Neutrophil extracellular traps: A novel target for the treatment of stroke.

Stroke is a threatening cerebrovascular disease caused by thrombus with high morbidity and mortality rates. Neutrophils are the first to be recruited in the brain after stroke, which aggravate brain injury through multiple mechanisms. Neutrophil extracellular traps (NETs), as a novel regulatory mechanism of neutrophils, can trap bacteria and secret antimicrobial molecules, thereby degrading pathogenic factors and killing bacteria. However, NETs also exacerbate certain non-infectious diseases by activating autoimmune or inflammatory responses. NETs have been found to play important roles in the pathological process of stroke in recent years. In this review, the mechanisms of NETs formation, the physiological roles of NETs, and the dynamic changes of NETs after stroke are summarized. NETs participate in stroke through various mechanisms. NETs promote the coagulation cascade and interact with platelets to induce thrombosis. tPA induces the degranulation of neutrophils to form NETs, leading to hemorrhagic transformation and thrombolytic resistance. NETs aggravate stroke by mediating inflammation, atherosclerosis and vascular injury. In addition, the regulation of NETs in stroke, the potential of NETs as biomarker and the treatment of stroke targeting NETs are discussed. The increasing evidences suggest that NETs may be a potential target for stroke treatment. Inhibition of NETs formation or promotion of NETs degradation plays protective effects in stroke. However, how to avoid the adverse effects of NETs-targeted therapy deserves further study. In summary, this review provides a reference for the pathogenesis, drug targets, biomarkers and drug development of NETs in stroke.

Long-term administration of salvianolic acid A promotes endogenous neurogenesis in ischemic stroke rats through activating Wnt3a/GSK3ß/ß-catenin signaling pathway.

Stroke is the major cause of death and disability worldwide. Most stroke patients who survive in the acute phase of ischemia display various extents of neurological deficits. In order to improve the prognosis of ischemic stroke, promoting endogenous neurogenesis has attracted great attention. Salvianolic acid A (SAA) has shown neuroprotective effects against ischemic diseases. In the present study, we investigated the neurogenesis effects of SAA in ischemic stroke rats, and explored the underlying mechanisms. An autologous thrombus stroke model was established by electrocoagulation. The rats were administered SAA (10 mg/kg, ig) or a positive drug edaravone (5 mg/kg, iv) once a day for 14 days. We showed that SAA administration significantly decreased infarction volume and vascular embolism, and ameliorated pathological injury in the hippocampus and striatum as well as the neurological deficits as compared with the model rats. Furthermore, we found that SAA administration significantly promoted neural stem/progenitor cells (NSPCs) proliferation, migration and differentiation into neurons, enhanced axonal regeneration and diminished neuronal apoptosis around the ipsilateral subventricular zone (SVZ), resulting in restored neural density and reconstructed neural circuits in the ischemic striatum. Moreover, we revealed that SAA-induced neurogenesis was associated to activating Wnt3a/GSK3ß/ß-catenin signaling pathway and downstream target genes in the hippocampus and striatum. Edaravone exerted equivalent inhibition on neuronal apoptosis in the SVZ, as SAA, but edaravone-induced neurogenesis was weaker than that of SAA. Taken together, our results demonstrate that long-term administration of SAA improves neurological function through enhancing endogenous neurogenesis and inhibiting neuronal apoptosis in ischemic stroke rats via activating Wnt3a/GSK3ß/ß-catenin signaling pathway. SAA may be a potential therapeutic drug to promote neurogenesis after stroke.

Hypoxia-inducible factor-1: Regulatory mechanisms and drug development in stroke.

Stroke is an acute cerebrovascular disease caused by sudden rupture of blood vessels in the brain or blockage of blood vessels, which has now become one of the main causes of adult death. During stroke, hypoxia-inducible factor-1 (HIF-1), as an important regulator under hypoxia conditions, is involved in the pathological process of stroke by regulating multi-pathways, such as glucose metabolism, angiogenesis, erythropoiesis, cell survival. However, the roles of HIF-1 in stroke are still controversial, which are related with ischemic time and degree of ischemia. The regulatory mechanisms of HIF-1 in stroke include inflammation, autophagy, oxidative stress, apoptosis and energy metabolism. The potential drugs targeting HIF-1 have attracted more attention, such as HIF-1 inhibitors, HIF-1 stabilizers and natural products. Based on the role of HIF-1 in stroke, HIF-1 is expected to be a potential target for stroke treatment. Resolving when and what interventions for HIF-1 to take during stroke will provide novel strategies for stroke treatment.

Neuroinflammation in hemorrhagic transformation after tissue plasminogen activator thrombolysis: Potential mechanisms, targets, therapeutic drugs and biomarkers.

Hemorrhagic transformation (HT) is a common and serious complication following ischemic stroke, especially after tissue plasminogen activator (t-PA) thrombolysis, which is associated with increased mortality and disability. Due to the unknown mechanisms and targets of HT, there are no effective therapeutic drugs to decrease the incidence of HT. In recent years, many studies have found that neuroinflammation is closely related to the occurrence and development of HT after t-PA thrombolysis, including glial cell activation in the brain, peripheral inflammatory cell infiltration and the release of inflammatory factors, involving inflammation-related targets such as NF-κB, MAPK, HMGB1, TLR4 and NLRP3. Some drugs with anti-inflammatory activity have been shown to protect the BBB and reduce the risk of HT in preclinical experiments and clinical trials, including minocycline, fingolimod, tacrolimus, statins and some natural products. In addition, the changes in MMP-9, VAP-1, NLR, sICAM-1 and other inflammatory factors are closely related to the occurrence of HT, which may be potential biomarkers for the diagnosis and prognosis of HT. In this review, we summarize the potential inflammation-related mechanisms, targets, therapeutic drugs, and biomarkers associated with HT after t-PA thrombolysis and discuss the relationship between neuroinflammation and HT, which provides a reference for research on the mechanisms, prevention and treatment drugs, diagnosis and prognosis of HT.

Impact of liver fibrosis score on prognosis after common therapies for intrahepatic cholangiocarcinoma: a propensity score matching analysis.

BACKGROUND: Liver fibrosis or cirrhosis is associated with the dismal prognosis of hepatocellular carcinoma (HCC), and it might also be involved in intrahepatic cholangiocarcinoma (ICC). The effect of hepatic fibrosis on the survival of ICC patients is still unclear. This study aims to explore whether liver fibrosis impacts the overall survival (OS) and disease-specific survival (DSS) of ICC patients. METHODS: Data of 729 eligible ICC patients receiving different therapies from the Surveillance, Epidemiology, and End Results database (2004-2015) were analyzed. Unmatched, propensity score-matched, and propensity score-weighted cohorts were used to investigate the relationships of different fibrosis scores (low fibrosis score vs. high fibrosis score) and survival. A Cox regression and Kaplan-Meier curves were used to explore the influence of fibrosis score on patients' survival. Stratified analyses based on treatment modality were conducted to compare the survival difference in ICC patients with different fibrosis scores. RESULTS: Before matching, the one-, three-, and five-year OS were 50.9, 28.0, and 16.1% in the low fibrosis score group (n = 465) and 39.3, 20.1, and 8.0% in the high fibrosis score group (n = 264) (P < 0.001), respectively. After propensity score matching, the one-, three-, and five-year OS were 45.0, 26.0, and 10.2% in the low fibrosis score group and 36.0, 8.1, and 2.3% in the high fibrosis score group (P = 0.008), respectively. The multivariate Cox regression results showed that a high fibrosis score was an independent risk factor of OS. Additionally, patients with high fibrosis scores achieved low DSS after matching (P = 0.032). The survival benefits of the low fibrosis score group were consistent across treatment cohorts. CONCLUSIONS: High fibrosis scores were associated with poor clinical outcomes of ICC patients receiving different common therapies.

Clinical significance of wound infiltration with ropivacaine for elderly patients in china underwent total laparoscopic radical gastrectomy: A retrospective cohort study.

The study aimed to evaluate analgesic effects and postoperative recovery of ropivacaine wound infiltration for elderly patients in China after total laparoscopic radical gastrectomy.We retrospectively received clinical data of 132 elderly patients who received total laparoscopic gastrectomy and tracheal intubation general anesthesia from cancer center of First Affiliated Hospital of Xiamen University between September 2014 and September 2017, patients were divided into 2 groups according to local injection of drug: group I (ropivacaine group, 0.5% ropivacaine, 40 mL in total, n = 69), group II (control group, no analgesic, n = 63). The demographics, postoperative pain using numeric ratings scale (NRS), rescue analgesics as well as incidence of complications were investigated.Significantly lower pain scores were observed in group I than in group II at 6, 12, 24, and 48 h postoperatively; the use of remedy analgesia was less in group I than in group II; there was no statistical significance in the incidence of surgical-related complications between the 2 groups. The recovery time were shorter in group I than in group II, meanwhile, postoperative hospital stay, medical expenses, and anesthesia-related complications were significantly less in group I than in group II.This is a review of ropivacaine infiltration use in the elderly patients underwent total laparoscopic radical gastrectomy. This analysis describes the postoperative analgesic effect and postoperative recovery of wound infiltration with ropivacaine. Multicentered large sample prospective randomized controlled study is needed to evaluate the feasibility, security, and economic practicality.

Curcumin inhibits hepatocellular carcinoma growth by targeting VEGF expression.

Morbidity and mortality owing to hepatocellular carcinoma (HCC), the most common primary liver cancer, has increased in recent years. Curcumin is a polyphenol compound that has been demonstrated to exert effective antiangiogenic, anti-inflammatory, antioxidant, and antitumor effects. However, its clinical effects in HCC remain elusive. The main aim of the present study was to determine the antiangiogenic effects of curcumin in HCC. H22HCC cells were treated with different concentrations of curcumin in vitro. In addition, a mouse xenograft model was used and analyzed for expression levels of vascular endothelial growth factor (VEGF) protein and proteins of the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase 1 (AKT) signaling pathway. Curcumin treatment inhibited H22 cell proliferation and promoted H22 cell apoptosis in a dose-dependent manner in vitro. In addition, curcumin treatment inhibited tumor growth in vivo at the concentrations of 50 and 100 mg/kg. Furthermore, curcumin treatment significantly decreased VEGF expression and PI3K/AKT signaling. The present findings demonstrated that curcumin inhibited HCC proliferation in vitro and in vivo by reducing VEGF expression.

Totally laparoscopic verse laparoscopic assisted distal gastrostomy for gastric cancer: an update meta-analysis.

Totally laparoscopic distal gastrostomy (TLDG) and laparoscopic- assisted distal gastrostomy (LADG) are the minimally invasive surgical technology for gastric cancer. This study aimed to compare the surgical outcomes of these two methods. Relevant studies were selected through electronic searches of EMBASE, PubMed and Web of Science. In total, 21 non-randomized controlled studies containing 2475 patients in the totally laparoscopic distal gastrostomy and 1889 patients in the laparoscopic-assisted distal gastrostomy were included in this study. And operative time, operative blood loss, retrieved lymph nodes, time to liquid diet (days), postoperative hospital stay and overall complications were pooled and compared using meta-analysis. There were no significant differences between operative time (WMD = 0.38, 95% CI -10.43 -11.18, P = 0.95) and overall complications (RR = 1.09, 95% CI 0.91-1.30, P = 0.36). But totally laparoscopic distal gastrostomy had more advantages in aspects of intraoperative blood loss (WMD = 24.4, 95% CI 12.45-36.36, P < 0.0001), time to liquid diet (days) (WMD = 0.21, 95% CI 0.03-0.40, P = 0.03) and postoperative hospital stay (WMD = 0.72, 95% CI 0.31-1.13, P = 0.0006). Moreover, totally laparoscopic distal gastrostomy had more retrieved lymph nodes (WMD = -1.24, 95% CI-1.90 to-0.58, P = 0.0002). This meta-analysis indicates that totally laparoscopic distal gastrostomy may be a safe, feasible, and favorable surgical technology in terms of less blood loss, faster liquid diet, shorter postoperative hospital stay and more lymph nodes retrieved.