Pd-catalyzed divergent regioselective annulation of phosphinyl allenes accessing polyarylfurans and 2H-chromenes.

A novel and efficient regioselective annulation of phosphinyl allenes with 2-bromophenol or 1-bromo-2-naphthol is achieved by palladium catalysis. The divergent pathway delivers structurally diverse polyarylfurans and 2H-chromene skeletons via two different Heck-type annulations. This protocol represents regioselectivity-tunable transformation of allenes into functionalized O-containing heterocycles with excellent group compatibility.

Visible-Light-Induced Palladium-Catalyzed Construction of Polyarylfuran Skeletons via Cascade Aryl Radical Cyclization and C(sp3)-P(V) Bond Cleavage.

Herein, a novel and expedient method was established for the synthesis of polyarylfuran derivatives. The coupling of allenylphosphine oxide and bromophenol or bromonaphthol enabled by visible light and palladium catalysis directly furnishes polyarylfuran skeletons, which involves a radical tandem cyclization and cascade C(sp3)-P(V) bond cleavage. This protocol features easy operation, a broad substrate scope, and a high step economy, affording polyarylfurans in moderate to good yields.

Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/ß-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability.

BACKGROUND: Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells. METHODS: ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and EdU incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes' expression and prognosis of ESCC. RESULTS: Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P < 0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were detected significantly higher than the paired normal tissues from 148 ESCC patients (P < 0.001). Then, the Kaplan-Meier survival analyses suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (Log-rank P < 0.001). Co-IP and Western blotting analyses further revealed that HDAC7 physically deacetylated and activated ß-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/ß-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/ß-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells. CONCLUSIONS: Our findings elucidate that melatonin mitigates the HDAC7/ß-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.

Induction immune-checkpoint inhibitors for resectable oncogene-mutant NSCLC: A multicenter pooled analysis.

Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC.

Metabolic profiles of serum samples from ground glass opacity represent potential diagnostic biomarkers for lung cancer.

BACKGROUND: Lung cancer is a leading cause of cancer deaths worldwide. Low-dose computed tomography (LDCT) screening trials indicated that LDCT is effective for the early detection of lung cancer, but the findings were accompanied by high false positive rates. Therefore, the detection of lung cancer needs complementary blood biomarker tests to reduce false positive rates. METHODS: In order to evaluate the potential of metabolite biomarkers for diagnosing lung cancer and increasing the effectiveness of clinical interventions, serum samples from subjects participating in a low-dose CT-scan screening were analyzed by using untargeted liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). Samples were acquired from 34 lung patients with ground glass opacity diagnosed lung cancer and 39 healthy controls. RESULTS: In total, we identified 9 metabolites in electron spray ionization (ESI)(+) mode and 7 metabolites in ESI(-) mode. L-(+)-gulose, phosphatidylethanolamine (PE)(22:2(13Z,16Z)/15:0), cysteinyl-glutamine, S-japonin, threoninyl-glutamine, chlorate, 3-oxoadipic acid, dukunolide A, and malonic semialdehyde levels were observed to be elevated in serum samples of lung cancer cases when compared to those of healthy controls. By contrast, 1-(2-furanylmethyl)-1H-pyrrole, 2,4-dihydroxybenzoic acid, monoethyl carbonate, guanidinosuccinic acid, pseudouridine, DIMBOA-Glc, and 4-feruloyl-1,5-quinolactone levels were lower in serum samples of lung cancer cases compared with those of healthy controls. CONCLUSIONS: This study demonstrates evidence of early metabolic alterations that can possibly distinguish malignant ground glass opacity from benign ground glass opacity. Further studies in larger pools of samples are warranted.

Comparison of adipose­ and bone marrow­derived stem cells in protecting against ox­LDL­induced inflammation in M1­macrophage­derived foam cells.

Adipose­derived stem cells (ADSCs) and bone marrow­derived stem cells (BMSCs) are considered to be prospective sources of mesenchymal stromal cells (MSCs), that can be used in cell therapy for atherosclerosis. The present study investigated whether ADSCs co­cultured with M1 foam macrophages via treatment with oxidized low­density lipoprotein (ox­LDL) would lead to similar or improved anti­inflammatory effects compared with BMSCs. ADSCs, peripheral blood monocytes, BMSCs and ox­LDL were isolated from ten coronary heart disease (CHD) patients. After three passages, the supernatants of the ADSCs and BMSCs were collected and systematically analysed by liquid chromatography­quadrupole time­of­flight­mass spectrometry (6530; Agilent Technologies, Inc., Santa Clara, CA, USA). Cis­9, trans­11 was deemed to be responsible for the potential differences in the metabolic characteristics of ADSCs and BMSCs. These peripheral blood monocytes were characterized using flow cytometry. Following peripheral blood monocytes differentiation into M1 macrophages, the formation of M1 foam macrophages was achieved through treatment with ox­LDL. Overall, 2x106 ADSCs, BMSCs or BMSCs+cis­9, trans­11 were co­cultured with M1 foam macrophages. Anti­inflammatory capability, phagocytic activity, anti­apoptotic capability and cell viability assays were compared among these groups. It was demonstrated that the accumulation of lipid droplets decreased following ADSCs, BMSCs or BMSCs+cis­9, trans­11 treatment in M1 macrophages derived from foam cells. Consistently, ADSCs exhibited great advantageous anti­inflammatory capabilities, phagocytic activity, anti­apoptotic capability activity and cell viability over BMSCs or BMSCs+cis­9, trans­11. Additionally, BMSCs+cis­9, trans­11 also demonstrated marked improvement in anti­inflammatory capability, phagocytic activity, anti­apoptotic capability activity and cell viability in comparison with BMSCs. The present results indicated that ADSCs would be more appropriate for transplantation to treat atherosclerosis than BMSCs alone or BMSCs+cis­9, trans­11. This may be an important mechanism to regulate macrophage immune function.

Electric field exposure promotes epithelial­mesenchymal transition in human lens epithelial cells via integrin ß1­FAK signaling.

Electric field (EF) exposure can affect the elongation, migration, orientation, and division of cells. The present study tested the hypothesis that EF may also affect epithelial­mesenchymal transition (EMT) in lens epithelial cells and that this effect may be an important inducer in the pathological process of posterior capsule opacification (PCO). Human lens epithelial (HLE)­B3 cells were exposed to an EF. Experiments were performed in the presence or absence of an anti­integrin ß1 blocking antibody or a small molecule inhibitor targeting focal adhesion kinase (FAK). Cell morphology changes were observed by microscopy. The expression levels of integrin ß1, FAK, phosphorylated (p)FAK and of EMT markers, E­cadherin and Vimentin, were examined by immunofluorescence, reverse transcription­quantitative polymerase chain reaction and western blotting. Following exposure to EF, HLE­B3 cells appeared elongated and resembled more fibroblast­like cells. Expression of E­cadherin was decreased, while expression of Vimentin was increased in HLE­B3 cells exposed to EF, compared with control cells. In addition, the mRNA expression levels of integrin ß1 were increased, and the protein expression levels of integrin ß1 and pFAK were increased in HLE­B3 cells exposed to EF, compared with control cells. Blocking of integrin ß1 suppressed the EMT­related morphological changes of HLE­B3 cells and reduced the activation of FAK following EF exposure. However, blocking of pFAK did not affect the EMT status of HLE­B3 cells induced by EF. In conclusion, the present study demonstrated that EF exposure induced EMT in HLE­B3 cells and that this effect may partially be mediated by the activation of integrin ß1­FAK signaling. The present results may provide a new mechanistic approach to prevent the development of PCO.

Gankyrin promotes epithelial-mesenchymal transition and metastasis in NSCLC through forming a closed circle with IL-6/ STAT3 and TGF-ß/SMAD3 signaling pathway.

Our previous research showed that Gankyrin was overexpressed in NSCLC and significantly associated with clinicopathologic features and poor prognosis. In this study, we will explore potential effect of Gankyrin on EMT and metastasis in NSCLC. The ectopic higher expression of Gankyrin markedly increased the migration and invasion in NSCLC cells. In contrast, silencing Gankyrin inhibit this aggressive behavior in NSCLC cells. Further study demonstrated that overexpression of Gankyrin could decrease E-cadherin expression and increase expression of Vimentin and Twist1 at mRNA and protein levels. These data indicated that Gankyrin could facilitate occurrence and development of EMT. Also IHC analysis showed that Gankyrin expression was negatively correlated with E-cadherin expression, while positively correlated with Vimentin and Twist1 expression in NSCLC tissues. The mechanism study finally suggested that the Gankyrin-driven EMT was partially due to IL-6/p-STAT3 and TGF-ß/p-SMAD3 pathways activation. Taken together, our data provided a novel mechanism of Gankyrin promoting EMT and metastasis in NSCLC through forming a closed circle with IL-6/p-STAT3 and TGF-ß/p-SMAD3 signaling pathway.

Effect of cauterizing esophageal mucosa in "double-patch" treatment for acquired benign tracheoesophageal fistula/bronchogastric stump fistula.

BACKGROUND: The management of acquired benign tracheoesophageal fistula (TEF) and bronchogastric stump fistula (BGSF) is a challenge. This study aimed to assess the "double-patch" technique with or without esophageal mucosa in treating nonmalignant TEF and BGSF. MATERIALS AND METHODS: We established a dog model with TEF by incising the esophageal and tracheal membranes and suturing them together. The dogs were divided into three groups (n = 12 per group). Groups A and B received a double-patch 7 d later. The esophageal mucosa of the patches was cauterized in the group A dogs, kept intact in group B dogs, and group C dogs did not receive surgical intervention. Tissue healing was measured using hydroxyproline levels. RESULTS: Morphologic and histopathologic changes of the esophagus were assessed by gross observation of the specimens, hematoxylin and eosin staining, tracheal stenosis index, and hydroxyproline levels. On day 56 after surgery, group A showed a tracheal stenosis index comparable with that of group C (0.140 ± 0.009 versus 0.138 ± 0.014, P = 1.00), whereas group B showed a higher stenosis index (0.170 ± 0.007) than group C (P = 0.029). The hydroxyproline levels were higher in group A than in B and C on day 7 (P = 0.029), and this difference was statistically significant on days 14 and 56 (all P < 0.001). CONCLUSIONS: The use of an esophageal "double-patch" technique without mucosa showed faster and more stable recovery than patches with mucosa in the repair of acquired nonmalignant complicated TEF and BGSF.

A novel surgical method for acquired non-malignant complicated tracheoesophageal and bronchial-gastric stump fistula: the "double patch" technique.

BACKGROUND: To manage the acquired benign complicated tracheoesophageal fistula (TEF) and bronchial-gastric stump fistula (BGSF) are clinical technical challenge. The purpose of this study is to retrospectively review a surgical "double patch" technique in treating nonmalignant complicated TEF and BGSF, and then clarify the long-term curative effect of the technique. METHODS: Clinical records of 30 patients with non-malignant complicated TEF and BGSF treated by "double patch" technique in Tangdu Hospital between August 2004 and August 2014, were analyzed and summarized retrospectively. RESULTS: Thirty patients (19 males and 11 females) underwent "double patch" surgical repair of acquired benign complicated TEF and BGSF. The median age of the patients was 40.2±21.1 years. The most common causes were the following: TEF [22], BGSF [8]. Post-intubation injury [6], trauma [5], foreign body and stents [10], complications from prior esophageal surgery [8], and caustic ingestion [1]. The follow-up was completed for 24 months in all the patients (100%). The operative mortality was 0% (0/30). Twenty-six patients (86.7%) recovered uneventfully while four patients (13.3%) exhibited some major complications in the perioperative and postoperative periods. One patient (3.3%) developed recurrence of tracheal fistula in situ, two patients (6.7%) showed pneumonia, and one patient (3.3%) developed fistula esophageal anastomosis. All the 30 patients resumed oral intake finally. CONCLUSIONS: The double patch technique is an effective and safe method to repair the acquired non-malignant complicated TEF and BGSF.

Clinicopathologic features and prognostic implications of Gankyrin protein expression in non-small cell lung cancer.

PURPOSE: The expression of Gankyrin, a liver cancer-related oncoprotein, has been observed in several human malignancies including non-small cell lung cancer (NSCLC). However, the clinic relevance of Gankyrin expression in NSCLC remains unclear. METHODS: Gankyrin expression was assessed using immunohistochemical (IHC) methods in 166 paired paraffin-embedded NSCLC specimens and adjacent normal tissues. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were employed to measure the expression of Gankyrin in 24 paired fresh NSCLC specimens and the corresponding normal tissues. The association of Gankyrin expression with clinicopathological parameters was also evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of Gankyrin expression on survival. RESULTS: Data showed that Gankyrin was expressed in 78.3% (130/166) and 28.9% (48/166) of cancer lesions and corresponding adjacent normal tissue, respectively. And the Gankyrin overexpression in tumor tissue occurred in 53.6% (89/166) of patients, while overexpression of Gankyrin in normal tissue occurred only in 4.8% (8/166) of patients (P<0.001). Semi-quantitative RT-PCR and Western blotting showed that NSCLC specimens had increased Gankyrin mRNA and protein expression compared to the corresponding normal tissues. Out of all the clinicopathological factors analyzed, Gankyrin overexpression was significantly correlated with lymphatic metastasis (P<0.001) and p-TNM stage (P<0.001). Gankyrin-overexpressed NSCLC patients had a significantly shorter survival time (P<0.001, Log-rank test), and the prognostic significance of Gankyrin overexpression was apparent in both squamous cell carcinoma patients (P=0.028) and adenocarcinoma patients (P<0.001). Multivariate analysis indicated that Gankyrin overexpression may be an independent prognostic factor in NSCLC (hazard ratio [HR], 1.51; P=0.041). CONCLUSION: Our results indicate that Gankyrin overexpression is of clinical significance and can serve as a prognostic biomarker in NSCLC.

RTN4 3'-UTR insertion/deletion polymorphism and susceptibility to non-small cell lung cancer in Chinese Han population.

Nogo protein, encoded by gene reticulon-4 (RTN4), includes three major isoforms by different splicing, named Nogo-A Nogo-B and Nogo-C. Nogo proteins play an important role in the apoptosis of cells, especially in tumor cells. RTN4 single nucleotide polymorphisms (SNPs) can influence the efficiency of transcription and translation thus being related with an individual's predisposition to cancer. The CAA insertion/deletion polymorphism (rs34917480) within RTN4 3'-UTR has been reported to be associated with many cancer types. In order to investigate the relationship between this polymorphism and susceptibility to non-small cell lung cancer (NSCLC) in the Chinese population, we conducted the present case-control study including 411 NSCLC patients and 471 unrelated healthy controls. The genotype distributions were significantly different between cases and controls (p=0.014). We found that the del allele could significantly increase NSCLC risk (ins/ins vs ins/del: p=0.007, OR 1.46, 95%CI=1.11-1.93; dominant model: p=0.004, OR 1.47, 95%CI=1.13-1.92 and allele model: p=0.008, OR 1.35, 95%CI=1.08-1.67). This association was stronger in participants over 60 years old, males and smokers. We therefore conclude that the CAA insertion/deletion polymorphism (rs34917480) contributes to non-small cell lung cancer risk in Chinese population. Age, sex and environmental exposure are also related to carcinogenic effects of rs34917480.

Clinicopathologic features and prognostic implications of NOK/STYK1 protein expression in non-small cell lung cancer.

BACKGROUND: The expression of novel oncogenic kinase (NOK), a member of the protein tyrosine kinase (PTK) family, has been observed in several human malignancies including non-small cell lung cancer (NSCLC). However, the clinic relevance of NOK expression in NSCLC remains unclear. METHODS: In this study, NOK expression in tumor cells was assessed using immunohistochemical methods in 191 patients with resected NSCLC. The association of NOK expression with clinicopathological parameters, including the Ki-67 labeling index (LI), was also evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of NOK expression on survival. RESULTS: Data showed that NOK was expressed in 75.4% and 14.1% of cancer lesions and corresponding adjacent non-cancerous tissue, respectively. Out of all the clinicopathological factors analyzed, NOK expression was significantly correlated with the grade of tumor differentiation (P=0.035), pTNM stage (P=0.020), lymphatic metastasis (P=0.005) and high Ki-67 LI (P<0.001). NOK positive NSCLC patients had a significantly shorter survival time (P=0.004, Log-rank test) and the prognostic significance of NOK expression was apparent in squamous cell carcinoma patients (P=0.022). Multivariate analysis indicated that NOK expression may be an independent prognostic factor in NSCLC (hazard ratio [HR], 1.731; P=0.043). CONCLUSIONS: Our results indicate that NOK expression is of clinical significance and can serve as a prognostic biomarker in NSCLC.

An unusual cause of dysphagia: thoracic aorta aneurysm.

The vascular structure related compression of esophagus is rather rare. Aberrant right subclavicular artery accounts for the majority of the rare entity, while the thoracic aorta aneurysm is a more dangerous type, called as dysphagia aortica. Delay in diagnosis and treatment of the dysphagia aortica predisposes to rupture and death. Herein, we reported a female patient with thoracic aorta aneurysm. A quick diagnosis by using chest contrast computed tomography (CT) scan and angiography of heart was made, and followed by emergent surgery. In the process, there was no delay on the diagnosis and treatment. The patient is going on well in the follow up.

Effects of lipid emulsions in parenteral nutrition of esophageal cancer surgical patients receiving enteral nutrition: a comparative analysis.

BACKGROUND: Olive oil-based lipid emulsion (LE) and medium chain triglyceride/long chain triglyceride (MCT/LCT) emulsion are both LEs with low ω-6 polyunsaturated fat acids (PUFAs) content. However, which one of these LEs is associated with a lower infection risk in patients receiving parenteral nutrition (PN) remains unclear. The aim of the study was to compare the effects of the two LEs in PN in esophageal cancer patients undergoing surgery. METHODS: Patients with resectable esophageal carcinoma were recruited and allocated randomly to two groups. The test group was given enteral nutrition (EN) with PN containing olive oil-based LE after tumor resection for ≥7 days, and the patients in the control group were supported by EN with MCT/LCT emulsion-based PN after surgery for the same time period. Immunological markers and inflammatory indicators were tested and perioperative clinical outcomes were determined. The trial was registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-13003562. 94 Patients were recruited, and grouped (olive oil-based LE, n=46 and MCT/LCT, n=48), matched for sex, age, body mass index, histological type, TNM stage, and nutrition risk screening (NRS) 2002 score. RESULTS: There were no differences in perioperative fever (>38 °C), infectious complications, length of hospital stay (>14 days), length of critical care stay (>2 days), time for oral food intake, and in-hospital mortality between the two groups. The test group showed a higher increase in IgG level compared with the MCT/LCT group (p=0.028). There was no difference in other immunological markers and inflammatory indicators between the two groups. CONCLUSION: PN containing olive oil-based or MCT/LCT LEs had similar effects on perioperative outcome, cell-mediated immune function and inflammatory response in esophageal cancer patients who had undergone surgery and were receiving EN.

Protective effect of magnolol on lipopolysaccharide-induced acute lung injury in mice.

Magnolol, a tradition Chinese herb, displays an array of activities including antifungal, antibacterial, and antioxidant effects. To investigate the protective effect of magnolol on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg). The mice received intratracheal instillation of magnolol (5 µg/kg) 30 min before LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, and myeloperoxidase (MPO) activity were measured by enzyme-linked immunosorbent assay. Expression of cyclooxygenase (COX)-2 in lung tissues was determined by Western blot analysis. Magnolol pretreatment significantly attenuated the severity of lung injury and inhibited the production of TNF-α and IL-1ß in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by magnolol pretreatment. The expression of COX-2 was significantly suppressed by magnolol pretreatment. Magnolol potently protected against LPS-induced ALI and the protective effects of magnolol may attribute partly to the suppression of COX-2 expression.

[Risk factors of surgical interventions in patients with esophageal foreign bodies].

OBJECTIVE: To investigate the risk factors of surgical interventions in patients with esophageal foreign bodies(EFBs). METHODS: Forty-three cases with EFBs underwent surgical interventions from January 1962 to January 2011 in Department of Thoracic Surgery at the Tangdu Hospital were enrolled in the study group. Forty three cases with EFBs who received non-surgical treatment in the same hospital and during the same period matched by gender and age(the age difference between the paired patients was 5 years or less) were selected as the control group. Clinical data including type of EFBs, duration of impaction, location of EFBs, complications associated with EFBs were collected. Univariate and multivariate conditional logistic analysis were used for risk factors analysis. RESULTS: Univariate conditional logistic analysis showed that type of EFBs, duration of impaction, location of EFBs, and complications associated with EFBs were risk factors of surgical interventions in patients with EFBs(P<0.05). Further multivariate conditional logistic analysis showed that type of EFBs(sharp EFBs) was the independent factor of surgical interventions in patients with EFBs(P=0.043; OR=29.228, 95% CI:1.114-766.686). CONCLUSIONS: Physician should pay more attention to patients with sharp EFBs. Whether the patients need surgical interventions or not should base on factors including duration of impaction, location of EFBs, and complications associated with EFBs.

Integrin ß1 subunit signaling is involved in the directed migration of human retinal pigment epithelial cells following electric field stimulation.

AIMS: Direct current electric fields (EFs) can induce directed cell migration in a wide variety of cells, and this has been proven to be of importance in wound healing. Here we observed the effects of EFs on cultured human retinal pigment epithelial (RPE) cells and explored the possible involvement of integrin ß1 subunit signaling in the process. METHODS: Cultured human RPE cells were exposed to an EF at 5 V/cm for 3 h. The rate and directionality of cell migration were quantified. The distribution of integrin ß1 subunit was measured by immunohistochemistry and the expression of integrin ß1 subunit and phosphorylated focal adhesion kinase (FAK) was determined by PCR and Western blotting. Experiments were performed in the presence or absence of anti-integrin ß1 subunit antibody. RESULTS: During exposure to an EF at 5 V/cm for 3 h, the separated human RPE cells and wounded RPE monolayer demonstrated a cathodal-directed migration. The distribution of integrin ß1 subunit in the cells was also polarized to the cathode, and the expression in mRNA and its protein level were obviously increased. Furthermore, exposure to EFs of 5 V/cm triggered the phosphorylation of FAK in human RPE cells. In contrast, blocking of integrin ß1 subunit suppressed the directed migration of RPE cells and reduced the activation of FAK in EFs. CONCLUSIONS: These findings indicate that EF exposure results in directed migration of the separated RPE cells and RPE monolayer. These effects may partially act through the activation of integrin ß1 subunit signaling.

Glycyrrhizin treatment is associated with attenuation of lipopolysaccharide-induced acute lung injury by inhibiting cyclooxygenase-2 and inducible nitric oxide synthase expression.

Glycyrrhizin (GL), a major active constituent of licorice root, has been attributed numerous pharmacologic effects, including anti-inflammatory, anti-viral, anti-tumor, and hepatoprotective activities. In this study, we investigated the anti-inflammatory effect of GL on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. ALI was induced in Balb/c mice by intratracheal instillation of LPS (1 mg/kg). Before 1 h of LPS administration, the mice received intraperitoneal injection of GL at varied doses (10, 25, and 50 mg/kg). The severity of pulmonary injury was evaluated 12 h after LPS administration. GL pretreatment led to significant attenuation of LPS induced evident lung histopathologic changes, alveolar hemorrhage, and neutrophil infiltration with evidence of reduced myeloperoxidase (MPO) activity. The lung wet/dry weight ratios, as an index of lung edema, were markedly reduced by GL pretreatment. The concentrations of pro-inflammatory cytokines interleukin (IL)-1ß and tumor necrosis factor (TNF)-α were elevated in bronchoalveolar lavage fluid (BALF) after LPS administration, which were significantly inhibited by GL pretreatment. GL pretreatment also reduced the concentrations of nitric oxide (NO) in lung tissues. Furthermore, the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was suppressed by GL pretreatment. In conclusion, GL potently protected against LPS-induced ALI, and the protective effects of GL may attribute partly to the suppression of COX-2 and iNOS expression.

Protective effect of nicotine on lipopolysaccharide-induced acute lung injury in mice.

BACKGROUND: Recently, nicotine administration has been shown to be a potent inhibitor of a variety of innate immune responses, including endotoxin-induced sepsis. OBJECTIVE: It was the aim of this study to evaluate the effect of nicotine on attenuating lung injury and improving the survival in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI). METHODS: ALI was induced in mice by intratracheal instillation of LPS (3 mg/ml). The mice received intratracheal instillation of nicotine (50, 250 and 500 µg/kg) before or after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain, and lung wet/dry weight ratios were observed. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and high mobility group box (HMGB)-1, as well as myeloperoxidase (MPO) activity were measured by enzyme-linked immunosorbent assay. The mortality rate was recorded and analyzed by the Kaplan-Meier method. RESULTS: Nicotine pretreatment significantly attenuated the severity of lung injury and inhibited the production of TNF-α, IL-1ß and HMGB-1 in mice with ALI. After LPS administration, the lung wet/dry weight ratios, as an index of lung edema, and MPO activity were also markedly reduced by nicotine pretreatment. Early treatment with a high dose of nicotine (500 µg/kg) after LPS administration decreased the mortality in mice with ALI, even when treatment was started 24 h after LPS administration. CONCLUSION: Nicotine attenuated the lung injury and reduced mortality in mice with LPS-induced ALI.