Decreased DACH1 expression in glomerulopathy is associated with disease progression and severity.
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ABSTRACT:
SUBMITTER: Liu QQ
PROVIDER: S-EPMC5349934 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGenomic instability due to UV radiation is one of the leading causes for melanoma. Histone acetyltransferase p300 plays an indispensible role in DNA repair and maintenance of genomic integrity. The present study was performed to analyze the correlation between p300 expression, melanoma progression and patient survival.MethodsTissue microarray and immunohistochemical analysis was employed to study the expression of p300 in melanoma patients. A total of 358 melanoma patients (250 primary melanoma and 108 metastatic melanoma) were used for the study. Kaplan-Meier, univariate and multivariate Cox regression analysis, and receiver-operating characteristic curves, were used to elucidate the prognostic significance of p300 expression.ResultsOur results demonstrate that p300 is expressed in both nucleus and cytoplasm but the nuclear expression of p300 is predominant. The progression of disease from dysplastic nevi to primary melanoma and to metastatic melanoma was associated with decreased nuclear and increased cytoplasmic p300 expression. Especially, the loss of nuclear and gain in cytoplasmic p300 was correlated with the progression of melanoma from AJCC stage II to stage III, which requires the migration and metastasis of cancer cells from primary sites to lymph nodes. Similarly, decrease in nuclear, and increase in cytoplasmic p300 expression correlated with worse survival of melanoma patients. Nuclear p300 but not cytoplasmic p300 could predict the patient survival independent of AJCC stage, age and gender.ConclusionLoss of nuclear p300 expression is an indicator of worse patient survival and is an independent prognostic marker for melanoma.
| S-EPMC3787094 | biostudies-literature
Project description:Increasing human Adenovirus (HAdV) infections complicated with acute respiratory distress syndrome (ARDS) even fatal outcome were reported in immunocompetent adolescent and adult patients. Here, we characterized the cytokine/chemokine expression profiles of immunocompetent patients complicated with ARDS during HAdV infection and identified biomarkers for disease severity/progression. Forty-eight cytokines/chemokines in the plasma samples from 19 HAdV-infected immunocompetent adolescent and adult patients (ten complicated with ARDS) were measured and analyzed in combination with clinical indices. Immunocompetent patients with ARDS caused by severe acute respiratory disease coronavirus (SARS-CoV)-2, 2009 pandemic H1N1 (panH1N1) or bacteria were included for comparative analyses. Similar indices of disease course/progression were found in immunocompetent patients with ARDS caused by HAdV, SARS-CoV-2 or panH1N infections, whereas the HAdV-infected group showed a higher prevalence of viremia, as well as increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK). Expression levels of 33 cytokines/chemokines were increased significantly in HAdV-infected patients with ARDS compared with that in healthy controls, and many of them were also significantly higher than those in SARS-CoV-2-infected and panH1N1-infected patients. Expression of interferon (IFN)-γ, interleukin (IL)-1β, hepatocyte growth factor (HGF), monokine induced by IFN-γ (MIG), IL-6, macrophage-colony stimulating factor (M-CSF), IL-10, IL-1α and IL-2Ra was significantly higher in HAdV-infected patients with ARDS than that in those without ARDS, and negatively associated with the ratio of the partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2). Analyses of the receiver operating characteristic curve (ROC) showed that expression of IL-10, M-CSF, MIG, HGF, IL-1β, IFN-γ and IL-2Ra could predict the progression of HAdV infection, with the highest area under the curve (AUC) of 0.944 obtained for IL-10. Of note, the AUC value for the combination of IL-10, IFN-γ, and M-CSF reached 1. In conclusion, the "cytokine storm" occurred during HAdV infection in immunocompetent patients, and expression of IL-10, M-CSF, MIG, HGF, IL-1β, IFN-γ and IL-2Ra was closely associated with disease severity and could predict disease progression.
| S-EPMC8215364 | biostudies-literature
Project description:BackgroundMortality due to COVID-19 caused by SARS-CoV-2 infection varies among populations. Functional relevance of genetic variations in Angiotensin-converting enzyme 2 (ACE2) and Transmembrane serine protease 2 (TMPRSS2), two crucial host factors for viral entry, might explain some of this variation.MethodsIn this comparative study in Indian subjects, we recruited 510 COVID-19 patients and retrieved DNA from 520 controls from a repository. Associations between variants in ACE2 and TMPRSS2 with disease severity were identified by whole exome sequencing (WES, n = 20) and targeted genotyping (n = 1010). Molecular dynamic simulations (MDS) were performed to explore functional relevance of the variants. Cleavage of spike glycoprotein by wild and variant TMPRSS2 was determined in HEK293T cells. Potential effects of confounders on the association between genotype and disease severity were tested (Mantel-Haenszel test).ResultsWES identified deleterious variant in TMPRSS2 (rs12329760, G > A, p. V160M). The minor allele frequency (MAF) was 0·27 in controls, 0·31 in asymptomatic, 0·21 in mild-to-moderately affected and 0·19 in severely affected COVID-19 patients. Risk of severity increased with decreasing MAF: Asymptomatic: Odds ratio-0·69 (95% CI-0·52-0·93; p = 0·01); mild-to-moderate: Odds ratio-1·89 (95% CI-1·22-2.92;p = 0·004) and severe: Odds ratio-1·79 (95% CI-1·11-2.88;p = 0·01). No confounding effect of diabetes and hypertension were observed on the risk of developing severe COVID-19 disease with respect to genotype. MDS revealed decreased stability of TMPRSS2 with 160 M variant. Spike glycoprotein cleavage by TMPRSS2 reduced ~2·4-fold in cells expressing 160 M variant.ConclusionWe demonstrate association of TMPRSS2 variant rs12329760 with decreased disease severity in COVID-19 patients from India.
| S-EPMC8161869 | biostudies-literature
Project description:BackgroundThis study aimed to evaluate the value of urinary angiostatin levels for assessing disease severity and progression of IgA nephropathy (IgAN).MethodsUrinary angiostatin was identified as one of the distinct proteins in samples of patients with IgAN analyzed by Raybiotech protein array, and further confirmed by enzyme-linked immunosorbent assay (ELISA).ResultsUrinary angiostatin levels were significantly higher in IgAN patients than that in healthy controls (HC) subjects and lower than in disease controls (DC) patients. The concentrations of angiostatin in urine normalized to urinary creatinine (angiostatin/Cr) were positively associated with proteinuria level. With advancing chronic kidney disease (CKD) stage, urinary angiostatin/Cr levels were gradually increased. Urinary angiostatin/Cr levels in patients with Lee's grade IV-V were significantly higher than those in Lee's grade I-II and III. We further compared urinary angiostatin/Cr levels by using Oxford classification and found the expression in patients with mesangial proliferative score 1(M1) was significantly higher than that in M0 (P < 0.001). In addition, the levels of urinary angiostatin/Cr in patients with tubular atrophy/interstitial fibrosis score 1(T1) and T2 were significantly higher than those in T0 (P < 0.01, P < 0.001, respectively). After follow-up, renal survival was significantly worse in patients with higher levels of urinary angiostatin (P < 0.05).ConclusionsUrinary angiostatin may be a useful novel noninvasive biomarker to evaluate disease severity and progression of IgAN.
| S-EPMC6446319 | biostudies-literature
Project description:Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. We identified a novel homozygous deletion of DACH1 in gliomas. We generated U87TR-Da glioma cell line, where DACH1 expression could be activated by exposure of cells to doxycycline, and examined changing global gene expression by DACH1 expression. Expression of DACH1 in U87TR-Da cells can be induced by exposure of the cells to doxycycline. We analyzed gene expression profiles of DACH1-induced/repressed U87TR-Da cells. And we also compared gene expression profiles of DACH1-induced/repressed U87TR-Da cells under different culture condition, DMEMF(serum-containing) and NBE(serum-free)
| S-ECPF-GEOD-19678 | biostudies-other
Project description:AimsWe aimed to assess whether expression of whole-blood RNA of sodium proton exchanger 1 (NHE1) and glucose transporter 1 (GLUT1) is associated with COVID-19 infection and outcome in patients presenting to the emergency department with respiratory infections. Furthermore, we investigated NHE1 and GLUT1 expression in the myocardium of deceased COVID-19 patients.Methods and resultsWhole-blood quantitative assessment of NHE1 and GLUT1 RNA was performed using quantitative PCR in patients with respiratory infection upon first contact in the emergency department and subsequently stratified by SARS-CoV-2 infection status. Assessment of NHE1 and GLUT1 RNA using PCR was also performed in left ventricular myocardium of deceased COVID-19 patients. NHE1 expression is up-regulated in whole blood of patients with COVID-19 compared with other respiratory infections at first medical contact in the emergency department (control: 0.0021 ± 0.0002, COVID-19: 0.0031 ± 0.0003, P = 0.01). The ratio of GLUT1 to NHE1 is significantly decreased in the blood of COVID-19 patients who are subsequently intubated and/or die (severe disease) compared with patients with moderate disease (moderate disease: 0.497 ± 0.083 vs. severe disease: 0.294 ± 0.0336, P = 0.036). This ratio is even further decreased in the myocardium of patients who deceased from COVID-19 in comparison with the myocardium of non-infected donors.ConclusionsNHE1 and GLUT1 may be critically involved in the disease progression of SARS-CoV-2 infection. We show here that SARS-CoV-2 infection critically disturbs ion channel expression in the heart. A decreased ratio of GLUT1/NHE1 could potentially serve as a biomarker for disease severity in patients with COVID-19.
| S-EPMC7835506 | biostudies-literature
Project description:Background & Aims Variants in the tumor necrosis factor superfamily member 15 gene (TNFSF15, also called TL1A) have been associated with risk for inflammatory bowel diseases (IBD). TL1A affects expression of multiple cytokines to promote mucosal inflammation. Little is known about the TL1A-response pathways that regulate cytokine expression. We investigated T-cell gene expression patterns to determine the mechanisms by which TL1A regulates cytokine production, and whether these associate with outcomes of patients with Crohn’s disease (CD).Methods Peripheral T cells isolated from normal donors were cultured with TL1A. We performed gene expression profile analysis, by RNA sequencing, of subsets of interferon gamma (IFNG)-producing and non-producing cells, purified by flow cytometry. Unsupervised hierarchical clustering analysis was used to identify gene expression differences between these subsets. Ribonuclease T2 gene (RNASET2) expression and methylation were assessed by quantitative trait loci analyses. Clinical characteristics of patients (complications, resistance to therapy, recurrence time) were associated with single nucleotide polymorphisms in RNASET2. We performed motif screening to identify polymorphisms that disrupt transcription factor binding sites. Levels of RNASET2 were knocked down with small interfering RNA in CD4+ T cells and the effect on protein expression was determined by proteomic analysis and cytokine production. Cell aggregation was measured by flow cytometry. ResultsWe identified 764 genes with at least a 2-fold difference in TL1A-mediated expression between IFNG-secreting and non-secreting T cells (P<1 × 10−5). Many of these genes were located near IBD susceptibility variants. RNASET2 was the only IBD risk-associated gene with greater than 5-fold downregulation in the IFNG-secreting subset. RNASET2 disease risk variants were associated with decreased expression in peripheral and mucosal tissues and DNA hypermethylation in CD patients requiring surgical intervention. RNASET2 disease risk variants were associated in CD patients with more complicated disease or resistance to therapy, defined in part by failed response to treatment, increased length of intestinal resection, shorter time to repeat surgery, and high Rutgeerts score (>2) in post-operative endoscopy. The RNASET2 variant rs2149092 was predicted to disrupt a consensus binding site for the transcription factor ETS within an enhancer region. Expression of RNASET2 correlated with expression of ETS. RNASET2 knockdown in T cells increased expression of IFNG and ICAM1 and induced T cells aggregation. A blocking antibody against LFA1, disrupting the LFA1-ICAM1 interaction, reduced T-cell production of IFNG. Conclusions We identified decreased expression of RNASET2 as a component of TL1A-mediated increase in production of IFNG and as a potential biomarker for patients with severe CD. Further study of the role of RNASET2 in regulating mucosal inflammation may lead to development of novel therapeutic targets.
2022-10-11 | GSE215144 | GEO
Project description:Background & aimsVariants in the tumor necrosis factor superfamily member 15 gene (TNFSF15, also called TL1A) have been associated with risk for inflammatory bowel disease (IBD). TL1A affects expression of multiple cytokines to promote mucosal inflammation. Little is known about the TL1A-response pathways that regulate cytokine expression. We investigated T-cell gene expression patterns to determine the mechanisms by which TL1A regulates cytokine production, and whether these associate with outcomes of patients with Crohn's disease (CD).MethodsPeripheral T cells isolated from normal donors were cultured with TL1A. We performed gene expression profile analysis by RNA sequencing of subsets of interferon gamma (IFNG)-producing and non-producing cells purified by flow cytometry. Unsupervised hierarchical clustering analysis was used to identify gene expression differences between these subsets. Ribonuclease T2 gene (RNASET2) expression and methylation were assessed by quantitative trait loci analyses. Clinical characteristics of patients (complications, resistance to therapy, and recurrence time) were associated with single nucleotide polymorphisms in RNASET2. We performed motif screening to identify polymorphisms that disrupt transcription factor binding sites. Levels of RNASET2 were knocked down with small interfering RNA in CD4+ T cells and the effect on protein expression was determined by proteomic analysis and cytokine production. Cell aggregation was measured by flow cytometry.ResultsWe identified 764 genes with at least a 2-fold difference in TL1A-mediated expression between IFNG-secreting and non-secreting T cells (P < 1 × 10-5). Many of these genes were located near IBD susceptibility variants. RNASET2 was the only IBD risk-associated gene with >5-fold down-regulation in the IFNG-secreting subset. RNASET2 disease risk variants were associated with decreased expression in peripheral and mucosal tissues and DNA hypermethylation in CD patients requiring surgical intervention. RNASET2 disease risk variants were associated in CD patients with more complicated disease or resistance to therapy, defined in part by failed response to treatment, increased length of intestinal resection, shorter time to repeat surgery, and high Rutgeerts score (>2) in postoperative endoscopy. The RNASET2 variant rs2149092 was predicted to disrupt a consensus binding site for the transcription factor ETS within an enhancer region. Expression of RNASET2 correlated with expression of ETS. RNASET2 knockdown in T cells increased expression of IFNG and intercellular adhesion molecule 1 (ICAM1) and induced T-cell aggregation. A blocking antibody against (ILFA1), disrupting the lymphocyte function-associated antigen 1-intercellular adhesion molecule 1 interaction, reduced T-cell production of IFNG.ConclusionsWe identified decreased expression of RNASET2 as a component of TL1A-mediated increase in production of IFNG and as a potential biomarker for patients with severe CD. Further study of the role of RNASET2 in regulating mucosal inflammation may lead to development of novel therapeutic targets.
| S-EPMC5484733 | biostudies-literature
Project description:Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease (HD). Glutamate is the predominant excitatory neurotransmitter in the brain, and excess activation of glutamate receptors can cause neuronal dysfunction and death. Glutamate transporters regulate the extracellular concentration of glutamate. GLT-1 is the most abundant glutamate transporter, and accounts for most of the glutamate transport in the brain. Administration of ceftriaxone, an antibiotic that increases the functional expression of GLT-1, can improve the behavioral phenotype of the R6/2 mouse model of HD. To test the hypothesis that GLT-1 expression critically affects the HD disease process, we generated a novel mouse model that is heterozygous for the null allele of GLT-1 and carries the R6/2 transgene (double mutation). We demonstrated that the protein expression of total GLT-1, as well as two of its isoforms, is decreased within the cortex and striatum of 12-week-old R6/2 mice, and that the expression of EAAC1 was decreased in the striatum. Protein expression of GLT-1 was further decreased in the cortex and striatum of the double mutation mice compared with the R6/2 mice at 11 weeks. However, the effects of the R6/2 transgene on weight loss, accelerating rotarod, climbing and paw-clasping were not exacerbated in these double mutants. Na(+) -dependent glutamate uptake into synapatosomes isolated from the striatum and cortex of 11-week-old R6/2 mice was unchanged compared with controls. These results suggest that changes in GLT-1 expression or function per se are unlikely to potentiate or ameliorate the progression of HD.
| S-EPMC3735860 | biostudies-literature
Project description:InstructionInterleukin 27 (IL-27) is an important regulator of the proinflammatory T-cell response. In this study, we investigated its role in the pathogenesis of Behçet's disease (BD).MethodsIL-27 mRNA in peripheral blood mononuclear cells (PBMCs) was examined by performing RT-PCRs. Cytokine levels in sera or supernatants of PBMCs, naïve CD4(+) T cells, dendritic cells (DCs) and DC/T cells were determined by enzyme-linked immunosorbent assay. We used RNA interference in naïve CD4(+) T cells to study the role of interferon regulatory factor 8 (IRF8) in the inhibitory effect of IL-27 on Th17 cell differentiation. Flow cytometry was used to evaluate the frequency of IL-17- and interferon γ-producing T cells.ResultsThe expression of IL-27p28 mRNA by PBMCs and IL-27 in the sera and supernatants of cultured PBMCs were markedly decreased in patients with active BD. A higher frequency of IL-17-producing CD4(+) T (Th17) cells and increased IL-17 production under Th17 polarizing conditions were observed in patients with active BD. IL-27 significantly inhibited Th17 cell differentiation. Downregulation of IRF8 by RNA interference abrogated the suppressive effect of IL-27 on Th17 differentiation. IL-27 inhibited the production of IL-1β, IL-6 and IL-23, but promoted IL-10 production, by DCs. IL-27-treated DCs inhibited both the Th1 and Th17 cell responses.ConclusionsThe results of the present study suggest that a decreased IL-27 expression is associated with disease activity in BD patients. Low IL-27 expression may result in a higher Th1 and Th17 cell response and thereby promote the autoinflammatory reaction observed in BD. Manipulation of IL-27 may offer a new treatment modality for this disease.
| S-EPMC4095700 | biostudies-literature