scholarly journals Lipopolysaccharide-Induced Transcriptional Changes in LBP-Deficient Rat and Its Possible Implications for Liver Dysregulation during Sepsis

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Zhixiang He ◽  
Zichen Song ◽  
Leilei Meng ◽  
Wenhui Cheng ◽  
Fan Huang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Rna Sequencing ◽  
Liver Tissue ◽  
Serum Lactate ◽  
Functional Enrichment ◽  
Serum Lactate Dehydrogenase ◽  
Peroxisome Proliferator ◽  
Multiple Time ◽  
Ppar Signaling

Sepsis is an organ dysfunction caused by the dysregulated inflammatory response to infection. Lipopolysaccharide-binding protein (LBP) binds to lipopolysaccharide (LPS) and modulates the inflammatory response. A rare systematic study has been reported to detect the effect of LBP gene during LPS-induced sepsis. Herein, we explored the RNA sequencing technology to profile the transcriptomic changes in liver tissue between LBP-deficient rats and WT rats at multiple time points after LPS administration. We proceeded RNA sequencing of liver tissue to search differentially expressed genes (DEGs) and enriched biological processes and pathways between WT and LBP-deficient groups at 0 h, 6 h, and 24 h. In total, 168, 284, and 307 DEGs were identified at 0 h, 6 h, and 24 h, respectively, including Lrp5, Cyp7a1, Nfkbiz, Sigmar1, Fabp7, and Hao1, which are related to the inflammatory or lipid-related process. Functional enrichment analysis revealed that inflammatory response to LPS mediated by Ifng, Cxcl10, Serpine1, and Lbp was enhanced at 6 h, while lipid-related metabolism associated with C5, Cyp4a1, and Eci1 was enriched at 24 h after LPS administration in the WT samples. The inflammatory process was not found when the LBP gene was knocked out; lipid-related metabolic process and peroxisome proliferator-activated receptor (PPAR) signaling pathway mediated by Dhrs7b and Tysnd1 were significantly activated in LBP-deficient samples. Our study suggested that the invading LPS may interplay with LBP to activate the nuclear factor kappa B (NF-κB) signaling pathway and trigger uncontrolled inflammatory response. However, when inhibiting the activity of NF-κB, lipid-related metabolism would make bacteria removal via the effect on the PPAR signaling pathway in the absence of LBP gene. We also compared the serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels using the biochemistry analyzer and analyzed the expression of high mobility group box 1 (HMGB1) and cleaved-caspase 3 with immunohistochemistry, which further validated our conclusion.

scholarly journals RNA-seq profiles of LPS-induced transcriptional changes in LBP-deficient rat and its possible implications for the liver dysregulation during sepsis

2020 ◽  
Author(s):  
Zichen Song ◽  
Zhixiang He ◽  
Leilei Meng ◽  
Wenhui Cheng ◽  
Fan Huang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathway ◽  
Rna Sequencing ◽  
Liver Tissue ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Inflammatory Conditions ◽  
Ppar Signaling ◽  
Transcriptional Changes

Abstract Background Sepsis is an organ dysfunction caused by the dysregulated inflammatory response to infection. LBP binds to LPS, and modulates the inflammatory response. Rare systematic study has been reported to detect the effect of LBP gene during the LPS-induced sepsis. Herein, we explored the RNA sequencing technology to profile the transcriptomic changes in liver tissue between LBP-deficient rats and WT rats at multiple timepoints after LPS administration. Results We compared the serum ALT levels using the biochemistry analyzer and proceeded RNA sequencing of liver tissue to search differentially expressed genes and enriched biological processes and pathways between LBP-deficient and WT groups at 0 h, 6 h, and 24 h. In total, 168, 284, and 307 differential expressed genes (DEGs) were identified at 0 h, 6 h, and 24 h respectively, including Lrp5, Cyp7a1, Nfkbiz, Sigmar1, Fabp7, and Hao1, which are related to the inflammatory or lipid-related process. Functional enrichment analysis revealed that inflammatory response to LPS mediated by Ifng, Cxcl10, Serpine1, and Lbp was enhanced at 6 h, while lipid-related metabolism associated with C5, Cyp4a1, and Eci1 was enriched at 24 h after LPS administration in the WT samples. The inflammatory process was not found when the LBP gene was knocked out, lipid-related metabolic process and PPAR signaling pathway mediated by Dhrs7b and Tysnd1 were significantly activated in LBP-deficient samples. Conclusions Our study suggested that the invading LPS may interplay with LBP to activate NF-κB signaling pathway and trigger uncontrolled inflammatory response. However, when inhibiting the activity of NF-κB, lipid-related metabolism would make bacteria removal via the effect on PPAR signaling pathway in the absence of LBP gene. Moreover, we further found the potent implications of targeting the LBP gene may as a biomarker for inflammatory conditions induced by metabolic disorders.

scholarly journals Identification of a Potential PPAR-Related Multigene Signature Predicting Prognosis of Patients with Hepatocellular Carcinoma

PPAR Research ◽  
2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Wenfang Xu ◽  
Zhen Chen ◽  
Gang Liu ◽  
Yuping Dai ◽  
Xuanfu Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Target Genes ◽  
Prognostic Markers ◽  
Cox Regression ◽  
Clinical Information ◽  
Gene Signature ◽  
Peroxisome Proliferator ◽  
Clinical Indicators ◽  
Ppar Signaling

Peroxisome proliferator-activated receptors (PPARs) and part of their target genes have been reported to be related to the progression of hepatocellular carcinoma (HCC). The prognosis of HCC is not optimistic, and more accurate prognostic markers are needed. This study focused on discovering potential prognostic markers from the PPAR-related gene set. The mRNA data and clinical information of HCC were collected from TCGA and GEO platforms. Univariate Cox and lasso Cox regression analyses were used to screen prognostic genes of HCC. Three genes (MMP1, HMGCS2, and SLC27A5) involved in the PPAR signaling pathway were selected as the prognostic signature of HCC. A formula was established based on the expression values and multivariate Cox regression coefficients of selected genes, that was, risk   score = 0.1488 ∗ expression   value   of   M M P 1 + − 0.0393 ∗ expression   value   of   H M G C S 2 + − 0.0479 ∗ expression   value   of   S L C 27 A 5 . The prognostic ability of the three-gene signature was assessed in the TCGA HCC dataset and verified in three GEO sets (GSE14520, GSE36376, and GSE76427). The results showed that the risk score based on our signature was a risk factor with a HR (hazard ratio) of 2.72 ( 95 % CI   Confidence   Interval = 1.87 ~ 3.95 , p < 0.001 ) for HCC survival. The signature could significantly ( p < 0.0001 ) distinguish high-risk and low-risk patients with poor prognosis for HCC. In addition, we further explored the independence and applicability of the signature with other clinical indicators through multivariate Cox analysis ( p < 0.001 ) and nomogram analysis ( C ‐ index = 0.709 ). The above results indicate that the combination of MMP1, HMGCS2, and SLC27A5 selected from the PPAR signaling pathway could effectively, independently, and applicatively predict the prognosis of HCC. Our research provided new insights to the prognosis of HCC.

scholarly journals Investigation of Potential Genetic Biomarkers and Molecular Mechanism of Ulcerative Colitis Utilizing Bioinformatics Analysis

2019 ◽  
Author(s):  
Jiaqi Zhang ◽  
Xue Wang ◽  
Lin Xu ◽  
Zedan Zhang ◽  
Fengyun Wang ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Gene Therapy ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Functional Enrichment ◽  
Hub Genes ◽  
Amyloid A ◽  
Chemokine Signaling ◽  
Chemokine Signaling Pathway ◽  
Potential Biomarkers

Abstract Objectives: To reveal the molecular mechanisms of ulcerative colitis (UC) and provide potential biomarkers for UC gene therapy. Methods: We downloaded the GSE87473 microarray dataset from the Gene Expression Omnibus (GEO) and identified the differentially expressed genes (DEGs) between UC samples and normal samples. Then ,a module partition analysis was performed based on a weighted gene co-expression network analysis (WGCNA),followed by pathway and functional enrichment analyses. Furthermore, we investigated the hub genes . At last, data validation was performed to ensure the reliability of the hub genes. Results: Between UC group and normal group, 988 DEGs were investigated . The DEGs were clustered into 5 modules using WGCNA. These DEGs were mainly enriched in functions such as the immune response, the inflammatory response and chemotaxis, and they were mainly enriched in KEGG pathways such as the cytokine-cytokine receptor interaction , chemokine signaling pathway, and complement and coagulation cascades. The hub genes, including dual oxidase maturation factor 2(DUOXA2), serum amyloid A (SAA) 1 and SAA2, TNFAIP3-interacting protein 3(TNIP3), C-X-C motif chemokine (CXCL1), solute carrier family 6 member 14(SLC6A14) and complement decay-accelerating factor (CD antigen CD55),were revealed as potential tissue biomarkers for UC diagnosis or treatment. Conclusions: This study provides supportive evidence that DUOXA2, A-SAA, TNIP3, CXCL1, SLC6A14 and CD55 might be used as potential biomarkers for tissue biopsy of UC, especially SLC6A14 and CD55, which may be new targets for UC gene therapy. Moreover, the DUOX2/DUOXA2, NF-κB /TNIP3 and CXCL1/CXCR2 pathways might play an important role in the progression of UC through the chemokine signaling pathway and inflammatory response.

scholarly journals Genetic variants of the peroxisome proliferator‐activated receptor (PPAR) signaling pathway genes and risk of pancreatic cancer

2020 ◽  
Vol 59 (8) ◽  
pp. 930-939
Author(s):  
Xiaowen Liu ◽  
Danwen Qian ◽  
Hongliang Liu ◽  
James L. Abbruzzese ◽  
Sheng Luo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Genetic Variants ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Signaling

scholarly journals The Study of Yin-Chen-Hao-Tang Preventing and Treating Alcoholic Fatty Liver Disease Through PPAR Signaling Pathway Based on Network Pharmacology and RNA-Seq Transcriptomics

2021 ◽  
Author(s):  
Yi-Wei Zhu ◽  
Du Li ◽  
Ting-Jie Ye ◽  
Feng-Jun Qiu ◽  
Xiao-Ling Wang ◽  
...  
Keyword(s):  
Liver Disease ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Liver Tissue ◽  
Network Pharmacology ◽  
Rna Seq ◽  
Alcoholic Fatty Liver ◽  
Ppar Signaling ◽  
Alcoholic Fatty Liver Disease ◽  
Alt Activity

Abstract Background: Alcoholic fatty liver disease (AFLD) is the first stage of the alcoholic liver disease course. Yin-Chen-Hao-Tang (YCHT) has a good clinical effect on the treatment of AFLD, but its molecular mechanism has not been elucidated. In this study, we tried to explore the molecular mechanism of YCHT in improving hepatocyte steatosis in AFLD mice through network pharmacology and RNA sequencing (RNA-Seq) transcriptomics. Methods: Network pharmacological methods were used to analyze the potential therapeutic signaling pathways and targets of YCHT on AFLD. Then, the AFLD mice model was induced and YCHT was administered concurrently. Liver injury was measured by serum alanine aminotransferase (ALT) activity and liver tissue H&E staining, and liver steatosis was determined by serum triglyceride (TG) level and liver tissue Oil Red staining. The molecular mechanism of YCHT on prevention and treatment of mice AFLD was investigated according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the differential expression genes data obtained by liver tissue RNA-Seq. Finally, the key signaling pathway and targets of YCHT on AFLD were verified in the ethanol-induced AFLD hepatocyte model by pathway inhibition experiments.Results: The results of network pharmacology analysis showed that YCHT may exert its pharmacological effect on AFLD through 312 potential targets which are involved in many signaling pathways including the PPAR signaling pathway. AFLD mice experiments results showed that YCHT markedly decreased mice serum ALT activity and serum TG levels. YCHT also significantly improved alcohol-induced hepatic injury and steatosis in mice livers. Furthermore, both KEGG analysis of RNA-Seq and AFLD hepatocyte model experiments showed that the PPAR signaling pathway should be the most relevant pathway of YCHT in the prevention and treatment of AFLD. YCHT could remarkably reduce the expression of PPARγ which is related to the lipogenesis pathway. YCHT also could increase the expression of PPARα which is related to the lipolysis pathway. Conclusions: Our study discovered that PPARγ and PPARα are the key targets and the PPAR signaling pathway is the main signaling pathway for YCHT to prevent and treat AFLD.

Adipogenic Differentiation Was Inhibited by Downregulation of PPARγ Signaling Pathway in Aging Tendon Stem/ Progenitor Cells

2021 ◽  
Author(s):  
Fan Lai ◽  
Jingjing Wang ◽  
Hong Tang ◽  
Xuting Bian ◽  
Kang Lu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Signaling Pathway ◽  
Rna Sequencing ◽  
Adipogenic Differentiation ◽  
Immunofluorescent Staining ◽  
Peroxisome Proliferator ◽  
Fatty Acid Binding ◽  
Aging Rats ◽  
Oil Red O Staining ◽  
Oil Red O

Abstract Background: Tendon stem/progenitor cells (TSPCs) play a vital role in tendon repair and regeneration. Previously we found more adipocytes accumulated in the patellar tendon injury sites in aging rats compared with the young ones, of which the mechanism is still unknown. Here we want to identify whether erroneous differentiation of TSPCs by aging accounts for the adipocyte accumulation. Methods: TSPCs from young and aging rats were isolated and propagated. Both young and aging TSPCs were induced to differentiate into adipocytes, and Oil red O staining, quantitative real-time polymerase chain reaction(qRT-PCR), western-blot and immunofluorescent staining were used to evaluate the capability of TSPCs. RNA sequencing was utilized to screen out different genes and signaling pathways related to adipogenesis between young and aging TSPCs. Results: The Oil red O staining showed there were more adipocytes formed in young TSPCs. Besides, adipogenic markers perilipin, peroxisome proliferator-activated receptor γ(PPARγ), CCAAT/enhancer-binding proteins alpha (C/EBPα) and Fatty acid-binding protein 4(FABP4) were elevated both at gene and protein level. PPARγ signaling pathway was selected as our target via RNA sequencing. After adding the signaling activators, Rosiglitazone maleate (RM), inhibited adipogenesis of aging TSCs was reversed. Conclusions: In conclusion, aging inhibited adipogenesis of TSPCs by down‐regulating PPARγ signaling. It is not likely that the adipocyte accumulation in aging tendon during repair was due to the aging of TSPCs. This may provide new targets for curing aging tendon injuries or tendinopathies.

scholarly journals A Network-Based Analysis Reveals the Mechanism Underlying Vitamin D in Suppressing Cytokine Storm and Virus in SARS-CoV-2 Infection

2020 ◽  
Vol 11 ◽  
Author(s):  
Firoz Ahmed
Keyword(s):  
Vitamin D ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Host Response ◽  
Antiviral Response ◽  
Functional Enrichment ◽  
Literature Mining ◽  
Cytokine Storm ◽  
Number Of Patients ◽  
Depth Analysis

BackgroundSARS-CoV-2 causes ongoing pandemic coronavirus disease of 2019 (COVID-19), infects the cells of the lower respiratory tract that leads to a cytokine storm in a significant number of patients resulting in severe pneumonia, shortness of breathing, respiratory and organ failure. Extensive studies suggested the role of Vitamin D in suppressing cytokine storm in COVID-19 and reducing viral infection; however, the precise molecular mechanism is not clearly known. In this work, bioinformatics and systems biology approaches were used to understand SARS-CoV-2 induced cytokine pathways and the potential mechanism of Vitamin D in suppressing cytokine storm and enhancing antiviral response.ResultsThis study used transcriptome data and identified 108 differentially expressed host genes (DEHGs) in SARS-CoV-2 infected normal human bronchial epithelial (NHBE) cells compared to control. Then, the DEHGs was integrated with the human protein-protein interaction data to generate a SARS-CoV-2 induced host gene regulatory network (SiHgrn). Analysis of SiHgrn identified a sub-network “Cluster 1” with the highest MCODE score, 31 up-regulated genes, and predominantly associated immune and inflammatory response. Interestingly, the iRegulone tool identified that “Cluster 1” is under the regulation of transcription factors STAT1, STAT2, STAT3, POU2F2, and NFkB1, collectively referred to as “host response signature network”. Functional enrichment analysis with NDEx revealed that the “host response signature network” is predominantly associated with critical pathways, including “cytokines and inflammatory response”, “non-genomic action of Vitamin D”, “the human immune response to tuberculosis”, and “lung fibrosis”. Finally, in-depth analysis and literature mining revealed that Vitamin D binds with its receptor and could work through two different pathways: (i) it inhibits the expression of pro-inflammatory cytokines through blocking the TNF induced NFkB1 signaling pathway; and (ii) it initiates the expression of interferon-stimulating genes (ISGs) for antiviral defense program through activating the IFN-α induced Jak-STAT signaling pathway.ConclusionThis comprehensive study identified the pathways associated with cytokine storm in SARS-CoV-2 infection. The proposed underlying mechanism of Vitamin D could be promising in suppressing the cytokine storm and inducing a robust antiviral response in severe COVID-19 patients. The finding in this study urgently needs further experimental validations for the suitability of Vitamin D in combination with IFN-α to control severe COVID-19.

scholarly journals Short hairpin RNA attenuates liver fibrosis by regulating the peroxisome proliferator-activated receptor-γ and nuclear factor-κB pathways in hepatitis B virus-induced liver fibrosis in mice

2019 ◽  
Author(s):  
Lei Ye ◽  
Jiaqi Cao ◽  
Liying Sun ◽  
Ting Chen ◽  
Wuping Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Nuclear Factor Κb ◽  
Differentially Expressed ◽  
Peroxisome Proliferator ◽  
Differentially Expressed Proteins ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Ppar Signaling

Abstract Background: Progressive liver fibrosis, caused by chronic viral infection and metabolic disorders, results in the development of cirrhosis and hepatocellular carcinoma. However, no antifibrotic therapies have been approved to date. In our previous study, adeno-associated virus (AAV) short hairpin RNAs (shRNAs) targeting hepatitis B virus (HBV) and transforming growth factor (TGF)-β administration could persistently inhibit HBV replication and concomitantly prevent liver fibrosis. However, the differentially expressed proteins and critical regulatory networks of AAVshRNA treatment remain unclear. Accordingly, in this study, our major goal was we aimed to analyze differentially expressed proteins in the liver of AAV-shRNAs-treated mice with HBV infection and liver fibrosis using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics and to elucidate the underlying antifibrotic mechanisms. Results: In total 2743 proteins were recognized by iTRAQ-based quantitative proteomics analysis. Gene ontology analysis suggested that the differentially expressed proteins were mostly participated in peptide metabolism in the biological process category, cytosolic ribosomes in the cell component category, and structural constituents of ribosomes in the molecular function category. Kyoto Encyclopedia of Genes and Genomespathway analysis indicated that oxidative stress and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were actived after treatment. Verification studies showed that AAVshRNAs inhibited hepatic stellate cell activation and inflammation by suppressing nuclear factor-κB p65 phosphorylation and α-smooth muscle actin expression via upregulation of PPAR-γ. Hepatocytes steatosis was also decreased by activating PPAR signaling pathway and improving lipid metabolism. TGF-β level was decreased owning to increase PPAR-γ expression and directly inhibition using AAVshRNAs targeting TGF-β. TGF-β-induced oxidative stress was suppressed by increasing glutathione S-transferase Pi 1 and reducing peroxiredoxin 1. Conclusions: Our results indicated that AAV-shRNAs were effective for modulating liver fibrosis by reducing oxidative stress, inflammation and activating PPAR signaling pathway.

The decrease of MYPT1 is critical for impairment of NO-mediated vosodilation in mesenteric artery of the older spontaneously hypertensive rats

2021 ◽  
Author(s):  
Yiqin Cui ◽  
Liju Yang ◽  
Xiaoqin Liu ◽  
Chang Che ◽  
Jun Cheng ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Rna Sequencing ◽  
Mesenteric Artery ◽  
Spontaneously Hypertensive Rats ◽  
The Elderly ◽  
Functional Enrichment ◽  
Regulatory Subunit ◽  
Smooth Muscle Relaxation ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

Abstract Nitric oxide (NO) mediated vasodilatation is a fundamental response of vasculature, however, the regulation of NO signaling pathway on resistance vessels in the elderly hypertension is still unclear. The 16-weeks-spontaneously hypertensive rats (SHR), the 18-months-SHR (OldSHR), and the age matched Wistar-Kyoto rats were used to study the changes of mesenteric resistance artery dilatation caused by sodium nitroprusside (SNP). After pre-vasoconstriction by Norepinephrine (NE), the response of endothelium-denuded mesenteric artery ring to SNP was observed, and the changes in vascular response after pharmacological interventions of key nodes in the NO/sGC/cGMP/PKG1α signaling pathway were observed as well. RNA sequencing and functional enrichment analyses were used to provide information for conducting validation experiments. Vasodilation of NO in OldSHR was decreased, which significantly correlated with the reduction of PKG-mediated effect. Functional enrichment analysis of RNA sequencing showed that genes encoding important proteins such as sGC and MYPT1 (protein phosphatase 1 regulatory subunit 12A) were downregulated in OldSHR. Molecular biology validation results showed that mRNA expression of both α and β subunits of sGC were reduced, while mRNA and protein expression of PKG1α were reduced in OldSHR. More importantly, the expression of MYPT1 and p S668-MYPT1 was significantly reduced in OldSHR, even under the treatment of SNP. The experiment also revealed an enhanced cAMP system in vasodilatory in hypertension, while this function completely lost in the elderly hypertension. Therefore, a NO-mediated decrease in vascular smooth muscle relaxation was found in the elderly hypertension. The dysfunction in cGMP-PKG signaling, in particular, the decreased p S668-MYPT1 was mechanistically involved.

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