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Growing evidence indicated that single nucleotide polymorphisms (SNPs) in the apolipoprotein E (APOE) gene are related to increase the risk of many inflammatory-related diseases. However, few genetic studies have associated the APOE gene polymorphism with sepsis. This study was to investigate the clinical relevance of the APOE gene polymorphism in the onset and progression of sepsis. A multicenter case–control association study with a large sample size (601 septic patients and 699 healthy individuals) was conducted. Clinical data showed that the APOEε4 allele was overrepresented among all patients with septic shock (p = 0.031) compared with sepsis subtype, suggesting that APOEε4 allele may associated with increased susceptibility to the progression of sepsis. Moreover, the APOE mRNA levels decreased after lipopolysaccharide (LPS) stimulation in cells in culture. Then 21 healthy individuals to extract PBMC for genotype grouping (APOE4+ group 8; APOE4− group 13) was selected to evaluate the effect on APOE level, and results showed that the expression level of APOE in APOE4+ group and APOE4− group did not differ in mRNA levels after an LPS challenge, but the protein levels in APOE4+ group decreased slower than that in APOE4− group, and this process was accompanied by the upregulation of proinflammatory cytokines. These results provide evidence that the APOEε4 allele might be associated with the development of sepsis and a potential risk factor that can be used in the prognosis of sepsis.

Nucleotide-binding domain and leucine-rich repeat (LRR)-containing family protein 3 (NLRP3) regulated the maturation of inflammation-related cytokines by forming NLRP3 inflammasome, which plays pivotal roles in sepsis pathogenesis. In this study, we evaluated the genetic association of NLRP3 polymorphisms with sepsis (640 patients and 769 controls) and characterized the impact of NLRP3 polymorphisms on NLRP3 expression and inflammatory responses. No significant differences were observed in genotype/allelic frequencies of NLRP3 29940G>C between sepsis cases and controls. The G allele was significantly overrepresented in patients with septic shock than those in sepsis subgroup, and the GC/GG genetypes were related to the 28-day mortality of sepsis. Lipopolysaccharide challenge to peripheral blood mononuclear cells showed a significant suppression of NLRP3 mRNA expression and release of IL-1β and TNF-α in CC compared with the GC/GG genotype category. Functional experiments with luciferase reporter vectors containing the NLRP3 3′-UTR with the 29940 G-to-C variation in HUVECs and THP-1 cells showed a potential suppressive effect of miR-146a on NLRP3 transcription in the presence of the C allele. Taken together, these results demonstrated that the 29940 G-to-C mutation within the NLRP3 3′-UTR was a gain-of-function alteration that caused the suppression of NLRP3 expression and downstream inflammatory cytokine production via binding with miR-146a, which ultimately protected patients against susceptibility to sepsis progression and poor clinical outcome.

Aims We previously reported that fenugreek-derived 4-hydroxyisoleucine ameliorates insulin resistance via regulation of TNF-α converting enzyme (TACE) expression. In the present study, we further investigate the effects and mechanisms of fenugreek on obesity-induced inflammation and insulin signaling in the high-fat diet (HFD)-challenged obese mice. Main methods After 12 weeks of HFD intervention, mice were treated with the low or high dosages of fenugreek. Serum levels of glucose, insulin, lipid profile, inflammation cytokines, and adipokines were detected. Macrophage infiltration and adipose tissue morphology were observed. Western blot was conducted to investigate the expressions of inactive rhomboid 2 (iRhom2) and TACE as well as other signaling pathways in subcutaneous adipose tissue. Key findings We showed that fenugreek significantly suppressed body weight gain and fat accumulation in HFD-challenged obese mice. Meanwhile, fasting glucose, insulin, and HOMA-IR in fenugreek-treated mice were remarkably decreased, which were properly explained by fenugreek-induced activation of the insulin receptor signaling pathway. Moreover, the anti-inflammatory properties of fenugreek were shown by the decrease of systemic and local expressions of pro-inflammatory cytokines as well as reduced macrophage infiltration into adipose tissue. Additionally, fenugreek markedly deactivated NF-κB and JNK pathways. Finally, we demonstrated that fenugreek strikingly repressed the transcriptions and expressions of iRhom2 and TACE. Significance Fenugreek shows an encouraging and promising property in ameliorating insulin resistance and suppressing inflammation in obesity, which might be realized by fenugreek-mediated inhibition of iRhom2/TACE axis-facilitated TNF-α release from adipocytes.

BACKGROUND A disintegrin and metalloproteinase 17 (ADAM17) is a proteolytic cleaving protein with a crucial function in the inflammatory responses, especially sepsis. But the clear role of ADAM17 in sepsis and the underlying mechanism remained unknown. In this study, we aim to determine the clinical association of ADAM17 -172A > G (rs12692386) promoter polymorphism with sepsis and to further explore the effect and mechanism of the early growth response 1 (EGR1)/ADAM17 pathway in inflammatory process during sepsis. METHODS A total of 477 sepsis patients and 750 controls were enrolled in this study to determine the association of ADAM17 -172A > G polymorphism with sepsis. The transcription factor binding to the promoter region of ADAM17 gene was predicted by bioinformatics analysis and verified by Chromatin Immunoprecipitation (ChIP) and luciferase assays. Quantitative real-time PCR and Western blot were performed to detect EGR1 and ADAM17 expression. Cytokine production was detected by enzyme-linked immunosorbent assay. The effect of EGR1/ADAM17 pathway on sepsis-induced inflammatory responses was evaluated in EGR1-silenced cells and endotoxemia mouse model. RESULTS The frequencies of non-survivors among the sepsis patients with the -172AG/GG genotypes and G allele were distinctly higher than those among patients with the AA genotype (53.9% vs. 39.7%, OR = 1.779, 95% CI = 1.119-2.829, P = 0.0142) and A allele (30.9% vs. 22.2%, OR = 1.570, 95% CI = 1.095-2.251, P = 0.0136). The Kaplan-Meier survival analysis indicated that the 28-day survival in septic patients with -172AG/GG genotypes of this functional ADAM17 promoter polymorphism was much worse than in the AA genotype carriers (log-rank = 5.358, P = 0.021). The results of in vitro lipopolysaccharide-stimulated and luciferase assays indicated that the -172 A-to-G variation could functionally upregulate promoter activity and transcription of ADAM17 gene via enhancing the binding affinity of its promoter region with the EGR1. The ChIP assay identified the direct interaction. Further studies demonstrated that inhibition of EGR1 significantly decreased ADAM17 expression and the pro-inflammatory cytokine secretion in vitro, and improved the survival and inflammatory response of sepsis mouse model. CONCLUSIONS These results provided evidence that the ADAM17 -172A > G polymorphism functionally promoted ADAM17 expression and enhanced sepsis-induced inflammatory responses via the EGR1/ADAM17 pathway, which ultimately conferred susceptibility to sepsis mortality and poor prognosis.

Sepsis is characterized as life-threatening organ dysfunction, with unacceptably high mortality. Evidence has indicated that functional SNPs within inflammatory genes are associated with susceptibility, progression, and prognosis of sepsis. These mechanisms on which these susceptible sites depended often suggest the key pathogenesis and potential targets in sepsis. In the present study, we confirmed that a functional variant acts as an important genetic factor that confers the progression of sepsis in a large sample size and in multiple centers and revealed that the variants modulate the EGR1/ADAM10 pathway and influence the severity of sepsis. We believe that we provide an important insight into this new pathway involving the regulation of inflammatory process of sepsis based on the clinical genetic evidence, which will enhance the understanding of nosogenesis of sepsis and provide the potential target for inflammation-related diseases., Increasing evidence has indicated that single nucleotide polymorphisms (SNPs) are related to the susceptibility of sepsis and might provide potential evidence for the mechanisms of sepsis. Our recent preliminary study showed that the ADAM10 genetic polymorphism was clinically associated with the development of sepsis, and little is known about the underlying mechanism. The aim of this study was to confirm the association between the ADAM10 promoter rs653765 G→A polymorphism and the progression of sepsis and to discover the underlying mechanism. Clinical data showed that the rs653765 G→A polymorphism was positively correlated with the development of sepsis, as evidenced by a multiple-center case-control association study with a large sample size, and showed that EGR1 and ADAM10 levels were associated well with the different subtypes of sepsis patients. In vitro results demonstrated that the rs653765 G→A variants could functionally modulate ADAM10 promoter activity by altering the binding of the EGR1 transcription factor (TF) to the ADAM10 promoter, affecting the transcription and translation of the ADAM10 gene. Electrophoretic mobility shift assay (EMSA) followed by chromatin immunoprecipitation (ChIP) assay indicated the direct interaction. Functional studies further identified that the EGR1/ADAM10 pathway is important for the inflammatory response. EGR1 intervention in vivo decreased host proinflammatory cytokine secretion and rescued the survival and tissue injury of the mouse endotoxemia model.

Objective The purpose of this study was to examine the prevalence of smoking in a nationally representative sample of Chinese elementary and middle school students and to investigate its risk factors from families and schools. Method The data were from the National Children's Study of China (NCSC), in which 24,013 fourth- to ninth-grade students were recruited from 100 counties in 31 provinces in China. Chi-square tests and one-way ANOVAs were used to analyze the relationships between smoking and the risk factors. Logistic regressions were used to calculate odds ratios. Results The prevalence of ever smokers and current smokers were 19.0% and 5.4%. Focusing on current smokers, boys, middle school students, rural students, boarding students, non-only children and those owning parents with low educational levels reported smoking significantly more than girls, elementary school students, urban students, non-boarding students, only children and those owning parents with high educational levels. Lower trust and support from teachers and higher parent–child conflict positively predicted both smoking and smoking frequency. Lower trust and support from classmates was associated with higher possibility of smoking. However, higher trust and support from classmates was associated with higher smoking frequency. Teacher smoking and friend smoking were only predictive of smoking, but not of smoking frequency. Conclusions Boys, middle school students, rural students, boarding students, non-only children and those owning parents with low educational levels need special attention. The most risk factors for smoking and smoking frequency were lower trust and support from teachers and higher parent–child conflict.

The purpose of this study was to examine the prevalence of Internet addiction in a nationally representative sample of Chinese elementary and middle school students and to investigate Internet addiction among Internet users with different usages. The data were from the National Children's Study of China (NCSC) in which 24,013 fourth- to ninth-grade students were recruited from 100 counties in 31 provinces in China. Only 54.2% of the students had accessed the Internet. According to the criteria of Young's Diagnostic Questionnaire (YDQ), an eight-item instrument, the prevalence of Internet addiction in the total sample was 6.3%, and among Internet users was 11.7%. Among the Internet users, males (14.8%) and rural students (12.1%) reported Internet addiction more than females (7.0%) and urban students (10.6%). The percentage of Internet addicts in elementary school students (11.5%) was not significantly lower than the percentage of middle school students (11.9%). There was no statistically significant difference between the four geographical regions (9.6%, 11.5%, 12.3%, 11.1%) characterized by different levels of economy, health, education, and social environment. As the frequency of Internet use and time spent online per week increased, the percentage of Internet addicts increased. When considering the location and purpose of Internet use, the percentage of Internet addicts was highest in adolescents typically surfing in Internet cafes (18.1%) and playing Internet games (22.5%).

The contribution of covalently closed circular DNA (cccDNA) and dendritic cells (DCs) to the progression of chronic hepatitis B virus (HBV) infection remains largely unknown. A dynamic model with seven cell types was proposed based on the biological mechanisms of viral replication and the host immune response. The cccDNA self-amplification rate was found to be closely related to both the basic reproduction number of the virus and the immune response. The combination of the cccDNA self-amplification rate and the initial activated DC count induces rich dynamics. Applying our model to the clinical data of untreated patients, we found that chronic patients have a high cccDNA self-amplification rate. For antiviral treatment, an overall drug effectiveness was introduced and the critical drug effectiveness was obtained. The model predicts that timely long-term therapy is needed to reduce the symptoms of HBV and to maintain the benefits of treatment.