1H NMR-Based Analysis of Serum Metabolites in Monocrotaline-Induced Pulmonary Arterial Hypertensive Rats

Aims. To study the changes of the metabolic profile during the pathogenesis in monocrotaline (MCT) induced pulmonary arterial hypertension (PAH).Methods. Forty male Sprague-Dawley (SD) rats were randomly divided into 5 groups (n=8, each). PAH rats were induced by a single dose intraperitoneal injection of 60 mg/kg MCT, while 8 rats given intraperitoneal injection of 1 ml normal saline and scarified in the same day (W0) served as control. Mean pulmonary arterial pressure (mPAP) was measured through catherization. The degree of right ventricular hypertrophy and pulmonary hyperplasia were determined at the end of first to fourth weeks; nuclear magnetic resonance (NMR) spectra of sera were then acquired for the analysis of metabolites. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) were used to discriminate different metabolic profiles.Results. The prominent changes of metabolic profiles were seen during these four weeks. Twenty specific metabolites were identified, which were mainly involved in lipid metabolism, glycolysis, energy metabolism, ketogenesis, and methionine metabolism. Profiles of correlation between these metabolites in each stage changed markedly, especially in the fourth week. Highly activated methionine and betaine metabolism pathways were selected by the pathway enrichment analysis.Conclusions. Metabolic dysfunction is involved in the development and progression of PAH.

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Metabonomic-Transcriptome Integration Analysis on Osteoarthritis and Rheumatoid Arthritis

International Journal of Genomics ◽

10.1155/2020/5925126 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Ningyang Gao ◽

Li Ding ◽

Jian Pang ◽

Yuxin Zheng ◽

Yuelong Cao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gap Junction ◽

Molecular Mechanisms ◽

Linear Models ◽

Principal Component ◽

Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Nf Kappa B ◽

Linear Module ◽

Hedgehog Acyltransferase

Purpose. This study is aimed at exploring the potential metabolite/gene biomarkers, as well as the differences between the molecular mechanisms, of osteoarthritis (OA) and rheumatoid arthritis (RA). Methods. Transcriptome dataset GSE100786 was downloaded to explore the differentially expressed genes (DEGs) between OA samples and RA samples. Meanwhile, metabolomic dataset MTBLS564 was downloaded and preprocessed to obtain metabolites. Then, the principal component analysis (PCA) and linear models were used to reveal DEG-metabolite relations. Finally, metabolic pathway enrichment analysis was performed to investigate the differences between the molecular mechanisms of OA and RA. Results. A total of 976 DEGs and 171 metabolites were explored between OA samples and RA samples. The PCA and linear module analysis investigated 186 DEG-metabolite interactions including Glycogenin 1- (GYG1-) asparagine_54, hedgehog acyltransferase- (HHAT-) glucose_70, and TNF receptor-associated factor 3- (TRAF3-) acetoacetate_35. Finally, the KEGG pathway analysis showed that these metabolites were mainly enriched in pathways like gap junction, phagosome, NF-kappa B, and IL-17 pathway. Conclusions. Genes such as HHAT, GYG1, and TRAF3, as well as metabolites including glucose, asparagine, and acetoacetate, might be implicated in the pathogenesis of OA and RA. Metabolites like ethanol and tyrosine might participate differentially in OA and RA progression via the gap junction pathway and phagosome pathway, respectively. TRAF3-acetoacetate interaction may be involved in regulating inflammation in OA and RA by the NF-kappa B and IL-17 pathway.

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Elucidation of the mechanisms and molecular targets of Qishen Yiqi formula for the treatment of pulmonary arterial hypertension using a bioinformatics/network topology-based strategy

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666201019145354 ◽

2020 ◽

Vol 23 ◽

Author(s):

Peiliang Wu ◽

Xiaona Xie ◽

Mayun Chen ◽

Junwei Sun ◽

Luqiong Cai ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Network Topology ◽

Molecular Mechanisms ◽

Molecular Targets ◽

Enrichment Analysis ◽

Network Pharmacology ◽

Pathway Enrichment Analysis ◽

Bioactive Ingredients ◽

Pulmonary Arterial

Background and Objective: Qishen Yiqi formula (QSYQ) is used to treat cardiovascular disease in the clinical practice of traditional Chinese medicine. However, few studies have explored whether QSYQ affects pulmonary arterial hypertension (PAH), and the mechanisms of action and molecular targets of QSYQ for the treatment of PAH are unclear. A bioinformatics/network topology-based strategy was used to identify the bioactive ingredients, putative targets, and molecular mechanisms of QSYQ in PAH. Methods: A network pharmacology-based strategy was employed by integrating active component gathering, target prediction, PAH gene collection, network topology, and gene enrichment analysis to systematically explore the multicomponent synergistic mechanisms. Results: In total, 107 bioactive ingredients of QSYQ and 228 ingredient targets were identified. Moreover, 234 PAH-related differentially expressed genes with a |fold change| >2 and an adjusted P value < 0.005 were identified between the PAH patient and control groups, and 266 therapeutic targets were identified. The pathway enrichment analysis indicated that 85 pathways, including the PI3K-Akt, MAPK, and HIF-1 signaling pathways, were significantly enriched. TP53 was the core target gene, and 7 other top genes (MAPK1, RELA, NFKB1, CDKN1A, AKT1, MYC, and MDM2) were the key genes in the gene-pathway network based on the effects of QSYQ on PAH. Conclusion: An integrative investigation based on network pharmacology may elucidate the multicomponent synergistic mechanisms of QSYQ in PAH and lay a foundation for further animal experiments, human clinical trials and rational clinical applications of QSYQ.

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Tissue-based metabolomics profiling reveals metabolic signatures and major metabolic pathways of gastric cancer

10.21203/rs.3.rs-326163/v1 ◽

2021 ◽

Author(s):

Yaqin Wang ◽

Wenchao Chen ◽

Kun Li ◽

Gang Wu ◽

Wei Zhang ◽

...

Keyword(s):

Gastric Cancer ◽

Predictive Ability ◽

Principal Component ◽

Enrichment Analysis ◽

Pentose Phosphate ◽

P Value ◽

Pathway Enrichment Analysis ◽

Dodecanoic Acid ◽

Orthogonal Projections ◽

Latent Structures

Abstract Purpose This study was aimed to screen differential metabolites between gastric cancer (GC) and paracancerous (PC) tissues and find new biomarkers of GC. Methods GC (n = 28) and matched PC (n = 28) tissues were collected and LC-MS/MS analyses were performed to detect metabolites of GC and PC tissues in positive and negative models. Principal component analysis (PCA) and orthogonal projections to latent structures-discriminate analysis (OPLS-DA) were conducted to describe distribution of origin data and general separation and estimate the robustness and the predictive ability of our mode. Differential metabolites were screened based on criterion of variables with p value < 0.05 and VIP (variable importance in the projection) > 1.0. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic power of differential metabolites. Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to search for metabolite pathways and MetaboAnalyst was used for pathway enrichment analysis. Results Several metabolites were significantly changed in GC group compared with PC group. Thirteen metabolites with high VIP were chose and among which 1-methylnicotinamide, dodecanoic acid and sphinganine possessed high AUC values (AUC > 0.8) indicating an excellent discriminatory ability on GC. Pathways such as pentose phosphate pathway and histidine metabolism were focused based on differential metabolites demonstrating their effects on progress of GC. Conclusions In conclusion, we investigated the tissue-based metabolomics profile of GC and several differential metabolites and signaling pathways were focused. Further study is needed to verify those results.

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Pulmonary vascular pressure effects by endothelin-1 in normoxia and chronic hypoxia: a longitudinal study

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.6.h2246 ◽

1996 ◽

Vol 271 (6) ◽

pp. H2246-H2253 ◽

Cited By ~ 5

Author(s):

S. Tjen-A-Looi ◽

R. Ekman ◽

J. Osborn ◽

I. Keith

Keyword(s):

Pulmonary Hypertension ◽

Ventricular Hypertrophy ◽

Pressure Effects ◽

Blood Levels ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Calcitonin Gene ◽

Eta Receptor ◽

Pulmonary Arterial

The role of endothelin (ET)-1 in pulmonary arterial pressure (Ppa) homeostasis and hypoxia-induced pulmonary hypertension was examined. ET-1 was chronically infused (2 and 4 pmol.kg-1.min-1) into the pulmonary circulation of male Sprague-Dawley rats for 3, 7, and 14 days while they were exposed to normoxia or hypobaric hypoxia (inspired O2 fraction 10%). The role of endogenous ET was examined by infusion of ET antiserum (ET-AS; 0.25 and 0.5 microliter.rat-1.h-1; cross-reacting with ET-1, -2, and -3) or the ETA-receptor blocker BQ-123 (10 pmol.kg-1.min-1). ET-1 (4 pmol) increased Ppa at 3 and 7 days in normoxia and hypoxia and was ineffective at 14 days, probably from ETA-receptor downregulation. BQ-123 blunted the hypoxic Ppa rise at all times, confirming a role for ETA receptors. ET-AS (0.5 microliter) was mostly ineffective but exacerbated hypoxic Ppa at 14 days, in contrast to BQ-123, suggesting that a different ET receptor could be involved. ET-1 infusion (2 pmol) caused right ventricular hypertrophy (RVH) in normoxia and exacerbated RVH in hypoxia, whereas BQ-123 and ET-AS (0.25 microliter) reduced hypoxic RVH. In conclusion, endogenous ET-1 plays a role in hypoxia-induced pulmonary hypertension and RVH by augmenting the level of hypoxic response. ET-1 also affects hematocrit and may reduce blood levels of the vasodilator calcitonin gene-related peptide.

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Clinical study of patients with primary pulmonary hypertension (PPH)

Journal of the Faculty of Medicine Baghdad ◽

10.32007/19jfacmedbaghdad36.v60i2.9 ◽

2018 ◽

Vol 60 (2) ◽

pp. 80-84

Author(s):

Alaa A. Abbood AL-Kinani

Keyword(s):

Pulmonary Hypertension ◽

Ventricular Hypertrophy ◽

Primary Pulmonary Hypertension ◽

Term Therapy ◽

Heart Catheterization ◽

Mean Pulmonary Arterial Pressure ◽

Pulmonary Arterial ◽

The Mean ◽

Long Term Therapy

Background: Pulmonary hypertension (PH) is a hemodynamic and pathophysiological conditiondefined as an increase in mean pulmonary arterial pressure (PAP) ≥25 mmHg at rest as assessed byright heart catheterization (RHC). Although there is some underestimation and overestimation of PAPbetween transthoracic Doppler echo (DE) and RHC, Doppler echo remains an indispensable screeningtool for the assessment of PH.Objective: clinical evaluation of patients with primary pulmonary hypertension (PPH) and assessvasoreactivity testing to identify patients who may benefit from long term therapy with calcium channelblockers (CCBs).Patients and methods: This prospective study was performed in the cardiac catheterization division inAl-Zahraa teaching hospital in Al-Kut. We studied the prevalence of certain variables among forty twopatients with PPH from "March 2014 to Nov 2016" including the clinical triggers, electrocardiographic(ECG) changes, Echocardiographic variables , RHC and vasoreactivity test with intravenous adenosineto identify acute positive responders and long term responders to CCB.Results: A total of forty two patients, female to male ratio were 2.8:1 with a mean age of 38±10(years).Dyspnea is a common clinical trigger (85%). Abnormal ECG was found in (90.5%) of patients, themajority had right ventricular hypertrophy (RVH) (76.2%). Echocardiographically all patients hadRVH. There was some differences in mean PAP (36±4.9mmhg) derived by DE from that obtained byRHC (47±4.78mmhg). RHC reveal that 6 patients (15.78%) were acute positive responders tointravenous adenosine and about 4 patients (66%) were long term responders to CCB during 3monthsfollow up echocardiography.Conclusions: There is some discrepancy in the mean PAP between Doppler echo and RHC within ±10mm Hg for pulmonary artery pressure estimates. 15.7% of patients at RHC were acute positiveresponder to intravenous adenosine and half of them were long term responder to CCB.

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Nanopore Sequencing Reveals Global Transcriptome Signatures of Mitochondrial and Ribosomal Gene Expressions in Various Human Cancer Stem-like Cell Populations

Cancers ◽

10.3390/cancers13051136 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1136

Author(s):

Kaya E. Witte ◽

Oliver Hertel ◽

Beatrice A. Windmöller ◽

Laureen P. Helweg ◽

Anna L. Höving ◽

...

Keyword(s):

Human Cancer ◽

Principal Component ◽

Enrichment Analysis ◽

Therapy Resistance ◽

Ribosomal Gene ◽

Pathway Enrichment Analysis ◽

Nanopore Sequencing ◽

Gene Expressions ◽

Metastasis Therapy ◽

Novel Therapeutic Strategies

Cancer stem cells (CSCs) are crucial mediators of tumor growth, metastasis, therapy resistance, and recurrence in a broad variety of human cancers. Although their biology is increasingly investigated within the distinct types of cancer, direct comparisons of CSCs from different tumor types allowing comprehensive mechanistic insights are rarely assessed. In the present study, we isolated CSCs from endometrioid carcinomas, glioblastoma multiforme as well as adenocarcinomas of lung and prostate and assessed their global transcriptomes using full-length cDNA nanopore sequencing. Despite the expression of common CSC markers, principal component analysis showed a distinct separation of the CSC populations into three clusters independent of the specific type of tumor. However, GO-term and KEGG pathway enrichment analysis revealed upregulated genes related to ribosomal biosynthesis, the mitochondrion, oxidative phosphorylation, and glycolytic pathways, as well as the proteasome, suggesting a great extent of metabolic flexibility in CSCs. Interestingly, the GO term “NF-kB binding” was likewise found to be elevated in all investigated CSC populations. In summary, we here provide evidence for high global transcriptional similarities between CSCs from various tumors, which particularly share upregulated gene expression associated with mitochondrial and ribosomal activity. Our findings may build the basis for identifying novel therapeutic strategies targeting CSCs.

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Plasma Metabolic Profiling of Pediatric Sepsis in a Chinese Cohort

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.643979 ◽

2021 ◽

Vol 9 ◽

Author(s):

Guo-Bang Li ◽

Hong-Rong Hu ◽

Wen-Feng Pan ◽

Bo Li ◽

Zhi-Ying Ou ◽

...

Keyword(s):

Fatty Acids ◽

Pathogenic Bacteria ◽

Bacterial Species ◽

Disease Onset ◽

Principal Component ◽

Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Control Subjects ◽

Sepsis Survivors ◽

Pediatric Sepsis

Sepsis represents one of the most pressing problems in pediatrics, characterized by pathogenic bacteria invading the blood, growing and multiplying in the blood circulation, and ultimately causing severe infections. Most children with sepsis have a rapid disease onset and frequently exhibit sudden high fever or first chills. Here we performed comprehensive metabolomic profiling of plasma samples collected from pediatric sepsis patients to identify specific metabolic alterations associated with these patients (n = 84, designated as case subjects) as compared to healthy cohorts (n = 59, designated as control subjects). Diagnostic models were constructed using MetaboAnalyst, R packages, and multiple statistical methods, such as orthogonal partial least squares-discriminant analysis, principal component analysis, volcano plotting, and one-way ANOVA. Our study revealed a panel of metabolites responsible for the discrimination between case and control subjects with a high predictive value of prognosis. Moreover, significantly altered metabolites in sepsis survivors versus deceased patients (non-survivors) were identified as those involved in amino acids, fatty acids, and carbohydrates metabolism. Nine metabolites including organic acids and fatty acids were also identified with significantly higher abundance in sepsis patients with related microbes, implicating greater potentials to distinguish bacterial species using metabolomic analysis than blood culture. Pathway enrichment analysis further revealed that fatty acid metabolism might play an important role in the pathogenesis of sepsis.

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Comprehensive bioinformatic analysis identified m6A methylation as an important regulator in mediating immune response during idiopathic pulmonary arterial hypertension

10.21203/rs.3.rs-64337/v1 ◽

2020 ◽

Author(s):

Na Liu ◽

Yunhong Zeng ◽

Ting Huang ◽

Wanyun Zuo ◽

Yunbin Xiao ◽

...

Keyword(s):

Immune Response ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Immune Cell ◽

Enrichment Analysis ◽

Bioinformatic Analysis ◽

Pathway Enrichment Analysis ◽

Protein Protein Interaction ◽

M1 Macrophage ◽

Pulmonary Arterial

Abstract BackgroundDespite its functional importance in various fundamental bioprocesses, studies of N6-methyladenosine (m6A) in the pulmonary arterial hypertension (PAH) are lacking. Here we studied the potential relevance of m6A RNA methylation and immune response in PAH development.MethodsWe constructed a monocrotaline (MCT) induced PAH rat model and performed Methylated RNA immunoprecipitation sequencing (MeRIP-Seq). The 18 idiopathic PAH (IPAH) microarray data obtained from the GEO database was used to construct co-expression networks by weighted gene co-expression network analysis (WGCNA). CIBERSORT was used to investigate the effect of m6A methylation on immune cell infiltration during PAH.ResultsA differential pattern of m6A abundance, mainly up-methylation, was observed in the lung tissues of rats with MCT induced PAH. By WGCNA, multi-list pathway enrichment analysis and protein-protein interaction (PPI) analysis, we found that m6A methylation modification may play important roles in mediating immune response during PAH. CYBERSORT algorithm indicated that the m6A methylation can drive monocyte to form M1 macrophage, which may be mediated by CCR5 and CXCL9.ConclusionCollectively, m6A landscape is altered in PAH. We summarize newly discovered m6A in controlling immune response, which caused activation of M1 macrophage during PAH. It’s provided a novel insight into the therapeutic mechanisms of PAH.

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Multi-omics analysis of m6A modification-related patterns based on m6A regulators and tumor microenvironment infiltration in lung adenocarcinoma

Scientific Reports ◽

10.1038/s41598-021-00272-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xincheng Wu ◽

Zhengping Bai

Keyword(s):

Tumor Microenvironment ◽

Lung Adenocarcinoma ◽

Cytotoxic T Lymphocyte ◽

Principal Component ◽

Enrichment Analysis ◽

Comprehensive Analysis ◽

Survival Advantage ◽

Pathway Enrichment Analysis ◽

Mutation Burden

AbstractEpigenetic modifications, especially N6-methyladenosine (m6A) modification, play a key role in tumor microenvironment (TME) infiltration. However, the regulatory role of m6A modification in the TME of lung adenocarcinoma (LUAD) remains unclear. A total of 2506 patients with LUAD were included in the analysis and divided into different groups according to distinct m6A modification-related patterns based on 23 m6A regulators. A comprehensive analysis was performed to explore TME infiltration in different m6A modification-related patterns. Principal component analysis was performed to obtain the m6Ascore and to quantify m6A modification-related patterns in different individuals. Three distinct m6A modification-related patterns were identified by 23 m6A regulators. The pathway enrichment analysis showed that m6Acluster-A was associated with immune activation; m6Acluster-B was associated with carcinogenic activation; m6Acluster-C was prominently related to substance metabolism. M6Acluster-A was remarkably rich in TME-infiltrating immune cells and patients with this pattern showed a survival advantage. The m6Ascore could predict TME infiltration, tumor mutation burden (TMB), the effect of tumor immunotherapy, and the prognosis of patients in LUAD. High m6Ascore was characterized by increased TME infiltration, reduced TMB, and survival advantage. Patients with a high m6Ascore exhibited significantly improved clinical response to anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA4) immunotherapy. This study explored the regulatory mechanisms of TME infiltration in LUAD. The comprehensive analysis of m6A modification-related patterns may contribute to the development of individualized immunotherapy and the improvement of the overall effectiveness of immunotherapy for LUAD patients.

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Comprehensive Analyses of miRNA-mRNA Network and Potential Drugs in Idiopathic Pulmonary Arterial Hypertension

BioMed Research International ◽

10.1155/2020/5156304 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Chan Li ◽

Zeyu Zhang ◽

Qian Xu ◽

Ruizheng Shi

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Kegg Pathway ◽

Enrichment Analysis ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Differentially Expressed ◽

Pathway Enrichment Analysis ◽

Ppi Network ◽

Hub Genes ◽

Pulmonary Arterial

Introduction. Idiopathic pulmonary arterial hypertension (IPAH) is a severe cardiopulmonary disease with a relatively low survival rate. Moreover, the pathogenesis of IPAH has not been fully recognized. Thus, comprehensive analyses of miRNA-mRNA network and potential drugs in IPAH are urgent requirements. Methods. Microarray datasets of mRNA and microRNA (miRNA) in IPAH were searched and downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMIs) were identified. Then, the DEMI-DEG network was conducted with associated comprehensive analyses including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis, while potential drugs targeting hub genes were investigated using L1000 platform. Results. 30 DEGs and 6 DEMIs were identified in the lung tissue of IPAH. GO and KEGG pathway analyses revealed that these DEGs were mostly enriched in antimicrobial humoral response and African trypanosomiasis, respectively. The DEMI-DEG network was conducted subsequently with 4 DEMIs (hsa-miR-34b-5p, hsa-miR-26b-5p, hsa-miR-205-5p, and hsa-miR-199a-3p) and 16 DEGs, among which 5 DEGs (AQP9, SPP1, END1, VCAM1, and SAA1) were included in the top 10 hub genes of the PPI network. Nimodipine was identified with the highest CMap connectivity score in L1000 platform. Conclusion. Our study conducted a miRNA-mRNA network and identified 4 miRNAs as well as 5 mRNAs which may play important roles in the pathogenesis of IPAH. Moreover, we provided a new insight for future therapies by predicting potential drugs targeting hub genes.

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