Evaluation of TNF-α genetic polymorphisms as predictors for sepsis susceptibility and progression

Georgescu, Anca Meda; Bănescu, Claudia; Azamfirei, Răzvan; Huţanu, Adina; Moldovan, Valeriu; Badea, Iudita; Voidăzan, Septimiu; Dobreanu, Minodora; Chirteș, Ioana Raluca; Azamfirei, Leonard

doi:10.1186/s12879-020-4910-6

Cited by 44 publications

(39 citation statements)

References 77 publications

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“…This finding supports a prognostic biomarker role for this cytokine. 45 Th17 cytokine production is reduced in sepsis, which may adversely affect long-term mortality. 46 Treatment with IL-7 increases the responsiveness of Th17 cells and reduces the mortality of secondary fungal infections, making IL-17 a potential therapeutic agent.…”

Section: Discussionmentioning

confidence: 99%

Screening of Key Genes of Sepsis and Septic Shock Using Bioinformatics Analysis

Sun

Feng

Yang

et al. 2021

JIR

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Sepsis is a disease associated with high mortality. We performed bioinformatic analysis to identify key biomarkers associated with sepsis and septic shock. Methods: The top 20% of genes showing the greatest variance between sepsis and controls in the GSE13904 dataset (children) were screened by co-expression network analysis. The differentially expressed genes (DEGs) were identified through analyzing differential gene expression between sepsis patients and control in the GSE13904 (children) and GSE154918 (adult) data sets. Intersection analysis of module genes and DEGs was performed to identify common DEGs for enrichment analysis, protein-protein interaction network (PPI network) analysis, and Short Time-series Expression Miner (STEM) analysis. The PPI network genes were ranked by degree of connectivity, and the top 100 sepsis-associated genes were identified based on the area under the receiver operating characteristic curve (AUC). In addition, we evaluated differences in immune cell infiltration between sepsis patients and controls in children (GSE13904, GSE25504) and adults (GSE9960, GSE154918). Finally, we analyzed differences in DNA methylation levels between sepsis patients and controls in GSE138074 (adults). Results: The common genes were associated mainly with up-regulated inflammatory and metabolic responses, as well as down-regulated immune responses. Sepsis patients showed lower infiltration by most types of immune cells. Genes in the PPI network with AUC values greater than 0.9 in both GSE13904 (children) and GSE154918 (adults) were screened as key genes for diagnosis. These key genes (MAPK14, FGR, RHOG, LAT, PRKACB, UBE2Q2, ITK, IL2RB, and CD247) were also identified in STEM analysis to be progressively dysregulated across controls, sepsis patients and patients with septic shock. In addition, the expression of MAPK14, FGR, and CD247 was modified by methylation. Conclusion: This study identified several potential diagnostic genes and inflammatory and metabolic responses mechanisms associated with the development of sepsis.

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Section: Discussionmentioning

confidence: 99%

Screening of Key Genes of Sepsis and Septic Shock Using Bioinformatics Analysis

Sun

Feng

Yang

et al. 2021

JIR

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“…The level of TNF-a was positively correlated with WBC, SAA and IL-6 in the sepsis group, and was positively correlated with IL-6 in the infection group, which also indicated that the level of TNF-α could better re ect the progression of in ammation, and the correlation between TNF-α level and sepsis group was better than that of the infection group. TNF-α plays a central role in systemic in ammatory response due to its ability to release other cytokines in the early stage of infectious disease and its direct in uence in septic shock, and plasma levels of TNF-α are associated with sepsis induced death [32]. The level of PCT was positively correlated with IL-6 only in the sepsis group and CRP only in the infection group.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Value of sIL-2R, TNF-α and PCT for Sepsis Infection in Patients with Closed Abdominal Injury Complicated with Severe Multiple Abdominal Injuries

Shang

Zhang

Dai

et al. 2021

Preprint

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Objective: To evaluate the diagnostic value of soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-α (TNF-α), procalcitonin (PCT) and combined detection for sepsis infection in patients with closed abdominal injury complicated with severe multiple abdominal injuries.Patients and Methods: 140 patients with closed abdominal injury complicated with severe multiple abdominal injuries who were diagnosed and treated in 2015 to 2020, were divided into sepsis group (n = 70), and infection group (n = 70).Results: The levels of sIL-2R, TNF-α and PCT in sepsis group were higher than those in infection group (P < 0.05). ROC curve showed that the AUC values of sIL-2R, TNF-α, PCT and sIL-2R+TNF-a+PCT were 0.827, 0.781, 0.821 and 0.846, respectively, which were higher than those of WBC, CRP, SAA, and IL-6. AUC of the three combined tests was higher than that of TNF-α, and the difference was statistically significant (P < 0.05). There was no significant difference in AUC between sIL-2R and TNF-α, sIL-2R and PCT, TNF-α and PCT, three combined tests and sIL-2R, three combined tests and PCT (P > 0.05). When the median was used as the cut point, the corrected sIL-2R, TNF-α, PCT high level group was not better than the low level group in the risk of sepsis (P >0.05). When the four groups were classified by using quantile as cut point, the OR risk values of the high level of TNF-α and PCT (Q4) and the low level of PCT (Q1) after correction were 7.991 and 21.76, respectively, with statistical significance (P < 0.05).Conclusions: The detection of sIL-2R, TNF-α and PCT has a good value in the diagnosis for sepsis infection in patients with closed abdominal injury complicated with severe multiple abdominal injuries. The high concentrations of PCT and TNF-α can be used as predictors of septic infection risk.

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“…KEGG analysis has identified the TNF signaling pathway as the top one significantly enriched pathway from DEGs that were upregulated in LPS-treated group while suppressed in the DY131-treated group. TNF-α is the key inflammatory factor involved in the progression of sepsis (Ertel et al, 1994;Georgescu et al, 2020;Parameswaran and Patial, 2010;Spinas et al, 1992). In clinical research, TNF-α was considered as the initial factor that triggered and mediated the sepsis (Parameswaran and Patial, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…In clinical research, TNF-α was considered as the initial factor that triggered and mediated the sepsis (Parameswaran and Patial, 2010). TNF-α level was dramatically increased in the serum from patients with multiple causes-induced septic shock, and was positively correlated with disease severity and prognosis (Georgescu et al, 2020). Thus, TNF-α and its related signaling pathways are important targets for the treatment of sepsis.…”

Section: Discussionmentioning

confidence: 99%

Estrogen-Related Receptor γ Agonist DY131 Ameliorates Lipopolysaccharide-Induced Acute Liver Injury

Liu

et al. 2021

Front. Pharmacol.

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Sepsis-associated liver dysfunction remains a challenge in clinical practice with high mortality and limited specific therapies. DY131 is a pharmacological agonist of the orphan receptor estrogen-related receptor (ERR) γ which plays a crucial role in regulating energy generation, oxidative metabolism, cell apoptosis, inflammatory responses, etc. However, its role in acute liver injury is unknown. In this study, we evaluated the effect of DY131 on lipopolysaccharide (LPS)-induced liver injury. Mice were pretreated with DY131 through intraperitoneal injection at a dose of 5 mg/kg/day for 3 days prior to LPS challenge (10 mg/kg). 24 h later, they were anesthetized and sacrificed. Blood and liver tissues were collected for further studies. In a separate experiment, mice were treated with saline (vehicle) or DY131 for 3 days to evaluate the toxicity of DY131. We found that ERRγ was downregulated in the liver tissues from LPS-treated mice. Pretreatment with DY131 ameliorated LPS-induced liver injury as demonstrated by reduced liver enzyme release (ALT, AST, and LDH), improved liver morphological damage, and attenuated oxidative stress, inflammation and apoptosis. Meanwhile, DY131 had no significant side effects on hepatic and renal functions in mice. Finally, transcriptomics analysis revealed that the dysregulated pathways associated with inflammation and metabolism were significantly reversed by DY131 in LPS-treated mice, providing more evidence in favor of the protective effect of DY131 against LPS-induced liver injury. Altogether, these findings highlighted the protective effect of DY131 on LPS-induced hepatotoxicity possibly via suppressing oxidative stress, inflammation, and apoptosis.

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Evaluation of TNF-α genetic polymorphisms as predictors for sepsis susceptibility and progression

Cited by 44 publications

References 77 publications

Screening of Key Genes of Sepsis and Septic Shock Using Bioinformatics Analysis

Screening of Key Genes of Sepsis and Septic Shock Using Bioinformatics Analysis

Diagnostic Value of sIL-2R, TNF-α and PCT for Sepsis Infection in Patients with Closed Abdominal Injury Complicated with Severe Multiple Abdominal Injuries

Estrogen-Related Receptor γ Agonist DY131 Ameliorates Lipopolysaccharide-Induced Acute Liver Injury

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