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1.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299118

RESUMO

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed in all skin cell types, plays a key role in physiological and pathological processes. Several studies have shown that this receptor is involved in the prevention of inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, representing a potential therapeutic target. We tested the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two new synthetic AhR ligands structurally related to the natural agonist FICZ, known to be effective in psoriasis. NPD-0614-13 and NPD-0614-24 did not alter per se the physiological functions of the different skin cell populations involved in the pathogenesis of inflammatory skin diseases. In human primary keratinocytes stimulated with tumor necrosis factor-α or lipopolysaccharide the compounds were able to counteract the altered proliferation and to dampen inflammatory signaling by reducing the activation of p38MAPK, c-Jun, NF-kBp65, and the release of cytokines. Furthermore, the molecules were tested for their beneficial effects in human epidermal and full-thickness reconstituted skin models of psoriasis. NPD-0614-13 and NPD-0614-24 recovered the psoriasis skin phenotype exerting pro-differentiating activity and reducing the expression of pro-inflammatory cytokines and antimicrobial peptides. These data provide a rationale for considering NPD-0614-13 and NPD-0614-24 in the management of psoriasis.


Assuntos
Anti-Inflamatórios/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Catecóis/farmacologia , Diferenciação Celular , Inflamação/tratamento farmacológico , Compostos Organometálicos/farmacologia , Psoríase/tratamento farmacológico , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Ligantes , Psoríase/metabolismo , Psoríase/patologia , Pele/metabolismo , Pele/patologia
2.
Nutrients ; 13(6)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207960

RESUMO

Psoriasis is an immune-mediated systemic disease that may be treated with probiotics. In this study, probiotic strains that could or could not decrease interleukin (IL)-17 levels were applied to imiquimod (IMQ)-induced psoriasis-like mice via oral administration. Bifidobacteriumadolescentis CCFM667, B. breve CCFM1078, Lacticaseibacillusparacasei CCFM1074, and Limosilactobacillus reuteri CCFM1132 ameliorated psoriasis-like pathological characteristics and suppressed the release of IL-23/T helper cell 17 (Th17) axis-related inflammatory cytokines, whereas B. animalis CCFM1148, L. paracasei CCFM1147, and L. reuteri CCFM1040 neither alleviated the pathological characteristics nor reduced the levels of inflammatory cytokines. All effective strains increased the contents of short-chain fatty acids, which were negatively correlated with the levels of inflammatory cytokines. By performing 16S rRNA gene sequencing, the diversity of gut microbiota in psoriasis-like mice was found to decrease, but all effective strains made some specific changes to the composition of gut microbiota compared to the ineffective strains. Furthermore, except for B. breve CCFM1078, all other effective strains decreased the abundance of the family Rikenellaceae, which was positively correlated with psoriasis-like pathological characteristics and was negatively correlated with propionate levels. These findings demonstrated effects of strain-specificity, and how probiotics ameliorated psoriasis and provide new possibilities for the treatment of psoriasis.


Assuntos
Microbioma Gastrointestinal , Probióticos/uso terapêutico , Psoríase/dietoterapia , Psoríase/microbiologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bifidobacterium/fisiologia , Citocinas/imunologia , Citocinas/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Feminino , Imiquimode , Interleucinas/análise , Interleucinas/metabolismo , Lactobacillaceae/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Probióticos/farmacologia , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Células Th17/imunologia
3.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202251

RESUMO

Dysregulated cross-talk between immune cells and epithelial compartments is responsible for the onset and amplification of pathogenic auto-inflammatory circuits occurring in psoriasis. NAMPT-mediated NAD salvage pathway has been recently described as an immunometabolic route having inflammatory function in several disorders, including arthritis and inflammatory bowel diseases. To date, the role of NAD salvage pathway has not been explored in the skin of patients affected by psoriasis. Here, we show that NAD content is enhanced in lesional skin of psoriatic patients and is associated to high NAMPT transcriptional levels. The latter are drastically reduced in psoriatic skin following treatment with the anti-IL-17A biologics secukinumab. We provide evidence that NAMPT-mediated NAD+ metabolism fuels the immune responses executed by resident skin cells in psoriatic skin. In particular, intracellular NAMPT, strongly induced by Th1/Th17-cytokines, acts on keratinocytes by inducing hyper-proliferation and impairing their terminal differentiation. Furthermore, NAMPT-mediated NAD+ boosting synergizes with psoriasis-related cytokines in the upregulation of inflammatory chemokines important for neutrophil and Th1/Th17 cell recruitment. In addition, extracellular NAMPT, abundantly released by keratinocytes and dermal fibroblasts, acts in a paracrine manner on endothelial cells by inducing their proliferation and migration, as well as the expression of ICAM-1 membrane molecule and chemokines important for leukocyte recruitment into inflamed skin. In conclusion, our results showed that NAMPT-mediated NAD salvage pathway contributes to psoriasis pathogenic processes by amplifying epithelial auto-inflammatory responses in psoriasis.


Assuntos
Citocinas/genética , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Psoríase/etiologia , Psoríase/metabolismo , Transdução de Sinais , Adulto , Idoso , Biomarcadores , Citocinas/metabolismo , Suscetibilidade a Doenças , Células Endoteliais/metabolismo , Feminino , Fibroblastos/metabolismo , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/metabolismo , Psoríase/patologia
4.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199748

RESUMO

BACKGROUND: Psoriasis, a chronic inflammatory disease affecting 2-3% of the population, is characterised by epidermal hyperplasia, a sustained pro-inflammatory immune response and is primarily a T-cell driven disease. Previous work determined that Connexin26 is upregulated in psoriatic tissue. This study extends these findings. METHODS: Biopsies spanning psoriatic plaque (PP) and non-involved tissue (PN) were compared to normal controls (NN). RNA was isolated and subject to real-time PCR to determine gene expression profiles, including GJB2/CX26, GJB6/CX30 and GJA1/CX43. Protein expression was assessed by immunohistochemistry. Keratinocytes and fibroblasts were isolated and used in 3D organotypic models. The pro-inflammatory status of fibroblasts and 3D cultures was assessed via ELISA and RnD cytokine arrays in the presence or absence of the connexin channel blocker Gap27. RESULTS: Connexin26 expression is dramatically enhanced at both transcriptional and translational level in PP and PN tissue compared to NN (>100x). In contrast, CX43 gene expression is not affected, but the protein is post-translationally modified and accumulates in psoriatic tissue. Fibroblasts isolated from psoriatic patients had a higher inflammatory index than normal fibroblasts and drove normal keratinocytes to adopt a "psoriatic phenotype" in a 3D-organotypic model. Exposure of normal fibroblasts to the pro-inflammatory mediator peptidoglycan, isolated from Staphylococcus aureus enhanced cytokine release, an event protected by Gap27. CONCLUSION: dysregulation of the connexin26:43 expression profile in psoriatic tissue contributes to an imbalance of cellular events. Inhibition of connexin signalling reduces pro-inflammatory events and may hold therapeutic benefit.


Assuntos
Conexinas/genética , Regulação da Expressão Gênica , Psoríase/genética , Adulto , Idoso , Biópsia , Conexinas/metabolismo , Conexinas/farmacologia , Epiderme/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Células HaCaT , Humanos , Mediadores da Inflamação , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Pessoa de Meia-Idade , Modelos Biológicos , Oligopeptídeos/farmacologia , Peptidoglicano/isolamento & purificação , Fosforilação , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Psoríase/patologia , Staphylococcus aureus/fisiologia , Adulto Jovem
5.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298932

RESUMO

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1ß mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.


Assuntos
Psoríase/metabolismo , Psoríase/patologia , Ribonucleases/metabolismo , Adulto , Animais , Células Cultivadas , Citocinas/metabolismo , Epiderme/metabolismo , Epiderme/patologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , RNA Mensageiro/genética , Pele/metabolismo , Pele/patologia
6.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281197

RESUMO

Psoriasis, a long-lasting and multifactorial skin disease, is related to comorbidities such as metabolic disease, depression, and psoriatic arthritis. Psoriasis occurs due to a variety of factors including keratinocyte hyperproliferation, inflammation, and abnormal differentiation. Proinflammatory cytokines upregulated by increased activation of keratinocytes and immune cells in the skin trigger progression of psoriasis. This study aimed to investigate the effects of anoctamin1 (ANO1) on psoriasis development in vitro and in vivo. We analyzed the proliferation of HaCaT keratinocytes and ANO1-related ERK and AKT signaling pathways after ANO1 inhibitor (T16Ainh-A01 and Ani9) treatment and knock-down of ANO1. Furthermore, after applying imiquimod (IMQ) cream or coapplying IMQ cream and T16Ainh-A01 on mouse ears, we not only observed psoriatic symptoms, including ear thickening, but also quantified the effects of treatment on ERK and AKT signaling-involved proteins and proinflammatory cytokines. Inhibition of ANO1 attenuated the proliferation of HaCaT cells and induced reduction of pERK1/2. Coapplication of IMQ and T16Ainh-A01 on ears of mice reduced not only symptoms of IMQ-induced psoriasis such as thickening and erythema, but also expression of ANO1 and pERK1/2 compared to that of application of IMQ alone. In addition, the expression levels of IL-17A, IL-17F, IL-22, IL-23, IL-6, IL-1ß, and TNF-α increased after applying IMQ and were significantly reduced by coapplying IMQ and T16Ainh-A01. These results aid in understanding the underlying mechanisms of ANO1 in epidermal layer keratinocyte hyperproliferation and suggest the potential of ANO1 as a target to treat psoriasis.


Assuntos
Anoctamina-1/farmacologia , Queratinócitos/efeitos dos fármacos , Psoríase/induzido quimicamente , Acetamidas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HaCaT , Humanos , Hidrazonas/farmacologia , Imiquimode/efeitos adversos , Imiquimode/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Interleucinas/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/metabolismo , Psoríase/patologia , Pirimidinas/farmacologia , Tiazóis/farmacologia
7.
Mol Genet Genomics ; 296(5): 1027-1040, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34137900

RESUMO

Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation of keratinocytes (KCs). Onset of psoriasis is related to genetic, immune and environmental factors. The environment can interact with the genome through epigenetic modifications, including DNA methylation, and this modification is involved in the pathogenesis of psoriasis. In addition to a skin disease, psoriasis is also considered a systemic disease. We reviewed the current literature of psoriatic DNA methylation for studies from several aspects on the DNA methylation distribution patterns in different tissues/cells, single-nucleotide polymorphisms, and candidate disease genes and identified target genes regulated by DNA methylation that have been directly/indirectly validated. This review contributes to a comprehensive understanding of the important a role that DNA methylation plays in psoriasis from a holistic perspective and will promote the implementation of DNA methylation in diagnostic and therapeutic strategies for psoriatic patients.


Assuntos
Metilação de DNA , Epigênese Genética , Polimorfismo de Nucleotídeo Único , Psoríase/genética , Linfócitos T CD4-Positivos/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Leucócitos Mononucleares/fisiologia , Psoríase/patologia
9.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068434

RESUMO

(1) Background: Understanding the function of circular RNAs (circRNAs), a class of noncoding RNA, in psoriatic skin can provide important insights into the complex regulation of genes contributing to the pathogenesis of psoriasis. (2) Methods: A novel method was applied to RNA-seq datasets from 93 skin biopsy samples to comprehensively identify circRNAs of all types, i.e., canonical circRNAs from the intron-exon junctions of mRNAs and interior circRNAs (i-circRNAs) from the interior regions of exons, introns, and intergenic regions. Selected circRNAs were experimentally validated by qRT-PCR and Sanger sequencing. CircRNAs with abundant and differential expression were identified and their putative function as competing endogenous RNAs (ceRNAs) was analyzed by an integrated analysis of circRNAs, microRNAs, and mRNAs. (3) Results: With a comprehensive search using no information of splicing signals, we systematically identified 179 highly abundant circRNAs in psoriatic skin. Many of these were reported for the first time and many were differentially expressed in involved versus normal or uninvolved skin. Validation based on three additional RNA-seq datasets confirmed most of the identified circRNAs in psoriatic skin. Experimental analyses confirmed the expression of the well-known circRNA CDR1as, a canonical circRNA, and a novel i-circRNA in psoriasis. We also identified many circRNAs that may act as ceRNAs to regulate the expression of mRNA genes in psoriasis-related signaling pathways in psoriasis. (4) Conclusions: The result of the study suggested that circRNAs are abundant in psoriatic skin, have distinct characteristics, and contribute to psoriatic pathogenesis.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/metabolismo , Psoríase/genética , RNA Circular/genética , RNA Mensageiro/metabolismo , Pele/metabolismo , Estudos de Casos e Controles , Humanos , MicroRNAs/genética , Psoríase/patologia , RNA Circular/metabolismo , RNA Mensageiro/genética , RNA-Seq
10.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067151

RESUMO

Research in the pathogenesis of inflammatory skin diseases, such as skin dermatitis and psoriasis, has experienced some relevant breakthroughs in recent years. The understanding of age-related factors, gender, and genetic predisposition of these multifactorial diseases has been instrumental for the development of new pharmacological and technological treatment approaches. In this review, we discuss the molecular mechanisms behind the pathological features of psoriasis, also addressing the currently available treatments and novel therapies that are under clinical trials. Innovative therapies developed over the last 10 years have been researched. In this area, advantages of nanotechnological approaches to provide an effective drug concentration in the disease site are highlighted, together with microneedles as innovative candidates for drug delivery systems in psoriasis and other inflammatory chronic skin diseases.


Assuntos
Nanomedicina , Psoríase/etiologia , Psoríase/terapia , Animais , Ensaios Clínicos como Assunto , Humanos , Modelos Biológicos , Nanotecnologia , Psoríase/patologia , Psoríase/fisiopatologia
11.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067223

RESUMO

Alcohol affects the symptoms, compliance and comorbidities as well as the safety and efficacy of treatments in psoriatic patients. In this review, we aim to summarize and link clinical observations with a molecular background, such as signaling pathways at the cellular level and genetic variations, and to provide an overview of how this knowledge could influence our treatment selection and patient management.


Assuntos
Etanol/efeitos adversos , Psoríase/patologia , Pesquisa Médica Translacional , Animais , Predisposição Genética para Doença , Humanos , Modelos Biológicos , Cooperação do Paciente , Psoríase/genética , Psoríase/terapia
12.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072753

RESUMO

Inflammasomes are high-molecular-weight protein complexes that may cleave the two main proinflammatory cytokines, pro-interleukin-1ß and pro-interleukin-18, into active forms, and contribute to psoriasis. Despite recent advances made in the pathogenesis of psoriasis, mainly studied as an autoimmune condition, activation of immune response triggers of psoriasis is still not completely understood. Recently, focus was placed on the role of inflammasomes in the pathogenesis of psoriasis. Multiple types of inhibitors and activators of various inflammasomes, inflammasome-related genes, and genetic susceptibility loci were recognized in psoriasis. In this systemic review, we collect recent and comprehensive evidence from the inflammasomes, NLRP1, NLRP3, and AIM2, in pathogenesis of psoriasis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Suscetibilidade a Doenças , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Psoríase/etiologia , Psoríase/metabolismo , Animais , Biomarcadores , Humanos , Terapia de Alvo Molecular , Ligação Proteica , Psoríase/patologia , Psoríase/terapia , Transdução de Sinais
13.
Med Clin North Am ; 105(4): 627-641, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34059242

RESUMO

Psoriasis is a systemic inflammatory condition that negatively affects the quality of life and medical health of 125 million individuals globally. Although psoriasis has historically been viewed as a skin-limited disease and managed with topical agents (eg, coal tar, corticosteroids, and vitamin D analogues), the recontextualization of psoriasis as a systemic condition involving multiple organ systems has prompted the development of numerous immunomodulating, systemic agents with more targeted mechanisms of action. This article briefly discusses the indications and nuances of new and developing therapeutic agents for psoriasis management.


Assuntos
Interleucinas/antagonistas & inibidores , Psoríase/patologia , Psoríase/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Tópica , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Ensaios Clínicos como Assunto , Alcatrão/administração & dosagem , Alcatrão/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Psoríase/diagnóstico , Psoríase/psicologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Qualidade de Vida/psicologia , Receptores de Hidrocarboneto Arílico , Vitamina D/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico
14.
Life Sci ; 278: 119630, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34004257

RESUMO

Sortilin is found to regulate proliferation and death of different cells, while its role in regulating keratinocyte proliferation and apoptosis is still unknown. In this study, we found that sortilin levels significantly increased in psoriasis patients, and sortilin suppression eliminated the proliferation of HaCaT cells induced by M5 cocktail solution and enhanced the levels of cleaved caspase 3 protein and the Bax/Bcl-2 ratio; however, levels of p-PI3K and p-AKT were decreased. In addition, sortilin silencing remitted the characteristic changes associated with psoriasis-like skin lesions. In summary, suppressed sortilin expression helped inhibit keratinocyte proliferation in HaCaT cells by inactivating PI3K/AKT signaling, which provides a new target for the therapy of psoriasis.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/farmacologia , Apoptose , Proliferação de Células , Queratinócitos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Psoríase/patologia , Adolescente , Adulto , Idoso , Animais , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Adulto Jovem
15.
Front Immunol ; 12: 625617, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995349

RESUMO

Desmogleins are involved in cell adhesion conferring structural skin integrity. However, their role in inflammation has been barely studied, and whether desmoglein-4 modulates psoriasis lesions is completely unknown. In this study, we assessed the impact of desmoglein-4 deficiency on the severity of imiquimod (IMQ)-induced skin inflammation and psoriasiform lesions. To this end, desmoglein-4-/- Oncins France Colony A (OFA) with Sprague-Dawley (SD) genetic background were used. Additionally, human RNA-Seq datasets from psoriasis (PSO), atopic dermatitis (AD), and a healthy cohort were analyzed to obtain a desmosome gene expression overview. OFA rats displayed an intense skin inflammation while SD showed only mild inflammatory changes after IMQ treatment. We found that IMQ treatment increased CD3+ T cells in skin from both OFA and SD, being higher in desmoglein-4-deficient rats. In-depth transcriptomic analysis determined that PSO displayed twofold less DSG4 expression than healthy samples while both, PSO and AD showed more than three-fold change expression of DSG3 and DSC2 genes. Although underlying mechanisms are still unknown, these results suggest that the lack of desmoglein-4 may contribute to immune-mediated skin disease progression, promoting leukocyte recruitment to skin. Although further research is needed, targeting desmoglein-4 could have a potential impact on designing new biomarkers for skin diseases.


Assuntos
Desmogleínas/deficiência , Psoríase/metabolismo , Pele/metabolismo , Animais , Complexo CD3/metabolismo , Estudos de Casos e Controles , Quimiotaxia de Leucócito , Desmogleínas/genética , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Imiquimode , Mediadores da Inflamação/metabolismo , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Ratos Sprague-Dawley , Ratos Transgênicos , Pele/imunologia , Pele/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
16.
Expert Rev Clin Pharmacol ; 14(9): 1105-1112, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34006152

RESUMO

Introduction: Management of inflammatory rheumatic diseases has evolved based on improved treatment strategies and better management of comorbidities, specifically cardiovascular risk. Methotrexate is one of the first-line treatments in the management of inflammatory rheumatic diseases, but its cardiovascular effects are poorly understood. The purpose of this review is to assess the cardiovascular impact of methotrexate in inflammatory rheumatic disease.Areas covered: Current knowledge about the mechanism of action of methotrexate on cardiovascular tissue is presented. A review of the literature in the Medline, Cochrane and Embase databases was performed. Current data about the cardiovascular effects of methotrexate in rheumatoid arthritis, psoriatic arthritis, and psoriasis are presented.Expert opinion: Mechanism of action of methotrexate is based on the antagonism of purines. It reduces systemic inflammation and oxidative stress and improves the major cardiovascular risk factors. Methotrexate improves cardiovascular risk in rheumatoid arthritis, psoriasis and psoriatic arthritis, but the mechanisms involved are partially identified. Data are controversial regarding its effects on endothelial function and atherosclerosis. Conversely, in the general population and in patients with HIV infection, methotrexate does not modify cardiovascular outcomes. Thus, methotrexate only improves cardiovascular risk by reducing systemic inflammation, and should not be used to prevent cardiovascular events.


Assuntos
Antirreumáticos/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Metotrexato/administração & dosagem , Animais , Antirreumáticos/farmacologia , Artrite Psoriásica/complicações , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/patologia , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Doenças Cardiovasculares/etiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Metotrexato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Psoríase/complicações , Psoríase/tratamento farmacológico , Psoríase/patologia
17.
Life Sci ; 279: 119655, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34043988

RESUMO

Psoriasis is a chronic inflammatory disorder of the skin and is characterized by hyper-dividing keratinocytes. This hyper-proliferation of keratinocytes is due to the high level of inflammatory cytokines. In this study, we evaluated the effect of topically applied Baricitinib, JAK1/2 inhibitor on chronic 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced psoriasis model in mice. To our knowledge, this is the first report evaluating the topical route of administration of Baricitinib in the context of psoriasis in vivo. TPA-induced inflammation was induced by the topical application of TPA in both ears. Thirty minutes before the application of TPA, the inner and outer surface of each ear was treated with Baricitinib for 6 days. Topical application of Baricitinib inhibited the expression of inflammation markers up-regulated by TPA. Besides, Baricitinib substantially reduced ear swelling, infiltration of leukocytes, the proliferation of epidermal cells, and angiogenesis of the dermal layer. The results suggest that Baricitinib significantly reduced phosphorylation of STAT3 and STAT1 levels in turn attenuating the downstream expression of inflammatory cytokines. Collectively, these results suggest that Baricitinib can be a potential therapeutic through topical route for psoriasis progresses.


Assuntos
Azetidinas/administração & dosagem , Inflamação/prevenção & controle , Psoríase/prevenção & controle , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Pele/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Acetato de Tetradecanoilforbol/toxicidade , Administração Tópica , Animais , Carcinógenos/toxicidade , Inflamação/induzido quimicamente , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/induzido quimicamente , Psoríase/patologia , Pele/patologia
18.
Am J Hum Genet ; 108(6): 1026-1039, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34004138

RESUMO

Revertant mosaicism, or "natural gene therapy," refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only approximately 50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Replicação do DNA , Guanilato Ciclase/genética , Recombinação Homóloga , Proteínas de Membrana/genética , Mosaicismo , Mutação , Pitiríase Rubra Pilar/patologia , Psoríase/patologia , Estresse Fisiológico , Ciclo Celular , Humanos , Pitiríase Rubra Pilar/genética , Psoríase/genética
20.
J Dermatol Sci ; 102(2): 116-125, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33888401

RESUMO

BACKGROUND: Psoriasis is a chronic inflammatory skin disease. Interleukin (IL)-17A plays a key role in the pathogenesis of psoriasis. Fingolimod, which is available for the treatment of multiple sclerosis, exerts anti-inflammatory effects by sequestrating inflammatory lymphocytes in secondary lymphoid tissues and the thymus. The effect of fingolimod on psoriasis has not been reported yet. OBJECTIVE: Our objectives were to investigate the effect of fingolimod on psoriasis utilizing mice with imiquimod (IMQ)-induced psoriasiform dermatitis, and explore the possibility of fingolimod as a therapeutic agent for psoriasis. METHODS: Psoriasiform dermatitis was induced by imiquimod application on murine shaved back skin for six days. Fingolimod prepared in phosphate-buffered saline (PBS), or PBS alone as a control, was administered intraperitoneally daily from days 0 to 5. RESULTS: Fingolimod ameliorated IMQ-induced psoriasis dermatitis clinically and histologically. On day 6, the mRNA expression level of IL-17A was lower in the skin of fingolimod-treated mice than in that of PBS-treated mice, whereas it was higher in the inguinal lymph nodes of fingolimod-treated mice than in those of PBS-treated mice. Flow cytometric analyses revealed that fingolimod reduced IL-17A-producing ?d T cells infiltrating into the skin, whereas it increased these cells in the inguinal lymph nodes. Fingolimod inhibited egress of Langerhans cells from the skin to lymph nodes. CONCLUSION: Our results demonstrated that fingolimod showed effectiveness for IMQ-induced psoriasiform dermatitis by hindering the emigration of IL-17A-producing ?d T cells from the lymph nodes to the skin, and suggest that fingolimod is a promising candidate for the treatment of psoriasis.


Assuntos
Cloridrato de Fingolimode/farmacologia , Linfócitos Intraepiteliais/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Cloridrato de Fingolimode/uso terapêutico , Humanos , Imiquimode/administração & dosagem , Imiquimode/imunologia , Interleucina-17/metabolismo , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Células de Langerhans/imunologia , Células de Langerhans/metabolismo , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos , Psoríase/imunologia , Psoríase/patologia , Pele/citologia , Pele/imunologia , Pele/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
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