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1.
Sci Rep ; 13(1): 4384, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-36928592

RESUMO

Narrow band-ultraviolet B (NB-UVB) is an effective treatment for psoriasis. We aim to generate a potential mechanism of NB-UVB through comparing the transcriptomic profile before and after NB-UVB treatment between the peripheral edge of lesional skin (PE skin) and the center of lesional skin (CE skin) on the basis of molecular mechanisms of these two areas display different downstream functions. More than one-fourth of the NB-UVB-altered genes were found to be plaque-specific. Some of them were psoriasis signature genes that were downregulated by NB-UVB in, both, PE and CE skin (core alteration), such as IL36G, DEFB4A/B, S100A15, KRT16, and KRT6A. After NB-UVB treatment, the activity score of upstream cytokines, such as interferons, interleukin (IL)-6, IL-17, and IL-22 in pathogenesis decreased. In addition, NB-UVB could restore normal keratinization by upregulating LORICRIN and KRT2, particularly in the CE skin. Finally, we illustrated that NB-UVB is capable of suppressing molecules from the initiation to maintenance phase of plaque formation, thereby normalizing psoriatic plaques. This finding supports the usefulness of NB-UVB treatment in clinical practice and may help in the development of new treatment approaches in which NB-UVB treatment is included for patients with psoriasis or other inflammatory skin diseases.


Assuntos
Psoríase , Terapia Ultravioleta , Humanos , Transcriptoma , Pele/patologia , Psoríase/genética , Psoríase/radioterapia , Psoríase/tratamento farmacológico , Interferons/uso terapêutico , Interleucina-6/uso terapêutico
2.
J Dermatol Sci ; 107(3): 123-132, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35995712

RESUMO

BACKGROUND: Psoriasis is a chronic inflammatory skin condition. It is widely treated with phototherapy using narrowband ultraviolet B (NB-UVB). The therapeutic mechanisms of NB-UVB, however, remain unclear, particularly in the early phases of the disease. OBJECTIVE: To investigate the mechanisms underlying the effects of NB-UVB on psoriasis in a model of perilesional psoriasis. METHODS: Psoriatic patients that received NB-UVB treatment and were evaluated with the psoriasis area and severity index were included in the study. Skin biopsies obtained before and after treatment were subjected to RNA sequencing (RNA-seq) and Ingenuity Pathway Analyses for genome-wide transcriptome profiling to gain further insights into the signaling pathways underlying the improvement of psoriasis with therapeutic intervention. RESULTS: Our findings revealed that NB-UVB treatment may exert its effects by suppressing nuclear factor kappa B, which leads to upregulation of the sirtuin signaling pathway, as well as by decreasing the function of major upstream regulators associated with proinflammatory and inflammatory cytokines, which blocks the expression of downstream toll-like receptors. Psoriasis improvement after NB-UVB treatment was associated with decreased expression of NFKBIZ, SERPINB4, ATG13, and CTSS and increased expression of SKP1 gene. Our results also highlighted the expression of proposed genes associated with the modulation of autoinflammation. CONCLUSIONS: To the best of our knowledge, this is the first study to apply advanced molecular techniques to explore the effects of phototherapy on psoriasis in the early-phase, providing new insights into the disease pathogenesis and novel genetic information for the development of new therapeutic modalities and potential treatment targets.


Assuntos
Psoríase , Sirtuínas , Terapia Ultravioleta , Citocinas , Perfilação da Expressão Gênica , Humanos , NF-kappa B , Psoríase/tratamento farmacológico , Psoríase/genética , Psoríase/radioterapia , Terapia Ultravioleta/métodos
3.
Int J Mol Sci ; 23(10)2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35628259

RESUMO

BAM15 (a mitochondrial uncoupling agent) was tested on cecal ligation and puncture (CLP) sepsis mice with in vitro experiments. BAM15 attenuated sepsis as indicated by survival, organ histology (kidneys and livers), spleen apoptosis (activated caspase 3), brain injury (SHIRPA score, serum s100ß, serum miR370-3p, brain miR370-3p, brain TNF-α, and apoptosis), systemic inflammation (cytokines, cell-free DNA, endotoxemia, and bacteremia), and blood-brain barrier (BBB) damage (Evan's blue dye and the presence of green fluorescent E. coli in brain after an oral administration). In parallel, brain miR arrays demonstrated miR370-3p at 24 h but not 120 h post-CLP, which was correlated with metabolic pathways. Either lipopolysaccharide (LPS) or TNF-α upregulated miR370-3p in PC12 (neuron cells). An activation by sepsis factors (LPS, TNF-α, or miR370-3p transfection) damaged mitochondria (fluorescent color staining) and reduced cell ATP, possibly through profound mitochondrial activity (extracellular flux analysis) that was attenuated by BAM15. In bone-marrow-derived macrophages, LPS caused mitochondrial injury, decreased cell ATP, enhanced glycolysis activity (extracellular flux analysis), and induced pro-inflammatory macrophages (iNOS and IL-1ß) which were neutralized by BAM15. In conclusion, BAM15 attenuated sepsis through decreased mitochondrial damage, reduced neuronal miR370-3p upregulation, and induced anti-inflammatory macrophages. BAM15 is proposed to be used as an adjuvant therapy against sepsis hyperinflammation.


Assuntos
Encefalopatias , MicroRNAs , Sepse , Trifosfato de Adenosina/genética , Trifosfato de Adenosina/metabolismo , Animais , Encefalopatias/genética , Encefalopatias/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Punções , Sepse/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
Int J Mol Sci ; 23(9)2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35563374

RESUMO

Elucidating transcriptome in the peripheral edge of the lesional (PE) skin could provide a better understanding of the molecules or signalings that intensify inflammation in the PE skin. Full-thickness biopsies of PE skin and uninvolved (UN) skin were obtained from psoriasis patients for RNA-seq. Several potential differentially expressed genes (DEGs) in the PE skin compared to those in the UN skin were identified. These DEGs enhanced functions such as angiogenesis, growth of epithelial tissue, chemotaxis and homing of cells, growth of connective tissues, and degranulation of myeloid cells beneath the PE skin. Moreover, the canonical pathways of IL-17A, IL-6, and IL-22 signaling were enriched by the DEGs. Finally, we proposed that inflammation in the PE skin might be driven by the IL-36/TLR9 axis or IL-6/Th17 axis and potentiated by IL-36α, IL-36γ, IL-17C, IL-8, S100A7, S100A8, S100A9, S100A15, SERPINB4, and hBD-2. Along with IL-36α, IL-17C, and IκBζ, ROCK2 could be an equally important factor in the pathogenesis of psoriasis, which may involve self-sustaining circuits between innate and adaptive immune responses via regulation of IL-36α and IL-36γ expression. Our finding provides new insight into signaling pathways in PE skin, which could lead to the discovery of new psoriasis targets.


Assuntos
Perfilação da Expressão Gênica , Psoríase , Humanos , Inflamação/patologia , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Queratinócitos/metabolismo , Psoríase/genética , Psoríase/metabolismo , Pele/metabolismo , Transcriptoma
5.
Asian Pac J Allergy Immunol ; 40(1): 94-102, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32563236

RESUMO

BACKGROUND: Non-invasive diagnosis of interstitial fibrosis and tubular atrophy (IF/TA), a major cause of chronic allograft dysfunction in post-kidney transplantation (post-KT), is needed. OBJECTIVE: Several candidates of microRNAs (miRs) in plasma exosome or whole plasma were evaluated for IF/TA biomarker. METHODS: Kidney samples from biopsy and plasma were tested for miRs expression. RESULTS: Expression of miR-21, miR-142-3p and miR-221 in renal histology with high fibrosis score (Banff classification) was higher than the samples with lesser score (n = 17/group). However, expression of these miRs from plasma exosome or from whole plasma of post-KT patients with different severity of IF/TA as determined by percentage of IF/TA including; grade I (5-25%) (n = 15), grade II (26-50%) (n = 15), grade III (≥ 50%) (n = 6) versus stable graft function (no IF/TA) (n = 15) was not different. However, high expression of miR-21 in exosome, but not from whole plasma, was demonstrated in IF/TA grade II and III compared with IF/TA grade I. In contrast, serum creatinine (Scr) and proteinuria, the current standard biomarkers, could not differentiate IF/TA grade I out of grade II/III. There was no correlation between exosome miR-21 versus the current standard renal injury biomarkers, including Scr, blood urea nitrogen and proteinuria, in IF/TA grade II or grade III. CONCLUSIONS: High miR-21 in plasma exosome, but not in whole plasma, indicated high grade IF/TA in post-KT patients. This non-invasive monitoring biomarker allows the more frequent evaluation on IF/TA than renal biopsy (a standard but more invasive procedure) resulting in the earlier management. More studies on patients are warrant.


Assuntos
Exossomos , Transplante de Rim , MicroRNAs , Atrofia/metabolismo , Atrofia/patologia , Biomarcadores , Fibrose , Humanos , Transplante de Rim/efeitos adversos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , MicroRNAs/genética
6.
Shock ; 54(3): 347-357, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31743302

RESUMO

The diagnosis of sepsis-associated encephalopathy (SAE), an alteration of conscious from sepsis, is difficult due to the similarity to altered states of conscious that occur from other causes. Transcriptomic analyses between mouse brains at 24 h after cecal ligation and puncture (CLP) (SAE brain as evaluated by SHIRPA score) and at 120 h post-CLP (survivor) were performed to discover the SAE biomarker. Then, candidate microRNAs were validated in mouse and patient samples.As such, increased miR-370-3p in SAE mouse-brains (compared with recovery phase) was demonstrated by transcriptomic miR-profiling and was highly expressed in brain (but not other organs) of 24 h post-CLP mice. Plasma miR-370-3p also increased in CLP but was non-detectable in bilateral-nephrectomy (BiNx, a representative model of acute uremic encephalopathy) despite blood brain barrier permeability defect (determined by plasma s100ß and Evan blue dye assay) in both conditions. In parallel, high plasma miR-370-3p was demonstrated in patients with SAE (but not sepsis alone or uremia) suggesting the specificity toward SAE. The association among TNF-α, miR-370-3p and brain apoptosis was demonstrated by high serum TNF-α and increased brain apoptosis in SAE mice, TNF-α (but not other cytokines) activated miR-370-3p expression in PC-12 neuron cell, and increased cell apoptosis in miR-370-3p transfected PC-12 after incubation with TNF-α.In conclusion, miR-370-3p increased in brain and plasma of SAE mice but not uremic encephalopathy. Perhaps, TNF-α enhances cell susceptibility toward brain apoptosis in SAE, in part, through miR-370-3p induction in neuron. Our pilot results in patients with SAE supported the possibility that plasma miR-370-3p is an interesting SAE biomarker candidate. Further studies are warranted.


Assuntos
Biomarcadores/sangue , Encéfalo/metabolismo , MicroRNAs/sangue , Encefalopatia Associada a Sepse/sangue , Sepse/sangue , Transcriptoma/genética , Animais , Barreira Hematoencefálica/metabolismo , Camundongos , Encefalopatia Associada a Sepse/genética , Fator de Necrose Tumoral alfa/sangue
7.
J Dermatolog Treat ; 30(1): 81-86, 2019 Feb.
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.


Assuntos
Lasers de Corante/uso terapêutico , Lúpus Eritematoso Discoide/cirurgia , Adulto , Método Duplo-Cego , Feminino , Humanos , Lúpus Eritematoso Discoide/patologia , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante/métodos
8.
Asian Pac J Allergy Immunol ; 37(4): 189-197, 2019 Dec.
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.


Assuntos
Exossomos/genética , Nefrite Lúpica/urina , MicroRNAs/urina , Adulto , Regulação para Baixo , Feminino , Taxa de Filtração Glomerular , Humanos , Nefrite Lúpica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
9.
Biochem Biophys Res Commun ; 506(3): 739-745, 2018 11 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.


Assuntos
Moléculas de Adesão Celular/metabolismo , Hepatócitos/metabolismo , Neoplasias Hepáticas/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Regiões Promotoras Genéticas/genética , Transcriptoma/genética
10.
PLoS One ; 13(6): e0198609, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29889863

RESUMO

Macrophages exhibit diverse effector phenotypes depending on the stimuli and their microenvironment. Classically activated macrophages are primed with interferon (IFN)γ and stimulated with pathogen-associated molecular patterns. They produce inflammatory mediators and inflammatory cytokines, such as IL-12. In the presence of immune complexes (ICs), activated macrophages have decreased IL-12 production and increased IL-10 production and presumably act as regulatory macrophages. Notch signaling has been shown to regulate the effector functions of classically activated macrophages. In this study, we investigated whether Notch signaling is active in lipopolysaccharide (LPS)-stimulated macrophages in the presence of ICs. LPS/IC stimulation increased the level of cleaved Notch1 in murine macrophages, while IC stimulation alone did not. Delta-like 4, but not Jagged1, was responsible for generating cleaved Notch1. The activation of Notch signaling by LPS/ICs depended upon NF-κB and MEK/Erk pathway activation. Macrophages with the targeted deletion of Rbpj, which encodes a DNA-binding protein central to canonical Notch signaling, produced significantly less IL-10 upon LPS/IC stimulation. A similar impact on IL-10 production was observed when Notch signaling was inhibited with a gamma-secretase inhibitor (GSI). Defects in NF-κB p50 nuclear localization were observed in GSI-treated macrophages and in Rbpj-/- macrophages, suggesting cross-regulation between the Notch and NF-κB pathways. Transcriptomic analysis revealed that Notch signaling regulates the transcription of genes involved in the cell cycle, macrophage activation, leukocyte migration and cytokine production in LPS/IC-stimulated macrophages. Taken together, these results suggest that the Notch signaling pathway plays an important role in regulating the functions of macrophages activated by LPS and ICs.


Assuntos
Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Complexo Antígeno-Anticorpo/farmacologia , Células da Medula Óssea/citologia , Células Cultivadas , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/deficiência , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Interferon gama/farmacologia , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo
11.
Sci Rep ; 7(1): 14517, 2017 11 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.


Assuntos
Autoanticorpos/metabolismo , Interleucina-8/metabolismo , Nefrite Lúpica/imunologia , Células Mesangiais/imunologia , MicroRNAs/metabolismo , Adulto , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunoglobulina G/metabolismo , Interleucina-6/metabolismo , Masculino , RNA Mensageiro/metabolismo
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