Altered retinoid metabolism gene expression in chronic Stevens-Johnson syndrome

2019 ◽  
Vol 103 (8) ◽  
pp. 1015-1023 ◽  
Author(s):  
Gurumurthy Srividya ◽  
Narayanasamy Angayarkanni ◽  
Geetha Iyer ◽  
Bhaskar Srinivasan ◽  
Shweta Agarwal
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Mucous Membrane ◽  
Retinoic Acid Receptor ◽  
Stevens Johnson Syndrome ◽  
Bulbar Conjunctiva ◽  
Ppar Γ ◽  
Retinoid Metabolism ◽  
Johnson Syndrome ◽  
Alpha 1 Antitrypsin

BackgroundStevens-Johnson syndrome (SJS), a blistering disorder of the skin and mucous membrane, leads to ocular morbidity in >60% of cases. Retinoids are vital micronutrients for vision, regulating corneal and conjunctival cell proliferation, differentiation and immune function. This prospective case–control study probed for alterations in retinoid metabolism by evaluating retinoic acid receptor signalling in the conjunctival cells of patients with SJS.MethodsImprints were collected from the bulbar conjunctiva of patients with chronic SJS. The gene expression of retinoic acid receptors, namely, RXRA, RARA, RARG, RORA; the fibrosis marker TGFβ and its receptor TGFβRII; the transcription factors PPAR-γ, STRA6 and Stat3; the enzymes aldehyde dehydrogenase (ALDH1a1), alpha-1 antitrypsin (A1AT); and the Cyp genes Cyp26a1 and Cyp26b1 were assessed by quantitative PCR in patients with SJS pre-mucous (n = 34) and post-mucous membrane graft (MMG) intervention (n=19) in comparison with age-matched/sex-matched healthy controls (n=20). Western blot analysis of ALDH1a1, RARA and RARG were done in the conjunctival imprint cells.ResultsThe transcript levels of ALDH1a1, RXRA, RORA, STRA6, Cyp26a1 and Cyp26b1 were decreased around 4, 26, 17, 129, 9 and 8 folds, respectively, and RARA, RARG, PPAR-γ, TGFβ, TGFβRII were increased by 12, 15, 51, 16 and 87 folds, respectively, in SJS conjunctiva at the pre-MMG stage. The changes in RORA, Cyp26a1, Cyp26b1, RARA and Stat3 were statistically significant (p<0.05). Changes in protein expression of ALDH1a1, RARA and RARG supported the gene expression changes.ConclusionsThe study provides the first experimental insight into the role of retinoid metabolism in the ocular sequelae of chronic SJS.

scholarly journals Ocular surface cytokine profile in chronic Stevens-Johnson syndrome and its response to mucous membrane grafting for lid margin keratinisation

2017 ◽  
Vol 102 (2) ◽  
pp. 169-176 ◽  
Author(s):  
Srividya Gurumurthy ◽  
Geetha Iyer ◽  
Bhaskar Srinivasan ◽  
Shweta Agarwal ◽  
Narayanasamy Angayarkanni
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Mucous Membrane ◽  
Ocular Surface ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Stevens Johnson Syndrome ◽  
Gm Csf ◽  
Johnson Syndrome ◽  
Collagen Iii

BackgroundTo study the tear cytokine and the conjunctival and oral mucosal marker profile in chronic ocular Stevens-Johnson syndrome (SJS) and their alteration following mucous membrane grafting (MMG) for lid margin keratinisation (LMK).MethodsIn a 1-year prospective study, SJS cases (n=25) and age-matched/sex-matched healthy controls (n=25) were recruited. Tear specimen (Schirmer’s strip), conjunctival and oral mucosal imprints were collected from controls and SJS cases pre-MMG and post-MMG (at first follow-up, n=17). Tear cytokines were profiled using 27-bioplex array. Transforming growth factor-beta (TGF-β)-mediated extracellular matrix changes in conjunctival and oral mucosal cells were analysed by gene expression studies. 30ResultsTear cytokine profiling of chronic SJS cases at pre-MMG stage revealed significant upregulation of cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, IL-1β, monocyte chemoattractant protein-1, IL-15, IL-2, IL-17A and basic fibroblast growth factor (bFGF) with downregulation of IP-10 (interferon gamma-induced protein 10), tumour necrosis factor-α, interferon-γ, IL-10, vascular endothelial growth factor, regulated upon activation normal T-cell expressed and secreted (RANTES), IL-7, IL-12p70 and IL-13, with maximal increase in GM-CSF and maximal downregulation of IP-10, respectively. Of these, IL-2, IL-15, bFGF and IL-17A showed significant correlation with disease severity, pre-MMG. Conjunctival cells pre-MMG showed increase in TGF-β1, TGF-βRII, connective tissue growth factor and collagen-III gene expression by 10, 67, 173 and 184 folds, respectively, which dropped to 1.3, 11, 13.5 and 19 folds correspondingly, post-MMG. However, their expressions in oral mucosa were negligible.ConclusionA proinflammatory, profibrotic, antiapoptotic ocular surface milieu characterises chronic ocular SJS. IP-10, an antifibrotic cytokine was noted to be maximally downregulated, unlike in other forms of chronic dry eye disease. The alterations in the ocular surface are seen to reverse largely with MMG for LMK.

scholarly journals The Environmental Light Influences the Circulatory Levels of Retinoic Acid and Associates with Hepatic Lipid Metabolism

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6336-6342 ◽  
Author(s):  
Wenqiang Pang ◽  
Chunying Li ◽  
Yue Zhao ◽  
Shiming Wang ◽  
Wei Dong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Adenosine Receptors ◽  
Light Exposure ◽  
Retinoic Acid Receptor ◽  
Hepatic Lipase ◽  
Mouse Retina ◽  
Acid Receptor ◽  
Hepatic Lipid ◽  
Environmental Light

Environmental light is involved in the regulation of photochemical reaction in mouse retina. It remains unclear whether light-mediated increase in all-trans retinoic acid (ATRA) synthesis in retina will result in altering the circulatory levels of ATRA and regulating downstream gene expression and physiological function. Here we showed circulatory levels of ATRA decreased in mice under constant darkness and elevated by light exposure. Fat gene pancreatic lipase-related protein 2 (mPlrp2) and its partner procolipase (mClps), but not hepatic lipase (mHl), activated in livers for responding to lack of light illuminating. Light-triggered alterations in circulatory ATRA levels regulated ecto-5′-nucleotidase gene expression by retinoic acid receptor retinoic acid receptor-α and modulated 5′-AMP levels in blood and were associated with mPlrp2 and mClps expression in the livers. Mice deficient in adenosine receptors displayed mPlrp2 and mClps expression in livers under 12-h light, 12-h dark cycles. Caffeine blocked adenosine receptors and induced hepatic mPlrp2 and mClps expression in wild-type mice. Mice activated in hepatic mPlrp2 and mClps expression lowered hepatic and serum lipid levels and markedly elevated circulatory levels of all-trans retinol. Our results suggest environmental light influence hepatic lipid homeostasis by light-modulated retinoic acid signaling associated with mPlrp2 and mClps gene expression in livers.

scholarly journals Interplay of Protein Disorder in Retinoic Acid Receptor Heterodimer and Its Corepressor Regulates Gene Expression

Structure ◽  
2019 ◽  
Vol 27 (8) ◽  
pp. 1270-1285.e6 ◽  
Author(s):  
Tiago N. Cordeiro ◽  
Nathalie Sibille ◽  
Pierre Germain ◽  
Philippe Barthe ◽  
Abdelhay Boulahtouf ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Protein Disorder ◽  
Acid Receptor

scholarly journals Preventable Blindness due to Ankyloblepharonin Stevens- Johnson Syndrome–A Case Report

2017 ◽  
Vol 6 (2) ◽  
pp. 136-138
Author(s):  
Manash Kumar Goswami ◽  
Md Asaduzzaman
Keyword(s):  
Case Report ◽  
Dry Eye ◽  
Stevens Johnson Syndrome ◽  
Bulbar Conjunctiva ◽  
Ocular Complications ◽  
Johnson Syndrome ◽  
Department Of Ophthalmology ◽  
Corneal Opacities ◽  
Preventable Blindness

Stevens-Johnson syndrome (SJS) is common, having long term ocular complications ranging from dry eye to loss of vision due to ankyloblepharon or corneal opacities. Proper medical management and separating the bulbar conjunctiva from palpebral regularly by a glass rod during the acute phaseof the diseases can prevent the development of ankyloblepharonand symblepharon. Here we present a case of ankyloblepharon after SJS which was repaired after 6 months in the department of ophthalmology, BIRDEM General Hospital.Birdem Med J 2016; 6(2): 136-138

scholarly journals Retinoic acid receptor-related orphan receptor (ROR) α4 is the predominant isoform of the nuclear receptor RORα in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells

2002 ◽  
Vol 364 (2) ◽  
pp. 449-456 ◽  
Author(s):  
Caroline CHAUVET ◽  
Brigitte BOIS-JOYEUX ◽  
Jean-Louis DANAN
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Hepg2 Cells ◽  
Transcriptional Activity ◽  
Cobalt Chloride ◽  
Retinoic Acid Receptor ◽  
Orphan Receptor ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Acid Receptor

The retinoic acid receptor-related orphan receptor α (RORα) is critically involved in many physiological functions in several organs. We find that the main RORα isoform in the mouse liver is the RORα4 isoform, in terms of both mRNA and protein levels, while the RORα1 isoform is less abundant. Because hypoxia is a major feature of liver physiology and pathology, we examined the effect of this stress on Rora gene expression and RORα transcriptional activity. HepG2 human hepatoma cells were cultured for 24h under normoxia (20% O2) or hypoxia (10, 2, and 0.1% O2) and the abundance of the Rora transcripts measured by Northern blot and semi-quantitative RT-PCR. Hypoxic HepG2 cells contained more Rora mRNA than controls. This was also observed in rat hepatocytes in primary culture. Cobalt chloride and desferrioxamine also increased the amount of Rora mRNA in HepG2 cells. It is likely that these treatments increase the amount of the RORα4 protein in HepG2 cells as evidenced by Western blotting in the case of desferrioxamine. Transient transfection experiments indicated that hypoxia, cobalt chloride, and desferrioxamine all stimulate RORα transcriptional activity in HepG2 cells. Hence, we believe that RORα participates in the control of gene transcription in hepatic cells and modulates gene expression in response to hypoxic stress.

scholarly journals Synergistic and additive effect of retinoic acid in circumventing resistance to p53 restoration

2018 ◽  
Vol 115 (9) ◽  
pp. 2198-2203 ◽  
Author(s):  
Connie A. Larsson ◽  
Sydney M. Moyer ◽  
Bin Liu ◽  
Keith A. Michel ◽  
Vinod Pant ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Therapeutic Response ◽  
Retinoic Acid Receptor ◽  
Mutant P53 ◽  
Missense Mutations ◽  
Synthetic Retinoid ◽  
P53 Reactivation

TP53 mutations occur in ∼50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of p53R172H-mutant lymphomas, we identified retinoic acid receptor gamma (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.

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