scholarly journals The Angiostrongylus vasorum Excretory/Secretory and Surface Proteome Contains Putative Modulators of the Host Coagulation

2021 ◽  
Vol 11 ◽  
Author(s):  
Nina Gillis-Germitsch ◽  
Tobias Kockmann ◽  
Lars M. Asmis ◽  
Lucienne Tritten ◽  
Manuela Schnyder
Keyword(s):  
Parasitic Infection ◽  
Enrichment Analysis ◽  
Surface Proteins ◽  
Angiostrongylus Vasorum ◽  
Secretory Proteins ◽  
Pathway Enrichment Analysis ◽  
Type D ◽  
Factor Type ◽  
Coagulation And Fibrinolysis

Angiostrongylus vasorum is a cardiopulmonary nematode of canids and is, among others, associated with bleeding disorders in dogs. The pathogenesis of such coagulopathies remains unclear. A deep proteomic characterization of sex specific A. vasorum excretory/secretory proteins (ESP) and of cuticular surface proteins was performed, and the effect of ESP on host coagulation and fibrinolysis was evaluated in vitro. Proteins were quantified by liquid chromatography coupled to mass spectrometry and functionally characterized through gene ontology and pathway enrichment analysis. In total, 1069 ESP (944 from female and 959 from male specimens) and 1195 surface proteins (705 and 1135, respectively) were identified. Among these were putative modulators of host coagulation, e.g., von Willebrand factor type D domain protein orthologues as well as several proteases, including serine type proteases, protease inhibitors and proteasome subunits. The effect of ESP on dog coagulation and fibrinolysis was evaluated on canine endothelial cells and by rotational thromboelastometry (ROTEM). After stimulation with ESP, tissue factor and serpin E1 transcript expression increased. ROTEM revealed minimal interaction of ESP with dog blood and ESP did not influence the onset of fibrinolysis, leading to the conclusion that Angiostrongylus vasorum ESP and surface proteins are not solely responsible for bleeding in dogs and that the interaction with the host’s vascular hemostasis is limited. It is likely that coagulopathies in A. vasorum infected dogs are the result of a multifactorial response of the host to this parasitic infection.

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

PeerJ ◽  
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.

scholarly journals Decoding molecular markers and transcriptional circuitry of naive and primed states of human pluripotency

2020 ◽  
Author(s):  
Arindam Ghosh ◽  
Anup Som
Keyword(s):  
Transcription Factors ◽  
Molecular Mechanisms ◽  
System Development ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
List Type ◽  
Metabolic Processes ◽  
Primed State

ABSTRACTPluripotent stem cells (PSCs) have been observed to occur in two distinct states — naive and primed. Both naive and primed state PSCs can give rise to tissues of all the three germ layers in vitro but differ in their potential to generate germline chimera in vivo. Understanding the molecular mechanisms that govern these two states of pluripotency in human can open up a plethora of opportunities for studying early embryonic development and in biomedical applications. In this work, we use weighted gene co-expression network (WGCN) approach to identify the key molecular makers and their interactions that define the two distinct pluripotency states. Signed-hybrid WGCN was reconstructed from transcriptomic data (RNA-seq) of naive and primed state pluripotent samples. Our analysis revealed two sets of genes that are involved in establishment and maintenance of naive (4791 genes) and primed (5066 genes) states. The naive state genes were found to be enriched for biological processes and pathways related to metabolic processes while primed state genes were associated with system development. Further, we identified the top 10% genes by intra-modular connectivity as hubs and the hub transcription factors for each group, thus providing a three-tier list of genes associated with naive and primed states of pluripotency in human.HIGHLIGHTSWeighted gene co-expression network analysis (WGCNA) identified 4791 and 5066 genes to be involved in naive and primed states of human pluripotency respectively.Functional and pathway enrichment analysis revealed the naive genes were mostly related to metabolic processes and primed genes to system development.The top 10% genes based on intra-modular connectivity from each group were defined as hubs.Identified 52 and 33 transcription factors among the naive and primed module hubs respectively.The transcription factors might play a switch on-off mechanism in induction of the two pluripotent states.

scholarly journals A genome-wide screen for human salicylic acid (SA)-binding proteins reveals targets through which SA may influence development of various diseases

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hyong Woo Choi ◽  
Lei Wang ◽  
Adrian F. Powell ◽  
Susan R. Strickler ◽  
Dekai Wang ◽  
...  
Keyword(s):  
Salicylic Acid ◽  
Binding Proteins ◽  
Enrichment Analysis ◽  
Hek293 Cells ◽  
Pathway Enrichment Analysis ◽  
Genome Wide ◽  
Glycolytic Activity ◽  
A Genome ◽  
Human Disorder

Abstract Salicylic acid (SA) is the major metabolite and active ingredient of aspirin; both compounds reduce pain, fever, and inflammation. Despite over a century of research, aspirin/SA’s mechanism(s) of action is still only partially understood. Here we report the results of a genome-wide, high-throughput screen to identify potential SA-binding proteins (SABPs) in human HEK293 cells. Following photo-affinity crosslinking to 4-azidoSA and immuno-selection with an anti-SA antibody, approximately 2,000 proteins were identified. Among these, 95 were enriched more than 10-fold. Pathway enrichment analysis with these 95 candidate SABPs (cSABPs) revealed possible involvement of SA in multiple biological pathways, including (i) glycolysis, (ii) cytoskeletal assembly and/or signaling, and (iii) NF-κB-mediated immune signaling. The two most enriched cSABPs, which corresponded to the glycolytic enzymes alpha-enolase (ENO1) and pyruvate kinase isozyme M2 (PKM2), were assessed for their ability to bind SA and SA’s more potent derivative amorfrutin B1 (amoB1). SA and amoB1 bound recombinant ENO1 and PKM2 at low millimolar and micromolar concentrations, respectively, and inhibited their enzymatic activities in vitro. Consistent with these results, low millimolar concentrations of SA suppressed glycolytic activity in HEK293 cells. To provide insights into how SA might affect various human diseases, a cSABP-human disorder/disease network map was also generated.

scholarly journals A System Pharmacology Model for Decoding the Synergistic Mechanisms of Compound Kushen Injection in Treating Breast Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi Li ◽  
Kexin Wang ◽  
Yupeng Chen ◽  
Jieqi Cai ◽  
Xuemei Qin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Malignant Tumors ◽  
Differentially Expressed Gene ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Active Components ◽  
System Pharmacology ◽  
Compound Kushen Injection

Breast cancer (BC) is one of the most common malignant tumors among women worldwide and can be treated using various methods; however, side effects of these treatments cannot be ignored. Increasing evidence indicates that compound kushen injection (CKI) can be used to treat BC. However, traditional Chinese medicine (TCM) is characterized by “multi-components” and “multi-targets”, which make it challenging to clarify the potential therapeutic mechanisms of CKI on BC. Herein, we designed a novel system pharmacology strategy using differentially expressed gene analysis, pharmacokinetics synthesis screening, target identification, network analysis, and docking validation to construct the synergy contribution degree (SCD) and therapeutic response index (TRI) model to capture the critical components responding to synergistic mechanisms of CKI in BC. Through our designed mathematical models, we defined 24 components as a high contribution group of synergistic components (HCGSC) from 113 potentially active components of CKI based on ADME parameters. Pathway enrichment analysis of HCGSC targets indicated that Rhizoma Heterosmilacis and Radix Sophorae Flavescentis could synergistically target the PI3K-Akt signaling pathway and the cAMP signaling pathway to treat BC. Additionally, TRI analysis showed that the average affinity of HCGSC and targets involved in the key pathways reached -6.47 kcal/mmol, while in vitro experiments proved that two of the three high TRI-scored components in the HCGSC showed significant inhibitory effects on breast cancer cell proliferation and migration. These results demonstrate the accuracy and reliability of the proposed strategy.

scholarly journals Combination of Systems Pharmacology and Experimental Evaluation to Explore the Mechanism of Synergistic Action of Frankincense-Myrrh in the Treatment of Cerebrovascular Diseases

2022 ◽  
Vol 12 ◽  
Author(s):  
Yucheng Liao ◽  
Jingwen Wang ◽  
Chao Guo ◽  
Min Bai ◽  
Bowei Ju ◽  
...  
Keyword(s):  
Target Genes ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Blood Stasis ◽  
Enrichment Analysis ◽  
Cerebrovascular Diseases ◽  
Pathway Enrichment Analysis ◽  
Systems Pharmacology

Frankincense-Myrrh is a classic drug pair that promotes blood circulation, and eliminates blood stasis. The combination of the two drugs has a definite clinical effect on the treatment of cerebrovascular diseases (CBVDs), but its mechanism of action and compatibility have not been elucidated. In this study, the bioactive components, core targets, and possible synergistic mechanisms of Frankincense-Myrrh in the treatment of CBVDs are explored through systems pharmacology combined with in vivo and in vitro experiments. Comparing target genes of components in Frankincense and Myrrh with CBVD-related genes, common genes were identified; 15 core target genes of Frankincense-Myrrh for the treatment of CBVDs were then identified using protein-protein interaction (PPI) analysis. It was also predicted through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis that the molecular mechanism of Frankincense-Myrrh action on CBVDs was mainly related to the regulation of neurotrophic factors and inflammatory responses. Frankincense-Myrrh significantly improved neurological function, decreased infarct volume, alleviated histopathological damage, inhibited microglial expression, and promoted the expression of neurons in middle cerebral artery occlusion (MCAO)-induced rats. The results of this study not only provide important theoretical support and experimental basis for the synergistic effect of Frankincense-Myrrh, but also provide new ideas for the prevention and treatment of cerebral ischemic injuries.

scholarly journals Network Pharmacology-Based Prediction of the Active Ingredients and Potential Targets of Chinese Herbal Danyu Gukang Pills for Application to Osteonecrosis of the Femoral Head Disease

2021 ◽  
Author(s):  
Yongchang Guo ◽  
Dapeng Zhang ◽  
Yuju Cao ◽  
Xiaoyan Feng ◽  
Caihong Shen ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Femoral Head ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
In Vitro Experiments ◽  
Active Components

Abstract Ethnopharmacological relevanceOsteonecrosis of the femoral head (ONFH) is still a challenge for orthopedists worldwide, which may lead to disability in patients without effective treatment. A newly developed formula of Chinese medicine, Danyu Gukang Pills (DGP), was recognized to be effective for ONFH. Nevertheless, its molecular mechanisms remain to be clarified. MethodsNetwork pharmacology was adopted to detect the mechanism of DGP on ONFH. The compounds of DGP were collected from the online databases, and active components were selected based on their OB and DL index. The potential proteins of DGP were acquired from TCMSP database, while the potential genes of ONFH were obtained from Gene Cards and Pubmed Gene databases. The function of Gene and potential pathways were researched by GO and KEGG pathway enrichment analysis. The compounds-targets and targets-pathways network were constructed in an R and Cytosacpe software. The mechanism was further investigated via molecular docking. Finally, in-vitro experiments were validated in the BMSCs. ResultsA total of 2305 compounds in DGP were gained, among which, 370 were selected as active components for which conforming to criteria. Combined the network analysis, molecular docking and in-vitro experiments, the results firstly demonstrated that the treatment effect of DGP on ONFH may be closely related to HIF-1α, VEGFA and HIF-1 signaling pathway. ConclusionThe current study firstly researched the molecular mechanism of DGP on ONFH based on network pharmacology. The results indicated that DGP may exert the effect on ONFH targeting on HIF-1α and VEGFA via HIF-1 signaling pathway.

scholarly journals Identification of FEZ2 as a potential oncogene in pancreatic ductal adenocarcinoma

PeerJ ◽  
2022 ◽  
Vol 9 ◽  
pp. e12736
Author(s):  
Chaozhi Yang ◽  
Xuebing Wang ◽  
Chenjie Qiu ◽  
Ziruo Zheng ◽  
Kai Lin ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Malignant Tumors ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Pathway Enrichment Analysis ◽  
Conserved Gene

Pancreatic ductal adenocarcinoma (PDAC) is one of the common malignant tumors with high lethal rate and poor prognosis. Dysregulation of many genes have been reported to be involved in the occurrence and development of PDAC. However, as a highly conserved gene in eukaryotes, the role of Fasciculation and Elongation protein Zeta 2 (FEZ2) in pancreatic cancer progression is not clear. In this study, we identified the oncogenic effect of FEZ2 on PDAC. By mining of The Cancer Genome Atlas (TCGA) database, we found that FEZ2 was upregulated in PDAC tissues and FEZ2 expression was negatively regulated by its methylation. Moreover, high expression and low methylation of FEZ2 correlated with poor prognosis in PDAC patients. Besides, we found that FEZ2 could promote PDAC cells proliferation, migration and 5-FU resistance in vitro. Furthermore, Gene pathway enrichment analysis demonstrated a positive correlation between Wnt signaling activation and FEZ2 expression in PDAC patients. Western blot showed that FEZ2 knockdown significantly suppressed β-catenin expression. Collectively, our finding revealed that FEZ2 functioned as a potential oncogene on PDAC progression and migration, and the expression of FEZ2 had guidance value for the treatment and chemotherapy program of PDAC patients.

scholarly journals Upregulation of FEN1 Is Associated with the Tumor Progression and Prognosis of Hepatocellular Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Yingying Zhang ◽  
Xin Liu ◽  
Liwen Liu ◽  
Jianan Chen ◽  
Qiuyue Hu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Cox Regression ◽  
Malignant Tumors ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Functional Roles ◽  
Protein Levels ◽  
And Migration

Background. Studies show that patients with hepatocellular carcinoma (HCC) have poor prognosis, particularly when patients are diagnosed at late stages of the disease development. The flap endonuclease 1 (FEN1) gene is overexpressed in multiple malignant tumors and may promote tumor aggressiveness. However, its expression profile and functional roles in HCC are still unclear. Here, we evaluated the molecular mechanisms of FEN1 in HCC. Methods. The expression of FEN1 in HCC was evaluated using HCC mRNA expression data from TCGA and GEO databases. The expression of FEN1 was also confirmed by immunohistochemistry (IHC) using a tissue microarray (TMA) cohort with a total of 396 HCC patients. Kaplan-Meier analysis and univariate and multivariate Cox regression analyses were used to determine the correlation between FEN1 expression and survival rate of HCC patients. The molecular mechanism and biological functions of FEN1 in HCC were predicted using functional and pathway enrichment analysis in vitro experiments. Results. FEN1 was overexpressed in multiple HCC cohorts at both mRNA and protein levels. The receiver operating characteristic (ROC) curve showed that FEN1 can serve as a diagnostic predictor of HCC. Meanwhile, patients with high FEN1 expression levels showed lower overall survival (OS) and relapse-free survival (RFS) rates than those with low FEN1 expression. More importantly, we found that FEN1 elevation was an independent prognostic factor for OS and RFS in HCC patients based on univariate and multivariate analyses, indicating that FEN1 might be a potential prognostic marker in HCC. Furthermore, knocking down FEN1 resulted in suppressed cell proliferation and migration in vitro. This could have been due to regulation expressions of c-Myc, survivin, and cyclin D1 genes, indicating that FEN1 may function as an oncogene through its role in the cell cycle and DNA replication pathway. Conclusion. Our study indicated that high FEN1 expression might function as a biomarker for diagnosis and prognosis. In addition, the study confirms that FEN1 is an oncogene in HCC progression.

scholarly journals Attachment Ligands of Viable Toxoplasma gondii Induce Soluble Immunosuppressive Factors in Human Monocytes

1999 ◽  
Vol 67 (5) ◽  
pp. 2547-2551 ◽  
Author(s):  
Jacqueline Y. Channon ◽  
Edward I. Suh ◽  
Rosanne M. Seguin ◽  
Lloyd H. Kasper
Keyword(s):  
Toxoplasma Gondii ◽  
Surface Antigen ◽  
Marked Decrease ◽  
In Vitro Assay ◽  
Surface Proteins ◽  
Secretory Proteins ◽  
Human Monocytes ◽  
Vitro Assay ◽  
Monocyte Cell

ABSTRACT Previous studies have demonstrated that surface antigen proteins, in particular SAG-1, of Toxoplasma gondii are important to this parasite as attachment ligands for the host cell. An in vitro assay was developed to test whether these ligands and other secretory proteins are involved in the immune response of human cells to toxoplasma. Human monocytes were infected with tachyzoites in the presence of antiparasite antibodies, and their effect on mitogen-induced lymphoproliferation was examined. The presence of antibody to either parasite-excreted proteins (MIC-1 and MIC-2) or surface proteins (SAG-1 and SAG-2) during infection neutralized the marked decrease seen in mitogen-induced lymphoproliferation in the presence of infected monocytes. Conversely, antibodies to other secreted proteins (ROP-1) and cytoplasmic molecules had no effect on parasite-induced, monocyte-mediated downregulation. Fluorescence microscope analysis detected microneme and surface antigen proteins on the monocyte cell surface during infection. These results suggest that microneme and surface antigen proteins trigger monocytes to downregulate mitogen-induced lymphoproliferation.

scholarly journals Transcriptome Profiling of Atlantic Salmon Adherent Head Kidney Leukocytes Reveals That Macrophages Are Selectively Enriched During Culture

2021 ◽  
Vol 12 ◽  
Author(s):  
Nicole C. Smith ◽  
Navaneethaiyer Umasuthan ◽  
Surendra Kumar ◽  
Nardos T. Woldemariam ◽  
Rune Andreassen ◽  
...  
Keyword(s):  
Atlantic Salmon ◽  
Target Prediction ◽  
Head Kidney ◽  
Enrichment Analysis ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Pathway Enrichment Analysis ◽  
In The Wild ◽  
And Function

The Atlantic salmon (Salmo salar) is an economically important fish, both in aquaculture and in the wild. In vertebrates, macrophages are some of the first cell types to respond to pathogen infection and disease. While macrophage biology has been characterized in mammals, less is known in fish. Our previous work identified changes in the morphology, phagocytic ability, and miRNA profile of Atlantic salmon adherent head kidney leukocytes (HKLs) from predominantly “monocyte-like” at Day 1 of in vitro culture to predominantly “macrophage-like” at Day 5 of culture. Therefore, to further characterize these two cell populations, we examined the mRNA transcriptome profile in Day 1 and Day 5 HKLs using a 44K oligonucleotide microarray. Large changes in the transcriptome were revealed, including changes in the expression of macrophage and immune-related transcripts (e.g. csf1r, arg1, tnfa, mx2), lipid-related transcripts (e.g. fasn, dhcr7, fabp6), and transcription factors involved in macrophage differentiation and function (e.g. klf2, klf9, irf7, irf8, stat1). The in silico target prediction analysis of differentially expressed genes (DEGs) using miRNAs known to change expression in Day 5 HKLs, followed by gene pathway enrichment analysis, supported that these miRNAs may be involved in macrophage maturation by targeting specific DEGs. Elucidating how immune cells, such as macrophages, develop and function is a key step in understanding the Atlantic salmon immune system. Overall, the results indicate that, without the addition of exogenous factors, the adherent HKL cell population differentiates in vitro to become macrophage-like.

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