Cytosolic Cadherin 4 promotes angiogenesis and metastasis in papillary thyroid cancer by suppressing the ubiquitination/degradation of ß-catenin.

BACKGROUND: Although the long-term prognosis of papillary thyroid cancer (PTC) is favorable, distant metastasis significantly compromises the prognosis and quality of life for patients with PTC. The Cadherin family plays a pivotal role in tumor metastasis; however, the involvement of Cadherin 4 (CDH4) in the metastatic cascade remains elusive. METHODS: The expression and subcellular localization of CDH4 were determined through immunohistochemistry, immunofluorescence, and western blot analyses. The impact of CDH4 on cell migration, invasion, angiogenesis, and metastasis was assessed using transwell assays, tube formation assays, and animal experiments. Immunoprecipitation assay and mass spectrometry were employed to examine protein associations. The influence of CDH4 on the subcellular expression of ß-catenin and active ß-catenin was investigated via western blotting and immunofluorescence. Protein stability and ubiquitination assay were employed to verify the impact of CDH4 on ß-catenin degradation. Rescue experiments were performed to ensure the significance of CDH4 in regulating nuclear ß-catenin signaling. RESULTS: CDH4 was found to be significantly overexpressed in PTC tissues and predominantly localized in the cytoplasm. Furthermore, the overexpression of CDH4 in tumor tissues is associated with lymph node metastasis in PTC patients. Cytosolic CDH4 promoted the migration, invasion, and lung metastasis of PTC cells and stimulated the angiogenesis and tumorigenesis of PTC; however, this effect could be reversed by Tegavivint, an antagonist of ß-catenin. Mechanistically, cytosolic CDH4 disrupted the interaction between ß-catenin and ß-TrCP1, consequently impeding the ubiquitination process of ß-catenin and activating the nuclear ß-catenin signaling. CONCLUSIONS: CDH4 induces PTC angiogenesis and metastasis via the inhibition of ß-TrCP1-dependent ubiquitination of ß-Catenin.

Neutrophil extracellular traps promote intestinal barrier dysfunction by regulating macrophage polarization during trauma/hemorrhagic shock via the TGF-ß signaling pathway.

The mechanism by which neutrophil extracellular traps (NETs) may cause intestinal barrier dysfunction in response to trauma/hemorrhagic shock (T/HS) remains unclear. In this study, the roles and mechanisms of NETs in macrophage polarization were examined to determine whether this process plays a role in tissue damage associated with T/HS. Rat models of T/HS and macrophage polarization were developed and the levels of NETs formation in the intestinal tissue of T/HS rats were assessed. NET formation was inhibited in models of T/HS to examine the effect on intestinal inflammation and barrier injury. The proportions of pro-inflammatory and anti-inflammatory macrophages in the damaged intestinal tissues were measured. Finally, high-throughput sequencing was performed to investigate the underlying mechanisms involved in this process. The study revealed that the level of NETs formation was increased and that inhibition of NETs formation alleviated the intestinal inflammation and barrier injury. Moreover, the number of pro-inflammatory macrophages increased and the number of anti-inflammatory macrophages decreased. RNA sequencing analysis indicated that NETs formation decreased the expression of transforming growth factor-beta receptor 2 (TGFBR2), bioinformatic analyses revealed that TGFBR2 was significantly enriched in the transforming growth factor-beta (TGF-ß) signaling pathway. Verification experiments showed that NETs impeded macrophage differentiation into the anti-inflammatory/M2 phenotype and inhibited TGFBR2 and TGF-ß expression in macrophages. However, treatment with DNase I and overexpression of TGFBR2, and inhibition of TGF-ß promoted and prevented this process, respectively. NETs may regulate the macrophage polarization process by promoting intestinal barrier dysfunction in T/HS rats through the TGFBR2-mediated TGF-ß signaling pathway.

Hesperetin attenuates sepsis-induced intestinal barrier injury by regulating neutrophil extracellular trap formation via the ROS/autophagy signaling pathway.

Background: Hesperetin (HES), one of the major flavonoids that has various biological activities, such as anti-inflammatory and antioxidant activities, may preserve the intestinal barrier during sepsis. However, the detailed mechanism remains unclear. Our previous studies confirmed that neutrophil extracellular traps (NETs) may jeopardize the intestinal barrier via a reactive oxygen species (ROS)-dependent pathway during sepsis. Therefore, we hypothesized that HES may inhibit NET formation and protect the intestinal barrier function during sepsis. Methods: Mice were pretreated with HES (50 mg kg-1) intraperitoneally for one week, and sepsis models were then induced using lipopolysaccharides (LPS) (10 mg kg-1). The mice were randomly divided into three groups: (1) sham group; (2) LPS group; and (3) HES + LPS group. Twenty-four hours after LPS injection, the serum and terminal ileum specimens were collected for subsequent studies. To detect ROS production and NET formation in vitro, human neutrophils were collected and incubated with phorbol-12-myristate-13-acetate (PMA) and various concentrations of HES. The level of autophagy was measured by an immunofluorescence assay and western blot analysis. TUNEL staining was utilized to analyze cell apoptosis. Results: The outcomes demonstrated that HES decreased inflammatory cytokine and myeloperoxidase (MPO) levels in serum and attenuated distant organ dysfunction in LPS-induced septic mice. Meanwhile, HES treatment reversed intestinal histopathological damage in septic mice, improving intestinal permeability and enhancing tight junction expression. Moreover, we found that neutrophil infiltration and NET formation in the intestine were suppressed during sepsis after HES pretreatment. In vitro, HES treatment reduced PMA-induced ROS production and NET formation, which were reversed by hydrogen peroxide (H2O2) administration. Notably, HES also inhibited NET formation by reducing the microtubule-associated protein light chain 3 (LC3)-II/LC3-I ratio (an indicator of autophagy) in PMA-induced neutrophils, which was reversed by rapamycin. Moreover, when autophagy was suppressed by chloroquine or induced by rapamycin, apoptosis in cells will be switched with autophagy. Conclusion: Taken together, these findings suggest that HES may inhibit NET formation in a ROS/autophagy-dependent manner and switch neutrophil death from NETosis to apoptosis, which reduced NETs-related intestinal barrier damage, providing a novel protective role in intestinal barrier dysfunction during sepsis.

Persistent fibrinolysis shutdown is associated with increased mortality in traumatic pancreatic injury.

PURPOSE: The features of fibrinolytic system modifications and their relationship with prognosis are still unknown in traumatic pancreatic injury. The object of this prospective cohort research was to identify fibrinolytic characteristics in patients with pancreatic trauma and to identify the correlation to mortality. METHOD: A prospective screening of traumatic pancreatic injury patients was done for five years. The fibrinolytic status of patients was determined by thromboelastography (TEG). The percentage reduction in clot strength 30 min (LY30) after the time of maximal clot strength was utilized to distinguish the fibrinolytic phenotype of individuals, including fibrinolytic shutdown (SD), physiologic fibrinolysis (PHYS) and hyperfibrinolysis (HF). Two cohorts, transient fibrinolytic shutdown (TSD) and persistent fibrinolytic shutdown (PSD), were divided according to whether fibrinolytic shutdown persisted within one week. Demographics, injury severity, characteristics of pancreatic injury, treatment, and outcomes were compared. RESULT: A total of 180 cases enrolled, aged 42(interquartile range 32-51) years, 88% males, 97% were blunt trauma. The median ISS was 19(IQR 10-25), and 76% were AAST grade III to V (high-grade). At admission, there were 159 cases of SD (88%), 15 cases of PHYS (8%) while 6 cases of HF (3%). Of these, the TSD cohort included 54 patients (34%), while the PSD cohort included 105 patients (66%). Compared with the TSD cohort, the PSD cohort had more severe injury (ISS 21[IQR 12-27] vs 16[IQR 9-22], p = 0.006) and a higher proportion of AAST high-grade (83% vs 67%, p = 0.035). Persistent fibrinolytic shutdown was associated with operative treatment (odds ratio [OR] 3.111; 95%CI 1.146-8.447; p = 0.026), associated intra-abdominal injury (OR 8.331; 95% CI 1.301-53.336; p = 0.025) and admission LY30 (OR 0.016; 95% CI 0.002 - 0.120; p < 0.001). It was an independent predictor of mortality (adjusted odds ratio [AOR] 4.674; 95% CI 1.03 to 21.14; p = 0.045). CONCLUSION: Fibrinolytic shutdown especially persistence of this phenotype is more common in traumatic pancreatic injury than PHYS and HF, which related with mortality. Risk factors including LY30 at admission, intra-abdominal injury and operative treatment were associated with the persistent fibrinolytic shutdown. Sheltered the patients from these risk factors seems to be beneficial, which need to be confirmed by further large-scale studies.

Nonthyroidal illness syndrome in acute pancreatitis patients: an 8-year cohort study.

BACKGROUND: Nonthyroidal illness syndrome (NTIS) is common in critical illness and is associated with poor prognosis. The aim of this study was to find the prevalence, charateristics, and prognosis of NTIS and its correlation with outcomes in AP patients. METHODS: A retrospective review of AP patients with a diagnosis of NTIS from Jan 2012 to September 2020 was performed. The serum thyroidal hormone (TH) disturbances, as well as the demographic characteristics and clinical outcomes of the study patients, were collected and analyzed. RESULTS: Over the eight years, 183 included AP patients were diagnosed as NTIS, constituting an incidence of 64.7%. Patients with NTIS were admitted with worse condition based on the higher APACHE II score, SOFA score, Balthazar's CT score, CRP and lower albumin than euthyroid patients. Also, these patients had a longer ICU duration (3, 2-10 vs 2, 0-3, days, P = 0.039) and tended to be more likely to develop infected pancreatic necrosis (IPN) (15.3% vs 6.3%, P = 0.087) and gastrointestinal fistula (6% vs 0%, P = 0.082) than euthyroid patients. Free triiodothyronine (FT3) was found the best performance in predicting death compared by other well-recognized biomarkers. CONCLUSION: NTIS is common in AP patients within 7 days after the onset of the disease. NTIS is associated with the worse characteristics at admission and poor outcome during the course. FT3 should be investigate as a potential biomarker in the prediction of death in AP patients.

Neutrophil extracellular trap formation index predicts occurrences of deep surgical site infection after laparotomy.

BACKGROUND: Deep surgical site infections (DSSIs) are serious complications after laparotomy. Neutrophil extracellular traps (NETs) play a vital role in the development of DSSI. Here, we focused on a new approach to predicting the occurrence of DSSI through the detection of the NET formation index (NFI), and compared its prediction ability with other clinical infection indicators. METHODS: Patients who received laparotomy were prospectively enrolled in this study. General information, APACHE II score, SOFA score, and serum infection indicators were recorded. The postoperative abdominal drainage fluid was collected within 3 days after the operation for quantification of the NFI. RESULTS: A total of 92 consecutive patients were included, with 22 patients were diagnosed with DSSI. The NFI in the DSSI group was 32.70%±19.33% while the corresponding index was 10.70%±8.25% in the non-DSSI group (P<0.01). The mean APACHE II and SOFA score had significant differences between the two groups. The NFI was positively correlated with the APACHE II score (P<0.01, r=0.269) and SOFA score (P=0.013, r=0.258). Patients with a high NFI (NFI >13.86%) had a higher risk of developing DSSI. According to the receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC) of the NFI, C-reactive protein (CRP) and procalcitonin (PCT) were 0.912, 0.748 and 0.731, respectively. CONCLUSIONS: In this cohort of surgical patients, the quantification of the NFI had a considerable predictive value for early identification of DSSI. The NFI in drainage fluid turned out to be a more sensitive and specific predictor of DSSI than serum infection indicators including CRP and PCT.

De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis.

Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detailed mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular traps (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy in cecum ligation and puncture (CLP) models. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. In CLP models, de-escalation therapy resulted in an increased serum MPO-DNA level during the early stage and decreased MPO-DNA level during late stage, which exerted the reverse effects in escalation therapy. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAse I during the early stage of sepsis (p < 0.01). Histopathological analysis showed decreased injury in lung, liver, and intestine in de-escalation therapy compared with escalation therapy (p < 0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p < 0.01), however, no significant difference was found between de-escalation and escalation group (p = 0.051). The in vitro study showed that the imipenem could promote, while the ceftriaxone could inhibit the formation of NETs in PMA-activated PMNs through a ROS-dependent manner. We firstly demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage, and inhibiting NETs formation in the late stage of sepsis.

Bioelectrical impedance analysis-guided fluid management promotes primary fascial closure after open abdomen: a randomized controlled trial.

BACKGROUND: Fluid overload (FO) after resuscitation is frequent and contributes to adverse outcomes among postinjury open abdomen (OA) patients. Bioelectrical impedance analysis (BIA) is a promising tool for monitoring fluid status and FO. Therefore, we sought to investigate the efficacy of BIA-directed fluid resuscitation among OA patients. METHODS: A pragmatic, prospective, randomized, observer-blind, single-center trial was performed for all trauma patients requiring OA between January 2013 and December 2017 to a national referral center. A total of 140 postinjury OA patients were randomly assigned in a 1:1 ratio to receive either a BIA-directed fluid resuscitation (BIA) protocol that included fluid administration with monitoring of hemodynamic parameters and different degrees of interventions to achieve a negative fluid balance targeting the hydration level (HL) measured by BIA or a traditional fluid resuscitation (TRD) in which clinicians determined the fluid resuscitation regimen according to traditional parameters during 30 days of ICU management. The primary outcome was the 30-day primary fascial closure (PFC) rate. The secondary outcomes included the time to PFC, postoperative 7-day cumulative fluid balance (CFB) and adverse events within 30 days after OA. The Kaplan-Meier method and the log-rank test were utilized for PFC after OA. A generalized linear regression model for the time to PFC and CFB was built. RESULTS: A total of 134 patients completed the trial (BIA, n = 66; TRD, n = 68). The BIA patients were significantly more likely to achieve PFC than the TRD patients (83.33% vs. 55.88%, P < 0.001). In the BIA group, the time to PFC occurred earlier than that of the TRD group by an average of 3.66 days (P < 0.001). Additionally, the BIA group showed a lower postoperative 7-day CFB by an average of 6632.80 ml (P < 0.001) and fewer complications. CONCLUSION: Among postinjury OA patients in the ICU, the use of BIA-guided fluid resuscitation resulted in a higher PFC rate and fewer severe complications than the traditional fluid resuscitation strategy.

Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway.

Increased neutrophil extracellular traps (NETs) formation has been found to be associated with intestinal inflammation, and it has been reported that NETs may drive the progression of gut dysregulation in sepsis. However, the biological function and regulation of NETs in sepsis-induced intestinal barrier dysfunction are not yet fully understood. First, we found that both circulating biomarkers of NETs and local NETs infiltration in the intestine were significantly increased and had positive correlations with markers of enterocyte injury in abdominal sepsis patients. Moreover, the levels of local citrullinated histone 3 (Cit H3) expression were associated with the levels of BIP expression. To further confirm the role of NETs in sepsis-induced intestinal injury, we compared peptidylarginine deiminase 4 (PAD4)-deficient mice and wild-type (WT) mice in a lethal septic shock model. In WT mice, the Cit H3-DNA complex was markedly increased, and elevated intestinal inflammation and endoplasmic reticulum (ER) stress activation were also found. Furthermore, PAD4 deficiency alleviated intestinal barrier disruption and decreased ER stress activation. Notably, NETs treatment induced intestinal epithelial monolayer barrier disruption and ER stress activation in a dose-dependent manner in vitro, and ER stress inhibition markedly attenuated intestinal apoptosis and tight junction injury. Finally, TLR9 antagonist administration significantly abrogated NETs-induced intestinal epithelial cell death through ER stress inhibition. Our results indicated that NETs could contribute to sepsis-induced intestinal barrier dysfunction by promoting inflammation and apoptosis. Suppression of the TLR9-ER stress signaling pathway can ameliorate NETs-induced intestinal epithelial cell death.

Protective effect of ethyl pyruvate on gut barrier function through regulations of ROS-related NETs formation during sepsis.

BACKGROUND: Sepsis impairs the function of the intestinal barrier through neutrophil extracellular traps (NETs). Reactive oxygen species (ROS)-induced activation of mitogen-activated protein kinase (MAPK) is involved in NET formation. Ethyl pyruvate (EP), a potent and effective ROS scavenger, ameliorates sepsis-associated intestinal barrier dysfunction, but the detailed mechanism is unknown. The current study aimed to explore the eff ;ects of EP on sepsis-induced intestinal barrier dysfunction and whether ROS and NETs were involved. METHODS: A sepsis model was induced in mice by intraperitoneal injection of LPS (10 mg/kg). The mice were divided into 4 groups: (1) sham group; (2) LPS group; (3) DNase-1 + LPS group; and (4) EP + LPS group. EP or DNase-1 was intraperitoneally injected after the LPS model was established. After 24 h, the small intestine and blood were collected for analysis. Human neutrophils were harvested and incubated with phorbol-12-myristate-13-acetate (PMA) or PMA + EP, and ROS and NET generation was measured. RESULTS: EP significantly decreased proinflammatory cytokines and MPO-DNA in the LPS model. In addition, EP suppressed NET formation in the intestines of endotoxemic mice. The decrease in NETs induced by EP or DNase-1 alleviated histopathological damage, intestinal cell apoptosis and increased tight junction expression. In vitro, the treatment of EP abolished PMA-induced ROS production and NET formation which could be reversed by H2O2 treatment. Meanwhile, EP also abolished MAPK ERK1/2 and p38 activation during PMA-induced NET formation. CONCLUSION: This study was the first to demonstrate that EP alleviated NET formation and sepsis-induced intestinal damage through blockage of ROS mediated MAPK ERK1/2 and p38 activation.

Clinical characteristics and management of gastric outlet obstruction in acute pancreatitis.

OBJECTIVE: The aim of this study was to describe the clinical characteristics and management of gastric outlet obstruction following acute pancreatitis(AP). BACKGROUND: Gastric outlet obstruction (GOO) is not uncommon in acute pancreatitis (AP) and can occur throughout the course. However, the clinical features and related treatment of GOO is rarely reported. METHODS: A retrospective review of AP patients with a diagnosis of GOO from March 2017 to June 2020 was performed. The diagnosis and management of GOO, as well as the demographic characteristics and clinical outcomes of the study patients, were collected and analyzed. RESULTS: Over the three years, there were 60 AP patients developed GOO, constituting an incidence of 5.7%. Thirty-three patients (55.0%, 33/60) developed GOO in the first 4 weeks and 27 patients (45.0%, 27/60) after 4 weeks from onset. Pancreatic necrosis compression (60.6%; 20/33), gastric outlet gastrointestinal edema (27.3%, 9/33) are the main causes of early-onset GOO (≤4 weeks), while wall-off necrosis (92.6%, 25/27) is the leading cause in the late phase (>4 weeks). The management of GOO incorporates both supportive and specific treatment like gastric decompression, gastric juice reinfusion, percutaneous catheter drainage, etc. The mortality of AP patients with GOO (≤4 weeks) was 21.2% and none patients who developed GOO (>4 weeks) died. CONCLUSIONS: GOO, as a gastrointestinal complication developed in AP patients, has two peak incidences in the duration of AP and needs to be paid more attention to.

Serum magnesium level as a predictor of acute kidney injury in patients with acute pancreatitis.

BACKGROUND: Decreased serum magnesium (Mg2+) is commonly seen in critically ill patients. Hypomagnesemia is significantly more frequent in patients with severe acute pancreatitis. Acute kidney injury (AKI) in patients with acute pancreatitis (AP) is associated with an extremely high mortality. The association underlying serum Mg2+ and AKI in AP has not been elucidated. AIM: To explore the association between serum Mg2+ on admission and AKI in patients with AP. METHODS: A retrospective observational study was conducted in a cohort of patients (n = 233) with AP without any renal injury before admission to our center from August 2015 to February 2019. Demographic characteristics on admission, severity score, laboratory values and in-hospital mortality were compared between patients with and without AKI. RESULTS: A total of 233 patients were included for analysis, including 85 with AKI. Compared to patients without AKI, serum Mg2+ level was significantly lower in patients with AKI at admission [OR = 6.070, 95%CI: 3.374-10.921, P < 0.001]. Multivariate logistic analysis showed that lower serum Mg2+ was an independent risk factor for AKI [OR = 8.47, 95%CI: 3.02-23.72, P < 0.001]. CONCLUSION: Our analysis indicates that serum Mg2+ level at admission is independently associated with the development of AKI in patients with AP and may be a potential prognostic factor.

ß-Lactams modulate neutrophil extracellular traps formation mediated by mTOR signaling pathway.

BACKGROUND: Some biotics, like ß-Lactams, have shown immunomodulation effects during sepsis, but the detailed mechanism was still unclear. Here we postulated that neutrophils play an essential role and ß-Lactams exert immunomodulation effects through modulating neutrophil extracellular traps (NETs) formation. METHODS: NETs formation induced by two ß-Lactams, Meropenem (MEM) and ceftazidime/tazobactam (CAZ/TB) in neutrophils from healthy donors and HL-60 cells was performed. Reactive oxygen species (ROS) generation and the activity of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase were examined. Additionally, the upstream signal pathway of NETs formation, including protein kinase C (PKC), protein kinase B (Akt) and mammalian target of rapamycin (mTOR), were detected. RESULTS: MEM and CAZ/TB modulate NETs formation in activated PMNs, not resting PMNs. Both reduced ROS generation in resting PMNs and increased in activated PMNs. To test the activity of NADPH oxidase, we detected NADPH in MEM and CAZ/TB pre-cultivated activated PMNs, which showed that MEM and CAZ/TB modulates NETs formation through activation of NADHP oxidase by affecting the subunits of key enzymes. However, MEM reduced levels of phosho-PKC-Akt-mTOR, with no changes in CAZ/TB. CONCLUSIONS: We firstly demonstrate that ß-Lactams showed the definitive immunomodulation effects through modulating NETs formation, which is depended on PKC-Akt-mTOR signal pathway.

Early intravenous administration of tranexamic acid ameliorates intestinal barrier injury induced by neutrophil extracellular traps in a rat model of trauma/hemorrhagic shock.

BACKGROUND: Early intravenous administration of tranexamic acid has been shown to protect the intestinal barrier after a model of trauma-hemorrhagic shock in the rat, but the potential mechanism remains unclear. Our previous studies have demonstrated that neutrophil extracellular traps contribute to the intestinal barrier dysfunction during sepsis and other critical conditions. Meanwhile, there are high levels of neutrophil infiltration in the intestine during trauma-hemorrhagic shock. Here, we hypothesized that neutrophil extracellular trap formation played a vital role during trauma-hemorrhagic shock-induced intestinal injury and that tranexamic acid, a serine protease inhibitor, may inhibit neutrophil extracellular trap formation and protect intestinal barrier function in trauma-hemorrhagic shock. METHODS: A model of trauma-hemorrhagic shock in male rats was established. The rats were divided into 6 groups: (1) sham group; (2) trauma-hemorrhagic shock group; (3) trauma-hemorrhagic shock + DNase I group; (4) trauma-hemorrhagic shock + tranexamic acid group; (5) trauma-hemorrhagic shock + tranexamic acid (different time) group; and (6) trauma-hemorrhagic shock + tranexamic acid (different doses) group. The DNase I solution was injected intravenously to disrupt neutrophil extracellular traps immediately after the trauma-hemorrhagic shock model was completed. After 24 hours, the small intestine and blood were collected for analysis. Human neutrophils were harvested and incubated with phorbol-12-myristate-13-acetate or tranexamic acid, generation of reactive oxygen species, and key proteins expression were detected. RESULTS: Trauma-hemorrhagic shock induced the formation of intestinal neutrophil extracellular traps and disrupted the intestinal tight junction proteins. Clearing of neutrophil extracellular traps by DNase I resulted in increased expression of tight junction proteins and alleviated the intestinal injury. Early intravenous tranexamic acid administration (1 hour after trauma-hemorrhagic shock) decreased neutrophil extracellular trap formation and prevented tight junction protein disruption compared to the non-tranexamic acid group; however, after delayed administration of tranexamic acid (6 hours), there were no changes in neutrophil extracellular trap formation and intestinal injuries compared to the non-tranexamic acid group. Furthermore, tranexamic acid inhibited neutrophil extracellular trap formation and protected the intestinal barrier in a dose-dependent manner and high-dose (20 mg/kg) treatment of tranexamic acid showed a better effect compared with the therapeutic dose (10 mg/kg). The results of thromboelastography demonstrated that the R and K values in the high-dose group decreased (R, 1.85 ± 0.14 vs 3.87 ± 0.16 minutes, P < .001; K, 0.95 ± 0.04 vs 1.48 ± 0.07 minutes, P < .001), accompanied by a decrease in LY30, indicating that treatment with a high dose of tranexamic acid may cause hypercoagulability and shutdown of fibrinolysis. In addition, less neutrophil extracellular trap formation was detected in neutrophils incubated with neutrophils via an reactive oxygen species-dependent pathway. CONCLUSION: We first demonstrated a novel role of neutrophil extracellular traps in the pathophysiology of intestinal barrier dysfunction during trauma-hemorrhagic shock. Notably, early but not delayed intravenous administration of tranexamic acid effectively inhibits neutrophil extracellular trap formation and protects intestinal barrier function. Therefore, these results suggested a potential theoretic intervention for the protection of the intestinal barrier during trauma-hemorrhagic shock. In such a process, tranexamic acid appears to regulate neutrophil extracellular trap formation via the classic reactive oxygen species/mitogen-activated protein kinase pathway.

Outcomes and clinical characteristics of transmural intestinal necrosis in acute mesenteric ischemia.

Background: Acute mesenteric ischemia (AMI) is a rare life-threatening condition, especially for the patients with transmural intestinal necrosis (TIN). However, the optimal time for surgical intervention is controversial. As a series study, this study aimed to identify the outcomes and clinical characteristic of patients with TIN. Methods: Clinical data of 158 patients with AMI from January 2010 to December 2017 were retrospectively analyzed in a national gastrointestinal referral center in China to confirm the outcomes and identify predictors for TIN. Results: According to the results of pathological assessment and follow-up, 62 patients were TIN and 96 were non-TIN. Patients with TIN have a higher mortality and incidence of severe complications. The significant independent predictors for TIN were arterial lactate level (OR: 4.76 [2.29 ∼ 9.89]), free intraperitoneal fluid (OR: 9.49 [2.56 ∼ 35.24]) and pneumatosis intestinalis (OR: 7.08 [1.68 ∼ 29.82]) in computed tomography (CT) scan imaging. The overall area under the receiver operating characteristics (ROC) curve of the model was 0.934 (95% confidence interval: 0.893 ∼ 0.974). Using ROC curve, the cutoff value of arterial lactate level predicting the onset of TIN was 2.65 mmol/L. Conclusions: Patients concomitant with TIN manifest a higher risk of poor prognosis. The three predictors for TIN were arterial lactate level >2.65 mmol/L, free intraperitoneal fluid and pneumatosis intestinalis. Close monitoring these predictors would help identify AMI patients developed TIN and in urgent need for bowel resection.

[Advances in studies on autoimmune diseases treated by halofuginone].

Halofuginone (HF) is a derivative of dichroine which is the extract of traditional Chinese medicine. It is widely used as an efficient anticoccidial drug. Recent studies have found that HF has unique biological activities, showing great potential capacities in the treatment of autoimmune diseases. In the article, we summarized the therapeutic effects of HF in a variety of autoimmune diseases and its mechanism, providing references for further clinical studies of HF.