Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets.
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ABSTRACT:
SUBMITTER: Nguyen A
PROVIDER: S-EPMC6121942 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Adrenocortical carcinoma (ACC) is a rare aggressive tumor with poor prognosis when metastatic at diagnosis. The tumor biology is still mostly unclear, justifying the limited specificity and efficacy of the anti-cancer drugs currently available. This study reports the first proteomic analysis of ACC by using two-dimensional-differential-in-gel-electrophoresis (2D-DIGE) to evaluate a differential protein expression profile between adrenocortical carcinoma and normal adrenal. Mass spectrometry, associated with 2D-DIGE analysis of carcinomas and normal adrenals, identified 22 proteins in 27 differentially expressed 2D spots, mostly overexpressed in ACC. Gene ontology analysis revealed that most of the proteins concurs towards a metabolic shift, called the Warburg effect, in adrenocortical cancer. The differential expression was validated by Western blot for Aldehyde-dehydrogenase-6-A1,Transferrin, Fascin-1,Lamin A/C,Adenylate-cyclase-associated-protein-1 and Ferredoxin-reductase. Moreover, immunohistochemistry performed on paraffin-embedded ACC and normal adrenal specimens confirmed marked positive staining for all 6 proteins diffusely expressed by neoplastic cells, compared with normal adrenal cortex.In conclusion, our preliminary findings reveal a different proteomic profile in adrenocortical carcinoma compared with normal adrenal cortex characterized by overexpression of mainly metabolic enzymes, thus suggesting the Warburg effect also occurs in ACC. These proteins may represent promising novel ACC biomarkers and potential therapeutic targets if validated in larger cohorts of patients.
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Project description:Therapies directed against receptor tyrosine kinases are effective in many cancer subtypes, including lung and breast cancer. We used a phosphoproteomic platform to identify active receptor tyrosine kinases that might represent therapeutic targets in a panel of 25 melanoma cell strains. We detected activated receptors including TYRO3, AXL, MERTK, EPHB2, MET, IGF1R, EGFR, KIT, HER3, and HER4. Statistical analysis of receptor tyrosine kinase activation as well as ligand and receptor expression indicates that some receptors, such as FGFR3, may be activated via autocrine circuits. Short hairpin RNA knockdown targeting three of the active kinases identified in the screen, AXL, HER3, and IGF1R, inhibited the proliferation of melanoma cells and knockdown of active AXL also reduced melanoma cell migration. The changes in cellular phenotype observed on AXL knockdown seem to be modulated via the STAT3 signaling pathway, whereas the IGF1R-dependent alterations seem to be regulated by the AKT signaling pathway. Ultimately, this study identifies several novel targets for therapeutic intervention in melanoma.
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Project description:ObjectiveAlcoholic hepatitis (AH) is a severe clinical condition that needs novel therapies. The identification of targets for therapy is hampered by the lack of animal models of advanced AH. The authors performed a translational study through a transcriptome analysis in patients with AH to identify new molecular targets.DesignHepatic gene expression profiling was assessed by DNA microarray in patients with AH (n=15) and normal livers (n=7). Functional analysis was assessed by gene set enrichment analysis. Quantitative PCR was performed in patients with AH (n=40), hepatitis C (n=18), non-alcoholic steatohepatitis (n=20) and in mouse models of acute and chronic liver injury. Protein expression was assessed by immunohistochemistry and western blotting.ResultsGene expression analysis showed 207 genes >5-fold differentially expressed in patients with AH and revealed seven pathways differentially regulated including 'cytokine-cytokine receptor interaction'. Several tumour necrosis factor (TNF) superfamily receptors, but not ligands, were overexpressed in AH. Importantly, Fn14 was the only TNF superfamily receptor exclusively upregulated in AH compared with other liver diseases and correlated with both 90-day mortality and severity of portal hypertension. Fn14 protein expression was detected in areas of fibrogenesis and in a population of hepatocytes. Fn14 expression was increased in experimental models of liver injury and was detected in progenitor cells.ConclusionTranslational research revealed that TNF superfamily receptors are overexpressed in AH. Fn14, the receptor for TNF-like weak inducer of apoptosis, is selectively upregulated in patients with AH. TNF superfamily receptors could represent a potential target for therapy.
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Project description:Retinal pigment epithelium (RPE) is an important component of the outer blood-retinal barrier and plays a critical role in maintaining retinal homeostasis. Alterations in RPE can be detected during the early stages of diabetic retinopathy (DR). However, the molecular mechanisms underlying these early changes remain unclear. We investigated the molecular changes induced in the RPE by high glucose concentrations by constructing a high glucose-induced ARPE-19 cell injury model simulating the DR environment in vitro. Proteomic analysis was conducted to measure differences in protein expression between cells treated with normal (5 mM) and high (25 mM) glucose concentrations, and bioinformatics techniques were used to analyze the mechanism of action. The results of the proteomic analyses were validated using western blotting. High glucose levels inhibited the proliferation of ARPE-19 cells. We identified 88 upregulated proteins and 114 downregulated proteins. Six of these proteins were selected for further validation. Changes in the proteome mainly affected the lysosome and cell cycle pathways. Proteomic differences between ARPE-19 cells treated with normal and high glucose concentrations indicate that damage to the RPE in DR may be caused by specific mechanisms. Our study verified protein changes in ARPE-19 cells in a high-glucose environment and may provide new strategies for understanding the molecular mechanisms underlying DR.
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Project description:Although many host factors important for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported, the mechanisms by which the virus interacts with host cells remain elusive. Here, we identified tripartite motif containing (TRIM) 28, TRIM33, euchromatic histone lysine methyltransferase (EHMT) 1, and EHMT2 as proviral factors involved in SARS-CoV-2 infection by CRISPR-Cas9 screening. Our result suggested that TRIM28 may play a role in viral particle formation and that TRIM33, EHMT1, and EHMT2 may be involved in viral transcription and replication. UNC0642, a compound that specifically inhibits the methyltransferase activity of EHMT1/2, strikingly suppressed SARS-CoV-2 growth in cultured cells and reduced disease severity in a hamster infection model. This study suggests that EHMT1/2 may be a therapeutic target for SARS-CoV-2 infection.
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Project description:Respiratory viruses are transmitted and acquired via the nasal mucosa, and thereby may influence the nasal metabolome composed of biochemical products produced by both host cells and microbes. Studies of the nasal metabolome demonstrate virus-specific changes that sometimes correlate with viral load and disease severity. Here, we evaluate the nasopharyngeal metabolome of COVID-19 infected individuals and report several small molecules that may be used as potential therapeutic targets. Specimens were tested by qRT-PCR with target primers for three viruses: Influenza A (INFA), respiratory syncytial virus (RSV), and SARS-CoV-2, along with unaffected controls. The nasopharyngeal metabolome was characterized using an LC-MS/MS-based screening kit capable of quantifying 141 analytes. A machine learning model identified 28 discriminating analytes and correctly categorized patients with a viral infection with an accuracy of 96% (R2 = 0.771, Q2 = 0.72). A second model identified 5 analytes to differentiate COVID19-infected patients from those with INFA or RSV with an accuracy of 85% (R2 = 0.442, Q2 = 0.301). Specifically, Lysophosphatidylcholines-a-C18:2 (LysoPCaC18:2) concentration was significantly increased in COVID19 patients (P < 0.0001), whereas beta-hydroxybutyric acid, Methionine sulfoxide, succinic acid, and carnosine concentrations were significantly decreased (P < 0.0001). This study demonstrates that COVID19 infection results in a unique nasopharyngeal metabolomic signature with carnosine and LysoPCaC18:2 as potential therapeutic targets.
| S-EPMC9200216 | biostudies-literature
Project description:Despite advances in management, bladder cancer remains a major cause of cancer related complications. Characterisation of gene expression patterns in bladder cancer allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Hypergeometric analysis was used to identify canonical pathways and curated networks having statistically significant enrichment of differentially expressed genes. Osteopontin (OPN) expression was validated by immunohistochemistry. Hierarchical clustering defined signatures, which differentiated between cancer and healthy tissue, muscle-invasive or non-muscle invasive cancer and healthy tissue, grade 1 and grade 3. Pathways associated with cell cycle and proliferation were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer compared to healthy tissue. The present study contributes to a growing body of work on gene expression signatures in bladder cancer. The data support an important role for osteopontin in bladder cancer, and identify several pathways worthy of further investigation.
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Project description:BackgroundSepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI).MethodsTwo gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI.ResultsWe identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future.ConclusionsSeptic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.
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Project description:BackgroundCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a pandemic in many countries around the world. The virus is highly contagious and has a high fatality rate. Lung adenocarcinoma (LUAD) patients may have higher susceptibility and mortality to COVID-19. While Paxlovid is the first oral drug approved by the U.S. Food and Drug Administration (FDA) for COVID-19, its specific drug mechanism for lung cancer patients infected with COVID-19 remains to be further studied.MethodsCOVID-19 related genes were obtained from NCBI, GeneCards, and KEGG, and then the transcriptome data for LUAD was downloaded from TCGA. The drug targets of Paxlovid were revealed through BATMAN-TCM, DrugBank, SwissTargetPrediction, and TargetNet. The genes related to susceptibility to COVID-19 in LUAD patients were obtained through differential analysis. The interaction of LUAD/COVID-19 related genes was evaluated and displayed by STRING, and a COX risk regression model was established to screen and evaluate the correlation between genes and clinical characteristics. The Venn diagram was drawn to select the candidate targets of Paxlovid against LUAD/COVID-19, and the functional analysis of the target genes was performed using KEGG and GO enrichment analysis. Finally, Cytoscape was used to screen and visualize the Hub Gene, and Autodock was used for molecular docking between the drug and the target.ResultBioinformatics analysis was performed by combining COVID-19-related genes with the gene expression and clinical data of LUAD, including analysis of prognosis-related genes, survival rate, and hub genes screened out by the prognosis model. The key targets of Paxlovid against LUAD/COVID-19 were obtained through network pharmacology, the most important targets include IL6, IL12B, LBP. Furthermore, pathway analysis showed that Paxlovid modulates the IL-17 signaling pathway, the cytokine-cytokine receptor interaction, during LUAD/COVID-19 treatment.ConclusionsBased on bioinformatics and network pharmacology, the prognostic signature of LUAD/COVID-19 patients was screened. And identified the potential therapeutic targets and molecular pathways of Paxlovid Paxlovid in the treatment of LUAD/COVID. As promising features, prognostic signatures and therapeutic targets shed light on improving the personalized management of patients with LUAD.
| S-EPMC9493477 | biostudies-literature
Project description:SARS-CoV-2 is the causative agent behind the COVID-19 pandemic, responsible for over 170 million infections, and over 3.7 million deaths worldwide. Efforts to test, treat and vaccinate against this pathogen all benefit from an improved understanding of the basic biology of SARS-CoV-2. Both viral and cellular proteases play a crucial role in SARS-CoV-2 replication. Here, we study proteolytic cleavage of viral and cellular proteins in two cell line models of SARS-CoV-2 replication using mass spectrometry to identify protein neo-N-termini generated through protease activity. We identify previously unknown cleavage sites in multiple viral proteins, including major antigens S and N: the main targets for vaccine and antibody testing efforts. We discover significant increases in cellular cleavage events consistent with cleavage by SARS-CoV-2 main protease, and identify 14 potential high-confidence substrates of the main and papain-like proteases. We show that siRNA depletion of these cellular proteins inhibits SARS-CoV-2 replication, and that drugs targeting two of these proteins: the tyrosine kinase SRC and Ser/Thr kinase MYLK, show a dose-dependent reduction in SARS-CoV-2 titres. Overall, our study provides a powerful resource to understand proteolysis in the context of viral infection, and to inform the development of targeted strategies to inhibit SARS-CoV-2 and treat COVID-19.
| S-EPMC8455558 | biostudies-literature