Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure.

Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. We found that caspase-11, a cytosolic LPS receptor, activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores and subsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD pores mediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, or neutralization of phosphatidylserine or TF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1α and IL-1ß, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC.

The role of type 1 interferons in coagulation induced by gram-negative bacteria.

Bacterial infection not only stimulates innate immune responses but also activates coagulation cascades. Overactivation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons (IFNs), a widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC by amplifying the release of high-mobility group box 1 (HMGB1) into the bloodstream. Inhibition of the expression of type 1 IFNs and disruption of their receptor IFN-α/ßR or downstream effector (eg, HMGB1) uniformly decreased gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the procoagulant activity of tissue factor by promoting the externalization of phosphatidylserine to the outer cell surface, where phosphatidylserine assembles a complex of cofactor-proteases of the coagulation cascades. These findings not only provide novel insights into the link between innate immune responses and coagulation, but they also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.

Persistent Helicobacter pylori infection for more than 3 years leads to elevated serum homocysteine concentration: A retrospective cohort study based on a healthy Chinese population.

BACKGROUND AND AIM: The relationship between the Helicobacter pylori (H. pylori) infection and homocysteine is unclear. We evaluated the effect of H. pylori on serum homocysteine in a healthy Chinese population. METHODS: A total of 21 184 individuals aged over 18 years underwent 13 C/14 C urease breath test (13 C/14 C-UBT) and blood tests and 5042 individuals with follow-up intervals greater than 6 months. Homocysteine levels are classified according to the Chinese expert consensus. RESULTS: The rates of H. pylori infection of normal level, mild level, moderate level, and severe level were 40.9%, 43.8%, 45.8%, and 46.6%, respectively (P = 0.000). H. pylori infection increased the risk of higher homocysteine concentration (OR = 1.406, P = 0.000). In the case-control study, the rates of persistent negative, new infection, persistent infection, and eradication infection were 43.6%, 11.2%, 22.9%, and 22.3%, respectively. The percentage of changes in serum homocysteine levels varied significantly among the different H. pylori infection statuses only in mild level (P = 0.024). Mean changed homocysteine values were higher in the subgroup of persistent infection than in the persistent negative subgroup (P = 0.004) and the eradication infection subgroup (P = 0.034). Serum homocysteine values were elevated only in the subgroup with over 3 years interval time and persistent infection (n = 107, mean paired differences = 1.1 ± 4.6 µmol/L, P = 0.014). CONCLUSIONS: There is a relationship between H. pylori and serum homocysteine, and persistent infection leads to elevation of the latter.

Persistent infection of Helicobacter pylori affects weight loss in obese population compared with persistent negative: A case-control study based on healthy Chinese.

BACKGROUND: The relationship between Helicobacter pylori (H pylori) and body mass index (BMI) is still inconclusive. Not only the high rate of H pylori infection but also the increasing higher BMI levels are endangering Chinese today. METHODS: The aim of this research was to evaluate the association between different situations of H pylori infection and BMI values or levels in Chinese healthy population. A total of 39 091 individuals aged from 18 years to 80 years, performed healthy examination including a 13 C/14 C urease breath test (13 C/14 C-UBT), were included. Among them, 30 224 individuals only had one time of health examination, and 8867 had two or more times. A case-cohort data of 8752 with an interval time more than 6 months, collected by the first and the last time, were established from the latter. BMI groups are classified according to the China recommendation: low weight (<18.5 kg/m2 ), normal weight (18.5 ~ 23.9 kg/m2 ), overweight (24.0 ~ 27.9 kg/m2 ), and obesity (≥28.0 kg/m2 ). RESULTS: The rate of H pylori infection among low weight, normal weight, overweight, and obesity was 43.2%, 44.7%, 46.4%, and 48.0%, respectively (P = .000). H pylori infection increased the risk of higher level of BMI (OR = 1.077, 95% confidence interval = 1.036-1.119, χ2  = 14.048, P = .000) with adjustments for sex and age. In the case-control study, the rate of persistent negative, persistent infection, new infection, and eradicated infection was 39.5%, 25.8%, 15.8%, and 18.9%, respectively, with a median interval time of 13 months. The mean obesity BMI descend values in the persistent negative subgroup were lower than those in the persistent infection subgroup (-0.21 ± 1.19 kg/m2 vs -0.003 ± 1.01 kg/m2 , P = .021). But the change of BMI classifications had no difference between the subgroups of H pylori infection in different BMI levels. CONCLUSIONS: H pylori infection was positively correlated with higher BMI levels. And H pylori persistent infection had a negative effect on the fall of BMI values in Chinese obese population.

MIR503HG impeded ovarian cancer progression by interacting with SPI1 and preventing TMEFF1 transcription.

MIR503 host gene (MIR503HG) acts as an important tumor suppressor in many human cancers, but its role and regulatory mechanism in ovarian cancer need to be further studied. In this study, lower expressed MIR503HG was observed in ovarian tumor tissues and cells than in adjacent normal tissues and normal human ovarian epithelial cells. MIR503HG overexpression impaired the proliferative, invasive and EMT properties, and facilitated cell apoptosis in ovarian cancer cells. Nuclear and cytoplasmic separation test suggested that MIR503HG was mainly expressed in the nucleus. RNA immunoprecipitation and RNA pull-down assays confirmed that MIR503HG could bind to transcription factor SPI1 (Spi-1 proto-oncogene), and dual luciferase reporter gene and Chromatin immunoprecipitation assays verified that SPI1 could bind to TMEFF1 (Transmembrane protein with EGF like and two follistatin like domains 1) promoter, suggesting that MIR503HG suppressed TMEFF1 expression by competitively binding SPI1 and blocking transcriptional activation of TMEFF1. Moreover, interference with TMEFF1 reversed the promotion effect of MIR503HG silence on the malignant behaviors of ovarian cancer cells. Moreover, MIR503HG knockdown activated the MAPK and PI3K/AKT pathways by increasing the expression of TMEFF1. In addition, overexpression of MIR503HG in vivo suppressed the tumorigenic ability in nude mice. In conclusion, MIR503HG acted as a tumor suppressor lncRNA in ovarian cancer by suppressing transcription factor SPI1-mediated transcriptional activation of TMEFF1.

Glycyrrhizin attenuates caspase-11-dependent immune responses and coagulopathy by targeting high mobility group box 1.

Caspase-11, a cytosolic endotoxin (lipopolysaccharide: LPS) receptor, mediates pyroptosis, coagulopathy and lethality in endoxemia and bacterial sepsis. The activation of caspase-11 requires high mobility group box 1 (HMGB1)-mediated translocation of LPS from the extracellular space to the cytosol. Here we show that HMGB1-dependent cytosolic delivery of LPS was blocked by glycyrrhizin, a medication to treat liver diseases. Glycyrrhizin competitively bound HMGB1 and thereby inhibiting the physical interaction between HMGB1 and LPS. Treatment of glycyrrhizin significantly attenuated caspase-11-dependent immune responses, coagulopathy, organ injury and lethality in endotoxemia and experimental sepsis. Together, our data suggest that pharmacological inhibition of the cytosolic delivery of LPS by glycyrrhizin might be a potential therapeutic strategy to treat sepsis, which is a leading cause of death in hospitals worldwide.

Real-world outcomes of various regimens of recombinant human endostatin combined with chemotherapy in non-driver gene mutation advanced non-small cell lung cancer.

AIMS: This real-world study is conducted to evaluate the efficacy and safety of recombinant human endostatin (rh-endostatin) combined with chemotherapy as first-line treatment for non-driver genes mutation non-small cell lung cancer (NSCLC) patients, and establish evidence-based optimal regimen for rh-endostatin. PATIENTS AND METHODS: Using propensity score matching (cut-off: 0.01), 88 patients were eligible for our study, 34 of which received platinum-based chemotherapy alone (chemotherapy group), 54 patients received platinum-based chemotherapy plus rh-endostatin (rh-endostatin group). Among those 54 patients in the rh-endostatin group, 27 patients received rh-endostatin administered at 7.5 mg/m2 from day 1 to day 14 (rh-endostatin 14d group), and the other 27 patients were administered at 15 mg/m2 from day 1 to day 7 (rh-endostatin 7d group). The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. RESULTS: There were no differences in clinic characteristics among 3 groups. Compared with chemotherapy group, rh-endostatin group improved PFS and OS significantly. The median PFS was 6 months vs 4.5 months (P = 0.047), and median OS was 20 months vs 10 months (P < 0.001). The ORR was 33.3% vs 20.6% (P = 0.197) and DCR was 83.3% vs 64.7% (P = 0.046) in the rh-endostatin group and chemotherapy group, respectively. The comparisons between the rh-endostatin 7d and 14d groups revealed a significant improvement in PFS for the rh-endostatin 7d group (P = 0.044), but no significant differences in OS (P = 0.111), ORR (P = 0.074), or DCR (P = 0.234). The incidences of grade 3 and 4 adverse events were similar among 3 groups. CONCLUSION: Chemotherapy combined with rh-endostatin was more effective than chemotherapy alone for non-driver gene mutation NSCLC patients. The administration of rh-endostatin for 7 days at 15 mg/m2 was non-inferior to 14 days at 7.5 mg/m2 in prolonging patients' PFS. Further evaluation should be conducted before its application in clinical work.