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1.
Sci Prog ; : 36850419891046, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791191

RESUMO

Breast cancer, as one of the most malignant tumors, poses a serious threat to the lives of females. Nucleotide exchange factor SIL1 is an important regulator of endoplasmic reticulum function that might have a specific role in tumor progression. In this study, we aimed to investigate the effect of SIL1 on the proliferation, apoptosis, and metastasis of human breast cancer. SIL1-specific small interfering RNA was transfected into two breast cancer cell lines, MCF7 and MDA-MB-231, to generate SIL1 knockdown cells. Clone formation and Cell Counting Kit-8 assays were performed to determine cell proliferation. Wound healing and transwell assays were used to detect the cell migration and invasion, respectively. Cell cycle and apoptosis were determined by flow cytometry. The messenger RNA and protein levels of target genes were analyzed using quantitative real-time PCR and western blot. According to the results of TCGA and GTEx database analysis, we determined that SIL1 was overexpressed in 1085 breast cancer samples compared with 291 normal samples. Knockdown of SIL1 inhibited the proliferation, migration, and invasion of MCF7 and MDA-MB-231 cells, accordingly. The cell cycle was blocked at the G1 phase following transfection of SIL1-specific small interfering RNA through the inhibition of Cyclin D1, CDK4, and CDK6. SIL1 knockdown induced apoptosis and also promoted the activity of Caspase9 and Bax. Furthermore, SIL1 was able to promote phosphorylation of ERK1/2. Based on these results, SIL1 might act as an oncogene and accelerate the progression of human breast cancer.

2.
Plant Dis ; : PDIS04190753RE, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730411

RESUMO

Gummy stem blight (GSB), caused by Stagonosporopsis cucurbitacearum (syn. Didymella bryoniae), is a destructive foliar disease of watermelon in areas with hot and humid climates. The wild watermelon germplasm PI 189225 is a known source of resistance to GSB. The identification and use of molecular markers linked to resistance genes in the wild-type germplasm will speed up the introgression of GSB resistance into new watermelon varieties. An F2 segregating population was obtained from a cross between the resistant wild watermelon genotype PI 189225 and the susceptible genotype K3. The F2-derived F3 families were inoculated with a single isolate of S. cucurbitacearum (JS002) from Jiangsu Academy of Agricultural Sciences. The results of the genetic analysis demonstrated that GSB resistance in PI 189225 was controlled by a major quantitative trait locus (QTL), temporarily designated Qgsb8.1. Based on the results of bulk sergeant analysis and sequencing, one associated region spanning 5.7 Mb (10,358,659 to 16,101,517) on chromosome 8 was identified as responsible for the resistance to GSB using the Δ(single-nucleotide polymorphism [SNP]-index) method. The result of a QTL linkage analysis with Kompetitive allele-specific PCR (KASP) SNP markers further mapped the GSB resistance locus between the SNP markers KASP_JS9383 and KASP_JS9168 in a region of 571.27 kb on chromosome 8. According to the watermelon gene annotation database, the region contains approximately 19 annotated genes and, of these 19 genes, 2 are disease resistance gene analogs: Cla001017 (coiled-coil nucleotide-binding site leucine-rich repeat resistance protein) and Cla001019 (pathogenesis related). Reverse-transcription quantitative PCR demonstrated that the expression of the two genes changed following S. cucurbitacearum infection, suggesting that they play important roles in GSB resistance in watermelon. This result will facilitate fine mapping and cloning of the Qgsb8.1 locus, and the linked markers will further provide a useful tool for marker-assisted selection of this locus in watermelon breeding programs.

3.
J Cosmet Dermatol ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31769596

RESUMO

BACKGROUND: Patients are increasingly aware of the aesthetic appearance of aging hands. AIMS: To evaluate efficacy and safety of a hyaluronic acid gel for improving skin quality in aged skin of the dorsal hand. METHODS: This was a 15-month randomized, multi-center, evaluator-blinded, split-hand, no treatment-controlled study. Three treatments with hyaluronic acid gel were administered in the same hand in adult Chinese subjects with grade 2 or 3 (mild or moderate aging) on the Hand Grading Scale (HGS). The primary objective was to evaluate the difference at 3 months between treated and untreated hands, based on the blinded evaluator's HGS assessment. Secondary assessments included the Global Aesthetic Improvement Scale (GAIS), biophysical measurements (skin elasticity, skin roughness and hydration), and subject satisfaction. Safety was evaluated by incidence of adverse events. RESULTS: A total of 100 subjects were enrolled. Clinically relevant differences in HGS favored HA gel (P < .0001). At 15 months, 87%-96% of treated hands were still improved according to GAIS (per evaluator and subject, respectively). Objective measures of skin quality improved, confirmed by evaluators and highly satisfied subjects. Treatment was well tolerated. CONCLUSIONS: Hyaluronic acid treatment improved skin quality and reduced the aging appearance of the hand, with high subject satisfaction.

5.
Wounds ; 31(11): 279-284, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31730508

RESUMO

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a high prevalence in children worldwide. Resveratrol exerts various pharmacologic effects, and application of resveratrol has been suggested as an alternative treatment for microorganism infection and skin pathologies. OBJECTIVE: The present study examines the effect of resveratrol on AD using an in vivo murine model. MATERIALS AND METHODS: Atopic dermatitis was induced in 30 BALB/c mice by topical application of 2,4-dinitrochlorobenzene (DNCB) prior to treatment with 0 mg/kg, 5 mg/kg, or 25 mg/kg resveratrol. Histologic data changes were evaluated, and the levels of thymus- and activation-regulated chemokine; type 2 helper T cytokines interleukin (IL) 4, IL-5, and IL-13; and type 1 helper T cytokines IL-12 and interferon γ were examined by enzyme-linked immunosorbent assay. Messenger ribonucleic acid expression was evaluated with quantitative polymerase chain reaction. Filaggrin (FLG), envoplakin (EVPL), transglutaminase (TG), and kallikrein 7 (KLK7) protein expression were evaluated with Western blot. RESULTS: Resveratrol ameliorated the onset of AD-like skin lesions and significantly improved the DNCB-induced dermal destruction in mice. In addition, resveratrol reduced the levels of the above chemokines, downregulated the expression of the proinflammatory cytokine KLK7, and upregulated the expression of several cytokines, such as EVPL, FLG, and TG. CONCLUSIONS: These results suggest resveratrol has therapeutic effects in the treatment of AD.

7.
Artif Cells Nanomed Biotechnol ; 47(1): 3540-3547, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31437010

RESUMO

Allergen-specific immunotherapy is widely used for allergic rhinitis and asthma treatment worldwide. This study explored the efficacy and safety of sublingual immunotherapy (SLIT) with the extracts of Dermatophagoides Farinae (D. farinae Drops) on house dust mites (HDM)-induced atopic dermatitis (AD). 239 patients with HDM-induced AD were recruited and exposure to a multi-centre, randomized, double-blind, and placebo-controlled clinical trials for 36 weeks, which were randomly divided into placebo and sublingual D. farinae Drops groups (high-dose, medium-dose and low-dose), respectively. Statistical analysis was performed in three groups: Full Analysis Set, Per Protocol Set and Safety Set. 48 cases have withdrawn from the study before the end of study. As primary outcomes, significant decreases in scoring atopic dermatitis and total medication score were showed in medium-dose and high-dose D. farinae Drops groups. In the sixth visit, the skin lesion area showed a statistically significant difference between high-dose/medium-dose D. farinae Drops group and placebo group (p < .05). Most adverse events are slight, and no life-threatening adverse drug reaction happened. Our research demonstrates the beneficial effect of SLIT with high or medium dose D. farinae Drops on AD, and the treatment was well tolerated.

8.
J Dermatolog Treat ; 30(7): 677-684, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31218889

RESUMO

Background: Run Zao Zhi Yang capsule (RZZYC) has been widely applied for eczema treatment as a traditional Chinese medicine, while its efficacy has not been scientifically investigated. Objective: We conducted this multiple-centers, randomized, double-blind, placebo-controlled study to investigate the effectiveness and safety of RZZYC on the treatment of patients with mild to moderate chronic eczema. Methods: 240 patients were randomly assigned into the experimental group and the placebo group. The primary efficacy indicator was the Eczama Area and Severity Index (EASI) score at week 4. The patient with an EASI score that decreases more than 95% from baseline (EASI 95) was judged as cured. The cured patients were followed up for another 8 weeks. The differences on EASI, Visual Analogue Score (VAS), and Dermatology Life Quality Index (DLQI) score were compared. Results: The proportions of EASI 95 and EASI 60 in the experimental group were significantly higher than those of the control group at week4 (p = .002 and p < .001, respectively), the VAS score decreased more significantly in the experimental group at week 4. After 8 weeks follow-up, no difference on recurrence rate and adverse event rate between the two groups was observed. Conclusion: RZZYC provides a good effect on the treatment of mild-to-moderate chronic eczema with a low recurrence and tolerable adverse events, and is a potential treatment that may be implemented in clinical practice.


Assuntos
Eczema/tratamento farmacológico , Medicina Tradicional Chinesa , Adulto , Idoso , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
9.
J Clin Microbiol ; 57(9)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31189587

RESUMO

The Trichophyton rubrum species complex comprises commonly encountered dermatophytic fungi with a worldwide distribution. The members of the complex usually have distinct phenotypes in culture and cause different clinical symptoms, despite high genome similarity. In order to better delimit the species within the complex, molecular, phenotypic, and physiological characteristics were combined to reestablish a natural species concept. Three groups, T. rubrum, T. soudanense, and T. violaceum, could be distinguished based on the sequence of the internal transcribed spacer (ITS) ribosomal DNA barcode gene. On average, strains within each group were similar by colony appearance, microscopy, and physiology, but strains between groups showed significant differences. Trichophyton rubrum strains had higher keratinase activity, whereas T. violaceum strains tended to be more lipophilic; however, none of the phenotypic features were diagnostic. The results of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and amplified fragment length polymorphism (AFLP) were partially consistent with the ITS data but failed to distinguish the species unambiguously. Despite their close similarity, T. violaceum, T. soudanense, and T. rubrum can be regarded as independent species with distinct geographical distributions and clinical predilections. Trichophyton soudanense is pheno- and genotypically intermediate between T. rubrum and T. violaceum For routine diagnostics, ITS sequencing is recommended.

10.
Future Microbiol ; 14: 705-716, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31161794

RESUMO

Aim: Aspergillus fumigatus is one of the most common opportunistic fungi that can cause invasive infection. To profile the kinetic variation of immune cells and cytokines after exposure to A. fumigatus thoroughly, we established a pulmonary A. fumigatus infection model in temporarily immunosuppressed mice. Materials & methods: Systematic and kinetic studies of different immune cells and cytokines were performed. Results: We observed that the granulocytes and macrophages recruited to the site of infection played an important role in the infectious phase. There was a significant increase in the cytokines IFN-γ, IL-6, TNF-α as well as the chemokines CXCL1, MIP-1α, MIP-2 and CCL5 after infection. IL-10 was found to participate in balancing the anti-inflammatory response in the recovery phases. The immune response mediated by T cells was mainly presented by the Th1-type on day 7 after exposure with a high proportion of IFN-γ+ CD4+ T cells and CD4+CD44highCD62Llow effector T cells. Conclusion: These kinetic parameters of the immune response might provide diagnostic clues for A. fumigatus infection.


Assuntos
Aspergilose/imunologia , Aspergillus fumigatus/patogenicidade , Quimiocinas/metabolismo , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Animais , Linfócitos T CD4-Positivos , Quimiocina CCL3/metabolismo , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocinas/sangue , Citocinas/sangue , Modelos Animais de Doenças , Hospedeiro Imunocomprometido , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Cinética , Pulmão/microbiologia , Pulmão/patologia , Linfonodos/microbiologia , Linfonodos/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Linfócitos T/imunologia , Células Th1/imunologia , Fator de Necrose Tumoral alfa/metabolismo
11.
Biomater Sci ; 7(6): 2297-2307, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31050344

RESUMO

Transcranial magnetic stimulation (TMS) is a non-invasive and clinically approved method for treating neurological disorders. However, the relatively weak intracranial electric current induced by TMS is an obvious inferiority which can only produce limited treatment effects in clinical application. The present study aimed to investigate the possibility of enhancing the effects of TMS with intravenously administrated magnetic nanoparticles. To facilitate crossing of the blood-brain barrier (BBB), the superparamagnetic iron oxide nanoparticles (SPIONs) were coated with carboxylated chitosan and poly(ethylene glycol). To aid the nanoparticles in crossing the BBB and targeting the predesigned brain regions, an external permanent magnet was attached to the foreheads of the rats before the intravenous administration of SPIONs. The electrophysiological tests showed that the maximum MEP amplitude recorded in an individual rat was significantly higher in the SPIONs + magnet group than in the saline group (5.78 ± 2.54 vs. 1.80 ± 1.55 mV, P = 0.015). In the M1 region, biochemical tests detected that the number density of c-fos positive cells in the SPIONs + magnet group was 3.44 fold that of the saline group. These results suggest that intravenously injected SPIONs can enhance the effects of TMS in treating neurological disorders.

12.
J Immunol Res ; 2019: 1547578, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984790

RESUMO

Aims: This study is aimed at exploring the relation between IL-33 single-nucleotide polymorphisms (SNPs) and the risk of systemic lupus erythematosus (SLE). Methods: SNPStats (online software) was used to test the Hardy-Weinberg equilibrium in controls. Generalized multifactor dimensionality reduction (GMDR) was adopted to screen the preferable interaction between IL-33 SNPs and current smoking. Results: Logistic regression analysis based on the fundamental data of age, gender, BMI, current smoking, and alcohol drinking showed that both rs1929992-G and rs1891385-C alleles were correlated with an increasing risk of SLE, the ORs (95% CI) of which were 1.62 (1.21-2.05) and 1.64 (1.22-2.10), respectively. One two-locus model (rs1929992×current smoking) had a testing accuracy of 60.11% (P = 0.0010). Through an overall multidimensional model, optimum cross-validation consistency was obtained. The analysis indicated that current smoking status influenced the SLE risk depending on the genotypes at rs1929992. Pairwise LD analysis indicated that haplotype rs1929992G-rs7044343T was statistically related to the elevating risk of SLE (P < 0.05). Those subjects with the G-T haplotype had a higher SLE risk than those with other haplotypes, after correction with factors, including gender, alcohol drinking, age, BMI, and current smoking. Conclusions: The rs1929992-G and rs1891385-C allele, interaction between the rs1929992 gene and current smoking, and haplotype rs1929992G-rs7044343T were all risk factors of SLE.


Assuntos
Predisposição Genética para Doença , Interleucina-33/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Adulto , Consumo de Bebidas Alcoólicas , Alelos , Grupo com Ancestrais do Continente Asiático , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco
13.
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.

14.
Nanoscale ; 11(2): 552-567, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30543334

RESUMO

Quantum dots (QDs) have emerged as a major class of fluorescent probes with unique optical properties, but applying QDs for imaging specific intracellular entities in live cells has been hindered by the poor performance of targeted intracellular delivery of QDs due to various cellular transport barriers. We describe a novel QD nanoprobe design, which is termed a cosolvent-bare hydrophobic QD-biomolecule (cS-bQD-BM, or 'SDot' for short), combining a cosolvent, a bare hydrophobic nanoparticle surface, ultrasmall size and biomolecular function. SDots show extraordinary intracellular targeting performance with the nucleus as the model target, including near-perfect specificity, excellent efficiency and reproducibility, high-throughput ability, minimal toxicity, and ease of operation, as well as superb optical properties and colloidal stability. We introduce integrated single-particle tracking and pair-correlation function analysis of a spinning-disk confocal microscope platform (iSPT-pCF-SDCM) to study SDot's cellular transport. Endocytosed SDots can undergo a highly potent and noninvasive process of vesicle escape, yielding complete vesicle escape with no serious vesicle disruption. We exploit SDots' unprecedented ability to overcome cellular transport barriers to enhance drug and macromolecule delivery.


Assuntos
Núcleo Celular/metabolismo , Citoplasma/metabolismo , Pontos Quânticos/química , Pontos Quânticos/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Sistemas de Liberação de Medicamentos , Endocitose , Humanos , Reprodutibilidade dos Testes , Propriedades de Superfície
15.
Biomed Pharmacother ; 110: 546-553, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30530290

RESUMO

Systemic sclerosis (SSc) is a connective tissue disease characterized mainly by fibrosis of skin and internal organs. Our previous study has shown that salvianolic acid B (SAB), a bioactive component extracted from Salvia miltiorrhiza (SM), was one of the essential ingredients in the traditional Chinese medicine Yiqihuoxue formula, which has been used to treat SSc-related dermal and pulmonary fibrosis. The aim of the present study was to evaluate the effect of SAB on skin fibrosis and explore its underlying anti-fibrotic mechanism. We found that SAB was capable of alleviating skin fibrosis in a bleomycin-induced SSc mouse model, alleviating skin thickness and reducing collagen deposition. in vitro studies indicated that SAB reduced SSc skin fibroblast proliferation and downregulated extracellular matrix gene transcription and collagen protein expression. TGF-ß/SMAD and MAPK/ERK pathway activation were also shown to be suppressed in SAB treated fibroblasts. Moreover, RNA-seq revealed that the anti-fibrotic effect of SAB might be related to antioxidant activity, the cell cycle, and the p53 signaling pathway. Taken together, our results suggest that SAB has the ability to alleviate SSc-related skin fibrosis both in vivo and in vitro.


Assuntos
Benzofuranos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Pele/efeitos dos fármacos , Pele/patologia , Animais , Benzofuranos/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Escleroderma Sistêmico/metabolismo , Pele/metabolismo
16.
Mol Med Rep ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30483784

RESUMO

Previous studies demonstrated that puerarin represents a potential therapeutic drug for breast cancer treatment, due to its ability to inhibit the migration of MCF­7 and MDA­MB­231 cell lines. In order to investigate the mechanism of puerarin in breast cancer cells, the aim of the present study was to examine whether puerarin regulated the dual specificity phosphatase 1 (DUSP1) expression level by promoting the microRNA­133a­3p (miR­133a­3p) expression level in breast cancer. Cell viability and apoptosis were assessed in HCC38 cells by Cell Counting Kit­8 assays and a flow cytometry assay, respectively. In total, four treatment groups were considered: Puerarin treatment, miR­133a­3p mimics transfection, puerarin + miR­133a­3p mimics and negative control. miR­133a­3p expression and DUSP1 mRNA expression levels were analyzed by reverse transcription­quantitative polymerase chain reaction, and western blotting was used to detect the protein expression level. Furthermore, a luciferase reporter gene assay was used to test whether DUSP1 mRNA was a direct target of miR­133a­3p. The present results suggested that treatment with puerarin or miR­133a­3p mimics transfection affected the miR­133a­3p expression level and the activity of the DUSP1/p38 pathway, leading to inhibition of HCC38 cell viability and an increase in apoptosis. miR­133a­3p overexpression enhanced the drug action of peurarin. In conclusion, puerarin may increase DUSP1 expression by promoting the miR­133a­3p expression level in HCC38 breast cancer cells. Therefore, miR­133a­3p may represent a novel molecular marker for diagnosis and treatment of breast cancer, and puerarin may represent a promising clinical drug for treatment of patients with breast cancer.

17.
J Investig Dermatol Symp Proc ; 19(2): S83-S85, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30471759

RESUMO

Psoriasis is a common skin disease affecting 1-3% of the population (Gelfand et al., 2005; Ferrándiz et al., 2001). Approximately 30% of patients with psoriasis develop psoriatic arthritis (PsA), an inflammatory arthritis associated with psoriasis (Haroon et al., 2013; Prey et al., 2010). Generalized pustular psoriasis (GPP) affects about 1.3% of psoriasis patients. Recently, numerous novel susceptibility loci for psoriasis vulgaris (PsV) have been discovered thorough the application of genome-wide association studies (GWASs). Among them, the major histocompability complex is the locus with the strongest effect. Outside the major histocompability complex region, the novel susceptibility loci of PsV can be incorporated into an integrated pathogenic model comprising distinct signaling networks affecting skin barrier function, innate immune responses involving NF-κB signaling, and adaptive immune responses involving CD8 T cells and IL-23/IL-17-mediated lymphocyte signaling. Compared with PsV, only three GWASs were performed in PsA (Ellinghaus et al., 2012; Hüffmeier et al., 2010; Stuart et al., 2015), accompanied with other candidate gene studies, most of the PsA susceptibility loci have been proved to be associated with PsV. However, the genetic study of GPP is quite different. Up to now, IL36RN is the only associated gene of GPP that has been widely verified. The data are based on homozygosity mapping and direct sequencing in consanguineous Tunisian multiplex families with autosomal recessive GPP (Marrakchi et al., 2011). Some researchers suggested that GPP and PsV are etiologically distinct clinical entities (Capon, 2013), challenging the traditional understanding of psoriasis. The percentages of IL36RN-negative patients have been reported to range from 51% (Li et al., 2013) to 84% (Setta-Kaffetzi et al., 2013), implying that additional risk loci, genetic interactions, and other factors may account for the other GPP cases. Recently, more than 10 GWASs of PsV have identified a number of susceptibility loci, making PsV GWASs a rich source of potential risk loci for other subtypes of psoriasis. Here, we use information emerging form PsV GWASs to make inferences about the genetic etiology of PsA and GPP in a Chinese population.

18.
Cell Death Dis ; 9(11): 1080, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30348950

RESUMO

Alternatively activated macrophages have been reported to be helpful to alleviate systematic lupus erythematosus (SLE), and azithromycin could serve as an immunomodulator by promoting alternatively activated macrophage phenotype. However, the effect of azithromycin in SLE and the involved mechanism remain undetermined. The aim of this study is to characterize azithromycin and the underlying mechanism contributing to SLE therapy. First, we compared monocytes from SLE patients and matched healthy donors, and found monocytes from SLE patients exhibited more CD14+CD86+ cells, impaired phagocytic activity, and elevated interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α (the classical activated phenotype), which could be blocked by azithromycin. On the contrary, there were fewer CD14+CD163+ cells in SLE patients, accompanied by decreased arginase (Arg)-1 and found in inflammatory zone (Fizz)-1 (the alternatively activated phenotype). And IL-10, the crucial immune regulatory factor secreted by alternatively activated monocytes/macrophages, also showed a decreased trend in SLE patients. In addition, all these markers were up-regulated after azithromycin treatment. Next, we used activated lymphocyte-derived-DNA to imitate SLE macrophages in vitro to investigate the possible mechanism involved. Azithromycin showed the same effect in imitated SLE macrophages, with distinct Akt phosphorylation at 30 min and 12 h. After inhibiting Akt phosphorylation by LY294002, the down-regulation of CD80, IL-1ß, IL-6, and TNF-α caused by azithromycin raised again, meanwhile, the up-regulation of CD206, Arg-1, Fizz-1, and IL-10 due to azithromycin was abolished. Additionally, insulin-like growth factor 1 (IGF-1), the specific agonist of Akt, played a similar role to azithromycin in imitated SLE macrophages. Taken together, our data indicated a novel role of azithromycin in alleviating SLE by promoting alternatively activated macrophage phenotype, and the PI3K/Akt signaling pathway was involved. Our findings provide a rationale for further investigation of novel therapeutic strategy for SLE patients.

19.
Lab Invest ; 98(12): 1527-1537, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30206310

RESUMO

Vitamin D analogs have been widely utilized for the treatment of vitiligo, but the molecular mechanism underlying their pharmacological effects (especially their antioxidant properties) has not yet been investigated. We evaluated the relationship between serum vitamin D level and oxidative damage severity in vitiligo patients, and investigated the molecular mechanism of vitamin D in protecting melanocytes against oxidative stress. Serum levels of 25-hydroxyvitamin D and malondialdehyde (MDA) were first measured in patients. A variety of in vitro experiments such as intracellular reactive oxygen species (ROS), cellular viability, migration, and apoptotic assays were then performed to detect the effects of vitamin D or ß-catenin silencing on H2O2-treated melanocytes. Expression of Wnt/ß-catenin, Nrf2, apoptotic, and MITF pathways was finally examined using quantitative real-time PCR and western blot. In this study, we initially found that vitamin D insufficiency was closely associated with the severity of oxidative stress in vitiligo patients. Using ex vivo cell models, we further showed that vitamin D positively modulated ß-catenin signaling at both translational and posttranslational levels in melanocytes under oxidative stress. Like WNT agonists, vitamin D significantly inhibited ROS accumulation and cell apoptosis in H2O2-treated melanocytes and promoted their proliferative and migratory activity, while the protective effects of vitamin D against oxidative stress were abolished by ß-catenin silencing in melanocytes. Furthermore, ß-catenin deficiency also blocked the activation of Nrf2 and MITF as well as the inhibition of apoptosis induced by vitamin D. Taken together, vitamin D insufficiency was associated with severity of oxidative stress in vitiligo patients. Our work also provides new insights into the mechanism of vitamin D against vitiligo, in which vitamin D protects melanocytes against oxidative stress by activating Wnt/ß-catenin signaling.

20.
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.

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