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Genes related to inflammation and bone loss process in periodontitis suggested by bioinformatics methods.

ABSTRACT: Despite of numerous studies on periodontitis, the mechanism underlying the progression of periodontitis still remains largely unknown. This study aimed to have an expression profiling comparison between periodontitis and normal control and to identify more candidate genes involved in periodontitis and to gain more insights into the molecular mechanisms of periodontitis progression.The gene expression profile of GSE16134, comprising 241 gingival tissue specimens and 69 healthy samples as control which were obtained from 120 systemically healthy patients with periodontitis (65 with chronic and 55 with aggressive periodontitis), was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in periodontitis samples were screened using the limma package in R compared with control samples. Gene Ontology (GO) and pathway enrichment analysis upon the DEGs were carried out using Hypergeometric Distribution test. Protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape, followed by module selection from the PPI network using MCODE plugin. Moreover, transcription factors (TFs) of these DEGs were identified based on TRANSFAC database and then a regulatory network was constructed.Totally, 762 DEGs (507 up- and 255 down-regulated) in periodontitis samples were identified. DEGs were enriched in different GO terms and pathways, such as immune system process, cell activation biological processes, cytokine-cytokine receptor interaction, and metabolic pathways. Cathepsin S (CTSS) and pleckstrin (PLEK) were the hub proteins in the PPI network and 3 significant modules were selected. Moreover, 19 TFs were identified including interferon regulatory factor 8 (IRF8), and FBJ murine osteosarcoma viral oncogene homolog B (FOSB).This study identified genes (CTSS, PLEK, IRF-8, PTGS2, and FOSB) that may be involved in the development and progression of periodontitis.

SUBMITTER: Song L

PROVIDER: S-EPMC4559289 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Genes related to inflammation and bone loss process in periodontitis suggested by bioinformatics methods.

Song Liang L Yao Jueqi J He Zhijing Z Xu Bin B

BMC oral health 20150904

<h4>Background</h4>Despite of numerous studies on periodontitis, the mechanism underlying the progression of periodontitis still remains largely unknown. This study aimed to have an expression profiling comparison between periodontitis and normal control and to identify more candidate genes involved in periodontitis and to gain more insights into the molecular mechanisms of periodontitis progression.<h4>Methods</h4>The gene expression profile of GSE16134, comprising 241 gingival tissue specimens ...[more]

PMID: 26334995

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Project description:BackgroundCell survival or death is one of the key scientific issues of inflammatory response. To regulate cell death during the occurrence and development of periodontitis, various forms of programmed cell death, such as pyroptosis, ferroptosis, necroptosis, and apoptosis, have been proposed. It has been found that ferroptosis characterized by iron-dependent lipid peroxidation is involved in cancer, degenerative brain diseases and inflammatory diseases. Furthermore, NCOA4 is considered one of ferroptosis-related genes (FRGs) contributing to butyrate-induced cell death in the periodontitis. This research aims to analyze the expression of FRGs in periodontitis tissues and to explore the relationship between ferroptosis and periodontitis.MethodGenes associated with periodontitis were retrieved from two Gene Expression Omnibus datasets. Then, we normalized microarray data and removed the batch effect using the R software. We used R to convert the mRNA expression data and collected the expression of FRGs. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), transcription factor (TF) and protein-protein interaction (PPI) network analyses were used. In addition, we constructed a receiver operating characteristic curve and obtained relative mRNA expression verified by quantitative reverse-transcription polymerase chain reaction (PCR).ResultsEight and 10 FRGs related to periodontitis were upregulated and downregulated, respectively. GO analysis showed that FRGs were enriched in the regulation of glutathione biosynthetic, glutamate homeostasis, and endoplasmic reticulum-nucleus signaling pathway. The top TFs included CEBPB, JUND, ATF2. Based on the PPI network analysis, FRGs were mainly linked to the negative regulation of IRE1-mediated unfolded protein response, regulation of type IIa hypersensitivity, and regulation of apoptotic cell clearance. The expression levels of NCOA4, SLC1A5 and HSPB1 using PCR were significantly different between normal gingival samples and periodontitis samples. Furthermore, the diagnostic value of FRGs for periodontitis were "Good".ConclusionsWe found significant associations between FRGs and periodontitis. The present study not only provides a new possible pathomechanism for the occurrence of periodontitis but also offers a new direction for the diagnosis and treatment of periodontitis.

Project description:PurposeThe molecular mechanisms of age-related bone loss are unclear and without valid drugs yet. The aims of this study were to explore the molecular changes that occur in bone tissue during age-related bone loss, to further clarify the changes in function, and to predict potential therapeutic drugs.MethodsWe collected bone tissues from children, middle-aged individuals, and elderly people for protein sequencing and compared the three groups of proteins pairwise, and the differentially expressed proteins (DEPs) in each group were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). K-means cluster analysis was then used to screen out proteins that continuously increased/decreased with age. Canonical signaling pathways that were activated or inhibited in bone tissue along with increasing age were identified by Ingenuity Pathway Analysis (IPA). Prediction of potential drugs was performed using the Connectivity Map (CMap). Finally, DEPs from sequencing were verified by Western blot, and the drug treatment effect was verified by quantitative real-time PCR.ResultsThe GO and KEGG analyses show that the DEPs were associated with inflammation and bone formation with aging, and the IPA analysis shows that pathways such as IL-8 signaling and acute-phase response signaling were activated, while glycolysis I and EIF2 signaling were inhibited. A total of nine potential drugs were predicted, with rapamycin ranking the highest. In cellular experiments, rapamycin reduced the senescence phenotype produced by the H2O2-stimulated osteocyte-like cell MLO-Y4.ConclusionWith age, inflammatory pathways are activated in bone tissue, and signals that promote bone formation are inhibited. This study contributes to the understanding of the molecular changes that occur in bone tissue during age-related bone loss and provides evidence that rapamycin is a drug of potential clinical value for this disease. The therapeutic effects of the drug are to be further studied in animals.

Project description:SLIT2, a member of neuronal guidance cues, has been reported to regulate inflammation and cancer progression. Periodontitis is an oral inflammatory disease that degenerates periodontal tissue, alveolar bone and tooth. This study aims to explore the expression pattern of SLIT2 in periodontitis and its role in disease progression and bone loss. Gingival tissue of 20 periodontitis patients and 20 healthy-controls was obtained. Ligature-induced periodontitis (LIP) mice-model was developed in Slit2-Tg and wild-type mice. The effect of SLIT2 on inflammation, immune cell infiltration, M1 macrophage polarization, and alveolar bone loss in periodontitis was analyzed extensively. In periodontitis-affected gingival-tissue, SLIT2 expression was 4.4-fold higher compared to healthy-volunteers. LIP enhanced SLIT2 expression in mice periodontitis-affected periodontal tissue (PAPT) and blood circulation of wild-type mice by 4. 6-, and 5.0-fold, respectively. In Slit2-Tg-mice PAPT, SLIT2 expression was 1.8-fold higher compared to wild-type mice. Micro-CT and histomorphometric analysis revealed a 1.3-fold higher cement-enamel-junction to the alveolar-bone-crest (CEJ-ABC) distance and alveolar bone loss in LIP Slit2-Tg-mice compare to LIP wild-type mice. Results from RNA-sequencing, RT-qPCR, and ELISA showed a higher expression of Cxcr2, Il-18, TNF?, IL-6, and IL-1? in Slit2-Tg-mice PAPT compared to wild-type-mice. Slit2-Tg-mice PAPT showed a higher number of osteoclasts, M1 macrophages, and the upregulation of Robo1 expression. Slit2-Tg-mice PAPT showed upregulation of M1 macrophage marker CD16/32 and osteoclastogenic markers Acp5, Ctsk, and Nfatc1, but osteogenic markers (Alp, Bglap) remained unchanged. Immunohistochemistry unveiled the higher vasculature and infiltration of leucocytes and macrophages in Slit2-Tg-mice PAPT. RNA-sequencing, GO-pathway enrichment analysis, and western blot analysis revealed the activation of the MAPK signaling pathway in Slit2-Tg mice PAPT. In conclusion, SLIT2 overexpression in periodontitis intensifies inflammation, immune cells infiltration, M1 macrophage polarization, osteoclastogenesis, and alveolar bone loss, possibly via activation of MAPK signaling, suggesting the role of SLIT2 on exacerbation of periodontitis and alveolar bone loss.

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Genes related to inflammation and bone loss process in periodontitis suggested by bioinformatics methods.

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Genes related to inflammation and bone loss process in periodontitis suggested by bioinformatics methods.

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