Discharge Against Medical Advice After Hospitalization for Sepsis: Predictors, 30-Day Readmissions, and Outcomes.

BACKGROUND: Sepsis is a leading cause of death worldwide. However, little has been known concerning the status of discharge against medical advice (DAMA) in sepsis patients. OBJECTIVE: To identify factors associated with DAMA, evaluate the association of DAMA with 30-day unplanned readmission and readmitted outcomes after sepsis hospitalization. METHODS: Using the National Readmission Database, we identified sepsis patients who discharged routinely or DAMA in 2017. Multivariable models were used to identify factors related to DAMA, evaluate the association between DAMA and readmission, and elucidate the relationship between DAMA and outcomes in patients readmitted within 30 days. RESULTS: Among 1,012,650 sepsis cases, patients with DAMA accounted for 3.88% (n = 39,308). The unplanned 30-day readmission rates in patients who discharged home and DAMA were 13.08% and 27.21%, respectively. Predictors of DAMA in sepsis included Medicaid, diabetes, smoking, drug abuse, alcohol abuse, and psychoses. DAMA was statistically significantly associated with 30-day (odds ratio [OR] 2.18, 95% confidence interval [CI] 2.09-2.28), 60-day (OR 1.98, 95% CI 1.90-2.06), and 90-day (OR 1.88, 95% CI 1.81-1.96) readmission. DAMA is also associated with higher mortality in patients readmitted within 30 days (OR 1.38, 95% CI 1.17-1.63), whereas there were no statistically significant differences in length of stay and costs between patients who discharged home or DAMA. CONCLUSIONS: DAMA occurs in nearly 3.88% of sepsis patients and is linked to higher readmission and mortality. Those at high risk of DAMA should be early identified to motivate intervention to avoid premature discharges and associated adverse outcomes.

Ultrasound-Guided Dynamic Needle-Tip Positioning Method Is Superior to Conventional Palpation and Ultrasound Method in Arterial Catheterization.

Background: Dynamic needle-tip positioning (DNTP) was shown to improve arterial cannulation efficiency with fewer complications than conventional palpation and ultrasound methods by some studies. However, this is still controversial, and we performed this meta-analysis to comprehensively assess its value in arterial cannulation. Methods: A literature search of randomized controlled trials was conducted, and 11 studies were finally included. Efficiency outcomes (first-attempt success, overall success, and total cannulation time) and complications (hematoma, thrombosis, posterior wall puncture, and vasospasm) were separately analyzed. Subgroup analyses in different populations under cannulation were also performed. Results: DNTP was associated with increased first-attempt success (pooled RR = 1.792, p < 0.001), overall success (pooled RR = 1.368, p = 0.001), and decreased cannulation time (pooled SMD = −1.758, p = 0.001) than palpation. DNTP gained even more advantage in small children and infants. No significant difference in these outcomes between DNTP and conventional ultrasound method was detected. Fewer hematoma occurred in DNTP than palpation (pooled RR = 0.265, p < 0.001) or traditional ultrasound (pooled RR = 0.348, p < 0.001). DNPT was also associated with fewer posterior wall punctures (pooled RR = 0.495, p = 0.001) and vasospasm (pooled RR = 0.267, p = 0.007) than traditional ultrasound. Conclusions: DNTP was a better choice in artery cannulation than conventional palpation and ultrasound method, especially in small children and infants.

Activation of the endocannabinoid system mediates cardiac hypertrophy induced by rosiglitazone.

Rosiglitazone (RSG) is a synthetic agonist of peroxisome proliferator-activated receptor-γ (PPARγ), which plays a central role in the regulation of metabolism. Meta-analyses have suggested that RSG is associated with increased cardiovascular risk. However, the mechanisms underlying such adverse cardiac effects are still poorly understood. Here, we found that activation of PPARγ by RSG stimulated the endocannabinoid system (ECS), a membrane lipid signaling system, which induced cardiac hypertrophy. In neonatal rat cardiomyocytes, RSG increased the level of anandamide (AEA); upregulated the expression of N-acyl phosphatidylethanolamine phospholipase D (NapePLD), a key enzyme for AEA synthesis; and downregulated the expression of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of AEA. Importantly, PPARγ activation increased the expression of cannabinoid receptor type 1 (CB1) through an identified binding site for PPARγ in the CB1 promoter region. Moreover, both the in vitro and in vivo results showed that inhibition of the ECS by rimonabant, an antagonist of CB1, attenuated RSG-induced cardiac hypertrophy, as indicated by decreased expression of cardiac hypertrophy markers (ANP and BNP), deactivation of the mTOR pathway, and decreased cardiomyocyte size. Thus, these results demonstrated that the ECS functions as a novel target of PPARγ and that the AEA/CB1/mTOR axis mediates RSG-induced cardiac remodeling.

S-nitrosation impairs KLF4 activity and instigates endothelial dysfunction in pulmonary arterial hypertension.

Krüppel-like factor 4 (KLF4) is a transcription factor with conserved zinc finger domains. As an essential regulator of vascular homeostasis, KLF4 exerts a protective effect in endothelial cells (ECs), including regulating vasodilation, inflammation, coagulation and oxidative stress. However, the underlying mechanisms modifying KLF4 activity in mediating vascular function remain poorly understood. Recently, essential roles for S-nitrosation have been implicated in many pathophysiologic processes of cardiovascular disease. Here, we demonstrated that KLF4 could undergo S-nitrosation in response to nitrosative stress in ECs, leading to the decreased nuclear localization with compromised transactivity. Mass-spectrometry and site-directed mutagenesis revealed that S-nitrosation modified KLF4 predominantly at Cys437. Functionally, KLF4 dependent vasodilatory response was impaired after S-nitrosoglutathione (GSNO) treatment. In ECs, endothelin-1 (ET-1) induced KLF4 S-nitrosation, which was inhibited by an endothelin receptor antagonist Bosentan. In hypoxia-induced rat model of pulmonary arterial hypertension (PAH), S-nitrosated KLF4 (SNO-KLF4) was significantly increased in lung tissues, along with decreased nuclear localization of KLF4. In summary, we demonstrated that S-nitrosation is a novel mechanism for the post-translational modification of KLF4 in ECs. Moreover, these findings suggested that KLF4 S-nitrosation may be implicated in the pathogenesis of vascular dysfunction and diseases such as PAH.

Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway.

Krüppel-like factor 4 (KLF4) is a transcription factor and plays a vital role in cancer initiation and development. However, the role of Krüppel-like factor 4 in the metastasis of non-small cell lung cancer (NSCLC) is not clear. Here, we demonstrated that the expression of Krüppel-like factor 4 was significantly decreased in human non-small cell lung cancer tissues compared with that in normal tissues using Western blot. We performed immunohistochemical staining and observed the decreased expression of Krüppel-like factor 4 in human lung cancer tissues, and metastatic tumor tissues located in the trachea and main bronchus. We also found that the E-cadherin expression was decreased, while vimentin expression was increased in human NSCLC tissues and metastatic tumor tissues located in the trachea and main bronchus. Additionally, enforced expression of Krüppel-like factor 4 in mouse lungs significantly inhibited the metastasis of circulating Lewis lung carcinoma cells to the lungs by attenuating mesenchymal-epithelial transition (MET). Furthermore, cell scratch assays and Matrigel invasion assays revealed that overexpression of Krüppel-like factor 4 inhibited the migration and invasion of non-small cell lung cancer cell lines A549, H1299, H226, and H1650 cells. Moreover, overexpression of Krüppel-like factor 4 attenuated TGF-ß1-induced epithelial-mesenchymal transition (EMT) in A549, and inhibited the phosphorylation of c-Jun-NH2-terminal kinase (JNK), an important pathway in metastasis in non-small cell lung cancer. Our in vivo and in vitro findings illustrate that Krüppel-like factor 4 inhibited metastasis and migration of non-small cell lung cancer, and indicate that Krüppel-like factor 4 could be a potential therapeutic target for the treatment of non-small cell lung cancer.

A GA-based parameters tuning method for an ADRC controller of ISP for aerial remote sensing applications.

This paper presents a parameters tuning method based on the genetic algorithm (GA) for an active disturbance rejection control (ADRC) of a three-axis inertially stabilized platform (ISP) with imaging sensors. To improve the stabilization accuracy and robustness of an aerial ISP under multi-source disturbances environment, an ADRC control scheme is first proposed. Then, to accurately identify and tune the parameters in the ADRC controller, a GA-based parameters tuning method is proposed. In this way, the performance of the ADRC is superior to the empirical method. To validate the proposed method, the simulations and experiments are carried out. The results show that the proposed ADRC with GA-based parameters tuning method has significant disturbance rejection ability which can improve the stabilization accuracy obviously. Compared with the ADRC with empirically tuning method, the stabilization error (RMS) under movable base is decreased up to 50.09%.

Inhibition of mTOR ameliorates bleomycin-induced pulmonary fibrosis by regulating epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) plays a pivotal role in idiopathic pulmonary fibrosis (IPF). In bleomycin-induced pulmonary fibrosis mice, we observed that inhibition of mTOR (mammalia target of rapamycin) attenuated IPF. Rapamycin suppressed the down-regulation of E-cadherin and up-regulation of fibronectin in bleomycin-induced pulmonary fibrosis mice. In addition, dual immunofluorescence staining for E-cadherin and fibronectin demonstrated that rapamycin pretreatment decreased the proportions of AECs undergoing EMT in bleomycin-induced pulmonary fibrosis, indicating that mTOR inhibition suppressed EMT in vivo. In the setting of transforming growth factor (TGF)-ß1-induced EMT in AECs, we found that mTOR inhibitor attenuated TGF-ß1-induced EMT in AECs. This EMT was characterized by morphology and cell skeleton changes and the expression of EMT phenotype markers. Finally, mTOR blockade decreased S6k and TGF-ß1-induced Smad2/3 phosphorylation. Bleomycin induced pulmonary fibrosis and EMT in mice, while mTOR repression inhibited bleomycin-induced pulmonary fibrosis and attenuated EMT in vivo. Hence, our study provided evidence of a novel mechanism by which mTOR inhibitor ameliorates pulmonary fibrosis. Suppression of mTOR and EMT may be a target for treatment of pulmonary fibrosis.

Inhibition of 5-Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the ß-Arrestin2-Mammalian Target of Rapamycin/p70S6K Pathway.

BACKGROUND: As a monoamine neurotransmitter, 5-hydroxytryptamine (5-HT) or serotonin modulates mood, appetite, and sleep. Besides, 5-HT also has important peripheral functions. 5-HT receptor 2B (5-HT2BR) plays a key role in cardiovascular diseases, such as pulmonary arterial hypertension and cardiac valve disease. Percutaneous intervention has been used to restore blood flow in occlusive vascular disease. However, restenosis remains a significant problem. Herein, we investigated the role of 5-HT2BR in neointimal hyperplasia, a key pathological process in restenosis. METHODS AND RESULTS: The expression of 5-HT2BR was upregulated in wire-injured mouse femoral arteries. In addition, BW723C86, a selective 5-HT2BR agonist, promoted the injury response during restenosis. 5-HT and BW723C86 stimulated migration and proliferation of rat aortic smooth muscle cells. Conversely, LY272015, a selective antagonist, attenuated the 5-HT-induced smooth muscle cell migration and proliferation. In vitro study showed that the promigratory effects of 5-HT2BR were mediated through the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling in a ß-arrestin2-dependent manner. Inhibition of mammalian target of rapamycin or p70S6K mitigated 5-HT2BR-mediated smooth muscle cell migration. Mice with deficiency of 5-HT2BR showed significantly reduced neointimal formation in wire-injured arteries. CONCLUSIONS: These results demonstrated that activation of 5-HT2BR and ß-arrestin2-biased downstream signaling are key pathological processes in neointimal formation, and 5-HT2BR may be a potential target for the therapeutic intervention of vascular restenosis.

Rapid development of metastatic pulmonary calcifications in primary hyperparathyroidism: a case report and literature review.

BACKGROUND: Metastatic pulmonary calcification (MPC) is rarely reported in primary hyperparathyroidism, especially MPC develops quickly. We report such a case here with a literature review. CASE PRESENTATION: A 41-year-old woman presented with cough and dyspnea. Data from clinical, radiological, pathological, technetium (99mTc)-methylene diphosphonate (MDP) bone scintillation imaging, and 99mTc-methoxy isobutyl isonitrile (MIBI) thyroid imaging were studied. 99mTc-MIBI thyroid imaging indicated hyperparathyroidism. Chest computed tomography (CT) scans showed rapidly progressive bilateral pulmonary multiple high-density shadows with mass consolidation and exudation in only five days. 99mTc-MDP bone scintillation imaging indicated bilateral pulmonary calcifications. CT-guided lung biopsy showed multifocal irregularities of calcium deposition and calcified bodies in the pulmonary interstitium. The patient showed gradually clinical and radiological improvement after surgical removal of the parathyroid adenoma. CONCLUSION: Rapidly progressive MPC tends to be misdiagnosed as many primary pulmonary diseases. 99mTc-MDP bone scintillation imaging and pulmonary biopsy could be performed to differentiate metastatic pulmonary calcification from other diseases. Surgical resection of the parathyroid gland is helpful for treatment of MPC in patients with primary hyperparathyroidism and is regularly recommended.

A compound scheme on parameters identification and adaptive compensation of nonlinear friction disturbance for the aerial inertially stabilized platform.

A compound scheme is proposed to compensate the effect of nonlinear friction disturbance on the control precision of a three-axis inertially stabilized platform (ISP) for aerial remote sensing applications. The scheme consists of friction parameters identification and adaptive compensation. A LuGre model-based ISP friction model is first developed. Then, a comprehensive experimental scheme is proposed to obtain the static friction parameters. Further, the dynamic parameters are identified by experiments and dynamic optimization. On the basis of identified parameters and Lyapunov stability theory, a backstepping integral adaptive compensator is designed to compensate the nonlinear friction disturbance. Simulations and experiments are carried out to validate the scheme. The results show that the compound scheme can accurately obtain the friction parameters and improve the control precision and stability of ISP.

Important factors mediates the adhesion of aspergillus fumigatus to alveolar epithelial cells with E-cadherin.

Aspergillus is widely distributed in the Earth's biosphere. It has strong adaptive capacity, and lives as saprophytic or parasitic life. This study aims to investigate the role of E-cadherin for adhesion of Aspergillus fumigatus blastospores in a human epithelial cell line (A549) and search the correlated molecule in aspergillus. A. fumigatus blastospores were incubated with the total protein of A549 to investigate the binding of E-cadherin and blastospores followed by an affinity purification procedure. After establishing the adhesion model, the adhesion of A. fumigatus blastospores by A549 cells was evaluated by down-regulating E-cadherin of A549 cells with small interfering RNA (siRNA). FVB mice constructed with E-cadherin down-regulation were infected with aspergillus fumigatus. Preliminary exploration of E-cadherin interacting protein on the surface of aspergillus fumigates by immunoprecipitation and mass spectrometry analysis. E-cadherin was adhered to the surface of A. fumigatus blastospore. Adhesion of the blastospores was reduced by blocking or down-regulating E-cadherin in A549 cells. E-cadherin showed limited significance in the process of mice against aspergillus fumigates. Mass spectrometry (MS) analysis indicated the following proteins AFUA_8G07080, AfA24A6.130c, XP_747789 can bind to E-cadherin. In conclusion, E-cadherin is a receptor for adhesion of A. fumigatus blastospores in epithelial cells. This may open a new approach to treat this fungal infection.

Acute fibrinous and organizing pneumonia: A case report and literature review.

Acute fibrinous and organizing pneumonia (AFOP) is a rare lung disease with distinct histological characteristics that include the diffuse presence of intra-alveolar fibrin, and the absence of eosinophils and hyaline membrane. In the present study, a case of AFOP that was diagnosed by lung biopsy is described. The patient presented with high fever and a cough with expectoration. Computed tomography of the lung showed the presence of bilateral patchy infiltrates, predominantly in the lower lobes. Histopathological examination of lung biopsy from the lower pulmonary lobe confirmed the pathological diagnosis. The patient showed a poor response to treatment with prednisone. Based on a review of literature pertaining to documented AFOP cases, a summary of the clinical features, radiological characteristics, treatment outcomes and prognoses associated with AFOP are presented. The most common pulmonary symptoms included cough, dyspnea and fever. The primary imaging findings in AFOP were consolidation and ground-glass opacity in the bilateral lung.

Control Parameters Optimization Based on Co-Simulation of a Mechatronic System for an UA-Based Two-Axis Inertially Stabilized Platform.

This paper presents a method based on co-simulation of a mechatronic system to optimize the control parameters of a two-axis inertially stabilized platform system (ISP) applied in an unmanned airship (UA), by which high control performance and reliability of the ISP system are achieved. First, a three-dimensional structural model of the ISP is built by using the three-dimensional parametric CAD software SOLIDWORKS(®); then, to analyze the system's kinematic and dynamic characteristics under operating conditions, dynamics modeling is conducted by using the multi-body dynamics software ADAMS™, thus the main dynamic parameters such as displacement, velocity, acceleration and reaction curve are obtained, respectively, through simulation analysis. Then, those dynamic parameters were input into the established MATLAB(®) SIMULINK(®) controller to simulate and test the performance of the control system. By these means, the ISP control parameters are optimized. To verify the methods, experiments were carried out by applying the optimized parameters to the control system of a two-axis ISP. The results show that the co-simulation by using virtual prototyping (VP) is effective to obtain optimized ISP control parameters, eventually leading to high ISP control performance.

Activation of PPAR-δ induces microRNA-100 and decreases the uptake of very low-density lipoprotein in endothelial cells.

BACKGROUND AND PURPOSE: Increased level of very low-density lipoprotein (VLDL) is a key feature of the metabolic syndrome and is associated with cardiovascular diseases. PPAR-δ agonists play a protective role in lipid metabolism and vascular function. In this study, we aimed to investigate the role of PPAR-δ in the uptake of VLDL in endothelial cells and its underlying mechanism(s). EXPERIMENTAL APPROACH: Uptake of VLDL in HUVECs was assessed by Dil-fluorescent labelling of VLDL. Levels of VLDL receptor mRNA and microRNA (miR-100) were detected by quantitative PCR. The target genes of miR-100 were predicted using bioinformatics analysis. 3'-Untranslated region (3'-UTR) luciferase reporter and Argonaute 1 pull-down assays were used to validate the target of miR-100. KEY RESULTS: PPAR-δ agonist GW501516 decreased uptake of VLDL and expression of VLDL receptor at mRNA and protein levels. GW501516 inhibited the luciferase reporter activity of the 3'-UTR of VLDL receptor. VLDL receptor was a direct target of miR-100. miR-100 was significantly increased by GW501516 in HUVECs. Transfection of a miR-100 mimic decreased the mRNA and protein levels of VLDL receptor and uptake of VLDL. Furthermore, a miR-100 inhibitor abolished the inhibitory effect of PPAR-δ on VLDL receptor expression and VLDL uptake. CONCLUSIONS AND IMPLICATIONS: In endothelial cells, activation of PPAR-δ decreased VLDL receptor expression and VLDL uptake via the induction of miR-100. These results provided a novel mechanism for the vascular protective effect of PPAR-δ agonists.

Peroxisome Proliferator-Activated Receptor γ Regulates the Expression of Lipid Phosphate Phosphohydrolase 1 in Human Vascular Endothelial Cells.

Lipid phosphate phosphohydrolase 1 (LPP1), a membrane ectophosphohydrolase regulating the availability of bioactive lipid phosphates, plays important roles in cellular signaling and physiological processes such as angiogenesis and endothelial migration. However, the regulated expression of LPP1 remains largely unknown. Here, we aimed to examine a role of peroxisome proliferator-activated receptor γ (PPAR γ ) in the transcriptional control of LPP1 gene expression. In human umbilical vein endothelial cells (HUVECs), quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) demonstrated that activation of PPAR γ increased the mRNA level of LPP1. Chromatin immunoprecipitation assay showed that PPAR γ binds to the putative PPAR-responsive elements (PPREs) within the 5'-flanking region of the human LPP1 gene. Genomic fragment containing 1.7-kilobase of the promoter region was cloned by using PCR. The luciferase reporter assays demonstrated that overexpression of PPAR γ and rosiglitazone, a specific ligand for PPAR γ , could significantly upregulate the reporter activity. However, site-directed mutagenesis of the PPRE motif abolished the induction. In conclusion, our results demonstrated that PPAR γ transcriptionally activated the expression of LPP1 gene in ECs, suggesting a potential role of PPAR γ in the metabolism of phospholipids.

Metabonomic profiling revealed an alteration in purine nucleotide metabolism associated with cardiac hypertrophy in rats treated with thiazolidinediones.

Thiazolidinediones (TZDs) including rosiglitazone (RSG) and pioglitazone (PIO) are synthetic agonists selective for peroxisome proliferator-activated receptor-γ (PPARγ) and have been clinically used to treat type-II diabetes as insulin sensitizers. Recent meta-analyses have shown that TZDs are associated with an increased risk for the development of heart failure. To elucidate the mechanism underlying such a cardiac adverse effect, we used a (1)H NMR-based approach to examine the metabonomic profiles in the cardiac tissues treated with RSG (15 mg/kg body weight/day) or PIO (45 mg/kg/day) for 4 weeks and found that the TZD treatments resulted in a significantly altered metabolic profile in hearts, which was associated with cardiac hypertrophy. Multivariate analysis demonstrated that TZDs led to an accumulation in adenosine monophosphate (AMP) and a depletion of inosine. Consistently, AMP kinase, a signal pathway sensitive to the change in the intracellular concentrations of AMP, was activated in the cardiac tissues from the TZDs-treated rats. Quantitative real-time reverse-transcriptase polymerase chain reaction showed a significant induction of the genes involved in the de novo synthesis of purine nucleotide but a reduction of those for the catabolism. Furthermore, the putative PPAR-responsive elements were identified in the 5'-flanking regions of the TZD-up-regulated genes such as adenylosuccinate synthase gene (Adss) and phosphoribosl pyrophosphate synthetase 1 (Prps1), and the binding of PPARγ to these motifs was confirmed by using chromatin immunoprecipitation assay. In conclusion, these results demonstrated that TZDs induced alterations in purine nucleotide metabolism in rat hearts via transcriptional regulation of the PPARγ-target genes, which may play an important role in the development of cardiac hypertrophy associated with TZDs.

Epigallocatechin-3-O-gallate, a green tea polyphenol, induces expression of pim-1 kinase via PPARγ in human vascular endothelial cells.

Pim-1 is a serine/threonine kinase and involved in cell survival and proliferation. Recently, it has been shown that pim-1 signaling pathway plays an important role in cardiovascular protection and differentiation. In this study, we sought to explore the expression of pim-1 in human vascular endothelial cells (ECs) and its regulation by epigallocatechin-3-O-gallate (EGCG), a green tea polyphenol which has anti-oxidant, anti-inflammatory and vascular protective effects. By using quantitative reverse transcriptase PCR (qRT-PCR) and Western blotting, we showed that EGCG dose-dependently increased the expression of pim-1 in cultured umbilical vein endothelial cells. Next, we showed that EGCG activated a luciferase reporter driven by peroxisome proliferators-activated receptor (PPAR)-responsive elements. The induced expression of pim-1 was inhibited in ECs pretreated with GW9662, a specific antagonist of PPARγ. In addition, pim-1 was also up-regulated in endothelial cells treated with rosiglitazone, a specific agonist for PPARγ, or those infected with the adenovirus expressing a constitutively active PPARγ. Collectively, our results provided new evidence that pim-1 can be up-regulated by EGCG via a PPARγ-mediated mechanism and may mediate its vascular protective effects.

Shear stress activation of nuclear receptor PXR in endothelial detoxification.

Endothelial cells (ECs) are constantly exposed to xenobiotics and endobiotics or their metabolites, which perturb EC function, as well as to shear stress, which plays a crucial role in vascular homeostasis. Pregnane X receptor (PXR) is a nuclear receptor and a key regulator of the detoxification of xeno- and endobiotics. Here we show that laminar shear stress (LSS), the atheroprotective flow, activates PXR in ECs, whereas oscillatory shear stress, the atheroprone flow, suppresses PXR. LSS activation of PXR in cultured ECs led to the increased expression of a PXR target gene, multidrug resistance 1 (MDR1). An in vivo study using rats showed that the expression of MDR1 was significantly higher in the endothelium from the descending thoracic aorta, where flow is mostly laminar, than from the inner curvature of aortic arch, where flow is disturbed. Functionally, LSS-activated PXR protects ECs from apoptosis triggered by doxorubicin via the induction of MDR1 and other detoxification genes. PXR also suppressed the expression of proinflammatory adhesion molecules and monocyte adhesion in response to TNF-α and lipopolysaccharide. Overexpression of a constitutively active PXR in rat carotid arteries potently attenuated proinflammatory responses. In addition, cDNA microarray revealed a large number of the PXR-activated endothelial genes whose products are responsible for major steps of detoxification, including phase I and II metabolizing enzymes and transporters. These detoxification genes in ECs are induced by LSS in ECs in a PXR-dependent manner. In conclusion, our results indicate that PXR represents a flow-activated detoxification system to protect ECs against damage by xeno- and endobiotics.

E-cadherin mediates adhesion and endocytosis of Aspergillus fumigatus blastospores in human epithelial cells.

BACKGROUND: Aspergillus fumigatus (A. fumigatus) is a ubiquitous saprophytic fungus responsible for the majority of invasive mold infections in patients undergoing chemotherapy, organ transplantation or with persistent neutropenia. This study aimed to determine the role of E-cadherin for adhesion and endocytosis of A. fumigatus blastospores in the human epithelial cell line A549. METHODS: A. fumigatus blastospores were incubated with the total protein of A549 to investigate the binding of E-cadherin and blastospores followed by an affinity purification procedure. After establishing the adhesion model, the adhesion and endocytosis of A. fumigatus blastospores by A549 cells were evaluated by down-regulating E-cadherin of A549 cells using blocking antibody or small interfering RNA (siRNA). RESULTS: E-cadherin was adhered to the surface of A. fumigatus blastospore. Adhesion and endocytosis of the blastospores were reduced by blocking or down-regulating E-cadherin in A549 cells. CONCLUSIONS: E-cadherin is a receptor for adhesion and endocytosis of A. fumigatus blastospores in epithelial cells. This may open a new approach to treat this fungal infection.

Krüppel-like factor 4 is induced by rapamycin and mediates the anti-proliferative effect of rapamycin in rat carotid arteries after balloon injury.

BACKGROUND AND PURPOSE: The transcription factor, Krüppel-like factor 4 (KLF4), plays an important role in regulating the proliferation of vascular smooth muscle cells. This study aimed to examine the effect of rapamycin on the expression of KLF4 and the role of KLF4 in arterial neointimal formation. EXPERIMENTAL APPROACH: Expression of KLF4 was monitored using real-time PCR and immunoblotting in cultured vascular smooth muscle cells. and in rat carotid arteries in vivo after balloon injury. Adenovirus-mediated overexpression and siRNA-mediated knockdown of KLF4 were used to examine the role of KLF4 in mediating the anti-proliferative role of rapamycin . KLF4-regulated genes were identified using cDNA microarray. KEY RESULTS: Rapamycin induced the expression of KLF4 in vitro and in vivo. Overexpression of KLF4 inhibited cell proliferation and the activity of mammalian target of rapamycin (mTOR) and its downstream pathways, including 4EBP-1 and p70S6K in vascular smooth muscle cells and prevented the neointimal formation in the balloon-injured arteries. KLF4 up-regulated the expression of GADD45ß, p57(kip2) and p27(kip1) . Furthermore, knockdown of KLF4 attenuated the anti-proliferative effect of rapamycin both in vitro and in vivo. CONCLUSIONS AND IMPLICATIONS: KLF4 plays an important role in mediating the anti-proliferative effect of rapamycin in VSMCs and balloon-injured arteries. Thus, it is a potential target for the treatment of proliferative vascular disorders such as restenosis after angioplasty.