Erythropoietin-mediated IL-17 F attenuates sepsis-induced gut microbiota dysbiosis and barrier dysfunction.

Septic gut damage is critical in the progression of sepsis and multiple organ failure, characterized by gut microbiota dysbiosis and epithelium deficiency in the gut barrier. Recent studies highlight the protective effects of Erythropoietin (EPO) on multiple organs. The present study found that EPO treatment significantly alleviated the survival rate, suppressed inflammatory responses, and ameliorated intestine damage in mice with sepsis. EPO treatment also reversed sepsis-induced gut microbiota dysbiosis. The protective role of EPO in the gut barrier and microbiota was impaired after EPOR knockout. Notably, we innovatively demonstrated that IL-17 F screened by transcriptome sequencing could ameliorate sepsis and septic gut damage including gut microbiota dysbiosis and barrier dysfunction, which was verified by IL-17 F-treated fecal microbiota transplantation (FMT) as well. Our findings highlight the protection effects of EPO-mediated IL-17 F in sepsis-induced gut damage by alleviating gut barrier dysfunction and restoring gut microbiota dysbiosis. EPO and IL-17 F may be potential therapeutic targets in septic patients.

Dynamic monitoring of circulating CD8+ T and NK cell function in patients with septic shock.

BACKGROUND: Septic shock is a great threat to human life. Our aim is to explore the immune status and dynamic changes of circulating cytotoxic cells in septic shock patients. METHODS: Forty-eight septic shock patients (9 non-survivors and 39 survivors) and 30 healthy controls (HCs) were enroled in our study. The function of cytotoxic cells was dynamically monitored by flow cytometry. RESULTS: The number of circulating CD8+ T and NK cells decreased significantly in septic shock patients, while the number of CD8+ T cells rose in survivors 5 days after admission. The frequency of HLA-DR+CD8+ T/ NK cells increased in both groups after admission but decreased in non-survivors on day 3. Moreover, the frequency of GrA+/GrB+/perforin+NK and GrB+CD8+ T cells decreased to varying degrees in both groups, and the frequency of GrB+/perforin+CD8+ T cells on the second day of non-survivors was significantly lower than that of survival patients. Besides, the frequency of CXCR3+CD8+ T/ NK cells was decreased in both groups and remained low in non-survivors, but remarkably increased in survivors after day 3. And the concentrations of cytokines IL-6, IL-10, TNF-α and IFN-γ were significantly increased in septic shock patients. CONCLUSIONS: Circulating CD8+ T and NK cells reduced but activation function was compensatory enhanced in septic shock patients. The frequency of GrB+/PFP+CD8+ T and CXCR3+CD8+ T/NK cells may predict the progression of septic shock patients 2-3 days after admission.

IL-6 and IL-10 Closely Correlate with Bacterial Bloodstream Infection.

BACKGROUND: Given the high mortality of bacterial bloodstream infections (BSI), blood culture results do not meet clinical needs timely due to being time-consuming and having low positive rate. Whether we can identify the severity and type of bacterial infections by cytokines is a controversial issue. OBJECTIVE: To investigate the dynamic change of cytokines in BSI. METHODS: 55 patients with Gram-positive (GP) BSI, 64 patients with Gram-negative (GN) BSI and 52 healthy controls were enrolled. We quantitatively detected the cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) by flow cytometry in the sera. The levels of procalcitonin, C-reactive protein, leukocytes and neutrophils were also detected simultaneously. RESULTS: There were significantly up-regulated IL-6 and IL-10 expression in BSI patients, particularly in the GN-BSI, for instance Escherichia coli and Klebsiella pneumoniae infections; following the treatment, IL-6 and IL-10 decreased by 10-23 and 4-27 times, respectively. Additionally, IL-2, TNF-α and IFN-γ expression increased slightly in BSI patients and IFN-γ expression declined as GN-BSI progressed. CONCLUSION: IL-6 and IL-10 are closely associated with the severity and treatment efficacy of BSI, and can help to distinguish between GP-BSI and GN-BSI at an early stage.

CoQ10 ameliorates mitochondrial dysfunction in diabetic nephropathy through mitophagy.

The molecular signaling mechanisms of Coenzyme Q10 (CoQ10) in diabetic nephropathy (DN) remain poorly understood. We verified that mitochondrial abnormalities, like defective mitophagy, the generation of mitochondrial reactive oxygen species (mtROS) and the reduction of mitochondrial membrane potential, occurred in the glomerulus of db/db mice, accompanied by reduced PINK and parkin expression and increased apoptosis. These changes were partially reversed following oral administration of CoQ10. In inner fenestrated murine glomerular endothelial cells (mGECs), high glucose (HG) also resulted in deficient mitophagy, mitochondrial dysfunction and apoptosis, which were reversed by CoQ10. Mitophagy suppression mediated by Mdivi-1 or siPINK abrogated the renoprotective effects exerted by CoQ10, suggesting a beneficial role for CoQ10-restored mitophagy in DN. Mechanistically, CoQ10 restored the expression, activity and nuclear translocation of Nrf2 in HG-cultured mGECs. In addition, the reduced PINK and parkin expression observed in HG-cultured mGECs were partially elevated by CoQ10. CoQ10-mediated renoprotective effects were abrogated by the Nrf2 inhibitor ML385. When ML385 abolished mitophagy and the renoprotective effects exerted by CoQ10, mGECs could be rescued by treatment with mitoTEMPO, which is a mtROS-targeted antioxidant. These results suggest that CoQ10, as an effective antioxidant in mitochondria, exerts beneficial effects in DN via mitophagy by restoring Nrf2/ARE signaling.

[The correlation between ICAM-1 gene K469E polymorphism and coronary heart disease].

OBJECTIVE: To investigate the correlation between intercellular adhesion molecule1 (ICAM1) gene K469E polymorphism and coronary heart disease(CHD) in Han Chinese population. METHODS: Using the methods of polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP), 173 CHD patients and 141 controls were analyzed for the polymorphism, genotype and allele distribution of ICAM1 gene K469E. RESULTS: The distribution of ICAM1 genotypes was in Hardy-Weinberg equilibrium. The frequency of KK genotype in CHD group was significantly higher than that in control (64.2% vs 48.9%, P<0.01). Similarly, the frequency of K allele in CHD group was significantly higher than that in control (79.2% vs 69.9%, P<0.01). With Logistic Regression Analysis ruling out the influences of age, gender and other CHD risk factor, the homozygous individual with KK genotype was 2.35 folds of KE or EE genotype one suffering from CHD (OR: 2.35, 95%CI: 1.03-5.36, P<0.05). CONCLUSION: ICAM1 gene K469E polymorphism is associated with CHD risk of Han Chinese population, the K allele may serve as a genetic risk factor of coronary heart disease.