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Keywords = retinol dehydrogenase

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15 pages, 29548 KiB  
Article
A Comparative Study of a Potent CNS-Permeable RARβ-Modulator, Ellorarxine, in Neurons, Glia and Microglia Cells In Vitro
by Yunxi Zhang, Lilie Gailloud, Alexander Shin, Jessica Fewkes, Rosella Pinckney, Andrew Whiting and Paul Chazot
Int. J. Mol. Sci. 2025, 26(8), 3551; https://doi.org/10.3390/ijms26083551 - 10 Apr 2025
Viewed by 1166
Abstract
Vitamin A (retinol) and its derivatives (retinoids) assume critical roles in neural development, cellular differentiation, axon elongation, programmed cell apoptosis and various fundamental cellular processes. Retinoids function by binding to specific nuclear receptors, such as retinoic acid receptors (RARs) and retinoid X receptors [...] Read more.
Vitamin A (retinol) and its derivatives (retinoids) assume critical roles in neural development, cellular differentiation, axon elongation, programmed cell apoptosis and various fundamental cellular processes. Retinoids function by binding to specific nuclear receptors, such as retinoic acid receptors (RARs) and retinoid X receptors (RXRs), activating specific signalling pathways in the cells. The disruption of the retinoic acid signalling pathway can result in neuroinflammation, oxidative and ER stress and mitochondrial dysfunction and has been implicated in a wide range of neurodegenerative diseases. The present study explored the potential therapeutic application of our innovative CNS-permeable synthetic retinoid, Ellorarxine, for the treatment of neurodegenerative disorders in vitro. An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay, lactate dehydrogenase (LDH) assay, enzyme-linked immunosorbent assay (ELISA), immunocytochemistry and immunofluorescence staining were performed. Ellorarxine increased Cyp26 and, selectively, RARβ protein expression in neurons, glia and microglia. Ellorarxine significantly reduced cell death (neurons, glia), increased mitochondrial viability (neurons), modulated cytokine release (microglia), and positively regulated cellular autophagy (neurons, glia, microglia). These results suggest that Ellorarxine is a promising drug candidate that should be further investigated in the treatment of neurodegenerative diseases. Full article
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27 pages, 2454 KiB  
Article
Biochemical and Antioxidant Characteristics of Chlorococcum oleofaciens (Chlorophyceae, Chlorophyta) under Various Cultivation Conditions
by Irina Maltseva, Aleksandr Yakoviichuk, Svetlana Maltseva, Svetlana Cherkashina, Maxim Kulikovskiy and Yevhen Maltsev
Plants 2024, 13(17), 2413; https://doi.org/10.3390/plants13172413 - 29 Aug 2024
Cited by 2 | Viewed by 1514
Abstract
Abstract: The functional state of enrichment cultures of the Chlorophycean strain Chlorococcum oleofaciens CAMU MZ–Ch4 under various cultivation conditions was studied. Experiments with different aeration conditions, cultivation durations, and nitrogen and phosphorus concentrations in the medium were carried out to evaluate the growth [...] Read more.
Abstract: The functional state of enrichment cultures of the Chlorophycean strain Chlorococcum oleofaciens CAMU MZ–Ch4 under various cultivation conditions was studied. Experiments with different aeration conditions, cultivation durations, and nitrogen and phosphorus concentrations in the medium were carried out to evaluate the growth dynamics of the strain and its biochemical characteristics. The contents of chlorophylls, carotenoids, proteins, lipids, retinol, α-tocopherol, ascorbic acid, phenolic compounds, lipid peroxidation products, antioxidant enzymes (glutathione peroxidase, catalase, superoxide dismutase), and succinate dehydrogenase activity were measured. The lipid content on the fully supplemented Bold’s basal medium increased to 381.03 mg g−1 dry weight at the late stationary growth phase. This value is 1.3–2.8 times higher than in other experiments. The use of aeration was associated with an increased content of proteins at 283.56 mg g−1 and of carotenoids at 2.12 mg g−1. Also, cultures at the early stationary growth phase with aeration showed the ability to accumulate phenolic compounds and ascorbic acid in amounts up to 0.32 mg g−1 and 0.19 mg g−1. The 74-day-old cultures had the highest contents of retinol (0.16 mg g−1) and α-tocopherol (0.68 mg g−1). Growth in nitrogen- and phosphorus-depleted media increased catalase and superoxide dismutase activity. A comprehensive analysis of all data showed that the antioxidant defence system is stress-resistant and flexible under varying aeration conditions and nitrogen and phosphorus availabilities. Thus, the strain CAMU MZ–Ch4 can be considered a potential producer of lipids, pigments, proteins, and vitamins under various culturing conditions. Full article
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19 pages, 5415 KiB  
Article
Control of Mitochondrial Electron Transport Chain Flux and Apoptosis by Retinoic Acid: Raman Imaging In Vitro Human Bronchial and Lung Cancerous Cells
by Halina Abramczyk and Jakub Maciej Surmacki
Cancers 2023, 15(18), 4535; https://doi.org/10.3390/cancers15184535 - 13 Sep 2023
Cited by 4 | Viewed by 2336
Abstract
The multiple functions of cytochrome c (cyt c) and their regulation in life and death decisions of the mammalian cell go beyond respiration, apoptosis, ROS scavenging, and oxidation of cardiolipine. It has become increasingly evident that cyt c is involved in the [...] Read more.
The multiple functions of cytochrome c (cyt c) and their regulation in life and death decisions of the mammalian cell go beyond respiration, apoptosis, ROS scavenging, and oxidation of cardiolipine. It has become increasingly evident that cyt c is involved in the propagation of mitogenic signals. It has been proposed that the mitogenic signals occur via the PKCδ-retinoic acid signal complex comprising the protein kinase Cδ, the adapter protein Src homologous collagen homolog (p66Shc), and cyt c. We showed the importance of retinoic acid in regulating cellular processes monitored by the Raman bands of cyt c. To understand the role of retinoids in regulating redox status of cyt c, we recorded the Raman spectra and images of cells receiving redox stimuli by retinoic acid at in vitro cell cultures. For these purposes, we incubated bronchial normal epithelial lung (BEpC) and lung cancer cells (A549) with retinoic acid at concentrations of 1, 10, and 50 µM for 24 and 48 h of incubations. The new role of retinoic acid in a change of the redox status of iron ion in the heme group of cyt c from oxidized Fe3+ to reduced Fe2+ form may have serious consequences on ATPase effectiveness and aborting the activation of the conventional mitochondrial signaling protein-dependent pathways, lack of triggering programmed cell death through apoptosis, and lack of cytokine induction. To explain the effect of retinoids on the redox status of cyt c in the electron transfer chain, we used the quantum chemistry models of retinoid biology. It has been proposed that retinol catalyzes resonance energy transfer (RET) reactions in cyt c. The paper suggests that RET is pivotally important for mitochondrial energy homeostasis by controlling oxidative phosphorylation by switching between activation and inactivation of glycolysis and regulation of electron flux in the electron transport chain. The key role in this process is played by protein kinase C δ (PKCδ), which triggers a signal to the pyruvate dehydrogenase complex. The PKCδ-retinoic acid complex reversibly (at normal physiological conditions) or irreversibly (cancer) responds to the redox potential of cyt c that changes with the electron transfer chain flux. Full article
(This article belongs to the Section Cancer Biomarkers)
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12 pages, 3365 KiB  
Case Report
A Splicing Variant in RDH8 Is Associated with Autosomal Recessive Stargardt Macular Dystrophy
by Stefania Zampatti, Cristina Peconi, Giulia Calvino, Rosangela Ferese, Stefano Gambardella, Raffaella Cascella, Jacopo Sebastiani, Benedetto Falsini, Andrea Cusumano and Emiliano Giardina
Genes 2023, 14(8), 1659; https://doi.org/10.3390/genes14081659 - 21 Aug 2023
Cited by 5 | Viewed by 1616
Abstract
Stargardt macular dystrophy is a genetic disorder, but in many cases, the causative gene remains unrevealed. Through a combined approach (whole-exome sequencing and phenotype/family-driven filtering algorithm) and a multilevel validation (international database searching, prediction scores calculation, splicing analysis assay, segregation analyses), a biallelic [...] Read more.
Stargardt macular dystrophy is a genetic disorder, but in many cases, the causative gene remains unrevealed. Through a combined approach (whole-exome sequencing and phenotype/family-driven filtering algorithm) and a multilevel validation (international database searching, prediction scores calculation, splicing analysis assay, segregation analyses), a biallelic mutation in the RDH8 gene was identified to be responsible for Stargardt macular dystrophy in a consanguineous Italian family. This paper is a report on the first family in which a biallelic deleterious mutation in RDH8 is detected. The disease phenotype is consistent with the expected phenotype hypothesized in previous studies on murine models. The application of the combined approach to genetic data and the multilevel validation allowed the identification of a splicing mutation in a gene that has never been reported before in human disorders. Full article
(This article belongs to the Collection Genetics and Genomics of Rare Disorders)
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15 pages, 3987 KiB  
Article
Hif1α/Dhrs3a Pathway Participates in Lipid Droplet Accumulation via Retinol and Ppar-γ in Fish Hepatocytes
by Jingjing Tian, Yihui Du, Binbin Wang, Mengmeng Ji, Hongyan Li, Yun Xia, Kai Zhang, Zhifei Li, Wenping Xie, Wangbao Gong, Ermeng Yu, Guangjun Wang and Jun Xie
Int. J. Mol. Sci. 2023, 24(12), 10236; https://doi.org/10.3390/ijms241210236 - 16 Jun 2023
Cited by 3 | Viewed by 3297
Abstract
Excessive hepatic lipid accumulation is a common phenomenon in cultured fish; however, its underlying mechanisms are poorly understood. Lipid droplet (LD)-related proteins play vital roles in LD accumulation. Herein, using a zebrafish liver cell line (ZFL), we show that LD accumulation is accompanied [...] Read more.
Excessive hepatic lipid accumulation is a common phenomenon in cultured fish; however, its underlying mechanisms are poorly understood. Lipid droplet (LD)-related proteins play vital roles in LD accumulation. Herein, using a zebrafish liver cell line (ZFL), we show that LD accumulation is accompanied by differential expression of seven LD-annotated genes, among which the expression of dehydrogenase/reductase (SDR family) member 3 a/b (dhrs3a/b) increased synchronously. RNAi-mediated knockdown of dhrs3a delayed LD accumulation and downregulated the mRNA expression of peroxisome proliferator-activated receptor gamma (pparg) in cells incubated with fatty acids. Notably, Dhrs3 catalyzed retinene to retinol, the content of which increased in LD-enriched cells. The addition of exogenous retinyl acetate maintained LD accumulation only in cells incubated in a lipid-rich medium. Correspondingly, exogenous retinyl acetate significantly increased pparg mRNA expression levels and altered the lipidome of the cells by increasing the phosphatidylcholine and triacylglycerol contents and decreasing the cardiolipin, phosphatidylinositol, and phosphatidylserine contents. Administration of LW6, an hypoxia-inducible factor 1α (HIF1α) inhibitor, reduced the size and number of LDs in ZFL cells and attenuated hif1αa, hif1αb, dhrs3a, and pparg mRNA expression levels. We propose that the Hif-1α/Dhrs3a pathway participates in LD accumulation in hepatocytes, which induces retinol formation and the Ppar-γ pathway. Full article
(This article belongs to the Section Biochemistry)
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16 pages, 6058 KiB  
Article
Metabolic Engineering of Saccharomyces cerevisiae for Efficient Retinol Synthesis
by Xuan Wang, Xianhao Xu, Jiaheng Liu, Yanfeng Liu, Jianghua Li, Guocheng Du, Xueqin Lv and Long Liu
J. Fungi 2023, 9(5), 512; https://doi.org/10.3390/jof9050512 - 26 Apr 2023
Cited by 12 | Viewed by 5528
Abstract
Retinol, the main active form of vitamin A, plays a role in maintaining vision, immune function, growth, and development. It also inhibits tumor growth and alleviates anemia. Here, we developed a Saccharomyces cerevisiae strain capable of high retinol production. Firstly, the de novo [...] Read more.
Retinol, the main active form of vitamin A, plays a role in maintaining vision, immune function, growth, and development. It also inhibits tumor growth and alleviates anemia. Here, we developed a Saccharomyces cerevisiae strain capable of high retinol production. Firstly, the de novo synthesis pathway of retinol was constructed in S. cerevisiae to realize the production of retinol. Second, through modular optimization of the metabolic network of retinol, the retinol titer was increased from 3.6 to 153.6 mg/L. Then, we used transporter engineering to regulate and promote the accumulation of the intracellular precursor retinal to improve retinol production. Subsequently, we screened and semi-rationally designed the key enzyme retinol dehydrogenase to further increase the retinol titer to 387.4 mg/L. Lastly, we performed two-phase extraction fermentation using olive oil to obtain a final shaking flask retinol titer of 1.2 g/L, the highest titer reported at the shake flask level. This study laid the foundation for the industrial production of retinol. Full article
(This article belongs to the Special Issue Development and Utilization of Yeast Resources)
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16 pages, 1606 KiB  
Article
Novel Potential Markers of Myofibroblast Differentiation Revealed by Single-Cell RNA Sequencing Analysis of Mesenchymal Stromal Cells in Profibrotic and Adipogenic Conditions
by Olga Grigorieva, Nataliya Basalova, Maksim Vigovskiy, Mikhail Arbatskiy, Uliana Dyachkova, Maria Kulebyakina, Konstantin Kulebyakin, Pyotr Tyurin-Kuzmin, Natalia Kalinina and Anastasia Efimenko
Biomedicines 2023, 11(3), 840; https://doi.org/10.3390/biomedicines11030840 - 10 Mar 2023
Cited by 9 | Viewed by 5235
Abstract
Mesenchymal stromal cells (MSCs) are the key regulators of tissue homeostasis and repair after damage. Accumulating evidence indicates the dual contribution of MSCs into the development of fibrosis induced by chronic injury: these cells can suppress the fibrotic process due to paracrine activity, [...] Read more.
Mesenchymal stromal cells (MSCs) are the key regulators of tissue homeostasis and repair after damage. Accumulating evidence indicates the dual contribution of MSCs into the development of fibrosis induced by chronic injury: these cells can suppress the fibrotic process due to paracrine activity, but their promoting role in fibrosis by differentiating into myofibroblasts has also been demonstrated. Many model systems reproducing fibrosis have shown the ability of peroxisome proliferator-activated receptor (PPAR) agonists to reverse myofibroblast differentiation. Thus, the differentiation of multipotent cells into myofibroblasts and adipocytes can be considered as processes that require the activation of opposite patterns of gene expression. To test this hypothesis, we analyzed single cell RNA-Seq transcriptome of human adipose tissue MSCs after stimulation of the myofibroblast or adipogenic differentiation and revealed several genes that changed their expression in a reciprocal manner upon these conditions. We validated the expression of selected genes by RT-PCR, and evaluated the upregulation of several relevant proteins using immunocytochemistry, refining the results obtained by RNA-Seq analysis. We have shown, for the first time, the expression of neurotrimin (NTM), previously studied mainly in the nervous tissue, in human adipose tissue MSCs, and demonstrated its increased gene expression and clustering of membrane receptors upon the stimulation of myofibroblast differentiation. We also showed an increased level of CHD3 (Chromodomain-Helicase-DNA-binding protein 3) in MSCs under profibrotic conditions, while retinol dehydrogenase-10 (RDH10) was detected only in MSCs after adipogenic induction, which contradicted the data of transcriptomic analysis and again highlights the need to validate the data obtained by omics methods. Our findings suggest the further analysis of the potential contribution of neurotrimin and CHD3 in the regulation of myofibroblast differentiation and the development of fibrosis. Full article
(This article belongs to the Special Issue Biomedicines: 10th Anniversary)
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22 pages, 2023 KiB  
Article
Antioxidant Status and Biotechnological Potential of New Vischeria vischeri (Eustigmatophyceae) Soil Strains in Enrichment Cultures
by Aleksandr Yakoviichuk, Zinaida Krivova, Svetlana Maltseva, Angelica Kochubey, Maxim Kulikovskiy and Yevhen Maltsev
Antioxidants 2023, 12(3), 654; https://doi.org/10.3390/antiox12030654 - 6 Mar 2023
Cited by 4 | Viewed by 2318
Abstract
The functional state of enrichment cultures of the Eustigmatophycean strains Vischeria vischeri MZ–E3 and MZ–E4 after 25-day cultivation in the BBM medium was studied. The concentrations of chlorophyll a, total carotenoids, protein, vitamins A and E, fatty acid peroxidation product content, an [...] Read more.
The functional state of enrichment cultures of the Eustigmatophycean strains Vischeria vischeri MZ–E3 and MZ–E4 after 25-day cultivation in the BBM medium was studied. The concentrations of chlorophyll a, total carotenoids, protein, vitamins A and E, fatty acid peroxidation product content, an antioxidant enzyme, and succinate dehydrogenase activity were measured. MZ–E3 succinate dehydrogenase activity was significantly higher by 2.21 times; the MZ–E4 strain had 2.94 times higher glutathione peroxidase activity. The MZ–E3 antioxidant activity index and the MZ–E3 unsaturation of fatty acids were 1.3 and 1.25 times higher than the MZ–E4. The retinol and α-tocopherol content of the MZ–E3 was 28.6% and 38.76% higher than MZ–E4. The main fatty acid profile differences were the 3.46-fold and 3.92-fold higher stearic and eicosapentaenoic acid content in the MZ–E4 biomass. MZ–E3 had higher antioxidant, energy, and metabolic and photosynthetic status than MZ–E4. The antioxidant status of the studied strains showed the dependence of the adaptive mechanisms of each, associated with differences in the ecological conditions of the biotopes from which they were isolated. These strains are promising for producing α-tocopherol and biomass enriched with omega-3 and omega-6 fatty acids. Full article
(This article belongs to the Section Natural and Synthetic Antioxidants)
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18 pages, 1291 KiB  
Article
Weighted Single-Step GWAS Identifies Genes Influencing Fillet Color in Rainbow Trout
by Ridwan O. Ahmed, Ali Ali, Rafet Al-Tobasei, Tim Leeds, Brett Kenney and Mohamed Salem
Genes 2022, 13(8), 1331; https://doi.org/10.3390/genes13081331 - 26 Jul 2022
Cited by 12 | Viewed by 3557
Abstract
The visual appearance of the fish fillet is a significant determinant of consumers’ purchase decisions. Depending on the rainbow trout diet, a uniform bright white or reddish/pink fillet color is desirable. Factors affecting fillet color are complex, ranging from the ability of live [...] Read more.
The visual appearance of the fish fillet is a significant determinant of consumers’ purchase decisions. Depending on the rainbow trout diet, a uniform bright white or reddish/pink fillet color is desirable. Factors affecting fillet color are complex, ranging from the ability of live fish to accumulate carotenoids in the muscle to preharvest environmental conditions, early postmortem muscle metabolism, and storage conditions. Identifying genetic markers of fillet color is a desirable goal but a challenging task for the aquaculture industry. This study used weighted, single-step GWAS to explore the genetic basis of fillet color variation in rainbow trout. We identified several SNP windows explaining up to 3.5%, 2.5%, and 1.6% of the additive genetic variance for fillet redness, yellowness, and whiteness, respectively. SNPs are located within genes implicated in carotenoid metabolism (β,β-carotene 15,15′-dioxygenase, retinol dehydrogenase) and myoglobin homeostasis (ATP synthase subunit β, mitochondrial (ATP5F1B)). These genes are involved in processes that influence muscle pigmentation and postmortem flesh coloration. Other identified genes are involved in the maintenance of muscle structural integrity (kelch protein 41b (klh41b), collagen α-1(XXVIII) chain (COL28A1), and cathepsin K (CTSK)) and protection against lipid oxidation (peroxiredoxin, superoxide dismutase 2 (SOD2), sestrin-1, Ubiquitin carboxyl-terminal hydrolase-10 (USP10)). A-to-G single-nucleotide polymorphism in β,β-carotene 15,15′-dioxygenase, and USP10 result in isoleucine-to-valine and proline-to-leucine non-synonymous amino acid substitutions, respectively. Our observation confirms that fillet color is a complex trait regulated by many genes involved in carotenoid metabolism, myoglobin homeostasis, protection against lipid oxidation, and maintenance of muscle structural integrity. The significant SNPs identified in this study could be prioritized via genomic selection in breeding programs to improve fillet color in rainbow trout. Full article
(This article belongs to the Special Issue Functional Genomics in Aquaculture)
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16 pages, 1605 KiB  
Article
Tracking Prostate Carcinogenesis over Time through Urine Proteome Profiling in an Animal Model: An Exploratory Approach
by Alexandra Moreira-Pais, Rita Nogueira-Ferreira, Stephanie Reis, Susana Aveiro, António Barros, Tânia Melo, Bárbara Matos, José Alberto Duarte, Fernanda Seixas, Pedro Domingues, Francisco Amado, Margarida Fardilha, Paula A. Oliveira, Rita Ferreira and Rui Vitorino
Int. J. Mol. Sci. 2022, 23(14), 7560; https://doi.org/10.3390/ijms23147560 - 8 Jul 2022
Cited by 1 | Viewed by 3154
Abstract
Prostate cancer (PCa) is one of the most lethal diseases in men, which justifies the search for new diagnostic tools. The aim of the present study was to gain new insights into the progression of prostate carcinogenesis by analyzing the urine proteome. To [...] Read more.
Prostate cancer (PCa) is one of the most lethal diseases in men, which justifies the search for new diagnostic tools. The aim of the present study was to gain new insights into the progression of prostate carcinogenesis by analyzing the urine proteome. To this end, urine from healthy animals and animals with prostate adenocarcinoma was analyzed at two time points: 27 and 54 weeks. After 54 weeks, the incidence of pre-neoplastic and neoplastic lesions in the PCa animals was 100%. GeLC-MS/MS and subsequent bioinformatics analyses revealed several proteins involved in prostate carcinogenesis. Increased levels of retinol-binding protein 4 and decreased levels of cadherin-2 appear to be characteristic of early stages of the disease, whereas increased levels of enolase-1 and T-kininogen 2 and decreased levels of isocitrate dehydrogenase 2 describe more advanced stages. With increasing age, urinary levels of clusterin and corticosteroid-binding globulin increased and neprilysin levels decreased, all of which appear to play a role in prostate hyperplasia or carcinogenesis. The present exploratory analysis can be considered as a starting point for studies targeting specific human urine proteins for early detection of age-related maladaptive changes in the prostate that may lead to cancer. Full article
(This article belongs to the Collection Feature Papers in Materials Science)
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15 pages, 1495 KiB  
Article
Proteomic Analysis of Endometrial Cancer Tissues from Patients with Type 2 Diabetes Mellitus
by Muhammad Mujammami, Mohamed Rafiullah, Assim A. Alfadda, Khalid Akkour, Ibrahim O. Alanazi, Afshan Masood, Mohthash Musambil, Hani Alhalal, Maria Arafah, Anas M. Abdel Rahman and Hicham Benabdelkamel
Life 2022, 12(4), 491; https://doi.org/10.3390/life12040491 - 28 Mar 2022
Cited by 5 | Viewed by 3086
Abstract
Endometrial cancer (EC) is the most common form of gynecological cancer. Type 2 diabetes mellitus is associated with an increased risk of EC. Currently, no proteomic studies have investigated the role of diabetes in endometrial cancers from clinical samples. The present study aims [...] Read more.
Endometrial cancer (EC) is the most common form of gynecological cancer. Type 2 diabetes mellitus is associated with an increased risk of EC. Currently, no proteomic studies have investigated the role of diabetes in endometrial cancers from clinical samples. The present study aims to elucidate the molecular link between diabetes and EC using a proteomic approach. Endometrial tissue samples were obtained from age-matched patients (EC Diabetic and EC Non-Diabetic) during surgery. Untargeted proteomic analysis of the endometrial tissues was carried out using a two-dimensional difference in gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF). A total of 53 proteins were identified, with a significant difference in abundance (analysis of variance (ANOVA) test, p ≤ 0.05; fold-change ≥ 1.5) between the two groups, among which 30 were upregulated and 23 downregulated in the EC Diabetic group compared to EC Non-Diabetic. The significantly upregulated proteins included peroxiredoxin-1, vinculin, endoplasmin, annexin A5, calreticulin, and serotransferrin. The significantly downregulated proteins were myosin regulatory light polypeptide 9, Retinol dehydrogenase 12, protein WWC3, intraflagellar transport protein 88 homolog, superoxide dismutase [Cu-Zn], and retinal dehydrogenase 1. The network pathway was related to connective tissue disorder, developmental disorder, and hereditary disorder, with the identified proteins centered around dysregulation of ERK1/2 and F Actin signaling pathways. Cancer-associated protein alterations such as upregulation of peroxiredoxin-1, annexin 5, and iNOS, and downregulation of RDH12, retinaldehyde dehydrogenase 1, SOD1, and MYL 9, were found in the EC tissues of the diabetic group. Differential expression of proteins linked to cancer metastasis, such as the upregulation of vinculin and endoplasmin and downregulation of WWC3 and IFT88, was seen in the patients with diabetes. Calreticulin and alpha-enolase, which might have a role in the interplay between diabetes and EC, need further investigation. Full article
(This article belongs to the Section Genetics and Genomics)
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8 pages, 938 KiB  
Review
Towards a Better Vision of Retinoic Acid Signaling during Eye Development
by Gregg Duester
Cells 2022, 11(3), 322; https://doi.org/10.3390/cells11030322 - 19 Jan 2022
Cited by 23 | Viewed by 4434
Abstract
Retinoic acid (RA) functions as an essential signal for development of the vertebrate eye by controlling the transcriptional regulatory activity of RA receptors (RARs). During eye development, the optic vesicles and later the retina generate RA as a metabolite of vitamin A (retinol). [...] Read more.
Retinoic acid (RA) functions as an essential signal for development of the vertebrate eye by controlling the transcriptional regulatory activity of RA receptors (RARs). During eye development, the optic vesicles and later the retina generate RA as a metabolite of vitamin A (retinol). Retinol is first converted to retinaldehyde by retinol dehydrogenase 10 (RDH10) and then to RA by all three retinaldehyde dehydrogenases (ALDH1A1, ALDH1A2, and ALDH1A3). In early mouse embryos, RA diffuses to tissues throughout the optic placode, optic vesicle, and adjacent mesenchyme to stimulate folding of the optic vesicle to form the optic cup. RA later generated by the retina is needed for further morphogenesis of the optic cup and surrounding perioptic mesenchyme; loss of RA at this stage leads to microphthalmia and cornea plus eyelid defects. RA functions by binding to nuclear RARs at RA response elements (RAREs) that either activate or repress transcription of key genes. Binding of RA to RARs regulates recruitment of transcriptional coregulators such as nuclear receptor coactivator (NCOA) or nuclear receptor corepressor (NCOR), which in turn control binding of the generic coactivator p300 or the generic corepressor PRC2. No genes have been identified as direct targets of RA signaling during eye development, so future studies need to focus on identifying such genes and their RAREs. Studies designed to learn how RA normally controls eye development in vivo will provide basic knowledge valuable for determining how developmental eye defects occur and for improving strategies to treat eye defects. Full article
(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)
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17 pages, 3312 KiB  
Article
Similarities in DSG1 and KRT3 Downregulation through Retinoic Acid Treatment and PAX6 Knockdown Related Expression Profiles: Does PAX6 Affect RA Signaling in Limbal Epithelial Cells?
by Lorenz Latta, Igor Knebel, Constanze Bleil, Tanja Stachon, Priya Katiyar, Claire Zussy, Fabian Norbert Fries, Barbara Käsmann-Kellner, Berthold Seitz and Nóra Szentmáry
Biomolecules 2021, 11(11), 1651; https://doi.org/10.3390/biom11111651 - 8 Nov 2021
Cited by 15 | Viewed by 3195
Abstract
Congenital PAX6-aniridia is a rare panocular disease resulting from limbal stem cell deficiency. In PAX6-aniridia, the downregulation of the retinol-metabolizing enzymes ADH7 (All-trans-retinol dehydrogenase 7) and ALDH1A1/A3 (Retinal dehydrogenase 1, Aldehyde dehydrogenase family 1 member A3) have been described in limbal epithelial cells [...] Read more.
Congenital PAX6-aniridia is a rare panocular disease resulting from limbal stem cell deficiency. In PAX6-aniridia, the downregulation of the retinol-metabolizing enzymes ADH7 (All-trans-retinol dehydrogenase 7) and ALDH1A1/A3 (Retinal dehydrogenase 1, Aldehyde dehydrogenase family 1 member A3) have been described in limbal epithelial cells (LECs) and conjunctival epithelial cells. The aim of this study was to identify the role of retinol derivates in the differentiation of human LEC and its potential impact on aniridia-associated keratopathy development. Human LEC were isolated from healthy donor corneas and were cultured with retinol, retinoic acid, or pan-retinoic acid receptor antagonist (AGN 193109) acting on RARα, β, γ (NR1B1, NR1B2 NR1B3) or were cultured with pan-retinoid X receptor antagonist (UVI 3003) acting on RXR α, β, γ (retinoid X receptor, NR2B1, NR2B2, BR2B3). Using qPCR, differentiation marker and retinoid-/fatty acid metabolism-related mRNA expression was analysed. DSG1 (Desmoglein 1), KRT3 (Keratin 3), and SPINK7 (Serine Peptidase Inhibitor Kazal Type 7) mRNA expression was downregulated when retinoid derivates were used. AGN 193109 treatment led to the upregulation of ADH7, KRT3, and DSG1 mRNA expression and to the downregulation of KRT12 (Keratin 12) and KRT19 (Keratin 19) mRNA expression. Retinol and all-trans retinoic acid affect some transcripts of corneal LEC in a similar way to what has been observed in the LEC of PAX6-aniridia patients with the altered expression of differentiation markers. An elevated concentration of retinol derivatives in LEC or an altered response to retinoids may contribute to this pattern. These initial findings help to explain ocular surface epithelia differentiation disorders in PAX6-aniridia and should be investigated in patient cells or in cell models in the future in more detail. Full article
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16 pages, 2816 KiB  
Article
Involvement of Oxidative and Endoplasmic Reticulum Stress in RDH12-Related Retinopathies
by Hajrah Sarkar, Maria Toms and Mariya Moosajee
Int. J. Mol. Sci. 2021, 22(16), 8863; https://doi.org/10.3390/ijms22168863 - 18 Aug 2021
Cited by 16 | Viewed by 3869
Abstract
Retinol dehydrogenase 12 (RDH12) is expressed in photoreceptor inner segments and catalyses the reduction of all-trans retinal (atRAL) to all-trans retinol (atROL), as part of the visual cycle. Mutations in RDH12 are primarily associated with autosomal recessive Leber congenital amaurosis. To further our [...] Read more.
Retinol dehydrogenase 12 (RDH12) is expressed in photoreceptor inner segments and catalyses the reduction of all-trans retinal (atRAL) to all-trans retinol (atROL), as part of the visual cycle. Mutations in RDH12 are primarily associated with autosomal recessive Leber congenital amaurosis. To further our understanding of the disease mechanisms, HEK-293 cell lines expressing wildtype (WT) and mutant RDH12 were created. The WT cells afforded protection from atRAL-induced toxicity and oxidative stress. Mutant RDH12 cells displayed reduced protein expression and activity, with an inability to protect cells from atRAL toxicity, inducing oxidative and endoplasmic reticulum (ER) stress, with upregulation of sXBP1, CHOP, and ATF4. Pregabalin, a retinal scavenger, attenuated atRAL-induced ER stress in the mutant RDH12 cell lines. A zebrafish rdh12 mutant model (rdh12u533 c.17_23del; p.(Val6AlafsTer5)) was generated through CRISPR-Cas9 gene editing. Mutant fish showed disrupted phagocytosis through transmission electron microscopy, with increased phagosome size at 12 months post-fertilisation. Rhodopsin mislocalisation and reduced expression of atg12 and sod2 indicated early signs of a rod-predominant degeneration. A lack of functional RDH12 results in ER and oxidative stress representing key pathways to be targeted for potential therapeutics. Full article
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12 pages, 1910 KiB  
Article
Microbial Production of Bioactive Retinoic Acid Using Metabolically Engineered Escherichia coli
by Minjae Han and Pyung Cheon Lee
Microorganisms 2021, 9(7), 1520; https://doi.org/10.3390/microorganisms9071520 - 16 Jul 2021
Cited by 14 | Viewed by 4749
Abstract
Microbial production of bioactive retinoids, including retinol and retinyl esters, has been successfully reported. Previously, there are no reports on the microbial biosynthesis of retinoic acid. Two genes (blhSR and raldhHS) encoding retinoic acid biosynthesis enzymes [β-carotene 15,15′-oxygenase (Blh) [...] Read more.
Microbial production of bioactive retinoids, including retinol and retinyl esters, has been successfully reported. Previously, there are no reports on the microbial biosynthesis of retinoic acid. Two genes (blhSR and raldhHS) encoding retinoic acid biosynthesis enzymes [β-carotene 15,15′-oxygenase (Blh) and retinaldehyde dehydrogenase2 (RALDH2)] were synthetically redesigned for modular expression. Co-expression of the blhSR and raldhHS genes on the plasmid system in an engineered β-carotene-producing Escherichia coli strain produced 0.59 ± 0.06 mg/L of retinoic acid after flask cultivation. Deletion of the ybbO gene encoding a promiscuous aldehyde reductase induced a 2.4-fold increase in retinoic acid production to 1.43 ± 0.06 mg/L. Engineering of the 5’-UTR sequence of the blhSR and raldhHS genes enhanced retinoic acid production to 3.46 ± 0.16 mg/L. A batch culture operated at 37 °C, pH 7.0, and 50% DO produced up to 8.20 ± 0.05 mg/L retinoic acid in a bioreactor. As the construction and culture of retinoic acid–producing bacterial strains are still at an early stage in the development, further optimization of the expression level of the retinoic acid pathway genes, protein engineering of Blh and RALDH2, and culture optimization should synergistically increase the current titer of retinoic acid in E. coli. Full article
(This article belongs to the Special Issue Microorganisms Possibility for Future Bioproduction)
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