Novel insecticidal proteins from ferns resemble insecticidal proteins from Bacillus thuringiensis.

Lepidopterans affect crop production worldwide. The use of transgenes encoding insecticidal proteins from Bacillus thuringiensis (Bt) in crop plants is a well-established technology that enhances protection against lepidopteran larvae. Concern about widespread field-evolved resistance to Bt proteins has highlighted an urgent need for new insecticidal proteins with different modes or sites of action. We discovered a new family of insecticidal proteins from ferns. The prototype protein from Pteris species (Order Polypodiales) and variants from two other orders of ferns, Schizaeales and Ophioglossales, were effective against important lepidopteran pests of maize and soybean in diet-based assays. Transgenic maize and soybean plants producing these proteins were more resistant to insect damage than controls. We report here the crystal structure of a variant of the prototype protein to 1.98 Å resolution. Remarkably, despite being derived from plants, the structure resembles the 3-domain Cry proteins from Bt but has only two out of three of their characteristic domains, lacking the C-terminal domain which is typically required for their activities. Two of the fern proteins were effective against strains of fall armyworm that were resistant to Bt 3-domain Cry proteins Cry1Fa or Cry2A.127. This therefore represents a novel family of insecticidal proteins that have the potential to provide future tools for pest control.

DPP-4 exacerbates LPS-induced endothelial cells inflammation via integrin-α5ß1/FAK/AKT signaling.

Endothelial dysfunction plays a pivotal role in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Dipeptidyl peptidase IV (DPP-4), a cell surface glycoprotein, has been implicated in endothelial inflammation and barrier dysfunction. In this study, the role of DPP-4 on lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial cells (HPMECs) dysfunction and the underlying mechanism were investigated by siRNA-mediated knockdown of DPP-4. Our results indicated that LPS (1 µg/ml) challenge resulted in either the production and releasing of DPP-4, as well as the secretion of IL-6 and IL-8 in HPMECs. DPP-4 knockdown inhibited chemokine releasing and monolayer hyper-permeability in LPS challenged HPMECs. When cocultured with human polymorphonuclear neutrophils (PMNs), DPP4 knockdown suppressed LPS-induced neutrophil-endothelial adhesion, PMN chemotaxis and trans-endothelial migration. Western blotting showed that DPP-4 knockdown attenuated LPS-induced activation of TLR4/NF-κB pathway. Immunoprecipitation and liquid chromatography-tandem mass spectrometry revealed that DPP-4 mediated LPS-induced endothelial inflammation by interacting with integrin-α5ß1. Moreover, exogenous soluble DPP-4 treatment sufficiently activated integrin-α5ß1 downstream FAK/AKT/NF-κB signaling, thereafter inducing ICAM-1 upregulation in HPMECs. Collectively, our results suggest that endothelia synthesis and release DPP-4 under the stress of endotoxin, which interact with integrin-α5ß1 complex in an autocrine or paracrine manner to exacerbate endothelial inflammation and enhance endothelial cell permeability. Therefore, blocking DDP-4 could be a potential therapeutic strategy to prevent endothelial dysfunction in ALI/ARDS.

A novel PDGFR inhibitor WQ-C-401 prevents pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary arterial hypertension.

Platelet-derived growth factor (PDGF) is one of the most important cytokines associated with pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). PDGF receptor (PDGFR) inhibition exerted therapeutic effects on PAH in clinical trials, but serious side effects warrant the withdrawal of existing drugs. In this study, a novel highly selective PDGFR inhibitor WQ-C-401 was developed, and its effects on PDGFR signaling pathway and pulmonary vascular remodeling in PAH were investigated. Cell proliferation assays and Western blot analysis of PDGFRα/ß phosphorylation showed that WQ-C-401 inhibited PDGFR-mediated cell proliferation assay and suppressed PDGFR phosphorylation in a concentration-dependent manner. DiscoverX's KinomeScanTM technology confirmed the good kinome selectivity of WQ-C-401 (S score (1) of PDGFR = (0.01)). In monocrotaline (MCT)-induced PAH rats, intragastric administration of WQ-C-401 (25, 50, 100 mg/kg/d) or imatinib (50 mg/kg/d, positive control) significantly decreased right ventricular systolic pressure (RVSP). Histological analysis demonstrated that WQ-C-401 inhibited pulmonary vascular remodeling by reducing muscularization and fibrosis, as well as alleviated right ventricular hypertrophy in MCT-treated rats. In addition, WQ-C-401 suppressed MCT-induced cell hyperproliferation and CD68+ macrophage infiltration around the pulmonary artery. In vitro, WQ-C-401 inhibited PDGF-BB-induced proliferation and migration of human pulmonary arterial smooth muscle cells (PASMCs). Moreover, Western blot analysis showed that WQ-C-401 concertration-dependently inhibited PDGF-BB-induced phosphorylation of ERK1/2 and PDGFRß Y751, decreased collagen Ⅰ synthesis and increased alpha smooth muscle actin (α-SMA) expression in PASMCs. Collectively, our results suggest that WQ-C-401 is a selective and potent PDGFR inhibitor which could be a promising drug for the therapeutics of PAH by preventing pulmonary vascular remodeling.

Bio-Inspired Electro-Thermal-Hygro Responsive Rewritable Systems with Temporal/Spatial Control for Environment-Interactive Information Display.

Utilization of rewritable luminescent materials for secure information storage and delivery has long been envisaged to reduce the cost and environmental wastes. However, it remains challenging to realize a temporally/spatially controlled display of the written information, which is crucial for secure information encryption. Here, inspired by bioelectricity-triggered skin pattern switching in cephalopods, an ideal rewritable system consisting of conductive graphene film and carbon dots (CDs) gel with blue-to-red fluorescence-color changes via water-triggered CDs aggregation and re-dispersion is presented. Its rewritability is guaranteed by using water ink to write on the CDs-gel and employing Joule heat of graphene film to evaporate water. Due to the highly controlled electrical stimulus, temporally/spatially controlled display is achieved, enabling on-demand delivery and duration time regulation of the written information. Furthermore, new-concept environment-interactive rewritable system is obtained by integrating sensitive acoustic/optical sensors and multichannel electronic time-delay devices. This work opens unprecedented avenues of rewritable systems and expands potential uses for information encryption/delivery.

Adjunctive interleukin-2 for the treatment of drug-susceptible tuberculosis: a randomized control trial in China.

PURPOSE: Evaluation of the efficacy and safety of IL-2 in the treatment of drug-susceptible tuberculosis. METHODS: First, the cases of diagnosed drug-susceptible tuberculosis were randomized into two groups-the control group that received the background regimen of isoniazid, rifampin, pyrazinamide, and ethambutol, and the experimental group that received the background regimen plus IL-2. The efficacy and safety evaluations were performed throughout the therapy process as well as 12 months after the treatment completion. RESULTS: A total of 1151 patients underwent the randomization, among which 539 (96.2%) of the 560 in the experimental group achieved the sputum culture conversion to negative, compared to the 551 (93.2%) of the 591 in the control group, after 2 months of treatment, with significant difference observed between the groups (P = 0.025). Cavity closure after 2 months in the IL-2 (experimental) group was 60/211 (28.4%) compared to 46/248 (18.5%) in the control group, with a significant difference between the groups (P = 0.001). After treatment completion, the proportion of favorable outcomes was 559/560 (99.8%) in the experimental group and 587/591 (99.3%) in the control group, with no significant difference between the groups. Twelve months after treatment completion, relapse occurred in 15/560 (2.6%) in the IL-2 group and 19/591 (3.2%) in the control group, with no significant difference. CONCLUSION: IL-2 may enhance culture conversion and the cavity closure rate in the early treatment phase, although the enhancement may not be significant after treatment completion.

Paeoniflorin attenuates monocrotaline-induced pulmonary arterial hypertension in rats by suppressing TAK1-MAPK/NF-κB pathways.

Pulmonary arterial hypertension (PAH) characterized by pulmonary vascular remodeling is a lethal disease. Paeoniflorin (PF) is a monoterpene glycoside with numerous beneficial functions, such as vasodilation, anti-inflammation and immunomodulation. This study aims to investigate the effects of PF on monocrotaline (MCT)-induced PAH rats. Our data showed that both prophylactic or therapeutic administration of PF alleviated MCT-induced increasing of right ventricular systolic pressure (RVSP), prevented right ventricle hypertrophy and pulmonary arterial remodeling, as well as inhibited inflammatory cell infiltration around pulmonary arteries. Meanwhile, PF blocked MCT-induced endothelial-mesenchymal transition (EndMT) as indicated by the restored expression of endothelial markers in lung. Moreover, PF inhibited MCT-induced down-regulation of bone morphogenetic protein receptor 2 (BMPR2) and suppressed MCT-induced phosphorylation of transforming growth factor-ß (TGFß) activated kinase 1 (TAK1) in vivo. In vitro studies indicated that PF prevented human pulmonary arterial smooth muscle cells (PASMCs) from platelet-derived growth factor-BB (PDGF-BB)-stimulated proliferation and migration. PF also partially reversed TGFß1, interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF-α) co-stimulated endothelial-to-mesenchymal transition (EndMT) in cultured human pulmonary artery endothelial cells (HPAECs). Signaling pathway analysis demonstrated that the underlying mechanism might be associated with the inhibition of TAK1-MAPK/NF-κB pathways. Taken together, our results suggested that PF could be a potential drug for the treatment of PAH.

Prediction of heavy metal Cd and stress on minerals in rice by analysis of LIBS spectra.

To predict the nutrition and safety of agricultural products by laser-induced breakdown spectroscopy (LIBS), heavy metal Cd in rice was selected as an analytical target. Mature rice grain samples from 40 growing geographical areas around Poyang Lake were picked on-site and processed by grinding to obtain the edible rice. The content of Cd in rice samples was determined by graphite furnace atomic absorption spectrometry, and the rice pellets were detected by LIBS. The risk intake was estimated by the target hazard quotient and Chinese National Standard. Moreover, the samples were classified as clean, slight, and severe ones according to evaluation. The content of Cd was predicted by analyzing LIBS spectra coupled with the partial least square (PLS) model. The correlation coefficients (R2) reached 0.9036 and 0.9771 for the training and prediction sets, respectively, and the root mean square errors were 0.0487 and 0.027, respectively. It denotes that the PLS model has a higher prediction ability especially after LIBS spectra were processed by smoothing and multiplicative scatter correction. For the clean, slight, and severe rice samples, the LIBS intensity ratio between minerals Mg, K, Na, Si, and Mn to Ca was compared. The ratio was decreased in all samples as Cd stress increased. Correlation analysis results show that Mn displayed a highly significant negative correlation with Cd stress, while Mg, K, and Na displayed a significant negative correlation with Cd stress. The relationship between Si and Cd did not reach a significant level. This work indicated that it was feasible to use LIBS combined with a suitable data process to predict Cd content and the effect of Cd stress on minerals in rice. It is promising to evaluate the nutrition and safety of food products by analyzing LIBS spectra.

Acceptance of clinical decision support system to prevent venous thromboembolism among nurses: an extension of the UTAUT model.

BACKGROUND: Venous thromboembolism has been a major public health problem and caused a heavy disease burden. Venous thromboembolism clinical decision support system was proved to have a positive influence on the prevention and management of venous thromboembolism. As the direct users, nurses' acceptance of this system is of great importance to support the successful implementation of it. However, there are few relevant studies to investigate nurses' acceptance and the associated factors are still unclear. OBJECTIVE: To investigate the determinant factors of nurses' acceptance of venous thromboembolism clinical decision support system with the modified Unified Theory of Acceptance and Use of Technology. METHODS: We designed a questionnaire based on the modified Unified Theory of Acceptance and Use of Technology and then a cross-sectional survey was conducted among nurses in a tertiary hospital in Nanjing, China. Statistically, a Structural Equation Modeling -Partial Least Squares path modeling approach was applied to examine the research model. RESULTS: A total of 1100 valid questionnaires were recycled. The modified model explained 74.7%, 83.0% and 86% of the variance in user satisfaction, behavioral intention and user behavior, respectively. The results showed that performance expectancy (ß = 0.254, p = 0.000), social influence (ß = 0.136, p = 0.047), facilitating conditions (ß = 0.245, p = 0.000), self-efficacy (ß = 0.121, p = 0.048) and user satisfaction (ß = 0.193, p = 0.001) all had significant effects on nurses' intention. Although effort expectancy (ß = 0.010, p = 0.785) did not have a direct effect on nurses' intention, it could indirectly influence nurses' intention with user satisfaction as the mediator (ß = 0.296, p = 0.000). User behavior was significantly predicted by facilitating conditions (ß = 0.298, p = 0.000) and user intention (ß = 0.654, p = 0.001). CONCLUSION: The research enhances our understanding of the determinants of nurses' acceptance of venous thromboembolism clinical decision support system. Among these factors, performance expectancy was considered as the top priority. It highlights the importance of optimizing system performance to fit the users' needs. Generally, the findings in our research provide clinical technology designers and administrators with valuable information to better meet users' requirements and promote the implementation of venous thromboembolism clinical decision support system.

Subcutaneous Low-Density Foreign Bodies Detection via Grating-Based Multimodal X-ray Imaging.

Detecting low-density foreign bodies within soft tissues still stands for a serious challenge. Grating-based multimodal X-ray imaging typically has low hardware requirements while simultaneously providing three kinds of imaging information, i.e., absorption, phase-contrast, and dark-field. We aimed to explore the capacity of grating-based multimodal X-ray imaging technology for detecting common foreign bodies within subcutaneous tissues, and to assess the advantages as well as disadvantages of the three kinds of images obtained via grating-based X-ray multimodal technology in relation to diverse kinds of foreign bodies within different tissues. In this study, metal, glass, wood, plastic, graphite, and ceramic foreign bodies were injected into chunks of the pig adipose tissue and chicken thigh muscles. Next, a grating-based multimodal X-ray imaging device developed in our laboratory was used to detect the above foreign bodies within the adipose and muscle tissues. Our results show that grating-based multimodal X-ray imaging clearly revealed the subcutaneous foreign bodies within the adipose and muscle tissues by acquiring complementary absorption, phase-contrast, and dark-field imaging data in a single shot. Grating-based multimodal X-ray imaging has an exciting potential to detect foreign bodies underneath the epidermis.

The structure of blood-tumor barrier and distribution of chemotherapeutic drugs in non-small cell lung cancer brain metastases.

BACKGROUND: Brain metastasis is an important cause of increased mortality in patients with non-small cell lung cancer (NSCLC). In brain metastasis, the blood-brain barrier (BBB) is frequently impaired, forming blood-tumor barrier (BTB). The efficacy of chemotherapy is usually very poor. However, the characteristics of BTB and the impacts of BTB on chemotherapeutic drug delivery remain unclear. The present study investigated the structure of BTB, as well as the distribution of routine clinical chemotherapeutic drugs in both brain and peripheral tumors. METHODS: Bioluminescent image was used to monitor the tumor load after intracranial injection of lung cancer Lewis cells in mice. The permeability of BBB and BTB was measured by fluorescent tracers of evans blue and fluorescein sodium. Transmission electron microscopy (TEM), immunohistochemistry and immunofluorescence were performed to analyze structural differences between BBB and BTB. The concentrations of chemotherapeutic drugs (gemcitabine, paclitaxel and pemetrexed) in tissues were assayed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). RESULTS: Brain metastases exhibited increased BTB permeability compared with normal BBB detected by fluorescence tracers. TEM showed abnormal blood vessels, damaged endothelial cells, thick basement membranes, impaired intercellular endothelial tight junctions, as well as increased fenestrae and pinocytotic vesicles in metastatic lesions. Immunohistochemistry and immunofluorescence revealed that astrocytes were distributed surrounded the blood vessels both in normal brain and the tumor border, but no astrocytes were found in the inner metastatic lesions. By LC-MS/MS analysis, gemcitabine showed higher permeability in brain metastases. CONCLUSIONS: Brain metastases of lung cancer disrupted the structure of BBB, and this disruption was heterogeneous. Chemotherapeutic drugs can cross the BTB of brain metastases of lung cancer but have difficulty crossing the normal BBB. Among the three commonly used chemotherapy drugs, gemcitabine has the highest distribution in brain metastases. The permeability of chemotherapeutic agents is related to their molecular weight and liposolubility.

The first report of co-existence of pulmonary tuberculosis and lung malignancy in a kidney transplant recipient: a case report and literature review.

BACKGROUND: Along with the medical development, organ transplant patients increase dramatically. Since these transplant patients take immunosuppressants for a long term, their immune functions are in a suppressed state, prone to all kinds of opportunistic infections and cancer. However, it is rarely reported that the kidney transplant recipients (KTRs) have pulmonary tuberculosis and lung cancer simultaneously. CASE PRESENTATION: A 60-year-old male was admitted because of persistent lung shadow for 2 years without any obvious symptom 8 years after renal transplant. T-SPOT test was positive but other etiological examinations for Mycobacterium tuberculosis were negative. Chest CT scan revealed two pulmonary lesions in the right upper and lower lobe respectively. 18F-fluorodesoxyglucose positron-emission tomography (FDG-PET) CT found FDG intake increased in both pulmonary consolidation lesions. CT-guided percutaneous transthoracic needle biopsy revealed lung adenocarcinoma and tuberculosis. The video-assisted thoracoscopic surgery was operated to resect the malignancy lesions. The patient received specific anti-tuberculosis therapy and was discharged. At the follow-up of 6 months post drug withdrawal, the patient was recovered very well. CONCLUSIONS: We for the first time reported co-existence of smear-negative pulmonary TB and lung adenocarcinoma in a KTR, which highlighted the clinical awareness of co-occurrence of TB and malignancy after renal transplant and emphasized the value of biopsy and 18F-FDG-PET in early diagnosis of TB and cancer.

Primary leiomyosarcoma is a rare cause of femoral triangle mass: A case report.

OBJECTIVES: Primary leiomyosarcoma in the femoral vein is an extremely rare vascular disorder and is often misdiagnosed. In order to improve the knowledge and treatment of this disease, a case of leiomyosarcoma in the femoral vein was reported. METHODS: We report the case of a 58-year-old woman with a leiomyosarcoma of the femoral vein and treated successfully by surgical resection. After surgery, no recurrence had been noted follow-up.Subsequently, we reviewed information derived from 31 previously published cases from 1954 to 2019. RESULTS: A total of 31 patients diagnosed with femoral vein leiomyosarcoma were presented in previous studies; in all of these patients, 14 (45.2%, 14/31) patients were men. Of these, the median age was 51.6 years old (ranging from 3 to 84). CONCLUSIONS: Complete resection with adjuvant chemotherapeutic was the main strategy to treat the disease. Prognosis remains poor if metastasis was present, especially pulmonary metastasis.

Clinical features and management strategy of symptomatic spontaneous isolated celiac artery dissection.

OBJECTIVES: The aim of this study was to evaluate the clinical features and management strategy for patients with symptomatic spontaneous isolated celiac artery dissection (SICAD). METHODS: In this retrospective study, consecutive patients with symptomatic SICAD from two institutions were included. The demographics, clinical manifestations, comorbidities, imaging findings and treatment strategy selection were obtained from the medical records. The general epidemiological data, treatment regimens and clinical and follow-up outcomes were analysed. RESULTS: Patients were divided into the conservative treatment group (group A, n = 26) and endovascular treatment group (group B, n = 11). Of these 37 patients, extent of dissection in both groups included only celiac trunk (61.54%% vs. 18.18%, p = 0.03), common hepatic artery (CHA) and splenic artery (SA) (3.85%% vs. 54.55%, p = 0.001), CHA (7.69% vs. 18.18%, p = 0.57), SA (23.08% vs. 9.09, p = 0.65) and left gastric artery (LGA) (3.85% vs. 54.55%, p = 0.99). Of note, the extension of the lesion in group A was shorter than that in group B. In addition, there were significantly more type IIb in group A than in group B (42.31% vs. 9.09%, p = 0.06) and the mean length of dissection in group A was 42.3 ± 54.71 mm which was significantly shorter than that in the group B 58.45 ± 3.71 mm (p =0.04). During a median follow-up of 11.5 months, the 1, 3, 6 and 12 month follow-ups were completed in 100% (37/37), 100% (37/37), 94.59% (35/37) and 91.19% (34/37) of patients, respectively. The cumulative rate of persistent disease stability in patients with endovascular treatment group was higher than in that conservative treatment group at the 3, 6, 9 and 12 months (50% vs. 16.67%, p = 0.001; 80% vs. 37.5%, p =0.03; 100% vs. 62.5%, p = 0.012;100% vs. 91.67%, p = 0.02 respectively). CONCLUSION: Most symptomatic SICAD have a tendency to persistent disease stability after conservative treatment. Risk factors for failed conservative treatment were length of dissection and branch involvement. Furthermore, endovascular treatment was associated with a high technical success and persistent disease stability rate, which might be reserved for patients with failed conservative treatment.

Modeling the Moiré fringe visibility of Talbot-Lau X-ray grating interferometry for single-frame multi-contrast imaging.

Moiré fringe method in X-ray grating interferometry is characterized by its advantage to obtain multi-contrast data through single-frame imaging. However, how the visibility of the Moiré fringe is influenced by the system parameters, such as the misalignment angle, still lacks investigation, although it closely relates to the signal-to-noise ratio of the image data. In this paper, a simplified model of the Moiré fringe visibility is presented, which reveals that the Moiré fringe visibility can be expressed as the product of a misalignment-angle-related "sinc" function and a relatively independent factor. The following experimental results further suggest that the crosstalk between the detector pixels in the direction perpendicular to the Moiré fringe orientation is another main cause for the visibility reduction of the Moiré fringes.

Tillandsia-Inspired Hygroscopic Photothermal Organogels for Efficient Atmospheric Water Harvesting.

Tillandsia species with degenerated roots have evolved into hygroscopic leaves that absorb moisture from air. This interesting biological adaptability has inspired us to develop an integrated hygroscopic photothermal organogel (POG) to achieve a solar-powered atmospheric water harvesting (AWH). The well-designed hydrophilic co-polymeric skeleton is fabricated to accommodate hygroscopic glycerin medium, which enables the POG self-contained property, mechanically flexibility and synergistic enhancement of moisture sorption. The integration of interpenetrated photothermal component of poly-pyrrole-dopamine (P-Py-DA) can endow the POG an efficient solar-to-thermal property for controllable solar-driven interfacial water releasing. The integrated POG has an equilibrium moisture sorption of 16.01 kg m-2 at the RH of 90 %, and daily water production as high as 2.43 kg m-2 day-1 is achieved in actual outdoor experiments.

Glucagon-like peptide-1 receptor activation alleviates lipopolysaccharide-induced acute lung injury in mice via maintenance of endothelial barrier function.

Glucagon-like peptide-1 (GLP-1), which is well known for regulating glucose homeostasis, exhibits multiple actions in cardiovascular disorders and renal injury. However, little is known about the effect of GLP-1 receptor (GLP-1R) activation on acute lung injury (ALI). In this study, we investigated the effect of GLP-1R on ALI and the potential underlying mechanisms with the selective agonist liraglutide. Our results show that GLP-1 levels decreased in serum, though they increased in bronchoalveolar lavage fluid (BALF) and lung tissue in a mouse model of lipopolysaccharide (LPS)-induced ALI. Liraglutide prevented LPS-induced polymorphonuclear neutrophil (PMN) extravasation, lung injury, and alveolar-capillary barrier dysfunction. In cultured human pulmonary microvascular endothelial cells (HPMECs), liraglutide protected against LPS-induced endothelial barrier injury by restoring intercellular tight junctions and adherens junctions. Moreover, liraglutide prevented PMN-endothelial adhesion by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and thereafter suppressed PMN transendothelial migration. Furthermore, liraglutide suppressed LPS-induced activation of Rho/NF-κB signaling in HPMECs. In conclusion, our results show that GLP-1R activation protects mice from LPS-induced ALI by maintaining functional endothelial barrier and inhibiting PMN extravasation. These results also suggest that GLP-1R may be a potential therapeutic target for the treatment of ALI.

Glucagon-like peptide-1 (GLP-1) mediates the protective effects of dipeptidyl peptidase IV inhibition on pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease leading to death ultimately. Our recently published data demonstrated that inhibiting dipeptidyl peptidase IV (DPP-4) alleviated pulmonary vascular remodeling in experimental PH. However, whether glucagon-like peptide-1 (GLP-1) mediated the protective effect of DPP-4 inhibition (DPP-4i) on PH is unclear. RESULTS: In the present study, GLP-1 receptor antagonist (exendin-3) abolished the protective effects of DPP-4 inhibitor (sitagliptin) on right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling (PVR) in monocrotaline (MCT, 60 mg/kg)-induced PH in rat. Notably, activation of GLP-1 receptor by GLP-1 analogue liraglutide directly attenuated RVSP and PVR in MCT-induced PH, as well as bleomycin- and chronic hypoxia-induced PH. Moreover, liraglutide potently inhibited MCT-induced inflammation and suppressed MCT-induced down-regulation of vascular endothelial marker (VE-cadherin and vWF) in lung. In vitro studies showed liraglutide reversed TGF-ß1 (5 ng/ml) combining IL-1ß (5 ng/ml) induced endothelial-mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs), which could be abolished by GLP-1 receptor antagonist (exendin-3). Furtermore, liraglutide suppressed TGF-ß1-IL-1ß-induced phosphorylation of both Smad3 and ERK1/2. CONCLUSIONS: Our data suggest that GLP-1 mediated the protective effects of DPP-4i on pulmonary vascular and RV remodeling in experimental PH, which may be attributed to the inhibitory effect on EndMT.

Fasudil dichloroacetate (FDCA), an orally available agent with potent therapeutic efficiency on monocrotaline-induced pulmonary arterial hypertension rats.

Given the therapeutic efficacy of fasudil hydrochloride (F) and dichloroacetate (DCA) on pulmonary arterial hypertension (PAH), a new salt fasudil dichloroacetate (FDCA) was designed, synthesized and biologically evaluated. FDCA exhibited comparable ROCK II inhibitory activity relative to fasudil hydrochloride, and suppressed the expression of TNF-α and IL-6 in both PDGF-BB and hypoxia-treated pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (PAECs). Significantly, FDCA lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), and decreased right ventricular hypertrophy (RVH) in monocrotaline (MCT)-induced PAH rats. Meanwhile, FDCA remarkably decreased pulmonary artery medial thickness (PAMT) and hyperplasia, restoring the elasticity of elastic fiber, reduced cardiac hypertrophy, and attenuated fibrosis of heart and lung. Collectively, FDCA exhibited triple activities of pulmonary vasodilation, vascular remodeling inhibition and RVH inhibition, suggesting that it may be a promising agent for PAH intervention.

Fasudil inhibits neutrophil-endothelial cell interactions by regulating the expressions of GRP78 and BMPR2.

Regulation of leukocyte-endothelial cell interactions and of vascular permeability plays a critical role in the maintenance of functional pulmonary microvascular barriers. Little is yet known about the effect of the Rho-associated protein kinase (ROCK) inhibitor fasudil on leukocyte-endothelial cell interactions or the underlying mechanism. In the present study, as evaluated using co-culture systems of neutrophils and human pulmonary microvascular endothelial cells (HPMECs), fasudil dose-dependently suppressed neutrophil chemotaxis by decreasing the production of chemotactic factors in lipopolysaccharide (LPS)-treated HPMECs. The inhibitory role of fasudil in neutrophil chemotaxis was mediated by down-regulation of the chaperone glucose-regulated protein 78 (GRP78), since the inhibition was abolished by 4-phenyl butyric acid (a chemical chaperone mimicking GRP78). In addition, fasudil inhibited LPS-induced neutrophil-endothelial adhesion by reducing the expression of intercellular adhesion molecule (ICAM)-1. By use of lentiviral transfection in HPMECs, bone morphogenic protein receptor 2 (BMPR2) overexpression suppressed the LPS-induced increase of both ICAM-1 expression and neutrophil-endothelial adhesion, whereas knocking down BMPR2 abolished the inhibitory role of fasudil in both ICAM-1 expression and neutrophil-endothelial adhesion. Moreover, fasudil alleviated LPS-induced hyperpermeability of HPMEC monolayers by leading to the recovery of intercellular junctions, thereafter reduced neutrophil transendothelial cell migration. Therefore, fasudil inhibited leukocyte-endothelial cell interactions and vascular hyperpermeability through modulation of GRP78 and BMPR2 expression, suggesting a potential role for ROCK as a switch for inhibiting leukocyte-endothelial cell interactions.

NLRP3 inflammasome inhibition attenuates silica-induced epithelial to mesenchymal transition (EMT) in human bronchial epithelial cells.

Silicosis is an incurable and progressive lung disease characterized by chronic inflammation and fibroblasts accumulation. Studies have indicated a vital role for epithelial-mesenchymal transition (EMT) in fibroblasts accumulation. NLRP3 inflammasome is a critical mediator of inflammation in response to a wide range of stimuli (including silica particles), and plays an important role in many respiratory diseases. However, whether NLRP3 inflammasome regulates silica-induced EMT remains unknown. Our results showed that silica induced EMT in human bronchial epithelial cells (16HBE cells) in a dose- and time-dependent manner. Meanwhile, silica persistently activated NLRP3 inflammasome as indicated by continuously elevated extracellular levels of interleukin-1ß (IL-1ß) and IL-18. NLRP3 inflammasome inhibition by short hairpin RNA (shRNA)-mediated knockdown of NLRP3, selective inhibitor MCC950, and caspase-1 inhibitor Z-YVAD-FMK attenuated silica-induced EMT. Western blot analysis indicated that TAK1-MAPK-Snail/NF-κB pathway involved NLRP3 inflammasome-mediated EMT. Moreover, pirfenidone, a commercially and clinically available drug approved for treating idiopathic pulmonary fibrosis (IPF), effectively suppressed silica-induced EMT of 16HBE cells in line with NLRP3 inflammasome inhibition. Collectively, our results indicate that NLRP3 inflammasome is a promising target for blocking or retarding EMT-mediated fibrosis in pulmonary silicosis. On basis of this mechanism, pirfenidone might be a potential drug for the treatment of silicosis.