scholarly journals Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

2020 ◽  
Author(s):  
Vikramjeet Singh ◽  
Alexander Beer ◽  
Andreas Kraus ◽  
Xiaoni Zhang ◽  
Jinhua Xue ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Injury ◽  
Systemic Inflammation ◽  
Immune Cell ◽  
Risk Group ◽  
Tissue Injury ◽  
Lung Epithelial Cells ◽  
Experimental Stroke ◽  
Virus Surface ◽  
Protein Levels

AbstractBackgroundThe newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the virus surface. Recent clinical data have demonstrated that patients suffering from stroke are particularly susceptible to severe courses of SARS-CoV-2 infection, thus forming a defined risk group. However, a mechanistic explanation for this finding is lacking. Sterile tissue injuries including stroke induce lymphocytopenia and systemic inflammation that might modulate the expression levels of surface proteins in distant organs. Whether systemic inflammation following stroke can specifically modulate ACE2 expression in the lung has not been investigated.MethodsMice were subjected to transient middle cerebral artery occlusion (MCAO) for 45 min and sacrificed after 24 h and 72 h for analysis of brain and lung tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1β were measured by quantitative PCR and Western blot, respectively. Immune cell populations in lymphoid organs were analyzed by flow cytometry.ResultsStrikingly, 24 h after stroke, we observed a substantial increase in the expression of ACE2 both on the transcriptional and protein levels in the lungs of MCAO mice compared to sham-operated mice. This increased expression persisted until day 3 after stroke. In addition, MCAO increased the expression of inflammatory cytokines IL-6 and IL-1β in the lungs. Higher gene expression of cytokines IL-6 and IL-1β was found in ischemic brain hemispheres and a reduced number of T-lymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression.ConclusionsWe demonstrate significantly augmented ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings might explain the clinical observation that patients with pre-existing stroke represent a high-risk group for the development of severe SARS-CoV-2 infections. Our studies call for further investigations into the underlying signaling mechanisms and possible therapeutic interventions.HighlightsBrain tissue injury increases ACE2 levels in the lungsBrain injury induces pro-inflammatory cytokine expression in the lungsBrain injury causes parenchymal inflammation and systemic lymphopenia

Synergistic Up-Regulation of Heme Oxygenase-1 in Human Liver by Heme and siRNA to Bach1:Possible Therapeutic Implications.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1633-1633
Author(s):  
Tahereh Ghaziani ◽  
Ying Shan ◽  
Richard W. Lambrecht ◽  
Herbert L. Bonkovsky
Keyword(s):  
Gene Expression ◽  
Heme Oxygenase ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Negative Regulator ◽  
Heme Oxygenase 1 ◽  
Significant Finding ◽  
Mrna Levels ◽  
Protein Levels

Abstract Background: Heme oxygenase-1 (HO-1) is an antioxidant defense enzyme that converts toxic heme into antioxidants. HO-1 is strongly up-regulated by its physiologic substrate, heme, which is currently the treatment of choice for acute attacks of porphyria and which may have other therapeutic uses, as well (e.g., for cytoprotection or amelioration of ischemia/reperfusion injury by increasing supply of carbon monoxide, biliverdin, or bilirubin). Up-regulation of HO-1 expression has been associated with increased resistance to tissue injury. Bach1 is a bZip protein which forms heterodimers with small Maf proteins. HO-1 is expressed at higher levels in tissues of Bach1-deficient mice, indicating that Bach1 acts as a negative regulator of the mouse HO-1 gene. The molecular mechanism that confers repression of HO-1 by Bach1, and whether there are similar effects in human cells, has remained elusive. The aim of this study was to assess whether modulation of human hepatic Bach1 expression by siRNA technology influences HO-1 gene expression and whether such gene silencing would enhance the inducing effects of heme on HO-1. Methods: siRNAs targeted 4 different positions of human Bach1 mRNA were designed and synthesized. We transfected Bach1-siRNA (25–200 nM) into Huh-7 cells using Lipofectamine for 24–72 h, after which, cells were treated with or without heme. We quantified HO-1 and Bach1 mRNA and protein levels by quantitative RT-PCR and western blotting, respectively. Effects and specificity of Bach1-siRNA were analyzed and compared with those of non-Bach1 related siRNAs (non-specific control-duplex (NSCD) and LaminB2-siRNA). Results: Bach1-siRNAs (25–200 nM) transfected into Huh-7 cells for 24–72 h significantly reduced Bach1 mRNA and protein levels approximately 80%, compared with non siRNA treated cells. In contrast, transfection with same amounts of NSCD or LaminB2 siRNA did not reduce Bach1 mRNA or protein levels, confirming the specificity of Bach1-siRNA in Huh-7 cells. A significant finding of these studies was the 7-fold up-regulation of the HO-1 gene in Bach1-siRNA transfected cells, compared to cells without Bach1-siRNA or those transfected with NSCD or LaminB2. Bach1, NSCD, and LaminB2 siRNAs had no effect on HO-2 or 5-aminolevulinate synthase-1 mRNA levels (two genes that are not induced by heme). The effects of increasing concentrations of heme (up to 10 μM) in the presence or absence of Bach1-siRNA on the levels of HO-1 mRNA expression are shown in the Figure. For all of the heme concentrations tested, the levels of HO-1 mRNA were greater when Bach1 siRNA was present. Conclusions: Bach1 has a specific and selective effect to repress expression of human hepatic HO-1. Silencing of the Bach1 gene by siRNAs may be a useful method for up-regulating HO-1 gene expression. The combination of intravenous heme and Bach1 silencing may be useful for therapy of acute porphyrias in relapse or other conditions in which up-regulation of HO-1 may be beneficial. (Supported by grants from NIH [DK38825] and Ovation Pharmaceuticals, Inc.) Figure Figure

scholarly journals Identification of Immune-Related Risk Signatures for the Prognostic Prediction in Oral Squamous Cell Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Chen Zou ◽  
Dahong Huang ◽  
Haigang Wei ◽  
Siyuan Wu ◽  
Jing Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Squamous Cell Carcinoma ◽  
Growth Factor ◽  
Oral Squamous Cell Carcinoma ◽  
Signaling Pathway ◽  
Immune Cell ◽  
Risk Group ◽  
Growth Factor Receptor ◽  
Immune Cell Infiltration ◽  
Related Risk

Background. Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, which remains a major cause of morbidity and mortality in patients with head and neck cancers. However, the critical immune-related signatures and their prognostic values have rarely been investigated. Materials and Methods. Gene differential analysis was used to measure the differences of gene expression between the groups. Correlation analysis was used to assess the association between the gene expression levels and immune-related risk score/DNA methylation levels. The gene set enrichment analysis (GSEA) was used to identify the pathways or cell types enriched by those identified differentially expressed genes (DEGs). Results. In this study, we identified four immune-related gene signatures, including CTSG, TNFRSF4, LCORL, and PLAU, that were significantly associated with the overall survival in OSCC patients from the Cancer Genome Atlas (TCGA) OSCC cohort. Moreover, these four immune-related signatures were differentially expressed between the OSCC and nontumor tissues. The two groups (high and low risk) stratified by the immune-related risk scores had significantly different OS and mortality rates. The gene expression patterns and prognostic values of these immune-related signatures were also verified in two independent validation cohorts. Furthermore, the downregulated genes in the high-risk group (which were also upregulated in the low-risk group) were significantly enriched in the cell type-specific signatures of type 2 T helper cell (Th2), plasmacytoid dendritic cell (pDC), and memory B cell. In contrast, the upregulated genes in the high-score group were enriched in growth factor receptor-related signaling pathways, such as the VEGFA-VEGFR2 signaling pathway, PI3K-Akt signaling pathway, focal adhesion-PI3K-Akt-mTOR signaling pathway, and PDGF pathway, suggesting that those pathways were inversely correlated with immune cell infiltration. Conclusion. In summary, the immune-related signatures had the potential for predicting the risk of OSCC patients. Moreover, the present study also improved our understanding of the association between the growth factor receptor pathways and immune cell infiltration in OSCC.

scholarly journals Signature Based on Immune-Related LncRNA Can Predict Overall Survival of Osteosarcoma Patients

2020 ◽  
Author(s):  
Longqing Li ◽  
Lianghao Zhang ◽  
Manhas Adbul Khader ◽  
Yan Zhang ◽  
Xinchang Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Immune Checkpoint ◽  
High Throughput Sequencing ◽  
Immune Cell ◽  
Cox Regression ◽  
Risk Group ◽  
Low Risk ◽  
Checkpoint Gene ◽  
Cox Regression Analysis

Abstract Background: Osteosarcoma is a malignant bone tumor common in children and adolescents. Metastatic status remains the most important guideline for classifying patients and making clinical decisions. Despite many efforts, newly diagnosed patients receive the same therapy that patients have received over the last 4 decades. With the development of high-throughput sequencing technology and the rise of immunotherapy, it is necessary to deeply explore the immune molecular mechanism of osteosarcoma.Methods: We obtained RNA-seq data and clinical information of osteosarcoma patients from TCGA database and TARGET database. With the help of co-expression analysis we identified immune-related lncRNA and then by means of univariate Cox regression analysis prognostic-related lncRNA was screened out. And also by using least absolute shrinkage and selection operator regression method a model based on immune-related lncRNA was constructed. The differences in overall survival, immune infiltration, immune checkpoint gene expression, and tumor microenvironmental immunity type between the two groups were evaluated.Results: We constructed a signature consisting of 13 lncRNA. Our results show that signatures can reliably predict the overall survival of patients with osteosarcoma and can bring net clinical benefits. Further more, the signatures can be used for further risk stratification of the metastasis patients. Patients in the low-risk group had higher immune cell infiltration and immune checkpoint gene expression. The results from gene set variation analysis show that patients in low-risk group are closely related to immune-related pathways when compared with patients in high-risk group. Finally, patients in the low-risk group are more likely to be classified as TMIT I and hence more likely to benefit from immunotherapy.Conclusion: Our signature may be a reliable marker for predicting the overall survival of patients with osteosarcoma.

scholarly journals Novel Prognostic Biomarkers in Gastric Cancer: CGB5, MKNK2, and PAPPA2

2021 ◽  
Vol 11 ◽  
Author(s):  
Min Qin ◽  
Zhihai Liang ◽  
Heping Qin ◽  
Yifang Huo ◽  
Qing Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Regression Analysis ◽  
Immune Cells ◽  
Prognostic Model ◽  
Prognostic Markers ◽  
Immune Cell ◽  
Risk Group ◽  
P Value ◽  
Expression Data

IntroductionGastric cancer is one of the most common malignant tumors of the digestive tract. However, there are no adequate prognostic markers available for this disease. The present study used bioinformatics to identify prognostic markers for gastric cancer that would guide the clinical diagnosis and treatment of this disease.Materials and MethodsGene expression data and clinical information of gastric cancer patients along with the gene expression data of 30 healthy samples were downloaded from the TCGA database. The initial screening was performed using the WGCNA method combined with the analysis of differentially expressed genes, which was followed by univariate analysis, multivariate COX regression analysis, and Lasso regression analysis for screening the candidate genes and constructing a prognostic model for gastric cancer. Subsequently, immune cell typing was performed using CIBERSORT to analyze the expression of immune cells in each sample. Finally, we performed laboratory validation of the results of our analyses using immunohistochemical analysis.ResultsAfter five screenings, it was revealed that only three genes fulfilled all the screening requirements. The survival curves generated by the prognostic model revealed that the survival rate of the patients in the high-risk group was significantly lower compared to the patients in the low-risk group (P-value < 0.001). The immune cell component analysis revealed that the three genes were differentially associated with the corresponding immune cells (P-value < 0.05). The results of immunohistochemistry also support our analysis.ConclusionCGB5, MKNK2, and PAPPA2 may be used as novel prognostic biomarkers for gastric cancer.

Transcriptional regulation of pulmonary elastin gene expression in elastase-induced injury

2003 ◽  
Vol 285 (2) ◽  
pp. L354-L362 ◽  
Author(s):  
Celeste B. Rich ◽  
Isabel Carreras ◽  
Edgar C. Lucey ◽  
Julie A. Jaworski ◽  
Jo Ann Buczek-Thomas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tissue Injury ◽  
Gene Promoter ◽  
Activity Levels ◽  
Intratracheal Administration ◽  
Protein Levels ◽  
Elastin Gene ◽  
Pulmonary Fibroblast

Previously we have shown that treatment of confluent, pulmonary fibroblast cultures with elastase results in upregulation of elastin mRNA and protein levels. In the present study we focused on determining the level at which elastin expression is upregulated after elastase exposure. We examined as models for this investigation elastin gene expression in primary pulmonary fibroblast cells during the transition from subconfluent to confluent cultures and in confluent, matrix-laden cultures treated briefly with elastase. In addition, we extended our studies to mice that were given an intratracheal dose of elastase; the effects on lung elastin mRNA and elastin promoter activity levels were measured and compared with results from in vitro cell models. The results demonstrate that upregulation of elastin gene expression during the transition of subconfluent to confluent cultures and after elastase injury is associated with an increase in the level of transcription both in vitro and in vivo. Furthermore, intratracheal administration of elastase to transgenic mice illustrates that the increased levels of elastin mRNA are accompanied by increased activity of the elastin gene promoter in cells spatially positioned near major sites of tissue injury.

scholarly journals Immune Implication of ASF1B Gene in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Tao Meng ◽  
Zhong Tong ◽  
Ming-Ya Yang ◽  
Jing-Jing Wang ◽  
Li-Xin Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Risk Score ◽  
Immune Cell ◽  
Risk Group ◽  
External Validation ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Test Set

Abstract Background: Anti-silencing function 1B (ASF1B) has been demonstrated to contribute to tumorigenesis. However, its carcinogenic and immune effects in hepatocellular carcinoma (HCC) have not been reported. This study aimed to identify immune role of ASF1B in HCC.Methods: HCC datasets obtained from The Cancer Genome Atlas (TCGA) database were used to investigate the role of ASF1B gene in HCC, followed by validation using Gene Expression Omnibus (GEO) datasets and Gene Expression Profiling Interactive Analysis (GEPIA) website. CIBERSORT analysis was performed to evaluate immune cell infiltration levels. The TISIDB and cBioPortal network tool were used to seek ASF1B-associated immunomodulators and its co-expressed genes. TCGA cohort was divided into train set and test set according to the ratio of 7:3. Cox regression was used to identify ASF1B-associated prognostic immunomodulators in train set, followed by internal validation using the test set. Based on the median risk-score, HCC patients were divided into high- and low-risk group for the further survival curves and receiver operating characteristic (ROC) analysis, as well as nomogram and calibration curves analysis. Finally, the dataset collected from the GEO was adopted for external validation.Results: ASF1B was over-expressed in TCGA HCC cohort and contributed poor prognosis, which was verified in two GEO datasets (GSE14520 and GSE6764) and GEPIA, as well as Kaplan Meier Plotter network tool. The immune cell infiltration levels were found to be associated with the ASF1B copy numbers and mRNA expression. A total of 78 ASF1B-associated genes were screened out, including 7 immunoinhibitors, 21 immunostimulators and 50 tightly co-expressed genes. Finally, 5 ASF1B-associated genes (TNFSF4, TNFRSF4, KDR, MICB and CST7) were identified to be strongly related to HCC survival. Survival analysis demonstrated that the prognosis of patients in high-risk group was poor. The prognosis predict model, which was established by nomogram based on risk-score, and was validated in both TCGA test set and GEO validated datasets, exerted excellent predictive power in this study.Conclusion: Our findings showed that the ASF1B was associated with HCC immunity. The selected ASF1B-asociated immune markers could be promising biomarkers for the prognosis of HCC.

scholarly journals Identification of a novel autophagy signature for predicting survival in patients with lung adenocarcinoma

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11074
Author(s):  
Jin Duan ◽  
Youming Lei ◽  
Guoli Lv ◽  
Yinqiang Liu ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Immune Cell ◽  
Cox Regression ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Low Risk ◽  
Cell Analysis ◽  
Prognostic Signature

Background Lung adenocarcinoma (LUAD) is the most commonhistological lung cancer subtype, with an overall five-year survivalrate of only 17%. In this study, we aimed to identify autophagy-related genes (ARGs) and develop an LUAD prognostic signature. Methods In this study, we obtained ARGs from three databases and downloaded gene expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We used TCGA-LUAD (n = 490) for a training and testing dataset, and GSE50081 (n = 127) as the external validation dataset.The least absolute shrinkage and selection operator (LASSO) Cox and multivariate Cox regression models were used to generate an autophagy-related signature. We performed gene set enrichment analysis (GSEA) and immune cell analysis between the high- and low-risk groups. A nomogram was built to guide the individual treatment for LUAD patients. Results We identified a total of 83 differentially expressed ARGs (DEARGs) from the TCGA-LUAD dataset, including 33 upregulated DEARGs and 50 downregulated DEARGs, both with thresholds of adjusted P < 0.05 and |Fold change| > 1.5. Using LASSO and multivariate Cox regression analyses, we identified 10 ARGs that we used to build a prognostic signature with areas under the curve (AUCs) of 0.705, 0.715, and 0.778 at 1, 3, and 5 years, respectively. Using the risk score formula, the LUAD patients were divided into low- or high-risk groups. Our GSEA results suggested that the low-risk group were enriched in metabolism and immune-related pathways, while the high-risk group was involved in tumorigenesis and tumor progression pathways. Immune cell analysis revealed that, when compared to the high-risk group, the low-risk group had a lower cell fraction of M0- and M1- macrophages, and higher CD4 and PD-L1 expression levels. Conclusion Our identified robust signature may provide novel insight into underlying autophagy mechanisms as well as therapeutic strategies for LUAD treatment.

scholarly journals Signature based on immune-related LncRNA can predict overall survival of osteosarcoma patients

2020 ◽  
Author(s):  
Longqing Li ◽  
Lianghao Zhang ◽  
Manhas Adbul Khader ◽  
Yan Zhang ◽  
Xinchang Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Immune Checkpoint ◽  
High Throughput Sequencing ◽  
Immune Cell ◽  
Cox Regression ◽  
Risk Group ◽  
Low Risk ◽  
Checkpoint Gene ◽  
Cox Regression Analysis

Abstract Background: Osteosarcoma is a malignant bone tumor common in children and adolescents. Metastatic status remains the most important guideline for classifying patients and making clinical decisions. Despite many efforts, newly diagnosed patients receive the same therapy that patients have received over the last 4 decades. With the development of high-throughput sequencing technology and the rise of immunotherapy, it is necessary to deeply explore the immune molecular mechanism of osteosarcoma. Methods: We obtained RNA-seq data and clinical information of osteosarcoma patients from TCGA database and TARGET database. With the help of co-expression analysis we identified immune-related lncRNA and then by means of univariate Cox regression analysis prognostic-related lncRNA was screened out. And also by using least absolute shrinkage and selection operator regression method a model based on immune-related lncRNA was constructed. The differences in overall survival, immune infiltration, immune checkpoint gene expression, and tumor microenvironmental immunity type between the two groups were evaluated. Results: We constructed a signature consisting of 13 lncRNA. Our results show that signatures can reliably predict the overall survival of patients with osteosarcoma and can bring net clinical benefits. Further more, the signatures can be used for further risk stratification of the metastasis patients. Patients in the low-risk group had higher immune cell infiltration and immune checkpoint gene expression. The results from gene set variation analysis show that patients in low-risk group are closely related to immune-related pathways when compared with patients in high-risk group. Finally, patients in the low-risk group are more likely to be classified as TMIT I and hence more likely to benefit from immunotherapy. Conclusion: Our signature may be a reliable marker for predicting the overall survival of patients with osteosarcoma. Keywords: Osteosarcoma, TCGA, LncRNA, Tumor immunology, Prognosis.

scholarly journals Comprehensive Analysis of the Expression, Prognostic Value and Immune Microenvironment of CMTM Family Members in Ovarian Cancer

2021 ◽  
Author(s):  
Mengjun Zhang ◽  
Yue Yin ◽  
Zhenxing Sun ◽  
Yuan Liu ◽  
Yiru Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Prognostic Value ◽  
Immune Cell ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
High Expression ◽  
Immune Checkpoints ◽  
Immune Microenvironment ◽  
Protein Levels

Abstract Background: Ovarian cancer (OV) is one of the most common gynecological malignancies worldwide, and its immunotherapy has considerable prospects. Multiple members of the CMTM family were aberrantly expressed in human cancers and controled key malignant biological processes and immune regulation in cancer development. However, little is known about the function of this gene family in ovarian cancer, especially in terms of immunity.Methods: GEPIA, Oncomine, HPA, Kaplan-Meier plotter, cBioPortal, GeneMANIA and TIMER were used to analyze the differential gene expression, prognostic value, genetic alterations and alterations in the immune microenvironment of the CMTM family in patients with ovarian cancer. Importantly, RT-qPCR was used to verify the gene expression of the CMTM family.Results: CMTM1/3/4/6/7/8 showed abnormally high expression at the mRNA and protein levels in OV tissues based on the GEPIA and HPA databases. RT-qPCR showed that CMTM1/6/8 was highly expressed in ovarian cancer cell lines. Survival analysis showed that high expression of CMTM1/2/3/5/8 can lead to a significant reduction in overall survival and progression-free survival. There were many types of genetic alterations in the CMTM family. And CMTM1/2/3/6 had a certain correlation with the changes of immune microenvironment such as immune cell infiltration and immune checkpoint expression, which may be the potential mechanism of the CMTM family in ovarian cancer.Conclusion: This study confirmed that the CMTM family has abnormal expression in ovarian cancer and can be used as a biomarker for prognostic evaluation. And the CMTM family may be used as a potential target for immunotherapy based on the suppression of immune checkpoints.

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