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1.
Gene ; 722: 144127, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31525397

RESUMO

Complement factor H (CFH) serves as a major down-regulator in the complement system, often utilized by bacterial pathogens to evade complement attack. Yet, little is currently known about the genetic correlation of CFH polymorphisms with sepsis due to various microbial infections. A case-control method (488 septic patients and 527 healthy individuals) was carried out in this study to investigate the genetic relationship between CFH polymorphisms (rs3753394 C/T, rs1065489 G/T and rs1061170 C/T) and susceptibility to sepsis caused by bacterial infections in Chinese Han populations. Our findings indicated that the frequency of rs3753394 CT/TT genotype in the septic patients with P. aeruginosa was significantly higher than that in the control individuals (P = 0.033, OR = 2.668, 95%CI = 1.072-6.334). The rs3753394 T allele frequency in the P. aeruginosa-infected patients was significantly increased, compared to that in the healthy controls (P = 0.014, OR = 1.68, 95%CI = 1.118-2.538). Moreover, these significant differences of rs3753394 genotype and allele frequencies remained after multiple testing corrections [P (corr.) = 0.033 for genotype; P (corr.) = 0.033 for allele]. The current study highlighted the significance of CFH polymorphism rs3753394 as a potential biomarker for targeting P. aeruginosa infection in critically ill patients.


Assuntos
Predisposição Genética para Doença , Infecções por Pseudomonas/genética , Pseudomonas aeruginosa , Sepse/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/etnologia , Fator H do Complemento/genética , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Pseudomonas/diagnóstico , Infecções por Pseudomonas/etnologia , Sepse/diagnóstico , Sepse/etnologia , Sepse/microbiologia
3.
Medicine (Baltimore) ; 98(43): e17482, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651850

RESUMO

The aim of this study was to investigate the correlation between cluster of differentiation 86 (CD86) gene rs1129055 and rs2715267 single nucleotide polymorphisms and sepsis susceptibility.One hundred twenty-five sepsis patients and 120 healthy controls were enrolled in this case-control study. CD86 polymorphisms rs1129055 and rs2715267 were genotyped through polymerase chain reaction-restriction fragment length polymorphism approach. Chi-square test was used to analyze differences in genotype and allele frequencies of the 2 polymorphisms between case and control groups. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to present the association strength of the polymorphisms with sepsis susceptibility.AA genotype and A allele frequencies of CD86 rs1129055 were significantly lower in sepsis patients than in healthy controls (P < .05), revealing their significant associations with decreased disease susceptibility (OR = 0.351, 95% CI = 0.169-0.728; OR = 0.593, 95% CI = 0.415-0.847). Nevertheless, rs2715267 had no significant association with sepsis susceptibility (P > .05).AA genotype and A allele of CD86 polymorphism rs1129055 might be correlated with decreased sepsis susceptibility in Chinese Han population, but not rs2715267. Further study should be performed to verify our findings.


Assuntos
Antígenos CD/sangue , Antígeno B7-2/sangue , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Sepse/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Adulto Jovem
4.
BMC Infect Dis ; 19(1): 781, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492105

RESUMO

BACKGROUND: Genetic variant is one of the causes of sepsis patients' mortality. Now, many studies have identified several SNPs related to sepsis. However, none of these studies were identified in a genome-wide way. We aimed to detect genetic polymorphisms of sepsis patients. METHODS: The blood samples of eight normal controls and ten sepsis patients were collected for whole exome sequencing. Then, Single Nucleotide Polymorphisms (SNPs) were selected according to quality score and number of sepsis patients who had this variants. Synonymous mutations were removed. Genes including these remaining variants were used for functional analyses. After analyses, the remaining SNPs and indels were validated in 149 normal controls and 156 sepsis patients. Finally, serum levels of proteins coded by genes including these SNPs were evaluated. RESULTS: After whole exome sequencing, 97 SNPs and one indel site were left. Then, functional screening was performed. Only seven SNPs were used for further validation. As a result, the rs2721068 in dominant model and rs17446614 in recessive model were associated with sepsis, and the ORs of these two SNPs were 3.24 (95%CI, 1.25, 8.44) and 0.47 (0.026, 0.88), respectively. These two SNPs were both located in Forkhead box O1 (FOXO1) gene. For rs2721068 (T/T, T/C-C/C) and rs17446614 (A/A-A/G, G/G), serum levels of foxo1 in sepsis patients were both significantly lower in normal controls. CONCLUSIONS: We firstly reported that the rs2721068 and rs17446614 were correlated to genetic predisposition to sepsis.


Assuntos
Proteína Forkhead Box O1/genética , Polimorfismo de Nucleotídeo Único , Sepse/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Sepse/etnologia , Sequenciamento Completo do Exoma
5.
Adv Exp Med Biol ; 1193: 175-194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368104

RESUMO

Sepsis, defined as life-threatening tissue damage and organ dysfunction caused by a dysregulated host response to infection, is a critical disease which imposes global health burden. Sepsis-induced organ dysfunction, including circulatory and cardiac dysfunction, hepatic dysfunction, renal dysfunction, etc., contributes to high mortality and long-term disability of sepsis patients. Altered inflammatory response, ROS and reactive aldehyde stress, mitochondrial dysfunction, and programmed cell death pathways (necrosis, apoptosis, and autophagy) have been demonstrated to play crucial roles in septic organ dysfunction. Unfortunately, except for infection control and supportive therapies, no specific therapy exists for sepsis. New specific therapeutic targets are highly warranted. Emerging studies suggested a role of potential therapeutic target of ALDH2, a tetrameric enzyme located in mitochondria to detoxify aldehydes, in septic organ dysfunction. In this article, we will review the presentations and pathophysiology of septic organ dysfunction, as well as summarize and discuss the recent insights regarding ALDH2 in sepsis.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Sepse/genética , Apoptose , Autofagia , Humanos , Mitocôndrias/enzimologia
6.
Medicine (Baltimore) ; 98(33): e16744, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415369

RESUMO

MicroRNAs (miRNAs) play an important role in the pathogenesis of sepsis, but the association of miRNAs single nucleotide polymorphisms (SNPs) and sepsis risk is not clear. We analyzed plasma levels of miR-187, miR-21, and miR-145 in 180 patients with sepsis and 180 healthy controls were analyzed, and the SNPs: rs12605436, rs13137, and rs353291 were detected by sequencing. Plasma levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured in all subjects by enzyme-linked immunosorbent assay (ELISA). The results showed that the levels of TNF-α and IL-6 in the plasma of patients with sepsis were significantly higher than those in patients of the control group (P < .0001). Plasma levels of miR-187 in patients with sepsis were significantly lower than those in the control group, while those of miR-21 and miR-145 were significantly higher than those in the control group (P < .0001). Plasma levels of miR-187 in sepsis patients were inversely correlated with those of TNF-α and IL-6 (r = -0.2841, -0.2163), and plasma levels of miR-21 and miR-145 were positively correlated with those of TNF-α and IL-6 (r = 0.615, 0.3057, 0.4465, 0.2734). The T allele of the miR-187 SNP rs12605436 was found to be a risk factor for sepsis (OR = 1.403, 95% CI = 1.205-1.612, P < .001). The T allele of the miR-21 SNP rs13137 and the T allele of the miR-145 SNP rs353291 (OR = 0.685, 95% CI = 0.566-0.820, P < .001) were found to be a protective factor for sepsis (OR = 0.755, 95% CI = 0.632-0.896, P < .001). From our results, we can see that the plasma levels of miRNAs containing the SNPs rs12605436, rs13137, and rs353291 are associated with the occurrence of sepsis.


Assuntos
Predisposição Genética para Doença , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Sepse/genética , APACHE , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Sepse/sangue , Fator de Necrose Tumoral alfa/sangue
7.
Medicine (Baltimore) ; 98(33): e16807, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415393

RESUMO

BACKGROUND: Sepsis is a serious clinical condition with a poor prognosis, despite improvements in diagnosis and treatment.Therefore, novel biomarkers are necessary that can help with estimating prognosis and improving clinical outcomes of patients with sepsis. METHODS: The gene expression profiles GSE54514 and GSE63042 were downloaded from the GEO database. DEGs were screened by t test after logarithmization of raw data; then, the common DEGs between the 2 gene expression profiles were identified by up-regulation and down-regulation intersection. The DEGs were analyzed using bioinformatics, and a protein-protein interaction (PPI) survival network was constructed using STRING. Survival curves were constructed to explore the relationship between core genes and the prognosis of sepsis patients based on GSE54514 data. RESULTS: A total of 688 common DEGs were identified between survivors and non-survivors of sepsis, and 96 genes were involved in survival networks. The crucial genes Signal transducer and activator of transcription 5A (STAT5A), CCAAT/enhancer-binding protein beta (CEBPB), Myc proto-oncogene protein (MYC), and REL-associated protein (RELA) were identified and showed increased expression in sepsis survivors. These crucial genes had a positive correlation with patients' survival time according to the survival analysis. CONCLUSIONS: Our findings indicate that the genes STAT5A, CEBPB, MYC, and RELA may be important in predicting the prognosis of sepsis patients.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fator de Transcrição STAT5/metabolismo , Sepse/genética , Sepse/mortalidade , Fator de Transcrição RelA/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biologia Computacional , Bases de Dados Genéticas , Regulação para Baixo , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas , Fatores de Tempo , Transcriptoma , Regulação para Cima
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(6): 481-490, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31292051

RESUMO

Objective To identify key pathogenic differentially expressed genes and pathways in neutrophils of patients with sepsis. Methods Firstly, we screened and downloaded a total of 143 experimental and 65 control neutrophil samples from Gene Expression Omnibus (GEO) gene expression profile datasets GSE6535, GSE49755, GSE49756, GSE49757. Secondly, we identified differentially expressed genes (DEGs) via corresponding packages in R software. Finally, through intersecting DEGs from every two datasets of those four GEO datasets, we had got 93 DEGs as candidate DEGs, and subsequently conducted gene ontology and pathway enrichment analysis, PPI network analysis and hub gene analysis, using multiple methods containing DAVID, STRING, Cytoscape Apps such as ReactomeFIPlugIn and Cytohubba. Results We had identified most significant hub DEGs, including TLR2, SRC, MMP9, IL1R2, ARRB1, IRAK3, IL18R1, IL18RAP, and STK17B. Besides, we found that some pathogenicity-related pathways and immune-related biological processes were involved in sepsis. The hub genes found by this study might cause sepsis through a variety of signaling pathways and be implicate in the pathogenesis of sepsis. Conclusion These genes may cause the onset and development of sepsis through a variety of signaling pathways.


Assuntos
Biologia Computacional , Neutrófilos/citologia , Sepse/genética , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Transdução de Sinais , Transcriptoma
9.
J Sci Food Agric ; 99(13): 5870-5880, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31206687

RESUMO

BACKGROUND: Sepsis is a set of serious organic manifestations caused by an infection, whose progression culminates in exacerbated inflammation and oxidative stress, poor prognosis, and high hospital costs. Antioxidants used against sepsis have been evaluated, including essential oils such as ß-caryophyllene (BCP), and polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). The aim of this study was to evaluate the anti-inflammatory activity of the association of these two compounds. RESULTS: Treatment with BCP-DHA, at a dose of 200 µL/animal, significantly inhibited the migration of neutrophils in a Cg-induced peritonitis model. After Staphylococcus aureus infection, in the groups treated with BCP-DHA there was a significant decrease in the total and differential count of leukocytes, increased expression of cytokines TNF-α and IFN-γ in treated groups, an increase of IL-4 and IL-5 in B/D and B/D + SA groups, and an augmentation of IL-6 and IL-12 groups in B/D + SA groups. Histological and bacterial analysis revealed lower neutrophil migration and lower bacterial load in the infected and treated groups. CONCLUSION: In general, the BCP-DHA association presented anti-inflammatory activity against two different models of acute inflammation and infection, showing promising potential as a therapeutic adjuvant in sepsis. © 2019 Society of Chemical Industry.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Peritonite/tratamento farmacológico , Sepse/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Peritonite/genética , Peritonite/imunologia , Peritonite/microbiologia , Sepse/genética , Sepse/imunologia , Sepse/microbiologia , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
10.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(5): 650-653, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31198158

RESUMO

OBJECTIVE: Sepsis and septic shock are important clinical problems in critically ill patients, accounting for the first cause of death in intensive care unit (ICU). Therefore, early diagnosis and treatment are particularly important. Recently, genome-wide expression analysis of non-coding RNA in septic patients showed that more than 80% were differentially expressed compared with healthy individuals. These molecules play important roles in biological processes, including innate immunity, mitochondrial function and apoptosis. Therefore, a class of non-coding RNAs such as microRNA (miRNA), long-chain non-coding RNA (lncRNA) and circular non-coding RNA (circRNA) are increasingly recognized as a regulator of various signaling pathways. The potential of regulatory non-coding RNA target to treat sepsis was discussed by studying non-coding RNAs that might serve as molecular markers of sepsis, and its clinical value was evaluated.


Assuntos
Sepse/genética , Sepse/terapia , Biomarcadores , Humanos , MicroRNAs , RNA , RNA Longo não Codificante
11.
Biomed Res Int ; 2019: 2487921, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093495

RESUMO

Sepsis is a critical, complex medical condition, and the major causative pathogens of sepsis are both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Genome-wide studies identify differentially expressed genes for sepsis. However, the results for the identification of DEGs are inconsistent or discrepant among different studies because of heterogeneity of specimen sources, various data processing methods, or different backgrounds of the samples. To identify potential transcriptional biomarkers that are differently expressed in S. aureus- and E. coli-induced sepsis, we have analyzed four microarray datasets from GEO database and integrated results with bioinformatics tools. 42 and 54 DEGs were identified in both S. aureus and E. coli samples from any three different arrays, respectively. Hierarchical clustering revealed dramatic differences between control and sepsis samples. GO functional annotations suggested that DEGs in the S. aureus group were mainly involved in the responses of both defense and immune regulation, but DEGs in the E. coli group were mainly related to the regulation of endopeptidase activity involved in the apoptotic signaling pathway. Although KEGG showed inflammatory bowel disease in the E. coli group, the KEGG pathway analysis showed that these DEGs were mainly involved in the tumor necrosis factor signaling pathway, fructose metabolism, and mannose metabolism in both S. aureus- and E. coli-induced sepsis. Eight common genes were identified between sepsis patients with either S. aureus or E. coli infection and controls in this study. All the candidate genes were further validated to be differentially expressed by an ex-vivo human blood model, and the relative expression of these genes was performed by qPCR. The qPCR results suggest that GK and PFKFB3 might contribute to the progression of S. aureus-induced sepsis, and CEACAM1, TNFAIP6, PSTPIP2, SOCS3, and IL18RAP might be closely linked with E. coli-induced sepsis. These results provide new viewpoints for the pathogenesis of both sepsis and pathogen identification.


Assuntos
Biomarcadores/metabolismo , Escherichia coli/fisiologia , Sepse/genética , Sepse/microbiologia , Staphylococcus aureus/fisiologia , Transcrição Genética , Análise por Conglomerados , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Anotação de Sequência Molecular , Reprodutibilidade dos Testes , Transcriptoma/genética , Regulação para Cima/genética
12.
Mol Immunol ; 112: 72-81, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31078118

RESUMO

Myeloid-derived suppressor cells (MDSC) expand during sepsis, suppress both innate and adaptive immunity, and promote chronic immunosuppression, which characterizes the late/chronic phase of sepsis. We previously reported that the transcription factors Stat3 and C/EBPß synergize to induces the expression of microRNA (miR)-21 and miR-181b to promote MDSC expansion in a mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive stage. We also showed that Gr1+CD11b+ cells, the precursors of MDSCs, from mice genetically deficient in the inflammatory protein S100A9 lack miR-21 or miR-181b in late sepsis, and are not immunosuppressive. In the present study, we show that S100A9 induces miR-21 and miR-181b during the late sepsis phase. We find that S100A9 associates with and stabilizes the Stat3-C/EBPß protein complex that activates the miRNA promoters. Reconstituting Gr1+CD11b+ cells from S100A9 knockout mice with late sepsis with S100A9 protein restores the Stat3-C/EBPß protein complex and miRNA expressions, and switches the Gr1+CD11b+ cells into the immunosuppressive, MDSC phenotype. Importantly, we find that this process requires IL-10 mediated signaling, which induces S100A9 translocation from the cytosol to the nucleus. These results demonstrate that S100A9 promotes MDSC expansion and immunosuppression in late/chronic sepsis by inducing the expression of miR-21 and miR-181b.


Assuntos
Calgranulina B/genética , MicroRNAs/genética , Células Mieloides/metabolismo , Células Supressoras Mieloides/metabolismo , Sepse/genética , Animais , Antígenos Ly/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Antígeno CD11b/genética , Modelos Animais de Doenças , Imunossupressão/métodos , Inflamação/genética , Interleucina-10/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética
13.
Mol Med Rep ; 20(1): 584-592, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115557

RESUMO

The purpose of the present study was to investigate the differentially expressed proteins between endotoxin tolerance and sepsis. Cell models of an endotoxin tolerance group (ET group) and sepsis group [lipopolysaccharide (LPS) group] were established using LPS and evaluated using ELISA and flow cytometry methods. Differentially expressed proteins between the ET and the LPS groups were identified using isobaric tags for relative and absolute quantitation (iTRAQ) analysis and evaluated by bioinformatics analysis. The expression of core proteins was detected by western blotting. It was identified that the expression of tumor necrosis factor­α and interleukin­6 was significantly decreased in the ET group compared with the LPS group. Following high­dose LPS stimulation for 24 h, the positive rate of cluster of differentiation­16/32 in the ET group (79.07%) was lower when compared with that of the LPS group (94.27%; P<0.05). A total of 235 proteins were identified by iTRAQ, and 36 upregulated proteins with >1.2­fold differences and 27 downregulated proteins with <0.833­fold differences were detected between the ET and LPS groups. Furthermore, the expression of high mobility group (HMG)­A1 and HMGA2 in the ET group was higher compared with the LPS group following high­dose LPS stimulation for 4 h, while HMGB1 and HMGB2 exhibited the opposite expression trend under the same conditions. In conclusion, proteomics analysis using iTRAQ technology contributes to a deeper understanding of ET mechanisms. HMGA1, HMGA2, HMGB1 and HMGB2 may serve a crucial role in the development of ET.


Assuntos
Endotoxinas/farmacologia , Proteínas HMGA/genética , Lipopolissacarídeos/farmacologia , Sepse/tratamento farmacológico , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Biologia Computacional , Tolerância a Medicamentos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Proteômica , Sepse/genética , Sepse/patologia , Fator de Necrose Tumoral alfa/genética
14.
BMC Pulm Med ; 19(1): 93, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088429

RESUMO

BACKGROUND: Sepsis biomarkers have limited specificity and sensitivity. Few studies have investigated microRNA (miRNA) biomarkers for sepsis secondary to pneumonia. This study aims to investigate the diagnostic and prognostic values of miRNAs in sepsis secondary to pneumonia. METHODS: Sepsis 3.0 was used to diagnose sepsis. Screening was performed through the Agilent miRNA chip technology by using the following criteria: p < 0.05, fold ≥2 or < 0.5, or copy number > 50 change. This study recruited 52 patients with pneumonia, including 31 males (59.6%) and 21 females (40.4%), 44 patients with sepsis secondary to pneumonia were diagnosed via Sepsis 3.0 (34 [77.3%] males and 10 [22.7%] females), and 21 healthy controls were used for miRNA verification. The miRNA levels were detected through fluorescence real-time quantitative polymerase chain reaction (qRT-PCR). RESULTS: Fluorescence qRT-PCR detection showed that the miR-7110-5p and miR-223-3p expression levels in both patient groups were upregulated compared with those in the healthy controls. The expression levels differed between patients with pneumonia and those with sepsis secondary to pneumonia. The sensitivity and specificity of miR-7110-5p to differentiate sepsis from healthy controls were 84.2 and 90.5%, whereas those of miR-223-3p were 82.9 and 100%, respectively. Multivariate analysis of variance suggested that the presence of sepsis affected the miR-223-3p level (p = 0.041), whereas the presence of sepsis (p = 0.000) and the underlying disease (p = 0.025) influenced the miR-7110-5p level. CONCLUSIONS: MiR-223-3p could be utilized to predict sepsis secondary to pneumonia.


Assuntos
MicroRNA Circulante/sangue , MicroRNAs/sangue , Pneumonia/complicações , Sepse/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores/sangue , Estudos de Casos e Controles , MicroRNA Circulante/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Estudos Prospectivos , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Sepse/sangue , Regulação para Cima
15.
Mol Med Rep ; 19(6): 5133-5141, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059023

RESUMO

Sepsis is a type of systemic inflammatory response caused by infection. The present study aimed to identify novel targets for the treatment of sepsis. We conducted bioinformatic analysis of the microarray Gene Expression Omnibus dataset GSE12624, which includes data on 34 patients with sepsis and 36 healthy individuals without sepsis. Differentially expressed genes (DEGs) in sepsis patients were identified using Bayesian methods included in the limma package in R. Correlations among the expression values of DEGs were analyzed using the weighted gene co­expression network analysis (WGCNA) to construct a co­expression network. Subsequently, the generated co­expression network was visualized using Cytoscape 3.3 software. Additionally, a protein­protein interaction (PPI) network was constructed based on all the DEGs using STRING. Finally, the integrated regulatory network was constructed based on DEGs, microRNAs (miRNAs) and transcription factors (TFs). A total of 407 DEGs were identified in the sepsis samples, including 227 upregulated DEGs and 180 downregulated DEGs. WGCNA grouped the DEGs into 13 co­expressed modules. Additionally, MAP3K8 and RPS6KA5 in the MEyellow module were enriched in the MAPK and TNF signaling pathways. In addition, the PPI network comprised 48 nodes and 112 edges, which included the pairs MAP3K8­RPS6KA5, MAP3K8­IL10, RPS6KA5­EXOSC4 and EXOSC4­EXOSC5. Lastly, the TF­miRNA­target DEG regulatory network was constructed based on eight TFs (NF­κB), seven miRNAs (miR152, miR­148A/B), and 52 TF­miRNA­target gene triplets (17 upregulated genes, including MAP3K8, and 10 downregulated genes, including RPS6KA5). Our analysis showed that the members of the miR­148 family (miR­148A/B and miR­152) are candidate biomarkers for sepsis.


Assuntos
Biomarcadores/metabolismo , MicroRNAs/metabolismo , Sepse/diagnóstico , Biologia Computacional/métodos , Bases de Dados Genéticas , Regulação para Baixo , Redes Reguladoras de Genes , Humanos , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Sepse/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima
16.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075840

RESUMO

Timely and reliable distinction of sepsis from non-infectious systemic inflammatory response syndrome (SIRS) supports adequate antimicrobial therapy and saves lives but is clinically challenging. Blood transcriptional profiling promises to deliver insights into the pathomechanisms of SIRS and sepsis and to accelerate the discovery of urgently sought sepsis biomarkers. However, suitable reference genes for normalizing gene expression in these disease conditions are lacking. In addition, variability in blood leukocyte subtype composition complicates gene profile interpretation. Here, we aimed to identify potential reference genes in natural killer (NK) cells and granulocytes from patients with SIRS and sepsis on intensive care unit (ICU) admission. Discovery by a two-step probabilistic selection from microarray data followed by validation through branched DNA assays in independent patients revealed several candidate reference genes in NK cells including AKIRIN1, PPP6R3, TAX1BP1, and ADRBK1. Initially, no candidate genes could be validated in patient granulocytes. However, we determined highly similar AKIRIN1 expression also in SIRS and sepsis granulocytes and no change by in vitro LPS challenge in granulocytes from healthy donors. Inspection of external neutrophil transcriptome datasets further support unchanged AKIRIN1 expression in human systemic inflammation. As a potential new reference gene in NK cells and granulocytes in infectious and inflammatory diseases, AKIRIN1 may improve our pathomechanistic understanding of SIRS and sepsis and help identifying new sepsis biomarkers.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ligação a DNA/genética , Granulócitos/metabolismo , Células Matadoras Naturais/metabolismo , Proteínas Nucleares/genética , Sepse/genética , Sepse/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Padrões de Referência , Reprodutibilidade dos Testes , Síndrome de Resposta Inflamatória Sistêmica/genética , Síndrome de Resposta Inflamatória Sistêmica/patologia , Doadores de Tecidos , Transcriptoma/genética
17.
Am J Chin Med ; 47(3): 613-633, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30966773

RESUMO

High mobility group box 1 (HMGB1) is recognized as a late mediator of sepsis, and the inhibition of HMGB1 release and recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. We tested the hypothesis that aloin induces sirtuin 1 (SIRT1) and heme oxygenase (HO)-1, which inhibit HMGB1 release in lipopolysaccharide (LPS)-stimulated cells, thereby inhibiting HMGB1-induced hyperpermeability and increasing the survival of septic mice. Aloin was administered after LPS or HMGB1 challenge, and the antiseptic activity of aloin was determined from measurements of permeability, activation of pro-inflammatory proteins and production of markers for tissue injury in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model. Aloin significantly reduced HMGB1 release in LPS-activated HUVECs via SIRT1-mediated HMGB1 deacetylation and the PI3K/Nrf2/heme oxygenase (HO)-1 signaling axis. Aloin also suppressed the production of tumor necrosis factor (TNF)- α and interleukin (IL)-6, as well as the activation of nuclear factor (NF)- κ B and extracellular signal-regulated kinase 1/2 (ERK 1/2) by HMGB1. Moreover, aloin restored HMGB1-mediated vascular disruption and inhibited vascular hyperpermeability in mice. In addition, treatment with aloin reduced the CLP-induced release of HMGB1, sepsis-related mortality and tissue injury in vivo. Our results suggest that aloin reduces HMGB1 release and sepsis-related mortality by activating SIRT1 and PI3K/Nrf2/HO-1 signals, indicating that aloin has potential for the treatment of sepsis.


Assuntos
Emodina/análogos & derivados , Proteína HMGB1/metabolismo , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Sepse/tratamento farmacológico , Sepse/etiologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Aloe/química , Animais , Modelos Animais de Doenças , Emodina/administração & dosagem , Emodina/farmacologia , Proteína HMGB1/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Fitoterapia , Sepse/genética , Sepse/metabolismo
18.
Tohoku J Exp Med ; 247(4): 259-264, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31006736

RESUMO

Early-onset neonatal sepsis (EOS) is diagnosed during the first 7 days of neonatal life and is the major cause of morbidity and mortality among preterm infants. Genetic predisposition may have an impact on EOS susceptibility and outcome. The aim of our study was to explore the association between TNF-α -308 G/A or IL-6 -174 G/C gene polymorphism and the susceptibility and outcome of EOS in preterm infants. The study included 471 preterm infants: 282 with EOS (151 with culture proven sepsis and 131 with clinical sepsis) and 189 without infection (control group). TNF-α -308 G/A and IL-6 -174 G/C were genotyped using Real-time RCR method. We observed significantly higher frequency of A allele of TNF-α -308 G/A polymorphism in blood culture proven EOS (p = 0.017) or clinical EOS (p = 0.025) compared with the control group. Logistic regression confirmed significant association between TNF-α -308 GA+AA genotypes and development of culture proven EOS (B = -0.718, p = 0.013) or clinical EOS (B = -0.602, p = 0.027). No significant differences in IL6 -174G/C alleles or genotypes distribution have been observed between culture proven EOS group, clinical EOS group and the control group. An association between TNF-α -308 G/A or IL-6 -174 G/C genotypes and EOS lethal outcome was not observed (p = 0.652 and p = 0.384, respectively). According to our analysis of large cohort of preterm infants with clearly defined EOS groups, the TNF-α -308 A allele may be a risk factor for the EOS occurrence.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Recém-Nascido Prematuro/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Sepse/genética , Fator de Necrose Tumoral alfa/genética , Alelos , Feminino , Humanos , Recém-Nascido , Masculino
19.
J Steroid Biochem Mol Biol ; 191: 105360, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028792

RESUMO

Activation of the adrenal gland stress response is of utmost importance to survive sepsis. Experimental and clinical evidence exists demonstrating that adrenal gland often develops functional and structural damage due to sepsis with mechanisms remaining largely unknown. In the present study, we have used RNA Sequencing (RNA-Seq) technology to analyze changes in adrenal transcriptome elucidated by bacterial LPS. We aimed to find particularly alterations in genes that were previously not reported to be involved in the adrenal gland dysregulation in contexts of sepsis. Our results demonstrate that systemic administration of LPS significantly altered expression of 8458 genes as compared to saline injected animals. The subsequent quality and functional analysis of these gene signatures revealed that LPS-induced highly homogenous transcriptional response in total upregulating 4312 and downregulating 4146 genes. Furthermore, functional annotation analysis together with gene enrichment set analysis (GSEA) clearly demonstrated that adrenal response to LPS involved alterations in multiple pathways related to the inflammatory response along with previously unexplored activation of the hypoxia pathway. In addition, LPS strongly downregulated genes involved in the adrenal homeostasis, development, and regeneration. Those alterations were subsequently verified in clinically relevant cecal ligation and puncture (CLP)-induced sepsis model. Collectively, our study demonstrates that RNA-seq is a very useful method that can be applied to search for new unexplored pathways potentially involved in adrenal gland dysregulation during sepsis.


Assuntos
Sepse/genética , Transcriptoma , Glândulas Suprarrenais/imunologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiopatologia , Animais , Regulação da Expressão Gênica , Lipopolissacarídeos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Sepse/imunologia , Sepse/fisiopatologia , Análise de Sequência de RNA
20.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(3): 293-297, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-30914088

RESUMO

OBJECTIVE: To analyze the characteristics of skeletal muscle cells gene markers in septic patients by using bioinformatics. METHODS: The differential gene expression of marker microarrays (GSE13205) in skeletal muscle tissue of patients with sepsis was obtained from gene expression omnibus (GEO) database of National Center for Biotechnology Information (NCBI). Gene differential expression analysis was carried out using online GEO2R provided by NCBI. Data processing, analysis and mapping were carried out using online bioinformatics array research tool (BART) and Cytoscpe software, the software of the national resource for network biology. Functional annotation and pathway analysis of differential expression genes were performed using Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) provided by the database for annotation, visualization and integrated discovery (DAVID), and protein interaction analysis was further performed in search tool for the retrieve of interacting genes/proteins (STRING-DB). RESULTS: The TOP250 genes were extracted from the GSE13205 dataset. A total of 242 differentially expressed genes were included in the analysis. Among them, 78 up-regulated genes and 164 down-regulated genes were identified. After extensive data analysis, these differentially expressed genes were enriched into different biological processes or subsets of molecular functions, mainly enriched in the positive and negative regulation of growth, mineral absorption and other pathways. The 14 most closely related genes among differentially expressed genes were identified from the protein interaction network. CONCLUSIONS: The differential expression genes in patients with sepsis were mainly concentrated on cell growth and apoptosis and mediating tumor-related immune function regulation.


Assuntos
Músculo Esquelético/metabolismo , Sepse/genética , Biologia Computacional , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Marcadores Genéticos , Humanos
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