Metabolic Profiling Reveals Significant Perturbations of Intracellular Glucose Homeostasis in Enterovirus-Infected Cells

Enterovirus A71 (EV-A71) is a common cause of hand, foot, and mouth disease. Severe EV-A71 infections may be associated with life-threatening neurological complications. However, the pathogenic mechanisms underlying these severe clinical and pathological features remain incompletely understood. Metabolites are known to play critical roles in multiple stages of the replication cycles of viruses. The metabolic reprogramming induced by viral infections is essential for optimal virus replication and may be potential antiviral targets. In this study, we applied targeted metabolomics profiling to investigate the metabolic changes of induced pluripotent human stem cell (iPSC)-derived neural progenitor cells (NPCs) upon EV-A71 infection. A targeted quantitation of polar metabolites identified 14 candidates with altered expression profiles. A pathway enrichment analysis pinpointed glucose metabolic pathways as being highly perturbed upon EV-A71 infection. Gene silencing of one of the key enzymes of glycolysis, 6-phosphofructo-2-kinase (PFKFB3), significantly suppressed EV-A71 replication in vitro. Collectively, we demonstrated the feasibility to manipulate EV-A71-triggered host metabolic reprogramming as a potential anti-EV-A71 strategy.

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Distinctive Cellular and Metabolic Reprogramming in Porcine Lung Mononuclear Phagocytes Infected With Type 1 PRRSV Strains

Frontiers in Immunology ◽

10.3389/fimmu.2020.588411 ◽

2020 ◽

Vol 11 ◽

Author(s):

Elisa Crisci ◽

Marco Moroldo ◽

Thien-Phong Vu Manh ◽

Ammara Mohammad ◽

Laurent Jourdren ◽

...

Keyword(s):

Expression Profiles ◽

Enrichment Analysis ◽

Cellular Reprogramming ◽

Mononuclear Phagocytes ◽

Gene Set Enrichment Analysis ◽

Metabolic Reprogramming ◽

Specific Expression ◽

Data Set

Porcine reproductive and respiratory syndrome (PRRS) has an extensive impact on pig production. The causative virus (PRRSV) is divided into two species, PRRSV-1 (European origin) and PRRSV-2 (North American origin). Within PRRSV-1, PRRSV-1.3 strains, such as Lena, are more pathogenic than PRRSV-1.1 strains, such as Flanders 13 (FL13). To date, the molecular interactions of PRRSV with primary lung mononuclear phagocyte (MNP) subtypes, including conventional dendritic cells types 1 (cDC1) and 2 (cDC2), monocyte-derived DCs (moDC), and pulmonary intravascular macrophages (PIM), have not been thoroughly investigated. Here, we analyze the transcriptome profiles of in vivo FL13-infected parenchymal MNP subpopulations and of in vitro FL13- and Lena-infected parenchymal MNP. The cell-specific expression profiles of in vivo sorted cells correlated with their murine counterparts (AM, cDC1, cDC2, moDC) with the exception of PIM. Both in vivo and in vitro, FL13 infection altered the expression of a low number of host genes, and in vitro infection with Lena confirmed the higher ability of this strain to modulate host response. Machine learning (ML) and gene set enrichment analysis (GSEA) unraveled additional relevant genes and pathways modulated by FL13 infection that were not identified by conventional analyses. GSEA increased the cellular pathways enriched in the FL13 data set, but ML allowed a more complete comprehension of functional profiles during FL13 in vitro infection. Data indicates that cellular reprogramming differs upon Lena and FL13 infection and that the latter might keep antiviral and inflammatory macrophage/DC functions silent. Although the slow replication kinetics of FL13 likely contribute to differences in cellular gene expression, the data suggest distinct mechanisms of interaction of the two viruses with the innate immune system during early infection.

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A broadly neutralizing monoclonal antibody induces broad protection against heterogeneous PRRSV strains in piglets

Veterinary Research ◽

10.1186/s13567-021-00914-0 ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Zhigang Zhang ◽

Tianshu Zhai ◽

Mingshuo Li ◽

Kun Zhang ◽

Jingrui Li ◽

...

Keyword(s):

Monoclonal Antibody ◽

Neutralizing Antibodies ◽

Antigenic Variation ◽

Profile Analysis ◽

Expression Profiles ◽

Enrichment Analysis ◽

Antibody Isotype ◽

Hilar Lymph Node

AbstractNeutralizing antibodies (NAbs) have attracted attention as tools for achieving PRRSV control and prevention, but viral antigenic variation undermines the abilities of NAbs elicited by attenuated PRRSV vaccines to confer full protection against heterogeneous PRRSV field isolates. As demonstrated in this study, the monoclonal antibody (mAb) mAb-PN9cx3 exhibited broad-spectrum recognition and neutralizing activities against PRRSV-1 and PRRSV-2 strains in vitro. Furthermore, in vivo experiments revealed that the administration of two 10-mg doses of mAb-PN9cx3 before and after the inoculation of piglets with heterologous PRRSV isolates (HP-PRRSV-JXA1 or PRRSV NADC30-like strain HNhx) resulted in significant reduction of the PRRSV-induced pulmonary pathological changes and virus loads in porcine alveolar macrophages (PAMs) compared with the results obtained with mAb-treated isotype controls. Moreover, minimal hilar lymph node PRRSV antigen levels were observed in mAb-PN9cx3-treated piglets. A transcriptome profile analysis of PAMs extracted from lung tissues of piglets belonging to different groups (except for antibody-isotype controls) indicated that mAb-PN9cx3 treatment reversed the PRRSV infection-induced alterations in expression profiles. A gene ontology (GO) enrichment analysis of these genes traced their functions to pathways that included the immune response, inflammatory response, and response to steroid hormone, and their functions in oogenesis and positive regulation of angiogenesis have been implicated in PRRSV pathogenesis. Overall, NADC30-like HNhx infection affected more gene pathways than HP-PRRSV infection. In conclusion, our research describes a novel immunologic approach involving the use of mAbs that confer cross-protection against serious illness resulting from infection with heterogeneous PRRSV-2 isolates, which is a feat that has not yet been achieved through vaccination. Ultimately, mAb-PN9cx3 will be a powerful addition to our current arsenal for achieving PRRSV prevention and eradication.

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Knockdown of PGM1 Synergistically Enhances Anticancer Effects of Orlistat in Gastric Cancer Under Glucose Deprivation

10.21203/rs.3.rs-650761/v1 ◽

2021 ◽

Author(s):

Bo Cao ◽

Huan Deng ◽

Hao Cui ◽

Ruiyang Zhao ◽

Hanghang Li ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Lipid Metabolism ◽

Fatty Acid Synthase ◽

Enrichment Analysis ◽

Glucose Deprivation ◽

Metabolic Reprogramming ◽

The Cancer Genome Atlas

Abstract Background Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. MethodsCorrelation and enrichment analysis of PGM1 was conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan-Meier Plotter database were analyzed for correlations between PGM1 expression and survival time of GC patients. CCK-8, EdU, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and detection of lipid regulators levels by western blot were used to reflect on the cell lipid metabolism. ResultsCorrelation and enrichment analysis suggested that PGM1 was closely associated with cell proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients, which was also correlated with some clinicopathological features, including T stage and TNM stage. Under low glucose conditions, knockdown of PGM1 significantly suppressed cell proliferation and glycolysis levels, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity for obesity treatment, effectively induced apoptosis, suppressed FASN activity. However, orlistat conversely increased glycolytic levels in GC cells. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism. ConclusionsDownregulation of PGM1 expression under glucose deprivation synergistically enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.

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Bioinformatics-Based Study to Investigate Potential Differentially Expressed Genes and miRNAs in Hashimoto’s Thyroiditis

10.21203/rs.3.rs-1023446/v1 ◽

2021 ◽

Author(s):

Li Guoquan ◽

Du Junwei ◽

He Qi ◽

Fu Xinghao ◽

Ji Feihong ◽

...

Keyword(s):

Gene Expression ◽

Differentially Expressed Genes ◽

Inflammatory Responses ◽

Expression Profiles ◽

Treatment Options ◽

Enrichment Analysis ◽

Differentially Expressed ◽

Pathway Enrichment Analysis ◽

Chronic Lymphocytic Thyroiditis ◽

Hub Genes

Abstract BackgroundHashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, is a common autoimmune disease, which mainly occurs in women. The early manifestation was hyperthyroidism, however, hypothyroidism may occur if HT was not controlled for a long time. Numerous studies have shown that multiple factors, including genetic, environmental, and autoimmune factors, were involved in the pathogenesis of the disease, but the exact mechanisms were not yet clear. The aim of this study was to identify differentially expressed genes (DEGs) by comprehensive analysis and to provide specific insights into HT. MethodsTwo gene expression profiles (GSE6339, GSE138198) about HT were downloaded from the Gene Expression Omnibus (GEO) database. The DEGs were assessed between the HT and normal groups using the GEO2R. The DEGs were then sent to the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The hub genes were discovered using Cytoscape and CytoHubba. Finally, NetworkAnalyst was utilized to create the hub genes' targeted microRNAs (miRNAs). ResultsA total of 62 DEGs were discovered, including 60 up-regulated and 2 down-regulated DEGs. The signaling pathways were mainly engaged in cytokine interaction and cytotoxicity, and the DEGs were mostly enriched in immunological and inflammatory responses. IL2RA, CXCL9, IL10RA, CCL3, CCL4, CCL2, STAT1, CD4, CSF1R, and ITGAX were chosen as hub genes based on the results of the protein-protein interaction (PPI) network and CytoHubba. Five miRNAs, including mir-24-3p, mir-223-3p, mir-155-5p, mir-34a-5p, mir-26b-5p, and mir-6499-3p, were suggested as likely important miRNAs in HT. ConclusionsThese hub genes, pathways and miRNAs contribute to a better understanding of the pathophysiology of HT and offer potential treatment options for HT.

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Identification of Differentially Expressed Genes and associated pathways common to Eyelid and Non-Ocular Basal Cell Carcinoma to understand the Molecular Biology of BCC

10.1101/2021.05.01.442022 ◽

2021 ◽

Author(s):

Perumal Jayaraj ◽

Seema Sen ◽

Pranjal Vats ◽

Shefali Dahiya ◽

Vanshika Mohindroo

Keyword(s):

Basal Cell Carcinoma ◽

Cell Carcinoma ◽

Basal Cell ◽

Expression Profiles ◽

Enrichment Analysis ◽

Bioinformatic Analysis ◽

Malignant Neoplasms ◽

Pathway Enrichment Analysis ◽

Hub Genes ◽

Pathway Enrichment

Background: Eyelid BCC accounts for more than 90% of Eyelid malignant neoplasms. Various aberrant signalling pathways and genes in Non-Ocular BCC have been found whereas Eyelid bcc remains elusive. Objective: This study aims to find the common DEGs of Eyelid and Non-Ocular BCC using bioinformatic analysis and text mining to gain more insights into the molecular aspects common to both BCC non-ocular and Eyelid BCC and to identify common potential prognostic markers. Material and method: The Gene Expression profiles of Eyelid BCC (GSE103439) and Non-Ocular BCC (GSE53462) were obtained from the NCBI GEO database followed by identification of common DEGs. Protein-Protein interaction and Pathway Enrichment analysis of these screened genes was done using bioinformatic tools like STRING, Cytoscape and BiNGO, DAVID, KEGG respectively. Results: A total of 181 genes were found common in both datasets. A PPI network was formed for the screened genes and 20 HUB genes were sorted which included CTNNB1, MAPK14, BTRC, EGFR, ADAM17. Pathway enrichment of HUB genes showed that they were dysregulated in carcinogenic and apoptotic pathways that seem to play a role in the progression of both the BCC. Conclusion: The result and findings of bioinformatic analysis highlighted the molecular pathways and genes enriched in both Eyelid BCC as well as Non- Ocular BCC. The identified pathways should be studied further to recognise common molecular events that would lead to the progression of BCC. This may provide a window to explore the prognostic and therapeutic strategies common to both BCC. Keywords: Basal cell carcinoma (BCC), Cancer, Microarray, Ophthalmology, Tumour marker

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High expression of MCM10 is predictive of poor outcomes in lung adenocarcinoma

PeerJ ◽

10.7717/peerj.10560 ◽

2021 ◽

Vol 9 ◽

pp. e10560

Author(s):

Mingrui Shao ◽

Shize Yang ◽

Siyuan Dong

Keyword(s):

Lung Adenocarcinoma ◽

Complex Disease ◽

Enrichment Analysis ◽

Integrated Approach ◽

Replication Initiation ◽

Prognostic Biomarkers ◽

Normal Lung ◽

Pathway Enrichment Analysis ◽

Therapeutic Value

Backgrounds Lung adenocarcinoma is a complex disease that results in over 1.8 million deaths a year. Recent advancements in treating and managing lung adenocarcinoma have led to modest decreases in associated mortality rates, owing in part to the multifactorial etiology of the disease. Novel prognostic biomarkers are needed to accurately stage the disease and act as the basis of adjuvant treatments. Material and Methods The microarray datasets GSE75037, GSE31210 and GSE32863 were downloaded from the Gene Expression Omnibus (GEO) database to identify prognostic biomarkers for lung adenocarcinoma and therapy. The differentially expressed genes (DEGs) were identified by GEO2R. Functional and pathway enrichment analysis were performed by Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO). Validation was performed based on 72 pairs of lung adenocarcinoma and adjacent normal lung tissues. Results Results showed that the DEGs were mainly focused on cell cycle and DNA replication initiation. Forty-one hub genes were identified and further analyzed by CytoScape. Here, we provide evidence which suggests MCM10 is a potential target with prognostic, diagnostic and therapeutic value. We base this on an integrated approach of comprehensive bioinformatics analysis and in vitro validation using the A549 lung adenocarcinoma cell line. We show that MCM10 overexpression correlates with a poor prognosis, while silencing of this gene decreases aberrant growth by 2-fold. Finally, evaluation of 72 clinical biopsy samples suggests that overexpression of MCM10 in the lung adenocarcinoma highly correlates with larger tumor size. Together, this work suggests that MCM10 may be a clinically relevant gene with both predictive and therapeutic value in lung adenocarcinoma.

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Predicting functional circular RNA-based competitive endogenous RNA network in gastric carcinoma using novel bioinformatics analysis

Experimental Biology and Medicine ◽

10.1177/15353702211048757 ◽

2021 ◽

pp. 153537022110487

Author(s):

Zirui Zhu ◽

Rui Huang ◽

Baojun Huang

Keyword(s):

Messenger Rna ◽

Expression Profiles ◽

Clinical Stage ◽

Interaction Network ◽

Enrichment Analysis ◽

Rank Aggregation ◽

Circular Rnas ◽

Pathway Enrichment Analysis ◽

Hub Genes ◽

Competitive Endogenous Rna

Gastric cancer (GC) remains one of the most prevalent types of malignancies worldwide, and also one of the most reported lethal tumor-related diseases. Circular RNAs (circRNAs) have been certified to be trapped in multiple aspects of GC pathogenesis. Yet, the mechanism of this regulation is mostly undefined. This research is designed to discover the vital circRNA-microRNA (miRNA)-messenger RNA (mRNA) regulatory network in GC. Expression profiles with diverse levels including circRNAs, miRNAs, and mRNAs were all determined using microarray public datasets from Gene Expression Ominous (GEO). The differential circRNAs expressions were recognized against the published robust rank aggregation algorithm. Besides, a circRNA-based competitive endogenous RNA (ceRNA) interaction network was visualized via Cytoscape software (version 3.8.0). Functional and pathway enrichment analysis associated with differentially expressed targeted mRNAs were conducted using Cytoscape and an online bioinformatics database. Furthermore, an interconnected protein–protein interaction association network which consisted of 51 mRNAs was predicted, and hub genes were screened using STRING and CytoHubba. Then, several hub genes were chosen to explore their expression associated with survival rate and clinical stage in GEPIA and Kaplan-Meier Plotter databases. Finally, a carefully designed circRNA-related ceRNA regulatory subnetwork including four circRNAs, six miRNAs, and eight key hub genes was structured using the online bioinformatics tool.

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The Role of PAX2 in Breast Cancer: A Study Based on Bioinformatics Analysis and in Vitro Validation

10.21203/rs.3.rs-738037/v1 ◽

2021 ◽

Author(s):

Shan Yang ◽

Wei Gao ◽

Haoqi Wang ◽

Xi Zhang ◽

Yunzhe Mi ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Expression Profiles ◽

Enrichment Analysis ◽

Mapk Signaling ◽

Gene Set Enrichment Analysis ◽

Functional Enrichment ◽

Migration And Invasion ◽

Clinical Samples

Abstract Background: Breast cancer (BC) is the most frequently diagnosed cancer in women and is the second most common cancer among newly diagnosed cancers worldwide. Studies have shown that paired box 2 (PAX2) participates in the tumorigenesis of some cancer cells. However, the functions of PAX2 in the BC context are still unclear.Methods: Transcriptome expression proﬁles and clinicopathological information of BC were download from the TCGA database. Then the expression level and prognostic value in TCGA database were explored. Gene Set Enrichment Analysis (GSEA) and functional enrichment analysis were performed to investigate the functions and pathways of PAX2. Moreover, RT-qPCR was used to determine the expression of PAX2 in BC tissues, and the predictive value of PAX2 in clinical samples was assessed. CCK-8 assay was used to evaluate cell growth. The migration and invasion capacities of cells were assessed by wound healing assay and Transwell assay.Results: PAX2 was up-regulated in the TCGA-BC datasets. GSEA analysis suggested that PAX2 might be involved in the regulation of MAPK signaling pathways and so on. Moreover, PAX2 was overexpressed in BC tissues, and PAX2 expression was associated with menopause. PAX2 deficiency could inhibit the growth, migration, and invasion of BC cells.Conclusion: This study suggested that PAX2 was up-regulated in BC, which inhibited BC cell growth, migration, and invasion. Thus, PAX2 could be a potential therapeutic target for BC.

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In Silico Discovery of Candidate Drugs against Covid-19

Viruses ◽

10.3390/v12040404 ◽

2020 ◽

Vol 12 (4) ◽

pp. 404 ◽

Cited By ~ 42

Author(s):

Claudia Cava ◽

Gloria Bertoli ◽

Isabella Castiglioni

Keyword(s):

Gene Expression ◽

In Silico ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Interaction Network ◽

Enrichment Analysis ◽

Basic Mechanism ◽

Cell Receptor ◽

The Cancer Genome Atlas ◽

Pathway Enrichment Analysis

Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.

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Connecting gene expression subtypes of colorectal cancer (CRC) with cell lines and drug resistance.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14544 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14544-e14544

Author(s):

Eva Budinska ◽

Jenny Wilding ◽

Vlad Calin Popovici ◽

Edoardo Missiaglia ◽

Arnaud Roth ◽

...

Keyword(s):

Gene Expression ◽

Cell Line ◽

Clinical Significance ◽

Cell Lines ◽

Drug Response ◽

Drug Sensitivity ◽

Expression Profiles ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis

e14544 Background: We identified CRC gene expression subtypes (ASCO 2012, #3511), which associate with established parameters of outcome as well as relevant biological motifs. We now substantiate their biological and potentially clinical significance by linking them with cell line data and drug sensitivity, primarily attempting to identify models for the poor prognosis subtypes Mesenchymal and CIMP-H like (characterized by EMT/stroma and immune-associated gene modules, respectively). Methods: We analyzed gene expression profiles of 35 publicly available cell lines with sensitivity data for 82 drug compounds, and our 94 cell lines with data on sensitivity for 7 compounds and colony morphology. As in vitro, stromal and immune-associated genes loose their relevance, we trained a new classifier based on genes expressed in both systems, which identifies the subtypes in both tissue and cell cultures. Cell line subtypes were validated by comparing their enrichment for molecular markers with that of our CRC subtypes. Drug sensitivity was assessed by linking original subtypes with 92 drug response signatures (MsigDB) via gene set enrichment analysis, and by screening drug sensitivity of cell line panels against our subtypes (Kruskal-Wallis test). Results: Of the cell lines 70% could be assigned to a subtype with a probability as high as 0.95. The cell line subtypes were significantly associated with their KRAS, BRAF and MSI status and corresponded to our CRC subtypes. Interestingly, the cell lines which in matrigel created a network of undifferentiated cells were assigned to the Mesenchymal subtype. Drug response studies revealed potential sensitivity of subtypes to multiple compounds, in addition to what could be predicted based on their mutational profile (e.g. sensitivity of the CIMP-H subtype to Dasatinib, p<0.01). Conclusions: Our data support the biological and potentially clinical significance of the CRC subtypes in their association with cell line models, including results of drug sensitivity analysis. Our subtypes might not only have prognostic value but might also be predictive for response to drugs. Subtyping cell lines further substantiates their significance as relevant model for functional studies.

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