNA against RORα (miR-RORα) under the control of the PC-specific L7-6 promoter. The systemic AAV infusion led to extensive transduction of PCs. The RORα knock-down caused degeneration of PCs including disruption of the PC monolayer alignment and dendrite atrophy. In behavioral experiments, mice expressing miR-RORα showed motor learning deficits, and later, overt cerebellar ataxia. Thus, RORα in mature PCs plays pivotal roles in maintenance of PC dendrites and the monolayer alignment, and consequently, motor learning and motor function. Decrease in RORα expression in PCs could be a primary etiology of the cerebellar symptoms in patients with SCA1 and SCA3/MJD.

All-trans retinoic acid (ATRA), the biologically active form of vitamin A, is instrumental in regulating the patterning and specification of the vertebrate embryo. Various animal models demonstrate adverse developmental phenotypes following experimental retinoid depletion or excess during pregnancy. Windows of vulnerability for altered skeletal patterning coincide with early specification of the body plan (gastrulation) and regional specification of precursor cell populations forming the facial skeleton (cranial neural crest), vertebral column (somites), and limbs (lateral plate mesoderm) during organogenesis. A common theme in physiological roles of ATRA signaling is mutual antagonism with FGF signaling. Consequences of genetic errors or environmental disruption of retinoid signaling include stage- and region-specific homeotic transformations to severe deficiencies for various skeletal elements. This review derives from an annex in Detailed Review Paper (DRP) of the OECD Test Guidelines Programme (Project 4.97) to support recommendations regarding assay development for the retinoid system and the use of resulting data in a regulatory context for developmental and reproductive toxicity (DART) testing.

Lichen planus is a benign inflammatory disorder of unknown etiology that may affect the skin, mucosae, scalp, and nails. When the nails are affected, it may lead to permanent destruction with severe functional and psychosocial consequences. Therefore, prompt diagnosis and early treatment are essential, even in mild cases. There are currently no guidelines for the management of nail lichen planus and the published literature on treatment is limited. The aim of this review is to provide practical management recommendations for the classical form of nail lichen planus, especially when restricted to the nails. Topical treatment has poor short-term efficacy and may cause long-term side effects. Instead, intralesional and intramuscular triamcinolone acetonide should be considered first-line therapies. Oral retinoids are second-line choices, and immunosuppressive agents may also be considered., SCOPUS: re.j, info:eu-repo/semantics/published

Skin cancer is a broad term used to describe a number of different malignant indications of the skin. Skin cancers mostly comprise of the keratinocyte cancers [Basal Cell Carcinoma (BCC) and cutaneous Squamous Cell Carcinoma (SCC)], and melanoma. Surgical excision of these malignancies has been the preferred treatment of patients for decades. However, the decision to perform surgery can be affected by various considerations, including co-morbidities of the patient, the anatomical site of the lesion and potential intolerance for repeated excisions. Topical treatment of skin cancer may therefore be more appropriate in certain instances. Topical treatment potentially allows for higher drug levels at the tumor site, and may result in less overall toxicity than systemic agents. This review will specifically address the current agents used in topical treatment of skin cancers, and introduce emerging treatments from the natural product field that may also find utility in these indications.

Psoriasis is a chronic, multisystem, inflammatory disease that affects approximately 1% of children, with onset most common during adolescence. This guideline addresses important clinical questions that arise in psoriasis management and provides evidence-based recommendations. Attention will be given to pediatric patients with psoriasis, recognizing the unique physiology, pharmacokinetics, and patient-parent-provider interactions of patients younger than 18 years old. The topics reviewed here mirror those discussed in the adult guideline sections, excluding those topics that are irrelevant to, or lack sufficient information for, pediatric patients.

Conversion of dietary vitamin A (VA) into retinoic acid (RA) is essential for many biological processes and thus far studied largely in mammalian cells. Using targeted metabolomics, we found that commensal bacteria in the mouse gut lumen produced a high concentration of the active retinoids, all-trans-retinoic acid (atRA) and 13-cis-retinoic acid (13cisRA), as well as the principal circulating retinoid, retinol. Ablation of anerobic bacteria significantly reduced retinol, atRA, and 13cisRA, whereas introducing these bacteria into germ-free mice significantly enhanced retinoids. Remarkably, cecal bacterial supplemented with VA produced active retinoids in vitro, establishing that gut bacteria encode metabolic machinery necessary for multistep conversion of dietary VA into its active forms. Finally, gut bacteria Lactobacillus intestinalis metabolized VA and specifically restored RA levels in the gut of vancomycin-treated mice. Our work establishes vitamin A metabolism as an emergent property of the gut microbiome and lays the groundwork for developing probiotic-based retinoid therapy.

Despite the recent emergence of multiple cellular and molecular strategies to restore vision in retinal disorders, it remains unclear to what extent central visual circuits can recover when retinal defects are corrected in adulthood. We addressed this question in an Lrat

OBJECTIVE: Retinoid X receptors (RXR) are a family of nuclear receptors that play critical roles in the regulation of numerous fundamental biological processes including cell proliferation, differentiation, and death. Earlier studies suggested that treatment with RXR agonists attenuates platelet activation in all adults (male and femal) and mice; however, the underlying molecular mechanisms have remained insufficiently understood. To elaborate further on this issue, we characterized megakaryocyte and platelet-specific RXR knockout mice to study platelet function in vitro and arterial thrombosis in vivo. APPROACH AND RESULTS: First, we identified RXRbeta as the dominant RXR receptor in mouse platelets, prompting us to generate a megakaryocyte and platelet-specific PF4(Cre) ;RXRbeta(flox/flox) mouse. Second, we studied activation, spreading, and aggregation of platelets from C57Bl/6 wild-type mice (WT), PF4(Cre+) ;RXRbeta(flox/flox) mice, and PF4(Cre-) ;RXRbeta(flox/flox) littermate controls in the presence or absence of RXR ligands, that is, 9-cis-retinoic acid (9cRA) and methoprene acid (MA). We found that in vitro treatment with RXR ligands attenuates spreading and aggregation of platelets and increases proplatelet particle formation from megakaryocytes (MK). However, these effects are also observed in RXRbeta-deficient platelets and MKs and are thus independent of RXRbeta. Third, we investigated arterial thrombus formation in an iron chloride (FeCl3)-induced vascular injury model in vivo, which is also not affected by the absence of RXRbeta in platelets. CONCLUSIONS: Absence of the most abundant RXR receptor in mouse platelets, RXRbeta, does not affect platelet function in vitro and thrombus formation in vivo. Furthermore, RXR agonists' mediated effects on platelet function are independent of RXRbeta expression. Hence, our data do not support a significant contribution of RXRbeta to arterial thrombosis in mice.

Retinoids are essential for reproduction. Most research has focused on the role of retinoic acid signaling in the regulation of meiosis during early fetal germ cell development. However, less attention has been paid to the possible effects of retinoic acid signaling in adult female gonads. Retinoic acid, its receptors, and the key enzymes required for retinoic acid synthesis are expressed in the ovaries and they are involved in the regulation of folliculogenesis and steroidogenesis. Exposure to compounds that can interfere with normal retinoic acid signaling is associated with adverse ovarian outcomes, including altered steroidogenesis and reduction in indicators of ovarian reserve in women and laboratory animal models. These observations call for more attention to retinoids as regulators of adult ovarian physiology and as possible targets of endocrine disruption by environmental chemicals. In this review, we summarize the current knowledge of retinoids in folliculogenesis and steroidogenesis in post-pubertal mammalian ovaries.

Vertebrate vision starts with light absorption by visual pigments in rod and cone photoreceptor cells of the retina. Rhodopsin, in rod cells, responds to dim light, whereas three types of cone opsins (red, green, and blue) function under bright light and mediate color vision. Cone opsins regenerate with retinal much faster than rhodopsin, but the molecular mechanism of regeneration is still unclear. Recent advances in the area pinpoint transient intermediate opsin conformations, and a possible secondary retinal-binding site, as determinant factors for regeneration. In this Review, we compile previous and recent findings to discuss possible mechanisms of ligand entry in cone opsins, involving a secondary binding site, which may have relevant functional and evolutionary implications

Cyanobacterial blooms represent a worldwide problem in freshwater as well as marine ecosystems as producers of various toxic compounds. This study provides environmentally important information about the common presence of mixtures of retinoids in various water bodies associated with the occurrence of cyanobacterial blooms dominated by many different species. The study documents, for the first time, that retinoids are produced by environmental cyanobacterial blooms dominated by species belonging to different genera such as Microcystis, Dolichospermum, Planktothrix, Woronichinia, Pseudanabaena and others. Samples of biomass of cyanobacterial blooms and their surrounding water were collected from seventeen independent freshwater bodies across the Czech Republic during summer 2015. Retinoid-like activity was detected by an in vitro reporter gene bioassay in water samples from 8 out of 17 localities with a maximal activity of 263 ng all-trans retinoic acid equivalent (REQ)/L. In comparison, in vitro assessment of biomass extracts documented retinoid-like activity at 11 out of 17 localities with a maximal retinoid-like activity of 867 ng REQ/g dry mass (dm). Individual retinoids were detected by chemical analyses in all water samples and in 16 out of 17 biomass samples with 4keto-retinal and all-trans 5,6epoxy retinoic acid being detected in aquatic ecosystems for the first time. Further, all-trans 4keto retinoic acid and retinal were the most commonly detected compounds in both types of samples. With respect to retinoid-like activity, a large proportion was explained in some samples by contributions of individual detected retinoids calculated from their concentrations and relative potencies. However, results also indicate that other unknown compounds with a retinoic acid receptor-mediated mode of action were present. The revealed widespread production of retinoids by cyanobacterial blooms dominated by diverse species across various aquatic ecosystems and their common presence in both biomass and surrounding water raises concern namely because some retinoids belong to the most potent teratogens. These compounds need to be taken into consideration in the assessment of risks associated with massive cyanobacterial blooms.

Background In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results. Objective We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management. Methods Data were collected from an international cohort of 18 patients with CXCR4 mutations. Results The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively. Conclusions The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.

Laboratory monitoring for patients on isotretinoin should include creatinine kinase in athletic males and the more liver-specific gamma glutamyltransferase. There is mounting evidence that acne pathophysiology includes a barrier defect and subsequent microbiome disruption. Avoidance of acne scars with early and aggressive treatment is a more efficient and cost-effective option than subsequent treatment. Laser and light treatments for acne and acne scars are plentiful but poorly supported by evidence-based medicine. The acne pipeline is rich with new chemical entities, new formulations, and combinations of older agents. The gold standard for acne therapy may be changing its face.

ABCA4 is a member of the superfamily of ATP-binding cassette (ABC) transporters that is preferentially localized along the rim region of rod and cone photoreceptor outer segment disc membranes. It uses the energy from ATP binding and hydrolysis to transport N-retinylidene-phosphatidylethanolamine (N-Ret-PE), the Schiff base adduct of retinal and phosphatidylethanolamine, from the lumen to the cytoplasmic leaflet of disc membranes. This ensures that all-trans-retinal and excess 11-cis-retinal are efficiently cleared from photoreceptor cells thereby preventing the accumulation of toxic retinoid compounds. Loss-of-function mutations in the gene encoding ABCA4 cause autosomal recessive Stargardt macular degeneration, also known as Stargardt disease (STGD1), and related autosomal recessive retinopathies characterized by impaired central vision and an accumulation of lipofuscin and bis-retinoid compounds. High resolution structures of ABCA4 in its substrate and nucleotide free state and containing bound N-Ret-PE or ATP have been determined by cryo-electron microscopy providing insight into the molecular architecture of ABCA4 and mechanisms underlying substrate recognition and conformational changes induced by ATP binding. The expression and functional characterization of a large number of disease-causing missense ABCA4 variants have been determined. These studies have shed light into the molecular mechanisms underlying Stargardt disease and a classification that reliably predicts the effect of a specific missense mutation on the severity of the disease. They also provide a framework for developing rational therapeutic treatments for ABCA4-associated diseases.

Retinoids are newly detected compounds in aquatic ecosystems associated with cyanobacterial water blooms. Their potential health risks are only scarcely described despite numerous detections of all-trans retinoic acid (ATRA) and its derivatives in the environment. Besides the known teratogen ATRA there is only little or no information about their potency and namely their effects in vivo. We characterize ATRA and 8 other retinoids reported to occur in the environment for their bioactivity and teratogenicity using four in vitro reporter gene assays and zebrafish (Danio rerio) embryotoxicity assay. Our results document the ability of these compounds to interfere with retinoid signalling and cause teratogenicity at environmentally relevant levels with EC

Numerous studies have focused on the deteriorate role of amyloid-β (Aβ) on retina, implying the potential pathogenic mechanism underlying age-related macular degeneration (AMD). However, the mechanism underlying the Aβ deposition in AMD patients remains unknown. Beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), rate-limiting enzyme for Aβ production, plays an important role in Aβ deposition in the brain. In the current study, we aimed to clarify the regulation mechanism of BACE1 and explore potential drug targets using a lipofuscinfluorophore A2E-mediated photo-oxidation model. In this model, Aβ1-40 and Aβ1-42 levels increased simultaneously with the enhanced BACE1 expression. These changes were associated with the hypomethylation of specific loci within the BACE1 gene promoter and the decreased levels of DNA methyltransferase 1 (DNMT1). Furthermore, we noticed overlapping regions of differentially methylated CpG islands and specificity protein (Sp1) binding sites within the BACE1 promoter. We employed chromatin immunoprecipitation (ChIP) assay to verify that the decreased BACE1 promoter methylation by DNMT1 enabled increased binding between Sp1 and the BACE1 promoter, which further enhanced BACE1 transcription. The inhibition of Sp1 with mithramycin A (MTM) could down-regulate the expression of BACE1 as well as alleviate the RPE barrier morphology and function impairment. Our results for the first time show the competitive regulation of BACE1 by transcription factor Sp1 and DNMT1 after photo-oxidation and confirm the potential novel protective role of MTM on RPE cells.

The receptor tyrosine kinase Mer is expressed by retinal pigment epithelial (RPE) cells and participates in photoreceptor outer-segment phagocytosis, a process enabling membrane renewal. Mutations in the gene encoding MERTK cause blinding retinitis pigmentosa in humans. Targeted Mertk disruption in mice causes defective RPE-mediated phagocytosis of the outer segments, leading to deposition of autofluorescent debris at the RPE–photoreceptor cell interface, followed by photoreceptor cell degeneration. Here, we show that retinaldehyde adducts (bisretinoid fluorophores) that form in photoreceptor outer segments occupy the unphagocytosed outer-segment debris that accumulates in Mertk(−/−) mice. Bisretinoids measured by HPLC were elevated in Mertk(−/−) mice compared with WT animals. Bisretinoids were also more abundant in albino Mertk(−/−) mice expressing leucine at position 450 of the isomerase RPE65 (Rpe65-Leu450) rather than the variant methionine (Rpe65-450Met) that yields lower bisretinoid levels. In Royal College of Surgeons rats having dysfunctional Mertk, bisretinoids were higher than in WT rats. Intensities of in vivo fundus autofluorescence were higher in Mertk(−/−) mice than in WT mice and peaked earlier in albino Mertk(−/−)/Rpe65-Leu450 mice than in albino Mertk(−/−)/Rpe65-450Met mice. Of note, the rate of photoreceptor cell degeneration was more rapid in albino Mertk(−/−) mice exposed to higher levels of intraocular light (albino versus pigmented mice) and in mice carrying Rpe65-Leu450 than in Rpe65-450Met mice, revealing a link between bisretinoid accumulation and light-mediated acceleration of photoreceptor cell degeneration. In conclusion, the light sensitivity of photoreceptor cell degeneration arising from Mertk deficiency is consistent with the known phototoxicity of bisretinoids.

Background The etiology of frozen shoulder (FS) is unclear. Accordingly, this study used a label-free quantitative shotgun proteomic approach to elucidate the pathogenesis of FS based on protein expression levels. Methods Tissue samples from the rotator interval (RI), middle glenohumeral ligament (MGHL), and anterior-inferior glenohumeral ligament (IGHL) were collected from 12 FSs with severe stiffness and 7 shoulders with a rotator cuff tear (RCT) as controls. Protein mixtures were digested and analyzed by nano-liquid chromatography/electrospray ionization–tandem mass spectrometry. Relative protein expression levels were calculated by the signal intensity of identified peptide ions on mass spectra. Differentially expressed proteins between FS and RCT samples were evaluated by a gene enrichment analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Results We identified 1594 proteins, 1358 of which were expressed in all 6 tissue groups. We detected more upregulated proteins in the upper (RI and MGHL) FS groups and the lower (IGHL) RCT group than in the comparative groups, respectively. Various proteins with functions in tissue repair, collagen metabolism and fibrillation, cell–cell and cell–matrix adhesion, blood coagulation, and the immune response were expressed more highly in the RI and MGHL FS groups than in the RCT group. Proteins with functions in phagocytosis, glutathione metabolism, retinoid metabolism, and cholesterol metabolism were expressed more highly in the IGHL RCT group than in the FS group. Conclusions The pathophysiology of FS differs between the upper and lower parts of the joint capsule. Different treatment strategies for FS may be appropriate, depending on the location.

BACKGROUND: Nonvitamin A apocarotenoids occur in foods. Some function as retinoic acid receptor antagonists in vitro, though it is unclear if apocarotenoids are absorbed or accumulate to levels needed to elicit biological function. OBJECTIVE: The aim of this study was to quantify carotenoids and apocarotenoids (β-apo-8′-, -10′-, -12′-, and -14′-carotenal, apo-6′-, -8′-, -10′-, -12′-, and -14′-lycopenal, retinal, acycloretinal, β-apo-13-carotenone, and apo-13-lycopenone) in human plasma after controlled consumption of carotenoid-rich tomato juices. DESIGN: Healthy subjects (n = 35) consumed a low-carotenoid diet for 2 wk, then consumed 360 mL of high-β-carotene tomato juice (30.4 mg of β-carotene, 34.5 μg total β-apocarotenoids/d), high-lycopene tomato juice (42.5 mg of lycopene, 119.2 μg total apolycopenoids/d), or a carotenoid-free control (cucumber juice) per day for 4 wk. Plasma was sampled at baseline (after washout) and after 2 and 4 wk, and analyzed for carotenoids and apocarotenoids using high-pressure liquid chromatography (HPLC) and HPLC-tandem mass spectrometry, respectively. The methods used to analyze the apocarotenoids had limits of detection of ∼ 100 pmol/L. RESULTS: Apocarotenoids are present in tomato juices at 0.1–0.5% of the parent carotenoids. Plasma lycopene and β-carotene increased (P

The objective of this study was to determine if temporal variations in tissue metal concentrations are related to biomarkers of retinoid metabolism and oxidative stress responses in juvenile yellow perch (Perca flavescens). To this end, kidney metal (Cd, Cu and Zn) concentrations were measured in fish sampled in spring and fall 2012 in four lakes representing a wide range of water and sediment metal contamination in the Rouyn-Noranda (Quebec) region. Lakes Opasatica and Hélène were considered as reference lakes while lakes Dufault and Marlon were metal-contaminated. Kidney concentrations of Cd, Cu and Zn varied widely between spring and fall in fish from both clean and metal-contaminated lakes. An inter-lake difference in renal metal concentrations was only observed for Cd, with fish from Lake Marlon consistently displaying higher concentrations. In the spring, the concentrations of liver dehydroretinol, dehydroretinyl palmitate and total vitamin A esters were higher in fish sampled in the most contaminated lake. Strong temporal variations in the concentrations of these metabolites, as well as in the percentage of liver free dehydroretinol and the epidermal retinol dehydrogenase 2 transcription levels, were observed in fish living in the most metal-impacted lake, with generally higher values in the spring. In contrast to liver, in muscle, no clear seasonal variations in the concentrations of dehydroretinol, dehydroretinyl stearate or in the percentage of free dehydroretinol were observed in fish captured in the most contaminated lake. Temporal variations of traditional biomarkers of oxidative stress response were also observed in the most metal-impacted lake. For example, the transcription level of the gene encoding Cu/Zn superoxide dismutase-1 in liver and muscle catalase activity of perch sampled in the most contaminated lake were higher in spring than in fall. Positive relationships were found between kidney Cd concentrations and the transcription level of the gene encoding glucose 6-phosphate dehydrogenase, and all forms of retinoid concentrations in liver in spring, except with the percentage of free dehydroretinol where the correlation was negative. Our results translate to a state of stress caused by Cd and illustrate that temporal variations in tissue metal concentrations affect retinoid metabolism and antioxidant capacities in juvenile wild yellow perch. Overall this study contributes to highlight the importance of considering temporal variations when investigating the consequences of metal contamination on the physiology of wild fish.

A primary pathological defect in the heritable eye disorder Stargardt disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina. Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) matches the age-dependent increase in the incidence of the atrophic (dry) form of age-related macular degeneration (AMD) and therefore may be one of several pathogenic factors contributing to AMD progression. Lipofuscin bisretinoid synthesis in the retina depends on the influx of serum retinol from the circulation into the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)–transthyretin–retinol complex in the serum is required for this influx. Herein, we report the pharmacological effects of the non-retinoid RBP4 antagonist, BPN-14136. BPN-14136 dosing in the Abca4(−/−) mouse model of increased lipofuscinogenesis significantly reduced serum RBP4 levels and inhibited bisretinoid synthesis, and this inhibition correlated with a partial reduction in visual cycle retinoids such as retinaldehydes serving as bisretinoid precursors. BPN-14136 administration at doses inducing maximal serum RBP4 reduction did not produce changes in the rate of the visual cycle, consistent with minimal changes in dark adaptation. Abca4(−/−) mice exhibited dysregulation of the complement system in the retina, and BPN-14136 administration normalized the retinal levels of proinflammatory complement cascade components such as complement factors D and H, C-reactive protein, and C3. We conclude that BPN-14136 has several beneficial characteristics, combining inhibition of bisretinoid synthesis and reduction in retinaldehydes with normalization of the retinal complement system. BPN-14136, or a similar compound, may be a promising drug candidate to manage Stargardt disease and dry AMD.

Retinoids have a dominant role in topical acne therapy and to date, only RARβ and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known γ-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789.

Fasudil is a clinically approved Rho-associated protein kinase (ROCK) inhibitor that has been used widely to treat cerebral consequences of subarachnoid hemorrhage. It is known to have a positive effect on animal models of neurological disorders including Parkinson's disease and stroke. However, its cellular effect on progenitor populations and differentiation is not clearly understood. While recent studies suggest that fasudil promotes the mobilization of neural stem cells (NSCs) from the subventricular zone in vivo and promotes the differentiation of the C17.2 cerebellar neuroprogenitor line in vitro, it is unclear whether fasudil is involved in the differentiation of primary NSCs.Here, we tested the effect of fasudil on mouse NSCs in vitro, and observed increased gliogenesis in NSCs derived from lateral ventricles. Upon treatment, fasudil promoted characteristics of neurogenesis including phenotypic changes in neural outgrowth and interkinetic nuclear-like movements as an immediate response, while Sox2 expression was maintained and GFAP expression increased. Moreover, the gliogenic response to fasudil medium was observed in both early postnatal and adult NSC cultures.Taken together, our results show that fasudil promotes the differentiation of NSCs into astroglial lineage, suggesting that it could be used to develop novel vitro gliogenesis models and regulate differentiation for neural repair. Keywords: Fasudil, ROCK inhibitor, Neural stem cells, Differentiation, Gliogenesis, Primary cultures

Purpose To develop a microwave assisted method for the rapid synthesis of A2E and also to develop a method to quantify N-retinylidene-N-retinylethanolamine(A2E), all-trans retinal dimer (ATRD), A2-glycerophospho ethanolamine (A2GPE), dihydropyridine phosphatidyl ethanolamine (A2DHPE) and monofuran A2E (MFA2E) in age matched retina. Methods The development of microwave assisted synthesis of A2E, its purification and characterization for its utility in quantification in human retina. The semi-quantitative method development using LC-ESI–MS, LC-ESI–MS/MS and LC-APCI-MS/MS from pooled macula and peripheral retina for the bisretinoid analysis has been done. Results Maximum A2E conversion using microwave assisted process took place at 80 °C for 45 min with a yield of 55.01%. Highly sensitive and specific mass spectrometric method was developed using reverse phase C-18 separation with positive electrospray ionization and positive atmospheric phase chemical ionization of tandom mass spectrometry. A gradient mobile phase separation was achieved using water and methanol with 0.1% TFA. Multiple reaction monitoring acquisition for ESI and APCI was performed at ATRD m/z 551.2/522.2, A2GPE m/z 746.4/729.5, A2DHPEm/z 594.4/576.5, MFA2E m/z 608.2/591.2, A2E m/z 592.4/418.2. Method was validated using LC-ESI-SIM mode to determine selectivity, linearity, sensitivity, precision and accuracy. Conclusion An attempt towards optimization of the synthetic procedure of A2E was made so as to reduce the lengthy reaction time without compromising the yield. Developed method was capable enough for the detection of low level of bisretinids in retina.

Cytochrome P450 27C1 (P450 27C1) is a retinoid desaturase expressed in the skin that catalyzes the formation of 3,4-dehydroretinoids from all-trans retinoids. Within the skin, retinoids are important regulators of proliferation and differentiation. In vivo, retinoids are bound to cellular retinol-binding proteins (CRBPs) and cellular retinoic acid–binding proteins (CRABPs). Interaction with these binding proteins is a defining characteristic of physiologically relevant enzymes in retinoid metabolism. Previous studies that characterized the catalytic activity of human P450 27C1 utilized a reconstituted in vitro system with free retinoids. However, it was unknown whether P450 27C1 could directly interact with holo-retinoid-binding proteins to receive all-trans retinoid substrates. To assess this, steady-state kinetic assays were conducted with free all-trans retinoids and holo-CRBP-1, holo-CRABP-1, and holo-CRABP-2. For holo-CRBP-1 and holo-CRABP-2, the kcat/Km values either decreased 5-fold or were equal to the respective free retinoid values. The kcat/Km value for holo-CRABP-1, however, decreased ∼65-fold in comparison with reactions with free all-trans retinoic acid. These results suggest that P450 27C1 directly accepts all-trans retinol and retinaldehyde from CRBP-1 and all-trans retinoic acid from CRABP-2, but not from CRABP-1. A difference in substrate channeling between CRABP-1 and CRABP-2 was also supported by isotope dilution experiments. Analysis of retinoid transfer from holo-CRABPs to P450 27C1 suggests that the decrease in kcat observed in steady-state kinetic assays is due to retinoid transfer becoming rate-limiting in the P450 27C1 catalytic cycle. Overall, these results illustrate that, like the CYP26 enzymes involved in retinoic acid metabolism, P450 27C1 interacts with cellular retinoid-binding proteins.

4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, has been demonstrated that it had a variety of anti-tumor effects by exerting regulation on cellular proliferation, apoptosis and differentiation. Here, we found that ATPR is critical for alleviating myelodysplastic syndrome (MDS) and acute myelogenous leukemia. USO1, vesicle transport factor, belongs to tether protein family and involved in endoplasmic reticulum to Golgi trafficking of protein which is important to tumorigenesis. How USO1 contribute to MDS remain elusive. USO1 is aberrantly activated in MDS and AML in vivo and vitro, aberration of which might be a dominant mechanism for MDS cell survival. During the ATPR-induced remission of MDS, in vitro, USO1 presents a time and concentration-dependent decrease. Silencing of USO1 promotes myeloid differentiation of MDS cells and inhibits MDS cellular proliferation while USO1 over-expression has the opposite effect, suggesting that reduction of USO1 enhances the sensitivity of SKM-1 cells to ATPR treatment. Mechanistically, USO1 exerts its oncogenic role by inactivating Raf/ERK signaling, while ATPR is access to revise it. Notably, the activity of Raf/ERK pathway is required for the development and maintenance of MDS cell proliferation. Collectively, our results demonstrate the USO1- Raf/ERK signaling axis in MDS and highlight the negative role of USO1 in ATPR-regulated remission of MDS.

Blindness due to photoreceptor degeneration is observed in both genetic and acquired eye disorders. Long blue light exposure can contribute to increase levels of oxidative compounds within the retinal pigment epithelium (RPE), enhancing risk of retinal damage. In retina, reactive oxygen species contribute to the activation of inflammatory cascade. If chronic, this inflammatory response can result in photoreceptor death. Therefore, we investigated the effects of the endogenous adduct N-retinylidene-N-retinylethanolamine (A2E) on RPE cells, in order to identify the most dysregulated cytokines and their related inflammatory pathways. RPE cells were exposed to A2E and blue light for 3h and 6h. By transcriptome analysis, we identified differentially expressed genes in A2E-treated cells, when compared to untreated ones. Expression values were quantified by the Limma R package. Enrichment analysis was performed according to the “Reactome” and the Gene Ontology databases. Expression of pro-inflammatory cytokines increased after 3h of A2E treatment and pathways related to IL-6 and IL-1 signaling resulted enriched. Also the up-regulation of genes having a protective role against inflammation was observed. Moreover, our results show that ferroptosis could contribute to RPE degeneration induced by A2E and blue light. Dysregulated genes related to retinal degeneration triggered by oxidative damage and inflammatory response activation identified in this study can be considered as potential biomarkers for targeted therapies.

Some phytoplankton species were shown to produce teratogenic retinoids. This study assessed the variability in the extracellular production of compounds with retinoid-like activity for 50 independent cultivations of wide spectra of species including 12 cyanobacteria (15 strains) and 4 algae of different orders. Extracellular retinoid-like activity was detected for repeated cultivations of six cyanobacteria. The results were consistent for some species including Microcystis aeruginosa and Aphanizomenon gracile. The detected retinoid-like activities ranged from below the limit of quantification of 16 ng/L to over 6 µg all-trans retinoic acid (ATRA) equivalent/L. Nontargeted virtual fractionation together with suspect screening approach enabled to identify some retinoid-like compounds in exudates, including ATRA, 9/13-cis retinoic acid, all-trans 5,6-epoxy retinoic acid, 4keto-ATRA, 4keto-retinal, 4hydroxy-ATRA, and retinal. Most of them were for the first time repeatedly detected in exudates of all studied algae (at ng/L levels) and cyanobacteria. Their relative potencies ranged from 0.018 (retinal) to 1 compared to ATRA. They accounted for less than 0.1–50% of total detected retinoid-like activity. The high detected activities and concentrations of retinoids in some samples and their direct accessibility from exudates document potential risk of developmental toxicity for organisms in proximity of massive water blooms.

Systemic lupus erythematosus is a chronic inflammatory condition which affects predominantly women in their 30s. It has several clinical manifestations, including skin lesions that can be classified as acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous lupus erythematosus. A multifaceted approach to treating cutaneous lupus is advocated.

International audience; Introduction: The preterm premature rupture of membranes (PPROM) is a frequent pathology responsible of more than 30% of preterm births. Tobacco smoking is one of the most frequently described risk factors identified and contributes to the pre term weakening of fetal membranes. As previously demonstrated, all-trans retinoic acid (atRA) regulates several genes involved in the extracellular matrix dynamics, an essential actor in fetal membrane ruptures. We hypothesized that cigarette smoke may affect this pathway in human amnion. Methods: Amnion was obtained from full-term fetal membranes collected from non-smoking women after cesarean births and used either as explants or for the isolation of derived epithelial cells. The pro-healing and transcriptomic effects of atRA were studied by a scratch assay experiment and quantitative RT-PCR, respectively, after treatment with dimethyl sulfoxyde (DMSO), atRA, DMSO þ cigarette smoke condensate (CSC), or atRA þ CSC. Results: Our results show a strong alteration of the retinoid pathway after CSC treatment on amnion-derived epithelial cells and explants. We first demonstrated that CSC inhibits the activity of the RARE reporter gene in amnion-derived epithelial cells. Then, atRA's effects on both the transcription of its target genes and wound healing were demonstrated to be inhibited or at least decreased by the CSC in human amnion epithelial cells. Discussion: Here, we demonstrated that CSC altered the retinoid signal, already known to have roles in fetal membrane physiopathology. These results highlight a potential negative action of maternal smoking on the retinoid pathway in human amnion and more generally on pregnancy.

For mice, a maternal vitamin A (VA) deficient diet initiated from mid-gestation (GVAD) produces serum retinol deficiency in mature offspring. We hypothesize that the effects of GVAD arise from pre-weaning developmental changes. We compare the effect of this GVAD protocol in combination with a post-weaning high fat diet (HFD) or high carbohydrate diet (LF12). Each is compared to an equivalent VA sufficient combination. GVAD extensively decreased serum retinol and liver retinol, retinyl esters, and retinoid homeostasis genes (Lrat, Cyp26b1, and Cyp26a1). These suppressions were each more effective with LF12 than with HFD. Post-weaning initiation of VA deficiency with LF12 depleted liver retinoids, but serum retinol was unaffected. Liver retinoid depletion, therefore, precedes serum attenuation. Maternal LF12 decreased the obesity response to the HFD, which was further decreased by GVAD. LF12 fed to the mother and offspring extensively stimulated genes marking stellate activation (Col1a1, Timp2, and Cyp1b1) and novel inflammation markers (Ly6d, Trem2, Nupr1). The GVAD with LF12 diet combination suppressed these responses. GVAD in combination with the HFD increased these same clusters. A further set of expression differences on the HFD when compared to a high carbohydrate diet were prevented when GVAD was combined with HFD. Most of these GVAD gene changes match published effects from deletion of Nr0b2/Shp, a retinoid-responsive, nuclear co-repressor that modulates metabolic homeostasis. The stellate and inflammatory increases seen with the high carbohydrate, LF12 diet may represent postprandial responses. They depend on retinol and Shp, but the regulation reverses with a HFD.

Retinoids (retinol and its derivatives) are required for maintaining vision, immunity, barrier function, reproduction, embryogenesis, cell proliferation and differentiation. Furthermore, retinoid signaling plays a key role in initiating meiosis of germ cells of the mammalian fetal ovary. Recently, studies indicated that precise retinoid level regulation in the ovary provides a molecular control of ovarian development, steroidogenesis and oocyte maturation. Besides, abnormal retinoid signaling may be involved in the pathogenesis of polycystic ovary syndrome (PCOS), one of the most common ovarian endocrinopathies in reproductive-aged women worldwide. This review primarily summarizes recent advancements made in investigating the action of retinoid signaling in ovarian physiology as well as the abnormal retinoid signaling in PCOS.

Cellular binding-proteins (BP), including CRBP1, CRBP2, CRABP1, CRABP2, and FABP5, shepherd the poorly aqueous soluble retinoids during uptake, metabolism and function. Holo-BP promote efficient use of retinol, a scarce but essential nutrient throughout evolution, by sheltering it and its major metabolite all-trans-retinoic acid from adventitious interactions with the cellular milieu, and by imposing specificity of delivery to enzymes, nuclear receptors and other partners. Apo-BP reflect cellular retinoid status and modify activities of retinoid metabolon enzymes, or exert non-canonical actions. High ligand binding affinities and the nature of ligand sequestration necessitate external factors to prompt retinoid release from holo-BP. One or more of cross-linking, kinetics, and colocalization have identified these factors as RDH, RALDH, CYP26, LRAT, RAR and PPARβ/δ. Michaelis-Menten and other kinetic approaches verify that BP channel retinoids to select enzymes and receptors by protein-protein interactions. Function of the BP and enzymes that constitute the retinoid metabolon depends in part on retinoid exchanges unique to specific pairings. The complexity of these exchanges configure retinol metabolism to meet the diverse functions of all-trans-retinoic acid and its ability to foster contrary outcomes in different cell types, such as inducing apoptosis, differentiation or proliferation. Altered BP expression affects retinoid function, for example, by impairing pancreas development resulting in abnormal glucose and energy metabolism, promoting predisposition to breast cancer, and fostering more severe outcomes in prostate cancer, ovarian adenocarcinoma, and glioblastoma. Yet, the extent of BP interactions with retinoid metabolon enzymes and their impact on retinoid physiology remains incompletely understood.

Topical drugs have been used successfully to treat acne for decades. This review discusses the use, efficacy, and safety of options available via prescription. Topical antibiotics, dapsone, benzyl peroxide, azelaic acid, and topical retinoids are included. Topical antibiotics should not be used as monotherapy but rather be combined with other agents to avoid resistant Propionibacterium acnes strains. Benzoyl peroxide is effective in preventing bacteria resistance. Topical retinoids address primarily the comedonal but also the inflammatory lesions of acne. Azelaic acid is useful in treating acne lesions and for lightening postinflammatory hyperpigmentation that may accompany inflammatory acne lesions. Combinations of agents that address different aspects of acne pathogenesis may offer higher benefit to acne patients.

As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in treatment of acute promyelocytic leukemia (APL). However, clinical application of ATRA has limitations. Our previous studies suggested that 4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, could induce differentiation of APL cells in vivo and in vitro. To explore the underlying mechanism of ATPR, the effect of ATPR on autophagy of APL cells was observed in the present study. The results showed that the differentiation effect of ATPR on APL cells was accompanied with autophagy induction and PML-RARα degradation via activating Notch1 signaling pathway. Moreover, inhibition of autophagy using 3-methyladenine (3-MA) or small interfering RNA (siRNA) that targets essential autophagy gene ATG5 abrogated the ATPR-induced cell differentiation. Furthermore, when pretreated with DAPT, a γ-secretase inhibitor, the Notch1 signaling pathway was blocked in APL cells, followed by the reduction of ATPR-induced autophagy and differentiation. Taken together, these results suggested that autophagy play an important role in ATPR-induced cell differentiation, which may provide a novel approach to cure APL patients.

RPE65 is an indispensable component of the retinoid visual cycle in vertebrates, through which the visual chromophore 11-cis-retinal (11-cis-RAL) is generated to maintain normal vision. Various blinding conditions in humans, such as Leber congenital amaurosis and retinitis pigmentosa (RP), are attributed to either homozygous or compound heterozygous mutations in RPE65. Herein, we investigated D477G missense mutation, an unprecedented dominant-acting mutation of RPE65 identified in patients with autosomal dominant RP. We generated a D477G knock-in (KI) mouse and characterized its phenotypes. Although RPE65 protein levels were decreased in heterozygous KI mice, their scotopic, maximal, and photopic electroretinography responses were comparable to those of wild-type (WT) mice in stationary condition. As shown by high-performance liquid chromatography analysis, levels of 11-cis-RAL in fully dark-adapted heterozygous KI mice were similar to that in WT mice. However, kinetics of 11-cis-RAL regeneration after light exposure were significantly slower in heterozygous KI mice compared with WT and RPE65 heterozygous knockout mice. Furthermore, heterozygous KI mice exhibited lower A-wave recovery compared with WT mice after photobleaching, suggesting a delayed dark adaptation. Taken together, these observations suggest that D477G acts as a dominant-negative mutant of RPE65 that delays chromophore regeneration. The KI mice provide a useful model for further understanding of the pathogenesis of RP associated with this RPE65 mutant and for the development of therapeutic strategies.

International audience; The aim of this study was the characterization of transcriptional regulatory pathways mediated by retinoic acid (RA) in Senegalese sole larvae. For this purpose, pre-metamorphic larvae were treated with a low concentration of DEAB, an inhibitor of RALDH enzyme, until the end of metamorphosis. No differences in growth, eye migration or survival were observed. Nevertheless, gene expression analysis revealed a total of 20 transcripts differentially expressed during larval development and only six related with DEAB treatments directly involved in RA metabolism and actions (rdh10a, aldh1a2, crbp1, igf2r, rarg and cyp26a1) to adapt to a low-RA environment. In a second experiment, post-metamorphic larvae were exposed to the all-trans RA (atRA) observing an opposite regulation for those genes involved in RA synthesis and degradation (rdh10a, aldh1a2, crbp1 and cyp26a1) as well as other related with thyroid- (dio2) and IGF-axes (igfbp1, igt2r and igfbp5) to balance RA levels. In a third experiment, DEAB-pretreated post-metamorphic larvae were exposed to atRA and TTNPB (a specific RAR agonist). Both drugs down-regulated rdh10a and aldh1a2 and up-regulated cyp26a1 expression demonstrating their important role in RA homeostasis. Moreover, five retinoic receptors that mediate RA actions, the thyroid receptor thrb, and five IGF binding proteins changed differentially their expression. Overall, this study demonstrates that exogenous RA modulates the expression of some genes involved in the RA synthesis, degradation and cellular transport through RAR-mediated regulatory pathways establishing a negative feedback regulatory mechanism necessary to balance endogenous RA levels and gradients.

Contact dermatitis is a broad term that encompasses both nonimmunologic irritant contact dermatitis (ICD) and immunologically mediated allergic contact dermatitis (ACD). Both ICD and ACD can negatively affect a patient's quality of life and are a source of exorbitant medical and societal costs. Avoidance of inciting irritants and/or allergens and liberal use of emollients or humectants are the cornerstone of therapy. When an allergic cause is suspected, patch testing is highly encouraged. In this contribution, we highlight both the commonalities and differences of acral contact dermatitis as it relates to specific regions of the body. In addition, a review of the predisposing conditions, risk factors, and treatment options in the literature is presented to help with the care of these challenging patients.

Objective Vitamin A is commonly recommended as a treatment for diarrhea and undernutrition; however, little is known about the underlying cellular mechanisms. The aim of this study was to investigate the modulation of cell cycle by vitamin A derivatives (retinyl palmitate or retinol) in undernourished intestinal epithelial crypts (IEC-6). Methods IEC-6 cells were exposed to nutrient deprivation (no serum and no glutamine) and supplemented with retinyl palmitate or retinol at a range of 2 to 20 μM. Proliferation, apoptosis/necrosis, cell cycle process, and gene transcription were assessed. Results Nutrient deprivation for 6, 12, 24, or 48 h decreased cell proliferation, and retinyl palmitate further decreased it after 24 and 48 h. Apoptosis rates were reduced by undernourishment and further reduced by retinyl palmitate after 48 h; whereas necrosis rates were unaltered. Undernourishment induced overall cell quiescence, increased percentage of cells in G0/G1 phase and decreased percentage of cells in S phase after 12 h and in G2/M phases at 6, 12, and 24 h after treatment. Both retinoids also showed cell quiescence induction with less cells in G2/M phases after 48 h, whereas only retinol showed significant modulation of G0/G1 and S phases. Both retinoids also increased markers of cell differentiation Fabp and Iap gene transcriptions in about fivefold rates after 42 h. Furthermore, specific gene transcriptions related to MAP kinase signaling pathway regulation of cell differentiation and cell cycle regulation were triggered by retinoids in undernourished IEC-6, with higher levels of expression for Atf2 and C-jun genes. Conclusions These findings indicated that both vitamin A derivatives induce further survival mechanisms in undernourished intestinal epithelial crypt cells. These mechanisms include increased cell quiescence, decreased apoptosis, increased cell differentiation, and transcription of genes related to MAP kinase signaling pathway.

The photochemistry of vision employs opsins and geometric isomerization of their covalently bound retinylidine chromophores. In different animal classes, these light receptors associate with distinct G proteins that either hyperpolarize or depolarize photoreceptor membranes. Vertebrates also use the acidic form of chromophore, retinoic acid, as the ligand of nuclear hormone receptors that orchestrate eye development. To establish and sustain these processes, animals must acquire carotenoids from the diet, transport them, and metabolize them to chromophore and retinoic acid. The understanding of carotenoid metabolism, however, lagged behind our knowledge about the biology of their receptor molecules. In the past decades, much progress has been made in identifying the genes encoding proteins that mediate the transport and enzymatic transformations of carotenoids and their retinoid metabolites. Comparative analysis in different animal classes revealed how evolutionary tinkering with a limited number of genes evolved different biochemical strategies to supply photoreceptors with chromophore. Mutations in these genes impair carotenoid metabolism and induce various ocular pathologies. This review summarizes this advancement and introduces the involved proteins, including the homeostatic regulation of their activities.

Accumulation of bis-retinoids in the retinal pigmented epithelium (RPE) is a hallmark of aging and retinal disorders such as Stargardt disease and age-related macular degeneration. These aberrant fluorescent condensation products, including di-retinoid-pyridinium-ethanolamine (A2E), are thought to be transferred to RPE cells primarily through phagocytosis of the photoreceptor outer segments. However, we observed by two-photon microscopy that mouse retinas incapable of phagocytosis due to a deficiency of the c-Mer proto-oncogene tyrosine kinase (Mertk) nonetheless contained fluorescent retinoid condensation material in their RPE. Primary RPE cells from Mertk−/− mice also accumulated fluorescent products in vitro. Finally, quantification of A2E demonstrated the acquisition of retinal condensation products in Mertk−/− mouse RPE prior to retinal degeneration. In these mice, we identified activated microglial cells that likely were recruited to transport A2E-like condensation products to the RPE and dispose of the dying photoreceptor cells. These observations demonstrate a novel transport mechanism between photoreceptor cells and RPE that does not involve canonical Mertk-dependent phagocytosis.

Studies have documented practice gaps in acne management between pediatricians and dermatologists. Evidence-based recommendations for acne management were published by the American Acne and Rosacea Society and the American Academy of Pediatrics in 2013. We assess the impact of a case-based learning intervention on pediatrician knowledge and treatment of acne in accordance with published recommendations.Participants were recruited at four conferences for pediatric providers. Knowledge of the recommendations and confidence in utilizing them was assessed. Five case-based questions were presented, with providers choosing acne treatments before, immediately after, and 3 months after a case-based educational presentation. Answer selections consistent with the recommendations were scored as correct, and all responses were evaluated for patterns of medication selection.A total of 150 individuals participated, most with over 10 years experience. Knowledge of the recommendations and confidence in prescribing acne therapy was poor. The average preintervention management selections were 70% correct, increasing significantly to 86% 3 months after intervention (p.01). The most significant improvements were demonstrated in provider's ability to choose regimens for moderate acne consistent with published recommendations, and in recommendation-consistent usage of retinoids and benzoyl peroxide (p.05). Persisting practice gaps included a reluctance to use topical retinoids in preadolescents and lack of initiating oral combination therapies in patients with severe acne.A case-based educational intervention significantly increased providers choosing acne treatments in accordance with evidence-based recommendations in an examination setting. Limitations of the study include an inability to assess actual provider prescribing behavior through this methodology.

Vitamin A deficiency is known to affect 20 million pregnant women worldwide. However, the prenatal effects of maternal vitamin A deficiency on pancreas development have not been clearly determined. The present study examined how maternal vitamin A deficiency affects fetal islet development. Vitamin A-deficient mice were generated by feeding female mice with a chemically defined diet lacking vitamin A prior to mating as well as during pregnancy. We found that maternal vitamin A deficiency during pregnancy affected fetal pancreas development. Although the exocrine differentiation appeared normal, development of islet tissue was impaired. In the pancreas of neonatal mice, only a few endocrine cell clusters were formed, and these cell clusters lacked capillary endothelial cells. To further determine how vitamin A metabolites, such as retinoic acid, regulate vascularized islet development, ex vivo culture of embryonic pancreas either in the presence of 4-diethylaminobenzaldehyde (DEAB; an inhibitor of retinaldehyde dehydrogenase), all-trans retinoic acid (atRA) or retinoic acid receptor agonist (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid (TTNPB) was carried out. We found that the addition of DEAB blocked vascularization and suppressed β-cell differentiation. Conversely, atRA or TTNPB promoted β-cell differentiation accompanied by enhanced expression of vascular basement component, laminin. We further demonstrated that atRA regulated vascularization via upregulating vascular endothelial growth factor-A (VEGF-A) secretion in embryonic pancreas and treatment with VEGF-A was able to partially rescue vascularization and β-cell differentiation in DEAB-treated embryonic pancreas cultures. The findings explain why maternal vitamin A deficiency affects fetal islet development and support an essential role of retinoid signaling in regulating vascularized islet development.

Heterotopic ossification (HO) consists of ectopic cartilage and bone formation following severe trauma or invasive surgeries, and a genetic form of it characterizes patients with Fibrodysplasia Ossificans Progressiva (FOP). Recent mouse studies showed that HO was significantly inhibited by systemic treatment with a corticosteroid or the retinoic acid receptor γ agonist Palovarotene. Because these drugs act differently, the data raised intriguing questions including whether the drugs affected HO via similar means, whether a combination therapy would be more effective or whether the drugs may hamper each other's action. To tackle these questions, we used an effective HO mouse model involving subcutaneous implantation of Matrigel plus rhBMP2, and compared the effectiveness of prednisone, dexamathaosone, Palovarotene or combination of. Each corticosteroid and Palovarotene reduced bone formation at max doses, and a combination therapy elicited similar outcomes without obvious interference. While Palovarotene had effectively prevented the initial cartilaginous phase of HO, the steroids appeared to act more on the bony phase. In reporter assays, dexamethasone and Palovarotene induced transcriptional activity of their respective GRE or RARE constructs and did not interfere with each other's pathway. Interestingly, both drugs inhibited the activity of a reporter construct for the inflammatory mediator NF-κB, particularly in combination. In good agreement, immunohistochemical analyses showed that both drugs markedly reduced the number of mast cells and macrophages near and within the ectopic Matrigel mass and reduced also the number of progenitor cells. In sum, corticosteroids and Palovarotene appear to block HO via common and distinct mechanisms. Most importantly, they directly or indirectly inhibit the recruitment of immune and inflammatory cells present at the affected site, thus alleviating the effects of key HO instigators.