Chemical induced pathognomonic features observed in human vitiligo are mediated through miR-2909 RNomics pathway (original) (raw)
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Frontiers and controversies in the pathobiology of vitiligo: separating the wheat from the chaff
Experimental Dermatology, 2009
The pathogenesis of vitiligo is complex and not well understood. Genes play a role in all aspects of vitiligo pathogenesis, and studies are ongoing to identify these genes and understand their biology. There is a body of interlocking, compelling evidence supporting an autoimmune basis for most or all cases of generalized vitiligo. The development of an autoimmune disease generally involves three components; the immune system, environmental triggers and other exogenous precipitating factors, and the target tissue. In vitiligo, precipitating factors could induce melanocyte damage in genetically susceptible individuals and consequent cell death, loss of tolerance, and induction of melanocytedirected autoimmunity. Future research will more precisely define the multiple biological events that regulate development of vitiligo.
A Study of Plasma miR-23a Expression in Vitiligo Patients
Suez Canal University Medical Journal
Background: Vitiligo is a chronic autoimmune skin depigmentation disorder with multifactorial causation, involving genetic susceptibility, immunological events, and environmental triggers. The exact molecular mechanisms of vitiligo development and progression are poorly understood. Recent studies reported microRNAs as promising biomarkers for disease detection and molecular targets for future treatment. Aim: Evaluating the expression level of circulating miR-23a in vitiligo patients and its association with the clinical features of vitiligo. Subjects and Methods: This is a case-control study comprising 50 vitiligo patients and 44 healthy controls. Plasma miR-23a expression levels were estimated by quantitative real-time PCR. Bioinformatic analysis for the miR-23a gene was performed. Results: Vitiligo patients displayed significantly lower circulating miR-23a expression levels compared to healthy controls. There was a significant negative correlation between miR-23a fold change and Vitiligo Area Severity Index (p= 0.003). Plasma miR-23a levels discriminated between vitiligo patients and controls with 60 % specificity and 64% sensitivity at the optimal cutoff value of 0.23 and likelihood ratio 1.61 (AUC=0.67). Conclusion: miR-23a along with its putative target genes could play a role in vitiligo pathogenesis.
Scientific Reports
Translation of genes is regulated by many factors including microRNAs (miRNAs). miRNA profiling of lesional and non-lesional epidermal RNA from 18 vitiligo patients revealed significant upregulation of 29 miRNAs in the lesional epidermis, of which 6 miRNAs were transfected in normal human epidermal keratinocytes (NHEKs) to study their downstream effects using quantitative proteomics. Many proteins involved in oxidative stress, Vesicle trafficking, Cellular apoptosis, Mitochondrial proteins and Keratins were regulated after miRNA transfections in the keratinocytes. However, tyrosinase related protein-1 (TRP1/TYRP1), a melanogenesis protein, was consistently downregulated in NHEKs by all the six miRNAs tested, which was quite intriguing. TRP1 was also downregulated in lesional epidermis compared with non-lesional epidermis. Since melanocytes synthesize and transfer melanosomes to the surrounding keratinocytes, we hypothesized that downregulation of TRP1 in NHEKs may have a role in melanosome transfer, which was confirmed by our co-culture experiments. Downregulation of TRP1 in keratinocytes negatively affected the melanosome transfer from melanocytes to keratinocytes resulting in melanin accumulation which may be leading to melanin induced cytotoxicity in melanocytes. Regulation of key processes involved in aetiopathogenesis of vitiligo along with TRP1 suggests that miRNAs act in an integrated manner which may be detrimental for the loss of melanocytes in vitiligo. Translation of genes into functional proteins is regulated by many factors including MicroRNAs (miRNAs). Micro RNAs are small endogenous, non-coding gene regulatory RNAs that are involved in post transcriptional regulation of gene expression 1-3. They are approximately 21-23 nucleotides long, evolutionarily conserved RNA molecules which inhibit gene expression by affecting mRNA stability or post-transcriptional repression by base pairing with the "seed sequences" in 3′ UTR or 5′ UTR 4,5 of the gene. Each miRNA has multiple potential targets, since the seed match requires only 4-7 base complementarity 6. miRNAs constitute about 1-5% of human genome and are predicted to regulate more than 60% of protein coding genes 1,5,7. They have been reported to regulate several processes like cell proliferation, differentiation, signal transduction and Immune responses etc 8,9. miRNA biogenesis involves a sequential series of both nuclear and cytoplasmic cleavage events performed by ribonuclease III endonucleases, Drosha and Dicer 7 , ultimately leading to miRNA guided regulation via RNA-induced silencing complex (RISC) which induces gene silencing by either mRNA cleavage or translational blockage 7. Several miRNAs have been implicated in skin diseases and pigmentation. Micro RNA(miR)-434-5p homologue, miR-330-5p, miR-125, miR-145 and miR-203 have been shown to target major pigmentation genes like Tyrosinase 10,11 ,
MicroRNA-211 regulates oxidative phosphorylation and energy metabolism in human vitiligo
The Journal of investigative dermatology, 2017
Vitiligo is a common, chronic skin disorder characterized by loss of epidermal melanocytes and progressive depigmentation. Vitiligo has complex immune, genetic, environmental, and biochemical etiology, but the exact molecular mechanisms of vitiligo development and progression, particularly those related to metabolic control, are poorly understood. Here we characterized the human vitiligo cell line PIG3V and the normal human melanocytes, HEM-l by RNA-sequencing (RNA-seq), targeted metabolomics, and shotgun lipidomics. Melanocyte-enriched miR-211, a known metabolic switch in non-pigmented melanoma cells, was severely downregulated in vitiligo cell line PIG3V and skin biopsies from vitiligo patients, while its predicted targets transcriptional co-activator PGC1-α (PPARGC1A), ribonucleotide reductase regulatory subunit M2 (RRM2), and serine-threonine protein kinase TAO1 (TAOK1) were reciprocally upregulated. miR-211 binds to PGC1-α 3'UTR locus and represses it. Although mitochondria...
Mir-434-5p mediates skin whitening and lightening
Clinical, Cosmetic and Investigational Dermatology, 2008
Utilization of gene silencing effectors, such as microRNA (miRNA) and small hairpin RNA (shRNA), provides a powerful new strategy for human skin care in vivo, particularly for hyperpigmentation treatment and aging prevention. In this study, tyrosinase (Tyr), the rate-limiting enzyme of melanin (black pigment) biosynthesis, was served as a target for treatment of hyperpigmentation in mouse and human skins. There are over 54 native microRNA capable of silencing human tyrosinase for skin whitening and lightening. To this, we have designed a mir-434-5p homologue and used it to successfully demonstrate the feasibility of miRNA-mediated skin whitening and lightening in vitro and in vivo. Under the same experimental condition in the trials, Pol-II-directed intronic mir-434-5p expression did not cause any detectable sign of cytotoxicity, whereas siRNAs targeting the same sequence often induced certain nonspecifi c mRNA degradation as previously reported. Because the intronic miRNA-mediated gene silencing pathway is tightly regulated by multiple intracellular surveillance systems, including Pol-II transcription, RNA splicing, exosomal digestion and nonsense-mediated RNA decay (NMD), the current fi ndings underscore the fact that intronic miRNA agents, such as manually redesigned mir-434-5p homologues, are effective, target-specifi c and safe to be used for skin whitening without any detectable cytotoxic effect. Given that the human skins also express a variety of other native miRNAs, we may redesign these miRNAs based on their individual functions for skin care, which may provide signifi cant insights into areas of opportunity for new cosmetic and/or therapeutical applications.
Concise review of recent studies in vitiligo
Qatar Medical Journal, 2013
Vitiligo is an acquired pigmentry disorder of the skin and mucous membranes which manifests as white macules and patches due to selective loss of melanocytes. Etiological hypotheses of vitiligo include genetic, immunological, neurohormonal, cytotoxic, biochemical, oxidative stress and newer theories of melanocytorrhagy and decreased melanocytes survival. There are several types of vitiligo which are usually diagnosed clinically and by using a Wood's l& also vitiligo may be associated with autoimmune diseases, audiological and ophthalmological findings or it can be a part of polyendocrinopathy syndromes. Several interventions are available for the treatment for vitiligo to stop disease progression and/or to attain repigmentation or even depigmentation. In this article, we will present an overall view of current standing of vitiligo research work especially in the etiological factors most notably the genetic components, also, types and associations and various and newer treatment ...
Vitiligo: A Possible Model of Degenerative Diseases
PLoS ONE, 2013
Vitiligo is characterized by the progressive disappearance of pigment cells from skin and hair follicle. Several in vitro and in vivo studies show evidence of an altered redox status, suggesting that loss of cellular redox equilibrium might be the pathogenic mechanism in vitiligo. However, despite the numerous data supporting a pathogenic role of oxidative stress, there is still no consensus explanation underlying the oxidative stress-driven disappear of melanocytes from the epidermis. In this study, in vitro characterization of melanocytes cultures from non-lesional vitiligo skin revealed at the cellular level aberrant function of signal transduction pathways common with neurodegenerative diseases including modification of lipid metabolism, hyperactivation of mitogen-activated protein kinase (MAPK) and cAMP response element-binding protein (CREB), constitutive p53-dependent stress signal transduction cascades, and enhanced sensibility to pro-apoptotic stimuli. Notably, these long-term effects of subcytotoxic oxidative stress are also biomarkers of pre-senescent cellular phenotype. Consistent with this, vitiligo cells showed a significant increase in p16 that did not correlate with the chronological age of the donor. Moreover, vitiligo melanocytes produced many biologically active proteins among the senescence-associated secretory phenotype (SAPS), such as interleukin-6 (IL-6), matrix metallo proteinase-3 (MMP3), cyclooxygenase-2 (Cox-2), insulin-like growth factor-binding protein-3 and 7 (IGFBP3, IGFBP7). Together, these data argue for a complicated pathophysiologic puzzle underlying melanocytes degeneration resembling, from the biological point of view, neurodegenerative diseases. Our results suggest new possible targets for intervention that in combination with current therapies could correct melanocytes intrinsic defects. Citation: Bellei B, Pitisci A, Ottaviani M, Ludovici M, Cota C, et al. (2013) Vitiligo: A Possible Model of Degenerative Diseases. PLoS ONE 8(3): e59782.
Journal of Dermatological Treatment, 2020
Background: Factors contributing to the pathogenesis of vitiligo and factors affecting its response to treatment are still a major area of debate. Aim of the work: The study aimed to assess the serum levels of tyrosinase and Micro-RNAs (miRNAs) gene polymorphism in a sample of Egyptian vitiligo patients, and to determine factors affecting the response of vitiligo to treatment. Subjects and methods: This prospective case-control interventional study included 212 non-segmental vitiligo patients and 96 control subjects. Before treatment, vitiligo was evaluated using Vitiligo Area Severity Index. Detection of miRNA 196a-2 polymorphism was done using PCR-REELP and serum tyrosinase was measured using ELISA. After treatment, patients were reevaluated clinically and serum tyrosinase levels were re-measured. Results: The tyrosinase levels were significantly elevated in patients. The TT genotype was the most prevalent one in the patients. The percentage of improvement showed a significant positive correlation with patients' ages and age of the disease onset and a negative correlation with disease duration, baseline VASI scores and serum tyrosinase levels. Conclusion: MiRNA 196a-2 C/T (11614913) gene polymorphism and the elevated serum tyrosinase levels might be related to the pathogenesis of vitiligo and may affect its therapeutic response.
Neuro-immuno-endocrine processes in vitiligo pathogenesis
International journal of immunopathology and pharmacology
Vitiligo is a cutaneous disorder of depigmentation, clinically characterized by well-demarcated, white macules of varying size and distribution. It can affect up to 2 percent of the population, especially younger ages. In spite of recent findings implicating genetic, immune and oxidative stress factors, the exact pathogenesis of vitiligo remains obscure. Here, we briefly discuss the prevailing theories, and offer new suggestions that could explain in part the damage of melanocyte in the vitiliginous lesions. Our emerging hypothesis is that neuropeptides released from peripheral nerve endings could synergize with new cytokines to adversely affect melanocyte function and viability. These may include corticotropin- releasing hormone (CRH) and neurotensin (NT), as well as interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP). Such interactions could serve the basis for further research, possibly leading to new treatments.
Vitiligo: pathomechanisms and genetic polymorphism of susceptible genes
Indian journal of experimental biology, 2006
Vitiligo is a depigmenting disorder resulting from the loss of melanocytes in the skin and affects 1-4% of the world population. Incidence of vitiligo is found to be 0.5-2.5% in India with a high prevalence of 8.8% in Gujarat and Rajasthan states. The cellular and molecular mechanisms that lead to melanocyte destruction in this disorder are not yet been fully elucidated. Genetic factors, neural factors, toxic ROS metabolites, autoantibodies and autoreactive T lymphocytes may be the causative agents for the selective destruction of melanocytes. Three major hypotheses of pathogenesis of vitiligo are neural, autoimmune and oxidative stress hypotheses, however none of them explains the pathogenesis of vitiligo in toto. Genetics of vitiligo is characterized by incomplete penetrance, multiple susceptibility loci and genetic heterogeneity. Recent advances in this field are linkage and association of candidate gene studies. The linkage and association studies provide a strong evidence for t...