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1.
Int J Mol Med ; 44(1): 157-171, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31017270

RESUMO

The prevalence of psoriasis is increasing, and poses a serious risk to human health and quality of life. Psoriasis, a chronic immune­mediated skin disease with epidermal hyperkeratosis and parakeratosis, is associated with numerous complications, including metabolic syndromes that are regulated by sirtuins (SIRTs) via deacetylation. As they serve a necessary function in inflammation and metabolism, SIRTs are considered to link inflammation and metabolic syndrome. Previous studies have indicated that SIRTs serve a function in the pathophysiology of psoriasis, but to date no detailed research has been conducted investigating the expression levels and patterns of SIRTs in psoriasis. The present study investigated the abnormal expression of SIRTs in psoriasis and provided a theoretical foundation for the treatment and prognosis of psoriasis. Tumor necrosis factor (TNF)­α­stimulated HaCaT cells and an imiquimod­induced psoriasis mouse model were used to produce in vitro and in vivo models, respectively. Psoriasis clinical specimens (psoriasis area and severity index >10; n=22) and normal group specimens (n=22) were obtained from human subjects. The mRNA and protein expression levels in human and mouse skin lesions and TNF­α­stimulated HaCaT cells were detected using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and western blotting, and compared with the control groups. The expression patterns of SIRT proteins were investigated using immunofluorescence (IF) staining. The expression levels of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 were downregulated while those of SIRT6 and SIRT7 were upregulated in skin lesions and TNF­α­stimulated HaCaT cells compared with the control group as determined by RT­qPCR, western blotting and IF. Statistically significant differences were observed in vivo and in vitro. P­values of SIRT1­7 mRNA are less than 0.05 in RT­qPCR, and the P­values of SIRT1­7 proteins are less than 0.05 except for SIRT4 in the western blot analysis. SIRTs serve notable functions in severe psoriasis dermatitis, with the overexpression of SIRT6 and SIRT7 potentially induced by the adaptive immune response, and the downregulation of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 may be a result of an internal environment imbalance in vivo. Psoriasis is an inflammation and metabolism­associated disease mediated by the SIRT family. The present results provide a novel potential mechanism and strategy for the treatment of psoriasis by modulating the function and expression of SIRTs.


Assuntos
Psoríase/metabolismo , Sirtuínas/biossíntese , Animais , Linhagem Celular , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Humanos , Imiquimode/efeitos adversos , Imiquimode/farmacologia , Camundongos , Psoríase/induzido quimicamente , Psoríase/genética , Psoríase/patologia , Sirtuínas/genética
2.
JAMA Dermatol ; 155(3): 327-334, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698628

RESUMO

Importance: It is necessary to determine whether psoriasis responds to methotrexate in the same manner in patients with and without psoriatic arthritis. Objective: To evaluate the effectiveness and safety of methotrexate in treating patients with psoriasis with and without psoriatic arthritis. Design, Setting, and Participants: In this prospective, single-arm, interventional study, a total of 235 patients with psoriasis, 107 without psoriatic arthritis and 128 with psoriatic arthritis who were receiving methotrexate therapy from April 1, 2015, to December 31, 2017, were recruited from the outpatient department of a hospital at a large Chinese university. There were no significant demographic or clinical differences between the subgroups with the exception of diabetes. Interventions: A 12-week course of low-dosage oral methotrexate (7.5-15 mg weekly). Main Outcomes and Measures: Changes in disease severity, adverse events, blood cell counts, and liver and renal function. Results: A total of 235 patients with psoriasis (166 male [66.0%]; mean [SD] age, 49.6 [15.1] years) received methotrexate treatment for 12 weeks. The 90% reduction from baseline Psoriasis Area Severity Index response was significantly lower in patients with psoriatic arthritis than in patients without psoriatic arthritis at week 8 (4 0f 128 [3.1%] vs 12 of 107 [11.2%]; P = .02) and week 12 (19 of 128 [14.8%] vs 27 of 107 [25.2%]; P = .049). Furthermore, the incidence of adverse events, including dizziness (12 of 128 [9.4%] vs 1 of 107 [0.9%]; P = .007), gastrointestinal symptoms (32 of 128 [25.0%] vs 13 of 107 [12.1%]; P = .01), and hepatoxicity (34 of 128 [26.6%] vs 16 of 107 [15.0%]; P = .04), was significantly higher in patients with psoriatic arthritis than in patients without psoriatic arthritis. Methotrexate-induced elevation of alanine aminotransferase levels was associated with body mass index (mean [SD] body mass index, 26 [4] in patients with [P = .04] vs 26 [4] in those without [P = .005] psoriatic arthritis) and smoking (17 of 34 [50.0%] in patients with [P = .02] vs 9 of 16 [56.3%] in those without [P = .04] psoriatic arthritis). Conclusions and Relevance: In this study, methotrexate was well tolerated and effective in treating psoriasis. It was more effective, with fewer adverse effects, in patients with psoriasis who did not have psoriatic arthritis than in patients who presented with both psoriasis and psoriatic arthritis. Therefore, methotrexate can be recommended as first-line treatment for psoriasis without arthritis.

3.
Psychol Health Med ; 24(3): 269-280, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30293440

RESUMO

Previous studies have reported a higher incidence of depression and anxiety in psoriasis patients compared to the general population, which has important implications for assessment and treatment. In this study, we determined the frequency of depression and anxiety in Chinese patients with psoriasis and its relationship with disease severity and other demographic variables. The study included 208 Chinese patients with psoriasis vulgaris. The Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder scale (GAD-7) were used to screen for depression and anxiety. The Psoriasis Area and Severity Index (PASI) was used to assess the severity of psoriasis. Of the 208 patients included in the study, 29 patients (13.9%) were positive for moderate-to-severe depression (PHQ-9 ≥ 10) and 22 patients (10.6%) were positive for anxiety (GAD-7 ≥ 10) symptoms. Both positive stress reactors who perceived stress as an exacerbating factor of psoriasis and moderate-to-severe psoriasis were found to be positive predictors for the presence of moderate-to-severe depression or anxiety symptoms while longer duration and late onset age played a protective role. In the sample of Chinese patients with psoriasis there was a clinically significant prevalence of depression and anxiety. Our study suggests that Chinese psoriasis patients should be screened for psychiatric comorbidities.


Assuntos
Transtornos de Ansiedade/epidemiologia , Ansiedade/epidemiologia , Depressão/epidemiologia , Transtorno Depressivo/epidemiologia , Psoríase/epidemiologia , Estresse Psicológico/epidemiologia , Adulto , China/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Tempo , Adulto Jovem
4.
J Dermatol Sci ; 92(1): 106-113, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30072243

RESUMO

BACKGROUND: Few studies have explored the differences of immunopathogenesis in plaque vs guttate psoriasis, especially on the inhibitory role of regulatory T cells (Tregs) on IL-17/ IFN-γ production and the impact of CD4+T cells on keratinocytes. OBJECTIVE: To investigate the percentage and inhibitory function of CD4+CD25highTreg and differential expressions of IL-17/ IFN-γ in plaque vs guttate psoriasis, and the effects of CD4+T cells on the proliferation of keratinocytes. METHODS: Peripheral blood mononuclear cells (PBMCs) were prepared from patients with the plaque and guttate psoriasis. The percentage of CD4+CD25high Tregs, IL-17/IFN-γ- producing CD4+ or CD8+T cells, and apoptosis and cell cycle of Hacat cells were determined by flow cytometry. The level of IFN-γ in supernatants was analyzed by ELISA. RESULTS: The percentage of CD4+CD25highTregs in plaque psoriasis was significantly increased, and they can inhibit IFN-γ production from CD4+CD25- effector T cells. The percentage of CD8+IFN-γ+cells was also significantly increased in plaque psoriasis, and these cells positively correlated with disease severity. The percentage of CD4+CD25highTregs was decreased and CD4+IFN-γ+/IFN-γ+IL-17+ cells were predominantly increased in guttate psoriasis. CD4+T cells from guttate psoriasis induce apoptosis of keratinocytes while they promote the proliferation of keratinocytes in plaque psoriasis by decreasing late apoptosis and increasing the percentage of G1 phase. CONCLUSION: There was considerable discrepancy of the phenotype and function of T cells between plaque vs guttate psoriasis. IFN-γ and IL-17 from CD4+T cells play a crucial role in guttate psoriasis, however, IFN-γ and IL-17 from CD8+T cells are more important in the immunopathogenesis of plaque psoriasis.

5.
Australas J Dermatol ; 59(1): e31-e38, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28295154

RESUMO

BACKGROUND: CD39 and CD73 are two novel cell surface markers of CD25high Foxp3+ regulatory T-cells (Tregs). Concordant expression of these two ectoenzymes not only discriminate Tregs from other cell populations, but also generates pericellular adenosine, which has been reported to suppress proliferation of activated T effector (Teff) cells. Because it is currently unclear whether human ectoenzymes (CD39/CD73) are involved in the impaired suppressive activity of Tregs in psoriasis, we examined the frequencies and phenotypes of CD39/CD73-expressing Tregs and related receptor adenosine receptor 2A (A2A R) in peripheral blood of patients with different types of psoriasis. METHODS: Peripheral blood mononuclear cells (PMBC) were prepared from patients with three different types of psoriasis (psoriasis vulgaris, pustular psoriasis and erythrodermic psoriasis). CD4+ cells were separated from PBMC by negative selection on midiMACS columns, and the frequencies and phenotypes of CD39 and CD73 expressing Tregs, and A2A R expressing Teff were all determined by flow cytometry analysis. Blood from healthy volunteers served as controls. RESULTS: The expression of single CD73+ Tregs was markedly reduced (approximately 50%) in psoriasis vulgaris, compared to normal controls. In pustular psoriasis, the mean numbers of CD39+ Tregs and A2A R+ Teff was significantly lower than in normal controls. Among three different types of psoriasis, CD39 expression was strikingly reduced in the blood Treg population of pustular psoriasis patients. Decreased CD73+ Tregs levels were observed in psoriasis vulgaris compared to pustular psoriasis and erythrodermic psoriasis. CONCLUSIONS: The differences in the expression of CD39- and CD73- Tregs may be a factor in the pathogenesis of psoriasis.


Assuntos
5'-Nucleotidase/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Psoríase/imunologia , Receptores A2 de Adenosina/sangue , Linfócitos T Reguladores/metabolismo , Adulto , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Feminino , Fatores de Transcrição Forkhead/metabolismo , Proteínas Ligadas por GPI/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Psoríase/sangue
6.
Bioorg Med Chem ; 23(9): 1944-9, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25840795

RESUMO

A new benzohydrazone compound N'-(3-bromo-2-hydroxybenzylidene)-4-methoxybenzohydrazide (H2L) was prepared. Reaction of H2L and acetohydroxamic acid (HAHA) with VO(acac)2 in methanol gave the complex [VOL(AHA)]. Both H2L and the oxovanadium complex were characterized by elemental analysis, IR, UV-vis and (1)H NMR spectra, and single crystal X-ray diffraction. H2L was also characterized by high-resolution mass spectrum. Thermal analysis of the oxovanadium complex was carried out. The benzohydrazone ligand, in its dianionic form, coordinates to V atom through the phenolate oxygen, imino nitrogen and enolate oxygen. The acetohydroxamic acid coordinates to V atom through the carbonyl oxygen and deprotonated hydroxyl oxygen. The V atom is in octahedral coordination. H2L, HAHA and the oxovanadium complex were tested for their urease inhibitory activities. The percent inhibition at concentration of 100 µmol·L(-1) on Helicobacter pylori urease is 78% for the oxovanadium complex. The IC50 value for the complex is 36.5 µmol·L(-1). Molecular docking study was performed to study the inhibition.


Assuntos
Compostos de Benzilideno/química , Inibidores Enzimáticos/farmacologia , Hidrazonas/química , Ácidos Hidroxâmicos/farmacologia , Compostos Organometálicos/farmacologia , Urease/antagonistas & inibidores , Vanadatos/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Helicobacter pylori/enzimologia , Ácidos Hidroxâmicos/química , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade , Urease/metabolismo , Vanadatos/química
7.
Immunol Lett ; 148(2): 151-62, 2012 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-23018031

RESUMO

Psoriasis is a common chronic inflammatory skin disorder with dysregulation of miRNAs. The expression pattern of miR-146a and target gene IRAK1 in lesions and PBMCs of plaque psoriasis remains unclear. In our study, we found the expression of miR-146a was up-regulated both in lesions and PBMCs of psoriatic patients, and positively correlated with IL-17 expression, whereas the target gene IRAK1 expression was expressed differentially in lesions and peripheral blood. Inability of miR-146a inhibiting target gene IRAK1 may contribute to the persistent inflammation in lesions of psoriasis.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-17/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Psoríase/metabolismo , Adulto , Feminino , Regulação da Expressão Gênica , Humanos , Interferon gama/sangue , Quinases Associadas a Receptores de Interleucina-1/genética , Interleucina-17/sangue , Masculino , Psoríase/imunologia , Pele/metabolismo , Fator de Necrose Tumoral alfa/sangue
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