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1.
Cells ; 8(10)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640263

RESUMO

Tolerogenic dendritic cells (tolDCs) are central players in the initiation and maintenance of immune tolerance and subsequent prevention of autoimmunity. Recent advances in treatment of autoimmune diseases including systemic lupus erythematosus (SLE) have focused on inducing specific tolerance to avoid long-term use of immunosuppressive drugs. Therefore, DC-targeted therapies to either suppress DC immunogenicity or to promote DC tolerogenicity are of high interest. This review describes details of the typical characteristics of in vivo and ex vivo tolDC, which will help to select a protocol that can generate tolDC with high functional quality for clinical treatment of autoimmune disease in individual patients. In addition, we discuss the recent studies uncovering metabolic pathways and their interrelation intertwined with DC tolerogenicity. This review also highlights the clinical implications of tolDC-based therapy for SLE treatment, examines the current clinical therapeutics in patients with SLE, which can generate tolDC in vivo, and further discusses on possibility and limitation on each strategy. This synthesis provides new perspectives on development of novel therapeutic approaches for SLE and other autoimmune diseases.

2.
Sci Rep ; 9(1): 15205, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645587

RESUMO

Immunotherapy has emerged as a promising and effective treatment for cancer. The frequently used immunotherapy agents are immune checkpoint inhibitors, such as antibodies specific to PD1, PD-L1, or CTLA-4. However, these drugs are highly expensive, and most people in the world cannot access the treatment. The development of recombinant protein production platforms that are cost-effective, scalable, and safe is needed. Plant platforms are attractive because of their low production cost, speed, scalability, lack of human and animal pathogens, and post-translational modifications that enable them to produce effective monoclonal antibodies. In this study, an anti-PD1 IgG4 monoclonal antibody (mAb) was transiently produced in Nicotiana benthamiana leaves. The plant-produced anti-PD1 mAb was compared to the commercial nivolumab produced in CHO cells. Our results showed that both antibodies have similar protein structures, and the N-glycans on the plant-produced antibody lacks plant-specific structures. The PD1 binding affinity of the plant-produced and commercial nivolumab, determined by two different techniques, that is, enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR), are also comparable. Plant-produced nivolumab binds to human PD1 protein with high affinity and specificity, blocks the PD-1/PD-L1 interaction, and enhances T cell function, comparable to commercial nivolumab. These results confirmed that plant-produced anti-PD1 antibody has the potential to be effective agent for cancer immunotherapy.

3.
Shock ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31306346

RESUMO

BACKGROUND: Nosocomial aspergillosis in patients with sepsis have emerged in the past few years. Blockade of PD-1/PD-L pathway has tended to become a promising therapeutic strategy as it improved the outcome of bacterial sepsis and post-sepsis secondary fungal infection. Recently, the controversial effects of PD-1 blockade on infectious diseases, including aspergillosis, have been demonstrated, therefore, the efficacy of anti-PD-1 drug still remains to be elucidated. METHODS: Cecal ligation and puncture (CLP) was conducted as a mouse sepsis model. Aspergillus fumigatus spores were intravenously inoculated on day 5 post-CLP, when the immune cells succumbed to exhaustion. Amphotericin B was medicated together with or without anti-PD-1 treatment after Aspergillus infection. RESULTS: Amphotericin B alone was not effective to treat the CLP-mice with secondary aspergillosis. In contrast, anti-fungal medication with the adjunctive anti-PD-1 treatment attenuated the fungal burdens in blood and internal organs, and improved the survival rate of the mice with secondary aspergillosis. These outcomes of PD-1 blockade were concurring with the enhanced CD86 expression on splenocytes, the augmented serum IFN-γ and the dampened IL-10. Activated T cells from anti-PD-1 treated mice also highly increased IFN-γ and diminished IL-10 production. CONCLUSION: The blockade of PD-1 on post-sepsis aspergillosis presumably reinvigorated exhausted antigen-presenting cells and T cells by upregulating CD86 expression and IFN-γ production, and dampened IL-10 production, which consequently leaded to the attenuation of secondary aspergillosis. The adjunctive anti-PD-1 therapy may become a promising strategy for the advanced immunotherapy against lethal fungal infection.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30904000

RESUMO

BACKGROUND: Psoriasis is a chronic inflammatory skin disease arising from a complex interaction between genetics, epigenetics, the host's immune system and the environment. Recent accumulated data revealed the dysregulation of various microRNAs (miRNAs) in several diseases including psoriasis. OBJECTIVE: We explored the functional role and regulation of hsa-miR-155-5p (miR-155) in an immortalized keratinocyte cell line (HaCaT), in relation to the pathogenesis and treatment of psoriasis. METHODS: miR-155 expression in normal skin and psoriatic skin lesion before and after treatment with methotrexate (MTX) and narrow-band ultraviolet B phototherapy (NB-UVB) were analyzed using quantitative reverse transcription PCR (qRT-PCR). Apoptotic activity, cell cycle and viable cells of miR-155 transfected HaCaT were measured using flow cytometry and MTS assay. Since, caspase-3 (CASP3) gene was predicted as a target gene of miR-155, the expression of CASP3 was detected in transfected HaCaT using western blot. RESULTS: We discovered that both MTX and NB-UVB significantly down-regulated miR-155 expression in psoriatic skin lesions. We also found that overexpression of miR-155 in HaCaT led to suppression of cell apoptosis and induced cell arrest at G0/G1 phase. Moreover, CASP3 expression was down-regulated in miR-155 transfected HaCaT. CONCLUSION: This study demonstrates down-regulation of miR155 after treatment with MTX and NB-UVB in psoriatic skin lesion. miR155 plays significant role in apoptosis on HaCaT via CASP3. This finding provides a better understanding of the pathogenesis of psoriasis and might aid on developing the new monitoring tool or therapy for psoriasis in the future.

6.
Clin Infect Dis ; 2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30715261

RESUMO

Background & aims: (Peg)interferon ((Peg)IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. Methods: In this GWAS, CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centres from Europe, Asia and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined HBeAg-loss with HBVDNA <2,000 IU/mL, or an HBVDNA <2,000 IU/mL for HBeAg-negative patients. Results: Of 1,144 patients, 1,058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% HBsAg-loss. GWAS analysis stratified by HBeAg-status, adjusted for age, gender and the 4 ancestry components identified PRELID2rs371991 (B=-0.74, SE=0.16, p=3.44*10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2rs3821977 (B=1.13, SE=0.24, p=2.46*10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in PBMC of healthy controls stimulated with IFNα and TLR8. After stimulation less production of IP-10 and IL-10 proteins and more production of IL-8 was observed with the G3BP2 G-allele. Conclusions: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counselling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. Clinicaltrials.gov number: NCT01401400.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30660167

RESUMO

BACKGROUND: B-cell activating factor (BAFF), an important cytokine for B lymphocyte activation, has been shown to be increased in chronic hepatitis B virus (HBV) infection. OBJECTIVES: This study aimed at evaluating clinical correlation and prognostic role of plasma BAFF and related polymorphisms in patients with HBV-related hepatocellular carcinoma (HCC). METHODS: Plasma BAFF levels were measured from 100 healthy controls and 490 patients with chronic HBV infection (200 with HCC and 290 without HCC). The rs9514828 and rs12583006 polymorphisms were determined by allelic discrimination. RESULTS: The HCC group had significantly higher BAFF levels compared with the non-HCC group and healthy controls. Among the non-HCC group, the HBeAg-positive subgroup had higher BAFF levels compared with the HBeAg-negative subgroup. In the HCC group, high BAFF levels at initial presentation significantly correlated with alpha-fetoprotein levels, Child-Pugh classification, tumor size and BCLC stage. Multivariate analyses showed that elevated BAFF concentration (± 1,100 pg/ml) was a significant and independent prognostic factor of overall survival in patients with HCC (OR = 2.28, 95%CI: 1.07-4.87; P = 0.034). HCC patients with high BAFF levels (± 1,100 pg/ml) had a poorer median survival than those with low levels (P < 0.001, log-rank test). Regarding BAFF polymorphisms, the frequency of rs9514828 CT + TT genotypes was higher distributed in patients with chronic HBV infection compared with healthy controls (58.0% vs. 46.0%, P = 0.029). CONCLUSIONS: Our data demonstrate for the first time that elevated plasma BAFF levels at baseline exhibit clinical correlation in terms of disease severity and overall survival in HCC patients. Thus, plasma BAFF at initial diagnosis could serve as a prognostic marker for HBV-related HCC.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30660173

RESUMO

BACKGROUND: B-cell activating factor (BAFF), an essential cytokine for B lymphocytes activation, has been implicated in the pathogenesis of chronic viral hepatitis. However, the role of BAFF in patients with chronic hepatitis B (CHB) undergoing antiviral therapy is unknown. METHODS: Patients with HBeAg-positive CHB treated with 48-week pegylated interferon (PEG-IFN; n = 42), who had stored plasma samples during treatment were recruited. Serial plasma levels of BAFF and C-X-C motif chemokine 10 (CXCL10) during therapy were measured. RESULTS: Combined response (CR), defined as HBeAg seroconversion with HBV DNA < 2,000 IU/mL plus HBsAg decline ≥ 1 log10 IU/mL at 24 weeks post-treatment, was achieved in 11 (26.2%) patients. BAFF levels were elevated during treatment but decreased to pre-treatment levels after PEG-IFN cessation in both responders and non-responders. Low baseline BAFF (< 770 pg/ml) and high CXCL10 (≥ 320 pg/ml) levels were independently associated with CR in multivariate analysis. Baseline CXCL10/BAFF ratio of ≥ 0.45 was predictive of CR with positive and negative predictive values of 61.5 and 89.7%, respectively. CONCLUSIONS: In summary, low baseline BAFF and high CXCL10 levels were associated with treatment response to PEGIFN. The combined measurement of these immune markers may help individualized decision-making in patients with HBeAg-positive CHB.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30660174

RESUMO

BACKGROUND: Notch signaling has been linked to many cancers. However, there is still limited information about the expression and role of the Notch ligand in hepatocellular carcinoma (HCC). OBJECTIVE: To investigate the expression of JAG1 and DLL4 in HCC tissues. METHODS: One hundred and forty-five HCC tissues in paraffin block since 2009 to 2016 at King Chulalongkorn Memorial hospital were assayed for JAG1 and DLL4 by immunohistochemistry. All the sections were separately analyzed in tumor and adjacent non-tumor tissue and scoring based on intensity and quantity of immunoreaction. Kruskal-Wallis H test examined the correlation between JAG1 and DLL4 protein expression and clinical pathology. RESULTS: The expression of JAG1 and DLL4 of tumor cells is 57.2% (83/145) and 88.9% (129/145), respectively. The expression of JAG1 is significantly higher in tumor tissues than adjacent non-tumor tissues (P = 0.002), and significantly increased in patients with age < 60 years old (P = 0.007). Interestingly, the DLL4 expression is also expressed in the normal liver tissue and DLL4 expression is not associated with any of the clinical parameters. When we performed a subgroup analysis, in HCC patients without a viral infection analysis, JAG1 is significantly increased in HCC patients with low albumin level (≤ 3.5) (P = 0.043). CONCLUSIONS: JAG1 expression is increased in HCC and seems to correlate with HCC patients with earlier onset and lower albumin level, whereas DLL4 expression did not significantly correlate with any clinical features.

10.
Gastroenterol Res Pract ; 2018: 1064783, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524475

RESUMO

Background and Aim: The risks of post-ERCP pancreatitis (PEP) are identified as patient- and procedure-related factors. However, the genetic contribution for PEP is still unclear. Recent data show that the polymorphisms of PRSS1-PRSS2 (rs10273639) and MORC4 (rs12688220) are associated with recurrent acute pancreatitis and chronic pancreatitis. We aim to evaluate the association between these polymorphisms and post-ERCP pancreatitis in order to improve better prognosis and better care for these patients. Methods: This is a retrospective, case-control study which includes 49 cases and 97 controls that are age-, procedure-, and risk of PEP-matched with the cases in 1 : 2 fashion. The PEP was diagnosed and graded for severity according to the standard consensus, and the risk factors of PEP were identified according to the ESGE guideline. Polymorphisms at rs10273639 and rs12688220 were evaluated by TaqMan technique and were identified in 133 (40 cases and 93 controls) and 146 patients, respectively. Results: The demographic data between 2 groups are not significantly different. The genotype frequencies of PRSS1-PRSS2 (TT, TC, and CC) are 26, 13, and 1 vs. 67, 25, and 1 in cases and controls, respectively (p = 0.642). The genotype frequencies of MORC4 in female (TT, TC, and CC) are 8, 23, and 5 vs. 12, 26, and 21 in cases and controls, respectively (p = 0.071). The genotype frequencies of MORC4 in male (T and C) are 5 and 8 vs. 21 and 17 in cases and controls, respectively (p = 0.468). The allelic frequencies of MORC4 in combination of both genders (T, C) are 44 and 41 vs. 71 and 84 in cases and control, respectively (p = 0.431). In PEP cases, the allelic frequencies of PRSS1-PRSS2 (T and C) are 59 and 13 vs. 6 and 2 in mild and moderate/severe cases, respectively (p = 0.633). The allelic frequencies of MORC4 (T and C) are 38 and 39 vs. 4 and 4 in mild and moderate/severe cases, respectively (p = 0.972). Conclusion: Polymorphisms at PRSS1-PRSS2 and MORC4 are not associated with the risk or severity of post-ERCP pancreatitis.

11.
Biochem Biophys Res Commun ; 506(3): 739-745, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30384995

RESUMO

Notch signaling is involved in both differentiation of hepatocyte progenitors and hepatocellular carcinoma (HCC). The mechanism whereby Notch signaling regulates cellular transformation in hepatocytes is still controversial. This study investigated the impact of overexpressing truncated intracellular Notch1 (NICD1) on transcriptomic profiles of immortalized human hepatocytes. RNA sequencing and gene ontology enrichment analysis revealed that extracellular matrix organization and hyaluronan biosynthesis process gene sets are among those affected by Notch hyperactivation. The relationship between Notch signaling and periostin, an extracellular matrix protein highly expressed in HCC, were further studied. Modulating Notch signaling through NICD1 overexpression or treatment with a gamma secretase inhibitor resulted in increased or decreased periostin expression, respectively, in HCC and liver bile duct carcinoma cell lines. Based on The Cancer Genome Atlas database, mRNA levels of NOTCH1 and POSTN are positively correlated in tumor tissues but not in nontumor tissues. Two consensus RBPJ binding motifs were identified in the -3932/-3921 and + 2522/+2533 bp of POSTN regulatory regions, and NOTCH1 is associated with these binding sites in a liver bile duct carcinoma cell line. Taken together, these results indicate that Notch signaling directly regulates transcription of POSTN in hepatocytes and liver cancer cell lines and may be a candidate for drug targeting in liver cancer.

12.
World J Gastroenterol ; 24(34): 3861-3870, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30228780

RESUMO

AIM: To investigate the role of Delta-like ligand 4 (DLL4) on tumour growth in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) in vivo. METHODS: We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tumours in nude mice. The expression of tumour angiogenesis regulators, VEGF-A and VEGF-R2 in tumour xenografts were examined by western blotting. The tumour proliferation and neovasculature were examined by immunohistochemistry. The viral replication and viral protein expression were measured by quantitative PCR and western blotting, respectively. RESULTS: Eighteen days after implantation, tumour volume in mice implanted with shDLL4 HepG2.2.15 was significantly smaller than in mice implanted with control HepG2.2.15 (P < 0.0001). The levels of angiogenesis regulators, VEGF-A and VEGF-R2 were significantly decreased in implanted tumours with suppressed DLL4 compared with the control group (P < 0.001 and P < 0.05, respectively). Furthermore, the suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, increased viral replication was observed after suppression of DLL4 in the tumours. CONCLUSION: This study demonstrates that DLL4 is important in regulating the tumour growth of HBV-associated HCC as well as the neovascularization and suppression of HBV replication.


Assuntos
Carcinoma Hepatocelular/patologia , Vírus da Hepatite B/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Hepáticas/patologia , Replicação Viral , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/patologia , RNA Interferente Pequeno/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Virais/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Mol Cell Proteomics ; 17(11): 2197-2215, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30097535

RESUMO

Interferon lambda (IFN-λ) is a relatively unexplored, yet promising antiviral agent. IFN-λ has recently been tested in clinical trials of chronic hepatitis B virus infection (CHB), with the advantage that side effects may be limited compared with IFN-α, as IFN-λ receptors are found only in epithelial cells. To date, IFN-λ's downstream signaling pathway remains largely unelucidated, particularly via proteomics methods. Here, we report that IFN-λ3 inhibits HBV replication in HepG2.2.15 cells, reducing levels of both HBV transcripts and intracellular HBV DNA. Quantitative proteomic analysis of HBV-transfected cells was performed following 24-hour IFN-λ3 treatment, with parallel IFN-α2a and PBS treatments for comparison using a dimethyl labeling method. The depth of the study allowed us to map the induction of antiviral proteins to multiple points of the viral life cycle, as well as facilitating the identification of antiviral proteins not previously known to be elicited upon HBV infection (e.g. IFITM3, XRN2, and NT5C3A). This study also shows up-regulation of many effectors involved in antigen processing/presentation indicating that this cytokine exerted immunomodulatory effects through several essential molecules for these processes. Interestingly, the 2 subunits of the immunoproteasome cap (PSME1 and PSME2) were up-regulated whereas cap components of the constitutive proteasome were down-regulated upon both IFN treatments, suggesting coordinated modulation toward the antigen processing/presentation mode. Furthermore, in addition to confirming canonical activation of interferon-stimulated gene (ISG) transcription through the JAK-STAT pathway, we reveal that IFN-λ3 restored levels of RIG-I and RIG-G, proteins known to be suppressed by HBV. Enrichment analysis demonstrated that several biological processes including RNA metabolism, translation, and ER-targeting were differentially regulated upon treatment with IFN-λ3 versus IFN-α2a. Our proteomic data suggests that IFN-λ3 regulates an array of cellular processes to control HBV replication.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30118248

RESUMO

BACKGROUND: The contents of exosomes determine their biological functions and represent a new class of epigenetic modulation of renal cells considering as novel class of biomarker. OBJECTIVE: Our study aims to investigate the expression of microRNAs (miRNA), including miR-10a/b, let-7a, and miR-21, in urinary exosomes isolated from patients with active lupus nephritis (LN) compared to inactive LN. METHODS: The exosomes were obtained from long-term follow up LN patients during active and 4 months after treatment (n = 3). The expression of candidate miRNAs was validated in group of LN patients with renal flare (n = 13) and remission stage (n = 18) using qPCR. All exosomes were characterized by NanoSight and western blotting. The correlation between miRNA expressions and kidney functions was studied. RESULTS: We found that let-7a and miR-21, but not miR-10a/b, were significantly down-regulated in LN patients with active disease compared with inactive disease. Long-term follow-up patients also showed down-regulation of let-7a and miR-21 during disease flare while the expressions were elevated after complete course of treatment. Although the miRNA expressions were not significantly correlated with classical kidney injury markers, negative correlations were found in both protein leakages and glomerular filtration rate. CONCLUSION: Our result suggested that urinary exosome-associated miRNA, let-7a and miR-21, could be used to guide the clinical stage of LN patients and possibly plays a role in epigenetic regulation of the kidney during the disease. Its expression might be able to use as liquid biopsy, however, validation in large sample size is required to show it significant in clinical implication.

15.
Arthritis Res Ther ; 20(1): 92, 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29724251

RESUMO

BACKGROUND: Systemic lupus erythematous (SLE) is a complex autoimmune disease with female predominance, particularly affecting those of childbearing age. We performed analysis of three genome-wide genotyping datasets of populations of both Chinese and European origin. METHODS: This study involved 5695 cases and 10,357 controls in the discovery stage. The lead signal on chromosome X was followed by replication in three additional Asian cohorts, with 2300 cases and 4244 controls in total. Conditional analysis of the known associated loci on chromosome X was also performed to further explore independent signals. RESULTS: Single-nucleotide polymorphism rs13440883 in GPR173 was found to be significantly associated with SLE (Pmeta = 7.53 × 10- 9, ORmeta= 1.16), whereas conditional analysis provided evidence of a potential independent signal in the L1CAM-IRAK1-MECP2 region in Asian populations (rs5987175 [LCA10]). CONCLUSIONS: We identified a novel SLE susceptibility locus on the X chromosome. This finding emphasizes the importance of the X chromosome in disease pathogenesis and highlights the role of sex chromosomes in the female bias of SLE.

17.
J Dermatolog Treat ; : 1-6, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29676592

RESUMO

PURPOSE: To evaluate the efficacy and safety of pulsed-dye laser (PDL) for discoid lupus erythematosus (DLE) in a double blinded, randomized, controlled fashion. METHOD: Forty-eight DLE lesions from nine patients were recruited. The lesions on one side of the body were randomized into the treatment group and the other side served as a control. Treatments with the PDL (595 nm) were delivered every four weeks for four consecutive months. The patients were evaluated at weeks 0, 4, 8, 12, 16 and 24. Erythema index (EI) and Texture index (TI) were obtained by Antera3D®. Modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI) and physician global assessment (PGA) scores were assessed in every visit. Lesional skin biopsies before and after the PDL treatment were taken from four patients. RESULTS: The lesions treated with the PDL demonstrated significantly more decreases in EI, TI and improvement in PGA scores compared to the control. Though there was improvement of mCLASI in the laser group, the significance difference was not observed. Interestingly, real-time polymerase chain reaction showed a reduction in CXCL-9, 10, IFN-γ, IL-1ß, TNF-α and TGF-ß. Additionally, post-treatment DLE lesions demonstrated decreased CD3, CD4, CD8 and CXCR3-positive cells. CONCLUSIONS: Improvements of DLE can be achieved with PDL.

18.
J Ophthalmol ; 2018: 9171536, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29651348

RESUMO

Background/Aims: Epigenetic mechanisms via DNA methylation may be related to glaucoma pathogenesis. This study aimed to determine the global DNA methylation level of the trabeculectomy specimens among patients with different types of glaucoma and normal subjects. Methods: Trabeculectomy sections from 16 primary open-angle glaucoma (POAG), 12 primary angle-closure glaucoma (PACG), 16 secondary glaucoma patients, and 10 normal controls were assessed for DNA methylation using combined-bisulfite restriction analysis. The percentage of global methylation level of the interspersed repetitive sequences for LINE-1, Alu, HERV-E, and HERV-K were compared between the 4 groups. Results: There were no significant differences in the methylation for LINE-1 and HERV-E between patients and normal controls. For the Alu marker, the methylation was significantly lower in all types of glaucoma patients compared to controls (POAG 52.19% versus control 52.83%, p = 0.021; PACG 51.50% versus control, p = 0.005; secondary glaucoma 51.95% versus control, p = 0.014), whereas the methylation level of HERV-K was statistically higher in POAG patients compared to controls (POAG 49.22% versus control 48.09%, p = 0.017). Conclusions: The trabeculectomy sections had relative DNA hypomethylation of Alu in all glaucoma subtypes and relative DNA hypermethylation of HERV-K in POAG patients. These methylation changes may lead to the fibrotic phenotype in the trabecular meshwork.

19.
J Innate Immun ; 10(3): 189-201, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29393221

RESUMO

We investigated the influence of spontaneous gut leakage upon polymicrobial sepsis in a lupus model with Fc gamma receptor IIb-deficient (FcGRIIb-/-) mice aged 8 and 40 weeks, as representing asymptomatic and symptomatic lupus, respectively. Spontaneous gut leakage, determined by (i) the presence of FITC-dextran, (ii) elevated serum endotoxin, and (iii) elevated serum (1→3)-ß-D-glucan (BG), was demonstrated in symptomatic lupus but not in the asymptomatic group. In parallel, spontaneous gut leakage, detected by elevated serum BG without fungal infection, was demonstrated in patients with active lupus nephritis. Gut leakage induced by dextran sulfate solution (DSS) or endotoxin administration together with BG or endotoxin alone, but not BG alone, enhanced the severity of cecal ligation and puncture (CLP) sepsis more prominently in 8-week-old FcGRIIb-/- mice. Additionally, the bone marrow-derived macrophages of FcGRIIb-/- mice produced higher cytokine levels when coexposed to endotoxin and BG, when compared to wild-type mice. In summary, spontaneous gut leakage was demonstrated in symptomatic FcGRIIb-/- mice and the induction of gut permeability worsened sepsis severity. Gut translocation of endotoxin and BG had a minor effect on wild-type mice, but the synergistic effect of BG and endotoxin was prominent in FcGRIIb-/- mice. The data suggest that therapeutic strategies addressing gut leakage may be of interest in sepsis conditions in patients with lupus.

20.
Sci Rep ; 7(1): 14517, 2017 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-29109423

RESUMO

Autoantibody-mediated inflammation directed at resident kidney cells mediates lupus nephritis (LN) pathogenesis. This study investigated the role of miRNA in human mesangial cells (HMCs) stimulated with auto anti-dsDNA immunoglobulin (Ig)G antibodies. HMCs were treated with antibodies purified from active LN patients or non-specific IgG controls in the presence of normal serum. Aberrant miRNA was screened using high throughput sequencing. Anti-dsDNA IgG up-regulated 103 miRNAs and down-regulated 30 miRNAs. The miRNAs regulated genes in the cell cycle, catabolic processes, regulation of transcription and apoptosis signalling. miR-10a was highly abundant in HMCs but was specifically downregulated upon anti-dsDNA IgG induction. Interestingly, the expression of miR-10a in kidney biopsies from class III and IV LN patients (n = 26) was downregulated compared with cadaveric donor kidneys (n = 6). Functional studies highlighted the downstream regulator of miR-10a in the chemokine signalling and cell proliferation or apoptosis pathways. Luciferase assay confirmed for the first time that IL8 was a direct target of miR-10a in HMCs. In conclusion, anti-dsDNA IgG Ab down-regulated miR-10a expression in HMCs resulting in the induction of various target genes involved in HMC proliferation and chemokine expression.

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