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Sample records for elastase responsive delivery

  1. Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK-CHOP branch of the unfolded protein response.

    Science.gov (United States)

    Grechowa, Irina; Horke, Sven; Wallrath, Anja; Vahl, Christian-Friedrich; Dorweiler, Bernhard

    2017-09-01

    Human neutrophil elastase impacts on atherosclerotic plaque stability by inducing apoptosis in endothelial cells. Our aim was to investigate the proapoptotic mechanism of elastase on endothelial cells and to evaluate the presence of elastase in human plaque material. Human endothelial cells were treated with purified human neutrophil elastase. Apoptosis was assayed by capsase-3/7 activation, TUNEL, and sub-G 1 assay. Activation of unfolded protein response (UPR) effector molecules binding Ig protein, soluble X-binding protein-1, protein kinase RNA-like ER kinase (PERK), and C/EBP-homologous protein (CHOP) was analyzed by RT-PCR, immunocytochemistry, and Western blot. Genetic silencing of CHOP was achieved by small interfering RNA. Elastase induces autophagic-apoptotic forms of endothelial cell death in a time- and dose-dependent manner, in conjunction with a significant increase in phosphorylation/expression of the canonical UPR-activation markers PERK and CHOP. By using CHOP knockdown, we identified CHOP as a key mediator of elastase-induced endothelial cell death. Immunohistochemical analysis of human rupture-prone plaque specimens confirmed the presence of elastase and colocalization with apoptosis. We have demonstrated for the first time that the PERK-CHOP branch of the UPR is causally involved in elastase-induced apoptosis of endothelial cells. Ex vivo analysis of human rupture-prone plaques confirmed the presence of elastase and its colocalization with markers of apoptosis. This novel role of elastase underlines the potential of combined targeting of elastase and endoplasmic reticulum stress in the prevention of plaque progression and cardiovascular events.-Grechowa, I., Horke, S., Wallrath, A., Vahl, C.-F., Dorweiler, B. Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK-CHOP branch of the unfolded protein response. © FASEB.

  2. Elastase B of Pseudomonas aeruginosa stimulates the humoral immune response in the greater wax moth, Galleria mellonella.

    Science.gov (United States)

    Andrejko, Mariola; Mizerska-Dudka, Magdalena

    2011-05-01

    The role of Pseudomonas aeruginosa elastase B in activation of the humoral immune response in Galleria mellonella larvae was investigated. The results of our study showed that elastase B injected at a sublethal concentration was responsible for eliciting the humoral immune response in G. mellonella larvae. The insects exhibited increased antibacterial activity, namely, we observed appearance of antimicrobial peptides and a higher level of lysozyme in cell-free hemolymph. Elastase B seems to be a more potent elicitor than thermolysin because similar maximal antibacterial activity levels were observed at a 5-fold lower concentration. We also demonstrated that there were differences in the kinetics of induction of antimicrobial activity between thermolysin and elastase B. The maximum level was observed 18h post challenge of thermolysin and 38h after injection of elastase B. It was also shown that, 24h after elastase injection, the relative levels of apoLp-III in the hemolymph significantly increased in comparison with control G. mellonella larvae. The activation of immune responses in metalloproteinase-challenged larvae involved synthesis of metalloproteinase inhibitors which increased the survival rates of insects both against the lethal dose of thermolysin as well as against viable pathogenic bacterial cells of P. aeruginosa. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Pseudomonas aeruginosa elastase cleaves a C-terminal peptide from human thrombin that inhibits host inflammatory responses

    DEFF Research Database (Denmark)

    van der Plas, Mariena J A; Bhongir, Ravi K V; Kjellström, Sven

    2016-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen known for its immune evasive abilities amongst others by degradation of a large variety of host proteins. Here we show that digestion of thrombin by P. aeruginosa elastase leads to the release of the C-terminal thrombin-derived peptide FYT21...

  4. BACILLUS THURINGIENSIS ELASTASES WITH INSECTICIDE ACTIVITY

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    E. V. Matseliukh

    2015-10-01

    Full Text Available The purpose of the research was a screening of proteases with elastase activity among Bacillus thuringiensis strains, their isolation, partially purification, study of physicochemical properties and insecticide activity in relation to the larvae of the Colorado beetle. The objects of the investigation were 18 strains of B. thuringiensis, isolated from different sources: sea water, dry biological product "Bitoksibatsillin" and also from natural populations of Colorado beetles of the Crimea, Kherson, Odesa, Mykolaiv and Zaporizhiia regions of Ukraine. Purification of enzymes with elastase activity isolated from above mentioned strains was performed by gel-chromatography and insecticide activity was studied on the 3–4 larvae instar of Colorado beetle. The ability of a number of B. thuringiensis strains to synthesize the proteases with elastase activity has been established. The most active were enzymes obtained from strains IMV B-7465, IMV B-7324 isolated from sea water, and strains 9, 902, Bt-H and 0-239 isolated from Colorado beetles. The study of the physicochemical properties of the partially purified proteases of these strains showed that they belonged to enzymes of the serine type. Peptidases of a number of B. thuringiensis strains (IMV B-7324, IMV B-7465, 902, 0-239, 9 are metal-dependent enzymes. Optimal conditions of action of all tested enzymes are the neutral and alkaline рН values and the temperatures of 30–40 °С. The studies of influence of the complex enzyme preparations and partially purified ones of B. thuringiensis strains on the larvae instar of Colorado beetles indicated that enzymes with elastase activity could be responsible for insecticide action of the tested strains.

  5. Elastase-induced emphysema in guinea pigs

    International Nuclear Information System (INIS)

    Loscutoff, S.M.

    1979-01-01

    Pulmonary function changes measured in guinea pigs 4 to 5 wk following intratracheal instillation of crystalline porcine pancreatic elastase resembled comparable changes in humans with moderately severe pulmonary emphysema. Compared with saline-treated controls, elastase-treated animals had increased values for all divisions of lung volume, increased static compliance and prolonged time constants. Since humans with emphysema are especially sensitive to air pollutants, elastase-treated animals may be useful as sensitive animal models in inhalatio toxicology

  6. Ion-Responsive Drug Delivery Systems.

    Science.gov (United States)

    Yoshida, Takayuki; Shakushiro, Kohsuke; Sako, Kazuhiro

    2018-02-08

    Some kinds of cations and anions are contained in body fluids such as blood, interstitial fluid, gastrointestinal juice, and tears at relatively high concentration. Ionresponsive drug delivery is available to design the unique dosage formulations which provide optimized drug therapy with effective, safe and convenient dosing of drugs. The objective of the present review was to collect, summarize, and categorize recent research findings on ion-responsive drug delivery systems. Ions in body fluid/formulations caused structural changes of polymers/molecules contained in the formulations, allow formulations exhibit functions. The polymers/molecules responding to ions were ion-exchange resins/fibers, anionic or cationic polymers, polymers exhibiting transition at lower critical solution temperature, self-assemble supramolecular systems, peptides, and metalorganic frameworks. The functions of ion-responsive drug delivery systems were categorized to controlled drug release, site-specific drug release, in situ gelation, prolonged retention at the target sites, and enhancement of drug permeation. Administration of the formulations via oral, ophthalmic, transdermal, and nasal routes has showed significant advantages in the recent literatures. Many kinds of drug delivery systems responding to ions have been reported recently for several administration routes. Improvement and advancement of these systems can maximize drugs potential and contribute to patients in the world. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Neutrophil elastase induces inflammation and pain in mouse knee joints via activation of proteinase-activated receptor-2.

    Science.gov (United States)

    Muley, Milind M; Reid, Allison R; Botz, Bálint; Bölcskei, Kata; Helyes, Zsuzsanna; McDougall, Jason J

    2016-02-01

    Neutrophil elastase plays a crucial role in arthritis. Here, its potential in triggering joint inflammation and pain was assessed, and whether these effects were mediated by proteinase-activated receptor-2 (PAR2). Neutrophil elastase (5 μg) was injected into the knee joints of mice and changes in blood perfusion, leukocyte kinetics and paw withdrawal threshold were assessed. Similar experiments were performed in animals pretreated with the neutrophil elastase inhibitor sivelestat, the PAR2 antagonist GB83, the p44/42 MAPK inhibitor U0126 and in PAR2 receptor knockout (KO) mice. Neutrophil elastase activity was also evaluated in arthritic joints by fluorescent imaging and sivelestat was assessed for anti-inflammatory and analgesic properties. Intra-articular injection of neutrophil elastase caused an increase in blood perfusion, leukocyte kinetics and a decrease in paw withdrawal threshold. Sivelestat treatment suppressed this effect. The PAR2 antagonist GB83 reversed neutrophil elastase-induced synovitis and pain and these responses were also attenuated in PAR2 KO mice. The MAPK inhibitor U0126 also blocked neutrophil elastase-induced inflammation and pain. Active neutrophil elastase was increased in acutely inflamed knees as shown by an activatable fluorescent probe. Sivelestat appeared to reduce neutrophil elastase activity, but had only a moderate anti-inflammatory effect in this model. Neutrophil elastase induced acute inflammation and pain in knee joints of mice. These changes are PAR2-dependent and appear to involve activation of a p44/42 MAPK pathway. Blocking neutrophil elastase, PAR2 and p44/42 MAPK activity can reduce inflammation and pain, suggesting their utility as therapeutic targets. © 2015 The British Pharmacological Society.

  8. IL-17A is essential to the development of elastase-induced pulmonary inflammation and emphysema in mice

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    Kurimoto Etsuko

    2013-01-01

    Full Text Available Abstract Background Pulmonary emphysema is characterized by alveolar destruction and persistent inflammation of the airways. Although IL-17A contributes to many chronic inflammatory diseases, it’s role in the inflammatory response of elastase-induced emphysema remains unclear. Methods In a model of elastase-induced pulmonary emphysema we examined the response of IL-17A-deficient mice, monitoring airway inflammation, static compliance, lung histology and levels of neutrophil-related chemokine and pro-inflammatory cytokines in bronchoalveolar lavage (BAL fluid. Results Wild-type mice developed emphysematous changes in the lung tissue on day 21 after elastase treatment, whereas emphysematous changes were decreased in IL-17A-deficient mice compared to wild-type mice. Neutrophilia in BAL fluid, seen in elastase-treated wild-type mice, was reduced in elastase-treated IL-17A-deficient mice on day 4, associated with decreased levels of KC, MIP-2 and IL-1 beta. Elastase-treated wild-type mice showed increased IL-17A levels as well as increased numbers of IL-17A+ CD4 T cells in the lung in the initial period following elastase treatment. Conclusions These data identify the important contribution of IL-17A in the development of elastase-induced pulmonary inflammation and emphysema. Targeting IL-17A in emphysema may be a potential therapeutic strategy for delaying disease progression.

  9. Protective effects of an aptamer inhibitor of neutrophil elastase in lung inflammatory injury

    DEFF Research Database (Denmark)

    Bless, N M; Smith, D; Charlton, J

    1997-01-01

    Neutrophils play an important part in the development of acute inflammatory injury. Human neutrophils contain high levels of the serine protease elastase, which is stored in azurophilic granules and is secreted in response to inflammatory stimuli. Elastase is capable of degrading many components...... of extracellular matrix [1-4] and has cytotoxic effects on endothelial cells [5-7] and airway epithelial cells. Three types of endogenous protease inhibitors control the activity of neutrophil elastase, including alpha-1 protease inhibitor (alpha-1PI), alpha-2 macroglobulin and secreted leukoproteinase inhibitor...... (SLPI) [8-10]. A disturbed balance between neutrophil elastase and these inhibitors has been found in various acute clinical conditions (such as adult respiratory syndrome and ischemia-reperfusion injury) and in chronic diseases. We investigated the effect of NX21909, a selected oligonucleotide (aptamer...

  10. Nanoparticles for nasal delivery of vaccines : monitoring adaptive immune responses

    NARCIS (Netherlands)

    Keijzer, C.

    2013-01-01

    The continuous emergence of new pathogens and growing drug resistance of microorganisms asks for innovative vaccination strategies. An alternative to conventional multiple injection vaccines is the nasal route of vaccine delivery. The immune response induced following nasal antigen delivery depends

  11. Responsive crosslinked polymer nanogels for imaging and therapeutics delivery

    NARCIS (Netherlands)

    Ekkelenkamp, Antonie E.; Elzes, Marie-Louise Rachel; Engbersen, Johan F.J.; Paulusse, Jos M.J.

    2018-01-01

    Water-soluble, nano-sized crosslinked polymer networks, or nanogels, are delivery vehicles, which have highly interesting properties for therapeutic delivery and imaging. Nanogels may also possess responsive properties, depending on the employed polymers, allowing controlled release of therapeutics

  12. The professional responsibility model of obstetric ethics and caesarean delivery.

    Science.gov (United States)

    Chervenak, Frank A; McCullough, Laurence B

    2013-04-01

    In this chapter, we provide an account of the professional responsibility model of obstetric ethics, and identify its implications for two major topics: patient-choice caesarean delivery and trial of labour after caesarean delivery. The professional responsibility model of obstetric ethics is based on the ethical concept of medicine as a profession and the ethical principles of beneficence and respect for autonomy. The obstetrician has beneficence-based and autonomy-based obligations to the pregnant woman and beneficence-based obligations to the fetus when it is a patient. Because the viable fetus is a patient, the ethics of caesarean delivery requires balancing of obligations to the pregnant and fetal patient. The implication of the professional responsibility model for patient-choice caesarean delivery is that the obstetrician should respond to such requests with a recommendation against non-indicated caesarean delivery and for vaginal delivery. These recommendations should be explained and discussed in the informed consent process. It is ethically permissible to implement an informed, reflective decision for non-indicated caesarean delivery. The implication for trial of labour after caesarean delivery is that, in settings properly equipped and staffed, the obstetrician should offer both trial of labour after caesarean delivery and planned caesarean delivery to women who have had one previous low transverse incision. The obstetrician should recommend against trial of labour after caesarean delivery for women with a previous classical incision. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Pancreatic elastase in human serum. Determination by radioimmunoassay

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    Geokas, M.C. (Univ. of California, Davis); Brodrick, J.W.; Johnson, J.H.; Largman, C.

    1977-01-10

    This study demonstrates that a serine endopeptidase of pancreatic origin (elastase 2) circulates in human blood. A specific and highly sensitive radioimmunoassay has been developed for pancreatic elastase 2 in human serum. The inactivation of elastase 2 employed as radioiodinated tracer with an active site-specific reagent (phenylmethanesulfonyl fluoride) was necessary to prevent its binding by serum ..cap alpha../sub 1/-antitrypsin and ..cap alpha../sub 2/-macroglobulin while maintaining its immunoreactivity. The assay is based upon competition of standard human pancreatic elastase 2 with /sup 125/I-labeled phenylmethanesulfonyl elastase 2 for specific antibody binding sites, after which a second antibody precipitation step is used to separate bound from free /sup 125/I-labeled phenylmethanesulfonyl elastase 2. The minimum detectable concentration of elastase 2 was 0.9 ng/ml. The average normal fasting serum level determined was 71 ng/ml, approximately 80-fold greater than the minimum detectable amount.

  14. Responsive triggering systems for delivery in chronic wound healing.

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    Morey, Mangesh; Pandit, Abhay

    2018-03-02

    Non-communicable diseases including cancer, cardiovascular disease, diabetes, and neuropathy are chronic in nature. Treatment of these diseases with traditional delivery systems is limited due to lack of site-specificity, non-spatiotemporal release and insufficient doses. Numerous responsive delivery systems which respond to both physiological and external stimuli have been reported in the literature. However, effective strategies incorporating a multifactorial approach are required to control these complex wounds. This can be achieved by fabricating spatiotemporal release systems, multimodal systems or dual/multi-stimuli responsive delivery systems loaded with one or more bioactive components. Critically, these next generation stimuli responsive delivery systems that are at present not feasible are required to treat chronic wounds. This review provides a critical assessment of recent developments in the field of responsive delivery systems, highlighting their limitations and providing a perspective on how these challenges can be overcome. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Magnetic Responsive Hydrogel Material Delivery System II

    Science.gov (United States)

    2010-08-29

    agents, tissue repair, immunoassay, cell separation, biomagnetic separation of biomolecules, etc. 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17...hyperthermic treatment of tumors, magnetic resonance imaging (MRI) as contrasting agents, tissue repair, immunoassay, cell separation, biomagnetic ...potential step forward in the use of these core-shell MNPs in robust controlled drug delivery, tissue repair, immunoassay, cell separation, biomagnetic

  16. Polymorphonuclear leukocyte elastase in patients with stroke.

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    Vila, N; Elena, M; Deulofeu, R; Chamorro, A

    1999-12-01

    Polymorphonuclear leukocytes (PMNL) are involved in the pathogenesis of acute cerebral ischemia and atherosclerosis. Elastase is one of the proteolytic enzymes released by activated PMNL. We evaluated whether plasma levels of elastase-inhibitor complexes (EIC) are related to acute cerebral damage or with extension of carotid atherosclerosis in patients with stroke. Plasma levels of EIC were determined in 44 patients during acute and chronic phases of stroke. We recorded in all patients vascular risk factors, clinical severity on admission, infarct volume, and extension of carotid atherosclerosis using B-mode ultrasound exam. EIC levels were not different between acute and chronic phases of stroke. Eleven patients (25%) had increased values of EIC. On multiple regression analysis diabetes, dislipemia, and coronary disease were predictors of abnormal EIC levels. EIC levels were not related to neurological severity on admission, infarct volume, or carotid atherosclerosis. EIC levels in stroke patients are associated to the presence of vascular risk factors and may reflect cellular inflammatory aspects of chronic vessel disease. However, whether elastase contributes to the development of carotid atherosclerosis in patients with stroke remains unknown.

  17. Spheres of SA Government, responsibilities and delivery

    CSIR Research Space (South Africa)

    Oelofse, Suzanna HH

    2010-09-01

    Full Text Available are required to function as a single system of cooperative government for the country as a whole, while responsibility for refuse removal, refuse dumps and solid waste disposal are assigned to local government (Metropolitan, District and Local municipalities... (Section 26(h) and 26 (i)) to make regulations on waste disposal and treatment to protect the water resource (RSA, 1998). Other National Departments with waste-related responsibilities are the Department of Mineral Resources being responsible for mining...

  18. Faecal pancreatic elastase - 1 a non invasive measure of exocrine ...

    African Journals Online (AJOL)

    Objectives:- The major objective of this work was to establish the assay of faecal pancreatic elastase-1 in spot stool samples as an exocrine pancreatic function test at ... An ELISA technique which recognizes human pancreatic elastase-1 from spot stool samples was employed for the test and read photometrically at 405nm.

  19. [Pancreatic exocrine function in diabetes mellitus. Determination of fecal elastase].

    Science.gov (United States)

    Mancilla A, Carla; Hurtado H, Carmen; Tobar A, Eduardo; Orellana N, Ivonne; Pineda B, Pedro; Castillo M, Iván; Ledezma R, Rodrigo; Berger F, Zoltán

    2006-04-01

    One of the complications of diabetes mellitus is the development of pancreatic exocrine insufficiency. To study pancreatic exocrine function in diabetics patients. Seventy two diabetic patients were included in the protocol, but two were withdrawn because an abdominal CAT scan showed a chronic calcified pancreatitis, previously undiagnosed. Fecal elastase was measured by ELISA and the presence of fat in feces was assessed using the steatocrit. Mean age was 60+/-12 years and 67 (96%) patients had a type 2 diabetes. Fecal elastase was normal (elastase >200 microg/g) in 47 (67%) patients, mildly decreased (100-200 microg/g) in 10 (14%) and severely decreased in 13 (19%). There was a significant association between elastase levels and time of evolution of diabetes (p=0.049) and between lower elastase levels and the presence of a positive steatocrit (p=0.042). No significant association was found between elastase levels and other chronic complications of diabetes such as retinopathy, nephropathy, neuropathy, microangiopathy or with insulin requirement. One third of this group of diabetic patients had decreased levels of fecal elastase, that was associated with the time of evolution of diabetes. Patients with lower levels of elastase have significantly more steatorrhea. Among diabetics it is possible to find a group of patients with non diagnosed chronic pancreatitis.

  20. ROS-responsive drug delivery systems for biomedical applications

    OpenAIRE

    Wenhui Tao; Zhonggui He

    2018-01-01

    In the field of biomedicine, stimuli-responsive drug delivery systems (DDSs) have become increasingly popular due to their site-specific release ability in response to a certain physiological stimulus, which may result in both enhanced treatment outcome and reduced side effects. Reactive oxygen species (ROS) are the unavoidable consequence of cell oxidative metabolism. ROS play a crucial part in regulating biological and physiological processes, whereas excessive intracellular ROS usually lea...

  1. Stimuli-Responsive Cationic Hydrogels in Drug Delivery Applications

    Directory of Open Access Journals (Sweden)

    G. Roshan Deen

    2018-02-01

    Full Text Available Stimuli-responsive, smart, intelligent, or environmentally sensitive polymers respond to changes in external stimuli such as pH, temperature, ionic strength, surfactants, pressure, light, biomolecules, and magnetic field. These materials are developed in various network architectures such as block copolymers, crosslinked hydrogels, nanogels, inter-penetrating networks, and dendrimers. Stimuli-responsive cationic polymers and hydrogels are an interesting class of “smart” materials that respond reversibly to changes in external pH. These materials have the ability to swell extensively in solutions of acidic pH and de-swell or shrink in solutions of alkaline pH. This reversible swelling-shrinking property brought about by changes in external pH conditions makes these materials useful in a wide range of applications such as drug delivery systems and chemical sensors. This article focuses mainly on the properties of these interesting materials and their applications in drug delivery systems.

  2. Stimuli-Responsive Liposomes for Controlled Drug Delivery

    KAUST Repository

    Li, Wengang

    2014-09-01

    Liposomes are promising drug delivery vesicles due to their biodegradibility, large volume and biocompatibility towards both hydrophilic and hydrophobic drugs. They suffer, however, from poor stability which limits their use in controlled delivery applications. Herein, a novel method was devised for modification of liposomes with small molecules, polymers or nanoparticles to afford stimuli responsive systems that release on demand and stay relatively stable in the absence of the trigger.. This dissertation discusses thermosensitive, pH sensitive, light sensitive and magnetically triggered liposomes that have been prepared for controlled drug delivery application. RAFT polymerization was utilized for the preparation of thermosensitive liposomes (Cholesterol-PNIPAm) and acid-labile liposomes (DOPE-PAA). With low Mw Cholesterol-PNIPAm, the thermosensitive liposomes proved to be effective for controlled release and decreased the cytotoxicity of PNIPAm by eliciting the polymer doses. By crosslinking the DOPE-PAA on liposome surface with acid-labile diamine linkers, DOPE-PAA liposomes were verified to be sensitive at low pH. The effects of polymer structures (linear or hyperbranched) have also been studied for the stability and release properties of liposomes. Finally, a dual-responsive Au@SPIO embedded liposome hybrid (ALHs) was prepared with light-induced “on-and-off” function by photo-thermal process (visible light) and instant release properties triggered by alternating magnetic field, respectively. The ALH system would be further applied into the cellular imaging field as MRI contrast agent.

  3. Neutrophil elastase-mediated increase in airway temperature during inflammation

    DEFF Research Database (Denmark)

    Schmidt, Annika; Belaaouaj, Azzaq; Bissinger, Rosi

    2014-01-01

    in the exhaled air of cystic fibrosis (CF) patients. To further test our hypothesis, a pouch inflammatory model using neutrophil elastase-deficient mice was employed. Next, the impact of temperature changes on the dominant CF pathogen Pseudomonas aeruginosa growth was tested by plating method and RNAseq. Results...... Here we show a temperature of ~ 38 °C in neutrophil-dominated mucus plugs of chronically infected CF patients and implicate neutrophil elastase:α1-proteinase inhibitor complex formation as a relevant mechanism for the local temperature rise. Gene expression of the main pathogen in CF, P. aeruginosa......, under anaerobic conditions at 38 °C vs 30 °C revealed increased virulence traits and characteristic cell wall changes. Conclusion Neutrophil elastase mediates increase in airway temperature, which may contribute to P. aeruginosa selection during the course of chronic infection in CF....

  4. Potential and problems in ultrasound-responsive drug delivery systems

    Directory of Open Access Journals (Sweden)

    Zhao YZ

    2013-04-01

    Full Text Available Ying-Zheng Zhao,1,3 Li-Na Du,2 Cui-Tao Lu,1 Yi-Guang Jin,2 Shu-Ping Ge3 1Wenzhou Medical College, Wenzhou City, Zhejiang Province, 2Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China; 3St Christopher’s Hospital for Children/Drexel University College of Medicine, Philadelphia, PA, USA Abstract: Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems (URDDS have become an important research focus in targeted therapy. URDDS include many different formulations, such as microbubbles, nanobubbles, nanodroplets, liposomes, emulsions, and micelles. Drugs that can be loaded into URDDS include small molecules, biomacromolecules, and inorganic substances. Fields of clinical application include anticancer therapy, treatment of ischemic myocardium, induction of an immune response, cartilage tissue engineering, transdermal drug delivery, treatment of Huntington’s disease, thrombolysis, and disruption of the blood–brain barrier. This review focuses on recent advances in URDDS, and discusses their formulations, clinical application, and problems, as well as a perspective on their potential use in the future. Keywords: ultrasound, targeted therapy, clinical application

  5. Strongly increased levels of fibrinogen elastase degradation products in patients with ischemic stroke

    NARCIS (Netherlands)

    Lau, L.M.L. de; Cheung, E.Y.L.; Kluft, C.; Leebeek, F.W.G.; Meijer, P.; Laterveer, R.; Dippel, D.W.J.; Maat, M.P.M.de

    2008-01-01

    Ischemic stroke is associated with leucocyte activation. Activated leucocytes release elastase, an enzyme that can degrade fibrinogen. Fibrinogen elastase degradation products (FgEDP) may serve as a specific marker of elastase proteolytic activity. In a case-control study of 111 ischemic stroke

  6. Human neutrophil leukocyte elastase activity is inhibited by Phenol Red

    Science.gov (United States)

    Neutrophil elastase (NE) activity in urine, sputum and nasal mucous is used as an indicator of inflammation due to viral or bacterial infection. However, bovine nasal mucous neutrophils collected, lysed and stored in Dulbecco's minimal medium containing Phenol Red, showed no NE activity with methox...

  7. Activity of neutrophil elastase reflects the progression of acute pancreatitis

    DEFF Research Database (Denmark)

    Novovic, Srdan; Andersen, Anders M; Nord, Magnus

    2013-01-01

    Abstract Objective. Neutrophil elastase (NE) concentration is associated with progression of acute pancreatitis (AP), but measuring total NE concentration includes biologically inactive NE. This study aims to investigate the relationship between NE activity and the aetiology and severity of AP...... was associated with predicted severity of AP and AP-associated respiratory failure. Specific NE inhibitors may have therapeutic potential in acute pancreatitis....

  8. Neutrophil elastase and neurovascular injury following focal stroke and reperfusion

    NARCIS (Netherlands)

    Stowe, A.M.; Adair-Kirk, T.L.; Gonzales, E.R.; Perez, R.S.G.M.; Shah, A.M.; Park, T.S.; Gidday, J.M.

    2009-01-01

    Neutrophil elastase (NE) degrades basal lamina and extracellular matrix molecules, and recruits leukocytes during inflammation; however, a basic understanding of the role of NE in stroke pathology is lacking. We measured an increased number of extravascular NE-positive cells, as well as increased

  9. Elastase modifies bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Trajano, Larissa Alexsandra Silva Neto; Trajano, Eduardo Tavares Lima; Lanzetti, Manuella; Mendonça, Morena Scopel Amorim; Guilherme, Rafael Freitas; Figueiredo, Rodrigo Tinoco; Benjamim, Cláudia Farias; Valenca, Samuel Santos; Costa, Andréa Monte Alto; Porto, Luís Cristóvão

    2016-04-01

    Pulmonary fibrosis (PF) is characterized by excessive accumulation of collagen in the lungs. Emphysema is characterized by loss of the extracellular matrix (ECM) and alveolar enlargement. We studied the co-participation of elastase-induced mild emphysema in bleomycin-induced PF in mice by analyzing oxidative stress, inflammation and lung histology. C57BL/6 mice were divided into four groups: control; bleomycin (0.1U/mouse); elastase (using porcine pancreatic elastase (PPE)+bleomycin (3U/mouse 14 days before 0.1U/mouse of bleomycin; PPE+B); elastase (3U/mouse). Mice were humanely sacrificed 7, 14 and 21 days after treatment with bleomycin or vehicle. PF was observed 14 days and 21 days after bleomycin treatment but was observed after 14 days only in the PPE+B group. In the PPE+B group at 21 days, we observed many alveoli and alveolar septa with few PF areas. We also observed marked and progressive increases of collagens 7, 14 and 21 days after bleomycin treatment whereas, in the PPE+B group, collagen deposition was observed only at 14 days. There was a reduction in activities of the antioxidant enzymes superoxide dismutase (pbleomycin treatment compared with the control group. These endpoints were also reduced (pbleomycin) overall histology was improved to that of the nearest control group. Copyright © 2016. Published by Elsevier GmbH.

  10. Physicochemical properties of elastase isolated from clinical Pseudomonas Aeruginosa

    International Nuclear Information System (INIS)

    Elbazza, Z.E.; Moroz, A.F.

    1989-01-01

    Purified elastase was obtained from clinical Pseudomonas Aeruginosa (P.A.-283). The enzyme showed not only elasto lytic activity, but also a broad proteolytic activity against various proteins. The activity of the enzyme on collagen and gelatin was also observed. The optimum pH for elastase was 7.8 to 8.0 for both the proteolytic and elasto lytic activities. The elastase was stable in a pH range from 6.6 to 9.0. Optimum temperature for proteolytic and elasto lytic activities was 40 and inhibition of elastase occurs at 80 . The D 1 0 value of the P.A-283 was found to be 0.11 kGy. Increasing the dose level value of gamma-irradiation decrease the proteolytic activity in the culture filtrate reaching only 16% at the dose level 0.5 kGy. Chelating agents and some metal ions inhibited both proteolytic and elasto lytic activities. Selective inhibition of elasto lytic activity was observed in high concentrations of sodium and ammonium salts without concurrent decrease in the proteolytic activity of the enzyme.4 fig., 3 tab

  11. Effect of Elastase-induced Emphysema on the Force-generating Ability of the Diaphragm

    Science.gov (United States)

    Supinski, Gerald S.; Kelsen, Steven G.

    1982-01-01

    The effect of emphysema on the ability of the diaphragm to generate force was examined in costal diaphragm muscle strips from 10 Golden hamsters killed 18 mo after intratracheal injection of pancreatic elastase in a dose producing hyperinflation (mean total lung capacity [TLC] = 163% of control) and generalized panacinar emphysema. 13 saline-injected normal animals served as controls. The time course of isometric tension and the effect of alterations in muscle fiber and sarcomere length on the isometric tension (T) generated in response to tetanizing electrical stimuli (length-tension [L-T] relationship) were examined. Elastase administration caused an increase in diaphragm muscle thickness and reduction in the length of costal diaphragm muscle fibers measured in situ. Emphysema significantly increased the maximum tetanic tension as a result of hypertrophy. Maximal tension corrected for increases in muscle cross-sectional area (T/cm2), however, was the same in emphysematous (E) and control (C) animals. Emphysema also shifted the muscle fiber L-T curve of the diaphragm but not of a control muscle, the soleus, toward shorter lengths. In contrast to the effects of E on the diaphragm muscle fiber L-T curve, the sarcomere L-T curve was the same in E and C. Since the length at which tension was maximal correlated closely with sarcomere number (r = 0.94; P < 0.001) reduction in the number of sarcomeres in series in muscles from emphysematous animals appeared to explain the shift in the muscle fiber L-T curve. We conclude that in elastase-induced emphysema adaptive changes both in diaphragm cross-sectional area and sarcomere number augment the force-generating ability of the diaphragm. We speculate that changes in sarcomere number compensate for alterations in muscle fiber length resulting from chronic hyperinflation of the thorax, while diaphragmatic muscle hypertrophy represents a response to changes in respiratory load and/or diaphragm configuration (La

  12. Proteome of monocyte priming by lipopolysaccharide, including changes in interleukin-1beta and leukocyte elastase inhibitor

    Directory of Open Access Journals (Sweden)

    Beranova-Giorgianni Sarka

    2008-05-01

    Full Text Available Abstract Background Monocytes can be primed in vitro by lipopolysaccharide (LPS for release of cytokines, for enhanced killing of cancer cells, and for enhanced release of microbicidal oxygen radicals like superoxide and peroxide. We investigated the proteins involved in regulating priming, using 2D gel proteomics. Results Monocytes from 4 normal donors were cultured for 16 h in chemically defined medium in Teflon bags ± LPS and ± 4-(2-aminoethyl-benzenesulfonyl fluoride (AEBSF, a serine protease inhibitor. LPS-primed monocytes released inflammatory cytokines, and produced increased amounts of superoxide. AEBSF blocked priming for enhanced superoxide, but did not affect cytokine release, showing that AEBSF was not toxic. After staining large-format 2D gels with Sypro ruby, we compared the monocyte proteome under the four conditions for each donor. We found 30 protein spots that differed significantly in response to LPS or AEBSF, and these proteins were identified by ion trap mass spectrometry. Conclusion We identified 19 separate proteins that changed in response to LPS or AEBSF, including ATP synthase, coagulation factor XIII, ferritin, coronin, HN ribonuclear proteins, integrin alpha IIb, pyruvate kinase, ras suppressor protein, superoxide dismutase, transketolase, tropomyosin, vimentin, and others. Interestingly, in response to LPS, precursor proteins for interleukin-1β appeared; and in response to AEBSF, there was an increase in elastase inhibitor. The increase in elastase inhibitor provides support for our hypothesis that priming requires an endogenous serine protease.

  13. Equine neutrophil elastase in plasma, laminar tissue, and skin of horses administered black walnut heartwood extract.

    Science.gov (United States)

    de la Rebière de Pouyade, Geoffroy; Riggs, Laura M; Moore, James N; Franck, Thierry; Deby-Dupont, Ginette; Hurley, David J; Serteyn, Didier

    2010-06-15

    Laminitis is a local manifestation of a systemic inflammatory response that is characterized by neutrophil activation and movement of neutrophils into the laminar tissues. Given the evidence for the involvement of neutrophils in the development of laminitis, we measured concentrations of neutrophil elastase, a serine protease released from the azurophilic granules of neutrophils, in plasma, skin and laminar tissues obtained from control horses and horses given black walnut heartwood extract (BWHE) to induce laminitis. Healthy horses (5-15 years old) were randomly assigned to 4 groups: 3 experimental groups given BWHE via nasogastric tube, and a control group given an equal volume of water. The experimental groups consisted of horses euthanized 1.5h (n=5), 3h (n=6) or 12h (n=10) after BWHE administration. Control horses (n=7) were euthanized 12h after intragastric administration of water. Plasma samples were collected in all horses of the control and 12h BWHE groups at 0, 1, 2, 3, 4, 6, 8, 10, and 12h after treatment, and laminar tissue and skin from the middle region of the neck were harvested at the time of euthanasia in all 1.5 and 3h BWHE horses, in 6 of the 12h BWHE horses and in 5 of the control horses. Plasma and tissue concentrations of neutrophil elastase were determined using an equine specific ELISA, and statistical significance was set at plaminitis, and the systemic nature of the inflammatory process. Furthermore, neutrophil elastase may play a key role in the disintegration of the hoof basal membrane and be a target for the development of new treatments for laminitis. Copyright 2009 Elsevier B.V. All rights reserved.

  14. Changes in plasma level of human leukocyte elastase during leukocytosis from physical effort.

    Science.gov (United States)

    Biondi, R; Tassi, C; Rossi, R; Benedetti, C; Ferranti, C; Paolocci, N; Parisse, I; De Bellis, F; Capodicasa, E

    2003-08-01

    Physical exercise is known to induce immunological changes, mainly leukocytosis and neutrophil activation. However, it is not known to what extent the leukocytosis, observed after exertion, is associated with an increase in plasma neutrophil elastase, an early marker of inflammatory response and neutrophil degranulation. In the present study changes in circulating leukocyte and neutrophil counts and human neutrophil elastase plasma levels were evaluated in volley-ball players before and after 2 h and 12 h prolonged training, during a competition season. For comparison, the same parameters were evaluated in untrained subjects before and after a jogging session. Basal white blood cell WBC, polymorpho nuclear PMN, and human polymorpho nuclear-elastase PMN-ELA values were within the normal healthy reference range and no significant differences were found between the two groups studied. Venous blood samples of nine volley-ball players showed a statistically significant increase in blood WBCs after 2 h exercise. This effect was paralleled by a statistically significant increase in PMN-ELA concentration compared to the values observed in the same individuals at rest. The exercise did not significantly change the basal correlation parameters between PMN level and PMN-ELA concentration. More pronounced WBC, PMN, and PMN-ELA increases were observed in the seven inactive subjects after 2 h jogging. There was no linear correlation between increased PMN counts and increased PMN-ELA concentrations in untrained subjects after exercise. The results show that not only the leukocyte count but also PMN-ELA plasma levels can be higher after physical effort. This has a practical significance as regards differential diagnosis demonstrating that determination of these two laboratory parameters can give abnormally high values even in the absence of an existing inflammatory process. Besides, lack of correlation between PMN count and PMN-ELA plasma levels in the untrained group suggest a

  15. Controlled Delivery of Human Cells by Temperature Responsive Microcapsules

    Science.gov (United States)

    Mak, W.C.; Olesen, K.; Sivlér, P.; Lee, C.J.; Moreno-Jimenez, I.; Edin, J.; Courtman, D.; Skog, M.; Griffith, M.

    2015-01-01

    Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line—human umbilical vein endothelial cells (HUVECs). While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation. PMID:26096147

  16. Controlled Delivery of Human Cells by Temperature Responsive Microcapsules

    Directory of Open Access Journals (Sweden)

    W.C. Mak

    2015-06-01

    Full Text Available Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line—human umbilical vein endothelial cells (HUVECs. While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation.

  17. Synthesis of amphiphilic polysuccinimide star copolymers for responsive delivery in plants.

    Science.gov (United States)

    Chen, Mingsheng; Jensen, Shaun P; Hill, Megan R; Moore, Gloria; He, Zhenli; Sumerlin, Brent S

    2015-06-14

    While polymeric nanocarriers are widely used in medicine for controlled release and site-specific delivery, few reports have applied such delivery methods within agriculture, despite the urgent need for specific delivery of pesticides and nutrients. We report the synthesis of stimuli-responsive and biodegradable polymeric nanocarriers designed for delivery to the phloem of plants and describe methods employed to evaluate their toxicity in plant cells.

  18. Does human leukocyte elastase degrade intact skin elastin?

    DEFF Research Database (Denmark)

    Schmelzer, Christian E H; Jung, Michael C; Wohlrab, Johannes

    2012-01-01

    and organs, including the aorta, lung, cartilage, elastic ligaments and skin, and is thus critical for their long-term function. Mature elastin is an insoluble and extremely durable protein that undergoes very little turnover, but sustained exposure to proteases may lead to irreversible and severe damage......This study aimed to investigate the susceptibility of intact fibrillar human elastin to human leukocyte elastase and cathepsin G. Elastin is a vital protein of the extracellular matrix of vertebrates, and provides exceptional properties including elasticity and tensile strength to many tissues...... small tissue samples to test enzymes for their elastolytic potential. This workflow was applied to skin samples from variously aged individuals, and it was found that strong differences exist in the degradability of the elastins investigated. In summary, human leukocyte elastase was unable to degrade...

  19. 20 CFR 617.20 - Responsibilities for the delivery of reemployment services.

    Science.gov (United States)

    2010-04-01

    ... § 617.20 Responsibilities for the delivery of reemployment services. (a) State agency referral... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Responsibilities for the delivery of reemployment services. 617.20 Section 617.20 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION...

  20. Serum elastase activity, serum elastase inhibitors, and occurrence of carotid atherosclerotic plaques: the Etude sur le Vieillissement Artériel (EVA) study.

    Science.gov (United States)

    Zureik, Mahmoud; Robert, Ladislas; Courbon, Dominique; Touboul, Pierre-Jean; Bizbiz, Latifa; Ducimetière, Pierre

    2002-06-04

    In the last decades, interest has increased in the potential deleterious atherogenic effects of some cellular elastase activities. The results of experimental and clinical investigations were inconsistent. In this report, we assessed the associations of serum elastase activity and serum elastase inhibitors with carotid plaque occurrence during the 4-year follow-up in a population of 859 subjects free of coronary heart disease and stroke (age, 59 to 71 years). Serum elastase activity and serum elastase inhibitors were measured at baseline examination. Carotid B-mode ultrasound examination was performed at baseline and 2 years and 4 years later. The occurrence of carotid plaques in subjects with the lowest serum elastase activity values (quartile 1), in those with the intermediate values (quartiles 2 to 3), and in those with the highest values (quartile 4) was, respectively, 24.6%, 18.9%, and 12.2% (P<0.001 for trend). The multivariate odds ratios of carotid plaque occurrence associated with the three groups (adjusted for major known cardiovascular risk factors) were, respectively, 1.00, 0.67 (CI, 0.44 to 1.02; P<0.06), and 0.40 (CI, 0.23 to 0.70, P<0.001). For serum elastase inhibitors, the occurrence of carotid plaques in quartile 1 (lowest values), quartiles 2 to 3, and quartile 4 (highest values) was, respectively, 11.7%, 18.8%, and 25.2% (P for trend<0.001). The corresponding multivariate adjusted odds ratios were 1.00, 1.98 (CI, 1.19 to 3.31, P<0.01), and 3.18 (CI, 1.80 to 5.60, P<0.001). Low values of serum elastase activity and high values of serum elastase inhibitors were strongly and independently associated with increased 4-year carotid plaque occurrence. Further studies are necessary to elucidate the nature of the associations between elastase parameters and atherosclerosis.

  1. Magnetically responsive microparticles for targeted drug and radionuclide delivery

    International Nuclear Information System (INIS)

    Kaminski, M. D.; Ghebremeskel, A. N.; Nunez, L.; Kasza, K. E.; Chang, F.; Chien, T.-H.; Fisher, P. F.; Eastman, J. A.; Rosengart, A. J.; McDonald, L.; Xie, Y.; Johns, L.; Pytel, P.; Hafeli, U. O.

    2004-01-01

    We are currently investigating the use of magnetic particles--polymeric-based spheres containing dispersed magnetic nanocrystalline phases--for the precise delivery of drugs via the human vasculature. According to this review, meticulously prepared magnetic drug targeting holds promise as a safe and effective method of delivering drugs to specific organ, tissue or cellular targets. We have critically examined the wide range of approaches in the design and implementation of magnetic-particle-based drug delivery systems to date, including magnetic particle preparation, drug encapsulation, biostability, biocompatibility, toxicity, magnetic field designs, and clinical trials. However, we strongly believe that there are several limitations with past developments that need to be addressed to enable significant strides in the field. First, particle size has to be carefully chosen. Micrometer-sized magnetic particles are better attracted over a distance than nanometer sized magnetic particles by a constant magnetic field gradient, and particle sizes up to 1 (micro)m show a much better accumulation with no apparent side effects in small animal models, since the smallest blood vessels have an inner diameter of 5-7 (micro)m. Nanometer-sized particles <70 nm will accumulate in organ fenestrations despite an effective surface stabilizer. To be suitable for future human applications, our experimental approach synthesizes the magnetic drug carrier according to specific predefined outcome metrics: monodisperse population in a size range of 100 nm to 1.0 (micro)m, non-toxic, with appropriate magnetic properties, and demonstrating successful in vitro and in vivo tests. Another important variable offering possible improvement is surface polarity, which is expected to prolong particle half-life in circulation and modify biodistribution and stability of drugs in the body. The molecules in the blood that are responsible for enhancing the uptake of particles by the reticuloendothelial

  2. Inhibition of neutrophil elastase and metalloprotease-9 of human adenocarcinoma gastric cells by chamomile (Matricaria recutita L.) infusion.

    Science.gov (United States)

    Bulgari, Michela; Sangiovanni, Enrico; Colombo, Elisa; Maschi, Omar; Caruso, Donatella; Bosisio, Enrica; Dell'Agli, Mario

    2012-12-01

    This study investigated whether the antiinflammatory effect of chamomile infusion at gastric level could be ascribed to the inhibition of metalloproteinase-9 and elastase. The infusions from capitula and sifted flowers (250-1500 µg/mL) and individual flavonoids (10 µM) were tested on phorbol 12-myristate 13-acetate-stimulated AGS cells and human neutrophil elastase. The results indicate that the antiinflammatory activity associated with chamomile infusions from both the capitula and sifted flowers is most likely due to the inhibition of neutrophil elastase and gastric metalloproteinase-9 activity and secretion; the inhibition occurring in a concentration dependent manner. The promoter activity was inhibited as well and the decrease of metalloproteinase-9 expression was found to be associated with the inhibition of NF-kB driven transcription. The results further indicate that the flavonoid-7-glycosides, major constituents of chamomile flowers, may be responsible for the antiinflammatory action of the chamomile infusion observed here. Copyright © 2012 John Wiley & Sons, Ltd.

  3. Peritendinous elastase treatment induces tendon degeneration in rats: A potential model of tendinopathy in vivo.

    Science.gov (United States)

    Wu, Yen-Ting; Wu, Po-Ting; Jou, I-Ming

    2016-03-01

    The purpose of this study was to investigate the role of elastase on tendinopathy, as well as to evaluate the potential for peritendinous injections of elastase into rats to cause tendinopathy. We first investigated the expression of elastase in the tendons of patients with tendinopathy, and then established the effects of elastase injection on the Achilles tendons of rats. Ultrasonographic and incapacitance testing was used to conduct tests for 8 weeks. Tendon tissues were collected for histological observation and protein levels of collagen type I and type III were detected using Western blotting. The percentage of elastase-positive cells increased in human specimens with grades II and III tendinopathy. The rat model demonstrated that the thickness of the tendon increased after elastase injection during Week 2-8. Hypercellularity and focal lesions were detected after Week 2. The expression of elastase was increased and elastin was decreased in Week 8. Collagen type I expression was decreased, but type III was increased in Week 4. These results suggested that elastase may be involved in the development of chronic tendinopathy, and that peritendinous injection of elastase may result in tendinopathy in rats. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  4. Inhibitory effect of burdock leaves on elastase and tyrosinase activity

    Science.gov (United States)

    Horng, Chi-Ting; Wu, Hsing-Chen; Chiang, Ni-Na; Lee, Chiu-Fang; Huang, Yu-Syuan; Wang, Hui-Yun; Yang, Jai-Sing; Chen, Fu-An

    2017-01-01

    Burdock (Arctium lappa L.) leaves generate a considerable amount of waste following burdock root harvest in Taiwan. To increase the use of burdock leaves, the present study investigated the optimal methods for producing burdock leaf extract (BLE) with high antioxidant polyphenolic content, including drying methods and solvent extraction concentration. In addition, the elastase and tyrosinase inhibitory activity of BLE was examined. Burdock leaves were dried by four methods: Shadow drying, oven drying, sun drying and freeze-drying. The extract solution was then subjected to total polyphenol content analysis and the method that produced BLE with the highest amount of total antioxidant components was taken forward for further analysis. The 1,1-diphenyl-2-pycrylhydrazyl scavenging, antielastase and antityrosinase activity of the BLE were measured to enable the evaluation of the antioxidant and skin aging-associated enzyme inhibitory activities of BLE. The results indicated that the total polyphenolic content following extraction with ethanol (EtOH) was highest using the freeze-drying method, followed by the oven drying, shadow drying and sun drying methods. BLE yielded a higher polyphenol content and stronger antioxidant activity as the ratio of the aqueous content of the extraction solvent used increased. BLE possesses marked tyrosinase and elastase inhibitory activities, with its antielastase activity notably stronger compared with its antityrosinase activity. These results indicate that the concentration of the extraction solvent was associated with the antioxidant and skin aging-associated enzyme inhibitory activity of BLE. The reactive oxygen species scavenging theory of skin aging may explain the tyrosinase and elastase inhibitory activity of BLE. In conclusion, the optimal method for obtaining BLE with a high antioxidant polyphenolic content was freeze-drying followed by 30–50% EtOH extraction. In addition, the antielastase and antityrosinase activities of the

  5. Usefulness of a selective neutrophil elastase inhibitor, sivelestat, in acute lung injury patients with sepsis

    Directory of Open Access Journals (Sweden)

    Miyoshi S

    2013-04-01

    Full Text Available Seigo Miyoshi,1 Hironobu Hamada,1,2 Ryoji Ito,1 Hitoshi Katayama,1 Kazunori Irifune,1 Toshimitsu Suwaki,3 Norihiko Nakanishi,4 Takanori Kanematsu,5 Kentaro Dote,6 Mayuki Aibiki,7 Takafumi Okura,1 Jitsuo Higaki1 1Department of Integrated Medicine and Informatics, Ehime University, Graduate School of Medicine, Toon, 2Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 3Department of Respiratory Medicine, Sumitomo Besshi Hospital, Niihama, 4Department of Respiratory Medicine, Ehime Prefectural Central Hospital, Matsuyama, 5Department of Respiratory Medicine, Matsuyama Red Cross Hospital, Matsuyama, 6Intensive Care Division, Ehime University Hospital, Toon, 7Department of Emergency Medicine, School of Medicine, Ehime University, Toon, Japan Background: Neutrophil elastase plays a crucial role in the development of acute lung injury (ALI in patients with systemic inflammatory response syndrome (SIRS. The clinical efficacy of the neutrophil elastase inhibitor, sivelestat, for patients with ALI associated with SIRS has not been convincingly demonstrated. The aim of this study was to determine if there are clinical features of patients with this condition that affect the efficacy of sivelestat. Methods: This was a retrospective study of 110 ALI patients with SIRS. Clinical information, including the etiology of ALI, the number of organs failing, scoring systems for assessing the severity of illness, and laboratory data, was collected at the time of diagnosis. Information on the number of ventilator-free days (VFDs and changes in PaO2/FIO2 (ΔP/F before and 7 days after the time of ALI diagnosis was also collected. The effect of sivelestat on ALI patients was also examined based on whether they had sepsis and whether their initial serum procalcitonin level was ≥0.5 ng/mL. Results: There were 70 patients who were treated with sivelestat and 40 control patients. VFDs and ΔP/F were significantly higher in the treated

  6. The third serine proteinase with chymotrypsin specificity isolated from Atlantic cod (Gadus morhua) is a type-II elastase

    DEFF Research Database (Denmark)

    Asgeirsson, B; Leth-Larsen, Rikke; Thórólfsson, M

    1998-01-01

    efficiency of elastase C. The effects of several inhibitors on cod elastase C were identical to effects on chymotrypsins variants A and B, but dissimilar when compared with porcine pancreatic elastase. On the basis of the specificity and amino acid sequence, we conclude that the enzyme under study is most...

  7. Usefulness of a selective neutrophil elastase inhibitor, sivelestat, in acute lung injury patients with sepsis

    Science.gov (United States)

    Miyoshi, Seigo; Hamada, Hironobu; Ito, Ryoji; Katayama, Hitoshi; Irifune, Kazunori; Suwaki, Toshimitsu; Nakanishi, Norihiko; Kanematsu, Takanori; Dote, Kentaro; Aibiki, Mayuki; Okura, Takafumi; Higaki, Jitsuo

    2013-01-01

    Background Neutrophil elastase plays a crucial role in the development of acute lung injury (ALI) in patients with systemic inflammatory response syndrome (SIRS). The clinical efficacy of the neutrophil elastase inhibitor, sivelestat, for patients with ALI associated with SIRS has not been convincingly demonstrated. The aim of this study was to determine if there are clinical features of patients with this condition that affect the efficacy of sivelestat. Methods This was a retrospective study of 110 ALI patients with SIRS. Clinical information, including the etiology of ALI, the number of organs failing, scoring systems for assessing the severity of illness, and laboratory data, was collected at the time of diagnosis. Information on the number of ventilator-free days (VFDs) and changes in PaO2/FIO2 (ΔP/F) before and 7 days after the time of ALI diagnosis was also collected. The effect of sivelestat on ALI patients was also examined based on whether they had sepsis and whether their initial serum procalcitonin level was ≥0.5 ng/mL. Results There were 70 patients who were treated with sivelestat and 40 control patients. VFDs and ΔP/F were significantly higher in the treated patients than in the control patients. However, there was no significant difference in the patient survival rate between the two groups. Sivelestat was more effective in ALI patients with a PaO2/FIO2 ratio ≥ 140 mmHg or sepsis. Sivelestat significantly prolonged survival and led to higher VFDs and increased ΔP/F in septic patients and patients with initial serum procalcitonin levels ≥ 0.5 ng/mL. Conclusion The results may facilitate a future randomized controlled trial to determine whether sivelestat is beneficial for ALI patients with sepsis. PMID:23596346

  8. Blockade of RAGE ameliorates elastase-induced emphysema development and progressionviaRAGE-DAMP signaling.

    Science.gov (United States)

    Lee, Hanbyeol; Park, Jeong-Ran; Kim, Woo Jin; Sundar, Isaac K; Rahman, Irfan; Park, Sung-Min; Yang, Se-Ran

    2017-05-01

    The receptor for advanced glycan end products (RAGE) has been identified as a susceptibility gene for chronic obstructive pulmonary disease (COPD) in genome-wide association studies (GWASs). However, less is known about how RAGE is involved in the pathogenesis of COPD. To determine the molecular mechanism by which RAGE influences COPD in experimental COPD models, we investigated the efficacy of the RAGE-specific antagonist FPS-ZM1 administration in in vivo and in vitro COPD models. We injected elastase intratracheally and the RAGE antagonist FPS-ZM1 in mice, and the infiltrated inflammatory cells and cytokines were assessed by ELISA. Cellular expression of RAGE was determined in protein, serum, and bronchoalveolar lavage fluid of mice and lungs and serum of human donors and patients with COPD. Downstream damage-associated molecular pattern (DAMP) pathway activation in vivo and in vitro and in patients with COPD was assessed by immunofluorescence staining, Western blot analysis, and ELISA. The expression of membrane RAGE in initiating the inflammatory response and of soluble RAGE acting as a decoy were associated with up-regulation of the DAMP-related signaling pathway via Nrf2. FPS-ZM1 administration significantly reversed emphysema in the lung of mice. Moreover, FPS-ZM1 treatment significantly reduced lung inflammation in Nrf2 +/+ , but not in Nrf2 -/- mice. Thus, our data indicate for the first time that RAGE inhibition has an essential protective role in COPD. Our observation of RAGE inhibition provided novel insight into its potential as a therapeutic target in emphysema/COPD.-Lee, H., Park, J.-R., Kim, W. J., Sundar, I. K., Rahman, I., Park, S.-M., Yang. S.-R. Blockade of RAGE ameliorates elastase-induced emphysema development and progression via RAGE-DAMP signaling. © FASEB.

  9. [Effects of delivery nursing care using essential oils on delivery stress response, anxiety during labor, and postpartum status anxiety].

    Science.gov (United States)

    Hur, Myung-Haeng; Cheong, NamYoun; Yun, HyeSung; Lee, MiKyoung; Song, Youngshin

    2005-12-01

    This study was designed to investigate the effect of delivery nursing care using essential oils on labor stress response, labor anxiety and postpartum status anxiety for primipara. This study used nonequivalent control group pretest-posttest design. The subjects of this experiment consisted of forty eight primipara with single gestation, full term, & uncomplicated pregnancies. Twenty four primipra were in the experimental and control group each. Their mean age was 27.9 years old, their mean gestation period 279.9 days. As a treatment, delivery nursing care using essential oils was applied by nurses. Data collected epinephrine, norepinephrine, anxiety during labor. In the 24 hours after birth, the data for the postpartum mother's status anxiety was collected. Data was analyzed by t-test, repeated measures ANOVA, Mann-Whitney U test, & Wilcoxon signed ranks test with SPSS Program. Plasma epinephrine, norepinephrine were significantly low in the experimental group (P=0.001, P=0.033, respectively). There was no significant difference between the two groups in anxiety during labor and postpartum mother's status anxiety. These findings indicate that delivery nursing care using essential oils could be effective in decreasing plasma epinephrine, norepinephrine. But, that could not be verified in decreasing mother's anxiety.

  10. Stimuli-responsive hydrogels in drug delivery and tissue engineering.

    Science.gov (United States)

    Sood, Nikhil; Bhardwaj, Ankur; Mehta, Shuchi; Mehta, Abhinav

    2016-01-01

    Hydrogels are the three-dimensional network structures obtained from a class of synthetic or natural polymers which can absorb and retain a significant amount of water. Hydrogels are one of the most studied classes of polymer-based controlled drug release. These have attracted considerable attention in biochemical and biomedical fields because of their characteristics, such as swelling in aqueous medium, biocompatibility, pH and temperature sensitivity or sensitivity towards other stimuli, which can be utilized for their controlled zero-order release. The hydrogels are expected to explore new generation of self-regulated delivery system having a wide array of desirable properties. This review highlights the exciting opportunities and challenges in the area of hydrogels. Here, we review different literatures on stimuli-sensitive hydrogels, such as role of temperature, electric potential, pH and ionic strength to control the release of drug from hydrogels.

  11. Nicotine delivery and pharmacologic response from Verve, an oral nicotine delivery product☆

    Science.gov (United States)

    Koszowski, Bartosz; Viray, Lauren C.; Stanfill, Stephen B.; Lisko, Joseph G.; Rosenberry, Zach R.; Potts, Jennifer L.; Pickworth, Wallace B.

    2016-01-01

    Verve, an oral nicotine delivery product (ONDP), was introduced by Nu Mark (Altria Client Group, Richmond VA) for smokers to use in places where smoking is prohibited. This study assessed the effect of this ONDP on plasma nicotine levels, heart rate, product satisfaction, and ability to suppress smoking urge and cigarette cravings. Thirteen daily cigarette smokers [8 men and 5 women; average age 33.4 years] attended two laboratory sessions, one occurred after overnight tobacco abstinence. Plasma samples were collected before and after ONDP use and measured for nicotine. In non-abstinent smokers, mean plasma nicotine levels increased from 18.3 to 21.0 ng/mL. In abstinent smokers, average nicotine levels increased from 3.1 to 4.5 ng/mL. After overnight tobacco abstinence, ONDP use significantly (p < 0.01) increased heart rate from 69 beats per minute (bpm) to 75 bpm; while urge to smoke decreased significantly (p < 0.01) from a score of 8.6 to 4.9. Participants indicated moderate product satisfaction that was not changed by tobacco abstinence. Analysis of unused ONDP revealed total nicotine levels of 1.68 ± 0.09 mg/disc. Spent ONDP discs were also analyzed to determine % nicotine liberated during chewing; results were 80% in the non-abstinent and 82% in the abstinent conditions (ns). Our study results indicate that ONDP use can increase plasma nicotine levels and heart rate and reduce cigarette cravings in abstinent smokers. PMID:26096037

  12. Nicotine delivery and pharmacologic response from Verve, an oral nicotine delivery product.

    Science.gov (United States)

    Koszowski, Bartosz; Viray, Lauren C; Stanfill, Stephen B; Lisko, Joseph G; Rosenberry, Zach R; Potts, Jennifer L; Pickworth, Wallace B

    2015-09-01

    Verve, an oral nicotine delivery product (ONDP), was introduced by Nu Mark (Altria Client Group, Richmond VA) for smokers to use in places where smoking is prohibited. This study assessed the effect of this ONDP on plasma nicotine levels, heart rate, product satisfaction, and ability to suppress smoking urge and cigarette cravings. Thirteen daily cigarette smokers [8 men and 5 women; average age 33.4years] attended two laboratory sessions, one occurred after overnight tobacco abstinence. Plasma samples were collected before and after ONDP use and measured for nicotine. In non-abstinent smokers, mean plasma nicotine levels increased from 18.3 to 21.0ng/mL. In abstinent smokers, average nicotine levels increased from 3.1 to 4.5ng/mL. After overnight tobacco abstinence, ONDP use significantly (p<0.01) increased heart rate from 69beats per minute (bpm) to 75bpm; while urge to smoke decreased significantly (p<0.01) from a score of 8.6 to 4.9. Participants indicated moderate product satisfaction that was not changed by tobacco abstinence. Analysis of unused ONDP revealed total nicotine levels of 1.68±0.09mg/disc. Spent ONDP discs were also analyzed to determine % nicotine liberated during chewing; results were 80% in the non-abstinent and 82% in the abstinent conditions (ns). Our study results indicate that ONDP use can increase plasma nicotine levels and heart rate and reduce cigarette cravings in abstinent smokers. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Identification and Characterization of Roseltide, a Knottin-type Neutrophil Elastase Inhibitor Derived from Hibiscus sabdariffa

    Science.gov (United States)

    Loo, Shining; Kam, Antony; Xiao, Tianshu; Nguyen, Giang K. T.; Liu, Chuan Fa; Tam, James P.

    2016-01-01

    Plant knottins are of therapeutic interest due to their high metabolic stability and inhibitory activity against proteinases involved in human diseases. The only knottin-type proteinase inhibitor against porcine pancreatic elastase was first identified from the squash family in 1989. Here, we report the identification and characterization of a knottin-type human neutrophil elastase inhibitor from Hibiscus sabdariffa of the Malvaceae family. Combining proteomic and transcriptomic methods, we identified a panel of novel cysteine-rich peptides, roseltides (rT1-rT8), which range from 27 to 39 residues with six conserved cysteine residues. The 27-residue roseltide rT1 contains a cysteine spacing and amino acid sequence that is different from the squash knottin-type elastase inhibitor. NMR analysis demonstrated that roseltide rT1 adopts a cystine-knot fold. Transcriptome analyses suggested that roseltides are bioprocessed by asparagine endopeptidases from a three-domain precursor. The cystine-knot structure of roseltide rT1 confers its high resistance against degradation by endopeptidases, 0.2 N HCl, and human serum. Roseltide rT1 was shown to inhibit human neutrophil elastase using enzymatic and pull-down assays. Additionally, roseltide rT1 ameliorates neutrophil elastase-stimulated cAMP accumulation in vitro. Taken together, our findings demonstrate that roseltide rT1 is a novel knottin-type neutrophil elastase inhibitor with therapeutic potential for neutrophil elastase associated diseases. PMID:27991569

  14. Identification and Characterization of Roseltide, a Knottin-type Neutrophil Elastase Inhibitor Derived from Hibiscus sabdariffa.

    Science.gov (United States)

    Loo, Shining; Kam, Antony; Xiao, Tianshu; Nguyen, Giang K T; Liu, Chuan Fa; Tam, James P

    2016-12-19

    Plant knottins are of therapeutic interest due to their high metabolic stability and inhibitory activity against proteinases involved in human diseases. The only knottin-type proteinase inhibitor against porcine pancreatic elastase was first identified from the squash family in 1989. Here, we report the identification and characterization of a knottin-type human neutrophil elastase inhibitor from Hibiscus sabdariffa of the Malvaceae family. Combining proteomic and transcriptomic methods, we identified a panel of novel cysteine-rich peptides, roseltides (rT1-rT8), which range from 27 to 39 residues with six conserved cysteine residues. The 27-residue roseltide rT1 contains a cysteine spacing and amino acid sequence that is different from the squash knottin-type elastase inhibitor. NMR analysis demonstrated that roseltide rT1 adopts a cystine-knot fold. Transcriptome analyses suggested that roseltides are bioprocessed by asparagine endopeptidases from a three-domain precursor. The cystine-knot structure of roseltide rT1 confers its high resistance against degradation by endopeptidases, 0.2 N HCl, and human serum. Roseltide rT1 was shown to inhibit human neutrophil elastase using enzymatic and pull-down assays. Additionally, roseltide rT1 ameliorates neutrophil elastase-stimulated cAMP accumulation in vitro. Taken together, our findings demonstrate that roseltide rT1 is a novel knottin-type neutrophil elastase inhibitor with therapeutic potential for neutrophil elastase associated diseases.

  15. Purification and characterization of elastase from the pyloric caeca of rainbow trout (Oncorhynchus mykiss)

    DEFF Research Database (Denmark)

    Bassompierre, Marc; Nielsen, Henrik Hauch; Børresen, Torger

    1993-01-01

    1. An elastase-like enzyme was purified from the pyloric caeca of rainbow trout by hydrophobic interaction, cation exchange and gel-filtration chromatography. 2. The approximate molecular weight of the elastase was 27 kDa and the isoelectric point was remarkably basic. 3. The pH optimum of this e......1. An elastase-like enzyme was purified from the pyloric caeca of rainbow trout by hydrophobic interaction, cation exchange and gel-filtration chromatography. 2. The approximate molecular weight of the elastase was 27 kDa and the isoelectric point was remarkably basic. 3. The pH optimum...... of this enzyme was 8.0, when assayed with Succinyl-Ala-Ala-Ala-p-Nitroanilide. 4. When assayed with Succinyl-Ala-Ala-Ala-p-Nitroanilide, the enzyme activity had a temperature optimum of 45 degree C, and the enzyme was stable up to this temperature. 5. The trout elastase exhibited a higher specific activity than...... porcine elastase against Succinyl-Ala-Ala-Ala-p-Nitroanilide and elastin-orcein. 6. The trout elastase was inhibited by elastatinal, PMSF, TPCK, SBTI and Bowman-Birk inhibitor....

  16. pH-Responsive Micelle-Based Cytoplasmic Delivery System for Induction of Cellular Immunity

    Directory of Open Access Journals (Sweden)

    Eiji Yuba

    2017-11-01

    Full Text Available (1 Background: Cytoplasmic delivery of antigens is crucial for the induction of cellular immunity, which is an important immune response for the treatment of cancer and infectious diseases. To date, fusogenic protein-incorporated liposomes and pH-responsive polymer-modified liposomes have been used to achieve cytoplasmic delivery of antigen via membrane rupture or fusion with endosomes. However, a more versatile cytoplasmic delivery system is desired for practical use. For this study, we developed pH-responsive micelles composed of dilauroyl phosphatidylcholine (DLPC and deoxycholic acid and investigated their cytoplasmic delivery performance and immunity-inducing capability. (2 Methods: Interaction of micelles with fluorescence dye-loaded liposomes, intracellular distribution of micelles, and antigenic proteins were observed. Finally, antigen-specific cellular immune response was evaluated in vivo using ELIspot assay. (3 Results: Micelles induced leakage of contents from liposomes via lipid mixing at low pH. Micelles were taken up by dendritic cells mainly via macropinocytosis and delivered ovalbumin (OVA into the cytosol. After intradermal injection of micelles and OVA, OVA-specific cellular immunity was induced in the spleen. (4 Conclusions: pH-responsive micelles composed of DLPC and deoxycholic acid are promising as enhancers of cytosol delivery of antigens and the induction capability of cellular immunity for the treatment of cancer immunotherapy and infectious diseases.

  17. Neutrophil elastase-deficient mice form neutrophil extracellular traps in an experimental model of deep vein thrombosis.

    Science.gov (United States)

    Martinod, K; Witsch, T; Farley, K; Gallant, M; Remold-O'Donnell, E; Wagner, D D

    2016-03-01

    ESSENTIALS: Neutrophil elastase (NE) plays a role in extracellular trap formation (NETosis) triggered by microbes. The contribution of NE was evaluated in mouse NETosis models of sterile inflammation and thrombosis. NE is not required for mouse neutrophil NET production in vitro with non-infectious stimuli. NE deficiency had no significant effect on thrombosis in the inferior vena cava stenosis model. Neutrophil serine proteases have been implicated in coagulation and neutrophil extracellular trap (NET) formation. In human neutrophils, neutrophil elastase (NE) translocates to the nucleus during NETosis and cleaves histones, thus aiding in chromatin decondensation. NE(-/-) mice were shown not to release NETs in response to microbes. However, mouse studies evaluating the role of NE in NET formation in sterile inflammation and thrombosis are lacking. We wished to establish if neutrophils from NE(-/-) mice have a defect in NETosis, similar to peptidylarginine deiminase 4 (PAD4(-/-)) mice, and how this might have an impact on venous thrombosis, a model where NETs are produced and are crucial to thrombus development. We performed in vitro NET assays using neutrophils from wild-type (WT), NE(-/-), SerpinB1 (SB1)(-/-) and NE(-/-) SB1(-/-) mice. We compared WT and NE(-/-) animals using the inferior vena cava stenosis model of deep vein thrombosis (DVT). Neutrophil elastase deficiency resulted in a small reduction in ionomycin-induced NET formation in vitro without affecting histone citrullination. However, NET production in response to phorbol 12-myristate 13-acetate or platelet activating factor was normal in neutrophils from two independent NE-deficient mouse lines, and in NE(-/-) SB1(-/-) as compared with SB1(-/-) neutrophils. NE deficiency or inhibition did not prevent NETosis in vivo or DVT outcome. Neutrophil elastase is not required for NET formation in mice. NE(-/-) mice, which form pathological venous thrombi containing NETs, do not phenocopy PAD4(-/-) mice in in

  18. A Review of Thermo- and Ultrasound-Responsive Polymeric Systems for Delivery of Chemotherapeutic Agents

    Directory of Open Access Journals (Sweden)

    Az-Zamakhshariy Zardad

    2016-10-01

    Full Text Available There has been an exponential increase in research into the development of thermal- and ultrasound-activated delivery systems for cancer therapy. The majority of researchers employ polymer technology that responds to environmental stimuli some of which are physiologically induced such as temperature, pH, as well as electrical impulses, which are considered as internal stimuli. External stimuli include ultrasound, light, laser, and magnetic induction. Biodegradable polymers may possess thermoresponsive and/or ultrasound-responsive properties that can complement cancer therapy through sonoporation and hyperthermia by means of High Intensity Focused Ultrasound (HIFU. Thermoresponsive and other stimuli-responsive polymers employed in drug delivery systems can be activated via ultrasound stimulation. Polyethylene oxide/polypropylene oxide co-block or triblock polymers and polymethacrylates are thermal- and pH-responsive polymer groups, respectively but both have proven to have successful activity and contribution in chemotherapy when exposed to ultrasound stimulation. This review focused on collating thermal- and ultrasound-responsive delivery systems, and combined thermo-ultrasonic responsive systems; and elaborating on the advantages, as well as shortcomings, of these systems in cancer chemotherapy. The mechanisms of these systems are explicated through their physical alteration when exposed to the corresponding stimuli. The properties they possess and the modifications that enhance the mechanism of chemotherapeutic drug delivery from systems are discussed, and the concept of pseudo-ultrasound responsive systems is introduced.

  19. Crystal structures of the complex of porcine pancreatic elastase with two valine-derived benzoxazinone inhibitors.

    Science.gov (United States)

    Radhakrishnan, R; Presta, L G; Meyer, E F; Wildonger, R

    1987-12-05

    The crystal structures of porcine pancreatic elastase complexed to two similar benzoxazinone inhibitors are reported to 2.09 A and 1.76 A resolution, and refined to conventional R factors of 0.153 and 0.172.

  20. Starvation Selection Restores Elastase and Rhamnolipid Production in a Pseudomonas aeruginosa Quorum-Sensing Mutant

    Science.gov (United States)

    Van Delden, Christian; Pesci, Everett C.; Pearson, James P.; Iglewski, Barbara H.

    1998-01-01

    The las quorum-sensing system of Pseudomonas aeruginosa controls the expression of elastase and rhamnolipid. We report that starvation can select a mutant producing these virulence factors in spite of a lasR deletion. Expression of the autoinducer synthase gene rhlI was increased in this suppressor mutant, suggesting compensation by the rhl system. These data show that P. aeruginosa can restore elastase and rhamnolipid production in the absence of a functional las quorum-sensing system. PMID:9712807

  1. Elastase effect on the extracellular matrix of rat aortic smooth muscle cells in culture

    International Nuclear Information System (INIS)

    Kispert, J.; Mogayzel, P.J. Jr.; Pratt, C.A.; Toselli, P.; Wolfe, B.L.; Faris, B.; Franzblau, C.

    1986-01-01

    The effect of porcine pancreatic elastase on the extracellular matrix (ECM) of neonatal rat aortic smooth muscle cell cultures was monitored both chemically and ultrastructurally. Initially, the elastin appeared as non-coalesced material closely associated with filaments, presumably microfibrils. The insoluble elastin accumulated in the ECM of cells in culture for 6 weeks accounted for 40-45% of the total protein. After exposure to elastase for 30-60 minutes, the elastin content was reduced to 14-20%. The reduction in the total protein content of the cultures after elastase treatment was due primarily to the loss of elastin. Although the amino acid compositions of the elastin isolated from cultures both before and after elastase treatment were similar, there were striking ultrastructural differences in the amorphous elastin. The elastin assumed a mottled appearance after elastase exposure, similar to that seen in in vivo emphysema models. Pulse experiments with 3 H-valine demonstrated an increase in protein synthesis by the cells 20 hours after elastase exposure, suggesting the potential for elastin repair. The use of this culture system will aid in clarifying the role of elastolysis in pulmonary and vascular injuries

  2. Biochemical properties and primary structure of elastase inhibitor AFUEI from Aspergillus fumigatus.

    Science.gov (United States)

    Okumura, Yoshiyuki; Matsui, Takeshi; Ogawa, Kenji; Uchiya, Kei-ichi; Nikai, Toshiaki

    2008-07-01

    An elastase inhibitor from Aspergillus fumigatus (AFUEI) was isolated, and its biochemical properties and primary structure examined. The inhibitor was purified by column chromatography using DE52 cellulose and Sephadex G-75, and was found to be homogeneous as indicated by a single band following discontinuous PAGE and SDS-PAGE. A molecular mass of 7525.1 Da was observed by matrix-assisted desorption/ionization time-of-flight mass spectroscopy. The elastolytic activity of elastases from A. fumigatus, Aspergillus flavus and human leukocytes was inhibited by AFUEI. However, the elastolytic activity of porcine pancreas elastase, Pseudomonas aeruginosa elastase and elastase from snake venom was not affected by AFUEI. No inhibitory effect of DTT or 2-mercaptoethanol on the elastase inhibitory activity of AFUEI was observed. The amino acid sequence of AFUEI peptides derived from digests utilizing clostripain was determined by Edman sequencing. AFUEI was composed of 68 aa and had a calculated molecular mass of 7526.2 Da. The search for amino acid homology with other proteins demonstrated that aa 1-68 of AFUEI are 100 % identical to aa 20-87 of the hypothetical protein AFUA 3G14940 of A. fumigatus.

  3. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: A review.

    Science.gov (United States)

    Kanamala, Manju; Wilson, William R; Yang, Mimi; Palmer, Brian D; Wu, Zimei

    2016-04-01

    As the mainstay in the treatment of various cancers, chemotherapy plays a vital role, but still faces many challenges, such as poor tumour selectivity and multidrug resistance (MDR). Targeted drug delivery using nanotechnology has provided a new strategy for addressing the limitations of the conventional chemotherapy. In the last decade, the volume of research published in this area has increased tremendously, especially with functional nano drug delivery systems (nanocarriers). Coupling a specific stimuli-triggered drug release mechanism with these delivery systems is one of the most prevalent approaches for improving therapeutic outcomes. Among the various stimuli, pH triggered delivery is regarded as the most general strategy, targeting the acidic extracellular microenvironment and intracellular organelles of solid tumours. In this review, we discuss recent advances in the development of pH-sensitive nanocarriers for tumour-targeted drug delivery. The review focuses on the chemical design of pH-sensitive biomaterials, which are used to fabricate nanocarriers for extracellular and/or intracellular tumour site-specific drug release. The pH-responsive biomaterials bring forth conformational changes in these nanocarriers through various mechanisms such as protonation, charge reversal or cleavage of a chemical bond, facilitating tumour specific cell uptake or drug release. A greater understanding of these mechanisms will help to design more efficient drug delivery systems to address the challenges encountered in conventional chemotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Non inflammatory boronate based glucose-responsive insulin delivery systems.

    Directory of Open Access Journals (Sweden)

    Indrani Dasgupta

    Full Text Available Boronic acids, known to bind diols, were screened to identify non-inflammatory cross-linkers for the preparation of glucose sensitive and insulin releasing agglomerates of liposomes (Agglomerated Vesicle Technology-AVT. This was done in order to select a suitable replacement for the previously used cross-linker, ConcanavalinA (ConA, a lectin known to have both toxic and inflammatory effects in vivo. Lead-compounds were selected from screens that involved testing for inflammatory potential, cytotoxicity and glucose-binding. These were then conjugated to insulin-encapsulating nanoparticles and agglomerated via sugar-boronate ester linkages to form AVTs. In vitro, the particles demonstrated triggered release of insulin upon exposure to physiologically relevant concentrations of glucose (10 mmoles/L-40 mmoles/L. The agglomerates were also shown to be responsive to multiple spikes in glucose levels over several hours, releasing insulin at a rate defined by the concentration of the glucose trigger.

  5. Cardiovascular Responsivity, Physical and Psychosocial Job Stress, and the Risk of Preterm Delivery

    National Research Council Canada - National Science Library

    Hatch, Maureen

    2000-01-01

    .... The role of cardiovascular reactivity in the stress response and how this affects risk of pre term delivery will also be examined. Recruitment, now complete, took longer than anticipated due to a high rate of ineligibles. We propose to complete the analyses under a no-cost extension.

  6. Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Minghui; Qian, Junmin, E-mail: jmqian@mail.xjtu.edu.cn; Liu, Xuefeng; Liu, Ting; Wang, Hongjie

    2015-05-01

    In recent years, stimuli-sensitive prodrugs have been extensively studied for the rapid “burst” release of antitumor drugs to enhance chemotherapeutic efficiency. In this study, a novel stimuli-sensitive prodrug containing galactosamine as a targeting moiety, poly(ethylene glycol)–doxorubicin (PEG–DOX) conjugate, was developed for targeting HepG2 human liver cancer cells. To obtain the PEG–DOX conjugate, both galactosamine-decorated poly(ethylene glycol) aldehyde (Gal-PEG-CHO) and methoxy poly(ethylene glycol) aldehyde (mPEG-CHO) were firstly synthesized and functionalized with dithiodipropionate dihydrazide (TPH) through direct reductive amination via Schiff's base formation, and then DOX molecules were chemically conjugated to the hydrazide end groups of TPH-functionalized Gal-/m-PEG chains via pH-sensitive hydrazone linkages. The chemical structures of TPH-functionalized PEG and PEG–DOX prodrug were confirmed by {sup 1}H NMR analysis. The PEG–DOX conjugate could self-assemble into spherical nanomicelles with a mean diameter of 140 nm, as indicated by transmission electron microscopy and dynamic light scattering. The drug loading content and loading efficiency in the prodrug nanomicelles were as high as 20 wt.% and 75 wt.%, respectively. In vitro drug release studies showed that DOX was released rapidly from the prodrug nanomicelles at the intracellular levels of pH and reducing agent. Cellular uptake and MTT experiments demonstrated that the galactosamine-decorated prodrug nanomicelles were more efficiently internalized into HepG2 cells via a receptor-mediated endocytosis process and exhibited a higher toxicity, compared with pristine prodrug nanomicelles. These results suggest that the novel Gal-PEG–DOX prodrug nanomicelles have tremendous potential for targeted liver cancer therapy. - Highlights: • A novel stimuli-responsive PEGylated prodrugs is synthesized. • PEGylated prodrugs can self-assemble into spherical nanoparticles (140 nm

  7. A remotely operated drug delivery system with an electrolytic pump and a thermo-responsive valve

    OpenAIRE

    Yi, Ying; Zaher, Amir; Yassine, Omar; Kosel, Jurgen; Foulds, Ian G.

    2015-01-01

    Implantable drug delivery devices are becoming attractive due to their abilities of targeted and controlled dose release. Currently, two important issues are functional lifetime and non-controlled drug diffusion. In this work, we present a drug delivery device combining an electrolytic pump and a thermo-responsive valve, which are both remotely controlled by an electromagnetic field (40.5 mT and 450 kHz). Our proposed device exhibits a novel operation mechanism for long-term therapeutic treat...

  8. Inhibition of human neutrophil elastase by pentacyclic triterpenes.

    Directory of Open Access Journals (Sweden)

    Li Feng

    Full Text Available Inhibiting human neutrophil elastase (HNE is a promising strategy for treating inflammatory lung diseases, such as H1N1 and SARS virus infections. The use of sivelestat, the only clinically registered synthesized HNE inhibitor, is largely limited by its risk of organ toxicity because it irreversibly inhibits HNE. Therefore, potent reversible HNE inhibitors are promising alternatives to sivelestat.An in vitro HNE inhibition assay was employed to screen a series of triterpenes. Six pentacyclic triterpenes, but not tetracyclic triterpenes, significantly inhibited HNE. Of these pentacyclic triterpenes, ursolic acid exhibited the highest inhibitory potency (IC50 = 5.51 µM. The HNE inhibitory activity of ursolic acid was further verified using a mouse model of acute smoke-induced lung inflammation. The results of nuclear magnetic resonance and HNE inhibition kinetic analysis showed that the pentacyclic triterpenes competitively and reversibly inhibited HNE. Molecular docking experiments indicated that the molecular scaffold, 28-COOH, and a double bond at an appropriate location in the pentacyclic triterpenes are important for their inhibitory activity.Our results provide insights into the effects of pentacyclic triterpenes on lung inflammatory actions through reversible inhibition of HNE activity.

  9. Response to delivery stress is not mediated by beta-endorphin (1-31).

    Science.gov (United States)

    Harbach, Heinz; Antrecht, Kerstin; Boedeker, Rolf-Hasso; Hempelmann, Gunter; Markart, Philipp; Matejec, Reginald; Muehling, Joerg; Welters, Ingeborg; Zygmunt, Marek

    2008-01-01

    The aim of the study was to determine the reaction of the melanotroph and corticotroph-type pituitary proopiomelanocortin (POMC) response to vaginal delivery and caesarean section stress. Furthermore, the relationship between the release of pituitary POMC fragments, gonadotropins and sexual steroids were examined. Blood samples were obtained from 10 women in labour on arrival in the birth room (t(A)), at cervix dilatation of 5 cm (t(B)) and immediately after spontaneous delivery (t(C)) and in 16 patients undergoing elective caesarean section before induction of anaesthesia (t(B)) and immediately after delivery (t(C)). Samples were analysed for cortisol, ACTH, authentic beta-endorphin, beta-endorphin immunoreactive material (IRM), acetyl-N-beta-endorphin IRM (NAC), beta-lipotropin (beta-LPH) IRM, oestradiol (E(2)), progesterone (P), prolactin (PRL), FSH and LH. NAC representing the melanotroph-type pituitary POMC system did not increase during the course of caesarean section or spontaneous labour. In contrast, a significant increase of beta-endorphin IRM, beta-LPH IRM and ACTH were observed, representing an activation of the corticotroph-type POMC system. Highly significant correlations between POMC fragment concentrations during caesarean section and spontaneous labour were also observed. Sexual steroids (E(2) and P) decreased significantly. Except for beta-endorphin IRM and E(2) in course of spontaneous delivery no significant correlation was observed between POMC fragment and gonadotropins or sexual steroids. Caesarean section and spontaneous delivery activated the corticotroph but not the melanotroph POMC system.

  10. Mesoporous silica nanoparticles for stimuli-responsive controlled drug delivery: advances, challenges, and outlook

    Directory of Open Access Journals (Sweden)

    Song Y

    2016-12-01

    Full Text Available Yuanhui Song, Yihong Li, Qien Xu, Zhe Liu Wenzhou Institute of Biomaterials and Engineering (WIBE, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China Abstract: With the development of nanotechnology, the application of nanomaterials in the field of drug delivery has attracted much attention in the past decades. Mesoporous silica nanoparticles as promising drug nanocarriers have become a new area of interest in recent years due to their unique properties and capabilities to efficiently entrap cargo molecules. This review describes the latest advances on the application of mesoporous silica nanoparticles in drug delivery. In particular, we focus on the stimuli-responsive controlled release systems that are able to respond to intracellular environmental changes, such as pH, ATP, GSH, enzyme, glucose, and H2O2. Moreover, drug delivery induced by exogenous stimuli including temperature, light, magnetic field, ultrasound, and electricity is also summarized. These advanced technologies demonstrate current challenges, and provide a bright future for precision diagnosis and treatment. Keywords: mesoporous silica nanoparticle, drug delivery system, controlled release, stimuli-responsive, chemotherapy

  11. Western blot evaluation of siRNA delivery by pH-responsive peptides.

    Science.gov (United States)

    Liang, Wanling; Mason, A James; Lam, Jenny K W

    2013-01-01

    Gene silencing, via RNA interference (RNAi) technologies using small interfering RNA (siRNA), has been developed as an important tool for target identification and validation in drug discovery and has huge therapeutic potential. However, effective delivery into cells presents a major challenge to the use of siRNA. pH-responsive cell-penetrating peptides have attracted considerable attention in recent years as delivery vectors due to their ability to transport their cargos across the biological membrane and/or to promote endosomal escape and prevent lysosomal degradation. To evaluate the in vitro transfection efficiency of the pH-responsive peptide-based siRNA delivery system, the western blotting technique is commonly employed. This method offers a simple, efficient and economical way to study the gene silencing effect of the siRNA by analysing the protein of interest in a sample with minimum equipment requirement. This chapter provides a description of siRNA delivery and analysis by western blotting protocols for qualitatively and quantitatively assessing gene silencing efficiency and selectivity.

  12. Murine abdominal aortic aneurysm model by orthotopic allograft transplantation of elastase-treated abdominal aorta.

    Science.gov (United States)

    Liu, Zhenjie; Wang, Qiwei; Ren, Jun; Assa, Carmel Rebecca; Morgan, Stephanie; Giles, Jasmine; Han, Qi; Liu, Bo

    2015-12-01

    Murine models have proved instrumental in studying various aspects of abdominal aortic aneurysm (AAA), from identification of underlying pathophysiologic changes to the development of novel therapeutic strategies. In the current study, we describe a new model in which an elastase-treated donor aorta is transplanted to a recipient mouse and allowed to progress to aneurysm. We hypothesized that by transplanting an elastase-treated abdominal aorta of one genotype to a recipient mouse of a different genotype, one can differentiate pathophysiologic factors that are intrinsic to the aortic wall from those stemming from circulation and other organs. Elastase-treated aorta was transplanted to the infrarenal abdominal aorta of recipient mice by end-to-side microsurgical anastomosis. Heat-inactivated elastase-treated aorta was used as a control. Syngeneic transplants were performed with use of 12-week-old C57BL/6 littermates. Transplant grafts were harvested from recipient mice on day 7 or day 14 after surgery. The aneurysm outcome was measured by aortic expansion, elastin degradation, proinflammatory cytokine expression, and inflammatory cell infiltration and compared with that produced with the established, conventional elastase infusion model. The surgical technique success rate was 75.6%, and the 14-day survival rate was 51.1%. By day 14 after surgery, all of the elastase-treated transplanted abdominal aortas had dilated and progressed to AAAs, defined as 100% or more increase in the maximal external diameter compared with that measured before elastase perfusion, whereas none of the transplanted aortas pretreated with inactive elastase became aneurysmal (percentage increase in maximum aortic diameter: 159.36% ± 23.27%, transplanted elastase, vs 41.46% ± 9.34%, transplanted inactive elastase). Aneurysm parameters, including elastin degradation and infiltration of macrophages and T lymphocytes, were found to be identical to those observed in the conventional elastase

  13. Degradation of elastic fiber and elevated elastase expression in long head of biceps tendinopathy.

    Science.gov (United States)

    Wu, Yen-Ting; Su, Wei-Ren; Wu, Po-Ting; Shen, Po-Chuan; Jou, I-Ming

    2017-09-01

    Tendinopathy of the long head of the biceps (TLHB) involves various types of extracellular matrix degeneration, but previous studies have not evaluated elastic fibers. The purpose of this study was to investigate elastic fiber distribution in long head of the biceps (LHB). The TLHB tendons of 16 consecutive patients (eight men and eight women; average age of 55.75 years; age range of 40-71 years) were transected and harvested. Three cadaveric LHB tendons were used as the control group. The expression of collagen type I was decreased, but type III was increased in TLHB. Disruption of elastic fibers was particularly observed in grade II specimens where the level of elastase-positive staining was significantly higher than in grade I specimens. Elastic fibers were not observed in the grade III area, implying a higher expression of elastase than in the grade I area. Results of Western blotting showed that the expression of elastin was higher in the control group and the levels of elastin significantly decreased in grades II and III of TLHB. Levels of osteopontin and elastase were increased in primary culture of human tenocytes after experiencing elastic derived peptide treatment. These results suggested that elastase may be caused by the disruption of elastic fibers in the development of chronic tendinopathy and that elastic derived peptide may enhance elastase and osteopontin expression. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1919-1926, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  14. Iron Oxide Nanoparticles for Magnetically-Guided and Magnetically-Responsive Drug Delivery

    Directory of Open Access Journals (Sweden)

    Joan Estelrich

    2015-04-01

    Full Text Available In this review, we discuss the recent advances in and problems with the use of magnetically-guided and magnetically-responsive nanoparticles in drug delivery and magnetofection. In magnetically-guided nanoparticles, a constant external magnetic field is used to transport magnetic nanoparticles loaded with drugs to a specific site within the body or to increase the transfection capacity. Magnetofection is the delivery of nucleic acids under the influence of a magnetic field acting on nucleic acid vectors that are associated with magnetic nanoparticles. In magnetically-responsive nanoparticles, magnetic nanoparticles are encapsulated or embedded in a larger colloidal structure that carries a drug. In this last case, an alternating magnetic field can modify the structure of the colloid, thereby providing spatial and temporal control over drug release.

  15. Nanoparticle-Stabilized Liposomes for pH-Responsive Gastric Drug Delivery

    OpenAIRE

    Thamphiwatana, Soracha; Fu, Victoria; Zhu, Jingying; Lu, Diannan; Gao, Weiwei; Zhang, Liangfang

    2013-01-01

    We report a novel pH-responsive gold nanoparticle-stabilized liposome system for gastric antimicrobial delivery. By adsorbing small chitosan-modified gold nanoparticles (diameter ~ 10 nm) onto the outer surface of negatively charged phospholipid liposomes (diameter ~ 75 nm), we show that at gastric pH the liposomes have excellent stability with limited fusion ability and negligible cargo releases. However when the stabilized liposomes are present in an environment with neutral pH, the gold st...

  16. Glucose-Responsive Insulin Delivery by Microneedle-Array Patches Loaded with Hypoxia-Sensitive Vesicles.

    Science.gov (United States)

    Yu, Jicheng; Zhang, Yuqi; Gu, Zhen

    2017-01-01

    In this chapter, we describe the preparation of glucose-responsive vesicles (GRVs) and the fabrication of GRV-loaded microneedle-array patches for insulin delivery. The GRVs were formed of hypoxia-sensitive hyaluronic acid (HS-HA), the synthesis of which is presented in detail. We also describe the procedure to evaluate the in vivo efficacy of this smart patch in a mouse model of chemically induced type 1 diabetes through transcutaneous administration.

  17. Stabilization of porcine pancreatic elastase crystals by glutaraldehyde cross-linking.

    Science.gov (United States)

    Hofbauer, Stefan; Brito, José A; Mulchande, Jalmira; Nogly, Przemyslaw; Pessanha, Miguel; Moreira, Rui; Archer, Margarida

    2015-10-01

    Elastase is a serine protease from the chymotrypsin family of enzymes with the ability to degrade elastin, an important component of connective tissues. Excessive elastin proteolysis leads to a number of pathological diseases. Porcine pancreatic elastase (PPE) is often used for drug development as a model for human leukocyte elastase (HLE), with which it shares high sequence identity. Crystals of PPE were grown overnight using sodium sulfate and sodium acetate at acidic pH. Cross-linking the crystals with glutaraldehyde was needed to resist the soaking procedure with a diethyl N-(methyl)pyridinyl-substituted oxo-β-lactam inhibitor. Crystals of PPE bound to the inhibitor belonged to the orthorhombic space group P2₁2₁2₁, with unit-cell parameters a = 51.0, b = 58.3, c = 74.9 Å, and diffracted to 1.8 Å resolution using an in-house X-ray source.

  18. Elastolytic activity of human blood monocytes characterized by a new monoclonal antibody against human leucocyte elastase. Relationship to rheumatoid arthritis

    DEFF Research Database (Denmark)

    Jensen, H S; Christensen, L D

    1990-01-01

    The leucocyte elastase of human blood monocytes was investigated by applying a new monoclonal antibody which did not block the enzyme activity against elastin. In a fixed population of mononuclear cells (MNC) and using fluorescence activated cell sorting (FACS), the human leucocyte elastase (HLE...

  19. Neutrophil elastase processing of Gelatinase A is mediated by extracellular matrix

    Energy Technology Data Exchange (ETDEWEB)

    Rice, A.; Banda, M.J. [Univ. of California, San Franciso, CA (United States)

    1995-07-18

    Gelatinase A (72-kDa type IV collagenase) is a metalloproteinase that is expressed by many cells in culture and is overexpressed by some tumor cells. It has been suggested that the serine proteinase neutrophil elastase might play a role iii the posttranslational processing of gelatinase A and that noncatalytic interactions between gelatinase A and components of the extracellular matrix might alter potential processing pathways. These questions were addressed with the use of gelatin substrate zymography, gelatinolytic activity assays, and amino acid sequence analysis. We found that neutrophil elastase does proteolytically modify gelatinase A by cleaving at a number of sites within gelatinase A. Sequential treatment of gelatinase A with 4-aminophenylmercuric acetate (APMA) and neutrophil elastase yielded an active gelatinase with a 4-fold increase in gelatinolytic activity. The increased gelatinolytic activity correlated with that of a 40-kDa fragment of gelatinase A. Matrix components altered the proteolytic modifications in gelatinase A that were mediated by neutrophil elastase. In the absence of gelatin, neutrophil elastase destructively degraded gelatinase A by hydrolyzing at least two bonds within the fibronectin-like gelatin-binding domain of gelatinase A. In the presence of gelatin, these two inactivating cleavage sites were protected, and cleavage at a site within the hemopexin-like carboxyl-terminal domain resulted in a truncated yet active gelatinase. The results suggest a regulatory role for extracellular matrix molecules in stabilizing gelatinase A fragments and in altering the availability of sites susceptible to destructive proteolysis by neutrophil elastase. 32 refs., 10 figs.

  20. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery.

    Science.gov (United States)

    Cheng, Ru; Meng, Fenghua; Deng, Chao; Klok, Harm-Anton; Zhong, Zhiyuan

    2013-05-01

    In the past decades, polymeric nanoparticles have emerged as a most promising and viable technology platform for targeted and controlled drug delivery. As vehicles, ideal nanoparticles are obliged to possess high drug loading levels, deliver drug to the specific pathological site and/or target cells without drug leakage on the way, while rapidly unload drug at the site of action. To this end, various "intelligent" polymeric nanoparticles that release drugs in response to an internal or external stimulus such as pH, redox, temperature, magnetic and light have been actively pursued. These stimuli-responsive nanoparticles have demonstrated, though to varying degrees, improved in vitro and/or in vivo drug release profiles. In an effort to further improve drug release performances, novel dual and multi-stimuli responsive polymeric nanoparticles that respond to a combination of two or more signals such as pH/temperature, pH/redox, pH/magnetic field, temperature/reduction, double pH, pH and diols, temperature/magnetic field, temperature/enzyme, temperature/pH/redox, temperature/pH/magnetic, pH/redox/magnetic, temperature/redox/guest molecules, and temperature/pH/guest molecules have recently been developed. Notably, these combined responses take place either simultaneously at the pathological site or in a sequential manner from nanoparticle preparation, nanoparticle transporting pathways, to cellular compartments. These dual and multi-stimuli responsive polymeric nanoparticles have shown unprecedented control over drug delivery and release leading to superior in vitro and/or in vivo anti-cancer efficacy. With programmed site-specific drug delivery feature, dual and multi-stimuli responsive nanoparticulate drug formulations have tremendous potential for targeted cancer therapy. In this review paper, we highlight the recent exciting developments in dual and multi-stimuli responsive polymeric nanoparticles for precision drug delivery applications, with a particular focus

  1. Classification of stimuli-responsive polymers as anticancer drug delivery systems.

    Science.gov (United States)

    Taghizadeh, Bita; Taranejoo, Shahrouz; Monemian, Seyed Ali; Salehi Moghaddam, Zoha; Daliri, Karim; Derakhshankhah, Hossein; Derakhshani, Zaynab

    2015-02-01

    Although several anticancer drugs have been introduced as chemotherapeutic agents, the effective treatment of cancer remains a challenge. Major limitations in the application of anticancer drugs include their nonspecificity, wide biodistribution, short half-life, low concentration in tumor tissue and systemic toxicity. Drug delivery to the tumor site has become feasible in recent years, and recent advances in the development of new drug delivery systems for controlled drug release in tumor tissues with reduced side effects show great promise. In this field, the use of biodegradable polymers as drug carriers has attracted the most attention. However, drug release is still difficult to control even when a polymeric drug carrier is used. The design of pharmaceutical polymers that respond to external stimuli (known as stimuli-responsive polymers) such as temperature, pH, electric or magnetic field, enzymes, ultrasound waves, etc. appears to be a successful approach. In these systems, drug release is triggered by different stimuli. The purpose of this review is to summarize different types of polymeric drug carriers and stimuli, in addition to the combination use of stimuli in order to achieve a better controlled drug release, and it discusses their potential strengths and applications. A survey of the recent literature on various stimuli-responsive drug delivery systems is also provided and perspectives on possible future developments in controlled drug release at tumor site have been discussed.

  2. The encapsulation and intracellular delivery of trehalose using a thermally responsive nanocapsule

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Wujie; He Xiaoming [Department of Mechanical Engineering, University of South Carolina, 300 Main Street, Columbia, SC 29208 (United States); Rong Jianhua; Wang Qian [Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, SC 29208 (United States)], E-mail: xmhe@sc.edu

    2009-07-08

    The thermally responsive wall permeability of an empty core-shell structured Pluronic nanocapsule (together with its temperature dependent size and surface charge) was successfully utilized for encapsulation, intracellular delivery, and controlled release of trehalose, a highly hydrophilic small (M{sub W} = 342 D) molecule (a disaccharide of glucose) that is exceptional for long-term stabilization of biologicals (particularly at ambient temperatures). It was found that trehalose can be physically encapsulated in the nanocapsule using a soaking-freeze-drying-heating procedure. The nanocapsule is capable of physically withholding trehalose with negligible release in hours for cellular uptake at 37 deg. C when its wall permeability is low. A quick release of the encapsulated sugar can be achieved by thermally cycling the nanocapsule between 37 and 22 deg. C (or lower). A significant amount of trehalose (up to 0.3 M) can be delivered into NIH 3T3 fibroblasts by incubating the cells with the trehalose-encapsulated nanocapsules at 37 deg. C for 40 min. Moreover, cytotoxicity of the nanocapsule for the purpose of intracellular delivery of trehalose was found to be negligible. Altogether, the thermally responsive nanocapsule is effective for intracellular delivery of trehalose, which is critical for the long-term stabilization of mammalian cells at ambient temperatures and the eventual success of modern cell-based medicine.

  3. Is neutrophil elastase the missing link between emphysema and fibrosis? Evidence from two mouse models

    Directory of Open Access Journals (Sweden)

    Martorana Piero A

    2005-07-01

    Full Text Available Abstract Background The separation of emphysema from fibrosis is not as clear-cut as it was thought in early studies. These two pathologies may be present at the same time in human lungs and in mice either instilled with elastolytic enzymes or bleomycin or exposed to cigarette-smoke. According to a current view, emphysema originates from a protease/antiprotease imbalance, and a role for antiproteases has also been suggested in the modulation of the fibrotic process. In this study we investigate in experimental animal models of emphysema and fibrosis whether neutrophil elastase may constitute a pathogenic link between these two pathologies. Methods This study was done in two animal models in which emphysema and fibrosis were induced either by bleomycin (BLM or by chronic exposure to cigarette-smoke. In order to assess the protease-dependence of the BLM-induced lesion, a group mice was treated with 4-(2-aminoethyl-benzenesulfonyl fluoride hydrochloride, a serine proteinase inhibitor active toward neutrophil elastase. Lungs from each experimental group were used for the immunohistochemical assessment of transforming growth factor-β (TGF-β and transforming growth factor-α (TGF-α and for determination of the mean linear intercept as well as the percent volume densities of fibrosis and of emphysematous changes. Additionally, the lungs were also assessed for desmosine content and for the determination of elastase levels in the pulmonary interstitium by means of immunoelectron microscopy. Results We demonstrate that in BLM-treated mice (i the development of elastolytic emphysema precedes that of fibrosis; (ii significant amount of elastase in alveolar interstitium is associated with an increased expression of TGF-β and TGF-α; and finally, (iii emphysematous and fibrotic lesions can be significantly attenuated by using a protease inhibitor active against neutrophil elastase. Also, in a strain of mice that develop both emphysema and fibrosis after

  4. Systemic Inflammatory Response to Malaria During Pregnancy Is Associated With Pregnancy Loss and Preterm Delivery.

    Science.gov (United States)

    Fried, Michal; Kurtis, Jonathan D; Swihart, Bruce; Pond-Tor, Sunthorn; Barry, Amadou; Sidibe, Youssoufa; Gaoussou, Santara; Traore, Moussa; Keita, Sekouba; Mahamar, Almahamoudou; Attaher, Oumar; Dembele, Adama B; Cisse, Kadidia B; Diarra, Bacary S; Kanoute, Moussa B; Dicko, Alassane; Duffy, Patrick E

    2017-10-30

    Pregnancy malaria (PM) is associated with a proinflammatory immune response characterized by increased levels of cytokines and chemokines such as tumor necrosis factor-α, interferon-γ, interleukin 10 (IL-10), and CXCL9. These changes are associated with poor outcomes including low birthweight delivery and maternal anemia. However, it is unknown if inflammatory pathways during malaria are related to pregnancy loss and preterm delivery (PTD). Cytokine and chemokine levels were measured in maternal peripheral blood at enrollment, gestational week 30-32, and delivery, and in placental blood, of 638 women during a longitudinal cohort study in Ouelessebougou, Mali. Plasmodium falciparum infection was assessed by blood smear microscopy at all visits. PM was associated with increased levels of cytokines and chemokines including IL-10 and CXCL9. In a competing risks model adjusted for known covariates, high CXCL9 levels measured in the peripheral blood during pregnancy were associated with increased risk of pregnancy loss and PTD. At delivery, high IL-10 levels in maternal blood were associated with an increase in pregnancy loss, and increased IL-1β levels in placental blood were associated with pregnancy loss and PTD. PM is associated with increased proinflammatory cytokine and chemokine levels in placental and maternal peripheral blood. Systemic inflammatory responses to malaria during pregnancy predict increased risk of pregnancy loss and PTD. NCT01168271. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  5. Glutathione-responsive core cross-linked micelles for controlled cabazitaxel delivery

    Science.gov (United States)

    Han, Xiaoxiong; Gong, Feirong; Sun, Jing; Li, Yueqi; Liu, XiaoFei; Chen, Dan; Liu, Jianwen; Shen, Yaling

    2018-02-01

    Stimulus-responsive polymeric micelles (PMs) have recently received attention due to the controlled delivery of drug or gene for application in cancer diagnosis and treatment. In this work, novel glutathione-responsive PMs were prepared to encapsulate hydrophobic antineoplastic drug, cabazitaxel (CTX), to improve its solubility and toxicity. These CTX-loaded micelles core cross-linked by disulfide bonds (DCL-CTX micelles) were prepared by a novel copolymer, lipoic acid grafted mPEG-PLA. These micelles had regular spherical shape, homogeneous diameter of 18.97 ± 0.23 nm, and a narrow size distribution. The DCL-CTX micelles showed high encapsulation efficiency of 98.65 ± 1.77%, and the aqueous solubility of CTX was improved by a factor of 1:1200. In vitro release investigation showed that DCL-CTX micelles were stable in the medium without glutathione (GSH), whereas the micelles had burst CTX release in the medium with 10 mM GSH. Cell uptake results implied that DCL-CTX micelles were internalized into MCF-7 cells through clathrin-mediated endocytosis and released cargo more effectively than Jevtana (commercially available CTX) owing to GSH-stimulated degradation. In MTT assay against MCF-7 cells, these micelles inhibited tumor cell proliferation more effectively than Jevtana due to their GSH-responsive CTX release. All results revealed the potency of GSH-responsive DCL-CTX micelles for stable delivery in blood circulation and for intracellular GSH-trigged release of CTX. Therefore, DCL-CTX micelles show potential as safe and effective CTX delivery carriers and as a cancer chemotherapy formulation.

  6. pH-responsive biocompatible fluorescent polymer nanoparticles based on phenylboronic acid for intracellular imaging and drug delivery

    Science.gov (United States)

    Li, Shengliang; Hu, Kelei; Cao, Weipeng; Sun, Yun; Sheng, Wang; Li, Feng; Wu, Yan; Liang, Xing-Jie

    2014-10-01

    To address current medical challenges, there is an urgent need to develop drug delivery systems with multiple functions, such as simultaneous stimuli-responsive drug release and real-time imaging. Biocompatible polymers have great potential for constructing smart multifunctional drug-delivery systems through grafting with other functional ligands. More importantly, novel biocompatible polymers with intrinsic fluorescence emission can work as theranostic nanomedicines for real-time imaging and drug delivery. Herein, we developed a highly fluorescent nanoparticle based on a phenylboronic acid-modified poly(lactic acid)-poly(ethyleneimine)(PLA-PEI) copolymer loaded with doxorubicin (Dox) for intracellular imaging and pH-responsive drug delivery. The nanoparticles exhibited superior fluorescence properties, such as fluorescence stability, no blinking and excitation-dependent fluorescence behavior. The Dox-loaded fluorescent nanoparticles showed pH-responsive drug release and were more effective in suppressing the proliferation of MCF-7 cells. In addition, the biocompatible fluorescent nanoparticles could be used as a tool for intracellular imaging and drug delivery, and the process of endosomal escape was traced by real-time imaging. These pH-responsive and biocompatible fluorescent polymer nanoparticles, based on phenylboronic acid, are promising tools for intracellular imaging and drug delivery.To address current medical challenges, there is an urgent need to develop drug delivery systems with multiple functions, such as simultaneous stimuli-responsive drug release and real-time imaging. Biocompatible polymers have great potential for constructing smart multifunctional drug-delivery systems through grafting with other functional ligands. More importantly, novel biocompatible polymers with intrinsic fluorescence emission can work as theranostic nanomedicines for real-time imaging and drug delivery. Herein, we developed a highly fluorescent nanoparticle based on a

  7. Immune response to functionalized mesoporous silica nanoparticles for targeted drug delivery.

    Science.gov (United States)

    Heidegger, Simon; Gössl, Dorothée; Schmidt, Alexandra; Niedermayer, Stefan; Argyo, Christian; Endres, Stefan; Bein, Thomas; Bourquin, Carole

    2016-01-14

    Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized antigen-presenting cells such as dendritic cells. The silica nanoparticles showed a favorable toxicity profile and did not affect the viability of primary immune cells from the spleen in relevant concentrations. Cargo-free MSN induced only very low immune responses in primary cells as determined by surface expression of activation markers and release of pro-inflammatory cytokines such as Interleukin-6, -12 and -1β. In contrast, when surface-functionalized MSN with a pH-responsive polymer capping were loaded with an immune-activating drug, the synthetic Toll-like receptor 7 agonist R848, a strong immune response was provoked. We thus demonstrate that MSN represent an efficient drug delivery vehicle to primary immune cells that is both non-toxic and non-inflammagenic, which is a prerequisite for the use of these particles in biomedical applications.

  8. An interfacially plasticized electro-responsive hydrogel for transdermal electro-activated and modulated (TEAM) drug delivery

    NARCIS (Netherlands)

    Indermun, Sunaina; Choonara, Yahya E.; Kumar, Pradeep; du Toit, Lisa C.; Modi, Girish; Lüttge, Regina; Pillay, Viness

    2014-01-01

    This paper highlights the use of hydrogels in controlled drug delivery, and their application in stimuli responsive, especially electro-responsive, drug release. electro-conductive hydrogels (ECHs) displaying electro-responsive drug release were synthesized from semi-interpenetrating networks

  9. Effect of elastase and ventilation on elastic recoil of excised dog lungs.

    Science.gov (United States)

    Polzin, J K; Napier, J S; Taylor, J C; Rodarte, J R

    1979-03-01

    The effect of porcine pancreatic elastase and mechanical ventilation on tissue elastic recoil was examined in excised dog lung lobes. Lobes incubated for one hour with an elastase-buffer mixture showed a significant (P less than 0.001) left shift of the liquid-filled pressure-volume curve at all pressures measured (0 to 12 cm H2O) when compared to lobes treated with buffer only. These results suggest that the contribution of elastin to the elastic properties of lung tissue is greatest at mid-lung volumes, but that it also contributes to delimiting maximal lung volume. Elastase and buff-treated lobes were inflated cyclically with humidified air to a pressure of 20 cm H2O 6 times per min during a 16-hour period. This mechanical ventilation caused no further decrease of tissue elastic recoil. Ventilation did cause an unexpected increase in the elastic recoil of liquid-filled lobes that was significant at pressures of 4 cm H2O (P less than 0.025) or more (P less than 0.001). Elastase and buffer-treated lobes showed an almost identical rightward shift of the pressure-volume curve after ventilation when compared to the respective nonventilated control lobes. This increased recoil cannot be attributed to altered surface tension.

  10. In Vitro Activities against Cystic Fibrosis Pathogens of Synthetic Host Defence Propeptides Processed by Neutrophil Elastase.

    LENUS (Irish Health Repository)

    Desgranges, Stephane

    2011-02-22

    The antimicrobial and haemolytic activities of a host defence peptide can be controlled by modification as a propeptide of reduced net charge which can be processed by neutrophil elastase, a serine protease involved in chronic airway inflammation and infections associated with cystic fibrosis.

  11. Serological assessment of neutrophil elastase activity on elastin during lung ECM remodeling

    DEFF Research Database (Denmark)

    Kristensen, Jacob Hull; Karsdal, Morten A.; Sand, Jannie M. B.

    2015-01-01

    Background: During the pathological destruction of lung tissue, neutrophil elastase (NE) degrades elastin, one of the major constituents of lung parenchyma. However there are no non-invasive methods to quantify NE degradation of elastin. We selected specific elastin fragments generated by NE for ...

  12. Galactose-functionalized multi-responsive nanogels for hepatoma-targeted drug delivery

    Science.gov (United States)

    Lou, Shaofeng; Gao, Shan; Wang, Weiwei; Zhang, Mingming; Zhang, Ju; Wang, Chun; Li, Chen; Kong, Deling; Zhao, Qiang

    2015-02-01

    We report here a hepatoma-targeting multi-responsive biodegradable crosslinked nanogel, poly(6-O-vinyladipoyl-d-galactose-ss-N-vinylcaprolactam-ss-methacrylic acid) P(ODGal-VCL-MAA), using a combination of enzymatic transesterification and emulsion copolymerization for intracellular drug delivery. The nanogel exhibited redox, pH and temperature-responsive properties, which can be adjusted by varying the monomer feeding ratio. Furthermore, the volume phase transition temperature (VPTT) of the nanogels was close to body temperature and can result in rapid thermal gelation at 37 °C. Scanning electron microscopy also revealed that the P(ODGal-VCL-MAA) nanogel showed uniform spherical monodispersion. With pyrene as a probe, the fluorescence excitation spectra demonstrated nanogel degradation in response to glutathione (GSH). X-ray diffraction (XRD) showed an amorphous property of DOX within the nanogel, which was used in this study as a model anti-cancer drug. Drug-releasing characteristics of the nanogel were examined in vitro. The results showed multi-responsiveness of DOX release by the variation of environmental pH values, temperature or the availability of GSH, a biological reductase. An in vitro cytotoxicity assay showed a higher anti-tumor activity of the galactose-functionalized DOX-loaded nanogels against human hepatoma HepG2 cells, which was, at least in part, due to specific binding between the galactose segments and the asialoglycoprotein receptors (ASGP-Rs) in hepatic cells. Confocal laser scanning microscopy (CLSM) and flow cytometric profiles further confirmed elevated cellular uptake of DOX by the galactose-functionalised nanogels. Thus, we report here a multi-responsive P(ODGal-VCL-MAA) nanogel with a hepatoma-specific targeting ability for anti-cancer drug delivery.We report here a hepatoma-targeting multi-responsive biodegradable crosslinked nanogel, poly(6-O-vinyladipoyl-d-galactose-ss-N-vinylcaprolactam-ss-methacrylic acid) P(ODGal-VCL-MAA), using

  13. Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity.

    Science.gov (United States)

    Kurtagic, Elma; Jedrychowski, Mark P; Nugent, Matthew A

    2009-03-01

    Excessive neutrophil elastase (NE) activity and altered vascular endothelial growth factor (VEGF) signaling have independently been implicated in the development and progression of pulmonary emphysema. In the present study, we investigated the potential link between NE and VEGF. We noted that VEGF(165) is a substrate for NE. Digestion of purified VEGF(165) with NE generated a partially degraded disulfide-linked fragment of VEGF. Mass spectrometric analysis revealed that NE likely cleaves VEGF(165) at both the NH(2) and COOH termini to produce VEGF fragment chains approximately 5 kDa reduced in size. NE treatment of VEGF-laden endothelial cell cultures and smooth muscle cells endogenously expressing VEGF generated VEGF fragments similar to those observed with purified VEGF(165). NE-generated VEGF fragment showed significantly reduced binding to VEGF receptor 2 and heparin yet retained the ability to bind to VEGF receptor 1. Interestingly, VEGF fragment showed altered signaling in pulmonary artery endothelial cells compared with intact VEGF(165). Specifically, treatment with VEGF fragment did not activate extracellular-regulated kinases 1 and 2 (ERK1/2), yet resulted in enhanced activation of protein kinase B (Akt). Treatment of monocyte/macrophage RAW 264.7 cells with VEGF fragment, on the other hand, led to both Akt and ERK1/2 activation, increased VEGFR1 expression, and stimulated chemotaxis. These findings suggest that the tissue response to NE-mediated injury might involve the generation of diffusible VEGF fragments that stimulate inflammatory cell recruitment and activation via VEGF receptor 1.

  14. Tailoring stimuli-responsive delivery system driven by metal–ligand coordination bonding

    Directory of Open Access Journals (Sweden)

    Liang H

    2017-04-01

    Full Text Available Hongshan Liang,1–3 Bin Zhou,4 Yun He,1–3 Yaqiong Pei,1–3 Bin Li,1–3 Jing Li1–31College of Food Science and Technology, Huazhong Agricultural University, 2Key Laboratory of Environment Correlative Dietology, Huazhong Agricultural University, Ministry of Education, 3Functional Food Engineering & Technology Research Center of Hubei Province, Wuhan, Hubei, 4College of Food Science and Technology, Shanghai Ocean University, LinGang New City, Shanghai, People’s Republic of ChinaAbstract: In this study, a novel coordination bonding system based on metal–tannic acid (TA architecture on zein/carboxymethyl chitosan (CMCS nanoparticles (NPs was investigated for the pH-responsive drug delivery. CMCS has been reported to coat on zein NPs as delivery vehicles for drugs or nutrients in previous studies. The cleavage of either the “metal–TA” or “NH2–metal” coordination bonds resulted in significant release of guest molecules with high stimulus sensitivity, especially in mild acidic conditions. The prepared metal–TA-coated zein/CMCS NPs (zein/CMCS-TA/metal NPs could maintain particle size in cell culture medium at 37°C, demonstrating good stability compared with zein/CMCS NPs. In vitro release behavior of doxorubicin hydrochloride (DOX-loaded metal–TA film-coated zein/CMCS NPs (DOX-zein/CMCS-TA/metal NPs showed fine pH responsiveness tailored by the ratio of zein to CMCS as well as the metal species and feeding concentrations. The blank zein/CMCS-TA/metal NPs (NPs-TA/metal were of low cytotoxicity, while a high cytotoxic activity of DOX-zein/CMCS-TA/metal NPs (DOX-NPs-TA/metal against HepG2 cells was demonstrated by in vitro cell assay. Confocal laser scanning microscopy (CLSM and flow cytometry were combined to study the uptake efficiency of DOX-NPs or DOX-NPs-TA/metal. This system showed significant potential as a highly versatile and potent platform for drug delivery. Keywords: coordination bonding, pH-responsive, high stimulus

  15. Intranasal delivery of cholera toxin induces th17-dominated T-cell response to bystander antigens.

    Directory of Open Access Journals (Sweden)

    Jee-Boong Lee

    Full Text Available Cholera toxin (CT is a potent vaccine adjuvant, which promotes mucosal immunity to protein antigen given by nasal route. It has been suggested that CT promotes T helper type 2 (Th2 response and suppresses Th1 response. We here report the induction of Th17-dominated responses in mice by intranasal delivery of CT. This dramatic Th17-driving effect of CT, which was dependent on the B subunit, was observed even in Th1 or Th2-favored conditions of respiratory virus infection. These dominating Th17 responses resulted in the significant neutrophil accumulation in the lungs of mice given CT. Both in vitro and in vivo treatment of CT induced strongly augmented IL-6 production, and Th17-driving ability of CT was completely abolished in IL-6 knockout mice, indicating a role of this cytokine in the Th17-dominated T-cell responses by CT. These data demonstrate a novel Th17-driving activity of CT, and help understand the mechanisms of CT adjuvanticity to demarcate T helper responses.

  16. ROS-Responsive Polyprodrug Nanoparticles for Triggered Drug Delivery and Effective Cancer Therapy.

    Science.gov (United States)

    Xu, Xiaoding; Saw, Phei Er; Tao, Wei; Li, Yujing; Ji, Xiaoyuan; Bhasin, Sushant; Liu, Yanlan; Ayyash, Dana; Rasmussen, Jonathan; Huo, Marc; Shi, Jinjun; Farokhzad, Omid C

    2017-09-01

    The application of nanoparticles (NPs) to drug delivery has led to the development of novel nanotherapeutics for the treatment of various diseases including cancer. However, clinical use of NP-mediated drug delivery has not always translated into improved survival of cancer patients, in part due to the suboptimal properties of NP platforms, such as premature drug leakage during preparation, storage, or blood circulation, lack of active targeting to tumor tissue and cells, and poor tissue penetration. Herein, an innovative reactive oxygen species (ROS)-responsive polyprodrug is reported that can self-assemble into stable NPs with high drug loading. This new NP platform is composed of the following key components: (i) polyprodrug inner core that can respond to ROS for triggered release of intact therapeutic molecules, (ii) polyethylene glycol (PEG) outer shell to prolong blood circulation; and (iii) surface-encoded internalizing RGD (iRGD) to enhance tumor targeting and tissue penetration. These targeted ROS-responsive polyprodrug NPs show significant inhibition of tumor cell growth both in vitro and in vivo. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Nanoparticle-stabilized liposomes for pH-responsive gastric drug delivery.

    Science.gov (United States)

    Thamphiwatana, Soracha; Fu, Victoria; Zhu, Jingying; Lu, Diannan; Gao, Weiwei; Zhang, Liangfang

    2013-10-01

    We report a novel pH-responsive gold nanoparticle-stabilized liposome system for gastric antimicrobial delivery. By adsorbing small chitosan-modified gold nanoparticles (diameter ~10 nm) onto the outer surface of negatively charged phospholipid liposomes (diameter ~75 nm), we show that at gastric pH the liposomes have excellent stability with limited fusion ability and negligible cargo releases. However, when the stabilized liposomes are present in an environment with neutral pH, the gold stabilizers detach from the liposomes, resulting in free liposomes that can actively fuse with bacterial membranes. Using Helicobacter pylori as a model bacterium and doxycycline as a model antibiotic, we demonstrate such pH-responsive fusion activity and drug release profile of the nanoparticle-stabilized liposomes. Particularly, at neutral pH the gold nanoparticles detach, and thus the doxycycline-loaded liposomes rapidly fuse with bacteria and cause superior bactericidal efficacy as compared to the free doxycycline counterpart. Our results suggest that the reported liposome system holds a substantial potential for gastric drug delivery; it remains inactive (stable) in the stomach lumen but actively interacts with bacteria once it reaches the mucus layer of the stomach where the bacteria may reside.

  18. Adopting Continuous Delivery and Deployment: Impacts on Team Structures, Collaboration and Responsibilities

    DEFF Research Database (Denmark)

    Shahin, Mojtaba; Zahedi, Mansooreh; Babar, Muhammad Ali

    2017-01-01

    Context: Continuous Delivery and Deployment (CD) practices aim to deliver software features more frequently and reliably. While some efforts have been made to study different aspects of CD practices, a little empirical work has been reported on the impact of CD on team structures, collaboration...... and team members’ responsibilities. Goal: Our goal is to empirically investigate how Development (Dev) and Operations (Ops) teams are organized in software industry for adopting CD practices. Furthermore, we explore the potential impact of practicing CD on collaboration and team members’ responsibilities....... Method: We conducted a mixed-method empirical study, which collected data from 21 in- depth, semi-structured interviews in 19 organizations and a survey with 93 software practitioners. Results: There are four common types of team structures (i.e., (1) separate Dev and Ops teams with higher collaboration...

  19. PLGA nanoparticle-mediated delivery of tumor antigenic peptides elicits effective immune responses

    Directory of Open Access Journals (Sweden)

    Ma W

    2012-03-01

    Full Text Available Wenxue Ma1, Mingshui Chen1, Sharmeela Kaushal1,2, Michele McElroy1,2, Yu Zhang3, Cengiz Ozkan3, Michael Bouvet1,2, Carol Kruse4, Douglas Grotjahn5, Thomas Ichim6, Boris Minev1,7,81Moores Cancer Center, University of California San Diego, 2Department of Surgery, University of California San Diego, 3Laboratory of Biomaterials and Nanotechnology, University of California Riverside, 4UCLA Division of Neurosurgery, Los Angeles, 5Chemistry Department, San Diego State University, San Diego, 6MediStem Inc. San Diego, 7UCSD Division of Neurosurgery, San Diego, 8Genelux Corporation, San Diego, CA, USA Abstract: The peptide vaccine clinical trials encountered limited success because of difficulties associated with stability and delivery, resulting in inefficient antigen presentation and low response rates in patients with cancer. The purpose of this study was to develop a novel delivery approach for tumor antigenic peptides in order to elicit enhanced immune responses using poly(DL-lactide-co-glycolide nanoparticles (PLGA-NPs encapsulating tumor antigenic peptides. PLGA-NPs were made using the double emulsion-solvent evaporation method. Artificial antigen-presenting cells were generated by human dendritic cells (DCs loaded with PLGA-NPs encapsulating tumor antigenic peptide(s. The efficiency of the antigen presentation was measured by interferon-γ ELISpot assay (Vector Laboratories, Burlingame, CA. Antigen-specific cytotoxic T lymphocytes (CTLs were generated and evaluated by CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Fitchburg, WI. The efficiency of the peptide delivery was compared between the methods of emulsification in incomplete Freund’s adjuvant and encapsulation in PLGA-NPs. Our results showed that most of the PLGA-NPs were from 150 nm to 500 nm in diameter, and were negatively charged at pH 7.4 with a mean zeta potential of -15.53 ± 0.71 mV; the PLGA-NPs could be colocalized in human DCs in 30 minutes of incubation. Human DCs

  20. Dual-responsive polymer coated superparamagnetic nanoparticle for targeted drug delivery and hyperthermia treatment.

    Science.gov (United States)

    Patra, Santanu; Roy, Ekta; Karfa, Paramita; Kumar, Sunil; Madhuri, Rashmi; Sharma, Prashant K

    2015-05-06

    In this work, we have prepared water-soluble superparamgnetic iron oxide nanoparticles (SPIONs) coated with a dual responsive polymer for targeted delivery of anticancer hydrophobic drug (curcumin) and hyperthermia treatment. Herein, superparamagnetic mixed spinel (MnFe2O4) was used as a core material (15-20 nm) and modified with carboxymethyl cellulose (water-soluble component), folic acid (tagging agent), and dual responsive polymer (poly-N isopropylacrylamide-co-poly glutamic acid) by microwave radiation. Lower critical solution temperature (LCST) of the thermoresponsive copolymer was observed to be around 40 °C, which is appropriate for drug delivery. The polymer-SPIONs show high drug loading capacity (89%) with efficient and fast drug release at the desired pH (5.5) and temperature (40 °C) conditions. Along with this, the SPIONs show a very fast increase in temperature (45 °C in 2 min) when interacting with an external magnetic field, which is an effective and appropriate temperature for the localized hyperthermia treatment of cancer cells. The cytocompatibility of the curcumin loaded SPIONs was studied by the methyl thiazol tetrazolium bromide (MTT) assay, and cells were imaged by fluorescence microscopy. To explore the targeting behavior of curcumin loaded SPIONs, a simple magnetic capturing system (simulating a blood vessel) was constructed and it was found that ∼99% of the nanoparticle accumulated around the magnet in 2 min by traveling a distance of 30 cm. Along with this, to explore an entirely different aspect of the responsive polymer, its antibacterial activity toward an E. coli strain was also studied. It was found that responsive polymer is not harmful for normal or cancer cells but shows a good antibacterial property.

  1. Epithelial-to-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma and Pancreatic Tumor Cell Lines: The Role of Neutrophils and Neutrophil-Derived Elastase

    Directory of Open Access Journals (Sweden)

    Thomas Große-Steffen

    2012-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN and the tumor cell transition, biopsies of patients with PDAC (n=115 were analysed with regard to PMN infiltration and nuclear expression of β-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation of β-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated, β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMT in vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and—by implication—to tumor progression is possible.

  2. Revisiting structure-property relationship of pH-responsive polymers for drug delivery applications.

    Science.gov (United States)

    Bazban-Shotorbani, Salime; Hasani-Sadrabadi, Mohammad Mahdi; Karkhaneh, Akbar; Serpooshan, Vahid; Jacob, Karl I; Moshaverinia, Alireza; Mahmoudi, Morteza

    2017-05-10

    pH-responsive polymers contain ionic functional groups as pendants in their structure. The total number of charged groups on polymer chains determines the overall response of the system to changes in the external pH. This article reviews various pH-responsive polymers classified as polyacids (e.g., carboxylic acid based polymers, sulfonamides, anionic polysaccharides, and anionic polypeptides) and polybases (e.g., polyamines, pyridine and imidazole containing polymers, cationic polysaccharides, and cationic polypeptides). We correlate the pH variations in the body at the organ level (e.g., gastrointestinal tract and vaginal environment), tissue level (e.g., cancerous and inflamed tissues), and cellular level (e.g., sub-cellular organelles), with the intrinsic properties of pH-responsive polymers. This knowledge could help to select more effective ('smart') polymeric systems based on the biological target. Considering the pH differences in the body, various drug delivery systems can be designed by utilizing smart biopolymeric compounds with the required pH-sensitivity. We also review the pharmaceutical application of pH-responsive polymeric carriers including hydrogels, polymer-drug conjugates, micelles, dendrimers, and polymersomes. © 2016.

  3. Electrostatic wrapping of doxorubicin with curdlan to construct an efficient pH-responsive drug delivery system

    Science.gov (United States)

    Zhou, Jiang-Ling; Song, Fei; Tian, Jia-Feng; Nie, Wu-Cheng; Wang, Xiu-Li; Wang, Yu-Zhong

    2017-07-01

    The development of environmentally responsive drug delivery systems for the treatment of cancer has attracted particular interest in recent years. However, the enhancement of drug loading capacity and realization of pH-responsive drug delivery remain challenging. Herein, we employ carboxymethyl curdlan as a hydrophilic carrier to wrap doxorubicin (DOX) directly via electrostatic interaction. The sizes of the formed nanoparticles can be simply tuned by changing their feeding ratios. In particular, the nanoparticles are highly stable in aqueous solution without size variation. In vitro drug release and cytotoxicity assays illustrate that this delivery system can release DOX differentially under various environmental conditions and transport it into cell nuclei efficiently, with comparable therapeutic effect to the free drug. These results suggest that the carrying of antitumor drugs by polysaccharide via electrostatic interaction is a simple but effective way to construct a pH-dependent drug delivery platform.

  4. Immune response to functionalized mesoporous silica nanoparticles for targeted drug delivery

    Science.gov (United States)

    Heidegger, Simon; Gößl, Dorothée; Schmidt, Alexandra; Niedermayer, Stefan; Argyo, Christian; Endres, Stefan; Bein, Thomas; Bourquin, Carole

    2015-12-01

    Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized antigen-presenting cells such as dendritic cells. The silica nanoparticles showed a favorable toxicity profile and did not affect the viability of primary immune cells from the spleen in relevant concentrations. Cargo-free MSN induced only very low immune responses in primary cells as determined by surface expression of activation markers and release of pro-inflammatory cytokines such as Interleukin-6, -12 and -1β. In contrast, when surface-functionalized MSN with a pH-responsive polymer capping were loaded with an immune-activating drug, the synthetic Toll-like receptor 7 agonist R848, a strong immune response was provoked. We thus demonstrate that MSN represent an efficient drug delivery vehicle to primary immune cells that is both non-toxic and non-inflammagenic, which is a prerequisite for the use of these particles in biomedical applications.Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized

  5. Acidity-responsive gene delivery for "superfast" nuclear translocation and transfection with high efficiency.

    Science.gov (United States)

    Zhu, Jing-Yi; Zeng, Xuan; Qin, Si-Yong; Wan, Shuang-Shuang; Jia, Hui-Zhen; Zhuo, Ren-Xi; Feng, Jun; Zhang, Xian-Zheng

    2016-03-01

    In principle, not only efficient but rapid transfection is required since it can maximize the bioavailability of vector-carried gene prior to the cellular excretion. However, the "rapid" goal has been paid few attentions so far in the research field of vector-aided transfection. As a pioneering attempt, the present study designed a lysosome-targeting acidity-responsive nanoassembly as gene vectors, which proved the amazing potency to mediate the "Superfast" transnuclear gene transport and gene transfection with high efficiency in vitro and in vivo. The nanoassembly was constructed on the pH-reversible covalent boronic acid-diol coupling between 1,3-diol-rich oligoethylenimine (OEI-EHDO) and phenylboronic acid modified cholesterol (Chol-PBA). The rapid and efficient nuclei-tropic delivery and transfection was demonstrated to highly rely on the lysosome-acidity induced assembly destruction followed by the easy liberation of gene payloads inside cells. The nanoassembly-mediated transfection at 8 h can afford the outcome even comparable to that achieved at 48 h by the golden standard of PEI25k, and the transfection efficiency can still remain at a high level during 48 h. In contrast, time-dependent efficiency enhancement was identified for the transfections using PEI25k and OEI-EHDO as delivery vectors. Moreover, owing to the hydroxyl-rich surface, this delivery nanosystem presented strong tolerance to the serum-induced transfection inhibition that frequently occurred for the polycationic gene vectors such as PEI25k. The in vitro and in vivo results manifested the low toxicity of this bio-decomposable nanoassembly. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Magnetic responsive of paclitaxel delivery system based on SPION and palmitoyl chitosan

    Energy Technology Data Exchange (ETDEWEB)

    Mansouri, Mona [Department of Biomedical Engineering, Amirkabir University of Technology, P.O. Box: 15875/4413, Tehran 159163/4311 (Iran, Islamic Republic of); Nazarpak, Masoumeh Haghbin, E-mail: haghbin@aut.ac.ir [New Technologies Research Center (NTRC), Amirkabir University of Technology, Tehran 15875-4413 (Iran, Islamic Republic of); Solouk, Atefeh [Department of Biomedical Engineering, Amirkabir University of Technology, P.O. Box: 15875/4413, Tehran 159163/4311 (Iran, Islamic Republic of); Akbari, Somaye [Department of Textile Engineering, Amirkabir University of Technology, P.O. Box: 15875/4413, Tehran 15916/34311 (Iran, Islamic Republic of); Hasani-Sadrabadi, Mohammad Mahdi [Parker H. Petit Institute for Bioengineering and Bioscience, G. W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332-0295 (United States)

    2017-01-01

    Concerns over cancer treatment have largely focused on chemotherapy and its consequent side effects. Utilizing nanocarriers is thought to be a panacea for mitigating the limitations of chemotherapy, and increasing its safety and efficacy. Magnetically driven Paclitaxel delivery systems are among the commonly investigated types of nanocarriers over the last two decades. In this context, we tried to highlight the application of an AC magnetic field and validate its consequential effects on drug delivery pattern and cell death in such nanodevices. So the aim of this study is to develop an appropriate matrix (Palmitoyl chitosan) co-encapsulated with superparamagnetic iron oxide nanoparticles (SPIONs) and anticancer drug, Paclitaxel (PTX) via the nanoprecipitation process. Synthesized nanoparticles were characterized by Dynamic Light Scattering (DLS) and their magnetic properties were investigated by Vibrating Sample Magnetometer (VSM). At initial loading of 10 wt% Paclitaxel, the maximum loading efficiency of nanoparticles with and without SPIONs was in the range of 69% and 72.3%, respectively. In addition, in vitro release data revealed that by the application of a magnetic field, release kinetic changed to the magnetic responsive pattern. Encapsulating anticancer drug in a synthesized nanosystem not only increased the amount of drug in cancer cells but also enhanced cell death (MCF-7) due to hyperthermic effects of SPIONs in the presence of an external magnetic field. In summary, these findings indicate that the resultant nanoparticles may serve as a biocompatible and biodegradable carrier for the precise delivery of powerful cytotoxic anticancer agents such as PTX. - Highlights: ●This paper focuses on using an AC magnetic field to enhance the drug entry and to increase its concentration in the cell. ●The rate of drug release is highly dependent on the amount of available pores for transporting molecules.

  7. Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater

    International Nuclear Information System (INIS)

    Yun, Jumi; Lee, Dae Hoon; Im, Ji Sun; Kim, Hyung-Il

    2012-01-01

    Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater. - Graphical abstract: The high-performance transdermal drug delivery system could be prepared by combining temperature-responsive hydrogel, thermally conductive graphite oxide with improved interfacial affinity, and efficient micro heater fabricated by a joule heating method. Highlights: ► High performance of transdermal drug delivery system with an easy control of voltage. ► Improved thermal response of hydrogel by graphite oxide incorporation. ► Efficient micro heater fabricated by a joule heating method.

  8. Intelligently targeted drug delivery and enhanced antitumor effect by gelatinase-responsive nanoparticles.

    Directory of Open Access Journals (Sweden)

    Rutian Li

    Full Text Available AIMS: The matrix metalloproteinase (MMP 2/9, also known as collagenases IV and gelatinases A/B, play a key role in cancer invasion and metastasis. However, the clinical trials of the MMP inhibitors (MMPIs ended up with disappointing results. In this paper, we synthesized a gelatinase-responsive copolymer (mPEG-PCL by inserting a gelatinase cleavable peptide (PVGLIG between mPEG and PCL blocks of mPEG-PCL for anticancer drug delivery to make use of MMP2/9 as an intelligent target for drug delivery. MATERIALS AND METHODS: mPEG-pep-PCL copolymer was synthesized via ring-opening copolymerization and double-amidation. To evaluate whether Nanoparticles (NPs prepared from this copolymer are superior to NPs prepared from mPEG-PCL, NPs prepared from mPEG-PCL copolymer were used as positive control. Docetaxel-loading NPs using mPEG-pep-PCL and mPEG-PCL were prepared by nano-precipitation method, mentioned as Gel-NPs and Con-NPs, respectively. The morphologic changes of the NPs after treatment with gelatinases were observed macroscopically by spectrophotometer and microscopically by transmission electron microscopy (TEM and atomic force microscopy (AFM. The cellular uptake amount and cytotoxicity of Gel-NPs and Con-NPs, respectively, in cell lines with different levels of gelatinase expression were studied. Moreover, the cytotoxicity study on the primary cancer cells isolated from pericardial fluids from a patient with late-stage lung cancer was conducted. RESULTS: The Gel-NPs aggregated in response to gelatinases, which was confirmed macroscopically and microscopically. The cellular uptake amount of Gel-NPs was correlated with the level of gelatinases. The in vitro antitumor effect of Gel-NPs was also correlated with the level of gelatinases and was superior to Taxotere (commercially available docetaxel as well as the Con-NPs. The cytotoxicity study on the primary lung cancer cells also confirmed the effectiveness of Gel-NPs. CONCLUSION: The results in

  9. Thermo-responsive magnetic liposomes for hyperthermia-triggered local drug delivery.

    Science.gov (United States)

    Dai, Min; Wu, Cong; Fang, Hong-Ming; Li, Li; Yan, Jia-Bao; Zeng, Dan-Lin; Zou, Tao

    2017-06-01

    We prepared and characterised thermo-responsive magnetic liposomes, which were designed to combine features of magnetic targeting and thermo-responsive control release for hyperthermia-triggered local drug delivery. The particle size and zeta-potential of the thermo-responsive magnetic ammonium bicarbonate (MagABC) liposomes were about 210 nm and -14 mV, respectively. The MagABC liposomes showed encapsulation efficiencies of about 15% and 82% for magnetic nanoparticles (mean crystallite size 12 nm) and doxorubicin (DOX), respectively. The morphology of the MagABC liposomes was visualised using transmission electron microscope (TEM). The MagABC liposomes showed desired thermo-responsive release. The MagABC liposomes, when physically targeted to tumour cells in culture by a permanent magnetic field yielded a substantial increase in intracellular accumulation of DOX as compared to non-magnetic ammonium bicarbonate (ABC) liposomes. This resulted in a parallel increase in cytotoxicity for DOX loaded MagABC liposomes over DOX loaded ABC liposomes in tumour cells.

  10. Stimulus-responsive liposomes as smart nanoplatforms for drug delivery applications.

    Science.gov (United States)

    Zangabad, Parham Sahandi; Mirkiani, Soroush; Shahsavari, Shayan; Masoudi, Behrad; Masroor, Maryam; Hamed, Hamid; Jafari, Zahra; Taghipour, Yasamin Davatgaran; Hashemi, Hura; Karimi, Mahdi; Hamblin, Michael R

    2018-02-01

    Liposomes are known to be promising nanoparticles (NPs) for drug delivery applications. Among different types of self-assembled NPs, liposomes stand out for their non-toxic nature, and their possession of dual hydrophilic-hydrophobic domains. Advantages of liposomes include the ability to solubilize hydrophobic drugs, the ability to incorporate different hydrophilic and lipophilic drugs at the same time, lessening the exposure of host organs to potentially toxic drugs and allowing modification of the surface by a variety of different chemical groups. This modification of the surface, or of the individual constituents, may be used to achieve two important goals. Firstly, ligands for active targeting can be attached that are recognized by cognate receptors over-expressed on the target cells of tissues. Secondly, modification can be used to impart a stimulus-responsive or "smart" character to the liposomes, whereby the cargo is released on demand only when certain internal stimuli (pH, reducing agents, specific enzymes) or external stimuli (light, magnetic field or ultrasound) are present. Here, we review the field of smart liposomes for drug delivery applications.

  11. Light-responsive micelles of spiropyran initiated hyperbranched polyglycerol for smart drug delivery.

    Science.gov (United States)

    Son, Suhyun; Shin, Eeseul; Kim, Byeong-Su

    2014-02-10

    Light-responsive polymeric micelles have emerged as site-specific and time-controlled systems for advanced drug delivery. Spiropyran (SP), a well-known photochromic molecule, was used to initiate the ring-opening multibranching polymerization of glycidol to afford a series of hyperbranched polyglycerols (SP-hb-PG). The micelle assembly and disassembly were induced by an external light source owing to the reversible photoisomerization of hydrophobic SP to hydrophilic merocyanine (MC). Transmission electron microscopy, atomic force microscopy, UV/vis spectroscopy, and dynamic light scattering demonstrated the successful assembly and disassembly of SP-hb-PG micelles. In addition, the critical micelle concentration (CMC) was determined through the fluorescence analysis of pyrene to confirm the amphiphilicity of respective SP-hb-PGn (n = 15, 29, and 36) micelles, with CMC values ranging from 13 to 20 mg/L, which is correlated to the length of the polar polyglycerol backbone. Moreover, the superior biocompatibility of the prepared SP-hb-PG was evaluated using WI-38 cells and HeLa cells, suggesting the prospective applicability of the micelles in smart drug delivery systems.

  12. Stimuli-Responsive Soft Untethered Grippers for Drug Delivery and Robotic Surgery

    Directory of Open Access Journals (Sweden)

    Arijit Ghosh

    2017-07-01

    Full Text Available Untethered microtools that can be precisely navigated into deep in vivo locations are important for clinical procedures pertinent to minimally invasive surgery and targeted drug delivery. In this mini-review, untethered soft grippers are discussed, with an emphasis on a class of autonomous stimuli-responsive gripping soft tools that can be used to excise tissues and release drugs in a controlled manner. The grippers are composed of polymers and hydrogels and are thus compliant to soft tissues. They can be navigated using magnetic fields and controlled by robotic path-planning strategies to carry out tasks like pick-and-place of microspheres and biological materials either with user assistance, or in a fully autonomous manner. It is envisioned that the use of these untethered soft grippers will translate from laboratory experiments to clinical scenarios and the challenges that need to be overcome to make this transition are discussed.

  13. Cotton Study: Albumin Binding and its Effect on Elastase Activity in the Chronic Non-Healing Wound

    Energy Technology Data Exchange (ETDEWEB)

    Castro, N.; Goheen, S.

    2005-01-01

    Cotton, as it is used in wound dressings is composed of nearly pure cellulose. During the wound-healing process, cotton is exposed to various blood components including water, salts, cells, and blood proteins. Albumin is the most prominent protein in blood. Elastase is an enzyme secreted by white blood cells and takes an active role in tissue reconstruction. In the chronic non-healing wound, elastase is often over-expressed such that this enzyme digests tissue and growth factors, and interferes with the normal healing process. Our goal is to design a cotton wound dressing that will sequester elastase or assist in reducing elastase activity in the presence of other blood proteins such as albumin. The ability of cotton and various cotton derivatives to sequester elastase and albumin has been studied by examining the adsorption of these two proteins separately. We undertook the present work to confirm the binding of albumin to cotton and to quantify the activity of elastase in the presence of various derivatives of cotton. We previously observed a slight increase in elastase activity when exposed to cotton. We also observed a continuous accumulation of albumin on cotton using high-performance liquid chromatography methods. In the present study, we used an open-column-absorption technique coupled with a colorimetric protein assay to confirm losses of albumin to cotton. We have also confirmed increased elastase activity after exposure to cotton. The results are discussed in relation to the porosity of cotton and the use of cotton for treating chronic non-healing wounds.

  14. Multifunctional pH-Responsive Folate Receptor Mediated Polymer Nanoparticles for Drug Delivery.

    Science.gov (United States)

    Cai, Xiaoqing; Yang, Xiaoye; Wang, Fang; Zhang, Chen; Sun, Deqing; Zhai, Guangxi

    2016-07-01

    Multifunctional pH-responsive folate receptor mediated targeted polymer nanoparticles (TPNps) were developed for docetaxel (DTX) delivery based on poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)poly (β-amino ester) (P123-PAE) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)-folate (P123-FA) copolymers. The DTX was loaded into the TPNps with a decent drug loading content of 15.02 ± 0.14 wt%. In vitro drug release results showed that the DTX was released from the TPNps at a pH-dependent manner. Tetrazolium dye (MTT) assay revealed that the bland polymer nanoparticles displayed almost nontoxicity at 200 μg/mL concentration. However, the DTX-loaded TPNps showed high anti-tumor activity at low IC50 (0.72 μg/mL) for MCF-7 cells following 48 h incubation. Cellular uptake experiments revealed that the TPNps had higher degree of cellular uptake than nontargeted polymer nanoparticles, indicating that the nanoparticles were internalized into the cells via FA receptor-mediated endocytosis. Moreover, the cellular uptake pathways for the FA grafted polymer were involved in energy-dependent, clathrin-mediated and caveolae-mediated endocytosis. The cell killing effect and cellular uptake of the DTX-TPNps by the MCF-7 cells were all enhanced by about two folds at pH 5.5 when compared with pH 7.4. The TPNps also significantly prolonged the in vivo retention time for the DTX. These results suggest that the biocompatible pH responsive folate-modified polymer nanoparticles present a promising safe nanosystem for intracellular targeted delivery of DTX.

  15. 41 CFR 60-300.84 - Responsibilities of appropriate employment service delivery system.

    Science.gov (United States)

    2010-07-01

    ... appropriate employment service delivery system. 60-300.84 Section 60-300.84 Public Contracts and Property... of appropriate employment service delivery system. By statute, appropriate employment service... referrals. The employment service delivery systems shall provide OFCCP, upon request, information pertinent...

  16. The Potential of Stimuli-Responsive Nanogels in Drug and Active Molecule Delivery for Targeted Therapy

    Directory of Open Access Journals (Sweden)

    Marta Vicario-de-la-Torre

    2017-05-01

    Full Text Available Nanogels (NGs are currently under extensive investigation due to their unique properties, such as small particle size, high encapsulation efficiency and protection of active agents from degradation, which make them ideal candidates as drug delivery systems (DDS. Stimuli-responsive NGs are cross-linked nanoparticles (NPs, composed of polymers, natural, synthetic, or a combination thereof that can swell by absorption (uptake of large amounts of solvent, but not dissolve due to the constituent structure of the polymeric network. NGs can undergo change from a polymeric solution (swell form to a hard particle (collapsed form in response to (i physical stimuli such as temperature, ionic strength, magnetic or electric fields; (ii chemical stimuli such as pH, ions, specific molecules or (iii biochemical stimuli such as enzymatic substrates or affinity ligands. The interest in NGs comes from their multi-stimuli nature involving reversible phase transitions in response to changes in the external media in a faster way than macroscopic gels or hydrogels due to their nanometric size. NGs have a porous structure able to encapsulate small molecules such as drugs and genes, then releasing them by changing their volume when external stimuli are applied.

  17. Recent Advances in Stimuli-Responsive Release Function Drug Delivery Systems for Tumor Treatment

    Directory of Open Access Journals (Sweden)

    Chendi Ding

    2016-12-01

    Full Text Available Benefiting from the development of nanotechnology, drug delivery systems (DDSs with stimuli-responsive controlled release function show great potential in clinical anti-tumor applications. By using a DDS, the harsh side effects of traditional anti-cancer drug treatments and damage to normal tissues and organs can be avoided to the greatest extent. An ideal DDS must firstly meet bio-safety standards and secondarily the efficiency-related demands of a large drug payload and controlled release function. This review highlights recent research progress on DDSs with stimuli-responsive characteristics. The first section briefly reviews the nanoscale scaffolds of DDSs, including mesoporous nanoparticles, polymers, metal-organic frameworks (MOFs, quantum dots (QDs and carbon nanotubes (CNTs. The second section presents the main types of stimuli-responsive mechanisms and classifies these into two categories: intrinsic (pH, redox state, biomolecules and extrinsic (temperature, light irradiation, magnetic field and ultrasound ones. Clinical applications of DDS, future challenges and perspectives are also mentioned.

  18. Crystal structure of the complex of porcine pancreatic elastase with TEI-8362.

    Science.gov (United States)

    Koizumi, Masahiro; Muratani, Emiko; Fujii, Katsuhiko; Takimoto-Kamimura, Midori

    2004-01-01

    The crystal structure of porcine pancreatic elastase (PPE) complexed with a new benzoxazinone inhibitor, TEI-8362, of human neutrophil elastase (HNE) was determined at 1.8 A resolution. The hydroxyl oxygen of Ser195 opened the benzoxazinone by nucleophilic attack and formed a covalent bond with the carbonyl carbon. Hydrophobic interaction between the terminal benzene of TEI-8362 and the S4 pocket is reinforced by the side chain of Arg217 and has an impact on the ligand binding conformation. Two additional interactions with the oxyanion hole and His57 are introduced to the benzoxazinone structure of TEI-8362. These combinatorial interactions will also exist in HNE and cause high preference of TEI-8362 for HNE.

  19. Eosinophil-derived neurotoxin, elastase, and cytokine profile in effusion from eosinophilic otitis media.

    Science.gov (United States)

    Uchimizu, Hirotaka; Matsuwaki, Yoshinori; Kato, Masahiko; Otori, Nobuyosi; Kojima, Hiromi

    2015-09-01

    Eosinophilic otitis media (EOM) is an intractable disease characterized by a remarkably viscous effusion and accumulation of numerous eosinophils in both the middle ear effusion and the mucosa. The key factors in EOM pathogenesis remain unclear. The purpose of this study is to identify the important factors involved in EOM pathogenesis. Middle ear effusion samples were collected from 12 patients with EOM and 9 patients with secretory otitis media (SOM), as controls. Multiple cytokines in the effusion were measured using a Bio-Plex™ Human Cytokine 27-Plex panel. Eosinophil-derived neurotoxin (EDN) and elastase were measured by ELISA. The concentrations of EDN, elastase, and each cytokine were compared between the EOM and SOM groups. Furthermore, in the EOM group, each cytokine was examined for correlation with EDN and elastase. EDN and elastase concentrations were significantly higher in the EOM group than in the SOM group (p < 0.05). IL-5, IL-1β, MIP-1α, G-CSF, IL-1ra, IL-4, IFN-γ, MIP-1β, IL-10, TNF-α, VEGF, and IL-2 concentration was significantly higher in the EOM group than in the SOM group (p < 0.05). Significant positive correlations were found between EDN and IL-1ra, IL-2, IL-5, IL-9, IL-13, eotaxin, MIP-1α, PDGF-BB, and RANTES in the EOM group (p < 0.05). Our study showed that IL-5, IL-2, MIP-1α, and IL-1ra are the important factors involved in EOM pathogenesis. Furthermore, not only eosinophil, but also neutrophil are involved in middle ear inflammation of EOM. Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  20. Localization and stretch-dependence of lung elastase activity in development and compensatory growth.

    Science.gov (United States)

    Young, Sarah Marie; Liu, Sheng; Joshi, Rashika; Batie, Matthew R; Kofron, Matthew; Guo, Jinbang; Woods, Jason C; Varisco, Brian Michael

    2015-04-01

    Synthesis and remodeling of the lung matrix is necessary for primary and compensatory lung growth. Because cyclic negative force is applied to developing lung tissue during the respiratory cycle, we hypothesized that stretch is a critical regulator of lung matrix remodeling. By using quantitative image analysis of whole-lung and whole-lobe elastin in situ zymography images, we demonstrated that elastase activity increased twofold during the alveolar stage of postnatal lung morphogenesis in the mouse. Remodeling was restricted to alveolar walls and ducts and was nearly absent in dense elastin band structures. In the mouse pneumonectomy model of compensatory lung growth, elastase activity increased threefold, peaking at 14 days postpneumonectomy and was higher in the accessory lobe compared with other lobes. Remodeling during normal development and during compensatory lung growth was different with increased major airway and pulmonary arterial remodeling during development but not regeneration, and with homogenous remodeling throughout the parenchyma during development, but increased remodeling only in subpleural regions during compensatory lung growth. Left lung wax plombage prevented increased lung elastin during compensatory lung growth. To test whether the adult lung retains an innate capacity to remodel elastin, we developed a confocal microscope-compatible stretching device. In ex vivo adult mouse lung sections, lung elastase activity increased exponentially with strain and in peripheral regions of lung more than in central regions. Our study demonstrates that lung elastase activity is stretch-dependent and supports a model in which externally applied forces influence the composition, structure, and function of the matrix during periods of alveolar septation. Copyright © 2015 the American Physiological Society.

  1. Effect of some antiinflammatory plant species on elastase and myeloperoxidase enzyme activity

    OpenAIRE

    Cárdenas, Paola Andrea; Aragón, Diana Marcela; Ospina, Luis Fernando; Isaza, Gustavo; Pérez, Jorge Enrique

    2012-01-01

    In this work, the effect of aqueous and methanolic extracts of the plants species Critoniella acuminata, Salvia rubescens, Phenax rugosus (Poir.) Wedd and Tabebuia chrysanta G. on the enzymes elastase and myeloperoxidase, involved in degranulation leukocyte process, was evaluated, identifying the potential direct inhibitory effect on the enzyme and/or inhibition of the desgranulation of polymorphonuclear neutrophils. Extracts of Critoniella acuminata andSalvia rubescens presented effects on t...

  2. Inhibitory effects of polyphenols from grape pomace extract on collagenase and elastase activity.

    Science.gov (United States)

    Wittenauer, Judith; Mäckle, Sonja; Sußmann, Daniela; Schweiggert-Weisz, Ute; Carle, Reinhold

    2015-03-01

    Breakdown and disorganization of extracellular matrix proteins like collagen, fibronectin and elastin are main characteristics of skin aging due to the enhanced activation of proteolytic enzymes such as collagenases and elastases. Inhibition of their enzymatic activities by natural plant compounds might be a promising approach to prevent extrinsic skin aging. Especially polyphenols are supposed to interact with those enzymes due to their molecular nature. In our investigation, extracts of pomace from Riesling grapes were analyzed for their inhibitory properties on collagenase as well as elastase. Crude grape pomace extract showed a dose-dependent inhibitory activity against both enzymes with IC50-values of 20.3μg/ml and 14.7μg/ml for collagenase and elastase activity, respectively. The extracts were fractionated into four fractions containing phenolic compounds differing in chemical structure and polarity. Except for the stilbene containing fraction, all other fractions showed inhibitory effects on both enzyme activities. The most pronounced impact was found for the hydrophilic low molecular weight polyphenols containing the free phenolic acids. In particular, gallic acid showed considerable inhibition values. EGCG was used as a positive control and showed a dose-dependent inhibition of collagenase activity (IC50=0.9mM). Copyright © 2015 Elsevier B.V. All rights reserved.

  3. A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Takemasa, Akihiro; Ishii, Yoshiki; Fukuda, Takeshi

    2012-12-01

    Neutrophil elastase plays pivotal roles in the pathogenesis of pulmonary fibrosis. The neutrophil elastase inhibitor, sivelestat, could alleviate pulmonary fibrosis; however, the antifibrotic mechanisms have not yet been clarified. We examined the antifibrotic mechanisms, mainly focusing on a key fibrotic cytokine, transforming growth factor (TGF)-β1, in this study. To elucidate the antifibrotic mechanisms of sivelestat, we examined a murine model of bleomycin-induced early-stage pulmonary fibrosis. After intratracheal instillation of bleomycin, sivelestat was administered intraperitoneally once a day for 7 or 14 days. Bronchoalveolar lavage fluid and lung samples were examined on day 7 or day 14 after bleomycin instillation. In the bleomycin-induced early-stage pulmonary fibrosis model, the neutrophil elastase level was increased in the lungs. Sivelestat significantly inhibited the increase in lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils and lymphocytes), the levels of the active form of TGF-β1 and phospho-Smad2 in bleomycin-induced early-stage pulmonary fibrosis. The total TGF-β1 levels and relative changes of TGF-β1 mRNA expression, however, were not decreased significantly by sivelestat. These results suggest that sivelestat alleviated bleomycin-induced pulmonary fibrosis via inhibition of both TGF-β activation and inflammatory cell recruitment in the lung.

  4. Quantification of Lung Damage in an Elastase-Induced Mouse Model of Emphysema

    Directory of Open Access Journals (Sweden)

    Arrate Muñoz-Barrutia

    2012-01-01

    Full Text Available Objective. To define the sensitivity of microcomputed tomography- (micro-CT- derived descriptors for the quantification of lung damage caused by elastase instillation. Materials and Methods. The lungs of 30 elastase treated and 30 control A/J mice were analyzed 1, 6, 12, and 24 hours and 7 and 17 days after elastase instillation using (i breath-hold-gated micro-CT, (ii pulmonary function tests (PFTs, (iii RT-PCR for RNA cytokine expression, and (iv histomorphometry. For the latter, an automatic, parallel software toolset was implemented that computes the airspace enlargement descriptors: mean linear intercept (Lm and weighted means of airspace diameters (D0, D1, and D2. A Support Vector Classifier was trained and tested based on three nonhistological descriptors using D2 as ground truth. Results. D2 detected statistically significant differences (P<0.01 between the groups at all time points. Furthermore, D2 at 1 hour (24 hours was significantly lower (P<0.01 than D2 at 24 hours (7 days. The classifier trained on the micro-CT-derived descriptors achieves an area under the curve (AUC of 0.95 well above the others (PFTS AUC = 0.71; cytokine AUC = 0.88. Conclusion. Micro-CT-derived descriptors are more sensitive than the other methods compared, to detect in vivo early signs of the disease.

  5. Pathogen-mimicking vaccine delivery system designed with a bioactive polymer (inulin acetate) for robust humoral and cellular immune responses.

    Science.gov (United States)

    Kumar, Sunny; Kesharwani, Siddharth S; Kuppast, Bhimanna; Bakkari, Mohammed Ali; Tummala, Hemachand

    2017-09-10

    New and improved vaccines are needed against challenging diseases such as malaria, tuberculosis, Ebola, influenza, AIDS, and cancer. The majority of existing vaccine adjuvants lack the ability to significantly stimulate the cellular immune response, which is required to prevent the aforementioned diseases. This study designed a novel particulate based pathogen-mimicking vaccine delivery system (PMVDS) to target antigen-presenting-cells (APCs) such as dendritic cells. The uniqueness of PMVDS is that the polymer used to prepare the delivery system, Inulin Acetate (InAc), activates the innate immune system. InAc was synthesized from the plant polysaccharide, inulin. PMVDS provided improved and persistent antigen delivery to APCs as an efficient vaccine delivery system, and simultaneously, activated Toll-Like Receptor-4 (TLR-4) on APCs to release chemokine's/cytokines as an immune-adjuvant. Through this dual mechanism, PMVDS robustly stimulated both the humoral (>32 times of IgG1 levels vs alum) and the cell-mediated immune responses against the encapsulated antigen (ovalbumin) in mice. More importantly, PMVDS stimulated both cytotoxic T cells and natural killer cells of cell-mediated immunity to provide tumor (B16-ova-Melanoma) protection in around 40% of vaccinated mice and significantly delayed tumor progression in rest of the mice. PMVDS is a unique bio-active vaccine delivery technology with broader applications for vaccines against cancer and several intracellular pathogens, where both humoral and cellular immune responses are desired. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. A remotely operated drug delivery system with an electrolytic pump and a thermo-responsive valve

    KAUST Repository

    Yi, Ying

    2015-07-22

    Implantable drug delivery devices are becoming attractive due to their abilities of targeted and controlled dose release. Currently, two important issues are functional lifetime and non-controlled drug diffusion. In this work, we present a drug delivery device combining an electrolytic pump and a thermo-responsive valve, which are both remotely controlled by an electromagnetic field (40.5 mT and 450 kHz). Our proposed device exhibits a novel operation mechanism for long-term therapeutic treatments using a solid drug in reservoir approach. Our device also prevents undesired drug liquid diffusions. When the electromagnetic field is on, the electrolysis-induced bubble drives the drug liquid towards the Poly (N-Isopropylacrylamide) (PNIPAM) valve that consists of PNIPAM and iron micro-particles. The heat generated by the iron micro-particles causes the PNIPAM to shrink, resulting in an open valve. When the electromagnetic field is turned off, the PNIPAM starts to swell. In the meantime, the bubbles are catalytically recombined into water, reducing the pressure inside the pumping chamber, which leads to the refilling of the fresh liquid from outside the device. A catalytic reformer is included, allowing more liquid refilling during the limited valve\\'s closing time. The amount of body liquid that refills the drug reservoir can further dissolve the solid drug, forming a reproducible drug solution for the next dose. By repeatedly turning on and off the electromagnetic field, the drug dose can be cyclically released, and the exit port of the device is effectively controlled.

  7. Diagnostic Performance of Measurement of Fecal Elastase-1 in Detection of Exocrine Pancreatic Insufficiency - Systematic Review and Meta-analysis.

    Science.gov (United States)

    Vanga, Rohini R; Tansel, Aylin; Sidiq, Saad; El-Serag, Hashem B; Othman, Mohamed

    2018-01-25

    Tests to quantify fecal levels of chymotrypsin like elastase family member 3 (CELA3 or elastase-1) in feces are widely used to identify patients with exocrine pancreatic insufficiency (EPI). However, the diagnostic accuracy of this test, an ELISA, is not clear. We performed a systematic review and meta-analysis to determine the accuracy of measurement of fecal elastase-1 in detection of EPI. We searched PubMed, Embase, and reference lists for articles through November 2016 describing studies that compared fecal level of elastase-1 with results from a reference standard, direct method (secretin stimulation test), or indirect method (measurement of fecal fat) for detection of EPI. Sensitivity and specificity values were pooled statistically using bivariate diagnostic meta-analysis. We included total of 428 cases of EPI and 673 individuals without EPI (controls), from 14 studies, in the meta-analysis. The assay for elastase-1, compared to secretin stimulation test, identified patients with pancreatic insufficiency with a pooled sensitivity value of 0.77 (95% CI, 0.58-0.89) and specificity value of 0.88 (95% CI, 0.78-0.93). In an analysis of 345 cases of EPI and 312 controls, from 6 studies, the fecal elastase-1 assay identified patients with EPI with a pooled sensitivity value of 0.96 (95% CI, 0.79-0.99) and specificity value of 0.88 (95% CI, 0.59-0.97), compared to quantitative fecal fat estimation. In patients with low pre-test probability of EPI (5%), the fecal elastase-1 assay would have a false-negative rate of 1.1% and a false-positive rate of 11%, indicating a high yield in ruling out EPI but not in detection of EPI. In contrast, in patients with high pre-test probability of EPI (40%), approximately 10% of patients with EPI would be missed (false negatives). In a systematic review and meta-analysis of studies that compared fecal level of elastase-1 for detection of EPI, we found that normal level of elastase-1 (above 200 mcg/g) can rule out EPI in patients with

  8. pH-Responsive PLGA Nanoparticle for Controlled Payload Delivery of Diclofenac Sodium

    Directory of Open Access Journals (Sweden)

    Shalil Khanal

    2016-08-01

    Full Text Available Poly(lactic-co-glycolic acid (PLGA based nanoparticles have gained increasing attention in delivery applications due to their capability for controlled drug release characteristics, biocompatibility, and tunable mechanical, as well as degradation, properties. However, thorough study is always required while evaluating potential toxicity of the particles from dose dumping, inconsistent release and drug-polymer interactions. In this research, we developed PLGA nanoparticles modified by chitosan (CS, a cationic and pH responsive polysaccharide that bears repetitive amine groups in its backbone. We used a model drug, diclofenac sodium (DS, a nonsteroidal anti-inflammatory drug (NSAID, to study the drug loading and release characteristics. PLGA nanoparticles were synthesized by double-emulsion solvent evaporation technique. The nanoparticles were evaluated based on their particle size, surface charge, entrapment efficacy, and effect of pH in drug release profile. About 390–420 nm of average diameters and uniform morphology of the particles were confirmed by scanning electron microscope (SEM imaging and dynamic light scattering (DLS measurement. Chitosan coating over PLGA surface was confirmed by FTIR and DLS. Drug entrapment efficacy was up to 52%. Chitosan coated PLGA showed a pH responsive drug release in in vitro. The release was about 45% more at pH 5.5 than at pH 7.4. The results of our study indicated the development of chitosan coating over PLGA nanoparticle for pH dependent controlled release DS drug for therapeutic applications.

  9. Impact of surface coated magnetite used in magnetic drug delivery system on immune response

    Science.gov (United States)

    Oaku, Yoshihiro; Tamada, Junya; Mishima, Fumihito; Akiyama, Yoko; Osako, Mariana Kiomy; Koriyama, Hiroshi; Nakagami, Hironori; Nishijima, Shigehiro

    2015-05-01

    Magnetic drug delivery system (MDDS) is a technique to effectively accumulate drugs, which are combined with ferromagnetic particles, into the affected area using magnetic force control. This study intends to apply MDDS for immunotherapy by enhancing immune responses by a surface treatment of a ferromagnetic particle. The objective of this study is to give the adjuvant effect to a ferromagnetic particle by the surface treatment with alum, which is known as one of the common adjuvants that activates inflammasome pathway. First, magnetite was prepared as a ferromagnetic particle and coated with alum. Alum-coated magnetite increased the expression of caspase-1, which is an activated indicator of inflammasome, in the culture of human monocyte cell (THP-1 cell). To evaluate the potential of the surface coated particles, the particles were subcutaneously injected to mice with a peptide vaccine. As a result, the antibody titer was increased by the surface coated particles as assessed by ELISA. Although a magnetic force has not yet applied in this study, the administration experiment to mice using magnetic force control is our next step. In conclusion, we modified the immune response to magnetite by coating the surface with alum. This can lead to a clinical application for vaccine therapy in future.

  10. Analysis of the murine immune response to pulmonary delivery of precisely fabricated nano- and microscale particles.

    Science.gov (United States)

    Roberts, Reid A; Shen, Tammy; Allen, Irving C; Hasan, Warefta; DeSimone, Joseph M; Ting, Jenny P Y

    2013-01-01

    Nanomedicine has the potential to transform clinical care in the 21(st) century. However, a precise understanding of how nanomaterial design parameters such as size, shape and composition affect the mammalian immune system is a prerequisite for the realization of nanomedicine's translational promise. Herein, we make use of the recently developed Particle Replication in Non-wetting Template (PRINT) fabrication process to precisely fabricate particles across and the nano- and micro-scale with defined shapes and compositions to address the role of particle design parameters on the murine innate immune response in both in vitro and in vivo settings. We find that particles composed of either the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) or the biocompatible polymer polyethylene glycol (PEG) do not cause release of pro-inflammatory cytokines nor inflammasome activation in bone marrow-derived macrophages. When instilled into the lungs of mice, particle composition and size can augment the number and type of innate immune cells recruited to the lungs without triggering inflammatory responses as assayed by cytokine release and histopathology. Smaller particles (80×320 nm) are more readily taken up in vivo by monocytes and macrophages than larger particles (6 µm diameter), yet particles of all tested sizes remained in the lungs for up to 7 days without clearance or triggering of host immunity. These results suggest rational design of nanoparticle physical parameters can be used for sustained and localized delivery of therapeutics to the lungs.

  11. Analysis of the murine immune response to pulmonary delivery of precisely fabricated nano- and microscale particles.

    Directory of Open Access Journals (Sweden)

    Reid A Roberts

    Full Text Available Nanomedicine has the potential to transform clinical care in the 21(st century. However, a precise understanding of how nanomaterial design parameters such as size, shape and composition affect the mammalian immune system is a prerequisite for the realization of nanomedicine's translational promise. Herein, we make use of the recently developed Particle Replication in Non-wetting Template (PRINT fabrication process to precisely fabricate particles across and the nano- and micro-scale with defined shapes and compositions to address the role of particle design parameters on the murine innate immune response in both in vitro and in vivo settings. We find that particles composed of either the biodegradable polymer poly(lactic-co-glycolic acid (PLGA or the biocompatible polymer polyethylene glycol (PEG do not cause release of pro-inflammatory cytokines nor inflammasome activation in bone marrow-derived macrophages. When instilled into the lungs of mice, particle composition and size can augment the number and type of innate immune cells recruited to the lungs without triggering inflammatory responses as assayed by cytokine release and histopathology. Smaller particles (80×320 nm are more readily taken up in vivo by monocytes and macrophages than larger particles (6 µm diameter, yet particles of all tested sizes remained in the lungs for up to 7 days without clearance or triggering of host immunity. These results suggest rational design of nanoparticle physical parameters can be used for sustained and localized delivery of therapeutics to the lungs.

  12. Analysis of the Murine Immune Response to Pulmonary Delivery of Precisely Fabricated Nano- and Microscale Particles

    Science.gov (United States)

    Roberts, Reid A.; Shen, Tammy; Allen, Irving C.; Hasan, Warefta; DeSimone, Joseph M.; Ting, Jenny P. Y.

    2013-01-01

    Nanomedicine has the potential to transform clinical care in the 21st century. However, a precise understanding of how nanomaterial design parameters such as size, shape and composition affect the mammalian immune system is a prerequisite for the realization of nanomedicine's translational promise. Herein, we make use of the recently developed Particle Replication in Non-wetting Template (PRINT) fabrication process to precisely fabricate particles across and the nano- and micro-scale with defined shapes and compositions to address the role of particle design parameters on the murine innate immune response in both in vitro and in vivo settings. We find that particles composed of either the biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) or the biocompatible polymer polyethylene glycol (PEG) do not cause release of pro-inflammatory cytokines nor inflammasome activation in bone marrow-derived macrophages. When instilled into the lungs of mice, particle composition and size can augment the number and type of innate immune cells recruited to the lungs without triggering inflammatory responses as assayed by cytokine release and histopathology. Smaller particles (80×320 nm) are more readily taken up in vivo by monocytes and macrophages than larger particles (6 µm diameter), yet particles of all tested sizes remained in the lungs for up to 7 days without clearance or triggering of host immunity. These results suggest rational design of nanoparticle physical parameters can be used for sustained and localized delivery of therapeutics to the lungs. PMID:23593509

  13. Single Intramammary Infusion of Recombinant Bovine Interleukin-8 at Dry-Off Induces the Prolonged Secretion of Leukocyte Elastase, Inflammatory Lactoferrin-Derived Peptides, and Interleukin-8 in Dairy Cows

    Directory of Open Access Journals (Sweden)

    Atsushi Watanabe

    2012-01-01

    Full Text Available A single intramammary infusion of recombinant bovine interleukin-8 (IL-8 at 50 μg/quarter/head, but not 10 μg/quarter/head, induced clinical mastitis in three of four cows during the dry-off period, resulting in an elevated rectal temperature, redness and swelling of the mammary gland, extensive polymorphonuclear leukocyte (PMNL infiltration, and milk clot formation from 1 to 28 days post infusion (PI. In the mammary secretions of the mastitic glands, high levels of IL-8 were sustained from 8 hours to 28 days PI, peaking at 1–3 days PI. The levels of leukocyte-derived elastase and inflammatory 22 and 23 kDa lactoferrin derived peptides (LDP were also increased in the mammary secretions from the mastitic glands. In addition to the experimentally induced mastitis, the mammary secretions from the glands of cattle with spontaneous Staphylococcus aureus dry-period mastitis displayed milk clot formations and significant increases in their levels of PMNL counts, elastase, LDP, and IL-8, compared with those of the mammary secretions from the uninfected glands. These results suggest that after an intramammary infusion of IL-8 has elicited inflammatory responses, it induces the prolonged secretion of elastase, inflammatory LDP, and IL-8, and that long-lasting IL-8-induced inflammatory reactions are involved in the pathogenesis of S. aureus dry-period mastitis.

  14. Extensive Analysis of Elastase-Induced Pulmonary Emphysema in Rats: ALP in the Lung, a New Biomarker for Disease Progression?

    Science.gov (United States)

    Inoue, Ken-ichiro; Koike, Eiko; Yanagisawa, Rie; Takano, Hirohisa

    2010-01-01

    It is accepted that pulmonary exposure of rodents to porcine pancreatic elastase (ELT) induces lesions that morphologically resemble human emphysema. Nonetheless, extensive analysis of this model has rarely been conducted. The present study was designed to extensively examine the effects of ELT on lung inflammation, cell damage, emphysematous change, and cholinergic reactivity in rats. Intratracheal administration of two doses of ELT induced 1) a proinflammatory response in the lung that was characterized by significant infiltration of macrophages and an increased level of interleukin-1β in lung homogenates, 2) lung cell damage as indicated by higher levels of total protein, lactate dehydrogenase, and alkaline phosphatase (ALP) in lung homogenates, 3) emphysema-related morphological changes including airspace enlargement and progressive destruction of alveolar wall structures, and 4) airway responsiveness to methacholine including an augmented Rn value. In addition, ELT at a high dose was more effective than that at a low dose. This is the novel study to extensively analyze ELT-induced lung emphysema, and the analysis might be applied to future investigations that evaluate new therapeutic agents or risk factors for pulmonary emphysema. In particular, ALP in lung homogenates might be a new biomarker for the disease progression/exacerbation. PMID:20216950

  15. 27 CFR 44.64 - Responsibility for delivery or exportation of tobacco products, and cigarette papers and tubes.

    Science.gov (United States)

    2010-04-01

    ... delivery or exportation of tobacco products, and cigarette papers and tubes. 44.64 Section 44.64 Alcohol... (CONTINUED) TOBACCO EXPORTATION OF TOBACCO PRODUCTS AND CIGARETTE PAPERS AND TUBES, WITHOUT PAYMENT OF TAX... products, and cigarette papers and tubes. Responsibility for compliance with the provisions of this part...

  16. Multifunctional polymer-capped mesoporous silica nanoparticles for pH-responsive targeted drug delivery

    Science.gov (United States)

    Niedermayer, Stefan; Weiss, Veronika; Herrmann, Annika; Schmidt, Alexandra; Datz, Stefan; Müller, Katharina; Wagner, Ernst; Bein, Thomas; Bräuchle, Christoph

    2015-04-01

    A highly stable modular platform, based on the sequential covalent attachment of different functionalities to the surface of core-shell mesoporous silica nanoparticles (MSNs) for targeted drug delivery is presented. A reversible pH-responsive cap system based on covalently attached poly(2-vinylpyridine) (PVP) was developed as drug release mechanism. Our platform offers (i) tuneable interactions and release kinetics with the cargo drug in the mesopores based on chemically orthogonal core-shell design, (ii) an extremely robust and reversible closure and release mechanism based on endosomal acidification of the covalently attached PVP polymer block, (iii) high colloidal stability due to a covalently coupled PEG shell, and (iv) the ability to covalently attach a wide variety of dyes, targeting ligands and other functionalities at the outer periphery of the PEG shell. The functionality of the system was demonstrated in several cell studies, showing pH-triggered release in the endosome, light-triggered endosomal escape with an on-board photosensitizer, and efficient folic acid-based cell targeting.A highly stable modular platform, based on the sequential covalent attachment of different functionalities to the surface of core-shell mesoporous silica nanoparticles (MSNs) for targeted drug delivery is presented. A reversible pH-responsive cap system based on covalently attached poly(2-vinylpyridine) (PVP) was developed as drug release mechanism. Our platform offers (i) tuneable interactions and release kinetics with the cargo drug in the mesopores based on chemically orthogonal core-shell design, (ii) an extremely robust and reversible closure and release mechanism based on endosomal acidification of the covalently attached PVP polymer block, (iii) high colloidal stability due to a covalently coupled PEG shell, and (iv) the ability to covalently attach a wide variety of dyes, targeting ligands and other functionalities at the outer periphery of the PEG shell. The

  17. Long-Term Antibody and Immune Memory Response Induced by Pulmonary Delivery of the Influenza Iscomatrix Vaccine

    OpenAIRE

    Vujanic, Ana; Snibson, Kenneth J.; Wee, Janet L. K.; Edwards, Stirling J.; Pearse, Martin J.; Scheerlinck, Jean-Pierre Y.; Sutton, Philip

    2012-01-01

    Pulmonary delivery of an influenza Iscomatrix adjuvant vaccine induces a strong systemic and mucosal antibody response. Since an influenza vaccine needs to induce immunological memory that lasts at least 1 year for utility in humans, we examined the longevity of the immune response induced by such a pulmonary vaccination, with and without antigen challenge. Sheep were vaccinated in the deep lung with an influenza Iscomatrix vaccine, and serum and lung antibody levels were quantified for up to...

  18. Electromagnetically powered electrolytic pump and thermo-responsive valve for drug delivery

    KAUST Repository

    Yi, Ying

    2015-04-01

    A novel drug delivery device is presented, implementing an electrolytic pump and a thermo-responsive valve. The device is remotely operated by an AC electromagnetic field (40.5∼58.5 mT, 450 kHz) that provides the power for the pump and the valve. It is suitable for long-term therapy applications, which use a solid drug in reservoir (SDR) approach and avoids unwanted drug diffusion. When the electromagnetic field is on, the electrolytic pump drives the drug towards the valve. The valve is made of a magnetic composite consisting of a smart hydrogel: Poly (N-Isopropylacrylamide) (PNIPAm) and iron powder. The heat generated in the iron powder via magnetic losses causes the PNIPAm to shrink, allowing the drug to flow past it. When the electromagnetic field is off, the PNIPAm swells, sealing the outlet. In the meantime, the bubbles generated by electrolysis recombine into water, causing a pressure reduction in the pumping chamber. This draws fresh fluid from outside the pump into the drug reservoir before the valve is fully sealed. The recombination can be accelerated by a platinum (Pt) coated catalytic reformer, allowing more fluid to flow back to the drug reservoir and dissolve the drug. By repeatedly turning on and off the magnetic field, the drug solution can be delivered cyclically. © 2015 IEEE.

  19. MRI-guided targeting delivery of doxorubicin with reduction-responsive lipid-polymer hybrid nanoparticles

    Directory of Open Access Journals (Sweden)

    Wu B

    2017-09-01

    Full Text Available Bo Wu,1,2 Shu-Ting Lu,1 Kai Deng,2 Hui Yu,2 Can Cui,2 Yang Zhang,2 Ming Wu,2 Ren-Xi Zhuo,2 Hai-Bo Xu,1 Shi-Wen Huang2 1Department of Radiology, Zhongnan Hospital of Wuhan University, 2Key Laboratory of Biomedical Polymers, Ministry of Education, Department of Chemistry, Wuhan University, Wuhan, People’s Republic of China Abstract: In recent years, there has been increasing interest in developing a multifunctional nanoscale platform for cancer monitoring and chemotherapy. However, there is still a big challenge for current clinic contrast agents to improve their poor tumor selectivity and response. Herein, we report a new kind of Gd complex and folate-coated redox-sensitive lipid-polymer hybrid nanoparticle (Gd-FLPNP for tumor-targeted magnetic resonance imaging and therapy. Gd-FLPNPs can simultaneously accomplish diagnostic imaging, and specific targeting and controlled release of doxorubicin (DOX. They exhibit good monodispersity, excellent size stability, and a well-defined core-shell structure. Paramagnetic nanoparticles based on gadolinium-diethylenetriaminepentaacetic acid-bis-cetylamine have paramagnetic properties with an approximately two-fold enhancement in the longitudinal relaxivity compared to clinical used Magnevist. For targeted and reduction-sensitive drug delivery, Gd-FLPNPs released DOX faster and enhanced cell uptake in vitro, and exhibited better antitumor effect both in vitro and in vivo. Keywords: redox-sensitive, tumor-targeted, gadolinium, contrast agents, PLGA

  20. Delivery of siRNAs to Dendritic Cells Using DEC205-Targeted Lipid Nanoparticles to Inhibit Immune Responses.

    Science.gov (United States)

    Katakowski, Joseph A; Mukherjee, Gayatri; Wilner, Samantha E; Maier, Keith E; Harrison, Michael Travis; DiLorenzo, Teresa P; Levy, Matthew; Palliser, Deborah

    2016-02-01

    Due to their ability to knock down the expression of any gene, siRNAs have been heralded as ideal candidates for treating a wide variety of diseases, including those involving "undruggable" targets. However, the therapeutic potential of siRNAs remains severely limited by a lack of effective delivery vehicles. Recently, lipid nanoparticles (LNPs) containing ionizable cationic lipids have been developed for hepatic siRNA delivery. However, their suitability for delivery to other cell types has not been determined. We have modified LNPs for preferential targeting to dendritic cells (DCs), central regulators of immune responses. To achieve directed delivery, we coated LNPs with a single-chain antibody (scFv; DEC-LNPs), specific to murine DEC205, which is highly expressed on distinct DC subsets. Here we show that injection of siRNAs encapsulated in DEC-LNPs are preferentially delivered to DEC205(+) DCs. Gene knockdown following uptake of DEC-LNPs containing siRNAs specific for the costimulatory molecules CD40, CD80, and CD86 dramatically decreases gene expression levels. We demonstrate the functionality of this knockdown with a mixed lymphocyte response (MLR). Overall, we report that injection of LNPs modified to restrict their uptake to a distinct cell population can confer profound gene knockdown, sufficient to inhibit powerful immune responses like the MLR.

  1. A novel thermal and pH responsive drug delivery system based on ZnO@PNIPAM hybrid nanoparticles

    International Nuclear Information System (INIS)

    Tan, Licheng; Liu, Jian; Zhou, Weihua; Wei, Junchao; Peng, Zhiping

    2014-01-01

    A smart ZnO@PNIPAM hybrid was prepared by grafting thermal responsive poly(N-isopropylacrylamide) (PNIPAM) on zinc oxide (ZnO) nanoparticles via surface-initiated atom transfer radical polymerization (ATRP). The thermal gravimetric analysis (TGA) shows that the grafting amount of PNIPAM was about 38%, and the SEM images show that the PNIPAM chains can prevent the aggregation of ZnO nanoparticles. The responsive properties of ZnO@PNIPAM were measured by photoluminescence spectra, and the results demonstrate that the PNIPAM chains grafted on ZnO surfaces can realize reversible thermal responsive and photoluminescence properties. An anticancer drug, doxorubicin (Dox), was used as a model drug and loaded into the hybrid nanoparticles, and an in vitro drug release test implied that ZnO@PNIPAM could work as a thermal responsive drug delivery system. Furthermore, pH sensitive drug releases were carried out in acetate buffer at pH 5.0 and pH 6.0 and in water at pH 7.0, and the results showed evident pH dependency, showing its pH responsive properties. - Graphical abstract: In this manuscript, thermal responsive poly(N-isopropylacrylamide) (PNIPAM) was grafted on the surface of ZnO nanoparticles. The obtained ZnO@PNIPAM hybrid showed reversible thermal responsive photoluminescent properties, and can also work as a thermal and pH responsive drug delivery system. - Highlights: • The ZnO@PNIPAM hybrid was prepared via ATRP. • The ZnO@PNIPAM hybrid showed thermal responsive properties. • The ZnO@PNIPAM hybrid can work as a thermal and pH responsive drug delivery system

  2. A novel thermal and pH responsive drug delivery system based on ZnO@PNIPAM hybrid nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Licheng; Liu, Jian; Zhou, Weihua [Department of Chemistry, Nanchang University, Nanchang 330031 (China); Wei, Junchao, E-mail: weijunchao@ncu.edu.cn [Department of Chemistry, Nanchang University, Nanchang 330031 (China); State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, 220 Handan Road, Shanghai 200433 (China); Peng, Zhiping [Department of Chemistry, Nanchang University, Nanchang 330031 (China)

    2014-12-01

    A smart ZnO@PNIPAM hybrid was prepared by grafting thermal responsive poly(N-isopropylacrylamide) (PNIPAM) on zinc oxide (ZnO) nanoparticles via surface-initiated atom transfer radical polymerization (ATRP). The thermal gravimetric analysis (TGA) shows that the grafting amount of PNIPAM was about 38%, and the SEM images show that the PNIPAM chains can prevent the aggregation of ZnO nanoparticles. The responsive properties of ZnO@PNIPAM were measured by photoluminescence spectra, and the results demonstrate that the PNIPAM chains grafted on ZnO surfaces can realize reversible thermal responsive and photoluminescence properties. An anticancer drug, doxorubicin (Dox), was used as a model drug and loaded into the hybrid nanoparticles, and an in vitro drug release test implied that ZnO@PNIPAM could work as a thermal responsive drug delivery system. Furthermore, pH sensitive drug releases were carried out in acetate buffer at pH 5.0 and pH 6.0 and in water at pH 7.0, and the results showed evident pH dependency, showing its pH responsive properties. - Graphical abstract: In this manuscript, thermal responsive poly(N-isopropylacrylamide) (PNIPAM) was grafted on the surface of ZnO nanoparticles. The obtained ZnO@PNIPAM hybrid showed reversible thermal responsive photoluminescent properties, and can also work as a thermal and pH responsive drug delivery system. - Highlights: • The ZnO@PNIPAM hybrid was prepared via ATRP. • The ZnO@PNIPAM hybrid showed thermal responsive properties. • The ZnO@PNIPAM hybrid can work as a thermal and pH responsive drug delivery system.

  3. Matrix metalloproteinase, hyaluronidase and elastase inhibitory potential of standardized extract of Centella asiatica.

    Science.gov (United States)

    Nema, Neelesh Kumar; Maity, Niladri; Sarkar, Birendra Kumar; Mukherjee, Pulok Kumar

    2013-09-01

    Centella asiatica (L.) Urban (Apiaceae), a valuable herb described in Ayurveda, is used in the indigenous system of medicine as a tonic to treat skin diseases. Centella asiatica methanol extract and its ethyl acetate, n-butanol and aqueous fraction, were subjected for the evaluation of skin care potential through the in vitro hyaluronidase, elastase and matrix metalloproteinase-1 (MMP-1) inhibitory assay. The C. asiatica plant was extracted with methanol and fractionated with ethyl acetate, n-butanol and water. The enzymatic activities were evaluated using ursolic acid and oleanolic acid as standards. Isolate molecule asiaticoside was quantified in the crude extract and fractions through high-performance liquid chromatography (HPLC) and structural was characterized by liquid chromatography-mass spectroscopy (LC-MS) and ¹H nuclear magnetic resonance (NMR). Isolated compound was also evaluated for in vitro enzyme assays. Extract exhibited anti-hyaluronidase and anti-elastase activity with IC₅₀ of 19.27 ± 0.37 and 14.54 ± 0.39 µg/mL, respectively, as compared to ursolic acid. Centella asiatica n-butanol fraction (CAnB) and isolated compound showed significant hyaluronidase (IC₅₀ = 27.00 ± 0.43 and 18.63 ± 0.33 µg/mL) and elastase (IC₅₀ = 29.15 ± 0.31 and 19.45 ± 0.25 µg/mL) inhibitory activities, respectively, and also showed significant MMP-1 inhibition (p asiatica may be a prospective agent for skin care.

  4. Characterization of cucurbita maxima phloem serpin-1 (CmPS-1). A developmentally regulated elastase inhibitor.

    Science.gov (United States)

    Yoo, B C; Aoki, K; Xiang, Y; Campbell, L R; Hull, R J; Xoconostle-Cázares, B; Monzer, J; Lee, J Y; Ullman, D E; Lucas, W J

    2000-11-10

    We report on the molecular, biochemical, and functional characterization of Cucurbita maxima phloem serpin-1 (CmPS-1), a novel 42-kDa serine proteinase inhibitor that is developmentally regulated and has anti-elastase properties. CmPS-1 was purified to near homogeneity from C. maxima (pumpkin) phloem exudate and, based on microsequence analysis, the cDNA encoding CmPS-1 was cloned. The association rate constant (k(a)) of phloem-purified and recombinant His(6)-tagged CmPS-1 for elastase was 3.5 +/- 1.6 x 10(5) and 2.7 +/- 0.4 x 10(5) m(-)(1) s(-)(1), respectively. The fraction of complex-forming CmPS-1, X(inh), was estimated at 79%. CmPS-1 displayed no detectable inhibitory properties against chymotrypsin, trypsin, or thrombin. The elastase cleavage sites within the reactive center loop of CmPS-1 were determined to be Val(347)-Gly(348) and Val(350)-Ser(351) with a 3:2 molar ratio. In vivo feeding assays conducted with the piercing-sucking aphid, Myzus persicae, established a close correlation between the developmentally regulated increase in CmPS-1 within the phloem sap and the reduced ability of these insects to survive and reproduce on C. maxima. However, in vitro feeding experiments, using purified phloem CmPS-1, failed to demonstrate a direct effect on aphid survival. Likely roles of this novel phloem serpin in defense against insects/pathogens are discussed.

  5. Myosin heavy chain and physiological adaptation of the rat diaphragm in elastase-induced emphysema

    Directory of Open Access Journals (Sweden)

    Stedman Hansell H

    2003-02-01

    Full Text Available Abstract Background Several physiological adaptations occur in the respiratory muscles in rodent models of elastase-induced emphysema. Although the contractile properties of the diaphragm are altered in a way that suggests expression of slower isoforms of myosin heavy chain (MHC, it has been difficult to demonstrate a shift in MHCs in an animal model that corresponds to the shift toward slower MHCs seen in human emphysema. Methods We sought to identify MHC and corresponding physiological changes in the diaphragms of rats with elastase-induced emphysema. Nine rats with emphysema and 11 control rats were studied 10 months after instillation with elastase. MHC isoform composition was determined by both reverse transcriptase polymerase chain reaction (RT-PCR and immunocytochemistry by using specific probes able to identify all known adult isoforms. Physiological adaptation was studied on diaphragm strips stimulated in vitro. Results In addition to confirming that emphysematous diaphragm has a decreased fatigability, we identified a significantly longer time-to-peak-tension (63.9 ± 2.7 ms versus 53.9 ± 2.4 ms. At both the RNA (RT-PCR and protein (immunocytochemistry levels, we found a significant decrease in the fastest, MHC isoform (IIb in emphysema. Conclusion This is the first demonstration of MHC shifts and corresponding physiological changes in the diaphragm in an animal model of emphysema. It is established that rodent emphysema, like human emphysema, does result in a physiologically significant shift toward slower diaphragmatic MHC isoforms. In the rat, this occurs at the faster end of the MHC spectrum than in humans.

  6. Cardiovascular Responsivity, Physical and Psychosocial Job Stress, and the Risk of Preterm Delivery

    National Research Council Canada - National Science Library

    Hatch, MauMaureen

    1998-01-01

    The overall goal of this grant is to examine the effects of physical and psychological stress as risk factors for preterm delivery among an ethnically diverse population of 1 000 active duty military...

  7. Cardiovascular Responsivity, Physical and Psychosocial Job Stress, and the Risk of Preterm Delivery

    National Research Council Canada - National Science Library

    Hatch, Maureen

    1999-01-01

    .... The study in progress, a military/civilian collaboration, will assess the effect of various sources of job stress as risk factors for preterm delivery among 1000 military women seeking prenatal care...

  8. Cardiovascular Responsivity, Physical and Psychosocial Job Stress, and the Risk of Preterm Delivery

    National Research Council Canada - National Science Library

    Hatch, Maureen

    2000-01-01

    .... This study, a military/civilian collaboration, will assess the effect of various sources of job stress as risk factors for pre term delivery among military women seeking prenatal care at Wilford Hall Medical Center...

  9. Cardiovascular Responsivity, Physical and Psychosocial Job Stress, and the Risk of Preterm Delivery

    National Research Council Canada - National Science Library

    Hatch, Maureen

    2001-01-01

    ..., was 2.0 (95% Confidence Interval (CI) 0.9, 4.4). Of the job stressors we studied, including long hours, only a High Workload and Low Job Satisfaction had elevated relative risks for preterm delivery...

  10. Cardiovascular Responsivity, Physical and Psychosocial Job Stress, and the Risk of Preterm Delivery

    National Research Council Canada - National Science Library

    Hatch, Maureen

    2000-01-01

    .... and one that appears to be quite prevalent among defense women. While defense women as a group are young, healthy, fit and have excellent access to prenatal care, their pre term delivery rates are higher than average...

  11. Cardiovascular Responsivity, Physical and Psychosocial Job Stress, and the Risk of Preterm Delivery

    National Research Council Canada - National Science Library

    Hatch, Maureen

    1999-01-01

    .... and one that appears to be quite prevalent among defense women. While defense woman as a group are young, healthy, fit and have excellent access to prenatal care, their preterm delivery rates are higher than average...

  12. Cardiovascular Responsivity, Physical and Psychosocial Job Stress, and the Risk of Preterm Delivery

    National Research Council Canada - National Science Library

    Hatch, Maureen

    2001-01-01

    We recruited a cohort of over 600 active-duty military women attending the prenatal clinic at Wilbur Hall Medical Center and followed them until delivery to assess associations between stress, cardio...

  13. Electrically responsive microreservoires for controllable delivery of dexamethasone in bone tissue engineering

    Science.gov (United States)

    Paun, Irina Alexandra; Zamfirescu, Marian; Luculescu, Catalin Romeo; Acasandrei, Adriana Maria; Mustaciosu, Cosmin Catalin; Mihailescu, Mona; Dinescu, Maria

    2017-01-01

    A major concern in orthopedic implants is to decrease the chronic inflammation using specific drug therapies. The newest strategies rely on the controlled delivery of antiinflammatory drugs from carrier biointerfaces designed in the shape of 3D architectures. We report on electrically responsive microreservoires (ERRs) acting as microcontainers for antiinflammatory drugs, as potential biointerfaces in orthopedic implants. The ERRs consist in arrays of vertical microtubes produced by laser direct writing using two photon polymerization effects (2PP_LDW) of a commercially available photoresist, IP-L780. A polypyrrole (conductive)/dexamethasone (drug model) (PPy/Dex) mixture was loaded into the ERRs via a simple immersion process. Then, the ERRs were sealed with a poly(lactic-co-glycolic acid)(PLGA) layer by Matrix Assisted Pulsed Laser Evaporation. ERRs stimulation using voltage cycles between -1 V and +1 V, applied at specific time intervals, at a scan rate of 0.1 V s-1, enabled to control the Dex release. The release time scales were between 150 and 275 h, while the concentrations of Dex released were between 450-460 nM after three applied voltage cycles, for different microreservoires dimensions. The proposed approach was validated in osteoblast-like MG-63 cell cultures. Cell viability and adhesion assays showed that the Dex-loaded ERRs sustained the cells growth and preserved their characteristic polygonal shape. Importantly, for the electrically-stimulated Dex release, the level of the alkaline phosphatase activity increased twice, the osteogenic differentiation surpassed by 1.6 times and the relative level of osteocalcin gene expression was 2.2 times higher as compared with the unstimulated drug release. Overall, the ERRs were able to accelerate the cells osteogenic differentiation via electrically controlled release of Dex.

  14. TGF-β1 and granulocyte elastase in the evaluation of activity of inflammatory bowel disease. A pilot study

    Directory of Open Access Journals (Sweden)

    Irena Ciećko-Michalska

    2014-01-01

    Full Text Available Introduction: The aim was to assess the usefulness of TGF-β1 and elastase in the evaluation of activity of ulcerative colitis (UC and Crohn’s disease (CD.Material and Methods: 32 patients diagnosed with UC, 31 with CD and 30 healthy volunteers were enrolled in this study. Diagnosis of the disease was confirmed by videocolonoscopy and histopathological evaluation of intestinal biopsies. Disease activity was assessed by use of the Mayo Scoring System for Assessment of Ulcerative Colitis Activity in UC patients and by CDAI in CD patients. hsCRP was determined by the immunonephelometric method, TGF-β1 and elastase plasma concentration by ELISA. The results of the study were analyzed using Statistica and R statistical language.Results: In UC a positive correlation between disease activity and platelet level, hsCRP and TGF-β1 concentration was noted. Elastase concentration in UC patients was significantly higher than in CD, but there was no correlation with the activity of the disease. In CD patients we observed a positive correlation between disease activity and leukocytes, platelet levels and elastase concentration, and a very low correlation with hsCRP and TGF-β1.Discussion: Determination of TGF-β1 can be used for evaluation of inflammatory activity in UC and it is connected with elevated concentrations of CRP and platelets. To a lower extent TGF-β1 can also be used for evaluation of inflammatory activity in CD. Examination of elastase concentration may be useful in the assessment of CD activity. Plasma elastase concentration may be helpful in UC and CD differentiation. The preliminary results of this investigation seem promising; nevertheless, more studies are necessary.

  15. Electrically responsive microreservoires for controllable delivery of dexamethasone in bone tissue engineering

    Energy Technology Data Exchange (ETDEWEB)

    Paun, Irina Alexandra, E-mail: irina.paun@physics.pub.ro [Faculty of Applied Sciences, University Politehnica of Bucharest, RO-060042 (Romania); National Institute for Laser, Plasma and Radiation Physics, Magurele, Bucharest RO-077125 (Romania); Zamfirescu, Marian [National Institute for Laser, Plasma and Radiation Physics, Magurele, Bucharest RO-077125 (Romania); Luculescu, Catalin Romeo, E-mail: catalin.luculescu@inflpr.ro [National Institute for Laser, Plasma and Radiation Physics, Magurele, Bucharest RO-077125 (Romania); Acasandrei, Adriana Maria; Mustaciosu, Cosmin Catalin [Horia Hulubei National Institute for Physics and Nuclear Engineering IFIN-HH, Magurele, Bucharest RO-077125 (Romania); Mihailescu, Mona [Faculty of Applied Sciences, University Politehnica of Bucharest, RO-060042 (Romania); Dinescu, Maria, E-mail: dinescum@nipne.ro [National Institute for Laser, Plasma and Radiation Physics, Magurele, Bucharest RO-077125 (Romania)

    2017-01-15

    Highlights: • Electrically-responsive microreservoires (ERRs) for controlled release of Dex. • ERRs made of microtubes produced by two photon polymerization of IP-L780 photoresist. • Microtubes loaded with PPy/Dex mixture and sealed with a thin PLGA layer. • Kinetics of Dex release controlled by electrical stimulation of the ERRs. • Controlled Dex release accelerates the cells osteogenic differentiation. - Abstract: A major concern in orthopedic implants is to decrease the chronic inflammation using specific drug therapies. The newest strategies rely on the controlled delivery of antiinflammatory drugs from carrier biointerfaces designed in the shape of 3D architectures. We report on electrically responsive microreservoires (ERRs) acting as microcontainers for antiinflammatory drugs, as potential biointerfaces in orthopedic implants. The ERRs consist in arrays of vertical microtubes produced by laser direct writing using two photon polymerization effects (2PP-LDW) of a commercially available photoresist, IP-L780. A polypyrrole (conductive)/dexamethasone (drug model) (PPy/Dex) mixture was loaded into the ERRs via a simple immersion process. Then, the ERRs were sealed with a poly(lactic-co-glycolic acid)(PLGA) layer by Matrix Assisted Pulsed Laser Evaporation. ERRs stimulation using voltage cycles between −1 V and +1 V, applied at specific time intervals, at a scan rate of 0.1 V s{sup −1}, enabled to control the Dex release. The release time scales were between 150 and 275 h, while the concentrations of Dex released were between 450–460 nM after three applied voltage cycles, for different microreservoires dimensions. The proposed approach was validated in osteoblast-like MG-63 cell cultures. Cell viability and adhesion assays showed that the Dex-loaded ERRs sustained the cells growth and preserved their characteristic polygonal shape. Importantly, for the electrically-stimulated Dex release, the level of the alkaline phosphatase activity increased

  16. Electrically responsive microreservoires for controllable delivery of dexamethasone in bone tissue engineering

    International Nuclear Information System (INIS)

    Paun, Irina Alexandra; Zamfirescu, Marian; Luculescu, Catalin Romeo; Acasandrei, Adriana Maria; Mustaciosu, Cosmin Catalin; Mihailescu, Mona; Dinescu, Maria

    2017-01-01

    Highlights: • Electrically-responsive microreservoires (ERRs) for controlled release of Dex. • ERRs made of microtubes produced by two photon polymerization of IP-L780 photoresist. • Microtubes loaded with PPy/Dex mixture and sealed with a thin PLGA layer. • Kinetics of Dex release controlled by electrical stimulation of the ERRs. • Controlled Dex release accelerates the cells osteogenic differentiation. - Abstract: A major concern in orthopedic implants is to decrease the chronic inflammation using specific drug therapies. The newest strategies rely on the controlled delivery of antiinflammatory drugs from carrier biointerfaces designed in the shape of 3D architectures. We report on electrically responsive microreservoires (ERRs) acting as microcontainers for antiinflammatory drugs, as potential biointerfaces in orthopedic implants. The ERRs consist in arrays of vertical microtubes produced by laser direct writing using two photon polymerization effects (2PP-LDW) of a commercially available photoresist, IP-L780. A polypyrrole (conductive)/dexamethasone (drug model) (PPy/Dex) mixture was loaded into the ERRs via a simple immersion process. Then, the ERRs were sealed with a poly(lactic-co-glycolic acid)(PLGA) layer by Matrix Assisted Pulsed Laser Evaporation. ERRs stimulation using voltage cycles between −1 V and +1 V, applied at specific time intervals, at a scan rate of 0.1 V s −1 , enabled to control the Dex release. The release time scales were between 150 and 275 h, while the concentrations of Dex released were between 450–460 nM after three applied voltage cycles, for different microreservoires dimensions. The proposed approach was validated in osteoblast-like MG-63 cell cultures. Cell viability and adhesion assays showed that the Dex-loaded ERRs sustained the cells growth and preserved their characteristic polygonal shape. Importantly, for the electrically-stimulated Dex release, the level of the alkaline phosphatase activity increased twice

  17. The LasB Elastase of Pseudomonas aeruginosa Acts in Concert with Alkaline Protease AprA To Prevent Flagellin-Mediated Immune Recognition.

    Science.gov (United States)

    Casilag, Fiordiligie; Lorenz, Anne; Krueger, Jonas; Klawonn, Frank; Weiss, Siegfried; Häussler, Susanne

    2016-01-01

    The opportunistic pathogen Pseudomonas aeruginosa is capable of establishing severe and persistent infections in various eukaryotic hosts. It encodes a wide array of virulence factors and employs several strategies to evade immune detection. In the present study, we screened the Harvard Medical School transposon mutant library of P. aeruginosa PA14 for bacterial factors that modulate interleukin-8 responses in A549 human airway epithelial cells. We found that in addition to the previously identified alkaline protease AprA, the elastase LasB is capable of degrading exogenous flagellin under calcium-replete conditions and prevents flagellin-mediated immune recognition. Our results indicate that the production of two proteases with anti-flagellin activity provides a failsafe mechanism for P. aeruginosa to ensure the maintenance of protease-dependent immune-modulating functions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  18. Lysophosphatidic acid inhibition of the accumulation of Pseudomonas aeruginosa PAO1 alginate, pyoverdin, elastase and LasA

    DEFF Research Database (Denmark)

    Laux, D.C.; Corson, J.M.; Givskov, Michael Christian

    2002-01-01

    The pathogenesis of Pseudomonas aeruginosa is at least partially attributable to its ability to synthesize and secrete the siderophore pyoverdin and the two zinc metal loproteases elastase and LasA, and its ability to form biofilms in which bacterial cells are embedded in an alginate matrix....... In the present study, a lysophospholipid, 1-paimitoyl-2-hydroxy-sn-glycero-3-phosphate [also called monopalmitoylphosphatidic acid (MPPA)], which accumulates in inflammatory exudates, was shown to inhibit the extracellular accumulation of P. aeruginosa PAO1 alginate, elastase, LasA protease and the siderophore...

  19. Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids

    OpenAIRE

    Lam, JKW; Chan, HK; Chow, YT; Tang, P; Liang, W; Kwok, PCL; Mason, AJ

    2014-01-01

    Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar fluid (BALF), making this class of peptides ...

  20. Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids.

    Science.gov (United States)

    Liang, Wanling; Kwok, Philip C L; Chow, Michael Y T; Tang, Patricia; Mason, A James; Chan, Hak-Kim; Lam, Jenny K W

    2014-01-01

    Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease, but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar lavage fluid (BALF), making this class of peptides attractive candidates for delivering nucleic acids to lung tissues. To further assess the suitability of pH responsive peptides for pulmonary delivery by inhalation, dry powder formulations of pH responsive peptides and plasmid DNA, with mannitol as carrier, were produced by either spray drying (SD) or spray freeze drying (SFD). The properties of the two types of powders were characterised and compared using scanning electron microscopy (SEM), next generation impactor (NGI), gel retardation and in vitro transfection via a twin stage impinger (TSI) following aerosolisation by a dry powder inhaler (Osmohaler™). Although the aerodynamic performance and transfection efficacy of both powders were good, the overall performance revealed SD powders to have a number of advantages over SFD powders and are the more effective formulation with potential for efficient nucleic acid delivery through inhalation. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater.

    Science.gov (United States)

    Yun, Jumi; Lee, Dae Hoon; Im, Ji Sun; Kim, Hyung-Il

    2012-08-01

    Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Multitriggered Tumor-Responsive Drug Delivery Vehicles Based on Protein and Polypeptide Coassembly for Enhanced Photodynamic Tumor Ablation.

    Science.gov (United States)

    Zhang, Ning; Zhao, Fenfang; Zou, Qianli; Li, Yongxin; Ma, Guanghui; Yan, Xuehai

    2016-11-01

    Tumor-responsive nanocarriers are highly valuable and demanded for smart drug delivery particularly in the field of photodynamic therapy (PDT), where a quick release of photosensitizers in tumors is preferred. Herein, it is demonstrated that protein-based nanospheres, prepared by the electrostatic assembly of proteins and polypeptides with intermolecular disulfide cross-linking and surface polyethylene glycol coupling, can be used as versatile tumor-responsive drug delivery vehicles for effective PDT. These nanospheres are capable of encapsulation of various photosensitizers including Chlorin e6 (Ce6), protoporphyrin IX, and verteporfin. The Chlorin e6-encapsulated nanospheres (Ce6-Ns) are responsive to changes in pH, redox potential, and proteinase concentration, resulting in multitriggered rapid release of Ce6 in an environment mimicking tumor tissues. In vivo fluorescence imaging results indicate that Ce6-Ns selectively accumulate near tumors and the quick release of Ce6 from Ce6-Ns can be triggered by tumors. In tumors the fluorescence of released Ce6 from Ce6-Ns is observed at 0.5 h postinjection, while in normal tissues the fluorescence appeared at 12 h postinjection. Tumor ablation is demonstrated by in vivo PDT using Ce6-Ns and the biocompatibility of Ce6-Ns is evident from the histopathology imaging, confirming the enhanced in vivo PDT efficacy and the biocompatibility of the assembled drug delivery vehicles. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Role of α-Helical Structure in Organic Solvent-Activated Homodimer of Elastase Strain K

    Directory of Open Access Journals (Sweden)

    Chee Fah Wong

    2011-09-01

    Full Text Available Recombinant elastase strain K overexpressed from E. coli KRX/pCon2(3 was purified to homogeneity by a combination of hydrophobic interaction chromatography and ion exchange chromatography, with a final yield of 48% and a 25-fold increase in specific activity. The purified protein had exhibited a first ever reported homodimer size of 65 kDa by SDS-PAGE and MALDI-TOF, a size which is totally distinct from that of typically reported 33 kDa monomer from P. aeruginosa. The organic solvent stability experiment had demonstrated a stability pattern which completely opposed the rules laid out in previous reports in which activity stability and enhancement were observed in hydrophilic organic solvents such as DMSO, methanol, ethanol and 1-propanol. The high stability and enhancement of the enzyme in hydrophilic solvents were explained from the view of alteration in secondary structures. Elastinolytic activation and stability were observed in 25 and 50% of methanol, respectively, despite slight reduction in α-helical structure caused upon the addition of the solvent. Further characterization experiments had postulated great stability and enhancement of elastase strain K in broad range of temperatures, pHs, metal ions, surfactants, denaturing agents and substrate specificity, indicating its potential application in detergent formulation.

  4. Characterization and primary structure of elastase inhibitor, AFLEI, from Aspergillus flavus.

    Science.gov (United States)

    Okumura, Yoshiyuki; Ogawa, Kenji; Uchiya, Kei-ichi

    2007-01-01

    The amino acid sequence of elastase inhibitor, AFLEI, isolated from Aspergillus flavus was determined by the Edman sequencing procedure of peptides derived from digests utilizing clostripain. A molecular weight of 7,525.8 was observed by TOF-MS. AFLEI contained 68 amino acid residues and has a calculated molecular weight of 7,526.2. The search for amino acid homology with other proteins demonstrated that amino acid residues 1 to 51 of AFLEI are 100% identical to residues 20 to 70 of the hypothetical protein Afu3g14940. The Michaelis constant (Km) for succinyl L-alanyl- L-alanyl- L-alanyl p-nitroanilide (STANA), and inhibition constant (Ki), for elastase of AFLEI, were found to be 6.7 x 10(2) microM and 4.0 x 10(-2) microM, respectively. Inhibitory activity was compared with six protease inhibitors (ulinastatin, nafamostat mesilate, sivelestat sodium hydrate, gabexate mesilate, elastatinal and elafin). The other six protease inhibitors demonstrated very weak inhibitory activity by comparison with AFLEI.

  5. Triterpenes from Meliosma oldhamii Miquel Branches and their Elastase Inhibitory Activities

    Directory of Open Access Journals (Sweden)

    Sang-Hee Byeon

    2015-06-01

    Full Text Available Phytochemical investigation o n the ethanol extracts of Meliosma oldhamii Miquel branches led to the isolation of seven triterpene constituents: betulin ( 1 , lupeol ( 2 , oleanolic acid ( 3 , 3 b -acetoxyolean-12-en-28-acid (4, 3 b -acetoxyolean-12-en-28-aldehyde (5, 3 b -acetoxy-28-hydroxyolean-12-ene (6 and maslinic acid ( 7 . Their chemical structures were determined based on the spectr oscopic studies, as well as by comparison with literature data. Elastase inhibition activities were examined for the isolates using ursolic acid as a positive control . In this test , the compounds 1 and 3 proved to inhibit porcine pancreatic elastase with an IC 50 values of 39.3 and 39.5 m g/mL, indicating comparable activities to ursolic acid (IC 50 = 28.5 m g/mL. This study demonstrated that the M. oldhamii extract including triterpenes has potentials applicable as anti-wrinkle ingredient in cosmetic formulations. All of the compounds 1 - 7 were isolated for the first time from M. oldhamii .

  6. In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles

    Science.gov (United States)

    Su, Xingfang; Fricke, Jennifer; Kavanagh, Daniel; Irvine, Darrell J.

    2012-01-01

    Biodegradable core-shell structured nanoparticles with a poly(β-amino-ester) (PBAE) core enveloped by a phospholipid bilayer shell were developed for in vivo mRNA delivery, with a view toward delivery of mRNA-based vaccines. The pH-responsive PBAE component was chosen to promote endosome disruption, while the lipid surface layer was selected to minimize toxicity of the polycation core. Messenger RNA was efficiently adsorbed via electrostatic interactions onto the surface of these net positively-charged nanoparticles. In vitro, mRNA-loaded particle uptake by dendritic cells (DCs) led to mRNA delivery into the cytosol with low cytotoxicity, followed by translation of the encoded protein in these difficult-to-transfect cells at a frequency of ~30%. Particles loaded with mRNA administered intranasally in mice led to the expression of the reporter protein luciferase in vivo as soon as 6 h after administration, a timepoint when naked mRNA given i.n. showed no expression. At later timepoints, luciferase expression was detected in naked mRNA-treated mice, but this group showed a wide variation in levels of transfection, compared to particle-treated mice. This system may thus be promising for non-invasive delivery of mRNA-based vaccines. PMID:21417235

  7. SU-F-R-56: Early Assessment of Treatment Response During Radiation Therapy Delivery for Esophageal Cancer Using Quantitative CT

    Energy Technology Data Exchange (ETDEWEB)

    Li, D [Henan Province Tumor Hospital, Zhengzhou, Henan (China); Chen, X; Li, X [Medical College of Wisconsin, Milwaukee, WI (United States); Wu, H [Medical college of Wisconsin, Milwaukee, WI (United States); Wang, J [Henan province Tumor hospital, Zhengzhou, Henan (China)

    2016-06-15

    Purpose: To investigate the feasibility of assessing treatment response using CTs during delivery of radiation therapy (RT) for esophageal cancer. Methods: Daily CTs acquired using a CT-on-Rails during the routine CT-guided RT for 20 patients with stage II to IV esophageal cancers were analyzed. All patients were treated with combined chemotherapy and IMRT of 45–50 Gy in 25 fractions, and were followed up for two years. Contours of GTV, spinal cord, and non-specified tissue (NST) irradiated with low dose were generated on each daily CT. A series of CT-texture metrics including Hounsfield Unit (HU) histogram, mean HU, standard derivation (STD), entropy, and energy were obtained in these contours on each daily CT. The changes of these metrics and GTV volume during RT delivery were calculated and correlated with treatment outcome. Results: Changes in CT texture (e.g., HU histogram) in GTV and spinal cord (but not in NST) were observed during RT delivery and were consistently increased with radiation dose. For the 20 cases studied, the mean HU in GTV was reduced on average by 4.0HU from the first to the last fractions, while 8 patients (responders) had larger reductions in GTV mean HU (average 7.8 HU) with an average GTV reduction of 51% and had increased consistently in GTV STD and entropy with radiation dose. The rest of 12 patients (non-responders) had lower reductions in GTV mean HU (average 1.5HU) and almost no change in STD and entropy. For the 8 responders, 2 experienced complete response, 7 (88%) survived and 1 died. In contrast, for the 12 non-responders, 4 (33%) survived and 8 died. Conclusion: Radiation can induce changes in CT texture in tumor (e.g., mean HU) during the delivery of RT for esophageal cancer. If validated with more data, such changes may be used for early prediction of RT response for esophageal cancer.

  8. Intracellular redox-responsive nanocarrier for plasmid delivery: in vitro characterization and in vivo studies in mice

    Directory of Open Access Journals (Sweden)

    Zhang L

    2016-10-01

    Full Text Available Lifen Zhang,1,2 Yushun Zhang,1,2 Zhenzhen Chen,3 Yuling He1 1State Key Laboratory of Applied Organic Chemistry, 2Key Laboratory of Nonferrous Metals Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 3Department of Bioengineering, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China Abstract: Although some modifications of polyethyleneimine (PEI properties have been explored to balance the transfection efficiency and cytotoxicity, its successful plasmid delivery in vitro and in vivo to realize its true therapeutic potentials remains a major challenge, mainly due to intracellular trafficking barriers. Herein, we present a delivery nanocarrier Pluronic-PEI-SS by conjugating reducible disulfide-linked PEI (PEI-SS to biocompatible Pluronic for enhanced DNA delivery and transfection efficiency in vitro and in vivo. Pluronic-PEI-SS strongly condensed plasmid DNA to low positively charged nanocomplexes, exhibited good stability against deoxyribonuclease I digestion, and tended to be easily degraded in the presence of reducing agent 1,4-dithiothreitol. The in vitro transfection of the complex Pluronic-PEI-SS/DNA into HeLa and 293T cells resulted in lower cytotoxicity as well as significantly higher cellular uptake, nucleus transfection, and gene expression than Pluronic-PEI (25 kDa, PEI-SS, and PEI 25 kDa given alone. Furthermore, the in vivo transfection study demonstrated that Pluronic-PEI-SS/DNA complexes induced a higher enrichment than the commercial PEI/DNA complex in the tumor, indicating their potential application as biocompatible vector in gene delivery. Keywords: responsive, gene delivery, polycation, Pluronic, disulfide-linked 

  9. Intracellular responsive dual delivery by endosomolytic polyplexes carrying DNA anchored porous silicon nanoparticles

    DEFF Research Database (Denmark)

    Shahbazi, Mohammad Ali; Almeida, Patrick Vingadas; Correia, Alexandra

    2017-01-01

    -alt-maleic acid)) and a cationic endosomolytic polymer (polyethyleneimine). This combined nanocomposite is successfully tested for the co-delivery of hydrophobic (sorafenib) or hydrophilic (calcein) molecules loaded within the porous core, and an imaging agent covalently integrated into the polyplex shell...

  10. Cell responses to the mechanochemical microenvironment—Implications for regenerative medicine and drug delivery

    Czech Academy of Sciences Publication Activity Database

    Rehfeldt, F.; Engler, A. J.; Eckhardt, Adam; Fariyal, C.; Discher, D. E.

    2007-01-01

    Roč. 59, č. 13 (2007), s. 1329-1339 ISSN 0169-409X R&D Projects: GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : cell s * tissue regeneration * drug delivery Subject RIV: CE - Biochemistry Impact factor: 8.224, year: 2007

  11. Effect of preoperative pregabalin on post-caesarean delivery analgesia: a dose-response study.

    Science.gov (United States)

    El Kenany, S; El Tahan, M R

    2016-05-01

    We hypothesised that preoperative administration of a single-dose of pregabalin would be associated with lower morphine consumption after uncomplicated caesarean delivery. After Institutional Ethics Committee approval, 135 parturients scheduled for elective caesarean delivery under spinal anaesthesia were randomly allocated to receive either placebo, or oral pregabalin 150mg or 300mg, one hour before induction of anaesthesia. Maternal cumulative morphine requirement at 24h, pain scores, sedation scores, nausea and vomiting, pruritus, pregabalin-related adverse effects, Apgar scores, Neurologic and Adaptive Capacity scores and umbilical cord acid-base status were recorded. Compared with placebo or pregabalin 150mg, the use of a preoperative dose of pregabalin 300mg resulted in significantly lower cumulative morphine consumption at 24h (mean dose: placebo 12.9mg [95% CI 11.6 to 14.2]; pregabalin 150mg 11.9mg; [95% CI 10.7 to 13.1]; pregabalin 300mg 6mg [95% CI 5.4 to 7.3]; Ppain scores at 4h and 6h after delivery (Pumbilical cord acid-base status. Three babies in the pregabalin 300mg group (6.7%) experienced short-term poor latching-on for breastfeeding. In our study, preoperative administration of pregabalin 300mg reduced postoperative morphine consumption and early postoperative pain in parturients undergoing elective caesarean delivery, although maternal side effects were more common. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Treating Childhood Anxiety in Schools: Service Delivery in a Response to Intervention Paradigm

    Science.gov (United States)

    Sulkowski, Michael L.; Joyce, Diana K.; Storch, Eric A.

    2012-01-01

    Millions of youth who attend schools in the United States suffer from clinically significant anxiety. Left untreated, these students often experience significant disruptions in their academic, social, and family functioning. Fortunately, promising treatments exist for childhood anxiety that are amenable for delivery in school settings. However,…

  13. Activation of Pseudomonas aeruginosa elastase in Pseudomonas putida by triggering dissociation of the propeptide-enzyme complex

    NARCIS (Netherlands)

    Braun, P; Bitter, W; Tommassen, J

    2000-01-01

    The propeptide of Pseudomonas aeruginosa elastase functions both as an intramolecular chaperone required for the folding of the enzyme and as an inhibitor that prevents activity of the enzyme before its secretion into the extracellular medium. Since expression of the lasB gene, which encodes

  14. UV-crosslinkable and thermo-responsive chitosan hybrid hydrogel for NIR-triggered localized on-demand drug delivery.

    Science.gov (United States)

    Wang, Lei; Li, Baoqiang; Xu, Feng; Xu, Zheheng; Wei, Daqing; Feng, Yujie; Wang, Yaming; Jia, Dechang; Zhou, Yu

    2017-10-15

    Innovative drug delivery technologies based on smart hydrogels for localized on-demand drug delivery had aroused great interest. To acquire smart UV-crosslinkable chitosan hydrogel for NIR-triggered localized on-demanded drug release, a novel UV-crosslinkable and thermo-responsive chitosan was first designed and synthesized by grafting with poly N-isopropylacrylamide, acetylation of methacryloyl groups and embedding with photothermal carbon. The UV-crosslinkable unit (methacryloyl groups) endowed chitosan with gelation via UV irradiation. The thermo-responsive unit (poly N-isopropylacrylamide) endowed chitosan hydrogel with temperature-triggered volume shrinkage and reversible swelling/de-swelling behavior. The chitosan hybrid hydrogel embedded with photothermal carbon exhibited distinct NIR-triggered volume shrinkage (∼42% shrinkage) in response to temperature elevation as induced by NIR laser irradiation. As a demonstration, doxorubicin release rate was accelerated and approximately 40 times higher than that from non-irradiated hydrogels. The UV-crosslinkable and thermal-responsive hybrid hydrogel served as in situ forming hydrogel-based drug depot is developed for NIR-triggered localized on-demand release. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Neutrophil elastase and cathepsin G protein and messenger RNA expression in bone marrow from a patient with Chediak-Higashi syndrome

    Science.gov (United States)

    Burnett, D; Ward, C J; Stockley, R A; Dalton, R G; Cant, A J; Hoare, S; Crocker, J

    1995-01-01

    Aims—To determine whether neutrophil elastase and cathepsin G are expressed, at transcriptional or translational levels, in the bone marrow from a patient with Chediak-Higashi syndrome. Methods—Blood neutrophils were isolated from three patients with Chediak-Higashi disease and bone marrow was collected from one. Cell lysates were analysed for neutrophil elastase and cathepsin G activity by enzyme linked immunosorbent assay and western immunoblotting. Northern blotting was used to detect messenger RNA (mRNA) for cathepsin G, elastase and β-actin in bone marrow extracts, and immunohistochemistry was used to localise the enzymes in marrow myeloid cells. Results—Elastase and cathepsin G were not detected in blood neutrophils from the patients with Chediak-Higashi disease, but were present in bone marrow cells, although immunohistochemistry showed they were not within cytoplasmic granules. The concentrations of elastase and cathepsin G in Chediak-Higashi bone marrow were about 25 and 15%, respectively, of those in normal marrow. Quantitative scanning of northern blots showed that elastase and cathepsin G mRNA, corrected for β-actin mRNA, were expressed equally in normal marrow. Conclusions—Transcription of elastase and cathepsin G mRNA in promyelocytes of patients with Chediak-Higashi disease is normal, but the protein products are deficient in these cells and absent in mature neutrophils. This suggests that the translated proteins are not packaged into azurophil granules but are degaded or secreted from the cells. Images PMID:16695972

  16. A Dual Bioconjugated Virus-Like Nanoparticle as a Drug Delivery System and Comparison with a pH-Responsive Delivery System

    Directory of Open Access Journals (Sweden)

    Roya Biabanikhankahdani

    2018-04-01

    Full Text Available Modifications of virus-like nanoparticles (VLNPs using chemical conjugation techniques have brought the field of virology closer to nanotechnology. The huge surface area to volume ratio of VLNPs permits multiple copies of a targeting ligand and drugs to be attached per nanoparticle. By exploring the chemistry of truncated hepatitis B core antigen (tHBcAg VLNPs, doxorubicin (DOX was coupled covalently to the external surface of these nanoparticles via carboxylate groups. About 1600 DOX molecules were conjugated on each tHBcAg VLNP. Then, folic acid (FA was conjugated to lysine residues of tHBcAg VLNPs to target the nanoparticles to cancer cells over-expressing folic acid receptor (FR. The result demonstrated that the dual bioconjugated tHBcAg VLNPs increased the accumulation and uptake of DOX in the human cervical and colorectal cancer cell lines compared with free DOX, resulting in enhanced cytotoxicity of DOX towards these cells. The fabrication of these dual bioconjugated nanoparticles is simple, and drugs can be easily conjugated with a high coupling efficacy to the VLNPs without any limitation with respect to the cargo’s size or charge, as compared with the pH-responsive system based on tHBcAg VLNPs. These dual bioconjugated nanoparticles also have the potential to be modified for other combinatorial drug deliveries.

  17. Magnetic stimulus responsive vancomycin drug delivery system based on chitosan microbeads embedded with magnetic nanoparticles.

    Science.gov (United States)

    Mohapatra, Ankita; Harris, Michael A; LeVine, David; Ghimire, Madhav; Jennings, Jessica A; Morshed, Bashir I; Haggard, Warren O; Bumgardner, Joel D; Mishra, Sanjay R; Fujiwara, Tomoko

    2017-10-20

    Local antibiotic delivery can overcome some of the shortcomings of systemic therapy, such as low local concentrations and delivery to avascular sites. A localized drug delivery system (DDS), ideally, could also use external stimuli to modulate the normal drug release profile from the DDS to provide efficacious drug administration and flexibility to healthcare providers. To achieve this objective, chitosan microbeads embedded with magnetic nanoparticles were loaded with the antibiotic vancomycin and stimulated by a high frequency alternating magnetic field. Three such stimulation sessions separated by 1.5 h were applied to each test sample. The chromatographic analysis of the supernatant from these stimulated samples showed more than approximately 200% higher release of vancomycin from the DDS after the stimulation periods compared to nonstimulated samples. A 16-day long term elution study was also conducted where the DDS was allowed to elute drug through normal diffusion over a period of 11 days and stimulated on day 12 and day 15, when vancomycin level had dropped below therapeutic levels. Magnetic stimulation boosted elution of test groups above minimum inhibitory concentration (MIC), as compared to control groups (with no stimulation) which remained below MIC. The drug release from test groups in the intervals where no stimulation was given showed similar elution behavior to control groups. These results indicate promising possibilities of controlled drug release using magnetic excitation from a biopolymer-based DDS. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2017. © 2017 Wiley Periodicals, Inc.

  18. Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain.

    Science.gov (United States)

    Zhao, Peishen; Lieu, TinaMarie; Barlow, Nicholas; Sostegni, Silvia; Haerteis, Silke; Korbmacher, Christoph; Liedtke, Wolfgang; Jimenez-Vargas, Nestor N; Vanner, Stephen J; Bunnett, Nigel W

    2015-05-29

    Proteases that cleave protease-activated receptor-2 (PAR(2)) at Arg(36)↓Ser(37) reveal a tethered ligand that binds to the cleaved receptor. PAR(2) activates transient receptor potential (TRP) channels of nociceptive neurons to induce neurogenic inflammation and pain. Although proteases that cleave PAR(2) at non-canonical sites can trigger distinct signaling cascades, the functional importance of the PAR(2)-biased agonism is uncertain. We investigated whether neutrophil elastase, a biased agonist of PAR(2), causes inflammation and pain by activating PAR2 and TRP vanilloid 4 (TRPV4). Elastase cleaved human PAR(2) at Ala(66)↓Ser(67) and Ser(67)↓Val(68). Elastase stimulated PAR(2)-dependent cAMP accumulation and ERK1/2 activation, but not Ca(2+) mobilization, in KNRK cells. Elastase induced PAR(2) coupling to Gαs but not Gαq in HEK293 cells. Although elastase did not promote recruitment of G protein-coupled receptor kinase-2 (GRK(2)) or β-arrestin to PAR(2), consistent with its inability to promote receptor endocytosis, elastase did stimulate GRK6 recruitment. Elastase caused PAR(2)-dependent sensitization of TRPV4 currents in Xenopus laevis oocytes by adenylyl cyclase- and protein kinase A (PKA)-dependent mechanisms. Elastase stimulated PAR(2)-dependent cAMP formation and ERK1/2 phosphorylation, and a PAR(2)- and TRPV4-mediated influx of extracellular Ca(2+) in mouse nociceptors. Adenylyl cyclase and PKA-mediated elastase-induced activation of TRPV4 and hyperexcitability of nociceptors. Intraplantar injection of elastase to mice caused edema and mechanical hyperalgesia by PAR(2)- and TRPV4-mediated mechanisms. Thus, the elastase-biased agonism of PAR(2) causes Gαs-dependent activation of adenylyl cyclase and PKA, which activates TRPV4 and sensitizes nociceptors to cause inflammation and pain. Our results identify a novel mechanism of elastase-induced activation of TRPV4 and expand the role of PAR(2) as a mediator of protease-driven inflammation and pain.

  19. Reductively Responsive Hydrogel Nanoparticles with Uniform Size, Shape, and Tunable Composition for Systemic siRNA Delivery in Vivo.

    Science.gov (United States)

    Ma, Da; Tian, Shaomin; Baryza, Jeremy; Luft, J Christopher; DeSimone, Joseph M

    2015-10-05

    To achieve the great potential of siRNA based gene therapy, safe and efficient systemic delivery in vivo is essential. Here we report reductively responsive hydrogel nanoparticles with highly uniform size and shape for systemic siRNA delivery in vivo. "Blank" hydrogel nanoparticles with high aspect ratio were prepared using continuous particle fabrication based on PRINT (particle replication in nonwetting templates). Subsequently, siRNA was conjugated to "blank" nanoparticles via a disulfide linker with a high loading ratio of up to 18 wt %, followed by surface modification to enhance transfection. This fabrication process could be easily scaled up to prepare large quantity of hydrogel nanoparticles. By controlling hydrogel composition, surface modification, and siRNA loading ratio, siRNA conjugated nanoparticles were highly tunable to achieve high transfection efficiency in vitro. FVII-siRNA conjugated nanoparticles were further stabilized with surface coating for in vivo siRNA delivery to liver hepatocytes, and successful gene silencing was demonstrated at both mRNA and protein levels.

  20. Analogues of Cucurbita maxima trypsin inhibitor III (CMTI-III) with elastase inhibitory activity.

    Science.gov (United States)

    Rózycki, J; Kupryszewski, G; Rolka, K; Ragnarsson, U; Zbyryt, T; Krokoszyńska, I; Wilusz, T

    1994-04-01

    Three new CMTI-III analogues containing the Val residue in the reactive site (position 5) were synthesized by the solid-phase method. The analogues displayed an elastase inhibitory activity. It is shown that the removal of the N-terminal Arg residue and the introduction of the Gly-Pro-Gln tripeptide in the region 23-25 decreases the antielastase activity by two orders of magnitude. The removal of the disulfide bridge in positions 16-28 and the substitution of Ala for Cys16 and Gly for Cys28 decreases the activity (measured as Ka with HLE) by five orders of magnitude as compared with [Val5]CMTI-III.

  1. Serum and salivary matrix metalloproteinases, neutrophil elastase, myeloperoxidase in patients with chronic or aggressive periodontitis.

    Science.gov (United States)

    Nizam, Nejat; Gümüş, Pınar; Pitkänen, Jari; Tervahartiala, Taina; Sorsa, Timo; Buduneli, Nurcan

    2014-10-01

    Salivary, serum matrix metalloproteinase-8 (MMP-8), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), neutrophil elastase (NE), and myeloperoxidase (MPO) levels were investigated in generalized chronic periodontitis (GCP), generalized aggressive periodontitis (GAgP), and healthy groups. Whole-mouth clinical periodontal measurements were recorded. Salivary, serum concentrations of MMP-8, MPO, TIMP-1, and NE were determined by immunofluorometric assay or ELISA in 18 patients with GCP, 23 patients with GAgP, 18 individuals with healthy periodontium. Patients in the GAgP group were younger than the other groups (pperiodontitis groups. Salivary, serum MPO, and salivary NE concentrations were higher; TIMP-1 concentrations were lower in the periodontitis groups than the controls (pperiodontal parameters in patients with generalized periodontitis.

  2. Sericins exhibit ROS-scavenging, anti-tyrosinase, anti-elastase, and in vitro immunomodulatory activities.

    Science.gov (United States)

    Chlapanidas, Theodora; Faragò, Silvio; Lucconi, Giulia; Perteghella, Sara; Galuzzi, Marta; Mantelli, Melissa; Avanzini, Maria Antonietta; Tosca, Marta Cecilia; Marazzi, Mario; Vigo, Daniele; Torre, Maria Luisa; Faustini, Massimo

    2013-07-01

    Some biological properties of Bombyx mori sericins from twenty strains were investigated, fourteen fed with artificial diet, two with fresh mulberry leaves and four with both diets. Sericin exhibited ROS-scavenging, anti-tyrosinase and anti-elastase properties, the strain significantly influenced these properties, while diet only influenced the anti-tyrosinase activity. Sericins were clustered into 5 groups and one sericin from each group was further studied: sericins showed anti-proliferative activity on in vitro stimulated peripheral blood mononuclear cells; some strains decreased in vitro secretion of IFNγ, while no effects were observed on TNFα and IL10 release. Therefore, a mixture of sericins extracted from the most promising strains may be useful for dermatological and cosmetic use. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Intracellular antioxidants dissolve man-made antioxidant nanoparticles: using redox vulnerability of nanoceria to develop a responsive drug delivery system.

    Science.gov (United States)

    Muhammad, Faheem; Wang, Aifei; Qi, Wenxiu; Zhang, Shixing; Zhu, Guangshan

    2014-01-01

    Regeneratable antioxidant property of nanoceria has widely been explored to minimize the deleterious influences of reactive oxygen species. Limited information is, however, available regarding the biological interactions and subsequent fate of nanoceria in body fluids. This study demonstrates a surprising dissolution of stable and ultrasmall (4 nm) cerium oxide nanoparticles (CeO2 NPs) in response to biologically prevalent antioxidant molecules (glutathione, vitamin C). Such a redox sensitive behavior of CeO2 NPs is subsequently exploited to design a redox responsive drug delivery system for transporting anticancer drug (camptothecin). Upon exposing the CeO2 capped and drug loaded nanoconstruct to vitamin c or glutathione, dissolution-accompanied aggregation of CeO2 nanolids unleashes the drug molecules from porous silica to achieve a significant anticancer activity. Besides stimuli responsive drug delivery, immobilization of nanoceria onto the surface of mesoporous silica also facilitates us to gain a basic insight into the biotransformation of CeO2 in physiological mediums.

  4. Attenuation of cardiovascular stress response to endotracheal intubation by the use of remifentanil in patients undergoing Cesarean delivery.

    Science.gov (United States)

    Kutlesic, Marija S; Kutlesic, Ranko M; Mostic-Ilic, Tatjana

    2016-04-01

    The induction-delivery time during Cesarean section is traditionally conducted under light anesthesia because of the possibility of anesthesia-induced neonatal respiratory depression. The serious consequences of such an approach could be the increased risk of maternal intraoperative awareness and exaggerated neuroendocrine and cardiovascular stress response to laryngoscopy, endotracheal intubation, and surgical stimuli. Here, we briefly discuss the various pharmacological options for attenuation of stress response to endotracheal intubation during Cesarean delivery and then focus on remifentanil, its pharmacokinetic properties, and its use in anesthesia, both in clinical studies and case reports. Remifentanil intravenous bolus doses of 0.5-1 μg/kg before the induction to anesthesia provide the best compromise between attenuating maternal stress response and minimizing the possibility of neonatal respiratory depression. Although neonatal respiratory depression, if present, usually resolves in a few minutes without the need for prolonged resuscitation measures, health care workers skilled at neonatal resuscitation should be present in the operating room whenever remifentanil is used.

  5. On the chemical synthesis and drug delivery response of folate receptor-activated, polyethylene glycol-functionalized magnetite nanoparticles.

    Science.gov (United States)

    Zhang, J; Rana, S; Srivastava, R S; Misra, R D K

    2008-01-01

    We describe here the chemical synthesis and in vitro drug delivery response of polyethylene glycol (PEG)-functionalized magnetite (Fe(3)O(4)) nanoparticles, which were activated with a stable ligand, folic acid, and conjugated with an anticancer drug, doxorubicin. The functionalization and conjugation steps in the chemical synthesis were confirmed using Fourier transform infrared spectroscopy. The drug-release behavior of PEG-functionalized and folic acid-doxorubicin-conjugated magnetic nanoparticles was characterized by two stages involving an initial rapid release, followed by a controlled release.

  6. Characterization of a Mouse Model of Emphysema Induced by Multiple Instillations of Low-Dose Elastase

    Directory of Open Access Journals (Sweden)

    Milena V. Oliveira

    2016-10-01

    Full Text Available Many experimental models have been proposed to study the pathophysiological features of emphysema, as well as to search for new therapeutic approaches for acute or chronically injured lung parenchyma. We aimed to characterize an emphysema model induced by multiple instillations of elastase by tracking the changes in inflammation, remodeling, and cardiac function after each instillation. Forty-eight C57BL/6 mice were randomly assigned across 2 groups. Emphysema (ELA animals received 1, 2, 3, or 4 intratracheal instillations of pancreatic porcine elastase (PPE, 0.2 IU with a 1-week interval between them. Controls (C received saline following the same protocol. Before and after implementation of the protocol, animals underwent echocardiographic analysis. After the first instillation of PPE, the percentage of mononuclear cells in the lung parenchyma was increased compared to C (p = 0.0001. The second instillation resulted in hyperinflated alveoli, increased mean linear intercept, and reduced elastic fiber content in lung parenchyma compared to C (p=0.0197. Following the third instillation, neutrophils and collagen fiber content in alveolar septa and airways were increased, whereas static lung elastance was reduced compared to C (p=0.0094. After the fourth instillation, the percentage of M1 macrophages in lungs; levels of interleukin-1beta, keratinocyte-derived chemokine, hepatocyte growth factor, and vascular endothelial growth factor; and collagen fiber content in the pulmonary vessel wall were increased compared to C (p=0.0096. At this time point, pulmonary arterial hypertension was apparent, with increased diastolic right ventricular wall thickness. In conclusion, the initial phase of emphysema was characterized by lung inflammation with predominance of mononuclear cells, whereas at the late stage, impairment of pulmonary and cardiovascular functions was observed. This model enables analysis of therapies at different time points during controlled

  7. Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis.

    LENUS (Irish Health Repository)

    Guyot, Nicolas

    2008-11-21

    Elafin is a neutrophil serine protease inhibitor expressed in lung and displaying anti-inflammatory and anti-bacterial properties. Previous studies demonstrated that some innate host defense molecules of the cystic fibrosis (CF) and chronic obstructive pulmonary disease airways are impaired due to increased proteolytic degradation observed during lung inflammation. In light of these findings, we thus focused on the status of elafin in CF lung. We showed in the present study that elafin is cleaved in sputum from individuals with CF. Pseudomonas aeruginosa-positive CF sputum, which was found to contain lower elafin levels and higher neutrophil elastase (NE) activity compared with P. aeruginosa-negative samples, was particularly effective in cleaving recombinant elafin. NE plays a pivotal role in the process as only NE inhibitors are able to inhibit elafin degradation. Further in vitro studies demonstrated that incubation of recombinant elafin with excess of NE leads to the rapid cleavage of the inhibitor. Two cleavage sites were identified at the N-terminal extremity of elafin (Val-5-Lys-6 and Val-9-Ser-10). Interestingly, purified fragments of the inhibitor (Lys-6-Gln-57 and Ser-10-Gln-57) were shown to still be active for inhibiting NE. However, NE in excess was shown to strongly diminish the ability of elafin to bind lipopolysaccharide (LPS) and its capacity to be immobilized by transglutamination. In conclusion, this study provides evidence that elafin is cleaved by its cognate enzyme NE present at excessive concentration in CF sputum and that P. aeruginosa infection promotes this effect. Such cleavage may have repercussions on the innate immune function of elafin.

  8. Fabrication and Characterization of a Porous Silicon Drug Delivery System with an Initiated Chemical Vapor Deposition Temperature-Responsive Coating.

    Science.gov (United States)

    McInnes, Steven J P; Szili, Endre J; Al-Bataineh, Sameer A; Vasani, Roshan B; Xu, Jingjing; Alf, Mahriah E; Gleason, Karen K; Short, Robert D; Voelcker, Nicolas H

    2016-01-12

    This paper reports on the fabrication of a pSi-based drug delivery system, functionalized with an initiated chemical vapor deposition (iCVD) polymer film, for the sustainable and temperature-dependent delivery of drugs. The devices were prepared by loading biodegradable porous silicon (pSi) with a fluorescent anticancer drug camptothecin (CPT) and coating the surface with temperature-responsive poly(N-isopropylacrylamide-co-diethylene glycol divinyl ether) (pNIPAM-co-DEGDVE) or non-stimulus-responsive poly(aminostyrene) (pAS) via iCVD. CPT released from the uncoated oxidized pSi control with a burst release fashion (∼21 nmol/(cm(2) h)), and this was almost identical at temperatures both above (37 °C) and below (25 °C) the lower critical solution temperature (LCST) of the switchable polymer used, pNIPAM-co-DEGDVE (28.5 °C). In comparison, the burst release rate from the pSi-pNIPAM-co-DEGDVE sample was substantially slower at 6.12 and 9.19 nmol/(cm(2) h) at 25 and 37 °C, respectively. The final amount of CPT released over 16 h was 10% higher at 37 °C compared to 25 °C for pSi coated with pNIPAM-co-DEGDVE (46.29% vs 35.67%), indicating that this material can be used to deliver drugs on-demand at elevated temperatures. pSi coated with pAS also displayed sustainable drug delivery profiles, but these were independent of the release temperature. These data show that sustainable and temperature-responsive delivery systems can be produced by functionalization of pSi with iCVD polymer films. Benefits of the iCVD approach include the application of the iCVD coating after drug loading without causing degradation of the drug commonly caused by exposure to factors such as solvents or high temperatures. Importantly, the iCVD process is applicable to a wide array of surfaces as the process is independent of the surface chemistry and pore size of the nanoporous matrix being coated.

  9. The intracellular fate of an amphipathic pH-responsive polymer: Key characteristics towards drug delivery.

    Science.gov (United States)

    Mercado, S A; Orellana-Tavra, C; Chen, A; Slater, N K H

    2016-12-01

    Biopolymers have become important drug delivery systems for therapeutic molecules by enhancing their accessibility and efficacy intracellularly. However, the transport of these drugs across the cell membrane and their release into the cytosol remain a challenge. The trafficking of poly (l-lysine iso-phthalamide) grafted with phenylalanine (PP-50) was investigated using an osteosarcoma cell line (SAOS-2). Colocalisation of this amphipathic biopolymer with endocytosis tracers, such as transferrin and lactosylceramide, suggested that PP-50 is partially internalised by both clathrin and caveolin-mediated endocytosis. Macropinocytosis was also investigated, but a smaller correlation was found between this mechanism and PP-50 transport. A significant decrease in polymer-mediated calcein uptake was found when cells were pre-incubated with endocytosis inhibitors, suggesting also the use of a combination of mechanisms for cell internalisation. In addition, PP-50 colocalisation with endosome and lysosome pathway markers showed that the polymer was able to escape the endolysosomal compartment before maturation. This is a critical characteristic of a biopolymer towards use as drug delivery systems and biomedical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Mapping the AAV capsid host antibody response towards the development of second generation gene delivery vectors

    Directory of Open Access Journals (Sweden)

    Yu-Shan eTseng

    2014-01-01

    Full Text Available The recombinant Adeno-associated virus (rAAV gene delivery system is entering a crucial and exciting phase with the promise of more than 20 years of intense research now realized in a number of successful human clinical trials. However, as a natural host to AAV infection, anti-AAV antibodies are prevalent in the human population. For example, ~70% of human sera samples are positive for AAV serotype 2 (AAV2. Furthermore, low levels of pre-existing neutralizing antibodies in the circulation are detrimental to the efficacy of corrective therapeutic AAV gene delivery. A key component to overcoming this obstacle is the identification of regions of the AAV capsid that participate in interactions with host immunity, especially neutralizing antibodies, to be modified for neutralization escape. Three main approaches have been utilized to map antigenic epitopes on AAV capsids. The first is directed evolution in which AAV variants are selected in the presence of monoclonal antibodies or pooled human sera. This results in AAV variants with mutations on important neutralizing epitopes. The second is epitope searching, achieved by peptide scanning, peptide insertion or site-directed mutagenesis. The third, a structure biology-based approach, utilizes cryo-electron microscopy and image reconstruction of AAV capsids complexed to fragment antibodies, which are generated from monoclonal antibodies, to directly visualize the epitopes. In this review, the contribution of these three approaches to the current knowledge of AAV epitopes and success in their use to create second generation vectors will be discussed.

  11. Anti–elastase, anti–tyrosinase and matrix metalloproteinase–1 inhibitory activity of earthworm extracts as potential new anti–aging agent

    Directory of Open Access Journals (Sweden)

    Nurhazirah Azmi

    2014-05-01

    Conclusions: Earthworms extract showed effective inhibition of tyrosinase, elastase and MMP-1 activities. Therefore, this experiment further rationalizes the traditional use of this worm extracts which may be useful as an anti-wrinkle agent.

  12. The Alpha-Tocopherol Form of Vitamin E Boosts Elastase Activity of Human PMNs and Their Ability to Kill Streptococcus pneumoniae

    Directory of Open Access Journals (Sweden)

    Elsa N. Bou Ghanem

    2017-05-01

    with increased activity of neutrophil elastase, a serine protease that is required to kill pneumococci. Notably, incubation with α-Toc increased PMN elastase activity from young donors and boosted their ability to kill complement-opsonized pneumococci. These findings demonstrate that α-Toc is a potent modulator of PMN responses and is a potential nutritional intervention to combat pneumococcal infection.

  13. Transcutaneous Noninvasive Device for the Responsive Delivery of Melatonin in Microgravity., Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — Our goal is develop a smart, transcutaneous device for individualized circadian (sleep) therapy by responsive release of melatonin, in microgravity. Additionally,...

  14. Transcutaneous Noninvasive Device for the Responsive Delivery of Melatonin in Microgravity. Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Our goal is develop a smart, transcutaneous device for individualized circadian (sleep) therapy by responsive release of melatonin, in microgravity. Additionally,...

  15. Evaluation of the effect of gain on the meal response of an automated closed-loop insulin delivery system.

    Science.gov (United States)

    Panteleon, Antonios E; Loutseiko, Mikhail; Steil, Garry M; Rebrin, Kerstin

    2006-07-01

    A continuous closed-loop insulin delivery system using subcutaneous insulin delivery was evaluated in eight diabetic canines. Continuous glucose profiles were obtained by extrapolation of blood glucose measurements. Insulin delivery rate was calculated, using a model of beta-cell insulin secretion, and delivered with a Medtronic MiniMed subcutaneous infusion pump. The model acts like a classic proportional-integral-derivative controller, delivering insulin in proportion to glucose above target, history of past glucose values, and glucose rate of change. For each dog, a proportional gain was set relative to the open-loop total daily dose (TDD) of insulin. Additional gains based on 0.5 x TDD and 1.5 x TDD were also evaluated (gain dose response). Control was initiated 4 h before the meal with a target of 6.7 mmol/l. At the time of the meal, glucose was similar for all three gains (6.0 +/- 0.3, 5.2 +/- 0.3, and 4.9 +/- 0.5 mmol/l for 0.5 x TDD, TDD, and 1.5 x TDD, respectively; P > 0.05) with near-target values restored at the end of experiments (8.2 +/- 0.9, 6.0 +/- 0.6, and 6.0 +/- 0.5, respectively). The peak postprandial glucose level decreased significantly with increasing gain (12.1 +/- 0.6, 9.6 +/- 1.0, and 8.5 +/- 0.6 mmol/l, respectively; P glycemic control within a range of gain.

  16. Storage Effect on Phenols and on the Antioxidant Activity of Extracts from Anemopsis californica and Inhibition of Elastase Enzyme

    Directory of Open Access Journals (Sweden)

    Carmen Lizette Del-Toro-Sánchez

    2015-01-01

    Full Text Available The amount of total phenols and flavonoids and the antioxidant activity of leaf, stem, and rhizome methanolic extracts from a commonly consumed Anemopsis californica under different storage conditions were investigated. Storage conditions were at 50, 25, 4, and −20°C, protected or not from light, during 180 days. The inhibition of the elastase enzyme was also evaluated. The results demonstrated that leaf, stem, and rhizome methanolic extracts of Anemopsis californica maintain approximately up to 97 and 95% stability in phenolic content and antioxidant activity, respectively, when stored during 60 days at −20°C in the dark. Additionally, these extracts, principally from leaf and rhizome, showed an elastase inhibitory effect by 75 and 71.8%, respectively. Therefore, this study provides the basis for further research on the anti-inflammatory activity. On the other hand, Anemopsis californica could comprise a good alternative of use as antioxidant in foods.

  17. The oxygen delivery response to acute hypoxia during incremental knee extension exercise differs in active and trained males.

    Science.gov (United States)

    Kennedy, Michael D; Warburton, Darren Er; Boliek, Carol A; Esch, Ben Ta; Scott, Jessica M; Haykowsky, Mark J

    2008-08-12

    It is well known that hypoxic exercise in healthy individuals increases limb blood flow, leg oxygen extraction and limb vascular conductance during knee extension exercise. However, the effect of hypoxia on cardiac output, and total vascular conductance is less clear. Furthermore, the oxygen delivery response to hypoxic exercise in well trained individuals is not well known. Therefore our aim was to determine the cardiac output (Doppler echocardiography), vascular conductance, limb blood flow (Doppler echocardiography) and muscle oxygenation response during hypoxic knee extension in normally active and endurance-trained males. Ten normally active and nine endurance-trained males (VO2max = 46.1 and 65.5 mL/kg/min, respectively) performed 2 leg knee extension at 25, 50, 75 and 100% of their maximum intensity in both normoxic and hypoxic conditions (FIO2 = 15%; randomized order). Results were analyzed with a 2-way mixed model ANOVA (group x intensity). The main finding was that in normally active individuals hypoxic sub-maximal exercise (25 - 75% of maximum intensity) brought about a 3 fold increase in limb blood flow but decreased stroke volume compared to normoxia. In the trained group there were no significant changes in stroke volume, cardiac output and limb blood flow at sub-maximal intensities (compared to normoxia). During maximal intensity hypoxic exercise limb blood flow increased approximately 300 mL/min compared to maximal intensity normoxic exercise. Cardiorespiratory fitness likely influences the oxygen delivery response to hypoxic exercise both at a systemic and limb level. The increase in limb blood flow during maximal exercise in hypoxia (both active and trained individuals) suggests a hypoxic stimulus that is not present in normoxic conditions.

  18. The effect of garlic extract on the expression of genes elastase and exotoxin A in Pseudomonas aeruginosa

    Directory of Open Access Journals (Sweden)

    Batoul Kavyani

    2016-11-01

    Full Text Available Background: Multidrug-resistant bacteria make many problems in clinical therapy, design and manufacture of synthetic drugs. Pseudomonas aeruginosa is one of the most important multidrug-resistance bacteria leads to variety infections in human especially in immunocompromised, patients with severe burns, and nosocomial infections. It Recent years, this organism makes a big challenge in clinical treatment of infections using a wide range of antibiotics. Medicinal herbs for thousands of years to prevent or treat infectious diseases were considered. Today, pharmacists have high interest of using medicinal herbs to prepare a new antimicrobial compounds. The goal of this study was to investigation the effect of aqueous and alcoholic extract of fresh garlic on the expression of genes encoding elastase and exotoxin A virulence factors, in P. aeruginosa PAO1 strain. Methods: Present study was an experimental study and performed from 2015 to 2016 in Hamadan University of Medical Science, Iran. The minimal inhibitory concentration (MIC and minimal bactericidal concentration (MBC of aqueous and alcoholic extract of garlic was determined. Then in order to investigation the gene expression of elastase and exotoxin A genes, quantitative real-time polymerase chain reaction (qPCR method was performed at sub-MBC concentrations. Results: According to the results aqueous extracts of garlic had better impact in comparison with alcoholic alone. At concentration of 64 and 8 mg/ml of aqueous extract the expression of both elastase and exotoxin A genes were decreased. Although, the expression of elastase gene was most affected by garlic at different concentrations than exotoxin A. Conclusion: The results suggested that the compositions of garlic extracts can inhibit the production of virulence factors in P. aeruginosa. So in order to treat infectious diseases in the near future, medicinal plants known as new antimicrobial drugs can be used alone or with antibiotic drugs

  19. Stimuli-responsive protamine-based biodegradable nanocapsules for enhanced bioavailability and intracellular delivery of anticancer agents

    Energy Technology Data Exchange (ETDEWEB)

    Radhakrishnan, Krishna; Thomas, Midhun B.; Pulakkat, Sreeranjini [Indian Institute of Science, Department of Materials Engineering (India); Gnanadhas, Divya P.; Chakravortty, Dipshikha [Indian Institute of Science, Department of Microbiology and Cell Biology (India); Raichur, Ashok M., E-mail: amr@materials.iisc.ernet.in [Indian Institute of Science, Department of Materials Engineering (India)

    2015-08-15

    Enzyme- and pH-responsive polyelectrolyte nanocapsules having diameters in the range of 200 ± 20 nm were fabricated by means of Layer-by-Layer assembly of biopolymers, protamine, and heparin, and then loaded with anticancer drug doxorubicin. The incorporation of the FDA-approved peptide drug protamine as a wall component rendered the capsules responsive to enzyme stimuli. The stimuli-responsive drug release from these nanocapsules was evaluated, and further modulation of capsule permeability to avoid premature release was demonstrated by crosslinking the wall components. The interaction of the nanocapsules with cancer cells was studied using MCF-7 breast cancer cells. These capsules were readily internalized and disintegrated inside the cells, culminating in the release of the loaded doxorubicin and subsequent cell death as observed by confocal microscopy and MTT Assay. The bioavailability studies performed using BALB/c mice revealed that the encapsulated doxorubicin exhibited enhanced bioavailability compared to free doxorubicin. Our results indicate that this stimuli-responsive system fabricated from clinically used FDA-approved molecules and exhibiting minimal premature release has great potential for drug-delivery applications.

  20. Fabrication and in vivo evaluation of highly pH-responsive acrylic microparticles for targeted gastrointestinal delivery.

    Science.gov (United States)

    Kendall, Richard A; Alhnan, Mohamed A; Nilkumhang, Suchada; Murdan, Sudaxshina; Basit, Abdul W

    2009-06-28

    Acrylic enteric microparticles for oral drug delivery were prepared by an oil-in-oil emulsion solvent evaporation process. The novel use of sorbitan sesquioleate as a surfactant produced Eudragit L55, L and S (pH thresholds of 5.5, 6 and 7, respectively) microparticles of good morphology (spherical, smooth surfaced), size (pH-responsive drug release in dissolution studies (negligible drug release at pH 1.2; rapid drug release above the polymers' pH thresholds). In contrast, Eudragit L55 particles aggregated in fluid and showed poor control of drug release. In vivo in rats, Eudragit L microparticles released their drug load rapidly (T(max)pH of Eudragit S was not reached in the rat intestine and drug release was therefore incomplete. It was concluded that although the rat is an inappropriate model for the investigation of Eudragit S microparticles, the positive results seen with the Eudragit L microparticles indicate its potential use in pH-targeted drug delivery.

  1. pH-Responsive Hyaluronic Acid-Based Mixed Micelles for the Hepatoma-Targeting Delivery of Doxorubicin

    Directory of Open Access Journals (Sweden)

    Jing-Liang Wu

    2016-03-01

    Full Text Available The tumor targetability and stimulus responsivity of drug delivery systems are crucial in cancer diagnosis and treatment. In this study, hepatoma-targeting mixed micelles composed of a hyaluronic acid–glycyrrhetinic acid conjugate and a hyaluronic acid-l-histidine conjugate (HA–GA/HA–His were prepared through ultrasonic dispersion. The formation and characterization of the mixed micelles were confirmed via 1H-NMR, particle size, and ζ potential measurements. The in vitro cellular uptake of the micelles was evaluated using human liver carcinoma (HepG2 cells. The antitumor effect of doxorubicin (DOX-loaded micelles was investigated in vitro and in vivo. Results indicated that the DOX-loaded HA–GA/HA–His micelles showed a pH-dependent controlled release and were remarkably absorbed by HepG2 cells. Compared with free DOX, the DOX-loaded HA–GA/HA–His micelles showed a higher cytotoxicity to HepG2 cells. Moreover, the micelles effectively inhibited tumor growth in H22 cell-bearing mice. These results suggest that the HA–GA/HA–His mixed micelles are a good candidate for drug delivery in the prevention and treatment of hepatocarcinoma.

  2. Empowering teachers to change youth practices: evaluating teacher delivery and responses to the FLHE programme in Edo State, Nigeria.

    Science.gov (United States)

    Dlamini, Nombuso; Okoro, Felicia; Ekhosuehi, Uyi Oni; Esiet, Adenike; Lowik, A J; Metcalfe, Karen

    2012-06-01

    School-based programming is one of the most common approaches to HIV/AIDS prevention among youth. This paper presents the history and development of the Family Life and HIV Education (FLHE) programme in Edo State, Nigeria and results of evaluation of teacher actions and responses to training in its delivery. Results indicate that teachers benefited from the training, were aware of new and/or existing teaching resources and began to teach about HIV/AIDS. Teachers expressed that the programme facilitated open dialogue about HIV/AIDS. However, given limited human resources, FLHE was viewed as additional work to already overloaded teaching schedules. It is recommended that the Ministry of Education channel resources to enhance teachers' efforts towards combating HIV/AIDS. To facilitate learning about sexual health and family life, it is recommended that FLHE-based training be viewed as the first rather than the only step towards teacher professional development in this area.

  3. Magnetically-responsive, multifunctional drug delivery nanoparticles for elastic matrix regenerative repair.

    Science.gov (United States)

    Sivaraman, Balakrishnan; Swaminathan, Ganesh; Moore, Lee; Fox, Jonathan; Seshadri, Dhruv; Dahal, Shataakshi; Stoilov, Ivan; Zborowski, Maciej; Mecham, Robert; Ramamurthi, Anand

    2017-04-01

    Arresting or regressing growth of abdominal aortic aneurysms (AAAs), localized expansions of the abdominal aorta are contingent on inhibiting chronically overexpressed matrix metalloproteases (MMPs)-2 and -9 that disrupt elastic matrix within the aortic wall, concurrent with providing a stimulus to augmenting inherently poor auto-regeneration of these matrix structures. In a recent study we demonstrated that localized, controlled and sustained delivery of doxycycline (DOX; a tetracycline-based antibiotic) from poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), enhances elastic matrix deposition and MMP-inhibition at a fraction of the therapeutically effective oral dose. The surface functionalization of these NPs with cationic amphiphiles, which enhances their arterial uptake, was also shown to have pro-matrix regenerative and anti-MMP effects independent of the DOX. Based on the hypothesis that the incorporation of superparamagnetic iron oxide NPs (SPIONs) within these PLGA NPs would enhance their targetability to the AAA site under an applied external magnetic field, we sought to evaluate the functional effects of NPs co-encapsulating DOX and SPIONs (DOX-SPION NPs) on elastic matrix regeneration and MMP synthesis/activity in vitro within aneurysmal smooth muscle cell (EaRASMC) cultures. The DOX-SPION NPs were mobile under an applied external magnetic field, while enhancing elastic matrix deposition 1.5-2-fold and significantly inhibiting MMP-2 synthesis and MMP-2 and -9 activities, compared to NP-untreated control cultures. These results illustrate that the multifunctional benefits of NPs are maintained following SPION co-incorporation. Additionally, preliminary studies carried out demonstrated enhanced targetability of SPION-loaded NPs within proteolytically-disrupted porcine carotid arteries ex vivo, under the influence of an applied external magnetic field. Thus, this dual-agent loaded NP system proffers a potential non-surgical option for treating small

  4. Research support for effective state and community tobacco control programme response to electronic nicotine delivery systems.

    Science.gov (United States)

    Schmitt, Carol L; Lee, Youn Ok; Curry, Laurel E; Farrelly, Matthew C; Rogers, Todd

    2014-07-01

    To identify unmet research needs of state and community tobacco control practitioners pertaining to electronic nicotine delivery systems (ENDS or e-cigarettes) that would inform policy and practice efforts at the state and community levels, and to describe ENDS-related research and dissemination activities of the National Cancer Institute-funded State and Community Tobacco Control Research Initiative. To determine specific research gaps relevant to state and community tobacco control practice, we analysed survey data collected from tobacco control programmes (TCPs) in all 50 U.S. states and the District of Columbia (N=51). Survey items covered a range of ENDS issues: direct harm to users, harm of secondhand vapour, cessation, flavours, constituents and youth access. There is no ENDS topic on which a majority of state TCP managers feel very informed. They feel least informed about harms of secondhand vapour while also reporting that this information is among the most important for their programme. A majority (N=31) of respondents indicated needs for research on the implications of ENDS products for existing policies. TCP managers report that ENDS research is highly important for practice and need research-based information to inform decision making around the inclusion of ENDS in existing tobacco control policies. For optimal relevance to state and community TCPs, research on ENDS should prioritise study of the health effects of ENDS use and secondhand exposure to ENDS vapour in the context of existing tobacco control policies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  5. Dual responsive PNIPAM–chitosan targeted magnetic nanopolymers for targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Yadavalli, Tejabhiram, E-mail: tejabhiram@gmail.com [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Ramasamy, Shivaraman [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); School of Physics, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009 (Australia); Chandrasekaran, Gopalakrishnan; Michael, Isaac; Therese, Helen Annal [Nanotechnology Research Centre, SRM University, Chennai 603203 (India); Chennakesavulu, Ramasamy [Department of Pharmacy practice, SRM College of Pharmacy, Chennai 603203 (India)

    2015-04-15

    A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation. - Highlights: • The use of gadolinium doped nickel ferrite with the suggested doping level. • The use of PNIPMA–chitosan polymer with folic acid and fluorescein as a drug carrier complex. • Magnetic hyperthermia studies of gadolinium doped nickel ferrites are being reported for the first time. • Proton relaxivity studies which indicate the MRI contrasting properties on the reported system are new. • Use of curcumin, a hydrophobic Indian spice as a cancer killing agent inside the reported magnetic polymer complex.

  6. A Colon Targeted Delivery System for Resveratrol Enriching in pH Responsive-Model

    Directory of Open Access Journals (Sweden)

    Hashem Andishmand, Hamed Hamishehkar, Afshin Babazadeh, Arezou Taghvimi, Mohammad Amin Mohammadifar, Mahnaz Tabibiazar

    2017-03-01

    Full Text Available Background: Resveratrol effects on the prevention and treatment of colon cancer have been well documented recently, but low solubility, rapid absorption and metabolism of resveratrol limit its beneficial effects on colon cancer. Designing a formulation that enhances the solubility of resveratrol, protects resveratrol from oxidation and isomerization, and delivers it to the colon is a priority of food and drug industry. In this study, resveratrol-polyethylene glycol (PEG-loaded pectin-chitosan polyelectrolyte complex was designed as a colon targeted delivery system. Methods: The effects of adding PEG, ultra-sonication time, pH, and pectin to chitosan ratio were investigated on particle size, polydispersity index (PDI, zeta potential by particle size analyzer, and scanning electron microscopy (SEM. Encapsulation efficiency (EE, release of resveratrol in simulated gastrointestinal fluid, and different pHs were analyzed via High Performance Liquid Chromatography (HPLC. Antioxidant activity was measured by (2, 2-diphenyl-1-picryl-hydrazyl-hydrate DPPH free-radical method. Results: Results showed that colloidal stable micro-particles (725 ± 20 nm with PDI < 0.3 and zeta potential +27 ± 2 mV was formed in the ratio of 5:1 of pectin to chitosan w/v % after a 10-min sonication. Encapsulation efficiency was 81 ± 7 %. The reduction of antioxidant activity of resveratrol loaded micro-particles after one month was less than 13%. Micro-particles released about 33% of resveratrol in the simulated gastric and intestinal fluids. Conclusion: Two-thirds of the loaded resveratrol in Pectin-Chitosan complex reached colon. The developed system had enough specification for enriching fruit based drinks due to remarkable colloidal stability in the pH range of 3.5 to 4.5.

  7. Skin Permeation Enhancers and their Effects on Narcotic Transdermal Drug Delivery Systems through Response Surface Experimental Design

    Directory of Open Access Journals (Sweden)

    A. Moghimi

    2014-02-01

    Full Text Available Drug delivery through skin is often obstructed by low permeability of skin towards most drugs; however, such problem would be solved by application of skin penetration enhancers in the formulations. In the present study, a drug in adhesive patch with buprenorphine as active ingredient was prepared. Drug-in-adhesive transdermal drug delivery systems with different chemical penetration enhancers were designed. For this purpose a response-surface experimental design was used. Response surface methodology based on a three-level, three-variable Box–Behnken design was used to evaluate the interactive effects of dependent variables such as: the rate of skin permeation and adhesion properties including peel strength and tack value. The parameters such as drug release and adhesion were used as independent variables. Levulinic acid, lauryl alcohol and Tween 80 were used as penetration enhancers. In order to prepare samples, buprenorphine with constant concentration was incorporated into acrylic pressure sensitive adhesive with carboxylic functionality and this mixture was added to chemical penetration enhancer with different concentrations. The results show that the cumulative amount of drug release in presence of Tween 80 is 462.9 ± 0.006 μg so it is higher than cumulative amount of drug release in presence of levulinic acid (357.9 ± 0.005 μg and lauryl alcohol (269.5 ± 0.001 μg. Results of adhesion properties such as peel strength and tack reveal that using levulinic acid and lauryl alcohol will increase peel strength while Tween 80 will decrease it. Besides, the results show that all these permeation enhancers have increased tack values.

  8. Biodegradable nanoparticle delivery of inactivated swine influenza virus vaccine provides heterologous cell-mediated immune response in pigs.

    Science.gov (United States)

    Dhakal, Santosh; Hiremath, Jagadish; Bondra, Kathryn; Lakshmanappa, Yashavanth S; Shyu, Duan-Liang; Ouyang, Kang; Kang, Kyung-Il; Binjawadagi, Basavaraj; Goodman, Jonathan; Tabynov, Kairat; Krakowka, Steven; Narasimhan, Balaji; Lee, Chang Won; Renukaradhya, Gourapura J

    2017-02-10

    Swine influenza virus (SwIV) is one of the important zoonotic pathogens. Current flu vaccines have failed to provide cross-protection against evolving viruses in the field. Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable FDA approved polymer and widely used in drug and vaccine delivery. In this study, inactivated SwIV H1N2 antigens (KAg) encapsulated in PLGA nanoparticles (PLGA-KAg) were prepared, which were spherical in shape with 200 to 300nm diameter, and induced maturation of antigen presenting cells in vitro. Pigs vaccinated twice with PLGA-KAg via intranasal route showed increased antigen specific lymphocyte proliferation and enhanced the frequency of T-helper/memory and cytotoxic T cells (CTLs) in peripheral blood mononuclear cells (PBMCs). In PLGA-KAg vaccinated and heterologous SwIV H1N1 challenged pigs, clinical flu symptoms were absent, while the control pigs had fever for four days. Grossly and microscopically, reduced lung pathology and viral antigenic mass in the lung sections with clearance of infectious challenge virus in most of the PLGA-KAg vaccinated pig lung airways were observed. Immunologically, PLGA-KAg vaccine irrespective of not significantly boosting the mucosal antibody response, it augmented the frequency of IFN-γ secreting total T cells, T-helper and CTLs against both H1N2 and H1N1 SwIV. In summary, inactivated influenza virus delivered through PLGA-NPs reduced the clinical disease and induced cross-protective cell-mediated immune response in a pig model. Our data confirmed the utility of a pig model for intranasal particulate flu vaccine delivery platform to control flu in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Avoidance of Timeout from Response-Independent Food: Effects of Delivery Rate and Quality

    Science.gov (United States)

    Richardson, Joseph V.; Baron, Alan

    2008-01-01

    In three experiments, a rat's lever presses could postpone timeouts from food pellets delivered on response-independent schedules. In Experiment 1, the pellets were delivered at variable-time (VT) rates ranging from VT 0.5 to VT 8 min. Experiment 2 replicated the VT 1 min and VT 8 min conditions of Experiment 1 with new subjects. Finally, subjects…

  10. Premature delivery reduces intestinal cytoskeleton, metabolism, and stress response proteins in newborn formula-fed pigs

    DEFF Research Database (Denmark)

    Jiang, Pingping; Wan, Jennifer Man-Fan; Cilieborg, Malene Skovsted

    2013-01-01

    OBJECTIVE:: Preterm infants often show intolerance to the first enteral feeds, and the structural and functional basis of this intolerance remains unclear. We hypothesized that preterm and term neonates show similar gut trophic responses to feeding, but different expression of intestinal function...

  11. Multimodal imaging in the elastase-induced aneurysm model in rabbits: a comparative study using serial DSA, MRA and CTA

    International Nuclear Information System (INIS)

    Doerfler, A.; Becker, W.; Wanke, I.; Goericke, S.; Oezkan, N.; Forsting, M.

    2004-01-01

    Background and Purpose: The elastase-induced aneurysm model in rabbits has proved to be suitable for testing new endovascular occlusion devices. The purpose of this study was to evaluate different imaging modalities for the depiction of anatomy and size of elastase-induced aneurysms and for serial follow-up imaging. Materials and Methods: Elastase-induced aneurysms were created in eight Chinchilla bastard rabbits by endoluminal incubation of porcine elastase. Serial imaging was performed using intravenous DSA (IVDSA), contrast-enhanced MRA (CEMRA), and time-of-flight MRA (TOF) 14 days, 4 weeks and 3 months after aneurysm creation. Intraarterial DSA (IADSA) and CT angiography (CTA) were performed after 3 months. Aneurysm size and geometry (height H, width W, neck width N) were compared. Results: On IVDSA after two weeks mean aneurysm height was 6.2 mm (range 2.8-11.0 mm), mean aneurysm neck width was 2.7 mm (range 2.0-4.2 mm) and mean aneurysm neck width was 2.7 mm (range 2.0-4.2 mm). We did not observed any statistically significant change in aneurysm dimensions during follow-up at 4 weeks (CEMRA: H: 5.4, W: 2.4, N: 2.4; TOF: H: 5.7, W: 2.4, N: 2.7) and 3 months (CEMRA: H: 5.8, W: 2.6, N: 2.6; TOF: H: 6.9, W: 2.8, N: 3.0). Aneurysm dimensions could be best seen on IADSA (H: 6.2, W: 3.0, N: 2.7) with good correlation to CTA (r=0.94; H: 6.1, W: 2.8, N: 2.6), CE-MRA (r=0.92), and TOF (r=0.97). TOF was superior to CEMRA in delineating the aneurysm wall. Conclusions: Serial imaging using MRA, CTA or intravenous and intraarterial angiography is feasible in the elastase-induced aneurysm model. Contrast-enhanced MRA, TOF-MRA and CTA showed good correlation to IADSA and are all suitable for non-invasive pretherapeutic measurement of aneurysm size. (orig.) [de

  12. Specificity and sensitivity of serum canine pancreatic elastase-1 concentration in the diagnosis of pancreatitis.

    Science.gov (United States)

    Mansfield, Caroline S; Watson, Penny D; Jones, Boyd R

    2011-07-01

    The aim of the current study was to determine the sensitivity and specificity of serum canine pancreatic elastase-1 (cPE-1) for the diagnosis of pancreatitis in dogs. The study was prospective, assessing dogs presenting with clinical signs similar to pancreatitis. Sixty-one dogs were recruited (49 with pancreatic disease and 12 with non-pancreatic disease). There was no significant difference in serum cPE-1 between dogs with pancreatic disease and non-pancreatic disease. However, there was a significant difference in serum cPE-1 between severe acute pancreatitis and non-pancreatic disease. A cut-off value for serum cPE-1 > 17.24 ng/ml resulted in sensitivity of 61.4% and specificity of 91.7% for diagnosis of all types of pancreatic disease. The sensitivity rose to 65.85% and 78.26% for the diagnosis of all types of acute pancreatitis and severe acute pancreatitis, respectively. Serum cPE-1 is more sensitive at diagnosing severe acute pancreatitis than chronic or mild acute pancreatitis, and has a high positive likelihood ratio. Dogs with chronic pancreatitis tended to have lower serum cPE-1 concentration, suggesting decreased exocrine function.

  13. Delivery strategies to control inflammatory response: Modulating M1-M2 polarization in tissue engineering applications

    OpenAIRE

    Alvarez, Mario Moisés; Liu, Julie C.; Santiago, Grissel Trujillo-de; Cha, Byung-Hyun; Vishwakarma, Ajaykumar; Ghaemmaghami, Amir; Khademhosseini, Ali

    2016-01-01

    Macrophages are key players in many physiological scenarios including tissue homeostasis. In response to injury, typically the balance between macrophage sub-populations shifts from an M1 phenotype (pro-inflammatory) to an M2 phenotype (anti-inflammatory). In tissue engineering scenarios, after implantation of any device, it is desirable to exercise control on this M1-M2 progression and to ensure a timely and smooth transition from the inflammatory to the healing stage. In this review, we bri...

  14. Polymeric redox-responsive delivery systems bearing ammonium salts cross-linked via disulfides

    Directory of Open Access Journals (Sweden)

    Christian Dollendorf

    2013-08-01

    Full Text Available A redox-responsive polycationic system was synthesized via copolymerization of N,N-diethylacrylamide (DEAAm and 2-(dimethylaminoethyl methacrylate (DMAEMA. N,N’-bis(4-chlorobutanoylcystamine was used as disulfide-containing cross-linker to form networks by the quaternization of tertiary amine groups. The insoluble cationic hydrogels become soluble by reduction of disulfide to mercaptanes by use of dithiothreitol (DTT, tris(2-carboxyethylphosphine (TCEP or cysteamine, respectively. The soluble polymeric system can be cross-linked again by using oxygen or hydrogen peroxide under basic conditions. The redox-responsive polymer networks can be used for molecular inclusion and controlled release. As an example, phenolphthalein, methylene blue and reactive orange 16 were included into the network. After treatment with DTT a release of the dye could be recognized. Physical properties of the cross-linked materials, e.g., glass transition temperature (Tg, swelling behavior and cloud points (Tc were investigated. Redox-responsive behavior was further analyzed by rheological measurements.

  15. Investigating the adaptive immune response in influenza and secondary bacterial pneumonia and nanoparticle based therapeutic delivery

    Science.gov (United States)

    Chakravarthy, Krishnan V.

    In early 2000, influenza and its associated complications were the 7 th leading cause of death in the United States[1-4]. As of today, this major health problem has become even more of a concern, with the possibility of a potentially devastating avian flu (H5N1) or swine flu pandemic (H1N1). According to the Centers for Disease Control (CDC), over 10 countries have reported transmission of influenza A (H5N1) virus to humans as of June 2006 [5]. In response to this growing concern, the United States pledged over $334 million dollars in international aid for battling influenza[1-4]. The major flu pandemic of the early 1900's provided the first evidence that secondary bacterial pneumonia (not primary viral pneumonia) was the major cause of death in both community and hospital-based settings. Secondary bacterial infections currently account for 35-40% mortality following a primary influenza viral infection [1, 6]. The first component of this work addresses the immunological mechanisms that predispose patients to secondary bacterial infections following a primary influenza viral infection. By assessing host immune responses through various immune-modulatory tools, such as use of volatile anesthetics (i.e. halothane) and Apilimod/STA-5326 (an IL-12/Il-23 transcription blocker), we provide experimental evidence that demonstrates that the overactive adaptive Th1 immune response is critical in mediating increased susceptibility to secondary bacterial infections. We also present data that shows that suppressing the adaptive Th1 immune response enhances innate immunity, specifically in alveolar macrophages, by favoring a pro anti-bacterial phenotype. The second component of this work addresses the use of nanotechnology to deliver therapeutic modalities that affect the primary viral and associated secondary bacterial infections post influenza. First, we used surface functionalized quantum dots for selective targeting of lung alveolar macrophages both in vitro and in vivo

  16. Hypoxia Responsive, Tumor Penetrating Lipid Nanoparticles for Delivery of Chemotherapeutics to Pancreatic Cancer Cell Spheroids.

    Science.gov (United States)

    Kulkarni, Prajakta; Haldar, Manas K; Katti, Preeya; Dawes, Courtney; You, Seungyong; Choi, Yongki; Mallik, Sanku

    2016-08-17

    Solid tumors are often poorly irrigated due to structurally compromised microcirculation. Uncontrolled multiplication of cancer cells, insufficient blood flow, and the lack of enough oxygen and nutrients lead to the development of hypoxic regions in the tumor tissues. As the partial pressure of oxygen drops below the necessary level (10 psi), the cancer cells modulate their genetic makeup to survive. Hypoxia triggers tumor progression by enhancing angiogenesis, cancer stem cell production, remodeling of the extracellular matrix, and epigenetic changes in the cancer cells. However, the hypoxic regions are usually located deep in the tumors and are usually inaccessible to the intravenously injected drug carrier or the drug. Considering the designs of the reported nanoparticles, it is likely that the drug is delivered to the peripheral tumor tissues, close to the blood vessels. In this study, we prepared lipid nanoparticles (LNs) comprising the synthesized hypoxia-responsive lipid and a peptide-lipid conjugate. We observed that the resultant LNs penetrated to the hypoxic regions of the tumors. Under low oxygen partial pressure, the hypoxia-responsive lipid undergoes reduction, destabilizing the lipid membrane, and releasing encapsulated drugs from the nanoparticles. We demonstrated the results employing spheroidal cultures of the pancreatic cancer cells BxPC-3. We observed that the peptide-decorated, drug encapsulated LNs reduced the viability of pancreatic cancer cells of the spheroids to 35% under hypoxic conditions.

  17. Light-responsive polymer microcapsules as delivery systems for natural active agents

    Energy Technology Data Exchange (ETDEWEB)

    Bizzarro, Valentina; Carfagna, Cosimo; Cerruti, Pierfrancesco [Institute for Polymers, Composites and Biomaterials (IPCB-CNR), Via Campi Flegrei, 34, 80078 Pozzuoli, NA (Italy); Marturano, Valentina; Ambrogi, Veronica [Department of Chemical, Materials and Production Engineering (DICMAPI), University of Naples “Federico II”, P. le Tecchio, 80, 80125 Napoli (Italy); Institute for Polymers, Composites and Biomaterials (IPCB-CNR), Via Campi Flegrei, 34, 80078 Pozzuoli, NA (Italy)

    2016-05-18

    In this work we report the preparation and the release behavior of UV-responsive polymeric microcapsules containing essential oils as a core. The oil acted also as a monomer solvent during polymerization. Accordingly, the potentially toxic organic solvent traditionally used was replaced with a natural active substance, resulting in a more sustainable functional system. Polymer shell was based on a lightly cross-linked polyamide containing UV-sensitive azobenzene moieties in the main chain. The micro-sized capsules were obtained via interfacial polycondensation in o/w emulsion, and their mean size was measured via Dynamic Light Scattering. Shape and morphology were analyzed through Scanning Electron and Optical Microscopy. UV-responsive behavior was evaluated via spectrofluorimetry, by assessing the release kinetics of a fluorescent probe molecule upon UV light irradiation (λ{sub max}=360 nm). The irradiated samples showed an increase in fluorescence intensity, in accordance with the increase of the probe molecule concentration in the release medium. As for the un-irradiated sample, no changes could be detected demonstrating the effectiveness of the obtained releasing system.

  18. Light-responsive polymer microcapsules as delivery systems for natural active agents

    Science.gov (United States)

    Bizzarro, Valentina; Carfagna, Cosimo; Cerruti, Pierfrancesco; Marturano, Valentina; Ambrogi, Veronica

    2016-05-01

    In this work we report the preparation and the release behavior of UV-responsive polymeric microcapsules containing essential oils as a core. The oil acted also as a monomer solvent during polymerization. Accordingly, the potentially toxic organic solvent traditionally used was replaced with a natural active substance, resulting in a more sustainable functional system. Polymer shell was based on a lightly cross-linked polyamide containing UV-sensitive azobenzene moieties in the main chain. The micro-sized capsules were obtained via interfacial polycondensation in o/w emulsion, and their mean size was measured via Dynamic Light Scattering. Shape and morphology were analyzed through Scanning Electron and Optical Microscopy. UV-responsive behavior was evaluated via spectrofluorimetry, by assessing the release kinetics of a fluorescent probe molecule upon UV light irradiation (λmax=360 nm). The irradiated samples showed an increase in fluorescence intensity, in accordance with the increase of the probe molecule concentration in the release medium. As for the un-irradiated sample, no changes could be detected demonstrating the effectiveness of the obtained releasing system.

  19. Effects of gold nanoparticle-based vaccine size on lymph node delivery and cytotoxic T-lymphocyte responses.

    Science.gov (United States)

    Kang, Sukmo; Ahn, Sukyung; Lee, Jeewon; Kim, Jin Yong; Choi, Minsuk; Gujrati, Vipul; Kim, Hyungjun; Kim, Jinjoo; Shin, Eui-Cheol; Jon, Sangyong

    2017-06-28

    Although it has been shown that the size of nanoparticle-based vaccines is a key determining factor for the induction of immune responses, few studies have provided detailed analyses of thresholds or critical sizes of nanoparticle vaccines. Here we report effects of the size of gold nanoparticle (GNP)-based vaccines on their efficiency of delivery to lymph nodes (LNs) and induction of CD8 + T-cell responses. We further propose a threshold size of GNPs for use as an effective vaccine. To examine the effects of GNP size, we synthesized GNPs with diameters of 7, 14 and 28nm, and then conjugated them with recombinant ovalbumin (OVA) as a model antigen. The resulting OVA-GNPs had hydrodynamic diameter (HD) of ~10, 22, and 33nm for 7, 14 and 28nm GNPs, respectively and exhibited a size-dependent increase in cellular uptake by dendritic cells (DCs) and subsequent T-cell cross-priming and activation. Upon injection into a mouse footpad, both 22- and 33-nm OVA-GNPs showed much higher delivery efficiency to draining LNs than did 10-nm OVA-GNPs. An ex vivo restimulation assay using OVA as an antigen revealed that frequencies of OVA-specific CD8 + T cells were higher in mice immunized with 22- and 33-nm OVA-GNPs than in those immunized with 10-nm OVA-GNPs; moreover, these cells were shown to be poly-functional. In a tumor-prevention study, 22-nm OVA-GNPs showed greater antitumor efficacy, and higher infiltration of CD8 + T-cells and greater tumor cell apoptosis and cell death than 10-nm OVA-GNPs. Taken together, our results suggest that the size threshold for induction of potent cellular responses and T-cell poly-functionality by GNPs lies between 10nm and 22nm, and highlight the importance of nanoparticle size as a critical parameter in designing and developing nanoparticle-based vaccines. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Defective Lipid Delivery Modulates Glucose Tolerance and Metabolic Response to Diet in Apolipoprotein E–Deficient Mice

    Science.gov (United States)

    Hofmann, Susanna M.; Perez-Tilve, Diego; Greer, Todd M.; Coburn, Beth A.; Grant, Erin; Basford, Joshua E.; Tschöp, Matthias H.; Hui, David Y.

    2010-01-01

    OBJECTIVE Apolipoprotein E (ApoE) regulates plasma lipid levels via modulation of lipolysis and serving as ligand for receptor-mediated clearance of triglyceride (TG)-rich lipoproteins. This study tested the impact of modulating lipid delivery to tissues on insulin responsiveness and diet-induced obesity. RESEARCH DESIGN AND METHODS ApoE+/+ and apoE−/− mice were placed on high-fat–high-sucrose diabetogenic diet or control diet for 24 weeks. Plasma TG clearance, glucose tolerance, and tissue uptake of dietary fat and glucose were assessed. RESULTS Plasma TG clearance and lipid uptake by adipose tissue were impaired, whereas glucose tolerance was improved in control diet–fed apoE−/− mice compared with apoE+/+ mice after an oral lipid load. Fat mass was reduced in apoE−/− mice compared with apoE+/+ mice under both dietary conditions. The apoE−/− mice exhibited lower body weight and insulin levels than apoE+/+ mice when fed the diabetogenic diet. Glucose tolerance and uptake by muscle and brown adipose tissue (BAT) was also improved in mice lacking apoE when fed the diabetogenic diet. Indirect calorimetry studies detected no difference in energy expenditure and respiratory quotient between apoE+/+ and apoE−/− mice on control diet. Energy expenditure and uncoupling protein-1 expression in BAT were slightly but not significantly increased in apoE−/− mice on diabetogenic diet. CONCLUSIONS These results demonstrated that decreased lipid delivery to insulin-sensitive tissues improves insulin sensitivity and ameliorates diet-induced obesity. PMID:17914034

  1. Expanding the Delivery of Rapid Earthquake Information and Warnings for Response and Recovery

    Science.gov (United States)

    Blanpied, M. L.; McBride, S.; Hardebeck, J.; Michael, A. J.; van der Elst, N.

    2017-12-01

    Scientific organizations like the United States Geological Survey (USGS) release information to support effective responses during an earthquake crisis. Information is delivered to the White House, the National Command Center, the Departments of Defense, Homeland Security (including FEMA), Transportation, Energy, and Interior. Other crucial stakeholders include state officials and decision makers, emergency responders, numerous public and private infrastructure management centers (e.g., highways, railroads and pipelines), the media, and the public. To meet the diverse information requirements of these users, rapid earthquake notifications have been developed to be delivered by e-mail and text message, as well as a suite of earthquake information resources such as ShakeMaps, Did You Feel It?, PAGER impact estimates, and data are delivered via the web. The ShakeAlert earthquake early warning system being developed for the U.S. West Coast will identify and characterize an earthquake a few seconds after it begins, estimate the likely intensity of ground shaking, and deliver brief but critically important warnings to people and infrastructure in harm's way. Currently the USGS is also developing a capability to deliver Operational Earthquake Forecasts (OEF). These provide estimates of potential seismic behavior after large earthquakes and during evolving aftershock sequences. Similar work is underway in New Zealand, Japan, and Italy. In the development of OEF forecasts, social science research conducted during these sequences indicates that aftershock forecasts are valued for a variety of reasons, from informing critical response and recovery decisions to psychologically preparing for more earthquakes. New tools will allow users to customize map-based, spatiotemporal forecasts to their specific needs. Hazard curves and other advanced information will also be available. For such authoritative information to be understood and used during the pressures of an earthquake

  2. Smart Magnetically Responsive Hydrogel Nanoparticles Prepared by a Novel Aerosol-Assisted Method for Biomedical and Drug Delivery Applications

    Directory of Open Access Journals (Sweden)

    Ibrahim M. El-Sherbiny

    2011-01-01

    Full Text Available We have developed a novel spray gelation-based method to synthesize a new series of magnetically responsive hydrogel nanoparticles for biomedical and drug delivery applications. The method is based on the production of hydrogel nanoparticles from sprayed polymeric microdroplets obtained by an air-jet nebulization process that is immediately followed by gelation in a crosslinking fluid. Oligoguluronate (G-blocks was prepared through the partial acid hydrolysis of sodium alginate. PEG-grafted chitosan was also synthesized and characterized (FTIR, EA, and DSC. Then, magnetically responsive hydrogel nanoparticles based on alginate and alginate/G-blocks were synthesized via aerosolization followed by either ionotropic gelation or both ionotropic and polyelectrolyte complexation using CaCl2 or PEG-g-chitosan/CaCl2 as crosslinking agents, respectively. Particle size and dynamic swelling were determined using dynamic light scattering (DLS and microscopy. Surface morphology of the nanoparticles was examined using SEM. The distribution of magnetic cores within the hydrogels nanoparticles was also examined using TEM. In addition, the iron and calcium contents of the particles were estimated using EDS. Spherical magnetic hydrogel nanoparticles with average particle size of 811 ± 162 to 941 ± 2 nm were obtained. This study showed that the developed method is promising for the manufacture of hydrogel nanoparticles, and it represents a relatively simple and potential low-cost system.

  3. Smart Magnetically Responsive Hydrogel Nanoparticles Prepared by a Novel Aerosol-Assisted Method for Biomedical and Drug Delivery Applications.

    Science.gov (United States)

    El-Sherbiny, Ibrahim M; Smyth, Hugh D C

    2011-01-01

    We have developed a novel spray gelation-based method to synthesize a new series of magnetically responsive hydrogel nanoparticles for biomedical and drug delivery applications. The method is based on the production of hydrogel nanoparticles from sprayed polymeric microdroplets obtained by an air-jet nebulization process that is immediately followed by gelation in a crosslinking fluid. Oligoguluronate (G-blocks) was prepared through the partial acid hydrolysis of sodium alginate. PEG-grafted chitosan was also synthesized and characterized (FTIR, EA, and DSC). Then, magnetically responsive hydrogel nanoparticles based on alginate and alginate/G-blocks were synthesized via aerosolization followed by either ionotropic gelation or both ionotropic and polyelectrolyte complexation using CaCl(2) or PEG-g-chitosan/CaCl(2) as crosslinking agents, respectively. Particle size and dynamic swelling were determined using dynamic light scattering (DLS) and microscopy. Surface morphology of the nanoparticles was examined using SEM. The distribution of magnetic cores within the hydrogels nanoparticles was also examined using TEM. In addition, the iron and calcium contents of the particles were estimated using EDS. Spherical magnetic hydrogel nanoparticles with average particle size of 811 ± 162 to 941 ± 2 nm were obtained. This study showed that the developed method is promising for the manufacture of hydrogel nanoparticles, and it represents a relatively simple and potential low-cost system.

  4. Microencapsulation of alpha-mangostin into PLGA microspheres and optimization using response surface methodology intended for pulmonary delivery.

    Science.gov (United States)

    Elsaid Ali, Aimen Abdo; Taher, Muhammad; Mohamed, Farahidah

    2013-01-01

    Documented to exhibit cytotoxicity and poor oral bioavailability, alpha-mangostin was encapsulated into PLGA microspheres with optimization of formulation using response surface methodology. Mixed levels of four factors Face central composite design was employed to evaluate critical formulation variables. With 30 runs, optimized formula was 1% w/v polyvinyl alcohol, 1:10 ratio of oil to aqueous and sonicated at 2 and 5 min time for primary and secondary emulsion, respectively. Optimized responses for encapsulation efficiency, particle size and polydispersity index were found to be 39.12 ± 0.01%, 2.06 ± 0.017 µm and 0.95 ± 0.009, respectively, which matched values predicted by mathematical models. About 44.4% of the encapsulated alpha-mangostin was released over 4 weeks. Thermal analysis of the microspheres showed physical conversion of alpha-mangostin from crystallinity to amorphous with encapsulated one had lower in vitro cytotoxicity than free alpha-mangostin. Aerodynamic diameter (784.3 ± 7.5 nm) of this alpha-mangostin microsphere suggests suitability for peripheral pulmonary delivery.

  5. Coordination polymer nanocapsules prepared using metal-organic framework templates for pH-responsive drug delivery

    Science.gov (United States)

    Tang, Lei; Shi, Jiafu; Wang, Xiaoli; Zhang, Shaohua; Wu, Hong; Sun, Hongfan; Jiang, Zhongyi

    2017-07-01

    A facile, efficient, and versatile approach is presented to synthesize pH-responsive nanocapsules (˜120 nm) by combining the advantages of metal-organic frameworks (MOFs) and metal-organic thin films. ZIF-8 nanoparticles are used as templates on which a thin film coating of iron(III)-catechol complexes is derived from the coordination between dopamine-modified alginate (AlgDA) and iron(III) ions. After the template removal, nanocapsules with a pH-responsive wall are obtained. Doxorubicin (Dox), a typical anticancer drug, is first immobilized in ZIF-8 frameworks through coprecipitation and then encapsulated in nanocapsules after the removal of ZIF-8. The structure of the iron(III)-catechol complex varies with pH value, thus conferring the Dox@Nanocapsules with tailored release behavior in vitro. Cytotoxicity tests illustrate the highly effective cytotoxicity of Dox@Nanocapsules towards cancer cells. This study provides a new method for preparing smart nanocapsules and offers more opportunities for the controlled delivery of drugs.

  6. Enhanced mucosal immune responses against tetanus toxoid using novel delivery system comprised of chitosan-functionalized gold nanoparticles and botanical adjuvant: characterization, immunogenicity, and stability assessment.

    Science.gov (United States)

    Barhate, Ganesh; Gautam, Manish; Gairola, Sunil; Jadhav, Suresh; Pokharkar, Varsha

    2014-11-01

    Approaches based on combined use of delivery systems and adjuvants are being favored to maximize efficient mucosal delivery of antigens. Here, we describe a novel delivery system comprised of chitosan-functionalized gold nanoparticles (CsAuNPs) and saponin-containing botanical adjuvant; Asparagus racemosus extract (ARE) for oral delivery of tetanus toxoid (TT). A significant increase in TT-specific IgG (34.53-fold) and IgA (43.75-fold) was observed when TT-CsAuNPs were formulated with ARE (TT-ARE-CsAuNPs). The local IgA immune responses for TT also showed a significant increase (106.5-fold in intestine washes and 99.74-fold in feces) with ARE-based formulations as compared with plain TT group. No effect of ARE was observed on size, charge, and loading properties of CsAuNPs. Additionally, no effect of ARE and CsAuNPs was observed on antigenicity and secondary structure of TT as determined by fluorescence, circular dichroism, and Fourier transform infrared spectroscopy. The stability studies demonstrated excellent stability profile of formulation at recommended storage conditions. The study establishes the possible role of immunomodulatory adjuvants in particulate delivery systems for mucosal delivery of vaccines. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  7. Study on Chitosan-Polyvinyl Alcohol Inter polymeric ph-Responsive Hydrogels for Controlled Drug Delivery

    International Nuclear Information System (INIS)

    Abdel-Bary, E.M.; El-Sherbiny, I.M.; Abdelaal, M.Y.; Abdel-Razik, E.A.

    2005-01-01

    Two series of ph-responsive biodegradable interpenetrating polymeric (IPN) hydrogels composed of chitosan and poly(vinyl alcohol) (PVA) were prepared for controlled drug release investigations. The first series was chemically crosslinked with different concentrations of glutaraldehyde as a crosslinked and the second series was crosslinked by gamma-radiation. Degree of crosslinking has been controlled by the concentration of crosslinked as well as by gamma irradiation dose. The equilibrium swelling -reflecting the degree of crosslinks - were carried out for the gels at 37 degree C in buffer solutions of ph 2.1 and 7.4 (simulated gastric and intestinal fluids respectively). 5-fluorouracil (5- FU) was entrapped, as a model therapeutic agent, in the hydrogels and equilibrium-swelling studies were carried out for the drug-entrapped gels at 37 degree C. The in-vitro release profiles of the drug were established at 37 degree C in ph 2.1 and 7.4. FT-IR was employed to investigate the structural changes of the gels with different degrees of crosslinking

  8. Simultaneous delivery of therapeutic antagomirs with paclitaxel for the management of metastatic tumors by a pH-responsive anti-microbial peptide-mediated liposomal delivery system.

    Science.gov (United States)

    Zhang, Qianyu; Ran, Rui; Zhang, Li; Liu, Yayuan; Mei, Ling; Zhang, Zhirong; Gao, Huile; He, Qin

    2015-01-10

    The roles of microRNAs (miRNAs) in the regulation of metastasis have been widely recognized in the recent years. Mir-10b antagomir (antagomir-10b) was shown to impede metastasis through the down-regulation of mir-10b; however, it could not stunt the growth of primary tumors. In this study we showed that the co-delivery of antagomir-10b with paclitaxel (PTX) by a novel liposomal delivery system modified with an anti-microbial peptide [D]-H6L9 (D-Lip) could significantly both hinder the migration of 4T1 cells and induce evident cellular apoptosis and cell death in the meantime. The histidines in the sequence of [D]-H6L9 allowed the peptide to get protonated under pH5.0 (mimicking the lysosome/endosome environment), and strong membrane lytic effect could thus be activated, leading to the escape of liposomes from the lysosomes and the decrease of of mir-10b expression. The in vivo and ex vivo fluorescence imaging showed that D-Lip could reach 4T1 tumors efficaciously. Incorporation of PTX did not influence the antagomir-10b delivery effect of D-Lip; for the in vivo tumor inhibition assay, compared with all the other groups, the combination of antagomir-10b and PTX delivered by D-Lip could prominently delay the growth of 4T1 tumors and reduce the lung metastases at the same time, and the expression of Hoxd10 in tumors was also significantly up-regulated. Taken together, these results demonstrated that D-Lip could act as a sufficient tool in co-delivering antagomir-10b and PTX. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Neutrophil Cathepsin G, but Not Elastase, Induces Aggregation of MCF-7 Mammary Carcinoma Cells by a Protease Activity-Dependent Cell-Oriented Mechanism

    Directory of Open Access Journals (Sweden)

    Satoru Yui

    2014-01-01

    Full Text Available We previously found that a neutrophil serine protease, cathepsin G, weakens adherence to culture substrates and induces E-cadherin-dependent aggregation of MCF-7 human breast cancer cells through its protease activity. In this study, we examined whether aggregation is caused by degradation of adhesion molecules on the culture substrates or through an unidentified mechanism. We compared the effect of treatment with cathepsin G and other proteases, including neutrophil elastase against fibronectin- (FN- coated substrates. Cathepsin G and elastase potently degraded FN on the substrates and induced aggregation of MCF-7 cells that had been subsequently seeded onto the substrate. However, substrate-bound cathepsin G and elastase may have caused cell aggregation. After inhibiting the proteases on the culture substrates using the irreversible inhibitor phenylmethylsulfonyl fluoride (PMSF, we examined whether aggregation of MCF-7 cells was suppressed. PMSF attenuated cell aggregation on cathepsin G-treated substrates, but the effect was weak in cells pretreated with high concentrations of cathepsin G. In contrast, PMSF did not suppress cell aggregation on elastase-treated FN. Moreover, cathepsin G, but not elastase, induced aggregation on poly-L-lysine substrates which are not decomposed by these enzymes, and the action of cathepsin G was nearly completely attenuated by PMSF. These results suggest that cathepsin G induces MCF-7 aggregation through a cell-oriented mechanism.

  10. Co-loading and intestine-specific delivery of multiple antioxidants in pH-responsive microspheres based on TEMPO-oxidized polysaccharides

    NARCIS (Netherlands)

    Shi, Mengxuan; Bai, Jie; Zhao, Liyun; Yu, Xinrui; Liang, Jingjing; Liu, Ying; Norde, Willem; Li, Yuan

    2017-01-01

    In this study, pH-responsive microspheres loaded with multiple antioxidants were developed for intestine-specific delivery and exhibited synergistic activity. They consist of chitosan (CS)-coated microspheres made of TEMPO-oxidized Konjac glucomannan (OKGM) polymers, of which the carboxyl (COO−)

  11. Co-delivery of PLGA encapsulated invariant NKT cell agonist with antigenic protein induce strong T cell-mediated antitumor immune responses

    NARCIS (Netherlands)

    Dolen, Y.; Kreutz, M.; Gileadi, U.; Tel, J.; Vasaturo, A.; Dinther, E.A.W. van; Hout-Kuijer, M.A. van; Cerundolo, V.; Figdor, C.G.

    2016-01-01

    Antitumor immunity can be enhanced by the coordinated release and delivery of antigens and immune-stimulating agents to antigen-presenting cells via biodegradable vaccine carriers. So far, encapsulation of TLR ligands and tumor-associated antigens augmented cytotoxic T cell (CTLs) responses. Here,

  12. A murine model of elastase- and cigarette smoke-induced emphysema

    Directory of Open Access Journals (Sweden)

    Rubia Rodrigues

    Full Text Available ABSTRACT Objective: To describe a murine model of emphysema induced by a combination of exposure to cigarette smoke (CS and instillation of porcine pancreatic elastase (PPE. Methods: A total of 38 C57BL/6 mice were randomly divided into four groups: control (one intranasal instillation of 0.9% saline solution; PPE (two intranasal instillations of PPE; CS (CS exposure for 60 days; and CS + PPE (two intranasal instillations of PPE + CS exposure for 60 days. At the end of the experimental protocol, all animals were anesthetized and tracheostomized for calculation of respiratory mechanics parameters. Subsequently, all animals were euthanized and their lungs were removed for measurement of the mean linear intercept (Lm and determination of the numbers of cells that were immunoreactive to macrophage (MAC-2 antigen, matrix metalloproteinase (MMP-12, and glycosylated 91-kDa glycoprotein (gp91phox in the distal lung parenchyma and peribronchial region. Results: Although there were no differences among the four groups regarding the respiratory mechanics parameters assessed, there was an increase in the Lm in the CS + PPE group. The numbers of MAC-2-positive cells in the peribronchial region and distal lung parenchyma were higher in the CS + PPE group than in the other groups, as were the numbers of cells that were positive for MMP-12 and gp91phox, although only in the distal lung parenchyma. Conclusions: Our model of emphysema induced by a combination of PPE instillation and CS exposure results in a significant degree of parenchymal destruction in a shorter time frame than that employed in other models of CS-induced emphysema, reinforcing the importance of protease-antiprotease imbalance and oxidant-antioxidant imbalance in the pathogenesis of emphysema.

  13. Elevated Neutrophil Elastase in Tears of Ocular Graft-Versus-Host Disease Patients.

    Science.gov (United States)

    Arafat, Samer N; Robert, Marie-Claude; Abud, Tulio; Spurr-Michaud, Sandra; Amparo, Francisco; Dohlman, Claes H; Dana, Reza; Gipson, Ilene K

    2017-04-01

    To investigate the levels of neutrophil elastase (NE), matrix metalloproteinases (MMPs), and myeloperoxidase (MPO) in tear washes of patients with ocular graft-vs-host disease (oGVHD). Case-control study. Based on established criteria, oGVHD patients (n = 14; 28 eyes) and age-/sex-matched healthy controls (n = 14; 28 eyes) were enrolled. Tear washes were collected and analyzed for NE using a single-analyte enzyme-linked immunosorbent assay (ELISA). MMPs (1, 2, 3, 7, 8, 9, 12), MPO, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 were analyzed using multianalyte bead-based ELISA assays. Total MMP activity was measured using a fluorimetric assay. Correlation studies were performed between NE, MMP-8, MMP-9, and MPO within study groups. NE, MMP-8, MMP-9, and MPO levels were elevated in oGVHD tears when compared with controls (P < .0001). NE was the most elevated analyte. MMP activity was higher and TIMP-1 levels were lower in oGVHD than in control (P < .0001). In oGVHD, NE significantly correlated with MMP-8 (r = 0.92), MMP-9 (r = 0.90), and MPO (r = 0.79) (P < .0001). MMP-8 correlated with MMP-9 (r = 0.96, P < .0001), and MPO (r = 0.60, P = .001). MMP-9 correlated with MPO (r = 0.55, P = .002). In controls, NE, MMP-9, and MPO significantly correlated with each other (P < .0001). The marked increase in NE in oGVHD tears that correlated strongly with elevated MMP-8, MMP-9, and MPO suggests a common neutrophilic source and provides evidence of neutrophil activity on the ocular surface of oGVHD patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Pseudomonas aeruginosa elastase provides an escape from phagocytosis by degrading the pulmonary surfactant protein-A.

    Directory of Open Access Journals (Sweden)

    Zhizhou Kuang

    Full Text Available Pseudomonas aeruginosa is an opportunistic pathogen that causes both acute pneumonitis in immunocompromised patients and chronic lung infections in individuals with cystic fibrosis and other bronchiectasis. Over 75% of clinical isolates of P. aeruginosa secrete elastase B (LasB, an elastolytic metalloproteinase that is encoded by the lasB gene. Previously, in vitro studies have demonstrated that LasB degrades a number of components in both the innate and adaptive immune systems. These include surfactant proteins, antibacterial peptides, cytokines, chemokines and immunoglobulins. However, the contribution of LasB to lung infection by P. aeruginosa and to inactivation of pulmonary innate immunity in vivo needs more clarification. In this study, we examined the mechanisms underlying enhanced clearance of the ΔlasB mutant in mouse lungs. The ΔlasB mutant was attenuated in virulence when compared to the wild-type strain PAO1 during lung infection in SP-A+/+ mice. However, the ΔlasB mutant was as virulent as PAO1 in the lungs of SP-A⁻/⁻ mice. Detailed analysis showed that the ΔlasB mutant was more susceptible to SP-A-mediated opsonization but not membrane permeabilization. In vitro and in vivo phagocytosis experiments revealed that SP-A augmented the phagocytosis of ΔlasB mutant bacteria more efficiently than the isogenic wild-type PAO1. The ΔlasB mutant was found to have a severely reduced ability to degrade SP-A, consequently making it unable to evade opsonization by the collectin during phagocytosis. These results suggest that P. aeruginosa LasB protects against SP-A-mediated opsonization by degrading the collectin.

  15. Reactivity and selectivity in the inhibition of elastase by 3-oxo-beta-sultams and in their hydrolysis.

    Science.gov (United States)

    Tsang, Wing-Yin; Ahmed, Naveed; Hemming, Karl; Page, Michael I

    2007-12-21

    3-oxo-beta-sultams are both beta-sultams and beta-lactams and are a novel class of time-dependent inhibitors of elastase. The inhibition involves formation of a covalent enzyme-inhibitor adduct with transient stability by acylation of the active-site serine resulting from substitution at the carbonyl centre of the 3-oxo-beta-sultam, C-N fission, and expulsion of the sulfonamide. The lead compound, N-benzyl-4,4-dimethyl-3-oxo-beta-sultam 1 is a reasonably potent inhibitor against porcine pancreatic elastase with a second-order rate constant of 768 M(-1) s(-1) at pH 6, but also possesses high chemical reactivity with a half-life for hydrolysis of only 6 mins at the same pH in water. Interestingly, the hydrolysis of 3-oxo-beta-sultams occurs at the sulfonyl centre with S-N fission and expulsion of the amide leaving group, whereas the enzyme reaction occurs at the acyl centre. Increasing selectivity between these two reactive centres was explored by examining the effect of substituents on the reactivity of 3-oxo-beta-sultam towards hydrolysis and enzyme inhibition. The inhibition activity against porcine pancreatic elastase has a much higher sensitivity to substituent variation than does the rate of alkaline hydrolysis. A difference of 2000-fold is observed in the second-order rate constants, k(i), for inhibition whereas there is only a 100-fold difference in the second-order rate constants, k(OH), for alkaline hydrolysis within the series. The higher sensitivity of enzyme inhibition to substituents than that of simple chemical reactivity indicates a significant degree of molecular recognition of the 3-oxo-beta-sultams by the enzyme.

  16. The influence of hemodynamic forces on biomarkers in the walls of elastase-induced aneurysms in rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Kadirvel, Ramanathan; Ding, Yong-Hong; Dai, Daying; Danielson, Mark A.; Lewis, Debra A.; Cloft, Harry J.; Kallmes, David F. [Mayo Clinic College of Medicine, Department of Radiology, Rochester, MN (United States); Zakaria, Hasballah; Robertson, Anne M. [University of Pittsburgh, Department of Mechanical Engineering, Pittsburgh, PA (United States)

    2007-12-15

    Biological and biophysical factors have been shown to play an important role in the initiation, progression, and rupture of intracranial aneurysms. The purpose of this study was to evaluate the association between hemodynamic forces and markers of vascular remodeling in elastase-induced saccular aneurysms in rabbits. Elastase-induced aneurysms were created at the origin of the right common carotid artery in rabbits. Hemodynamic parameters were estimated using computational fluid dynamic simulations based on 3-D-reconstructed models of the vasculature. Expression of matrix metalloproteinases (MMPs), their inhibitors (TIMPs) and markers of vascular remodeling were measured in different spatial regions within the aneurysms. Altered expression of biological markers relative to controls was correlated with the locations of subnormal time-averaged wall shear stress (WSS) but not with the magnitude of pressure. In the aneurysms, WSS was low and expression of biological markers was significantly altered in a time-dependent fashion. At 2 weeks, an upregulation of active-MMP-2, downregulation of TIMP-1 and TIMP-2, and intact endothelium were found in aneurysm cavities. However, by 12 weeks, endothelial cells were absent or scattered, and levels of pro- and active-MMP-2 were not different from those in control arteries, but pro-MMP-9 and both TIMPs were upregulated. These results reveal a strong, spatially localized correlation between diminished WSS and differential expression of biological markers of vascular remodeling in elastase-induced saccular aneurysms. The ability of the wall to function and maintain a healthy endothelium in a low shear environment appears to be significantly impaired by chronic exposure to low WSS. (orig.)

  17. Selective modulation of the CD4 molecular complex by Pseudomonas aeruginosa alkaline protease and elastase

    DEFF Research Database (Denmark)

    Pedersen, B K; Kharazmi, A; Theander, T G

    1987-01-01

    The binding of monoclonal antibodies against CD4 was specifically inhibited by treatment of human CD4+ cells with either alkaline protease (AP) or elastase (Ela), purified from Pseudomonas aeruginosa. Binding of antibodies against CD3 (pan T), CD5 (pan T), CD8 (T suppressor/cytotoxic), HLA-ABC, HLA......-DR, HLA-DQ, HLA-DP/DR, and beta 2 microglobulin was not inhibited by AP or Ela. Heat-inactivation of the proteases at 65 degrees C for 20 min or treatment with the metal chelator EDTA abolished the inhibitory activity of both proteases. These findings may serve to develop novel immunological methods...

  18. Ensuring 3es and Responsiveness in the Delivery of Educational Services in the Autonomous Region in Muslim Mindanao, Philippines

    Directory of Open Access Journals (Sweden)

    Sapia Moalam Abdulrachman

    2013-08-01

    Full Text Available The Autonomous Region in Muslim Mindanao (ARMM is a public organization in the Philippines located in between the national government and the local governments. It performs unique functions quite distinct from other public organizations in the coun-try, as it performs both political and administrative functions. Using unobtrusive research design, as it relies on mostly secondary data, this paper analyzes the educational system in the region and proposes strategies in attaining administrative efficiency, economy, effectiveness and responsiveness. The paper starts with the introduction which consist of the background and statement of the problem. It is followed by a review of theoretical perspective and then by the research methodology. The fourth part portrays the findings of the study which include: DepEd ARMM resources; the management of DepEd ARMM, and the management outputs such as: net enrollment ratio, achievement rate and literacy rate. The fifth part of the paper deals with the analyses and conclusion. The paper concludes that in addition to certain structural innovation, inculcation of appropriate work ethics in accordance with the Ethi-cal Standards Act, the Anti-Corruption Law, the Civil Service Rules and Regulations as well as the Islamic Practices on Employment must be enshrined in the reform agenda. Finally, among other things that could facilitate the attainment of 3Es and R in the delivery of educational services is a strategy that requires the joint collaboration and teamwork between the civil society, non-government organizations and government organizations in the region.

  19. Biomimetic synthesis of sericin and silica hybrid colloidosomes for stimuli-responsive anti-cancer drug delivery systems.

    Science.gov (United States)

    Yang, Ying; Cai, Yurong; Sun, Ning; Li, Ruijing; Li, Wenhua; Kundu, Subhas C; Kong, Xiangdong; Yao, Juming

    2017-03-01

    Colloidosomes are becoming popular due to their significant flexibility with respect to microcapsule functionality. This study reports a facile approach for synthesizing silica colloidosomes by using sericin microcapsule as the matrix in an environment-friendly method. The silica colloid arrangement on the sericin microcapsules are orchestrated by altering the reaction parameters. Doxorubicin (DOX), used as a hydrophilic anti-cancer drug model, is encapsulated into the colloidosomes in a mild aqueous solution and becomes stimuli-responsive to different external environments, including pH values, protease, and ionic strength are also observed. Colloidosomes with sub-monolayers, close-packed monolayers, and close-packed multi-layered SiO 2 colloid shells can be fabricated under the optimized reaction conditions. A flexible DOX release from colloidosomes can be obtained via modulating the SiO 2 colloid layer arrangement and thickness. The close-packed and multi-layered SiO 2 colloid shells can best protect the colloidosomes and delay the rapid cargo release. MG-63 cells are killed when doxorubicin is released from the microcapsules due to degradation in the microenvironment of cancer cells. The drug release period is prolonged as SiO 2 shell thickness and integrity increase. This work suggests that the hybrid colloidosomes can be effective in a bioactive molecule delivery system. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Optimization of self nanoemulsifying drug delivery system for poorly water-soluble drug using response surface methodology

    DEFF Research Database (Denmark)

    Ren, Shan; Mu, Huiling; Alchaer, Fadi

    2013-01-01

    There is an increasing interest on self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of poorly water-soluble drugs. However, development of SNEDDS is often driven by empiric, pseudo-ternary diagrams and solubility of drugs, and it is lacking a systematic approach for evaluating...

  1. An amphiphilic graft copolymer-based nanoparticle platform for reduction-responsive anticancer and antimalarial drug delivery

    Science.gov (United States)

    Najer, Adrian; Wu, Dalin; Nussbaumer, Martin G.; Schwertz, Geoffrey; Schwab, Anatol; Witschel, Matthias C.; Schäfer, Anja; Diederich, François; Rottmann, Matthias; Palivan, Cornelia G.; Beck, Hans-Peter; Meier, Wolfgang

    2016-08-01

    Medical applications of anticancer and antimalarial drugs often suffer from low aqueous solubility, high systemic toxicity, and metabolic instability. Smart nanocarrier-based drug delivery systems provide means of solving these problems at once. Herein, we present such a smart nanoparticle platform based on self-assembled, reduction-responsive amphiphilic graft copolymers, which were successfully synthesized through thiol-disulfide exchange reaction between thiolated hydrophilic block and pyridyl disulfide functionalized hydrophobic block. These amphiphilic graft copolymers self-assembled into nanoparticles with mean diameters of about 30-50 nm and readily incorporated hydrophobic guest molecules. Fluorescence correlation spectroscopy (FCS) was used to study nanoparticle stability and triggered release of a model compound in detail. Long-term colloidal stability and model compound retention within the nanoparticles was found when analyzed in cell media at body temperature. In contrast, rapid, complete reduction-triggered disassembly and model compound release was achieved within a physiological reducing environment. The synthesized copolymers revealed no intrinsic cellular toxicity up to 1 mg mL-1. Drug-loaded reduction-sensitive nanoparticles delivered a hydrophobic model anticancer drug (doxorubicin, DOX) to cancer cells (HeLa cells) and an experimental, metabolically unstable antimalarial drug (the serine hydroxymethyltransferase (SHMT) inhibitor (+/-)-1) to Plasmodium falciparum-infected red blood cells (iRBCs), with higher efficacy compared to similar, non-sensitive drug-loaded nanoparticles. These responsive copolymer-based nanoparticles represent a promising candidate as smart nanocarrier platform for various drugs to be applied to different diseases, due to the biocompatibility and biodegradability of the hydrophobic block, and the protein-repellent hydrophilic block.Medical applications of anticancer and antimalarial drugs often suffer from low aqueous

  2. Microneedle arrays coated with charge reversal pH-sensitive copolymers improve antigen presenting cells-homing DNA vaccine delivery and immune responses.

    Science.gov (United States)

    Duong, Huu Thuy Trang; Kim, Nak Won; Thambi, Thavasyappan; Giang Phan, V H; Lee, Min Sang; Yin, Yue; Jeong, Ji Hoon; Lee, Doo Sung

    2018-01-10

    Successful delivery of a DNA vaccine to antigen-presenting cells and their subsequent stimulation of CD4 + and CD8 + T cell immunity remains an inefficient process. In general, the delivery of prophylactic vaccines is mainly mired by low transfection efficacy, poor immunogenicity, and safety issues from the materials employed. Currently, several strategies have been exploited to improve immunogenicity, but an effective strategy for safe and pain-free delivery of DNA vaccines is complicated. Herein, we report the rapid delivery of polyplex-based DNA vaccines using microneedle arrays coated with a polyelectrolyte multilayer assembly of charge reversal pH-responsive copolymer and heparin. The charge reversal pH-responsive copolymer, composed of oligo(sulfamethazine)-b-poly(ethylene glycol)-b-poly(amino urethane) (OSM-b-PEG-b-PAEU), was used as a triggering layer in the polyelectrolyte multilayer assembly on microneedles. Charge reversal characteristics of this copolymer, that is, the OSM-b-PEG-b-PAEU copolymer exhibit, positive charge at low pH (pH4.03) and becoming negative charge when exposed to physiological pH conditions (pH7.4), allowing the facile assembly and disassembly of polyelectrolyte multilayers. The electrostatic repulsion between heparin and OSM-b-PEG-b-PAEU charge reversal copolymer triggered the release of DNA vaccines. DNA vaccines laden on microneedles are effectively transfected into RAW 264.7 macrophage cells in vitro. Vaccination of BALB/c mice by DNA vaccine-loaded microneedle arrays coated with a polyelectrolyte multilayer generated antigen-specific robust immune responses. These findings provide potential strategy of charge reversal pH-responsive copolymers coated microneedles for DNA vaccine delivery. Copyright © 2017. Published by Elsevier B.V.

  3. Delivery presentations

    Science.gov (United States)

    Pregnancy - delivery presentation; Labor - delivery presentation; Occiput posterior; Occiput anterior; Brow presentation ... The mother can walk, rock, and try different delivery positions during labor to help encourage the baby ...

  4. Measurement of fecal elastase improves performance of newborn screening for cystic fibrosis.

    Science.gov (United States)

    Barben, Juerg; Rueegg, Corina S; Jurca, Maja; Spalinger, Johannes; Kuehni, Claudia E

    2016-05-01

    The aim of newborn screening (NBS) for CF is to detect children with 'classic' CF where early treatment is possible and improves prognosis. Children with inconclusive CF diagnosis (CFSPID) should not be detected, as there is no evidence for improvement through early treatment. No algorithm in current NBS guidelines explains what to do when sweat test (ST) fails. This study compares the performance of three different algorithms for further diagnostic evaluations when first ST is unsuccessful, regarding the numbers of children detected with CF and CFSPID, and the time until a definite diagnosis. In Switzerland, CF-NBS was introduced in January 2011 using an IRT-DNA-IRT algorithm followed by a ST. In children, in whom ST was not possible (no or insufficient sweat), 3 different protocols were applied between 2011 and 2014: in 2011, ST was repeated until it was successful (protocol A), in 2012 we proceeded directly to diagnostic DNA testing (protocol B), and 2013-2014, fecal elastase (FE) was measured in the stool, in order to determine a pancreas insufficiency needing immediate treatment (protocol C). The ratio CF:CFSPID was 7:1 (27/4) with protocol A, 2:1 (22/10) with protocol B, and 14:1 (54/4) with protocol C. The mean time to definite diagnosis was significantly shorter with protocol C (33days) compared to protocol A or B (42 and 40days; p=0.014 compared to A, and p=0.036 compared to B). The algorithm for the diagnostic part of the newborn screening used in the CF centers is important and affects the performance of a CF-NBS program with regard to the ratio CF:CFSPID and the time until definite diagnosis. Our results suggest to include FE after initial sweat test failure in the CF-NBS guidelines to keep the proportion of CFSPID low and the time until definite diagnosis short. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  5. SP-A binds alpha1-antitrypsin in vitro and reduces the association rate constant for neutrophil elastase

    Directory of Open Access Journals (Sweden)

    Carrabino Natalia

    2005-12-01

    Full Text Available Abstract Background α1-antitrypsin and surfactant protein-A (SP-A are major lung defense proteins. With the hypothesis that SP-A could bind α1-antitrypsin, we designed a series of in vitro experiments aimed at investigating the nature and consequences of such an interaction. Methods and results At an α1-antitrypsin:SP-A molar ratio of 1:1, the interaction resulted in a calcium-dependent decrease of 84.6% in the association rate constant of α1-antitrypsin for neutrophil elastase. The findings were similar when SP-A was coupled with the Z variant of α1-antitrypsin. The carbohydrate recognition domain of SP-A appeared to be a major determinant of the interaction, by recognizing α1-antitrypsin carbohydrate chains. However, binding of SP-A carbohydrate chains to the α1-antitrypsin amino acid backbone and interaction between carbohydrates of both proteins are also possible. Gel filtration chromatography and turnover per inactivation experiments indicated that one part of SP-A binds several molar parts of α1-antitrypsin. Conclusion We conclude that the binding of SP-A to α1-antitrypsin results in a decrease of the inhibition of neutrophil elastase. This interaction could have potential implications in the physiologic regulation of α1-antitrypsin activity, in the pathogenesis of pulmonary emphysema, and in the defense against infectious agents.

  6. A murine model of elastase- and cigarette smoke-induced emphysema.

    Science.gov (United States)

    Rodrigues, Rubia; Olivo, Clarice Rosa; Lourenço, Juliana Dias; Riane, Alyne; Cervilha, Daniela Aparecida de Brito; Ito, Juliana Tiyaki; Martins, Milton de Arruda; Lopes, Fernanda Degobbi Tenório Quirino Dos Santos

    2017-01-01

    To describe a murine model of emphysema induced by a combination of exposure to cigarette smoke (CS) and instillation of porcine pancreatic elastase (PPE). A total of 38 C57BL/6 mice were randomly divided into four groups: control (one intranasal instillation of 0.9% saline solution); PPE (two intranasal instillations of PPE); CS (CS exposure for 60 days); and CS + PPE (two intranasal instillations of PPE + CS exposure for 60 days). At the end of the experimental protocol, all animals were anesthetized and tracheostomized for calculation of respiratory mechanics parameters. Subsequently, all animals were euthanized and their lungs were removed for measurement of the mean linear intercept (Lm) and determination of the numbers of cells that were immunoreactive to macrophage (MAC)-2 antigen, matrix metalloproteinase (MMP)-12, and glycosylated 91-kDa glycoprotein (gp91phox) in the distal lung parenchyma and peribronchial region. Although there were no differences among the four groups regarding the respiratory mechanics parameters assessed, there was an increase in the Lm in the CS + PPE group. The numbers of MAC-2-positive cells in the peribronchial region and distal lung parenchyma were higher in the CS + PPE group than in the other groups, as were the numbers of cells that were positive for MMP-12 and gp91phox, although only in the distal lung parenchyma. Our model of emphysema induced by a combination of PPE instillation and CS exposure results in a significant degree of parenchymal destruction in a shorter time frame than that employed in other models of CS-induced emphysema, reinforcing the importance of protease-antiprotease imbalance and oxidant-antioxidant imbalance in the pathogenesis of emphysema. Descrever um modelo murino de enfisema induzido por exposição a fumaça de cigarro (FC) e instilação de elastase pancreática porcina (EPP). Trinta e oito camundongos C57BL/6 foram aleatoriamente divididos em quatro grupos: controle (uma instilação intranasal

  7. Health care delivery systems.

    NARCIS (Netherlands)

    Stevens, F.; Zee, J. van der

    2007-01-01

    A health care delivery system is the organized response of a society to the health problems of its inhabitants. Societies choose from alternative health care delivery models and, in doing so, they organize and set goals and priorities in such a way that the actions of different actors are effective,

  8. Ethical issues in cesarean delivery.

    Science.gov (United States)

    Chervenak, Frank A; McCullough, Laurence B

    2017-08-01

    Cesarean delivery is the most common and important surgical intervention in obstetric practice. Ethics provides essential guidance to obstetricians for offering, recommending, recommending against, and performing cesarean delivery. This chapter provides an ethical framework based on the professional responsibility model of obstetric ethics. This framework is then used to address two especially ethically challenging clinical topics in cesarean delivery: patient-choice cesarean delivery and trial of labor after cesarean delivery. This chapter emphasizes a preventive ethics approach, designed to prevent ethical conflict in clinical practice. To achieve this goal, a preventive ethics approach uses the informed consent process to offer cesarean delivery as a medically reasonable alternative to vaginal delivery, to recommend cesarean delivery, and to recommend against cesarean delivery. The limited role of shared decision making is also described. The professional responsibility model of obstetric ethics guides this multi-faceted preventive ethics approach. Copyright © 2017. Published by Elsevier Ltd.

  9. The role of secretory leukocyte proteinase inhibitor and elafin (elastase-specific inhibitor/skin-derived antileukoprotease as alarm antiproteinases in inflammatory lung disease

    Directory of Open Access Journals (Sweden)

    Sallenave Jean-Michel

    2000-08-01

    Full Text Available Abstract Secretory leukocyte proteinase inhibitor and elafin are two low-molecular-mass elastase inhibitors that are mainly synthesized locally at mucosal sites. It is thought that their physicochemical properties allow them to efficiently inhibit target enzymes, such as neutrophil elastase, released into the interstitium. Historically, in the lung, these inhibitors were first purified from secretions of patients with chronic obstructive pulmonary disease and cystic fibrosis. This suggested that they might be important in controlling excessive neutrophil elastase release in these pathologies. They are upregulated by 'alarm signals' such as bacterial lipopolysaccharides, and cytokines such as interleukin-1 and tumor necrosis factor and have been shown to be active against Gram-positive and Gram-negative bacteria, so that they have joined the growing list of antimicrobial 'defensin-like' peptides produced by the lung. Their site of synthesis and presumed functions make them very attractive candidates as potential therapeutic agents under conditions in which the excessive release of elastase by neutrophils might be detrimental. Because of its natural tropism for the lung, the use of adenovirus-mediated gene transfer is extremely promising in such applications.

  10. Influence of elastase-induced emphysema and the inhalation of an irritant aerosol on deposition and retention of an inhaled insoluble aerosol in Fischer-344 rats

    International Nuclear Information System (INIS)

    Damon, E.G.; Mokler, B.V.; Jones, R.K.

    1983-01-01

    The purpose of this study was to assess the effects of elastase-induced pulmonary emphysema and the inhalation of an irritant aerosol (Triton X-100, a nonionic surfactant similar to those used in a number of pressurized consumer products) on pulmonary deposition and retention of an insoluble test aerosol, 59 FE-labeled Fe 2 O 3 . Untreated rats or rats pretreated by intratracheal in stillation with elastase were exposed to an aerosol of 59 Fe-labeled Fe 2 O 3 either 18 hr or 7 days after exposure to aerosslized Triton X-100 which was administered in doses of 20, 100, or 200 μg/g of lung. Rats pretreated with elastase had significantly lower pulmonary deposition of 59 Fe than the untreated controls (p 2 O 3 was unaffected by pretreatment with Triton X-100. Elastase treatment alone had no effect on retention of Fe 2 O 3 . Triton X-100 administered 18 hr prior to exposure of rats to Fe 2 O 3 aerosol resulted in dose-related increases in whole-body retention of 59 Fe. When rats were exposed to Triton X-100 7 days before exposure to Fe 2 O 3 , increased retention of 59 Fe was noted only in those treated at the highest Triton X-100 dose level (200 μg/g). 20 references, 5 tables

  11. Theranostic nanoparticles based on bioreducible polyethylenimine-coated iron oxide for reduction-responsive gene delivery and magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Li D

    2014-07-01

    Full Text Available Dan Li,1,* Xin Tang,2,* Benjamin Pulli,1 Chao Lin,2 Peng Zhao,2 Jian Cheng,2 Zhongwei Lv,1 Xueyu Yuan,1 Qiong Luo,1 Haidong Cai,1 Meng Ye1 1Department of Nuclear Medicine, Shanghai 10th People’s Hospital, 2Shanghai East Hospital, The Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, People’s Republic of China *These authors contributed equally to this work Abstract: Theranostic nanoparticles based on superparamagnetic iron oxide (SPIO have a great promise for tumor diagnosis and gene therapy. However, the availability of theranostic nanoparticles with efficient gene transfection and minimal toxicity remains a big challenge. In this study, we construct an intelligent SPIO-based nanoparticle comprising a SPIO inner core and a disulfide-containing polyethylenimine (SSPEI outer layer, which is referred to as a SSPEI-SPIO nanoparticle, for redox-triggered gene release in response to an intracellular reducing environment. We reveal that SSPEI-SPIO nanoparticles are capable of binding genes to form nano-complexes and mediating a facilitated gene release in the presence of dithiothreitol (5–20 mM, thereby leading to high transfection efficiency against different cancer cells. The SSPEI-SPIO nanoparticles are also able to deliver small interfering RNA (siRNA for the silencing of human telomerase reverse transcriptase genes in HepG2 cells, causing their apoptosis and growth inhibition. Further, the nanoparticles are applicable as T2-negative contrast agents for magnetic resonance (MR imaging of a tumor xenografted in a nude mouse. Importantly, SSPEI-SPIO nanoparticles have relatively low cytotoxicity in vitro at a high concentration of 100 µg/mL. The results of this study demonstrate the utility of a disulfide-containing cationic polymer-decorated SPIO nanoparticle as highly potent and low-toxic theranostic nano-system for specific nucleic acid delivery inside cancer cells. Keywords

  12. Responsive and resilient supply chain network design under operational and disruption risks with delivery lead-time sensitive customers

    DEFF Research Database (Denmark)

    Fattahi, Mohammad; Govindan, Kannan; Keyvanshokooh, Esmaeil

    2017-01-01

    We address a multi-period supply chain (SC) network design where demands of customers depend on facilities serving them based on their delivery lead-times. Potential customer demands are stochastic, and facilities’ capacity varies randomly because of possible disruptions. Accordingly, we develop...

  13. Synthetic biocompatible polymers are an effective delivery platform that elicits potent antibody responses against HIV-1 glycopeptide immunogens

    Czech Academy of Sciences Publication Activity Database

    Francica, J.; Lynn, G.; Laga, Richard; Aussedat, B.; Meyerhoff, R.; Alam, M.; Danishefsky, S.; Haynes, B.; Seder, R.

    2016-01-01

    Roč. 32, Supplement 1 (2016), s. 221-P07.27 ISSN 0889-2229. [Conference on HIV Research for Prevention - HIV R4P. 17.10.2016-21.10.2016, Chicago] Institutional support: RVO:61389013 Keywords : biocompatible polymers * druh delivery Subject RIV: CD - Macromolecular Chemistry

  14. Labor and delivery service use: indigenous women's preference and the health sector response in the Chiapas Highlands of Mexico.

    Science.gov (United States)

    Ibáñez-Cuevas, Midiam; Heredia-Pi, Ileana B; Meneses-Navarro, Sergio; Pelcastre-Villafuerte, Blanca; González-Block, Miguel A

    2015-12-23

    Mexico has undertaken important efforts to decrease maternal mortality. Health authorities have introduced intercultural innovations to address barriersfaced by indigenous women accessing professional maternal and delivery services. This study examines, from the perspective of indigenous women, the barriers andfacilitators of labor and delivery care services in a context of intercultural and allopathic innovations. This is an exploratory study using a qualitative approach of discourse analysis with grounded theory techniques. Twenty-five semi-structured interviews were undertaken with users and non-users of the labor and delivery services, as well as with traditional birth attendants (TBAs) in San Andrés Larráinzar, Chiapas in 2012. The interviewees identified barriers in the availability of medical personnel and restrictive hours for health services. Additionally, they referred to barriers to access (economic, geographic, linguistic and cultural) to health services, as well as invasive and offensive hospital practices enacted by health system personnel, which limited the quality of care they can provide. Traditional birth attendants participating in intercultural settings expressed the lack of autonomy and exclusion they experience by hospital personnel, as a result of not being considered part of the care team. As facilitators, users point to the importance of having their traditional birth attendants and families present during childbirth, to allow them to use their clothing during the attention, that the staff of health care is of the female sex and speaking the language of the community. As limiting condition users referred the different medical maneuvers practiced in the attention of the delivery (vaginal examination, episiotomy, administration of oxytocin, etc.). Evidence from the study suggests the presence of important barriers to the utilization of institutional labor and delivery services in indigenous communities, in spite of the intercultural

  15. After Delivery

    Science.gov (United States)

    ... Size: A A A Listen En Español After Delivery After your baby arrives, your body begins to recover from the hard work of pregnancy and delivery. Some new mothers have better blood glucose control ...

  16. A pH- and temperature-responsive bioresorbable injectable hydrogel based on polypeptide block copolymers for the sustained delivery of proteins in vivo.

    Science.gov (United States)

    Turabee, Md Hasan; Thambi, Thavasyappan; Duong, Huu Thuy Trang; Jeong, Ji Hoon; Lee, Doo Sung

    2018-02-27

    Sustained delivery of protein therapeutics is limited owing to the fragile nature of proteins. Despite its great potential, delivery of proteins without any loss of bioactivity remains a challenge in the use of protein therapeutics in the clinic. To surmount this shortcoming, we report a pH- and temperature-responsive in situ-forming injectable hydrogel based on comb-type polypeptide block copolymers for the controlled delivery of proteins. Polypeptide block copolymers, composed of hydrophilic polyethylene glycol (PEG), temperature-responsive poly(γ-benzyl-l-glutamate) (PBLG), and pH-responsive oligo(sulfamethazine) (OSM), exhibit pH- and temperature-induced sol-to-gel transition behavior in aqueous solutions. Polypeptide block copolymers were synthesized by combining N-carboxyanhydride-based ring-opening polymerization and post-functionalization of the chain-end using N-hydroxy succinimide ester activated OSM. The physical properties of polypeptide-based hydrogels were tuned by varying the composition of temperature- and pH-responsive PBLG and OSM in block copolymers. Polypeptide block copolymers were non-toxic to human embryonic kidney cells at high concentrations (2000 μg mL -1 ). Subcutaneous administration of polypeptide block copolymer sols formed viscoelastic gel instantly at the back of Sprague-Dawley (SD) rats. The in vivo gels exhibited sustained degradation and were found to be bioresorbable in 6 weeks without any noticeable inflammation at the injection site. Anionic characteristics of hydrogels allow efficient loading of a cationic model protein, lysozyme, through electrostatic interaction. Lysozyme-loaded polypeptide block copolymer sols readily formed a viscoelastic gel in vivo and sustained lysozyme release for at least a week. Overall, the results demonstrate an elegant approach to control the release of certain charged proteins and open a myriad of therapeutic possibilities in protein therapeutics.

  17. Evaluation of pH-responsive liposomes containing amino acid-based zwitterionic lipids for improving intracellular drug delivery in vitro and in vivo.

    Science.gov (United States)

    Obata, Yosuke; Tajima, Shoji; Takeoka, Shinji

    2010-03-03

    We developed pH-responsive liposomes containing synthetic glutamic acid-based zwitterionic lipids and evaluated their properties both in vitro and in vivo with the aim of constructing an efficient liposome-based systemic drug delivery system. The glutamic acid-based lipids; 1,5-dihexadecyl N-glutamyl-L-glutamate (L1) and 1,5-dihexadecyl N,N-diglutamyl-lysyl-L-glutamate (L2) were synthesized as a pH-responsive component of liposomes that respond to endosomal pH. The zeta potential of liposomes containing L1 or L2 was positive when the solution pH was below 4.6 or 5.6, respectively, but negative at higher pH values. The pH-responsive liposomes showed improved fusogenic potential to an endosome-mimicking anionic membrane at acidic pH, where the zeta potential of the liposomes was positive. We then prepared doxorubicin (DOX)-encapsulating liposomes containing L1 or L2, and clarified by confocal microscopic studies that the contents were rapidly transferred into both the cytoplasm and nucleus. Release of DOX from the endosomes mediated by the pH-responsive liposomes dramatically inhibited cancer cell growth. The L2-liposomes were slightly more effective than L1-liposomes as a drug delivery system. Intravenously injected L2-liposomes displayed blood persistence comparable to that of conventional phospholipid (PC)-based liposomes. Indeed, the antitumor efficacy of L2-liposomes was higher than that of PC-based liposomes against a xenograft breast cancer tumor in vivo. Thus, the high performance of L2-liposomes results from both efficient intracellular drug delivery and comparable blood persistence in comparison with the conventional PC-based liposomes in vitro and in vivo. Copyright 2009 Elsevier B.V. All rights reserved.

  18. A pH-responsive chitosan-b-poly(p-dioxanone) nanocarrier: formation and efficient antitumor drug delivery

    International Nuclear Information System (INIS)

    Tang Daolu; Song Fei; Chen Cheng; Wang Xiuli; Wang Yuzhong

    2013-01-01

    Increasing attention has recently been paid to the fabrication of drug delivery systems with excellent cell internalization and intracellular drug release properties. In this study, an amphiphilic block copolymer of chitosan was synthesized for the first time, which can self-assemble into micelles in a neutral aqueous solution but partially disassemble in an acidic endosomal/lysosomal environment. The antitumor drug, camptothecin (CPT), was encapsulated in the cores of the micelles for tumor cell therapy. In vitro drug release studies demonstrated that the micelles presented a much faster release of CPT at pH 5.0 than at pH 7.4. Blank micelles were found to be nontoxic in preliminary in vitro cytotoxicity assays. Cell experiments showed that the CPT-loaded micelles could be effectively internalized by Hela cells and accomplished a potent antitumor cell efficacy, indicating that the chitosan-based micelles might be an attractive new platform for efficient intracellular drug delivery. (paper)

  19. Galactosylated LDL nanoparticles: a novel targeting delivery system to deliver antigen to macrophages and enhance antigen specific T cell responses.

    Science.gov (United States)

    Wu, Fang; Wuensch, Sherry A; Azadniv, Mitra; Ebrahimkhani, Mohammad R; Crispe, I Nicholas

    2009-01-01

    We aim to define the role of Kupffer cells in intrahepatic antigen presentation, using the selective delivery of antigen to Kupffer cells rather than other populations of liver antigen-presenting cells. To achieve this we developed a novel antigen delivery system that can target antigens to macrophages, based on a galactosylated low-density lipoprotein nanoscale platform. Antigen was delivered via the galactose particle receptor (GPr), internalized, degraded and presented to T cells. The conjugation of fluoresceinated ovalbumin (FLUO-OVA) and lactobionic acid with LDL resulted in a substantially increased uptake of FLUO-OVA by murine macrophage-like ANA1 cells in preference to NIH3T3 cells, and by primary peritoneal macrophages in preference to primary hepatic stellate cells. Such preferential uptake led to enhanced proliferation of OVA specific T cells, showing that the galactosylated LDL nanoscale platform is a successful antigen carrier, targeting antigen to macrophages but not to all categories of antigen presenting cells. This system will allow targeted delivery of antigen to macrophages in the liver and elsewhere, addressing the question of the role of Kupffer cells in liver immunology. It may also be an effective way of delivering drugs or vaccines directly at macrophages.

  20. Development of an anti-microbial peptide-mediated liposomal delivery system: a novel approach towards pH-responsive anti-microbial peptides.

    Science.gov (United States)

    Zhang, Qianyu; Tang, Jie; Ran, Rui; Liu, Yayuan; Zhang, Zhirong; Gao, Huile; He, Qin

    2016-05-01

    On one hand, the application of anti-microbial peptides (AMPs) in the construction of AMPs-mediated drug delivery system has not yet been fully exploited; on the other hand, its non-selectivity in vivo has also limited its clinical application. In this work, we chose one pH-responsive peptide, [D]-H6L9, and functionalized it onto the surface of liposomes (D-Lip). The protonation of histidines in the sequence of [D]-H6L9 under pH 6.3 could switch the surface charge of D-Lip from negative (under pH 7.4) to positive (under pH 6.3), and the cellular uptake and tumor spheroids uptake were increased accordingly. Lysosome co-localization assay suggested that there was only little overlap of D-Lip with lysosomes in 12 h, which indicated that D-Lip could escape lysosomes effectively. In vivo biodistribution assay on C26 tumor-bearing BALB/C mice showed that DiR-labeled D-Lip could reach tumors as much as PEG-Lip, and both tumor slices and quantitative measurement of dispersed cells of in vivo tumors by flow cytometry demonstrated that D-Lip could be taken up by tumors more efficiently. Therefore, we have established an anti-microbial peptide-mediated liposomal delivery system for tumor delivery.

  1. Inhibition of cell proliferation through an ATP-responsive co-delivery system of doxorubicin and Bcl-2 siRNA

    Science.gov (United States)

    Zhang, Jianxu; Wang, Yudi; Chen, Jiawen; Liang, Xiao; Han, Haobo; Yang, Yan; Li, Quanshun; Wang, Yanbo

    2017-01-01

    Herein, DNA duplex was constructed through the hybridization of adenosine triphosphate (ATP)-responsive aptamer and its cDNA in which GC-rich motif could be used to load doxorubicin (DOX), and then, cationic polymer PEI25K was used as a carrier to simultaneously condense DOX-Duplex and Bcl-2 siRNA to prepare the ternary nanocomplex polyethylenimine (PEI)/DOX-Duplex/siRNA. The ATP concentration gradient between the cytosol and extracellular environment could achieve the stable loading of DOX in duplex and the rapid drug release in an ATP-responsive manner. Using human prostate tumor cell line PC-3 as a model, an obvious induction of cell proliferation could be detected with a cell viability of 53.3%, which was stronger than single cargo delivery, indicating the synergistic effect between these two components. The enhanced anti-proliferative effect of ternary nanocomplex could be attributed to the improved induction of cell apoptosis in a mitochondria-mediated pathway and cell-cycle arrest at the G2 phase. Overall, the ATP-responsive nanocarrier for co-delivering DOX and Bcl-2 siRNA has been demonstrated to be a smart delivery system with favorable anti-proliferative effect, especially for solving the multidrug resistance of tumors. PMID:28740380

  2. Poly-functional and long-lasting anticancer immune response elicited by a safe attenuated Pseudomonas aeruginosa vector for antigens delivery

    Directory of Open Access Journals (Sweden)

    Xavier Chauchet

    2016-01-01

    Full Text Available Live-attenuated bacterial vectors for antigens delivery have aroused growing interest in the field of cancer immunotherapy. Their potency to stimulate innate immunity and to promote intracellular antigen delivery into antigen-presenting cells could be exploited to elicit a strong and specific cellular immune response against tumor cells. We previously described genetically-modified and attenuated Pseudomonas aeruginosa vectors able to deliver in vivo protein antigens into antigen-presenting cells, through Type 3 secretion system of the bacteria. Using this approach, we managed to protect immunized mice against aggressive B16 melanoma development in both a prophylactic and therapeutic setting. In this study, we further investigated the antigen-specific CD8+ T cell response, in terms of phenotypic and functional aspects, obtained after immunizations with a killed but metabolically active P. aeruginosa attenuated vector. We demonstrated that P. aeruginosa vaccine induces a highly functional pool of antigen-specific CD8+ T cell able to infiltrate the tumor. Furthermore, multiple immunizations allowed the development of a long-lasting immune response, represented by a pool of predominantly effector memory cells which protected mice against late tumor challenge. Overall, killed but metabolically active P. aeruginosa vector is a safe and promising approach for active and specific antitumor immunotherapy.

  3. SU-D-207B-07: Development of a CT-Radiomics Based Early Response Prediction Model During Delivery of Chemoradiation Therapy for Pancreatic Cancer

    International Nuclear Information System (INIS)

    Klawikowski, S; Christian, J; Schott, D; Zhang, M; Li, X

    2016-01-01

    Purpose: Pilot study developing a CT-texture based model for early assessment of treatment response during the delivery of chemoradiation therapy (CRT) for pancreatic cancer. Methods: Daily CT data acquired for 24 pancreatic head cancer patients using CT-on-rails, during the routine CT-guided CRT delivery with a radiation dose of 50.4 Gy in 28 fractions, were analyzed. The pancreas head was contoured on each daily CT. Texture analysis was performed within the pancreas head contour using a research tool (IBEX). Over 1300 texture metrics including: grey level co-occurrence, run-length, histogram, neighborhood intensity difference, and geometrical shape features were calculated for each daily CT. Metric-trend information was established by finding the best fit of either a linear, quadratic, or exponential function for each metric value verses accumulated dose. Thus all the daily CT texture information was consolidated into a best-fit trend type for a given patient and texture metric. Linear correlation was performed between the patient histological response vector (good, medium, poor) and all combinations of 23 patient subgroups (statistical jackknife) determining which metrics were most correlated to response and repeatedly reliable across most patients. Control correlations against CT scanner, reconstruction kernel, and gated/nongated CT images were also calculated. Euclidean distance measure was used to group/sort patient vectors based on the data of these trend-response metrics. Results: We found four specific trend-metrics (Gray Level Coocurence Matrix311-1InverseDiffMomentNorm, Gray Level Coocurence Matrix311-1InverseDiffNorm, Gray Level Coocurence Matrix311-1 Homogeneity2, and Intensity Direct Local StdMean) that were highly correlated with patient response and repeatedly reliable. Our four trend-metric model successfully ordered our pilot response dataset (p=0.00070). We found no significant correlation to our control parameters: gating (p=0.7717), scanner (p

  4. A Light-Responsive Self-Assembly Formed by a Cationic Azobenzene Derivative and SDS as a Drug Delivery System.

    Science.gov (United States)

    Geng, Shengyong; Wang, Yuzhu; Wang, Liping; Kouyama, Tsutomu; Gotoh, Toshiaki; Wada, Satoshi; Wang, Jin-Ye

    2017-01-04

    The structure of a self-assembly formed from a cationic azobenzene derivative, 4-cholesterocarbonyl-4'-(N,N,N-triethylamine butyloxyl bromide) azobenzene (CAB) and surfactant sodium dodecyl sulfate (SDS) in aqueous solution was studied by cryo-TEM and synchrotron radiation small-angle X-ray scattering (SAXS). Both unilamellar and multilamellar vesicles could be observed. CAB in vesicles were capable to undergo reversible trans-to-cis isomerization upon UV or visible light irradiation. The structural change upon UV light irradiation could be catched by SAXS, which demonstrated that the interlamellar spacing of the cis-multilamellar vesicles increased by 0.2-0.3 nm. Based on this microstructural change, the release of rhodamine B (RhB) and doxorubicin (DOX) could be triggered by UV irradiation. When incubated NIH 3T3 cells and Bel 7402 cells with DOX-loaded CAB/SDS vesicles, UV irradiation induced DOX release decreased the viability of both cell lines significantly compared with the non-irradiated cells. The in vitro experiment indicated that CAB/SDS vesicles had high efficiency to deliver loaded molecules into cells. The in vivo experiment showed that CAB/SDS vesicles not only have high drug delivery efficiency into rat retinas, but also could maintain high drug concentration for a longer time. CAB/SDS catanionic vesicles may find potential applications as a smart drug delivery system for controlled release by light.

  5. A Light-Responsive Self-Assembly Formed by a Cationic Azobenzene Derivative and SDS as a Drug Delivery System

    Science.gov (United States)

    Geng, Shengyong; Wang, Yuzhu; Wang, Liping; Kouyama, Tsutomu; Gotoh, Toshiaki; Wada, Satoshi; Wang, Jin-Ye

    2017-01-01

    The structure of a self-assembly formed from a cationic azobenzene derivative, 4-cholesterocarbonyl-4‧-(N,N,N-triethylamine butyloxyl bromide) azobenzene (CAB) and surfactant sodium dodecyl sulfate (SDS) in aqueous solution was studied by cryo-TEM and synchrotron radiation small-angle X-ray scattering (SAXS). Both unilamellar and multilamellar vesicles could be observed. CAB in vesicles were capable to undergo reversible trans-to-cis isomerization upon UV or visible light irradiation. The structural change upon UV light irradiation could be catched by SAXS, which demonstrated that the interlamellar spacing of the cis-multilamellar vesicles increased by 0.2-0.3 nm. Based on this microstructural change, the release of rhodamine B (RhB) and doxorubicin (DOX) could be triggered by UV irradiation. When incubated NIH 3T3 cells and Bel 7402 cells with DOX-loaded CAB/SDS vesicles, UV irradiation induced DOX release decreased the viability of both cell lines significantly compared with the non-irradiated cells. The in vitro experiment indicated that CAB/SDS vesicles had high efficiency to deliver loaded molecules into cells. The in vivo experiment showed that CAB/SDS vesicles not only have high drug delivery efficiency into rat retinas, but also could maintain high drug concentration for a longer time. CAB/SDS catanionic vesicles may find potential applications as a smart drug delivery system for controlled release by light.

  6. Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles

    Science.gov (United States)

    Colby, Aaron H.; Liu, Rong; Schulz, Morgan D.; Padera, Robert F.; Colson, Yolonda L.; Grinstaff, Mark W.

    2016-01-01

    Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a “two-step” nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional “drug-alone” administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

  7. The insulin response integrates increased TGF-β signaling through Akt-induced enhancement of cell surface delivery of TGF-β receptors

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    Budi, Erine H.; Muthusamy, Baby Periyanayaki; Derynck, Rik

    2015-01-01

    Increased activity of transforming growth factor β (TGF-β), which binds to and stimulates cell surface receptors, contributes to cancer progression and fibrosis by driving epithelial cells toward a migratory mesenchymal phenotype and increasing the abundance of extracellular matrix proteins. The abundance of TGF-β receptors at the cell surface determines cellular responsiveness to TGF-β, which is often produced by the same cells that have the receptors, and thus serves as an autocrine signal. We found that Akt-mediated phosphorylation of AS160, a RabGAP [guanosine triphosphatase (GTPase)-activating protein] promoted the translocation of TGF-β receptors from intracellular stores to the plasma membrane of mouse embryonic fibroblasts (MEFs) and NMuMG epithelial cells. Consequently, insulin, which is commonly used to treat hyperglycemia and activates Akt signaling, increased the amount of TGF-β receptors at the cell surface, thereby enhancing TGF-β responsiveness. This insulin-induced increase in autocrine TGF-β signaling contributed to insulin-induced gene expression responses, attenuated the epithelial phenotype, and promoted the migration of NMuMG cells. Furthermore, the enhanced delivery of TGF-β receptors at the cell surface enabled insulin to increase TGF-β-induced gene responses. The enhancement of TGF-β responsiveness in response to Akt activation may help to explain the biological effects of insulin, the progression of cancers in which Akt is activated, and the increased incidence of fibroses in diabetes. PMID:26420907

  8. Immunohistochemical study of tumor markers (CEA, TPA, CA19-9, POA and Ferritin) and pancreatic exocrine enzymes(Amylase and Elastase 1) in pancreatic tumors

    OpenAIRE

    脇谷, 勇夫

    1987-01-01

    The distribution of carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), carbohydrate antigen 19-9 (CA19-9), pancreatic oncofetal antigen (POA), Ferritin, Amylase and Elastase 1 was studied immunohistochemically using an immunoperoxidase method in 26 conventional histopathologic sections of pancreatic tumor. CEA and CA19-9 were regarded as markers secreted into the glandular lumina from cancer cells, but TPA and POA were not. The expression of these markers was different from one...

  9. Magnetic nanoparticles grafted pH-responsive poly (methacrylic acid-co-acrylic acid-grafted polyvinylpyrrolidone as a nano-carrier for oral controlled delivery of atorvastatin

    Directory of Open Access Journals (Sweden)

    Mitra Amoli Diva

    2017-02-01

    Full Text Available Objective(s: Researchers have intended to reformulate drugs so that they may be more safely used in human body. Polymer science and nanotechnology have great roles in this field. The aim of this paper is to introduce an efficient drug delivery vehicle which can perform both targeted and controlled antibiotic release using magnetic nanoparticles grafted pH-responsive polymer.  Methods: Fe3O4 nanoparticles were prepared via a simple co-precipitation method and coated with APTS. Then, it was used as a core in synthesis of a core-shell pH-responsive polymer. After that, atorvastatin was loaded into the carrier and its release rate, kinetic and mechanism were investigated.   Results: The results revealed that cumulative release of the drug from nano carrier was 78% at pH 1.2 while in pH 5.5 and 7.2, the drug release was only about 5 and 31% respectively. Effect of different parameters on the atorvastatin release such as amounts of MAA monomer, EGDMA as cross-linker, AIBN as initiator, and MNPs were also studied. Furthermore, release kinetics and mechanism investigation along with the swelling behavior studies of plain polymer reveal Fickian pattern and diffusion controlled mechanism. Conclusions: The results indicate that the prepared nano-carrier can be serving as a suitable candidate for controlled delivery of the drugs.

  10. The Role of IL-6, 8, and 10, sTNFr, CRP, and Pancreatic Elastase in the Prediction of Systemic Complications in Patients with Acute Pancreatitis

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    E. Fisic

    2013-01-01

    Full Text Available Background and Aim. Early assessment of severity in acute pancreatitis (AP is a key measure to provide rational and effective management. The aim of our study is to determine the prognostic value of interleukins (IL 6, 8, and 10, soluble receptor for tumor necrosis factor (sTNFr, pancreatic elastase (E1, and C-reactive protein (CRP as predictors of systemic complications in AP. Patients and Methods. A hundred and fifty patients with confirmed AP were enrolled in the study. The severity of AP was defined according to Atlanta criteria. Measurements of interleukins and sTNFr were performed on the first day of admission. CRP and E1 levels were assessed on admission and after 48 hours. ROC analysis was performed for all parameters. Results. Interleukins and sTNFr significantly differentiated patients with systemic complications from those without. Elevation of IL-6 showed the highest significance as a predictor (. CRP and elastase levels did not differ between mild and severe cases on admission, but reached statistical significance when measured on the third day ( and , resp.. Conclusion. Our study confirmed that IL-6, IL-8, IL-10, and sTNFr measured on admission, and CRP and pancreatic elastase measured on third day of admission represent valuable prognostic factors of severity and systemic complications of AP.

  11. The Role of IL-6, 8, and 10, sTNFr, CRP, and Pancreatic Elastase in the Prediction of Systemic Complications in Patients with Acute Pancreatitis.

    Science.gov (United States)

    Fisic, E; Poropat, G; Bilic-Zulle, L; Licul, V; Milic, S; Stimac, D

    2013-01-01

    Background and Aim. Early assessment of severity in acute pancreatitis (AP) is a key measure to provide rational and effective management. The aim of our study is to determine the prognostic value of interleukins (IL) 6, 8, and 10, soluble receptor for tumor necrosis factor (sTNFr), pancreatic elastase (E1), and C-reactive protein (CRP) as predictors of systemic complications in AP. Patients and Methods. A hundred and fifty patients with confirmed AP were enrolled in the study. The severity of AP was defined according to Atlanta criteria. Measurements of interleukins and sTNFr were performed on the first day of admission. CRP and E1 levels were assessed on admission and after 48 hours. ROC analysis was performed for all parameters. Results. Interleukins and sTNFr significantly differentiated patients with systemic complications from those without. Elevation of IL-6 showed the highest significance as a predictor (P = 0.001). CRP and elastase levels did not differ between mild and severe cases on admission, but reached statistical significance when measured on the third day (P = 0.002 and P = 0.001, resp.). Conclusion. Our study confirmed that IL-6, IL-8, IL-10, and sTNFr measured on admission, and CRP and pancreatic elastase measured on third day of admission represent valuable prognostic factors of severity and systemic complications of AP.

  12. Structurally Related Monoterpenes p-Cymene, Carvacrol and Thymol Isolated from Essential Oil from Leaves of Lippia sidoides Cham. (Verbenaceae Protect Mice against Elastase-Induced Emphysema

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    Ellen Games

    2016-10-01

    Full Text Available Background: Chronic obstructive pulmonary disease (COPD is characterized by irreversible airflow obstruction and inflammation. Natural products, such as monoterpenes, displayed anti-inflammatory and anti-oxidant activities and can be used as a source of new compounds to COPD treatment. Our aim was to evaluate, in an elastase-induced pulmonary emphysema in mice, the effects of and underlying mechanisms of three related natural monoterpenes (p-cymene, carvacrol and thymol isolated from essential oil from leaves Lippia sidoides Cham. (Verbenaceae. Methods: Mices received porcine pancreatic elastase (PPE and were treated with p-cymene, carvacrol, thymol or vehicle 30 min later and again on 7th, 14th and 28th days. Lung inflammatory profile and histological sections were evaluated. Results: In the elastase-instilled animals, the tested monoterpenes reduced alveolar enlargement, macrophages and the levels of IL-1β, IL-6, IL-8 and IL-17 in bronchoalveolar lavage fluid (BALF, and collagen fibers, MMP-9 and p-65-NF-κB-positive cells in lung parenchyma (p < 0.05. All treatments attenuated levels of 8-iso-PGF2α but only thymol was able to reduced exhaled nitric oxide (p < 0.05. Conclusion: Monoterpenes p-cymene, carvacrol and thymol reduced lung emphysema and inflammation in mice. No significant differences among the three monoterpenes treatments were found, suggesting that the presence of hydroxyl group in the molecular structure of thymol and carvacrol do not play a central role in the anti-inflammatory effects.

  13. Structurally Related Monoterpenes p-Cymene, Carvacrol and Thymol Isolated from Essential Oil from Leaves of Lippia sidoides Cham. (Verbenaceae) Protect Mice against Elastase-Induced Emphysema.

    Science.gov (United States)

    Games, Ellen; Guerreiro, Marina; Santana, Fernanda R; Pinheiro, Nathalia M; de Oliveira, Emerson A; Lopes, Fernanda D T Q S; Olivo, Clarice R; Tibério, Iolanda F L C; Martins, Mílton A; Lago, João Henrique G; Prado, Carla M

    2016-10-20

    Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and inflammation. Natural products, such as monoterpenes, displayed anti-inflammatory and anti-oxidant activities and can be used as a source of new compounds to COPD treatment. Our aim was to evaluate, in an elastase-induced pulmonary emphysema in mice, the effects of and underlying mechanisms of three related natural monoterpenes ( p -cymene, carvacrol and thymol) isolated from essential oil from leaves Lippia sidoides Cham. (Verbenaceae). Mices received porcine pancreatic elastase (PPE) and were treated with p -cymene, carvacrol, thymol or vehicle 30 min later and again on 7th, 14th and 28th days. Lung inflammatory profile and histological sections were evaluated. In the elastase-instilled animals, the tested monoterpenes reduced alveolar enlargement, macrophages and the levels of IL-1β, IL-6, IL-8 and IL-17 in bronchoalveolar lavage fluid (BALF), and collagen fibers, MMP-9 and p-65-NF-κB-positive cells in lung parenchyma ( p < 0.05). All treatments attenuated levels of 8-iso-PGF2α but only thymol was able to reduced exhaled nitric oxide ( p < 0.05). Monoterpenes p -cymene, carvacrol and thymol reduced lung emphysema and inflammation in mice. No significant differences among the three monoterpenes treatments were found, suggesting that the presence of hydroxyl group in the molecular structure of thymol and carvacrol do not play a central role in the anti-inflammatory effects.

  14. Design and statistical optimization of an effervescent floating drug delivery system of theophylline using response surface methodology

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    Srikanth Meka Venkata

    2016-03-01

    Full Text Available The aim of this research was to formulate effervescent floating drug delivery systems of theophylline using different release retarding polymers such as ethyl cellulose, Eudragit® L100, xanthan gum and polyethylene oxide (PEO N12K. Sodium bicarbonate was used as a gas generating agent. Direct compression was used to formulate floating tablets and the tablets were evaluated for their physicochemical and dissolution characteristics. PEO based formulations produced better drug release properties than other formulations. Hence, it was further optimized by central composite design. Further subjects of research were the effect of formulation variables on floating lag time and the percentage of drug released at the seventh hour (D7h. The optimum quantities of PEO and sodium bicarbonate, which had the highest desirability close to 1.0, were chosen as the statistically optimized formulation. No interaction was found between theophylline and PEO by Fourier Transformation Infrared spectroscopy (FTIR and Differential Scanning Calorimetry (DSC studies.

  15. Effect of maternal labor and mode of delivery on neutrophil actin response to N-formylmethionyl-leucyl-phenylalanine in healthy neonates.

    Science.gov (United States)

    Chen, W Y; Lu, C C

    1996-02-01

    Diminished actin response to N-formyl-methionyl-leucyl-phenylalanine (FMLP) has been used to explain the impaired chemotaxis of neonatal neutrophils, but the effect of labor on this response has not been evaluated before. Therefore, we tested the hypothesis that labor stress may have an effect on actin response of cord blood neutrophils to FMLP. This response is compared by phallacidin stain of neutrophil F-actin and flow cytometry analysis among 3 groups of healthy neonates: group I, 16 vaginally delivered neonates; group II, 16 neonates delivered by elective cesarean section without labor; and group III, 16 neonates delivered by cesarean section after labor. In the group III, 10 infants were delivered by an emergency cesarean section because of fetal heart rate deceleration indicating fetal distress (one minute Apgar score < 7 in 5 cases [50%]), and the other 6 infants were delivered because of failure of progression of labor (one minute Apgar score < 7 in 2 cases [33.3%]). Stimulated relative F-actin content of neutrophils in group III was increased compared with groups I and II. There was no such difference between neutrophils from infants of groups I and II. The results of this study indicate that fetal distress may enhance neutrophil actin response to FMLP, while labor or mode of delivery might not have such effect.

  16. Induction of CD8(+) T cell responses and protective efficacy following microneedle-mediated delivery of a live adenovirus-vectored malaria vaccine.

    Science.gov (United States)

    Pearson, Frances E; O'Mahony, Conor; Moore, Anne C; Hill, Adrian V S

    2015-06-22

    There is an urgent need for improvements in vaccine delivery technologies. This is particularly pertinent for vaccination programmes within regions of limited resources, such as those required for adequate provision for disposal of used needles. Microneedles are micron-sized structures that penetrate the stratum corneum of the skin, creating temporary conduits for the needle-free delivery of drugs or vaccines. Here, we aimed to investigate immunity induced by the recombinant simian adenovirus-vectored vaccine ChAd63.ME-TRAP; currently undergoing clinical assessment as a candidate malaria vaccine, when delivered percutaneously by silicon microneedle arrays. In mice, we demonstrate that microneedle-mediated delivery of ChAd63.ME-TRAP induced similar numbers of transgene-specific CD8(+) T cells compared to intradermal (ID) administration with needle-and-syringe, following a single immunisation and after a ChAd63/MVA heterologous prime-boost schedule. When mice immunised with ChAd63/MVA were challenged with live Plasmodium berghei sporozoites, microneedle-mediated ChAd63.ME-TRAP priming demonstrated equivalent protective efficacy as did ID immunisation. Furthermore, responses following ChAd63/MVA immunisation correlated with a specific design parameter of the array used ('total array volume'). The level of transgene expression at the immunisation site and skin-draining lymph node (dLN) was also linked to total array volume. These findings have implications for defining silicon microneedle array design for use with live, vectored vaccines. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Development of an Innovative Intradermal siRNA Delivery System Using a Combination of a Functional Stearylated Cytoplasm-Responsive Peptide and a Tight Junction-Opening Peptide

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    Hisako Ibaraki

    2016-09-01

    Full Text Available As a new category of therapeutics for skin diseases including atopic dermatitis (AD, nucleic acids are gaining importance in the clinical setting. Intradermal administration is noninvasive and improves patients′ quality of life. However, intradermal small interfering RNA (siRNA delivery is difficult because of two barriers encountered in the skin: intercellular lipids in the stratum corneum and tight junctions in the stratum granulosum. Tight junctions are the major barrier in AD; therefore, we focused on functional peptides to devise an intradermal siRNA delivery system for topical skin application. In this study, we examined intradermal siRNA permeability in the tape-stripped (20 times back skin of mice or AD-like skin of auricles treated with 6-carboxyfluorescein-aminohexyl phosphoramidite (FAM-labeled siRNA, the tight junction modulator AT1002, and the functional cytoplasm-responsive stearylated peptide STR-CH2R4H2C by using confocal laser microscopy. We found that strong fluorescence was observed deep and wide in the epidermis and dermis of back skin and AD-like ears after siRNA with STR-CH2R4H2C and AT1002 treatment. After 10 h from administration, brightness of FAM-siRNA was significantly higher for STR-CH2R4H2C + AT1002, compared to other groups. In addition, we confirmed the nontoxicity of STR-CH2R4H2C as a siRNA carrier using PAM212 cells. Thus, our results demonstrate the applicability of the combination of STR-CH2R4H2C and AT1002 for effective intradermal siRNA delivery.

  18. Grape-seed Polyphenols Play a Protective Role in Elastase-induced Abdominal Aortic Aneurysm in Mice.

    Science.gov (United States)

    Wang, Chao; Wang, Yunxia; Yu, Maomao; Chen, Cong; Xu, Lu; Cao, Yini; Qi, Rong

    2017-08-24

    Abdominal aortic aneurysm (AAA) is a kind of disease characterized by aortic dilation, whose pathogenesis is linked to inflammation. This study aimed to determine whether grape-seed polyphenols (GSP) has anti-AAA effects and what mechanism is involved, thus to find a way to prevent occurrence and inhibit expansion of small AAA. In our study, AAA was induced by incubating the abdominal aorta of the mice with elastase, and GSP was administrated to the mice by gavage at different doses beginning on the day of the AAA inducement. In in vivo experiments, 800 mg/kg GSP could significantly reduce the incidence of AAA, the dilatation of aorta and elastin degradation in media, and dramatically decrease macrophage infiltration and activation and expression of matrix metalloproteinase (MMP) -2 and MMP-9 in the aorta, compared to the AAA model group. Meanwhile, 400 mg/kg GSP could also but not completely inhibit the occurrence and development of AAA. In in vitro experiments, GSP dose-dependently inhibited mRNA expression of interleukin (IL)-1β, IL-6 and monocyte chemoattractant protein-1 (MCP-1), and significantly inhibited expression and activity of MMP-2 and MMP-9, thus prevented elastin from degradation. In conclusion, GSP showed great anti-AAA effects and its mechanisms were related to inhibition of inflammation.

  19. Prognostic Significance of Immunoreactive Neutrophil Elastase in Human Breast Cancer: Long-Term Follow-Up Results in 313 Patients

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    Miwa Akizuki

    2007-03-01

    Full Text Available OBJECTIVE: We have measured the concentration of immunoreactive neutrophil elastase (ir-NE in the tumor extracts of 313 primary human breast cancers. Sufficient time has elapsed, and we are now ready to analyze its prognostic value in human breast cancer. METHODS: ir-NE concentration in tumor extracts was determined with an enzyme-linked immunosorbent assay that enables a rapid measurement of both free-form ir-NE and the α1-protease inhibitor-complexed form of ir-NE. We analyzed the prognostic value of this enzyme in human breast cancer in univariate and multivariate analyses. RESULTS: Patients with breast cancer tissue containing a high concentration of ir-NE had poor survival compared to those with a low concentration of ir-NE at the cutoff point of 9.0 µg/100 mg protein (P = .0012, which had been previously determined in another group of 49 patients. Multivariate stepwise analysis selected lymph node status (P= .0004; relative risk = 1.46 and ir-NE concentration (P= .0013; relative risk = 1.43 as independent prognostic factors for recurrence. CONCLUSIONS: Tumor ir-NE concentration is an independent prognostic factor in patients with breast cancer who undergo curative surgery. This enzyme may play an active role in tumor progression that leads to metastasis in human breast cancer.

  20. Intramuscular delivery of a cholera DNA vaccine primes both systemic and mucosal protective antibody responses against cholera.

    Science.gov (United States)

    Xu, Guifang; Wang, Shixia; Zhuang, Ling; Hackett, Anthony; Gu, Ling; Zhang, Lu; Zhang, Chunhua; Wang, Hua; Huang, Zuhu; Lu, Shan

    2009-06-12

    Cholera is a potentially lethal diarrhea disease caused by the gram-negative bacterium Vibrio cholerae. The need for an effective cholera vaccine is clearly indicated but the challenges of eliciting both systemic and mucosal immune responses remains a significant challenge. In the current report, we discovered that a DNA vaccine expressing a protective cholera antigen, cholera toxin B subunit (CTB), delivered parenterally can elicit both systemic and mucosal anti-CTB antibody responses in mice. The priming effect by DNA immunization was demonstrated by higher mucosal antibody responses following one boost with the inactivated cholera vaccine (KWC-B) delivered orally when compared to the twice oral administration of KWC-B alone. This finding indicates that DNA vaccines delivered parenterally are effective in eliciting mucosal protective immune responses--a unique advantage for DNA vaccination that has not yet been well realized and should bring value to the development of novel vaccination approaches against mucosally transmitted diseases.

  1. Development of self-assembled molecular structures on polymeric surfaces and their applications as ultrasonically responsive barrier coatings for on-demand, pulsatile drug delivery

    Science.gov (United States)

    Kwok, Connie Sau-Kuen

    Nature in the form of DNA, proteins, and cells has the remarkable ability to interact with its environment by processing biological information through specific molecular recognition at the interface. As such, materials that are capable of triggering an appropriate biological response need to be engineered at the biomaterial surface. Chemically and structurally well-defined self-assembled monolayers (SAMs), biomimetics of the lipid bilayer in cell membranes, have been created and studied mostly on rigid metallic surfaces. This dissertation is motivated by the lack of methods to generate a molecularly designed surface for biomedical polymers and thus provides an enabling technology to engineer a polymeric surface precisely at a molecular and cellular level. To take this innovation one step further, we demonstrated that such self-assembled molecular structure coated on drug-containing polymeric devices could act as a stimulus-responsive barrier for controlled drug delivery. A simple, one-step procedure for generating ordered, crystalline methylene chains on polymeric surfaces via urethane linkages was successfully developed. The self-assemblies and molecular structures of these crystalline methylene chains are comparable to the SAM model surfaces, as evidenced by various surface characterization techniques (XPS, TOF-SIMS, and FTIR-ATR). For the first time, these self-assembled molecular structures are shown to function collectively as an ultrasound-responsive barrier membrane for pulsatile drug delivery, including delivery of low-molecular-weight ciprofloxacin and high-molecular-weight insulin. Encouraging results, based on the insulin-activated deoxyglucose uptakes in adipocytes, indicate that the released insulin remained biologically active. Both chemical and acoustic analyses suggest that the ultrasound-assisted release mechanism is primarily induced by transient cavitation, which causes temporary disruption of the self-assembled overlayer, and thus allows

  2. Redox-responsive core cross-linked prodrug micelles prepared by click chemistry for pH-triggered doxorubicin delivery

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    X. T. Cao

    2017-10-01

    Full Text Available A pH-triggered drug delivery system of degradable core cross-linked (CCL prodrug micelles was prepared by click chemistry. Doxorubicin conjugated block copolymers of azido functional poly(ethylene oxide-b-poly(glycidyl methacrylate were synthesized by the combination of RAFT polymerization, epoxide ring-opening reaction, and acid-cleavable hydrazone linkages. The CCL prodrug micelles were produced by the reaction of dipropargyl 3,3′-dithiodipropionate and dipropargyl adipate cross-linking agents with the azido groups of the micellar core via alkyne-azide click reaction, which were denoted as CCL/SS and CCL/noSS, respectively. The TEM images of CCL/SS prodrug micelles showed a spherical shape with the average diameter of 61.0 nm from water, and the shape was maintained with an increased diameter upon dilution with 5-fold DMF. The high DOX conjugation efficiency was 88.4%. In contrast to a very slow DOX release from CCL/SS prodrug micelles under the physiological condition (pH 7.4, the drug release is much faster (90% at pH 5.0 and 10 mM of GSH after 96 h. The cytotoxicity test and confocal laser scanning microscopy analysis revealed that CCL/SS prodrug micelles had much enhanced intracellular drug release capability in HepG2 cells than CCL/noSS prodrug micelles.

  3. Multi Drug Loaded Thermo-Responsive Fibrinogen-graft-Poly(N-vinyl Caprolactam) Nanogels for Breast Cancer Drug Delivery.

    Science.gov (United States)

    Rejinold, N Sanoj; Baby, Thejus; Chennazhi, K P; Jayakumar, R

    2015-03-01

    This study aims at the targeted delivery of 5-fluorouracil (5-FU) and Megestrol acetate (Meg) loaded fibrinogen-graft-poly(N-Vinyl caprolactam) nanogels (5-FU/Meg-fib-graft-PNVCL NGs) toward α5β1-integrins receptors expressed on breast cancer cells to have enhanced anti-cancer effect in vitro. To achieve this aim, we developed biocompatible thermoresponsive fib-graft-PNVCL NGs using fibrinogen and carboxyl terminated PNVCL via EDC/NHS amidation reaction. The Lower Critical Solution Temperature (LCST) of fib-graft-PNVCL could be tuned according to PNVCL/fibrinogen compositions. The 100-120 nm sized nanogels of fib-graft-PNVCL (LCST = 35 ?1 'C) was prepared using CaCl2 cross-linker. The 5-FU/Meg-fib-graft-PNVCL NGs showed a particle size of 150-170 nm size. The drug loading efficiency with 5-FU was 62% while Meg showed 74%. The 5-FU and Meg release was prominent above LCST than below LCST. The multi drug loaded fib-graft-PNVCL NGs showed enhanced toxicity, apoptosis and uptake by breast cancer (MCF-7) cells compared to their individual doses above their LCST. The in vivo assessment in Swiss albino mice showed sustained release of Meg and 5-FU as early as 3 days, confirming the therapeutic efficiency of the formulation. These results demonstrate an enhanced platform for the future animal studies on breast tumor xenograft model.

  4. Immune response induced by oral delivery of Bacillus subtilis spores expressing enolase of Clonorchis sinensis in grass carps (Ctenopharyngodon idellus).

    Science.gov (United States)

    Jiang, Hongye; Chen, Tingjin; Sun, Hengchang; Tang, Zeli; Yu, Jinyun; Lin, Zhipeng; Ren, Pengli; Zhou, Xinyi; Huang, Yan; Li, Xuerong; Yu, Xinbing

    2017-01-01

    Clonorchiasis, caused by the consumption of raw or undercooked freshwater fish containing infective metacercariae of Clonorchis sinensisis (C.sinensis), remains a common public health problem. New effective prevention strategies are still urgent to control this food-borne infectious disease. The previous studies suggested Bacillus subtilis (B. subtilis) spores was an ideal vaccines delivery system, and the C.sinensis enolase (CsENO) was a potential vaccine candidate against clonorchiasis. In the current study, we detected CsENO-specific IgM levels by ELISA in sera, intestinal mucus and skin mucus in grass carps (Ctenopharyngodon idella) through oral administration with B. subtilis spores surface expressing CsENO. In addition, immune-related genes expression was also measured by qRT-PCR. Grass carps orally treated with B. subtilis spores or normal forages were used as controls. The results of ELISA manifested that specific IgM levels of grass carps in CsENO group in sera, intestine mucus and skin mucus almost significantly increased from week 4 post the first oral administration when compared to the two control groups. The levels of specific IgM reached its peak in intestine mucus firstly, then in sera, and last in skin mucus. qRT-PCR results showed that 5 immune-related genes expression had different degree of rising trend in CsENO group when compared to the two control groups. Our study demonstrated that orally administrated with B. subtilis spores expressing CsENO induced innate and adaptive immunity, systemic and local mucosal immunity, and humoral and cellular immunity. Our work may pave the way to clarify the exact mechanisms of protective efficacy elicited by B. subtilis spores expressing CsENO and provide new ideas for vaccine development against C. sinensis infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Extraordinary sediment delivery and rapid geomorphic response following the 2008–2009 eruption of Chaitén Volcano, Chile

    Science.gov (United States)

    Major, Jon J.; Bertin, Daniel; Pierson, Thomas C.; Amigo, Alvaro; Iroume, Andres; Ulloa, Hector; Castro, Jonathan M.

    2016-01-01

    The 10 day explosive phase of the 2008–2009 eruption of Chaitén volcano, Chile, draped adjacent watersheds with a few cm to >1 m of tephra. Subsequent lava-dome collapses generated pyroclastic flows that delivered additional sediment. During the waning phase of explosive activity, modest rainfall triggered an extraordinary sediment flush which swiftly aggraded multiple channels by many meters. Ten kilometer from the volcano, Chaitén River channel aggraded 7 m and the river avulsed through a coastal town. That aggradation and delta growth below the abandoned and avulsed channels allow estimates of postdisturbance traction-load transport rate. On the basis of preeruption bathymetry and remotely sensed measurements of delta-surface growth, we derived a time series of delta volume. The initial flush from 11 to 14 May 2008 deposited 0.5–1.5 × 106 m3 of sediment at the mouth of Chaitén River. By 26 May, after channel avulsion, a second delta amassed about 2 × 106 m3 of sediment; by late 2011 it amassed about 11 × 106 m3. Accumulated sediment consists of low-density vesicular pumice and lithic rhyolite sand. Rates of channel aggradation and delta growth, channel width, and an assumed deposit bulk density of 1100–1500 kg m−3 indicate mean traction-load transport rate just before and shortly after avulsion (∼14–15 May) was very high, possibly as great as several tens of kg s−1 m−1. From October 2008 to December 2011, mean traction-load transport rate declined from about 7 to 0.4 kg−1 m−1. Despite extraordinary sediment delivery, disturbed channels recovered rapidly (a few years).

  6. Paclitaxel controlled delivery using a pH-responsive functional-AuNP/block-copolymer vesicular nanocarrier composite system.

    Science.gov (United States)

    Liaskoni, Athina; Angelopoulou, Athina; Voulgari, Efstathia; Popescu, Maria-Teodora; Tsitsilianis, Constantinos; Avgoustakis, Konstantinos

    2018-02-26

    Paclitaxel (PTX)-loaded gold nanoparticles functionalized with mercaptooctanoic acid (MOA) and folic acid (FA) (AuMOA-FA) were encapsulated within pH-sensitive poly(2-vinylpyridine)-b-poly(ethylene oxide) (P2VP-PEO) vesicles with the aim to develop a more selective injectable nano-formulation for PTX, lacking the side effects of the conventional PTX delivery system. The size of the resulting composite vesicles was lower than 200 nm, i.e. it is suitable for tumor targeting applications taking advantage of the enhanced permeability and retention (EPR) effect. The vesicles did not aggregate in the presence of high electrolyte concentrations, indicating the colloidal stability of the vesicles. The vesicles did not leak their AuMOA-FA or PTX content at physiological pH of 7.4. However, AuMOA-FA and PTX release were significantly accelerated at acidic pHs resembling tumor environment and acidic intracellular compartments. PTX release from the vesicles at acidic pH apparently follows AuMOA-FA release from the vesicles. Flow cytometry measurements and confocal laser scanning microscopy images showed that the vesicles could enter A549 cancer cells in culture and that cellular uptake increased with time. Blank vesicles did not exhibit cytotoxicity and did not induce apoptosis in A549 cancer cells. The PTX currying vesicles exhibited comparable or a little higher cytotoxicity than free PTX. Both the PTX currying vesicles and free PTX induced A549 cells apoptosis, however the vesicle-encapsulated PTX induced a higher percentage of late apoptotic cells than free PTX. Copyright © 2018. Published by Elsevier B.V.

  7. Development of pH-sensitive tamarind seed polysaccharide-alginate composite beads for controlled diclofenac sodium delivery using response surface methodology.

    Science.gov (United States)

    Nayak, Amit Kumar; Pal, Dilipkumar

    2011-11-01

    The present study deals with the development of novel pH-sensitive tamarind seed polysaccharide (TSP)-alginate composite beads for controlled diclofenac sodium delivery using response surface methodology by full 3(2) factorial design. The effect of polymer-blend ratio (sodium alginate:TSP) and cross-linker (CaCl(2)) concentration on the drug encapsulation efficiency (DEE, %) and drug release from diclofenac sodium loaded TSP-alginate composite beads prepared by ionotropic gelation was optimized. The observed responses were coincided well with the predicted values by the experimental design. The DEE (%) of these beads containing diclofenac sodium was within the range between 72.23±2.14 and 97.32±4.03% with sustained in vitro drug release (69.08±2.36-96.07±3.54% in 10 h). The in vitro drug release from TSP-alginate composite beads containing diclofenac sodium was followed by controlled-release pattern (zero-order kinetics) with case-II transport mechanism. Particle size range of these beads was 0.71±0.03-1.33±0.04 mm. The swelling and degradation of the developed beads were influenced by different pH of the test medium. The FTIR and NMR analyses confirmed the compatibility of the diclofenac sodium with TSP and sodium alginate used to prepare the diclofenac sodium loaded TSP-alginate composite beads. The newly developed TSP-alginate composite beads are suitable for controlled delivery of diclofenac sodium for prolonged period. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Hollow-core magnetic colloidal nanocrystal clusters with ligand-exchanged surface modification as delivery vehicles for targeted and stimuli-responsive drug release.

    Science.gov (United States)

    Li, Dian; Tang, Jing; Guo, Jia; Wang, Shilong; Chaudhary, Deeptangshu; Wang, Changchun

    2012-12-14

    The fabrication of hierarchical magnetic nanomaterials with well-defined structure, high magnetic response, excellent colloidal stability, and biocompatibility is highly sought after for drug-delivery systems. Herein, a new kind of hollow-core magnetic colloidal nanocrystal cluster (HMCNC) with porous shell and tunable hollow chamber is synthesized by a one-pot solvothermal process. Its novelty lies in the "tunability" of the hollow chamber and of the pore structure within the shell through controlled feeding of sodium citrate and water, respectively. Furthermore, by using the ligand-exchange method, folate-modified poly(acrylic acid) was immobilized on the surface of HMCNCs to create folate-targeted HMCNCs (folate-HMCNCs), which endowed them with excellent colloidal stability, pH sensitivity, and, more importantly, folate receptor-targeting ability. These assemblages exhibited excellent colloidal stability in plasma solution. Doxorubicin (DOX), as a model anticancer agent, was loaded within the hollow core of these folate-HMCNCs (folate-HMCNCs-DOX), and drug-release experiments proved that the folate-HMCNCs-DOX demonstrated pH-dependent release behavior. The folate-HMCNCs-DOX assemblages also exhibited higher potent cytotoxicity to HeLa cells than free doxorubicin. Moreover, folate-HMCNCs-DOX showed rapid cell uptake apart from the enhanced cytotoxicity to HeLa cells. Experimental results confirmed that the synthesized folate-HMCNCs are smart nanovehicles as a result of their improved folate receptor-targeting abilities and also because of their combined pH- and magnetic-stimuli response for applications in drug delivery. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Forceps Delivery

    Science.gov (United States)

    ... 2015. Related Signs of labor Forceps delivery About Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  10. Dissolving microneedle delivery of nanoparticle-encapsulated antigen elicits efficient cross-priming and Th1 immune responses by murine Langerhans cells.

    Science.gov (United States)

    Zaric, Marija; Lyubomska, Oksana; Poux, Candice; Hanna, Mary L; McCrudden, Maeliosa T; Malissen, Bernard; Ingram, Rebecca J; Power, Ultan F; Scott, Christopher J; Donnelly, Ryan F; Kissenpfennig, Adrien

    2015-02-01

    Dendritic cells (DCs) of the skin have an important role in skin-mediated immunity capable of promoting potent immune responses. We availed of polymeric dissolving microneedle (MN) arrays laden with nano-encapsulated antigen to specifically target skin DC networks. This modality of immunization represents an economic, efficient, and potent means of antigen delivery directly to skin DCs, which are inefficiently targeted by more conventional immunization routes. Following MN immunization, Langerhans cells (LCs) constituted the major skin DC subset capable of cross-priming antigen-specific CD8+ T cells ex vivo. Although all DC subsets were equally efficient in priming CD4+ T cells, LCs were largely responsible for orchestrating the differentiation of CD4+ IFN-γ- and IL-17-producing effectors. Importantly, depletion of LCs prior to immunization had a profound effect on CD8+ CTL responses in vivo, and vaccinated animals displayed reduced protective anti-tumor and viral immunity. Interestingly, this cross-priming bias was lost following MN immunization with soluble antigen, suggesting that processing and cross-presentation of nano-particulate antigen is favored by LCs. Therefore, these studies highlight the importance of LCs in skin immunization strategies and that targeting of nano-particulate immunogens through dissolvable polymeric MNs potentially provides a promising technological platform for improved vaccination strategies.

  11. Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice.

    Science.gov (United States)

    Soria, I; López-Relaño, J; Viñuela, M; Tudela, J-I; Angelina, A; Benito-Villalvilla, C; Díez-Rivero, C M; Cases, B; Manzano, A I; Fernández-Caldas, E; Casanovas, M; Palomares, O; Subiza, J L

    2018-01-10

    Polymerized allergoids coupled to nonoxidized mannan (PM-allergoids) may represent novel vaccines targeting dendritic cells (DCs). PM-allergoids are better captured by DCs than native allergens and favor Th1/Treg cell responses upon subcutaneous injection. Herein we have studied in mice the in vivo immunogenicity of PM-allergoids administered sublingually in comparison with native allergens. Three immunization protocols (4-8 weeks long) were used in Balb/c mice. Serum antibody levels were tested by ELISA. Cell responses (proliferation, cytokines, and Tregs) were assayed by flow cytometry in spleen and lymph nodes (LNs). Allergen uptake was measured by flow cytometry in myeloid sublingual cells. A quick antibody response and higher IgG2a/IgE ratio were observed with PM-allergoids. Moreover, stronger specific proliferative responses were seen in both submandibular LNs and spleen cells assayed in vitro. This was accompanied by a higher IFNγ/IL-4 ratio with a quick IL-10 production by submandibular LN cells. An increase in CD4 + CD25 high FOXP3 + Treg cells was detected in LNs and spleen of mice treated with PM-allergoids. These allergoids were better captured than native allergens by antigen-presenting (CD45 + MHC-II + ) cells obtained from the sublingual mucosa, including DCs (CD11b + ) and macrophages (CD64 + ). Importantly, all the differential effects induced by PM-allergoids were abolished when using oxidized instead of nonoxidized PM-allergoids. Our results demonstrate for the first time that PM-allergoids administered through the sublingual route promote the generation of Th1 and FOXP3 + Treg cells in a greater extent than native allergens by mechanisms that might well involve their better uptake by oral antigen-presenting cells. © 2018 The Authors. Allergy Published by John Wiley & Sons Ltd.

  12. Effect of a 120 km endurance race on plasma and muscular neutrophil elastase and myeloperoxidase concentrations in horses.

    Science.gov (United States)

    Serteyn, D; Sandersen, C; Lejeune, J-P; de la Rebière de Pouyade, G; Ceusters, J; Mouithys-Mickalad, A; Niesten, A; Fraipont, A; van Erck, E; Goachet, A G; Robert, C; Leclerc, J L; Votion, D-M; Franck, T

    2010-11-01

    Intense physical exercise can induce the degranulation of neutrophils leading to an increase in plasma concentration of the neutrophil marker enzymes myeloperoxidase (MPO) and elastase (ELT). These enzymes have pro-oxidative and pro-inflammatory properties and may play a role in the exercised-induced muscular damage. To measure MPO and ELT concentrations in plasma and muscles of endurance horses and to correlate them to the extent of exercise-induced muscular damage. Seven endurance horses qualified on 120 km races were tested in this study. Neutrophil count, serum creatine kinase (CK), plasmatic and muscular MPO and ELT concentrations were measured before and 2 h after a 120 km endurance race. The race produced a significant increase of neutrophils, CK, and plasma MPO and ELT levels. A significant correlation was observed between the MPO and ELT values in plasma (r(2) = 0.92, P ELT were not significantly correlated to muscular ones. An increase of mean concentrations (± s.e.) of MPO (T0: 9.85 ± 3.9, T1: 228.9 ± 95.9 ng/mg proteins) and ELT (T0: 8.4 ± 2.4, T1: 74.5 ± 39.7 ng/mg proteins) in the muscles were observed after the race. Interestingly, the individual data showed large differences between the horses. Muscular MPO and ELT concentrations were significantly correlated to plasma CK levels. The coefficient of correlation (r(2)) was 0.69 (P ELT, respectively. Results underline the possible role of MPO and ELT in exercise-induced muscular damage. Further studies should investigate the effect of exercise type and intensity, as well as the role of the training state on MPO and ELT involvement in muscular damage. The assessment of the intensity of exercise-induced neutrophilic degranulation may have a potential role in the monitoring of the athletic career. © 2010 EVJ Ltd.

  13. Mechanism of inactivation of human leukocyte elastase by a chloromethyl ketone: kinetic and solvent isotope effect studies

    International Nuclear Information System (INIS)

    Stein, R.L.; Trainor, D.A.

    1986-01-01

    The mechanism of inactivation of human leukocyte elastase (HLE) by the chloromethyl ketone MeOSuc-Ala-Ala-Pro-Val-CH 2 Cl was investigated. The dependence of the first-order rate constant for inactivation on concentration of chloromethyl ketone is hyperbolic and suggests formation of a reversible Michaelis complex prior to covalent interaction between the enzyme and inhibitor. However, the observed Ki value is 10 microM, at least 10-fold lower than dissociation constants for complexes formed from interaction of HLE with structurally related substrates or reversible inhibitors, and suggests that Ki is a complex kinetic constant, reflecting the formation and accumulation of both the Michaelis complex and a second complex. It is proposed that this second complex is a hemiketal formed from attack of the active site serine on the carbonyl carbon of the inhibitor. The accumulation of this intermediate may be a general feature of reactions of serine proteases and chloromethyl ketones derived from specific peptides and accounts for the very low Ki values observed for these reactions. The solvent deuterium isotope effect (SIE) on the inactivation step (ki) is 1.58 +/- 0.07 and is consistent with rate-limiting, general-catalyzed attack of the active site His on the methylene carbon of the inhibitor with displacement of chloride anion. The general catalyst is thought to be the active site Asp. In contrast, the SIE on the second-order rate constant for HLE inactivation, ki/Ki, is inverse and equals 0.64 +/- 0.05

  14. Pharmacokinetics of a ternary conjugate based pH-responsive 10-HCPT prodrug nano-micelle delivery system

    Directory of Open Access Journals (Sweden)

    Yang Liu

    2017-11-01

    Full Text Available A pH-responsive conjugate based 10-hydroxycamptothecin-thiosemicarbazide-polyethene glycol 2000 (10-HCPT-hydro-PEG nano-micelles were prepared in our previous study. In the present study, ultra-performance liquid chromatography (UPLC-MS method is developed to investigate its pharmacokinetics and biodistribution in tumor bearing mice. The results demonstrated that the conjugate circulated for a much longer time in the blood circulation system than commercial 10-HCPT injection, and bioavailability was significantly improved compared with 10-HCPT. In vivo biodistribution study showed that the conjugate could enhance the targeting and residence time in tumor site.

  15. Insulin-like growth factor-I gene delivery to astrocytes reduces their inflammatory response to lipopolysaccharide

    Directory of Open Access Journals (Sweden)

    Goya Rodolfo G

    2011-03-01

    Full Text Available Abstract Background Insulin-like growth factor-I (IGF-I exerts neuroprotective actions in the central nervous system that are mediated at least in part by control of activation of astrocytes. In this study we have assessed the efficacy of exogenous IGF-I and IGF-I gene therapy in reducing the inflammatory response of astrocytes from cerebral cortex. Methods An adenoviral vector harboring the rat IGF-I gene and a control adenoviral vector harboring a hybrid gene encoding the herpes simplex virus type 1 thymidine kinase fused to Aequorea victoria enhanced green fluorescent protein were used in this study. Primary astrocytes from mice cerebral cortex were incubated for 24 h or 72 h with vehicle, IGF-I, the IGF-I adenoviral vector, or control vector; and exposed to bacterial lipopolysaccharide to induce an inflammatory response. IGF-I levels were measured by radioimmunoassay. Levels of interleukin 6, tumor necrosis factor-α, interleukin-1β and toll-like receptor 4 mRNA were assessed by quantitative real-time polymerase chain reaction. Levels of IGF-I receptor and IGF binding proteins 2 and 3 were assessed by western blotting. The subcellular distribution of nuclear factor κB (p65 was assessed by immunocytochemistry. Statistical significance was assessed by one way analysis of variance followed by the Bonferroni pot hoc test. Results IGF-I gene therapy increased IGF-I levels without affecting IGF-I receptors or IGF binding proteins. Exogenous IGF-I, and IGF-I gene therapy, decreased expression of toll-like receptor 4 and counteracted the lipopolysaccharide-induced inflammatory response of astrocytes. In addition, IGF-I gene therapy decreased lipopolysaccharide-induced translocation of nuclear factor κB (p65 to the cell nucleus. Conclusion These findings demonstrate efficacy of exogenous IGF-I and of IGF-I gene therapy in reducing the inflammatory response of astrocytes. IGF-I gene therapy may represent a new approach to reduce inflammatory

  16. Hyaluronic acid functional amphipathic and redox-responsive polymer particles for the co-delivery of doxorubicin and cyclopamine to eradicate breast cancer cells and cancer stem cells

    Science.gov (United States)

    Hu, Kelei; Zhou, Huige; Liu, Ying; Liu, Zhu; Liu, Jing; Tang, Jinglong; Li, Jiayang; Zhang, Jiakun; Sheng, Wang; Zhao, Yuliang; Wu, Yan; Chen, Chunying

    2015-04-01

    Cancer stem cells (CSCs) have the ability to transform into bulk cancer cells, to promote tumor growth and establish tumor metastasis. To effectively inhibit tumor growth and prevent metastasis, treatments with conventional chemotherapy drugs should be combined with CSC targeted drugs. In this study, we describe the synthesis and characterization of a new amphiphilic polymer, hyaluronic acid-cystamine-polylactic-co-glycolic acid (HA-SS-PLGA), composed of a hydrophobic PLGA head and a hydrophilic HA segment linked by a bioreducible disulfide bond. With a double emulsion method, a nano delivery system was constructed to deliver doxorubicin (DOX) and cyclopamine (CYC, a primary inhibitor of the hedgehog signaling pathway of CSCs) to both a CD44-overexpressing breast CSC subpopulation and bulk breast cancer cells and allow an on-demand release. The resulting drug-loaded NPs exhibited a redox-responsive drug release profile. Dual drug-loaded particles potently diminished the number and size of tumorspheres and HA showed a targeting effect towards breast CSCs. In vivo combination therapy further demonstrated a remarkable synergistic anti-tumor effect and prolonged survival compared to mono-therapy using the orthotopic mammary fat pad tumor growth model. The co-delivery of drug and the CSC specific inhibitor towards targeted cancer chemotherapeutics provides an insight into anticancer strategy with facile control and high efficacy.Cancer stem cells (CSCs) have the ability to transform into bulk cancer cells, to promote tumor growth and establish tumor metastasis. To effectively inhibit tumor growth and prevent metastasis, treatments with conventional chemotherapy drugs should be combined with CSC targeted drugs. In this study, we describe the synthesis and characterization of a new amphiphilic polymer, hyaluronic acid-cystamine-polylactic-co-glycolic acid (HA-SS-PLGA), composed of a hydrophobic PLGA head and a hydrophilic HA segment linked by a bioreducible disulfide bond

  17. Esterase- and pH-responsive poly(β-amino ester)-capped mesoporous silica nanoparticles for drug delivery

    Science.gov (United States)

    Fernando, Isurika R.; Ferris, Daniel P.; Frasconi, Marco; Malin, Dmitry; Strekalova, Elena; Yilmaz, M. Deniz; Ambrogio, Michael W.; Algaradah, Mohammed M.; Hong, Michael P.; Chen, Xinqi; Nassar, Majed S.; Botros, Youssry Y.; Cryns, Vincent L.; Stoddart, J. Fraser

    2015-04-01

    Gating of mesoporous silica nanoparticles (MSNs) with the stimuli-responsive poly(β-amino ester) has been achieved. This hybrid nanocarrier releases doxorubicin (DOX) under acidic conditions or in the presence of porcine liver esterase. The DOX loaded poly(β-amino ester)-capped MSNs reduce cell viability when tested on MDA-MB-231 human breast cancer cells.Gating of mesoporous silica nanoparticles (MSNs) with the stimuli-responsive poly(β-amino ester) has been achieved. This hybrid nanocarrier releases doxorubicin (DOX) under acidic conditions or in the presence of porcine liver esterase. The DOX loaded poly(β-amino ester)-capped MSNs reduce cell viability when tested on MDA-MB-231 human breast cancer cells. Electronic supplementary information (ESI) available: Experimental details relating to (i) the synthesis and characterisation of the surface-functionalised MSN and POL (ii) cargo-loading and release studies in solution, (iii) cellular internalisation of nanomaterials, and (iv) cell viability tests. See DOI: 10.1039/c4nr07443b

  18. Stimuli-responsive hybrid nanocarriers developed by controllable integration of hyperbranched PEI with mesoporous silica nanoparticles for sustained intracellular siRNA delivery

    Directory of Open Access Journals (Sweden)

    Prabhakar N

    2016-12-01

    interference (RNAi therapy. Keywords: mesoporous silica nanoparticles, RNAi therapy, siRNA delivery, stimuli-responsive drug release, hybrid nanocarriers

  19. Sheep lung segmental delivery strategy demonstrates adenovirus priming of local lung responses to bacterial LPS and the role of elafin as a response modulator.

    Science.gov (United States)

    Brown, Thomas I; Collie, David S; Shaw, Darren J; Rzechorzek, Nina M; Sallenave, Jean-Michel

    2014-01-01

    Viral lung infections increase susceptibility to subsequent bacterial infection. We questioned whether local lung administration of recombinant adenoviral vectors in the sheep would alter the susceptibility of the lung to subsequent challenge with bacterial lipopolysaccharide (LPS). We further questioned whether local lung expression of elafin, a locally produced alarm anti-LPS/anti-bacterial molecule, would modulate the challenge response. We established that adenoviral vector treatment primed the lung for an enhanced response to bacterial LPS. Whereas this local effect appeared to be independent of the transgene used (Ad-o-elafin or Ad-GFP), Ad-o-elafin treated sheep demonstrated a more profound lymphopenia in response to local lung administration of LPS. The local influence of elafin in modulating the response to LPS was restricted to maintaining neutrophil myeloperoxidase activity, and levels of alveolar macrophage and neutrophil phagocytosis at higher levels post-LPS. Adenoviral vector-bacterial synergism exists in the ovine lung and elafin expression modulates such synergism both locally and systemically.

  20. Preparation of thermo-responsive graft copolymer by using a novel macro-RAFT agent and its application for drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Song, Cunfeng; Yu, Shirong [Department of Materials Science and Engineering, College of Materials, Xiamen University, Xiamen 361005 (China); Liu, Cheng; Deng, Yuanming; Xu, Yiting [Department of Materials Science and Engineering, College of Materials, Xiamen University, Xiamen 361005 (China); Fujian Provincial Key Laboratory of Fire Retardant Materials, Xiamen University, Xiamen 361005 (China); Chen, Xiaoling, E-mail: tinachen0628@163.com [Department of Endodontics, Xiamen Stomatology Hospital, Teaching Hospital of Fujian Medical University, Xiamen 361003 (China); Dai, Lizong, E-mail: lzdai@xmu.edu.cn [Department of Materials Science and Engineering, College of Materials, Xiamen University, Xiamen 361005 (China); Fujian Provincial Key Laboratory of Fire Retardant Materials, Xiamen University, Xiamen 361005 (China)

    2016-05-01

    A methodology to prepare thermo-responsive graft copolymer by using a novel macro-RAFT agent was proposed. The macro-RAFT agent with pendant dithioester (ZC(S)SR) was facilely prepared via the combination of RAFT polymerization and esterification reaction. By means of ZC(S)SR-initiated RAFT polymerization, the thermo-responsive graft copolymer consisting of poly(methyl methacrylate-co-hydroxylethyl methacrylate) (P(MMA-co-HEMA)) backbone and hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) side chains was constructed through the “grafting from” approach. The chemical compositions and molecular weight distributions of the synthesized polymers were respectively characterized by {sup 1}H nuclear magnetic resonance ({sup 1}H NMR) and gel permeation chromatography (GPC). Self-assembly behavior of the amphiphilic graft copolymers (P(MMA-co-HEMA)-g-PNIPAAm) was studied by transmission electron microscopy (TEM), dynamic light scattering (DLS) and spectrofluorimeter. The critical micelle concentration (CMC) value was 0.052 mg mL{sup −1}. These micelles have thermo-responsibility and a low critical solution temperature (LCST) of 33.5 °C. Further investigation indicated that the guest molecule release property of these micelles, which can be well described by a first-order kinetic model, was significantly affected by temperature. Besides, the micelles exhibited excellent biocompatibility and cellular uptake property. Hence, these micelles are considered to have potential application in controlled drug delivery. - Highlights: • A novel macro-RAFT agent with ZC(S)SR was used for preparing graft copolymer. • P(MMA-co-HEMA)-g-PNIPAAm was successful prepared via the “grafting from” approach. • Thermo-responsibility of the P(MMA-co-HEMA)-g-PNIPAAm micelles was investigated. • The drug release behavior of the P(MMA-co-HEMA)-g-PNIPAAm micelles was studied. • These micelles exhibited excellent biocompatibility and cellular uptake property.

  1. Side-chain amino-acid-based pH-responsive self-assembled block copolymers for drug delivery and gene transfer.

    Science.gov (United States)

    Kumar, Sonu; Acharya, Rituparna; Chatterji, Urmi; De, Priyadarsi

    2013-12-10

    Developing safe and effective nanocarriers for multitype of delivery system is advantageous for several kinds of successful biomedicinal therapy with the same carrier. In the present study, we have designed amino acid biomolecules derived hybrid block copolymers which can act as a promising vehicle for both drug delivery and gene transfer. Two representative natural chiral amino acid-containing (l-phenylalanine and l-alanine) vinyl monomers were polymerized via reversible addition-fragmentation chain transfer (RAFT) process in the presence of monomethoxy poly(ethylene glycol) based macro-chain transfer agents (mPEGn-CTA) for the synthesis of well-defined side-chain amino-acid-based amphiphilic block copolymers, monomethoxy poly(ethylene glycol)-b-poly(Boc-amino acid methacryloyloxyethyl ester) (mPEGn-b-P(Boc-AA-EMA)). The self-assembled micellar aggregation of these amphiphilic block copolymers were studied by fluorescence spectroscopy, atomic force microscopy (AFM) and scanning electron microscopy (SEM). Potential applications of these hybrid polymers as drug carrier have been demonstrated in vitro by encapsulation of nile red dye or doxorubicin drug into the core of the micellar nanoaggregates. Deprotection of side-chain Boc- groups in the amphiphilic block copolymers subsequently transformed them into double hydrophilic pH-responsive cationic block copolymers having primary amino groups in the side-chain terminal. The DNA binding ability of these cationic block copolymers were further investigated by using agarose gel retardation assay and AFM. The in vitro cytotoxicity assay demonstrated their biocompatible nature and these polymers can serve as "smart" materials for promising bioapplications.

  2. Assisted Vaginal Delivery

    Science.gov (United States)

    ... Events Advocacy For Patients About ACOG Assisted Vaginal Delivery Home For Patients Search FAQs Assisted Vaginal Delivery ... Delivery FAQ192, February 2016 PDF Format Assisted Vaginal Delivery Labor, Delivery, and Postpartum Care What is assisted ...

  3. Oral Delivery of a Novel Recombinant Streptococcus mitis Vector Elicits Robust Vaccine Antigen-Specific Oral Mucosal and Systemic Antibody Responses and T Cell Tolerance.

    Directory of Open Access Journals (Sweden)

    Emily Xie

    Full Text Available The pioneer human oral commensal bacterium Streptococcus mitis has unique biologic features that make it an attractive mucosal vaccine or therapeutic delivery vector. S. mitis is safe as a natural persistent colonizer of the mouth, throat and nasopharynx and the oral commensal bacterium is capable of inducing mucosal antibody responses. A recombinant S. mitis (rS. mitis that stably expresses HIV envelope protein was generated and tested in the germ-free mouse model to evaluate the potential usefulness of this vector as a mucosal vaccine against HIV. Oral vaccination led to the efficient and persistent bacterial colonization of the mouth and the induction of both salivary and systemic antibody responses. Interestingly, persistently colonized animals developed antigen-specific systemic T cell tolerance. Based on these findings we propose the use of rS. mitis vaccine vector for the induction of mucosal antibodies that will prevent the penetration of the mucosa by pathogens such as HIV. Moreover, the first demonstration of rS. mitis having the ability to elicit T cell tolerance suggest the potential use of rS. mitis as an immunotherapeutic vector to treat inflammatory, allergic and autoimmune diseases.

  4. Oral Delivery of a Novel Recombinant Streptococcus mitis Vector Elicits Robust Vaccine Antigen-Specific Oral Mucosal and Systemic Antibody Responses and T Cell Tolerance

    Science.gov (United States)

    Xie, Emily; Kotha, Abhiroop; Biaco, Tracy; Sedani, Nikita; Zou, Jonathan; Stashenko, Phillip; Duncan, Margaret J.; Campos-Neto, Antonio; Cayabyab, Mark J.

    2015-01-01

    The pioneer human oral commensal bacterium Streptococcus mitis has unique biologic features that make it an attractive mucosal vaccine or therapeutic delivery vector. S. mitis is safe as a natural persistent colonizer of the mouth, throat and nasopharynx and the oral commensal bacterium is capable of inducing mucosal antibody responses. A recombinant S. mitis (rS. mitis) that stably expresses HIV envelope protein was generated and tested in the germ-free mouse model to evaluate the potential usefulness of this vector as a mucosal vaccine against HIV. Oral vaccination led to the efficient and persistent bacterial colonization of the mouth and the induction of both salivary and systemic antibody responses. Interestingly, persistently colonized animals developed antigen-specific systemic T cell tolerance. Based on these findings we propose the use of rS. mitis vaccine vector for the induction of mucosal antibodies that will prevent the penetration of the mucosa by pathogens such as HIV. Moreover, the first demonstration of rS. mitis having the ability to elicit T cell tolerance suggest the potential use of rS. mitis as an immunotherapeutic vector to treat inflammatory, allergic and autoimmune diseases. PMID:26618634

  5. Dual photo- and pH-responsive supramolecular nanocarriers based on water-soluble pillar[6]arene and different azobenzene derivatives for intracellular anticancer drug delivery.

    Science.gov (United States)

    Hu, Xiao-Yu; Jia, Keke; Cao, Yu; Li, Yan; Qin, Shan; Zhou, Fan; Lin, Chen; Zhang, Dongmei; Wang, Leyong

    2015-01-12

    Two novel types of supramolecular nanocarriers fabricated by the amphiphilic host-guest inclusion complex formed from water-soluble pillar[6]arene (WP6) and azobenzene derivatives G1 or G2 have been developed, in which G1 is structurally similar to G2 but has an extra phenoxy group in its hydrophobic region. Supramolecular micelles can be initially formed by WP6 with G1, which gradually transform into layered structures with liquid-crystalline properties, whereas stable supramolecular vesicles are obtained from WP6 and G2, which exhibit dual photo- and pH-responsiveness. Notably, the resulting WP6⊃G2 vesicles can efficiently encapsulate anticancer drug mitoxantrone (MTZ) to achieve MTZ-loaded vesicles, which maintain good stability in a simulated normal physiological environment, whereas in an acid environment similar to that of tumor cells or with external UV irradiation, the encapsulated drug is promptly released. More importantly, cytotoxicity assay indicates that such vesicles have good biocompatibility and the MTZ-loaded vesicles exhibit comparable anticancer activity to free MTZ, especially with additional UV stimulus, whereas its cytotoxicity for normal cells was remarkably reduced. Flow cytometric analysis further confirms that the cancer cell death caused by MTZ-loaded vesicles is associated with apoptosis. Therefore, the dual pH- and UV-responsive supramolecular vesicles are a potential platform for controlled release and targeted anticancer drug delivery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Targeted delivery and pH-responsive release of stereoisomeric anti-cancer drugs using β-cyclodextrin assemblied Fe{sub 3}O{sub 4} nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Congli; Huang, Lizhen; Song, Shengmei; Saif, Bassam; Zhou, Yehong; Dong, Chuan; Shuang, Shaomin, E-mail: smshuang@sxu.edu.cn

    2015-12-01

    Graphical abstract: - Highlights: • β-Cyclodextrin assemblied magnetic Fe{sub 3}O{sub 4} nanoparticles (β-CD-MNPs) with good stability were successfully fabricated. • Stereoisomeric doxorubicin (DOX) and epirubicin (EPI) were used to explore the loading and release performance. • The loading properties of β-CD-MNPs were investigated using the Langmuir and Freundlich adsorption equilibrium models. • {sup 1}H NMR and the computer simulation were used to demonstrate the inclusion position between drug molecules and β-CD. - Abstract: The β-cyclodextrin assemblied magnetic Fe{sub 3}O{sub 4} nanoparticles (β-CD-MNPs) were successfully fabricated via a layer-by-layer method. Possessing an average size 14 nm, good stability and super-paramagnetic response (Ms 64 emu/g), the resultant nanocomposites could be served as a versatile biocompatible platform for selective loading, targeted delivery and pH-responsive release of stereoisomeric doxorubicin (DOX) and epirubicin (EPI). {sup 1}H-nuclear magnetic resonance ({sup 1}H NMR) and the computer simulation further give the evidence that partial anthracene ring of drug molecule is included by β-CD. In addition, non-toxic β-CD-MNPs have excellent biocompatibility on MCF-7 cells, and cellular uptake indicate that different amounts of DOX or EPI can be transported to targeting site and released from the internalized carriers. The results demonstrate that as-prepared β-CD-MNPs could be a very promising vehicle for DOX and EPI.

  7. A Near-Infrared Photothermal Effect-Responsive Drug Delivery System Based on Indocyanine Green and Doxorubicin-Loaded Polymeric Micelles Mediated by Reversible Diels-Alder Reaction.

    Science.gov (United States)

    Li, Hui; Li, Junjie; Ke, Wendong; Ge, Zhishen

    2015-10-01

    Near-infrared light (NIR) possesses great advantages for light-responsive controllable drug release, such as deep tissue penetration and low damage to healthy tissues. Herein, a NIR-responsive drug delivery system is developed based on a NIR dye, indocyanine green (ICG), and anticancer drug, doxorubicin (DOX)-loaded thermoresponsive block copolymer micelles, in which the drug release can be controlled via NIR irradiation. First, block copolymers, poly(oligo(ethylene glycol) methacrylate)-block-poly(furfuryl methacrylate) (POEGMA-b-PFMA), are synthesized by sequential reversible addition-fragmentation chain-transfer (RAFT) polymerization, followed by modification with N-octyl maleimide through Diels-Alder (DA) reaction to produce POEGMA-b-POMFMA. The self-assembly of POEGMA-b-POMFMA by nano-precipitation in aqueous solution affords the polymeric micelles which are used to simultaneously encapsulate ICG and DOX. Upon irradiation by NIR light (805 nm), the loaded DOX is released rapidly from the micelles due to partial retro DA reaction and local temperature increase-induced faster drug diffusion by the photothermal effect. Cytotoxicity evaluation and intracellular distribution observation demonstrate significant synergistic effects of NIR-triggered drug release, photothermal, and chemotherapy toward cancer cells under NIR irradiation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Sonophoresis in transdermal drug deliverys.

    Science.gov (United States)

    Park, Donghee; Park, Hyunjin; Seo, Jongbum; Lee, Seunghun

    2014-01-01

    Transdermal drug delivery (TDD) has several significant advantages compared to oral drug delivery, including elimination of pain and sustained drug release. However, the use of TDD is limited by low skin permeability due to the stratum corneum (SC), the outermost layer of the skin. Sonophoresis is a technique that temporarily increases skin permeability such that various medications can be delivered noninvasively. For the past several decades, various studies of sonophoresis in TDD have been performed focusing on parameter optimization, delivery mechanism, transport pathway, or delivery of several drug categories including hydrophilic and high molecular weight compounds. Based on these various studies, several possible mechanisms of sonophoresis have been suggested. For example, cavitation is believed to be the predominant mechanism responsible for drug delivery in sonophoresis. This review presents details of various studies on sonophoresis including the latest trends, delivery of various therapeutic drugs, sonophoresis pathways and mechanisms, and outlook of future studies. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Tailored design of multifunctional and programmable pH-responsive self-assembling polypeptides as drug delivery nanocarrier for cancer therapy.

    Science.gov (United States)

    Wang, Tzu-Wei; Yeh, Chia-Wei; Kuan, Chen-Hsiang; Wang, Li-Wen; Chen, Liang-Hsin; Wu, Hsi-Chin; Sun, Jui-Shen

    2017-08-01

    Breast cancer has become the second leading cause of cancer-related mortality in female wherein more than 90% of breast cancer-related death results from cancer metastasis to distant organs at advanced stage. The purpose of this study is to develop biodegradable nanoparticles composed of natural polypeptides and calcium phosphate (CaP) with sequential pH-responsivity to tumor microenvironments for active targeted drug delivery. Two different amphiphilic copolymers, poly(ethylene glycol) 3400 -aconityl linkage-poly(l-glutamic acid) 15 -poly(l-histidine) 10 -poly(l-leucine) 10 and LyP1-poly(ethylene glycol) 1100 -poly(l-glutamic acid) 15 -poly(l-histidine) 10 -poly(l-leucine) 10 , were exploited to self-assemble into micelles in aqueous phase. The bio-stable nanoparticles provide three distinct functional domains: the anionic PGlu shell for CaP mineralization, the protonation of PHis segment for facilitating anticancer drug release at target site, and the hydrophobic core of PLeu for encapsulation of anticancer drugs. Furthermore, the hydrated PEG outer corona is used for prolonging circulation time, while the active targeting ligand, LyP-1, is served to bind to breast cancer cells and lymphatic endothelial cells in tumor for inhibiting metastasis. Mineralized DOX-loaded nanoparticles (M-DOX NPs) efficiently prevent the drug leakage at physiological pH value and facilitate the encapsulated drug release at acidic condition when compared to DOX-loaded nanoparticles (DOX NPs). M-DOX NPs with LyP-1 targeting ligand effectively accumulated in MDA-MB-231 breast cancer cells. The inhibition effect on cell proliferation also enhances with time, illustrating the prominent anti-tumor efficacy. Moreover, the in vitro metastatic inhibition model shows the profound inhibition effect of inhibitory nanoparticles. In brief, this self-assembling peptide-based drug delivery nanocarrier with multifunctionality and programmable pH-sensitivity is of great promise and potential for anti

  10. Comparison of the heat shock response induced by conventional heating and two methods of delivery of pulsed radiofrequency energy

    International Nuclear Information System (INIS)

    Laurence, J.A.; University of Sydney, NSW; McKenzie, D.R.; Veas, L.; French, P.W.

    2002-01-01

    Full text: In 2001, we published a (hypothetical) mechanism by which radiofrequency (RF) radiation from mobile phones could induce cancer, via the chronic induction of the heat shock response (HSR). This hypothesis provides the focus for our research. Other groups have reported induction of the HSR by RF at apparently non thermal levels. The aim of this study was to determine whether the HSR induced by RF is (a) truly non thermal and (b) quantitatively or qualitatively different from that induced by conventional heating of cells. A rat mast cell line, RBL-2H3, was chosen as the target RBL-2H3 cells were exposed in an air incubator at 41.1 deg C for 45 minutes and 75 minutes, and then returned to a 37 deg C incubator. Sham exposures were performed in the same air incubator at 37 deg C. Cells were exposed for 1 hour in the two pulsed RF exposure systems. The first was a converted 750W microwave oven that emits a short burst of 2.45GHz pulses at the start of each contiguous six minute period. This exposes cells to an average specific energy absorption rate (SAR) of 20W/kg. The second system was a TEM cell, which simulates. GSM pulses - the earner frequency is 0.9GHz pulse modulated at 217Hz. The SAR was approx 0.1W/kg. Both of these exposure systems are housed in incubators maintained at 37 deg C. Sham exposures were performed in the two systems with the same conditions but with no RF radiation present. Cell samples for the conventional heating and microwave exposures were taken 0, 2. 5, 5 and 20 hours after exposure, and expression of heat shock proteins hsp 110, 90, 70, 60 and 56 were determined by Western Blotting and compared between exposures

  11. SU-E-QI-14: Quantitative Variogram Detection of Mild, Unilateral Disease in Elastase-Treated Rats

    Energy Technology Data Exchange (ETDEWEB)

    Jacob, R [Pacific Northwest National Laboraory, Richland, WA (United States); Carson, J [Texas Advanced Computing Center, Austin, TX (United States)

    2014-06-15

    Purpose: Determining the presence of mild or early disease in the lungs can be challenging and subjective. We present a rapid and objective method for evaluating lung damage in a rat model of unilateral mild emphysema based on a new approach to heterogeneity assessment. We combined octree decomposition (used in three-dimensional (3D) computer graphics) with variograms (used in geostatistics to assess spatial relationships) to evaluate 3D computed tomography (CT) lung images for disease. Methods: Male, Sprague-Dawley rats (232 ± 7 g) were intratracheally dosed with 50 U/kg of elastase dissolved in 200 μL of saline to a single lobe (n=6) or with saline only (n=5). After four weeks, 3D micro-CT images were acquired at end expiration on mechanically ventilated rats using prospective gating. Images were masked, and lungs were decomposed to homogeneous blocks of 2×2×2, 4×4×4, and 8×8×8 voxels using octree decomposition. The spatial variance – the square of the difference of signal intensity – between all pairs of the 8×8×8 blocks was calculated. Variograms – graphs of distance vs. variance - were made, and data were fit to a power law and the exponent determined. The mean HU values, coefficient of variation (CoV), and the emphysema index (EI) were calculated and compared to the variograms. Results: The variogram analysis showed that significant differences between groups existed (p<0.01), whereas the mean HU (p=0.07), CoV (p=0.24), and EI (p=0.08) did not. Calculation time for the variogram for a typical 1000 block decomposition was ∼6 seconds, and octree decomposition took ∼2 minutes. Decomposing the images prior to variogram calculation resulted in a ∼700x decrease in time as compared to other published approaches. Conclusions: Our results suggest that the approach combining octree decomposition and variogram analysis may be a rapid, non-subjective, and sensitive imaging-based biomarker for quantitative characterization of lung disease.

  12. Analyses of pancreas development by generation of gfp transgenic zebrafish using an exocrine pancreas-specific elastaseA gene promoter

    International Nuclear Information System (INIS)

    Wan Haiyan; Korzh, Svitlana; Li Zhen; Mudumana, Sudha Puttur; Korzh, Vladimir; Jiang Yunjin; Lin Shuo; Gong Zhiyuan

    2006-01-01

    In contrast to what we know on development of endocrine pancreas, the formation of exocrine pancreas remains poorly understood. To create an animal model that allows observation of exocrine cell differentiation, proliferation, and morphogenesis in living animals, we used the zebrafish elastaseA (elaA) regulatory sequence to develop transgenic zebrafish that display highly specific exocrine pancreas expression of GFP in both larvae and adult. By following GFP expression, we found that the pancreas in early development was a relatively compact organ and later extended posterior along the intestine. By transferring the elaA:gfp transgene into slow muscle omitted mutant that is deficient in receiving Hedgehog signals, we further showed that Hedgehog signaling is required for exocrine morphogenesis but not for cell differentiation. We also applied the morpholino knockdown and toxin-mediated cell ablation approaches to this transgenic line. We showed that the development of exocrine pancreas is Islet-1 dependent. Injection of the diphtheria toxin A (DTA) construct under the elastaseA promoter resulted in selective ablation of exocrine cells while the endocrine cells and other endodermal derivatives (liver and intestine) were not affected. Thus, our works demonstrated the new transgenic line provided a useful experimental tool in analyzing exocrine pancreas development

  13. Atrial natriuretic peptide-conjugated chitosan-hydrazone-mPEG copolymer nanoparticles as pH-responsive carriers for intracellular delivery of prednisone.

    Science.gov (United States)

    M, Gover Antoniraj; C, Senthil Kumar; Henry, Linda Jeeva Kumari; Natesan, Subramanian; Kandasamy, Ruckmani

    2017-02-10

    A chitosan-hydrazone-mPEG (CH-Hz-mPEG) copolymer which is stable at extracellular pH and cleaves at slightly acidic intracellular pH was synthesized and characterized. Blank polymeric nanoparticles (B-PNPs) and prednisone-loaded polymeric nanoparticles (P-PNPs) were then formulated by dialysis/precipitation method. The cell-specific ligand, atrial natriuretic peptide (ANP) was then conjugated to P-PNPs (ANP-P-PNPs) by a coupling reaction. Particle size and morphological analyses revealed uniform spherical shape of PNPs. In vitro pH dependent degradation of PNPs was investigated. Drug release profile of ANP-P-PNPs indicated a slow release of prednisone at pH 7.4, but a rapid release at pH 5.0 due to the cleavage of hydrazone linkage. Cytotoxicity studies demonstrated greater compatibility of B-PNPs compared to ANP-P-PNPs. Cellular internalization of ANP-P-PNPs was higher than P-PNPs owing to receptor-mediated endocytosis. The results from this investigation support the hypothesis that chitosan based ANP-P-PNPs could act as an intracellular pH-responsive and targeted drug delivery system. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Retroviral Replicating Vector Delivery of miR-PDL1 Inhibits Immune Checkpoint PDL1 and Enhances Immune Responses In Vitro

    Directory of Open Access Journals (Sweden)

    Amy H. Lin

    2017-03-01

    Full Text Available Tumor cells express a number of immunosuppressive molecules that can suppress anti-tumor immune responses. Efficient delivery of small interfering RNAs to treat a wide range of diseases including cancers remains a challenge. Retroviral replicating vectors (RRV can be used to stably and selectively introduce genetic material into cancer cells. Here, we designed RRV to express shRNA (RRV-shPDL1 or microRNA30-derived shRNA (RRV-miRPDL1 using Pol II or Pol III promoters to downregulate PDL1 in human cancer cells. We also designed RRV expressing cytosine deaminase (yCD2 and miRPDL1 for potential combinatorial therapy. Among various configurations tested, we showed that RRV-miRPDL1 vectors with Pol II or Pol III promoter replicated efficiently and exhibited sustained downregulation of PDL1 protein expression by more than 75% in human cancer cell lines with high expression of PDL1. Immunologic effects of RRV-miRPDL1 were assessed by a trans-suppression lymphocyte assay. In vitro data showed downregulation of PDL1+ tumor cells restored activation of CD8+ T cells and bio-equivalency compared to anti-PDL1 antibody treatment. These results suggest RRV-miRPDL1 may be an alternative therapeutic approach to enhance anti-tumor immunity by overcoming PDL1-induced immune suppression from within cancer cells and this approach may also be applicable to other cancer targets.

  15. Antigen delivery by filamentous bacteriophage fd displaying an anti-DEC-205 single-chain variable fragment confers adjuvanticity by triggering a TLR9-mediated immune response.

    Science.gov (United States)

    Sartorius, Rossella; D'Apice, Luciana; Trovato, Maria; Cuccaro, Fausta; Costa, Valerio; De Leo, Maria Giovanna; Marzullo, Vincenzo Manuel; Biondo, Carmelo; D'Auria, Sabato; De Matteis, Maria Antonietta; Ciccodicola, Alfredo; De Berardinis, Piergiuseppe

    2015-07-01

    Filamentous bacteriophage fd particles delivering antigenic determinants via DEC-205 (fdsc-αDEC) represent a powerful delivery system that induces CD8(+) T-cell responses even when administered in the absence of adjuvants or maturation stimuli for dendritic cells. In order to investigate the mechanisms of this activity, RNA-Sequencing of fd-pulsed dendritic cells was performed. A significant differential expression of genes involved in innate immunity, co-stimulation and cytokine production was observed. In agreement with these findings, we demonstrate that induction of proinflammatory cytokines and type I interferon by fdsc-αDEC was MYD88 mediated and TLR9 dependent. We also found that fdsc-αDEC is delivered into LAMP-1-positive compartments and co-localizes with TLR9. Thus, phage particles containing a single-strand DNA genome rich in CpG motifs delivered via DEC-205 are able to intercept and trigger the active TLR9 innate immune receptor into late endosome/lysosomes and to enhance the immunogenicity of the displayed antigenic determinants. These findings make fd bacteriophage a valuable tool for immunization without administering exogenous adjuvants. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  16. pH and reduction dual-responsive dipeptide cationic lipids with α-tocopherol hydrophobic tail for efficient gene delivery.

    Science.gov (United States)

    Liu, Qiang; Su, Rong-Chuan; Yi, Wen-Jing; Zheng, Li-Ting; Lu, Shan-Shan; Zhao, Zhi-Gang

    2017-03-31

    A series of tocopherol-based cationic lipid 3a-3f bearing a pH-sensitive imidazole moiety in the dipeptide headgroup and a reduction-responsive disulfide linkage were designed and synthesized. Acid-base titration of these lipids showed good buffering capacities. The liposomes formed from 3 and co-lipid 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) could efficiently bind and condense DNA into nanoparticles. Gel binding and HPLC assays confirmed the encapsulated DNA could release from lipoplexes 3 upon addition of 10 mM glutathione (GSH). MTT assays in HEK 293 cells demonstrated that lipoplexes 3 had low cytotoxicity. The in vitro gene transfection studies showed cationic dipeptide headgroups clearly affected the transfection efficiency (TE), and arginine-histidine based dipeptide lipid 3f give the best TE, which was 30.4 times higher than Lipofectamine 3000 in the presence of 10% serum. Cell-uptake assays indicated that basic amino acid containing dipeptide cationic lipids exhibited more efficient cell uptake than serine and aromatic amino acids based dipeptide lipids. Confocal laser scanning microscopy (CLSM) studies corroborated that 3 could efficiently deliver and release DNA into the nuclei of HeLa cells. These results suggest that tocopherol-based dipeptide cationic lipids with pH and reduction dual-sensitive characteristics might be promising non-viral gene delivery vectors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  17. Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock.

    Science.gov (United States)

    Mussack, Thomas; Briegel, Josef; Schelling, Gustav; Biberthaler, Peter; Jochum, Marianne

    2005-01-01

    Stress doses of hydrocortisone are known to have immunomodulatory effects in patients with hyperdynamic septic shock. The prognosis correlates with the presence and severity of septic encephalopathy. However, neurological evaluation is influenced by the use of analgesia sedation during artificial ventilation. The objective of this study was to demonstrate the effect of stress doses of hydrocortisone during the initial phase of human septic shock on the serum values of the neurospecific protein S-100B in comparison to the inflammation markers interleukin (IL)-8 in serum and polymorphonuclear (PMN) elastase in plasma. A total of 24 consecutive patients, who met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock, were enrolled in this prospective, randomized, double-blind, single-center trial. The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. Multi-organ dysfunction syndrome was described by the Sepsis-related Organ Failure Assessment (SOFA) score. All patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days. Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/mL at study entry to 0.07 ng/mL 6 days later without significant differences compared to the placebo group. Initial IL-8 serum levels were significantly higher in the hydrocortisone group up to 12 h after study entry, and significantly decreased from 715 to 17 pg/mL at the end of the observation period. Median PMN elastase plasma levels were not affected by hydrocortisone infusion. Patients with initial S-100B serum levels > 0.50 ng/mL revealed significantly higher SOFA scores up to 30 h, IL-8 serum levels up to 12 h, and PMN elastase plasma

  18. SU-F-R-54: CT-Texture Based Early Tumor Treatment Response Assessment During Radiation Therapy Delivery: Small Cell Versus Non-Small Cell Lung Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Paul, J; Gore, E; Li, X [Medical College of Wisconsin, Milwaukee, WI (United States)

    2016-06-15

    Purpose: Tumor treatment response may potentially be assessed during radiation therapy (RT) by analyzing changes in CT-textures. We investigated the different early RT-responses between small cell (SCLC) and non-small cell lung cancer (NSCLC) as assessed by CT-texture. Methods: Daily diagnostic-quality CT acquired during routine CT-guided RT using a CT-on-Rails for 13-NSCLC and 5-SCLC patients were analyzed. These patient had ages ranging from 45–78 and 38–63 years, respectively, for NSCLC and SCLC groups, and tumor-stages ranging from T2-T4, and were treated with either RT or chemotherapy and RT with 45–66Gy/ 20–34 fractions. Gross-tumor volume (GTV) contour was generated on each daily CT by populating GTV contour from simulation to daily CTs with manual editing if necessary. CT-texture parameters, such as Hounsfield Unit (HU) histogram, mean HU, skewness, kurtosis, entropy, and short-run high-gray level emphasis (SRHGLE), were calculated in GTV from each daily CT-set using an in house software tool. Difference in changes of these texture parameters during RT between NSCLC and SCLC was analyzed and compared with GTV volume changes. Results: Radiation-induced changes in CT-texture were different between SCLC and NSCLC. Average changes from first to the last fractions for NSCLC and SCLC in GTV were 28±10(12–44) and 30±15(11–47) HU (mean HU reduction), 12.7% and 18.3% (entropy), 50% and 55% (SRHGLE), 19% and 22% (kurtosis), and 5.2% and 22% (skewness), respectively. Good correlation in kurtosis changes and GTV was seen (R{sup 2}=0.8923) for SCLC, but not for NSCLC (R{sup 2}=0.4748). SCLC had better correlations between GTV volume reduction and entropy (SCLC R{sup 2}=0.847; NSCLC R{sup 2}=0.6485), skewness (SCLC R{sup 2}=0.935; NSCLC R{sup 2}=0.7666), or SRHGLE (SCLC R{sup 2}=0.9619; NSCLC R{sup 2}=0.787). Conclusion: NSCLC and SCLC exhibited different early RT-responses as assessed by CT-texture changes during RT-delivery. The observed larger changes in

  19. Aggressive re-warming at 38.5 degrees C following deep hypothermia at 21 degrees C increases neutrophil membrane bound elastase activity and pro-inflammatory factor release

    NARCIS (Netherlands)

    Tang, Min; Zhao, Xiao-gang; He, Yi; Gu, Yan; Mei, Ju

    2016-01-01

    Background: Cardiopulmonary bypass (CPB) is often performed under hypothermic condition. The effects of hypothermia and re-warming on neutrophil activity are unclear. This study aimed to compare the effects of different hypothermia and re-warming regimens on neutrophil membrane bound elastase (MBE)

  20. A robust strategy for preparation of sequential stimuli-responsive block copolymer prodrugs via thiolactone chemistry to overcome multiple anticancer drug delivery barriers.

    Science.gov (United States)

    Ke, Wendong; Yin, Wei; Zha, Zengshi; Mukerabigwi, Jean Felix; Chen, Weijian; Wang, Yuheng; He, Chuanxin; Ge, Zhishen

    2018-02-01

    Block copolymer prodrugs (BCPs) have attracted considerable attentions in clinical translation of nanomedicine owing to their self-assembly into well-defined core-shell nanoparticles for improved pharmacokinetics, stability in blood circulation without drug leakage, and optimized biodistribution. However, a cascade of physiological barriers against specific delivery of drugs into tumor cells limit the final therapeutic efficacy. Herein, we report a robust and facile strategy based on thiolactone chemistry to fabricate well-defined BCPs with sequential tumor pH-promoted cellular internalization and intracellular stimuli-responsive drug release. A series of BCPs were prepared through one-pot synthesis from clinically used small molecule anticancer drugs. The ring-opening reaction of drug-conjugated thiolactones releases mercapto groups via aminolysis by N-(3-aminopropyl)-imidazole, which further react with poly(ethylene glycol)-block-poly(pyridyldisulfide ethylmethacrylate) (PEG-PDSEMA) to produce imidazole and disulfide bonds-incorporated BCPs. Taking paclitaxel (PTX) for example, PTX BCPs exhibited high drug-loading content (>50%) and low critical micellization concentration (5 × 10 -3  g/L), which can self-assemble into micellar nanoparticles in aqueous solution with a small size (∼40 nm). The nanoparticles showed high tumor accumulation and uniform distribution in hypopermeable tumors via systemic administration. Meanwhile, imidazole moieties endow nanoparticles tumor pH-sensitive charge transition from nearly neutral to positive, which promoted cellular internalization. Disulfide bonds can be cleaved by intracellular glutathione (GSH) of cancer cells, which accelerate the release of active PTX drug inside cells. Finally, highly aggressive murine breast cancer 4T1 tumor and hypopermeable human pancreatic adenocarcinoma BxPC3 tumor were completely ablated after treatment by PTX BCP nanoparticles. Consequently, the robust and facile preparation strategy

  1. Comparison of concentrations of two proteinase inhibitors, porcine pancreatic elastase inhibitory capacity, and cell profiles in sequential bronchoalveolar lavage samples.

    Science.gov (United States)

    Morrison, H M; Kramps, J A; Dijkman, J H; Stockley, R A

    1986-01-01

    Bronchoalveolar lavage is used to obtain cells and proteins from the lower respiratory tract for diagnosis and research. Uncertainity exists about which site in the lung is sampled by the lavage fluid and what effect different lavage volumes have on recovery of the constituents of lavage fluid. Dilution of alveolar lining fluid by lavage fluid is variable and results are usually expressed as protein ratios to surmount this problem. We have compared cell profiles and the concentrations of two proteinase inhibitors--the low molecular weight bronchial protease inhibitor antileucoprotease and alpha 1 proteinase inhibitor, together with alpha 1 proteinase inhibitor function and its relationship to the cell profile in sequential bronchoalveolar lavage fluid samples from patients undergoing bronchoscopy. There was no difference in total or differential cell counts or albumin or alpha 1 proteinase inhibitor concentrations between the first and second halves of the lavage. Both the concentration of antileucoprotease and the ratio of antileucoprotease to albumin were, however, lower in the second half of the lavage (2p less than 0.01 and 2p less than 0.05 respectively). There was no difference in the function of alpha 1 proteinase inhibitor (assessed by inhibition of porcine pancreatic elastase--PPE) between aliquots (0.28 mole PPE inhibited/mol alpha 1 proteinase inhibitor; range 0-1.19 for the first half and 0.37 mol PPE inhibited/mol alpha 1 proteinase inhibitor; range 0.10-0.80 for the second half). About 60-70% of alpha 1 proteinase inhibitor in each half of the lavage fluid was inactive as an inhibitor. The function of alpha 1 proteinase inhibitor did not differ between bronchitic smokers and ex-smokers. Alpha 1 proteinase inhibitor function was not related to the number of total white cells, macrophages, or neutrophils in the lavage fluid. Contamination of lavage by red blood cells was found to alter the concentration of alpha 1 proteinase inhibitor but not its

  2. Synthetic sustained gene delivery systems.

    Science.gov (United States)

    Agarwal, Ankit; Mallapragada, Surya K

    2008-01-01

    Gene therapy today is hampered by the need of a safe and efficient gene delivery system that can provide a sustained therapeutic effect without cytotoxicity or unwanted immune responses. Bolus gene delivery in solution results in the loss of delivered factors via lymphatic system and may cause undesired effects by the escape of bioactive molecules to distant sites. Controlled gene delivery systems, acting as localized depot of genes, provide an extended sustained release of genes, giving prolonged maintenance of the therapeutic level of encoded proteins. They also limit the DNA degradation in the nuclease rich extra-cellular environment. While attempts have been made to adapt existing controlled drug delivery technologies, more novel approaches are being investigated for controlled gene delivery. DNA encapsulated in nano/micro spheres of polymers have been administered systemically/orally to be taken up by the targeted tissues and provide sustained release once internalized. Alternatively, DNA entrapped in hydrogels or scaffolds have been injected/implanted in tissues/cavities as platforms for gene delivery. The present review examines these different modalities for sustained delivery of viral and non-viral gene-delivery vectors. Design parameters and release mechanisms of different systems made with synthetic or natural polymers are presented along with their prospective applications and opportunities for continuous development.

  3. Characterization of Total Phenolic Constituents from the Stems of Spatholobus suberectus Using LC-DAD-MSn and Their Inhibitory Effect on Human Neutrophil Elastase Activity

    Directory of Open Access Journals (Sweden)

    Yiming Li

    2013-06-01

    Full Text Available Spatholobus suberectus Dunn, belonging to the legume family (Fabaceae, has been used as a Traditional Chinese Medicine for the treatment of anemia, menoxenia and rheumatism. A limited number of studies report that various types of flavonoids are the main characteristic constituents of this herb. We have now found that S. suberectus contains about 2% phenolic components and characterized the major phenolic components as homogeneous B-type procyanidin conjugates using a liquid chromatography with diode-array detection-ESI mass spectrometry (LC-DAD/ESI-MS method. This is the first report on occurrence of most B-type procyanidins in this herb. Moreover, the total phenolics extract was assayed for inhibitory activity on human neutrophil elastase and its IC50 was found to be 1.33 μg/mL.

  4. Synthesis and evaluation of benzoxazinone derivatives on activity of human neutrophil elastase and on hemorrhagic shock-induced lung injury in rats.

    Science.gov (United States)

    Hsieh, Pei-Wen; Yu, Huang-Ping; Chang, Yi-Ju; Hwang, Tsong-Long

    2010-07-01

    A new series of benzoxazinone analogs were designed, synthesized, and assayed to determine their effects on superoxide anion generation and neutrophil elastase (NE) release in formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-activated human neutrophils. Of these, compounds 6-10 showed a potent dual inhibitory effect on NE release and superoxide anion generation. In contrast, compounds 11-15 exhibited highly selective and potent inhibitory activities on NE release. These results indicate that the inhibitory activity on NE release in FMLP-activated human neutrophils depended on the position of chloro-substituent in the A ring. On the other hand, 13 significantly attenuated the increase in myeloperoxidase (MPO) activity and edema in the lung of rats after trauma-hemorrhagic shock. Therefore, these compounds could be developed as new NE inhibitors. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

  5. Quantitative structure-activity relationship analysis of human neutrophil elastase inhibitors using shuffling classification and regression trees and adaptive neuro-fuzzy inference systems.

    Science.gov (United States)

    Asadollahi-Baboli, M

    2012-07-01

    The purpose of this study was to develop quantitative structure-activity relationship models for N-benzoylindazole derivatives as inhibitors of human neutrophil elastase. These models were developed with the aid of classification and regression trees (CART) and an adaptive neuro-fuzzy inference system (ANFIS) combined with a shuffling cross-validation technique using interpretable descriptors. More than one hundred meaningful descriptors, representing various structural characteristics for all 51 N-benzoylindazole derivatives in the data set, were calculated and used as the original variables for shuffling CART modelling. Five descriptors of average Wiener index, Kier benzene-likeliness index, subpolarity parameter, average shape profile index of order 2 and folding degree index selected by the shuffling CART technique have been used as inputs of the ANFIS for prediction of inhibition behaviour of N-benzoylindazole derivatives. The results of the developed shuffling CART-ANFIS model compared to other techniques, such as genetic algorithm (GA)-partial least square (PLS)-ANFIS and stepwise multiple linear regression (MLR)-ANFIS, are promising and descriptive. The satisfactory results r2p = 0.845, Q2(LOO) = 0.861, r2(L25%O) = 0.829, RMSE(LOO)  = 0.305 and RMSE(L25%O)  = 0.336) demonstrate that shuffling CART-ANFIS models present the relationship between human neutrophil elastase inhibitor activity and molecular descriptors, and they yield predictions in excellent agreement with the experimental values.

  6. Design and Fabrication of Multifunctional Sericin Nanoparticles for Tumor Targeting and pH-Responsive Subcellular Delivery of Cancer Chemotherapy Drugs.

    Science.gov (United States)

    Huang, Lei; Tao, Kaixiong; Liu, Jia; Qi, Chao; Xu, Luming; Chang, Panpan; Gao, Jinbo; Shuai, Xiaoming; Wang, Guobin; Wang, Zheng; Wang, Lin

    2016-03-01

    The severe cytotoxicity of cancer chemotherapy drugs limits their clinical applications. Various protein-based nanoparticles with good biocompatibility have been developed for chemotherapy drug delivery in hope of reducing drugs' side effects. Sericin, a natural protein from silk, has no immunogenicity and possesses diverse bioactivities that have prompted sericin's application studies. However, the potential of sericin as a multifunctional nanoscale vehicle for cancer therapy have not been fully explored. Here we report the successful fabrication and characterization of folate-conjugated sericin nanoparticles with cancer-targeting capability for pH-responsive release of doxorubicin (these nanoparticles are termed "FA-SND"). DOX is covalently linked to sericin through pH-sensitive hydrazone bonds that render a pH-triggered release property. The hydrophobicity of DOX and the hydrophilicity of sericin promote the self-assembly of sericin-DOX (SND) nanoconjugates. Folate (FA) is then covalently grafted to SND nanoconjugates as a binding unit for actively targeting cancer cells that overexpress folate receptors. Our characterization study shows that FA-SND nanoparticles exhibit negative surface charges that would reduce nonspecific clearance by circulation. These nanoparticles possess good cytotoxicity and hemocompatibiliy. Acidic environment (pH 5.0) triggers effective DOX release from FA-SND, 5-fold higher than does a neutral condition (pH 7.4). Further, FA-SND nanoparticles specifically target folate-receptor-rich KB cells, and endocytosed into lysosomes, an acidic organelle. The acidic microenvironment of lysosomes promotes a rapid release of DOX to nuclei, producing cancer specific chemo-cytotoxicity. Thus, FA-mediated cancer targeting and lysosomal-acidity promoting DOX release, two sequentially-occurring cellular events triggered by the designed components of FA-SND, form the basis for FA-SND to achieve its localized and intracellular chemo

  7. Bioresponsive matrices in drug delivery

    Directory of Open Access Journals (Sweden)

    Ye George JC

    2010-11-01

    Full Text Available Abstract For years, the field of drug delivery has focused on (1 controlling the release of a therapeutic and (2 targeting the therapeutic to a specific cell type. These research endeavors have concentrated mainly on the development of new degradable polymers and molecule-labeled drug delivery vehicles. Recent interest in biomaterials that respond to their environment have opened new methods to trigger the release of drugs and localize the therapeutic within a particular site. These novel biomaterials, usually termed "smart" or "intelligent", are able to deliver a therapeutic agent based on either environmental cues or a remote stimulus. Stimuli-responsive materials could potentially elicit a therapeutically effective dose without adverse side effects. Polymers responding to different stimuli, such as pH, light, temperature, ultrasound, magnetism, or biomolecules have been investigated as potential drug delivery vehicles. This review describes the most recent advances in "smart" drug delivery systems that respond to one or multiple stimuli.

  8. Assisted delivery with forceps

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/patientinstructions/000509.htm Assisted delivery with forceps To use the sharing features on ... called vacuum assisted delivery . When is a Forceps Delivery Needed? Even after your cervix is fully dilated ( ...

  9. Vaginal delivery - discharge

    Science.gov (United States)

    Pregnancy - discharge after vaginal delivery ... return in: 4 to 9 weeks after your delivery if you're not breastfeeding 3 to 12 ... can start sexual activity around 6 weeks after delivery, if the discharge or lochia has stopped. Women ...

  10. A novel needleless liquid jet injection methodology for improving direct cardiac gene delivery: An optimization of parameters, AAV mediated therapy and investigation of host responses in ischemic heart failure

    Science.gov (United States)

    Fargnoli, Anthony Samuel

    Heart disease remains the leading cause of mortality and morbidity worldwide, with 22 million new patients diagnosed annually. Essentially, all present therapies have significant cost burden to the healthcare system, yet fail to increase survival rates. One key employed strategy is the genetic reprogramming of cells to increase contractility via gene therapy, which has advanced to Phase IIb Clinical Trials for advanced heart failure patients. It has been argued that the most significant barrier preventing FDA approval are resolving problems with safe, efficient myocardial delivery, whereby direct injection in the infarct and remote tissue areas is not clinically feasible. Here, we aim to: (1) Improve direct cardiac gene delivery through the development of a novel liquid jet device approach (2) Compare the new method against traditional IM injection with two different vector constructions and evaluate outcome (3) Evaluate the host response resulting from both modes of direct cardiac injection, then advance a drug/gene combination with controlled release nanoparticle formulations.

  11. SMS text pre-notification and delivery of reminder e-mails to increase response rates to postal questionnaires in the SUSPEND trial: a factorial design, randomised controlled trial.

    Science.gov (United States)

    Starr, Kathryn; McPherson, Gladys; Forrest, Mark; Cotton, Seonaidh C

    2015-07-08

    Patient-reported outcomes are vital in informing randomised controlled trials (RCTs) and health-care interventions and policies from the patient's perspective. However, participant non-response may introduce bias and can affect the generalisability of the trial. This study evaluates two interventions aimed at increasing response rates to postal questionnaires within a large, UK-wide RCT: pre-notification via short messenger service (SMS) text prior to sending the initial mailing of trial questionnaires versus no pre-notification; for non-responders to the initial mailing of the questionnaires, an e-mail reminder (containing a hyperlink to complete the questionnaire online) versus a postal reminder. This study is a 2 × 2 partial factorial design RCT nested within an RCT of medical expulsive therapy for ureteric stone disease. Participants who supplied a mobile telephone number were randomly assigned to receive an SMS text pre-notification of questionnaire delivery or no pre-notification. Those who supplied an e-mail address were randomly assigned to receive a questionnaire reminder by e-mail or post. Participants could be randomly assigned to the pre-notification comparison or the reminder comparison or both. The primary outcome measure was response rate at each questionnaire time point. Four hundred eighteen participants were randomly assigned to the SMS pre-notification comparison (80% were male, and the mean age was 41 years with a standard deviation (SD) of 11.1). The intervention had no effect on response rate at either questionnaire time point. In subgroup analyses, SMS pre-notification increased response rates in women but only at the first questionnaire time point. One hundred nineteen participants were randomly assigned to the reminder comparison (80% were male, and the mean age was 42 years with an SD of 12.1). There was no difference in response rate in those who received an e-mail reminder compared with those who received a postal reminder. SMS text pre

  12. Biological Mechanisms Underlying the Ultraviolet Radiation-Induced Formation of Skin Wrinkling and Sagging I: Reduced Skin Elasticity, Highly Associated with Enhanced Dermal Elastase Activity, Triggers Wrinkling and Sagging

    Science.gov (United States)

    Imokawa, Genji; Ishida, Koichi

    2015-01-01

    The repetitive exposure of skin to ultraviolet B (UVB) preferentially elicits wrinkling while ultraviolet A (UVA) predominantly elicits sagging. In chronically UVB or UVA-exposed rat skin there is a similar tortuous deformation of elastic fibers together with decreased skin elasticity, whose magnitudes are greater in UVB-exposed skin than in UVA-exposed skin. Comparison of skin elasticity with the activity of matrix metalloproteinases (MMPs) in the dermis of ovariectomized rats after UVB or UVA irradiation demonstrates that skin elasticity is more significantly decreased in ovariectomized rats than in sham-operated rats, which is accompanied by a reciprocal increase in elastase activity but not in the activities of collagenases I or IV. Clinical studies using animal skin and human facial skin demonstrated that topical treatment with a specific inhibitor or an inhibitory extract of skin fibroblast-derived elastase distinctly attenuates UVB and sunlight-induced formation of wrinkling. Our results strongly indicated that the upregulated activity of skin fibroblast-derived elastase plays a pivotal role in wrinkling and/or sagging of the skin via the impairment of elastic fiber configuration and the subsequent loss of skin elasticity. PMID:25856675

  13. Biocompatible chitosan nanoparticles as an efficient delivery vehicle for Mycobacterium tuberculosis lipids to induce potent cytokines and antibody response through activation of γδ T cells in mice

    Science.gov (United States)

    Das, Ishani; Padhi, Avinash; Mukherjee, Sitabja; Dash, Debi P.; Kar, Santosh; Sonawane, Avinash

    2017-04-01

    The activation of cell-mediated and humoral immune responses to Mycobacterium tuberculosis (Mtb) is critical for protection against the pathogen and nanoparticle-mediated delivery of antigens is a more potent way to induce different immune responses. Herein, we show that mice immunized with Mtb lipid-bound chitosan nanoparticles (NPs) induce secretion of prominent type-1 T-helper (Th-1) and type-2 T-helper (Th-2) cytokines in lymph node and spleen cells, and also induces significantly higher levels of IgG, IgG1, IgG2 and IgM in comparison to control mice. Furthermore, significantly enhanced γδ-T-cell activation was observed in lymph node cells isolated from mice immunized with Mtb lipid-coated chitosan NPs as compared to mice immunized with chitosan NPs alone or Mtb lipid liposomes. In comparison to CD8+ cells, significantly higher numbers of CD4+ cells were present in both the lymph node and spleen cells isolated from mice immunized with Mtb lipid-coated chitosan NPs. In conclusion, this study represents a promising new strategy for the efficient delivery of Mtb lipids using chitosan NPs to trigger an enhanced cell-mediated and antibody response against Mtb lipids.

  14. Buccal and sublingual vaccine delivery.

    Science.gov (United States)

    Kraan, Heleen; Vrieling, Hilde; Czerkinsky, Cecil; Jiskoot, Wim; Kersten, Gideon; Amorij, Jean-Pierre

    2014-09-28

    Because of their large surface area and immunological competence, mucosal tissues are attractive administration and target sites for vaccination. An important characteristic of mucosal vaccination is its ability to elicit local immune responses, which act against infection at the site of pathogen entry. However, mucosal surfaces are endowed with potent and sophisticated tolerance mechanisms to prevent the immune system from overreacting to the many environmental antigens. Hence, mucosal vaccination may suppress the immune system instead of induce a protective immune response. Therefore, mucosal adjuvants and/or special antigen delivery systems as well as appropriate dosage forms are required in order to develop potent mucosal vaccines. Whereas oral, nasal and pulmonary vaccine delivery strategies have been described extensively, the sublingual and buccal routes have received considerably less attention. In this review, the characteristics of and approaches for sublingual and buccal vaccine delivery are described and compared with other mucosal vaccine delivery sites. We discuss recent progress and highlight promising developments in the search for vaccine formulations, including adjuvants and suitable dosage forms, which are likely critical for designing a successful sublingual or buccal vaccine. Finally, we outline the challenges, hurdles to overcome and formulation issues relevant for sublingual or buccal vaccine delivery. Copyright © 2014. Published by Elsevier B.V.

  15. Future of Automated Insulin Delivery Systems

    NARCIS (Netherlands)

    Castle, Jessica R.; DeVries, J. Hans; Kovatchev, Boris

    2017-01-01

    Advances in continuous glucose monitoring (CGM) have brought on a paradigm shift in the management of type 1 diabetes. These advances have enabled the automation of insulin delivery, where an algorithm determines the insulin delivery rate in response to the CGM values. There are multiple automated

  16. Factors associated with delivery at or after 28 weeks gestation in women with bulging fetal membranes before 26 weeks gestation.

    Science.gov (United States)

    Ito, Akiko; Maseki, Yoshiaki; Ikeda, Sayako; Tezuka, Atsuko; Kuribayashi, Momoko; Furuhashi, Madoka

    2017-09-01

    To elucidate the factors that contribute to prolonged pregnancy and promote neonate survival in women with bulging fetal membranes. A database was reviewed to identify women with singleton pregnancies who underwent amniocentesis on admission to determine amniotic fluid neutrophil elastase levels before 26 + 0 weeks gestation between July 2001 and January 2015. Following delivery, the placentas of these patients were examined for histologic chorioamnionitis. Ninety-seven women delivered before 28 weeks gestation, and 117 women delivered at or after 28 weeks gestation. Rescue cerclage performed via the McDonald procedure (adjusted odds ratio [aOR]: 3.78; 95% confidence interval [CI]: 1.35-11.80) was associated with a higher likelihood of reaching at least 28 weeks gestation before delivery, whereas protruding membranes (aOR: 0.38; 95% CI: 0.18-0.78), elevated amniotic neutrophil elastase levels (≥0.15 μg/ml) (aOR, 0.41; 95% CI: 0.20-0.82) and elevated peripheral C-reactive protein levels (≥0.4 mg/dl) (aOR: 0.34; 95% CI: 0.180.65) were associated with a significantly reduced likelihood of reaching this gestational age before delivery. Among women who underwent rescue cerclage, amniorrhexis was associated with a negative prognosis (aOR: 0.18; 95% CI: 0.05-0.51). Intra-amniotic inflammation, protrusion of fetal membranes and amniorrhexis are factors that may prevent pregnancy prolongation. Rescue cerclage improves pregnancy outcomes.

  17. Keratinocyte Growth Factor Gene Electroporation into Skeletal Muscle as a Novel Gene Therapeutic Approach for Elastase-Induced Pulmonary Emphysema in Mice

    International Nuclear Information System (INIS)

    Tobinaga, Shuichi; Matsumoto, Keitaro; Nagayasu, Takeshi; Furukawa, Katsuro; Abo, Takafumi; Yamasaki, Naoya; Tsuchiya, Tomoshi; Miyazaki, Takuro; Koji, Takehiko

    2015-01-01

    Pulmonary emphysema is a progressive disease with airspace destruction and an effective therapy is needed. Keratinocyte growth factor (KGF) promotes pulmonary epithelial proliferation and has the potential to induce lung regeneration. The aim of this study was to determine the possibility of using KGF gene therapy for treatment of a mouse emphysema model induced by porcine pancreatic elastase (PPE). Eight-week-old BALB/c male mice treated with intra-tracheal PPE administration were transfected with 80 μg of a recombinant human KGF (rhKGF)-expressing FLAG-CMV14 plasmid (pKGF-FLAG gene), or with the pFLAG gene expressing plasmid as a control, into the quadriceps muscle by electroporation. In the lung, the expression of proliferating cell nuclear antigen (PCNA) was augmented, and surfactant protein A (SP-A) and KGF receptor (KGFR) were co-expressed in PCNA-positive cells. Moreover, endogenous KGF and KGFR gene expression increased significantly by pKGF-FLAG gene transfection. Arterial blood gas analysis revealed that the PaO 2 level was not significantly reduced on day 14 after PPE instillation with pKGF-FLAG gene transfection compared to that of normal mice. These results indicated that KGF gene therapy with electroporation stimulated lung epithelial proliferation and protected depression of pulmonary function in a mouse emphysema model, suggesting a possible method of treating pulmonary emphysema

  18. The System of Neutrophil Elastase and the Plasma Level of MMP-7 in Children with Pulmonary Arterial Hypertension and Chronic Cor Pulmonale

    Directory of Open Access Journals (Sweden)

    Еlena M. Vasilyeva

    2014-03-01

    Full Text Available A significant increase in the activity of neutrophil elastase (NE and anti-NE-protection in the plasma were detected in children having bronchopulmonary dysplasia (BPD complicated by pulmonary arterial hypertension (PAH and chronic cor pulmonale (CCP. The changes revealed were more pronounced in patients with CCP. The plasma concentration of the NE was slightly reduced, which was probably associated with the activation of anti-NE and an increase in the α1-antitrypsin level. A gradual increase was noted in the plasma level of the matrix metalloproteinase-7 (MMP-7 in patients with an increase in the severity of the condition. In patients with cystic fibrosis (with and without CCP, the pronounced increase in the MMP-7 level was observed. In patients with cystic fibrosis (CF, even without the additional complication with PAH and CCP, the MMP-7 level was significantly higher than in those with congenital broncho-pulmonary malformations (CBPM. The difference was increased in those patients with PAH and reached a maximum in those with CCP.

  19. pH-responsive CAP-co-poly(methacrylic acid)-based hydrogel as an efficient platform for controlled gastrointestinal delivery: fabrication, characterization, in vitro and in vivo toxicity evaluation.

    Science.gov (United States)

    Shah, Syed Ahmed; Sohail, Muhammad; Minhas, Muhammad Usman; Nisar-Ur-Rehman; Khan, Shahzeb; Hussain, Zahid; Mudassir; Mahmood, Arshad; Kousar, Mubeen; Mahmood, Asif

    2018-02-15

    Cellulose acetate phthalate-based pH-responsive hydrogel was synthesized for fabrication of polymeric matrix tablets for gastro-protective delivery of loxoprofen sodium. Cellulose acetate phthalate (CAP) was cross-linked with methacrylic acid (MAA) using free radical polymerization technique. Fourier transform infrared (FTIR) spectra confirmed the formation of cross-linked structure of CAP-co-poly(methacrylic acid). Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) confirmed the thermal stability of polymeric networks, and scanning electron microscopy (SEM) and energy-dispersive X-ray spectrum (EDS) images unveiled that the prepared formulations were porous in nature and thus the developed formulations had shown better diffusibility. Swelling and in vitro drug release was performed at various pHs and maximum swelling and release was obtained at pH 7.4, while swelling and release rate was very low at pH 1.2 which confirmed the pH-responsive behavior of CAP-co-poly(MAA). CAP-co-poly(MAA) copolymer prevents the release of loxoprofen sodium into the stomach due to reduced swelling at gastric pH while showing significant swelling and drug release in the colon. Cytotoxicity studies revealed higher biocompatibility of fabricated hydrogel. Acute oral toxicity studies were performed for the evaluation and preliminary screening of safety profile of the developed hydrogels. Matrix tablets were evaluated for release behavior at simulated body pH. The investigations performed for analysis of hydrogels and fabricated matrix tablets indicated the controlled drug release and gastro-protective drug delivery of CAP-co-poly(MAA) hydrogels and pH-sensitive matrix tablets for targeted delivery of gastro-sensitive/irritative agents. Graphical abstract ᅟ.

  20. Fabrication of Reductive-Responsive Prodrug Nanoparticles with Superior Structural Stability by Polymerization-Induced Self-Assembly and Functional Nanoscopic Platform for Drug Delivery.

    Science.gov (United States)

    Zhang, Wen-Jian; Hong, Chun-Yan; Pan, Cai-Yuan

    2016-09-12

    A highly efficient strategy, polymerization-induced self-assembly (PISA) for fabrication of the polymeric drug delivery systems in cancer chemotherapy is reported. Diblock prodrug copolymer, PEG-b-P(MEO2MA-co-CPTM) was used as the macro-RAFT agent to fabricate prodrug nanoparticles through PISA. The advantages of fabricating intelligent drug delivery system via this approach are as following: (1) Simultaneous fulfillment of polymerization, self-assembly, and drug encapsulation in one-pot at relatively high concentration (100 mg/mL); (2) Almost complete monomer conversion allows direct application of the resultant prodrug nanoparticles without further purification; (3) Robust structures of the resultant prodrug nanoparticles, because the cross-linker was used as the comonomer, resulted in core-cross-linking simultaneously with the formation of the prodrug nanoparticles; (4) The drug content in the resultant prodrug nanoparticles can be accurately modulated just via adjusting the feed molar ratio of MEO2MA/CPTM in the synthesis of PEG-b-P(MEO2MA-co-CPTM). The prodrug nanoparticles with similar diameters but various drug contents were obtained using different prodrug macro-CTA. In consideration of the long-term biological toxicity, the prodrug nanoparticles with higher drug content exhibit more excellent anticancer efficiency due to that lower dosage of them are enough for effectively killing HeLa cells.

  1. Folate-decorated PEGylated triblock copolymer as a pH/reduction dual-responsive nanovehicle for targeted intracellular co-delivery of doxorubicin and Bcl-2 siRNA.

    Science.gov (United States)

    Suo, Aili; Qian, Junmin; Xu, Minghui; Xu, Weijun; Zhang, Yaping; Yao, Yu

    2017-07-01

    Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a single nanovehicle has emerged as a promising combination therapy approach to treating cancers because of their synergistic effect. Nanocarrier delivery systems with low cytotoxicity and high efficiency are needed for such a purpose. In this study, a novel folate-conjugated PEGylated cationic triblock copolymer, poly(acrylhydrazine)-block-poly(3-dimethylaminopropyl methacrylamide)-block-poly(acrylhydrazine) (PAH-b-PDMAPMA-b-PAH), was synthesized and evaluated as a stimuli-sensitive vehicle for the targeted co-delivery of doxorubicin (DOX) and Bcl-2 siRNA into breast cancer MCF-7 cells. The synthetic process of the PEGylated triblock copolymer involved sequential reversible addition-fragmentation chain transfer polymerization, PEGylation and removal of tert-butoxy carbamate protecting groups. Folate-conjugated and/or -unconjugated poly(ethylene glycol) segments were grafted onto PAH-b-PDMAPMA-b-PAH via a reduction-sensitive disulfide linkage. The synthetic polymers were characterized by 1 H NMR and gel permeation chromatography. The PEGylated triblock copolymer could chemically conjugate DOX onto PAH blocks via pH-responsive hydrazone bonds and simultaneously complex negatively charged Bcl-2 siRNA with cationic PDMAPMA blocks through electrostatic interactions at N/P ratios≥32:1 to form multifunctional nanomicelleplexes. The nanomicelleplexes exhibited spherical shape, possessed a positively charged surface with a zeta potential of +22.5mV and had a desirable and uniform particle size of 187nm. In vitro release studies revealed that the nanomicelleplexes could release DOX and Bcl-2 siRNA in a reduction and pH dual-sensitive manner and the payload release was significantly enhanced in a reductive acidic environment mimicking the endosomes/lysosomes of cancer cells compared to under physiology conditions. Furthermore, the release of both DOX and siRNA was found to follow Higuchi kinetic

  2. Temperature-responsive and biodegradable PVA:PVP k30:poloxamer 407 hydrogel for controlled delivery of human growth hormone (hGH).

    Science.gov (United States)

    Taheri, Azade; Atyabi, Fatemeh; Dinarvnd, Rassoul

    2011-01-01

    Recombinant human growth hormone (rhGH) is used for replacement therapy of pediatric hypopituitary dwarfism. Growth rate in children was observed to be better on the daily injection schedule compared with the currently used therapeutic regimen of thrice a week injection. Thus, a controlled release formulation would overcome the drawback of traditional rhGH therapy such as the need for multiple injections. Poloxamers are a family of triblock copolymers consisting of two hydrophilic blocks of polyoxyethylene separated by a hydrophobic block of polyoxypropylene, which form micelles at low concentrations and form clear thermally reversible gels at high concentrations. We used poloxamer gels to develop a controlled release formulation of hGH. The objective of this study was to develop an in situ gel forming drug delivery system for hGH using the minimum possible ratio of poloxamer 407 (P407). Decreasing the concentration of poloxamer could reduce the risk of hypertriglyceridemia induction. Different additives were added to the poloxamer formulations. It was observed that among different additives polyvinylpyrrolidone k30 (PVP k30) and polyvinyl alcohol (PVA) decrease poloxamer concentration required to form in situ gelation from 18% to 10%. The dynamic viscoelastic properties of the samples were determined. Both the storage modulus and the loss modulus of the samples increased abruptly as the temperature passed a certain point. It can be concluded that combining P407 and PVP and PVA could be a promising strategy for preparation of thermally reversible in situ gel forming delivery systems of hGH with low poloxamer concentration.

  3. Accuracy of maternal recall of birth weight and selected delivery ...

    African Journals Online (AJOL)

    mr. faki

    birth weight data. This study was carried out to determine recall of birth weight and delivery complications among mothers in Unguja West District of Zanzibar. Methods: .... Considering confidence level of 95% and response rate of 90%, the ... delivery, delivery complications, child's birth date, birth's order and birth weight.

  4. eDelivery

    Data.gov (United States)

    US Agency for International Development — eDelivery provides the electronic packaging and delivery of closed and complete OPM investigation files to government agencies, including USAID, in a secure manner....

  5. Vacuum-assisted delivery

    Science.gov (United States)

    ... medlineplus.gov/ency/patientinstructions/000514.htm Vacuum-assisted delivery To use the sharing features on this page, ... through the birth canal. When is Vacuum-assisted Delivery Needed? Even after your cervix is fully dilated ( ...

  6. Delivery by Cesarean Section

    Science.gov (United States)

    ... Stages Listen Español Text Size Email Print Share Delivery by Cesarean Section Page Content Article Body More ... mother has had a previous baby by Cesarean delivery The obstetrician feels that the baby’s health might ...

  7. Recent Patents in Pulmonary Delivery of Macromolecules.

    Science.gov (United States)

    Ray, Animikh; Mandal, Abhirup; Mitra, Ashim K

    2015-01-01

    Pulmonary delivery is a non-invasive form of delivery that holds tremendous therapeutic promise for topical and systemic administration of several macromolecules. Oral administration of macromolecules has several limitations such as low bioavailability, degradation of drug before reaching circulation and insufficient absorption across intestinal membrane. Administration of macromolecules such as proteins, peptides and nucleic acids via inhalation offers great potential due to the avoidance of first pass metabolism, higher surface area and rapid clinical response. However, delivery of reproducible, uniform and safe doses of inhaled particles remains a major challenge for clinical translation. Recent advances in the fields of biotechnology and particle engineering led to progress in novel pulmonary drug delivery systems. Moreover, significant developments in carriers and delivery devices prevent denaturation of macromolecules and control their release within the lungs. This article reviews the advances in pulmonary drug delivery systems by focusing on the recent patents in delivery of macromolecules. Furthermore, recent patents in gene delivery to the lungs have also been discussed. List of patents included in this review is comprehensive in terms of pulmonary delivery of therapeutics. It includes inventions related to proteins and peptides, DNA therapeutics, siRNA and other genetic materials with therapeutic applications. The diseases targeted by these therapeutic molecules are varied including but not limited to different forms of cancer, respiratory diseases etc.

  8. Articulating feedstock delivery device

    Science.gov (United States)

    Jordan, Kevin

    2013-11-05

    A fully articulable feedstock delivery device that is designed to operate at pressure and temperature extremes. The device incorporates an articulating ball assembly which allows for more accurate delivery of the feedstock to a target location. The device is suitable for a variety of applications including, but not limited to, delivery of feedstock to a high-pressure reaction chamber or process zone.

  9. Evaluation of the ability of N-terminal fragment of lethal factor of Bacillus anthracis for delivery of Mycobacterium T cell antigen ESAT-6 into cytosol of antigen presenting cells to elicit effective cytotoxic T lymphocyte response

    International Nuclear Information System (INIS)

    Chandra, Subhash; Kaur, Manpreet; Midha, Shuchi; Bhatnagar, Rakesh; Banerjee-Bhatnagar, Nirupama

    2006-01-01

    We report the ability of N-terminal fragment of lethal factor of Bacillus anthracis to deliver genetically fused ESAT-6 (early secretory antigen target), a potent T cell antigen of Mycobacterium tuberculosis, into cytosol to elicit Cytotoxic T lymphocyte (CTL) response. In vitro Th1 cytokines data and CTL assay proved that efficient delivery of LFn.ESAT-6 occurs in cytosol, in the presence of protective antigen (PA), and leads to generation of effective CTL response. Since CTL response is essential for protection against intracellular pathogens and, it is well known that only single T cell epitope or single antigenic protein is not sufficient to elicit protective CTL response due to variation or polymorphism in MHC-I alleles among the individuals, we suggest that as a fusion protein LFn can be used to deliver multiepitopes of T cells or multiproteins which can generate effective CTLs against intracellular pathogens like M. tuberculosis. It can be used to enhance the protective efficacy of BCG vaccine

  10. Immunologic responses of bison to vaccination with Brucella abortus strain RB51: comparison of parenteral to ballistic delivery via compressed pellets or photopolymerized hydrogels.

    Science.gov (United States)

    Olsen, Steven C; Christie, R J; Grainger, D W; Stoffregen, W S

    2006-02-27

    This study compared responses of bison calves to 10(10)CFU of Brucella abortus strain RB51 (SRB51) delivered by parenteral or ballistic methods. Two types of biobullet payloads were evaluated; compacted SRB51 pellets or SRB51 encapsulated in photopolymerized poly(ethylene glycol) hydrogels. Bison were vaccinated with saline, parenteral SRB51 alone, or in combination with Spirovac, or ballistically with compressed SRB51 or hydrogel biobullets. Bison parenterally vaccinated with SRB51 had greater (P<0.05) immunologic responses when compared to control bison. Co-administration of Spirovac as an adjuvant did not influence immunologic responses. As compared to compressed SRB51 biobullets, ballistic vaccination with hydrogel biobullets increased cellular immune responses at some sampling times. Our data suggest that hydrogel formulations of SRB51 may be a superior alternative to compressed SRB51 tablets for ballistic vaccination of bison. Although preliminary, data suggests that immunologic responses of bison to SRB51 hydrogel bullets are similar to responses after parenteral vaccination with SRB51.

  11. Synthesis, Characterization, and Application in HeLa Cells of an NIR Light Responsive Doxorubicin Delivery System Based on NaYF4:Yb,Tm@SiO2-PEG Nanoparticles.

    Science.gov (United States)

    Alonso-Cristobal, Paulino; Oton-Fernandez, Olalla; Mendez-Gonzalez, Diego; Díaz, J Fernando; Lopez-Cabarcos, Enrique; Barasoain, Isabel; Rubio-Retama, Jorge

    2015-07-15

    Herein, we present a phototriggered drug delivery system based on light responsive nanoparticles, which is able to release doxorubicin upon NIR light illumination. The proposed system is based on upconversion fluorescence nanoparticles of β-NaYF4:Yb,Tm@SiO2-PEG with a mean diameter of 52±2.5 nm that absorb the NIR light and emit UV light. The UV radiation causes the degradation of photodegradable ortho-nitrobenzyl alcohol derivates, which are attached on one side to the surface of the nanoparticles and on the other to doxorubicin. This degradation triggers the doxorubicin release. This drug delivery system has been tested "in vitro" with HeLa cells. The results of this study demonstrated that this system caused negligible cytotoxicity when they were not illuminated with NIR light. In contrast, under NIR light illumination, the HeLa cell viability was conspicuously reduced. These results demonstrated the suitability of the proposed system to control the release of doxorubicin via an external NIR light stimulus.

  12. Evaluation of occurring complications after flow diverter treatment of elastase-induced aneurysm in rabbits using micro-CT and MRI at 9.4 T

    Energy Technology Data Exchange (ETDEWEB)

    Simgen, Andreas; Ley, Desiree; Muehl-Benninghaus, Ruben; Koerner, Heiko; Reith, Wolfgang; Yilmaz, Umut [Saarland University Hospital, Department of Neuroradiology, Homburg, Saar (Germany); Roth, Christian [Clinic Bremen-Mitte, Department of Neuroradiology, Bremen (Germany); Cattaneo, Giorgio Franco Maria [Acandis GmbH, Pforzheim (Germany); Mueller, Andreas [Saarland University Hospital, Department of Experimental Surgery, Homburg, Saar (Germany); Kim, Yoo-Jin [Saarland University Hospital, Department of Pathology, Homburg, Saar (Germany); Scheller, Bruno [Saarland University Hospital, Department of Cardiology, Homburg, Saar (Germany)

    2016-10-15

    Flow diverters are increasingly being used to treat intracranial aneurysms. This study evaluates occurring complications of flow-diverting devices in the treatment of experimental aneurysms, involving the use of micro-CT and small animal MRI at 9.4 T, in correlation to angiographic and histological findings. We previously published two preclinical studies, in which we assessed two different flow diverters in the treatment of elastase-induced aneurysms. Devices have been implanted across the aneurysm neck as well as in the abdominal aorta. From these studies, a total of 65 devices (prototype FD (n = 30) and Derivo embolization device (n = 35)) additionally underwent micro-CT and MRI after angiographic follow-up and before being histologically examined. The different architectures of both devices were precisely comparable due to high-resolution micro-CT imaging. Micro-CT revealed wire fractures in nine cases (30 %) only with the prototype FD. In three cases (10 %), severe wire fractures correlated with an in-stent stenosis due to intimal hyperplasia. Other complications, like distal stent occlusions and post-stent stenosis, were seen in both groups and verified with both imaging techniques. Osseous metaplasia were correlated to calcifications seen with micro-CT. MRI enabled visualization of the position of the implanted devices relative to the aneurysm and revealed incomplete aneurysm neck coverage with the prototype FD in two cases (6.7 %). Micro-CT and 9.4-T MRI are valid to discover and understand occurring complications of flow diverters in the preclinical phase and can serve as evaluation tools to minimize complication rates of endovascular devices in the future. (orig.)

  13. Assessment of systemic inflammation by time-trends of blood granulocyte count and plasma myeloperoxidase and elastase concentrations following colic surgery in horses.

    Science.gov (United States)

    Salciccia, Alexandra; Grulke, Sigrid; de la Rebière de Pouyade, Geoffroy; Franck, Thierry; Detilleux, Johann; Serteyn, Didier; Sandersen, Charlotte

    2016-07-01

    To determine changes in blood granulocyte counts and in plasma myeloperoxidase (MPO) and elastase (ELT) concentrations in surgical colic cases, and to determine the relationship between these changes and the surgical procedure performed, occurrence of postoperative ileus, and final outcome. Prospective clinical study conducted over a 12-month period. University teaching hospital. Fifty-three horses undergoing emergency laparotomy and surviving at least 12 hours postoperatively. Blood samples were taken before surgery, during surgery, at the recovery from anesthesia, and then serially until the 150th hour after the first blood sampling. Granulocyte counts were performed by an automated cell hematology analyzer. Specific ELISAs were performed for the MPO and ELT measurements. Mixed models were used to compare the time-trends of the 3 parameters. Taking all horses together, the time-trends of MPO and ELT were not significantly different from each other, but they were significantly different from the granulocyte time-trend. The type of surgical procedure did not influence the time-trends of the 3 parameters. Significant changes in the granulocyte time-trends were associated with postoperative ileus and outcome. Significant changes in the MPO time-trends were associated with outcome. The ELT time-trends were not influenced by ileus or outcome. Granulocyte counts and MPO change over time and are related to the severity of the inflammatory reaction in surgical colic cases. These time-trends may allow evaluation of treatment efficacy in an effort to modulate excessive granulocyte activation and degranulation. © Veterinary Emergency and Critical Care Society 2016.

  14. Results from in vitro and ex vivo skin aging models assessing the antiglycation and anti-elastase MMP-12 potential of glycylglycine oleamide

    Directory of Open Access Journals (Sweden)

    Bogdanowicz P

    2016-06-01

    Full Text Available Patrick Bogdanowicz, Marie-José Haure, Isabelle Ceruti, Sandrine Bessou-Touya, Nathalie Castex-Rizzi Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse, France Background: Glycation is an aging reaction of naturally occurring sugars with dermal proteins. Type I collagen and elastin are most affected by glycation during intrinsic chronological aging. Aim: To study the in vitro and ex vivo assays in human skin cells and explants and the antiaging effects of glycylglycine oleamide (GGO. Materials and methods: The antiglycation effect of GGO was assessed in a noncellular in vitro study on collagen and, ex vivo, by immunohistochemical staining on human skin explants (elastin network glycation. The ability of GGO to contract fibroblasts was assessed in a functional assay, and its anti-elastase (MMP-12 activity was compared to that of oleic acid alone, glycylglycine (GG alone, and oleic acid associated with GG. Results: In vitro, GGO reduced the glycation of type I collagen. Ex vivo, GGO restored the expression of fibrillin-1 inhibited by glycation. Furthermore, GGO induced a tissue retraction of almost 30%. Moreover, the MMP-12 activity was inhibited by up to 60%. Conclusion: Under the present in vitro and ex vivo conditions, GGO prevents glycation of the major structural proteins of the dermis, helping to reduce the risk of rigidification. By maintaining the elastic function of the skin, GGO may be a promising sparring partner for other topical antiaging agents. Keywords: extracellular matrix, glycylglycine oleamide, glycation, fibrillin-1, matrix metalloproteinase-12, skin aging

  15. Duox2-induced innate immune responses in the respiratory epithelium and intranasal delivery of Duox2 DNA using polymer that mediates immunization.

    Science.gov (United States)

    Jeon, Yung Jin; Kim, Hyun Jik

    2018-03-30

    Respiratory mucosa especially nasal epithelium is well known as the first-line barrier of air-borne pathogens. High levels of reactive oxygen species (ROS) are detected in in vitro cultured human epithelial cells and in vivo lung. With identification of NADPH oxidase (Nox) system of respiratory epithelium, the antimicrobial role of ROS has been studied. Duox2 is the most abundant Nox isoform and produces the regulated amount of ROS in respiratory epithelium. Duox2-derived ROS are involved in antiviral innate immune responses but more studies are needed to verify the mechanism. In respiratory epithelium, Duox2-derived ROS is critical for recognition of virus through families retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) at the early stage of antiviral innate immune responses. Various secreted interferons (IFNs) play essential roles for antiviral host defense by downstream cell signaling, and transcription of IFN-stimulated genes is started to suppress viral replication. Type I and type III IFNs are verified more responsible for influenza A virus (IAV) infection in respiratory epithelium and Duox2 is required to regulate IFN-related immune responses. Transient overexpression of Duox2 using cationic polymer polyethylenimine (PEI) induces secretion of type I and type III IFNs and significantly attenuated IAV replication in respiratory epithelium. Here, we discuss Duox2-mediated antiviral innate immune responses and the role of Duox2 as a mucosal vaccine to resist respiratory viral infection.

  16. UAV Delivery Monitoring System

    Directory of Open Access Journals (Sweden)

    San Khin Thida

    2018-01-01

    Full Text Available UAV-based delivery systems are increasingly being used in the logistics field, particularly to achieve faster last-mile delivery. This study develops a UAV delivery system that manages delivery order assignments, autonomous flight operation, real time control for UAV flights, and delivery status tracking. To manage the delivery item assignments, we apply the concurrent scheduler approach with a genetic algorithm. The present paper describes real time flight data based on a micro air vehicle communication protocol (MAVLink. It also presents the detailed hardware components used for the field tests. Finally, we provide UAV component analysis to choose the suitable components for delivery in terms of battery capacity, flight time, payload weight and motor thrust ratio.

  17. Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin.

    Science.gov (United States)

    Maes, Michael; Twisk, Frank N M; Kubera, Marta; Ringel, Karl

    2012-02-01

    There is evidence that inflammatory pathways and cell-mediated immunity (CMI) play an important role in the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Activation of inflammatory and CMI pathways, including increased levels of cytokines, is known to induce fatigue and somatic symptoms. Given the broad spectrum inflammatory state in ME/CFS, the aim of this study was to examine whether inflammatory and CMI biomarkers are increased in individuals with ME/CFS. In this study we therefore measured plasma interleukin-(IL)1, tumor necrosis factor (TNF)α, and PMN-elastase, and serum neopterin and lysozyme in 107 patients with ME/CFS, 37 patients with chronic fatigue (CF), and 20 normal controls. The severity of ME/CFS was measured with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Serum IL-1, TNFα, neopterin and lysozyme are significantly higher in patients with ME/CFS than in controls and CF patients. Plasma PMN-elastase is significantly higher in patients with ME/CFS than in controls and CF patients and higher in the latter than in controls. Increased IL-1 and TNFα are significantly correlated with fatigue, sadness, autonomic symptoms, and a flu-like malaise; neopterin is correlated with fatigue, autonomic symptoms, and a flu-like malaise; and increased PMN-elastase is correlated with concentration difficulties, failing memory and a subjective experience of infection. The findings show that ME/CFS is characterized by low-grade inflammation and activation of CMI. The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flu-like malaise, may be caused by inflammatory mediators, e.g. IL-1 and TNFα. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and anti-tumor effects

    Science.gov (United States)

    Osada, Takuya; Berglund, Peter; Morse, Michael A.; Hubby, Bolyn; Lewis, Whitney; Niedzwiecki, Donna; Hobeika, Amy; Burnett, Bruce; Devi, Gayathri R.; Clay, Timothy M.; Smith, Jonathan; Lyerly, H. Kim

    2013-01-01

    We recently demonstrated that Venezuelan equine encephalitis (VEE) virus-based replicon particles (VRP) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP expressing Interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and anti-tumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)) and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12 and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing anti-tumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted. PMID:22488274

  19. A polyvalent influenza DNA vaccine applied by needle-free intradermal delivery induces cross-reactive humoral and cellular immune responses in pigs

    DEFF Research Database (Denmark)

    Borggren, Marie; Nielsen, Jens; Karlsson, Ingrid

    2016-01-01

    BACKGROUND: Pigs are natural hosts for influenza A viruses, and the infection is widely prevalent in swine herds throughout the world. Current commercial influenza vaccines for pigs induce a narrow immune response and are not very effective against antigenically diverse viruses. To control...... with the optimized DNA vaccine resulted in specific, dose-dependent immunity down to the lowest dose (200μg DNA/vaccination). Both the antibody-mediated and the recall lymphocyte immune responses demonstrated high reactivity against vaccine-specific strains and cross-reactivity to vaccine-heterologous strains...

  20. Building Stable MMP2-Responsive Multifunctional Polymeric Micelles by an All-in-One Polymer-Lipid Conjugate for Tumor-Targeted Intracellular Drug Delivery.

    Science.gov (United States)

    Yao, Qing; Dai, Zhi; Hoon Choi, Jong; Kim, Dongin; Zhu, Lin

    2017-09-27

    In this study, we described an "all-in-one" polymer-lipid conjugate (PEG2k-ppTAT-PEG1k-PE) that could self-assemble to matrix metalloproteinase 2 (MMP2)-sensitive multifunctional micelles. The assembled micelles had several key features, including a protective long chain poly(ethylene glycol) (PEG2k) (the outer shell), an MMP2-sensitive peptide linker (pp) (the tumor-targeting middle layer), a trans-activating transcriptional activator (TAT) peptide (the cell-penetrating middle layer), and a stable PEG1k-PE micelle for drug loading (the inner core). In the absence of MMP2, the PEG2k-ppTAT-PEG1k-PE micelles were intact and showed low bioactivity due to the surface-anchored PEG2k, whereas in the presence of MMP2, the pp was cleaved, resulting in the PEG2k deshielding and exposure of the previously hidden TAT for enhanced intracellular drug delivery. Even if completely cleaved by MMP2, the remaining PEG1k-PE micelles were stable and the micelles' particle size and drug release were not significantly influenced. The paclitaxel (PTX)-loaded PEG2k-ppTAT-PEG1k-PE micelles showed significant MMP2-dependent cellular uptake, tumor penetration, and anticancer activity in various cancer cells and three-dimensional multicellular spheroids. Because of the enhanced intracellular drug accumulation, these multifunctional micelles were able to sensitize the drug-resistant cancer cells and their spheroids to PTX treatments. Furthermore, in vivo tumor uptake and retention data indicated that the PEG2k-ppTAT-PEG1k-PE micelles could dramatically increase the residence time of their payloads in the tumor.

  1. Delivery of HIV care during the 2007 post-election crisis in Kenya: a case study analyzing the response of the Academic Model Providing Access to Healthcare (AMPATH) program.

    Science.gov (United States)

    Goodrich, Suzanne; Ndege, Samson; Kimaiyo, Sylvester; Some, Hosea; Wachira, Juddy; Braitstein, Paula; Sidle, John E; Sitienei, Jackline; Owino, Regina; Chesoli, Cleophas; Gichunge, Catherine; Komen, Fanice; Ojwang, Claris; Sang, Edwin; Siika, Abraham; Wools-Kaloustian, Kara

    2013-12-01

    Widespread violence followed the 2007 presidential elections in Kenya resulting in the deaths of a reported 1,133 people and the displacement of approximately 660,000 others. At the time of the crisis the United States Agency for International Development-Academic Model Providing Access to Healthcare (USAID-AMPATH) Partnership was operating 17 primary HIV clinics in western Kenya and treating 59,437 HIV positive patients (23,437 on antiretroviral therapy (ART)). This case study examines AMPATH's provision of care and maintenance of patients on ART throughout the period of disruption. This was accomplished by implementing immediate interventions including rapid information dissemination through the media, emergency hotlines and community liaisons; organization of a Crisis Response leadership team; the prompt assembly of multidisciplinary teams to address patient care, including psychological support staff (in clinics and in camps for internally displaced persons (IDP)); and the use of the AMPATH Medical Records System to identify patients on ART who had missed clinic appointments. These interventions resulted in the opening of all AMPATH clinics within five days of their scheduled post-holiday opening dates, 23,949 patient visits in January 2008 (23,259 previously scheduled), uninterrupted availability of antiretrovirals at all clinics, treatment of 1,420 HIV patients in IDP camps, distribution of basic provisions, mobilization of outreach services to locate missing AMPATH patients and delivery of psychosocial support to 300 staff members and 632 patients in IDP camps. Key lessons learned in maintaining the delivery of HIV care in a crisis situation include the importance of advance planning to develop programs that can function during a crisis, an emphasis on a rapid programmatic response, the ability of clinics to function autonomously, patient knowledge of their disease, the use of community and patient networks, addressing staff needs and developing effective

  2. Functionalization of Strongly Interacting Magnetic Nanocubes with (Thermo)responsive Coating and their Application in Hyperthermia and Heat-Triggered Drug Delivery

    KAUST Repository

    Kakwere, Hamilton

    2015-04-03

    Herein we prepare nanohybrids by incorporating iron oxide nanocubes (cubic-IONPs) within a thermo-responsive polymer shell that can act as drug carriers for doxorubicin(doxo). The cubic-shaped nanoparticles employed are at the interface between superparamagnetic and ferromagnetic behavior and have an exceptionally high specific absorption rate (SAR) but their functionalization is extremely challenging compared to bare superparamagnetic iron oxide nanoparticles as they strongly interact with each other. By conducting the polymer grafting reaction using reversible addition-fragmentation chain transfer (RAFT) polymerization in a viscous solvent medium, we have here developed a facile approach to decorate the nanocubes with stimuli-responsive polymers. When the thermo-responsive shell is composed of poly(N-isopropyl acrylamide-co-polyethylene glycolmethylether acrylate), nanohybrids have a phase transition temperature, the lower critical solution temperature (LCST), above 37 °C in physiological conditions. Doxo loaded nanohybrids exhibited a negligible drug release below 37 °C but showed a consistent release of their cargo on demand by exploiting the capability of the nanocubes to generate heat under an alternating magnetic field (AMF). Moreover, the drug free nanocarrier does not exhibit cytotoxicity even when administered at high concentration of nanocubes (1g/L of iron) and internalized at high extent (260 pg of iron per cell). We have also implemented the synthesis protocol to decorate the surface of nanocubes with poly(vinylpyridine) polymer and thus prepare pH-responsive shell coated nanocubes.

  3. Student Award for Outstanding Research Winner in the Undergraduate Category for the 2017 Society for Biomaterials Annual Meeting and Exposition, April 5-8, 2017, Minneapolis, Minnesota: Development and characterization of stimuli-responsive hydrogel microcarriers for oral protein delivery.

    Science.gov (United States)

    O'Connor, Colleen; Steichen, Stephanie; Peppas, Nicholas A

    2017-05-01

    A family of pH-responsive terpolymers composed of methacrylic acid (MAA), N-vinyl pyrrolidone (NVP), and poly(ethylene glycol) monomethylether monomethacrylate (PEGMMA) have been developed and evaluated for their pH-responsive swelling behavior, protein-loading capabilities, and cytocompatibility. These terpolymer hydrogels, designated as P((MAA-co-NVP)-g-EG), were synthesized with varying PEG chain lengths and monomer feed ratios. The incorporation of MAA into the terpolymer structure was quantified with potentiometric titration. Equilibrium and dynamic swelling studies confirmed the pH-responsive behavior of the hydrogel, with the system remaining collapsed/complexed in acidic pH conditions and swollen/decomplexed in neutral pH conditions. The ability of the hydrogels to partition protein into the swollen network was assessed for two model proteins of varying molecular weight: insulin and porcine growth hormone. Finally, the cytocompatibility of the hydrogels in the presence of two model intestinal cell lines was investigated and confirmed minimal cytotoxicity at and below 2.5 mg/mL. The developed P((MAA-co-NVP)-g-EG) hydrogels exhibit unique properties that could potentially be utilized for drug delivery and separation applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1243-1251, 2017. © 2017 Wiley Periodicals, Inc.

  4. Tumor Destruction and In Situ Delivery of Antigen Presenting Cells Promote Anti-Neoplastic Immune Responses: Implications for the Immunotherapy of Pancreatic Cancer

    OpenAIRE

    Manfredi AA; Rovere-Querini P

    2004-01-01

    Antigen presenting cells (APCs) activate helper and cytotoxic T cells specific for antigens expressed by tissue cells, including neoplastic cells. This event occurs after the antigen transfer from tissue cells to APC, and is referred to as "cross-presentation". The number and the state of activation of APC in the tumor control the outcome of cross-presentation, including the establishment of protective immune responses. Cell death favors cross-presentation. Cancer cells normally die, either s...

  5. Selective pH-Responsive Core-Sheath Nanofiber Membranes for Chem/Bio/Med Applications: Targeted Delivery of Functional Molecules.

    Science.gov (United States)

    Han, Daewoo; Steckl, Andrew J

    2017-12-13

    Core-sheath fibers using different Eudragit materials were successfully produced, and their controlled multi-pH responses have been demonstrated. Core-sheath fibers made of Eudragit L 100 (EL100) core and Eudragit S 100 (ES100) sheath provide protection and/or controlled release of core material at pH 6 by adjusting the sheath thickness (controlled by the flow rate of source polymer solution). The thickest sheath (∼250 nm) provides the least core release ∼1.25%/h, while the thinnest sheath (∼140 nm) provides much quicker release ∼16.75%/h. Furthermore, switching core and sheath material dramatically altered the pH response. Core-sheath fibers made of ES100 core and EL100 sheath can provide a consistent core release rate, while the sheath release rate becomes higher as the sheath layer becomes thinner. For example, the thinnest sheath (∼120 nm) provides a core and sheath release ratio of 1:2.5, while the thickest sheath (∼200 nm) shows only a ratio of 1:1.7. All core-sheath Eudragit fibers show no noticeable release at pH 5, while they are completely dissolved at pH 7. Extremely high surface area in the porous network of the fiber membranes provides much faster (>30 times) response to external pH changes as compared to that of equivalent cast films.

  6. The therapeutic T-cell response induced by tumor delivery of TNF and melphalan is dependent on early triggering of natural killer and dendritic cells.

    Science.gov (United States)

    Balza, Enrica; Zanellato, Silvia; Poggi, Alessandro; Reverberi, Daniele; Rubartelli, Anna; Mortara, Lorenzo

    2017-04-01

    The fusion protein L19mTNF (mouse TNF and human antibody fragment L19 directed to fibronectin extra domain B) selectively targets the tumor vasculature, and in combination with melphalan induces a long-lasting T-cell therapeutic response and immune memory in murine models. Increasing evidence suggests that natural killer (NK) cells act to promote effective T-cell-based antitumor responses. We have analyzed the role of NK cells and dendritic cells (DCs) on two different murine tumor models: WEHI-164 fibrosarcoma and C51 colon carcinoma, in which the combined treatment induces high and low rejection rates, respectively. In vivo NK-cell depletion strongly reduced the rejection of WEHI-164 fibrosarcoma and correlated with a decrease in mature DCs, CD4 + , and CD8 + T cells in the tumor-draining LNs and mature DCs and CD4 + T cells in the tumor 40 h after initiation of the therapy. NK-cell depletion also resulted in the impairment of the stimulatory capability of DCs derived from tumor-draining LNs of WEHI-164-treated mice. Moreover, a significant reduction of M2-type infiltrating macrophages was detected in both tumors undergoing therapy. These results suggest that the efficacy of L19mTNF/melphalan therapy is strongly related to the early activation of NK cells and DCs, which are necessary for an effective T-cell response. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Project delivery system (PDS)

    CERN Document Server

    2001-01-01

    As business environments become increasingly competitive, companies seek more comprehensive solutions to the delivery of their projects. "Project Delivery System: Fourth Edition" describes the process-driven project delivery systems which incorporates the best practices from Total Quality and is aligned with the Project Management Institute and ISO Quality Standards is the means by which projects are consistently and efficiently planned, executed and completed to the satisfaction of clients and customers.

  8. The impact of self-interviews on response patterns for sensitive topics: a randomized trial of electronic delivery methods for a sexual behaviour questionnaire in rural South Africa.

    Science.gov (United States)

    Harling, Guy; Gumede, Dumile; Mutevedzi, Tinofa; McGrath, Nuala; Seeley, Janet; Pillay, Deenan; Bärnighausen, Till W; Herbst, Abraham J

    2017-08-17

    Self-interviews, where the respondent rather than the interviewer enters answers to questions, have been proposed as a way to reduce social desirability bias associated with interviewer-led interviews. Computer-assisted self-interviews (CASI) are commonly proposed since the computer programme can guide respondents; however they require both language and computer literacy. We evaluated the feasibility and acceptability of using electronic methods to administer quantitative sexual behaviour questionnaires in the Somkhele demographic surveillance area (DSA) in rural KwaZulu-Natal, South Africa. We conducted a four-arm randomized trial of paper-and-pen-interview, computer-assisted personal-interview (CAPI), CASI and audio-CASI with an age-sex-urbanicity stratified sample of 504 adults resident in the DSA in 2015. We compared respondents' answers to their responses to the same questions in previous surveillance rounds. We also conducted 48 cognitive interviews, dual-coding responses using the Framework approach. Three hundred forty (67%) individuals were interviewed and covariates and participation rates were balanced across arms. CASI and audio-CASI were significantly slower than interviewer-led interviews. Item non-response rates were higher in self-interview arms. In single-paper meta-analysis, self-interviewed individuals reported more socially undesirable sexual behaviours. Cognitive interviews found high acceptance of both self-interviews and the use of electronic methods, with some concerns that self-interview methods required more participant effort and literacy. Electronic data collection methods, including self-interview methods, proved feasible and acceptable for completing quantitative sexual behaviour questionnaires in a poor, rural South African setting. However, each method had both benefits and costs, and the choice of method should be based on context-specific criteria.

  9. The impact of self-interviews on response patterns for sensitive topics: a randomized trial of electronic delivery methods for a sexual behaviour questionnaire in rural South Africa

    Directory of Open Access Journals (Sweden)

    Guy Harling

    2017-08-01

    Full Text Available Abstract Background Self-interviews, where the respondent rather than the interviewer enters answers to questions, have been proposed as a way to reduce social desirability bias associated with interviewer-led interviews. Computer-assisted self-interviews (CASI are commonly proposed since the computer programme can guide respondents; however they require both language and computer literacy. We evaluated the feasibility and acceptability of using electronic methods to administer quantitative sexual behaviour questionnaires in the Somkhele demographic surveillance area (DSA in rural KwaZulu-Natal, South Africa. Methods We conducted a four-arm randomized trial of paper-and-pen-interview, computer-assisted personal-interview (CAPI, CASI and audio-CASI with an age-sex-urbanicity stratified sample of 504 adults resident in the DSA in 2015. We compared respondents’ answers to their responses to the same questions in previous surveillance rounds. We also conducted 48 cognitive interviews, dual-coding responses using the Framework approach. Results Three hundred forty (67% individuals were interviewed and covariates and participation rates were balanced across arms. CASI and audio-CASI were significantly slower than interviewer-led interviews. Item non-response rates were higher in self-interview arms. In single-paper meta-analysis, self-interviewed individuals reported more socially undesirable sexual behaviours. Cognitive interviews found high acceptance of both self-interviews and the use of electronic methods, with some concerns that self-interview methods required more participant effort and literacy. Conclusions Electronic data collection methods, including self-interview methods, proved feasible and acceptable for completing quantitative sexual behaviour questionnaires in a poor, rural South African setting. However, each method had both benefits and costs, and the choice of method should be based on context-specific criteria.

  10. Treatment of the Cornea Using Transcytotic Delivery into the Tear Film

    Science.gov (United States)

    2015-12-01

    6265-6270. [7] C. Ding, N. Chang, Y.C. Fong, Y. Wang, M.D. Trousdale, A.K. Mircheff, J.E. Schechter, Interacting influences of pregnancy and corneal...chymotrypsin, tryptase, human leukocyte elastase, pig pancreatic elastase, stratum corneum chymotryptic enzyme. In one embodiment, the protease is thrombin

  11. Catehol-o-methyltransferase gene Val158met polymorphism as a potential predictor of response to computer-assisted delivery of cognitive-behavioral therapy among cocaine-dependent individuals: Preliminary findings from a randomized controlled trial.

    Science.gov (United States)

    Carroll, Kathleen M; Herman, Aryeh; DeVito, Elise E; Frankforter, Tami L; Potenza, Marc N; Sofuoglu, Mehmet

    2015-08-01

    Findings from uncontrolled studies suggest that the COMT Val108/158Met polymorphism may affect response to cognitive behavioral therapy (CBT) in some populations. Using data from a randomized controlled trial evaluating computerized CBT (CBT4CBT), we evaluated treatment response by COMT genotype, with the a priori hypothesis that Val carriers would have improved response to computerized delivery of CBT. 101 cocaine-dependent individuals, of whom 81 contributed analyzable genetic samples, were randomized to standard methadone maintenance treatment plus CBT4CBT or standard treatment alone in an 8 week trial. There was a significant genotype by time effect on frequency of cocaine use from baseline to the end of the 6 month follow-up, suggesting greater reductions over time for Val carriers relative to individuals with the Met/Met genotype. There was a significant treatment condition by genotype interactions for rates of participants attaining 21 or more days of continuous abstinence as well as self-reported percent days of abstinence, suggesting less cocaine use among Val carriers when assigned to CBT compared to standard treatment. Exploration of possible mechanisms using measures of attentional biased also pointed to greater change over time in these measures among the Val carriers assigned to CBT. These are the first data from a randomized controlled trial indicating significant interactions of COMT polymorphism and behavioral therapy condition on treatment outcome, where Val carriers appeared to respond particularly well to computerized CBT. These preliminary data point to a potential biomarker of response to CBT linked to its putative mechanism of action, enhanced cognitive control. © American Academy of Addiction Psychiatry.

  12. Isolation of Microsporum gypseum in soil samples from different geographical regions of Brazil, evaluation of the extracellular proteolytic enzymes activities (keratinase and elastase and molecular sequencing of selected strains

    Directory of Open Access Journals (Sweden)

    Mauro Cintra Giudice

    2012-09-01

    Full Text Available A survey of Microsporum gypseum was conducted in soil samples in different geographical regions of Brazil. The isolation of dermatophyte from soil samples was performed by hair baiting technique and the species were identified by morphology studies. We analyzed 692 soil samples and the recuperating rate was 19.2%. The activities of keratinase and elastase were quantitatively performed in 138 samples. The sequencing of the ITS region of rDNA was performed in representatives samples. M. gypseum isolates showed significant quantitative differences in the expression of both keratinase and elastase, but no significant correlation was observed between these enzymes. The sequencing of the representative samples revealed the presence of two teleomorphic species of M. gypseum (Arthroderma gypseum and A. incurvatum. The enzymatic activities may play an important role in the pathogenicity and a probable adaptation of this fungus to the animal parasitism. Using the phenotypical and molecular analysis, the Microsporum identification and their teleomorphic states will provide a useful and reliable identification system.

  13. Immunomodulation of bivalent Newcastle disease DNA vaccine induced immune response by co-delivery of chicken IFN-γ and IL-4 genes.

    Science.gov (United States)

    Sawant, P M; Verma, P C; Subudhi, P K; Chaturvedi, U; Singh, M; Kumar, Rajeev; Tiwari, A K

    2011-11-15

    The basic objective of this study was to enumerate whether co-administration of interferon-γ (IFN-γ) and/or interleukin-4 (IL-4) gene along with a bivalent Newcastle disease (ND) DNA vaccine construct could modulate the immune response to the DNA vaccine in chickens. pVIVO2 vector carrying Haemaglutinin-Neuraminidase (HN) and Fusion (F) genes of Newcastle disease virus (NDV) at its two cloning sites was used as a DNA vaccine. The same vector was used to clone the chicken IFN-γ and IL-4 genes at the multiple cloning site-1 separately. In vitro expression of IFN-γ and IL-4 gene constructs was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and that of HN and F genes by indirect fluorescent antibody technique (IFAT) in addition to RT-PCR. The chickens were immunized thrice intramuscularly at 21, 36 and 46 days of age with the bivalent DNA vaccine alone, or in combination with IFN-γ/IL-4 or both cytokine gene constructs. The bivalent DNA vaccine led to increase in both NDV specific antibodies as assessed by enzyme linked immunosorbent assay (ELISA) and haemagglutination inhibition test (HI) and cell mediated immune (CMI) response as assessed by lymphocyte transformation test (LTT) employing MTT assay. Co-administration of the DNA vaccine with IL-4 gene resulted in highest IgY levels while IFN-γ produced highest CMI response. The DNA vaccine alone could afford only 10% protection against challenge infection by velogenic NDV. This protection was increased to 40% when IL-4 gene construct was co-administered with the DNA vaccine. Co-injection of IFN-γ as well as the combination of IFN-γ and IL-4 gene constructs with the DNA vaccine yielded 20% protection. Our study suggests that IL-4 may prove to be more appropriate as a genetic adjuvant than IFN-γ for ND DNA vaccine. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Smart surface coating of drug nanoparticles with cross-linkable polyethylene glycol for bio-responsive and highly efficient drug delivery.

    Science.gov (United States)

    Wei, Weijia; Zhang, Xiujuan; Chen, Xianfeng; Zhou, Mengjiao; Xu, Ruirui; Zhang, Xiaohong

    2016-04-21

    Many drug molecules can be directly used as nanomedicine without the requirement of any inorganic or organic carriers such as silica and liposome nanostructures. This new type of carrier-free drug nanoparticles (NPs) has great potential in clinical treatment because of its ultra-high drug loading capacity and biodegradability. For practical applications, it is essential for such nanomedicine to possess robust stability and minimal premature release of therapeutic molecules during circulation in the blood stream. To meet this requirement, herein, we develop GSH-responsive and crosslinkable amphiphilic polyethylene glycol (PEG) molecules to modify carrier-free drug NPs. These PEG molecules can be cross-linked on the surface of the NPs to endow them with greater stability and the cross-link is sensitive to intracellular environment for bio-responsive drug release. With this elegant design, our experimental results show that the liberation of DOX from DOX-cross-linked PEG NPs is dramatically slower than that from DOX-non-cross-linked PEG NPs, and the DOX release profile can be controlled by tuning the concentration of the reducing agent to break the cross-link between PEG molecules. More importantly, in vivo studies reveal that the DOX-cross-linked PEG NPs exhibit favorable blood circulation half-life (>4 h) and intense accumulation in tumor areas, enabling effective anti-cancer therapy. We expect this work will provide a powerful strategy for stabilizing carrier-free nanomedicines and pave the way to their successful clinical applications in the future.

  15. Intratumoral delivery of IL-18 naked DNA induces T-cell activation and Th1 response in a mouse hepatic cancer model

    International Nuclear Information System (INIS)

    Chang, Chi-Young; Lee, Jienny; Kim, Eun-Young; Park, Hae-Jung; Kwon, Choon-Hyuck; Joh, Jae-Won; Kim, Sung-Joo

    2007-01-01

    The novel cytokine, interleukin (IL)-18, is a strong interferon-γ inducer and costimulatory factor in Th1 cell activation. IL-18 triggers IFN-γ production and enhances cytolytic activity in both T and NK cells. However, the exact mechanism of antitumor action of IL-18 remains to be clarified. To determine the effects of IL-18 plasmid DNA on hepatic cancer in mice, CT26 murine colon adenocarcinoma cells were established in mouse liver. Plasmid vectors encoding IL-18 were transferred directly into the liver 7 days after tumor injection to restrict IL-18 expression within the tumor site. The IL-18 protein level was increased in the liver 4 days after plasmid injection, and a marked antitumoral effect was observed at day 7. Antitumor effects were evaluated by measuring tumor regression, immune cell population, and IFN-γ production. The IL-18 plasmid controlled the growth of hepatic tumors and proliferation of splenic immune cells. Moreover, treatment of CT26 tumors with the IL-18 plasmid significantly enhanced the population of the effector T and NK cells in the spleen and peripheral blood. In spleen, the population of CD4 + CD62 Low cells was augmented in response to IL-18 on day 7. These results are consistent with the increase in CD4 + T cells secreting IFN-γ, but not CD8 + T cells. The marked reduction of tumor growth in tumor-bearing mice was associated with the maintenance of IFN-γ production in spleen in response to IL-18. These antitumoral effects were maintained until 14 days after plasmid injection. Our results suggest that direct plasmid DNA transfer of IL-18 with no accompanying reagents to augment transfection efficiency may be useful in tumor immunotherapy

  16. Recovering from Delivery

    Science.gov (United States)

    ... site Sitio para adolescentes Body Mind Sexual Health Food & Fitness Diseases & Conditions Infections Drugs & Alcohol School & Jobs Sports Expert Answers (Q&A) Staying Safe Videos for Educators Search English Español Recovering From Delivery KidsHealth / For Parents / Recovering From Delivery What's in ...

  17. Global Delivery Models

    DEFF Research Database (Denmark)

    Manning, Stephan; Larsen, Marcus M.; Bharati, Pratyush

    2013-01-01

    This article examines antecedents and performance implications of global delivery models (GDMs) in global business services. GDMs require geographically distributed operations to exploit both proximity to clients and time-zone spread for efficient service delivery. We propose and empirically show...... digitalized services, time zones increasingly affect....

  18. 6. Home deliveries

    African Journals Online (AJOL)

    Sitwala

    determine factors associated with home deliveries. Main outcome .... Multiple logistic regression analyses were used to assess and estimate the factors and magnitude of effect on home deliveries. The variables in the model were age or age group, marital .... This finding coupled with lack of transport, made it very difficult for ...

  19. Prediction of preterm delivery

    NARCIS (Netherlands)

    Wilms, F.F.

    2014-01-01

    Preterm delivery is in quantity and in severity an important issue in the obstetric care in the Western world. There is considerable knowledge on maternal and obstetric risk factors of preterm delivery. Of the women presenting with preterm labor, the majority is pregnant with a male fetus and in

  20. Delivery is key

    DEFF Research Database (Denmark)

    Godfrey, Caroline; Desviat, Lourdes R.; Smedsrød, Bård

    2017-01-01

    is the relatively poor delivery of antisense oligonucleotides to target tissues after systemic delivery. We are a group of researchers closely involved in the development of these therapies and would like to communicate our discussions concerning the validity of standard methodologies currently used in their pre...

  1. Temperature and magnetism bi-responsive molecularly imprinted polymers: Preparation, adsorption mechanism and properties as drug delivery system for sustained release of 5-fluorouracil.

    Science.gov (United States)

    Li, Longfei; Chen, Lin; Zhang, Huan; Yang, Yongzhen; Liu, Xuguang; Chen, Yongkang

    2016-04-01

    Temperature and magnetism bi-responsive molecularly imprinted polymers (TMMIPs) based on Fe3O4-encapsulating carbon nanospheres were prepared by free radical polymerization, and applied to selective adsorption and controlled release of 5-fluorouracil (5-FU) from an aqueous solution. Characterization results show that the as-synthesized TMMIPs have an average diameter of about 150 nm with a typical core-shell structure, and the thickness of the coating layer is approximately 50 nm. TMMIPs also displayed obvious magnetic properties and thermo-sensitivity. The adsorption results show that the prepared TMMIPs exhibit good adsorption capacity (up to 96.53 mg/g at 25 °C) and recognition towards 5-FU. The studies on 5-FU loading and release in vitro suggest that the release rate increases with increasing temperature. Meanwhile, adsorption mechanisms were explored by using a computational analysis to simulate the imprinted site towards 5-FU. The interaction energy between the imprinted site and 5-FU is -112.24 kJ/mol, originating from a hydrogen bond, Van der Waals forces and a hydrophobic interaction between functional groups located on 5-FU and a NIPAM monomer. The electrostatic potential charges and population analysis results suggest that the imprinted site of 5-FU can be introduced on the surface of TMMIPs, confirming their selective adsorption behavior for 5-FU. Copyright © 2015. Published by Elsevier B.V.

  2. Obesity Appears to Be Associated With Altered Muscle Protein Synthetic and Breakdown Responses to Increased Nutrient Delivery in Older Men, but Not Reduced Muscle Mass or Contractile Function.

    Science.gov (United States)

    Murton, Andrew J; Marimuthu, Kanagaraj; Mallinson, Joanne E; Selby, Anna L; Smith, Kenneth; Rennie, Michael J; Greenhaff, Paul L

    2015-09-01

    Obesity is increasing, yet despite the necessity of maintaining muscle mass and function with age, the effect of obesity on muscle protein turnover in older adults remains unknown. Eleven obese (BMI 31.9 ± 1.1 kg · m(-2)) and 15 healthy-weight (BMI 23.4 ± 0.3 kg · m(-2)) older men (55-75 years old) participated in a study that determined muscle protein synthesis (MPS) and leg protein breakdown (LPB) under postabsorptive (hypoinsulinemic-euglycemic clamp) and postprandial (hyperinsulinemic hyperaminoacidemic-euglycemic clamp) conditions. Obesity was associated with systemic inflammation, greater leg fat mass, and patterns of mRNA expression consistent with muscle deconditioning, whereas leg lean mass, strength, and work done during maximal exercise were no different. Under postabsorptive conditions, MPS and LPB were equivalent between groups, whereas insulin and amino acid administration increased MPS in only healthy-weight subjects and was associated with lower leg glucose disposal (LGD) (63%) in obese men. Blunting of MPS in the obese men was offset by an apparent decline in LPB, which was absent in healthy-weight subjects. Lower postprandial LGD in obese subjects and blunting of MPS responses to amino acids suggest that obesity in older adults is associated with diminished muscle metabolic quality. This does not, however, appear to be associated with lower leg lean mass or strength. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  3. Nanocomposite thin films for triggerable drug delivery.

    Science.gov (United States)

    Vannozzi, Lorenzo; Iacovacci, Veronica; Menciassi, Arianna; Ricotti, Leonardo

    2018-05-01

    Traditional drug release systems normally rely on a passive delivery of therapeutic compounds, which can be partially programmed, prior to injection or implantation, through variations in the material composition. With this strategy, the drug release kinetics cannot be remotely modified and thus adapted to changing therapeutic needs. To overcome this issue, drug delivery systems able to respond to external stimuli are highly desirable, as they allow a high level of temporal and spatial control over drug release kinetics, in an operator-dependent fashion. Areas covered: On-demand drug delivery systems actually represent a frontier in this field and are attracting an increasing interest at both research and industrial level. Stimuli-responsive thin films, enabled by nanofillers, hold a tremendous potential in the field of triggerable drug delivery systems. The inclusion of responsive elements in homogeneous or heterogeneous thin film-shaped polymeric matrices strengthens and/or adds intriguing properties to conventional (bare) materials in film shape. Expert opinion: This Expert Opinion review aims to discuss the approaches currently pursued to achieve an effective on-demand drug delivery, through nanocomposite thin films. Different triggering mechanisms allowing a fine control on drug delivery are described, together with current challenges and possible future applications in therapy and surgery.

  4. Future of Automated Insulin Delivery Systems.

    Science.gov (United States)

    Castle, Jessica R; DeVries, J Hans; Kovatchev, Boris

    2017-06-01

    Advances in continuous glucose monitoring (CGM) have brought on a paradigm shift in the management of type 1 diabetes. These advances have enabled the automation of insulin delivery, where an algorithm determines the insulin delivery rate in response to the CGM values. There are multiple automated insulin delivery (AID) systems in development. A system that automates basal insulin delivery has already received Food and Drug Administration approval, and more systems are likely to follow. As the field of AID matures, future systems may incorporate additional hormones and/or multiple inputs, such as activity level. All AID systems are impacted by CGM accuracy and future CGM devices must be shown to be sufficiently accurate to be safely incorporated into AID. In this article, we summarize recent achievements in AID development, with a special emphasis on CGM sensor performance, and discuss the future of AID systems from the point of view of their input-output characteristics, form factor, and adaptability.

  5. What Is a Cesarean Delivery?

    Science.gov (United States)

    ... Twitter Pinterest Email Print What is a cesarean delivery? A cesarean delivery is a surgical procedure in which a fetus ... 32.2% of U.S. births were by cesarean delivery. 2 The CDC also found that the number ...

  6. Ultrasound mediated nanoparticle drug delivery

    Science.gov (United States)

    Mullin, Lee B.

    Ultrasound is not only a powerful diagnostic tool, but also a promising therapeutic technology that can be used to improve localized drug delivery. Microbubble contrast agents are micron sized encapsulated gas filled bubbles that are administered intravenously. Originally developed to enhance ultrasound images, microbubbles are highly echogenic due to the gas core that provides a detectable impedance difference from the surrounding medium. The core also allows for controlled response of the microbubbles to ultrasound pulses. Microbubbles can be pushed using acoustic radiation force and ruptured using high pressures. Destruction of microbubbles can increase permeability at the cellular and vascular level, which can be advantageous for drug delivery. Advances in drug delivery methods have been seen with the introduction of nanoparticles, nanometer sized objects often carrying a drug payload. In chemotherapy, nanoparticles can deliver drugs to tumors while limiting systemic exposure due to abnormalities in tumor vasculature such large gaps between endothelial cells that allow nanoparticles to enter into the interstitial space; this is referred to as the enhanced permeability and retention (EPR) effect. However, this effect may be overestimated in many tumors. Additionally, only a small percentage of the injected dose accumulates in the tumor, which most the nanoparticles accumulating in the liver and spleen. It is hypothesized that combining the acoustic activity of an ultrasound contrast agent with the high payload and extravasation ability of a nanoparticle, localized delivery to the tumor with reduced systemic toxicity can be achieved. This method can be accomplished by either loading nanoparticles onto the shell of the microbubble or through a coadministration method of both nanoparticles and microbubbles. The work presented in this dissertation utilizes novel and commercial nanoparticle formulations, combined with microbubbles and a variety of ultrasound systems

  7. Global Delivery Models

    DEFF Research Database (Denmark)

    Manning, Stephan; Møller Larsen, Marcus; Bharati, Pratyush

    We investigate antecedents and contingencies of location configurations supporting global delivery models (GDMs) in global outsourcing. GDMs are a new form of IT-enabled client-specific investment promoting services provision integration with clients by exploiting client proximity and time......-zone spread allowing for 24/7 service delivery and access to resources. Based on comprehensive data we show that providers are likely to establish GDM configurations when clients value access to globally distributed talent pools and speed of service delivery, and in particular when services are highly...... commoditized. Findings imply that coordination across time zones increasingly affects international operations in business-to-business and born-global industries....

  8. Preparation of thermo and pH-responsive polymer@Au/Fe{sub 3}O{sub 4} core/shell nanoparticles as a carrier for delivery of anticancer agent

    Energy Technology Data Exchange (ETDEWEB)

    Ghorbani, Marjan [University of Tabriz, Laboratory of Polymer, Faculty of Chemistry (Iran, Islamic Republic of); Hamishehkar, Hamed, E-mail: hamishehkarh@tbzmed.ac.ir [Tabriz University of Medical Sciences, Drug Applied Research Center (Iran, Islamic Republic of); Arsalani, Naser; Entezami, Ali Akbar, E-mail: aentezami@tabrizu.ac.ir [University of Tabriz, Laboratory of Polymer, Faculty of Chemistry (Iran, Islamic Republic of)

    2015-07-15

    In this work, a thermo and pH-responsive poly-N-isopropylacrylamide-co-itaconic acid containing thiol side groups were successfully synthesized to prepare Doxorubicin-loaded polymer@Au/Fe{sub 3}O{sub 4} core/shell nanoparticles (DOX-NPs). Copolymer and NPs were fully characterized by FT-IR, HNMR, photo-correlation spectroscopy, SEM, X-ray diffraction, vibrating-sample magnetometer, thermal gravimetric analysis, and UV–Vis spectroscopy. The stimuli-responsive characteristics of NPs were evaluated by in vitro release study in simulated cancerous environment. The biocompatibility and cytotoxic properties of NPs and DOX-NPs are explored by MTT method. The prepared NPs with the size of 50 nm showed paramagnetic characteristics with suitable and stable dispersion at physiological medium and high loading capacity (up to 55 %) of DOX. DOX-NPs yielded a pH- and temperature-triggered release of entrapped drugs at tumor tissue environment (59 % of DOX release) compared to physiological condition (20 % of DOX release) during 48 h. In vitro cytotoxicity studies indicated that the NPs showed no cytotoxicity on A549 cells at different amounts after incubation for 72 h confirming its suitability as a drug carrier. DOX-NPs, on the other hand, caused an efficient anticancer performance as verified by MTT assay test. It was concluded that developed NPs by us in this study may open the possibilities for targeted delivery of DOX to the cancerous tissues.

  9. Oral delivery of Bacillus subtilis spores expressing cysteine protease of Clonorchis sinensis to grass carp (Ctenopharyngodon idellus): Induces immune responses and has no damage on liver and intestine function.

    Science.gov (United States)

    Tang, Zeli; Sun, Hengchang; Chen, TingJin; Lin, Zhipeng; Jiang, Hongye; Zhou, Xinyi; Shi, Cunbin; Pan, Houjun; Chang, Ouqin; Ren, Pengli; Yu, Jinyun; Li, Xuerong; Xu, Jin; Huang, Yan; Yu, Xinbing

    2017-05-01

    Clonorchis sinensis (C. sinensis) is a fish-borne trematode. Human can be infected by ingestion of C. sinensis metacercariae parasitized in grass carp (Ctenopharyngodon idella). For induction of effective oral immune responses, spores of Bacillus subtilis (B. subtilis) WB600 were utilized as vehicle to delivery CsCP (cysteine protease of C. sinensis) cooperated with CotC (B.s-CotC-CP), one of coat proteins, to the gastrointestinal tract. After routine culture of 8-12 h in LB medium, B. subtilis containing CotC-CsCP was transferred into the sporulation culture medium. SDS-PAGE, western blotting and the growth curve indicated that the best sporulation time of recombinant WB600 was 24-30 h at 37 °C with continuous shaking (250 rpm). Grass carp were fed with three levels of B.s-CotC-CP (1 × 10 6 , 1 × 10 7 , and 1 × 10 8  CFU g -1 ) incorporated in the basal pellets diet. The commercial pellets or supplemented with spores just expressing CotC (1 × 10 7  CFU g -1 ) were served as control diet. Our results showed that grass carp orally immunized with the feed-based B.s-CotC-CP developed a strong specific immune response with significantly (P sinensis in fish body. Therefore, this study demonstrated that the feed-based recombinant spores could trigger high levels of mucosal and humoral immunity, and would be a promising candidate vaccine against C. sinensis metacercariae formation in freshwater fish. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. [Ileocystoplasty, pregnancy and delivery].

    Science.gov (United States)

    Walder, R; Mouriquand, P; Ruffion, A; Rudigoz, R-C

    2016-04-01

    Bladder augmentation is commonly used in neurological and other congenital anomalies of the lower urinary tract. In pregnant women, this reconstructive surgery may affect pregnancy and delivery. The obstetrical consequences of these urological procedures are scarcely reported in literature. Eight pregnancies in 6 pregnant women with ileocystoplasty were followed in our institution between 1998 and 2014. Urinary tract infections were the most frequent undesirable record event (5 patients, 7 pregnancies). Obstetrical complications were not more frequent compared to common pregnancies. Delivery was programmed at 37WA. Cesarean section was favoured in this group although natural delivery is possible. Urological complications were the major problem in this series. The type of delivery depends on the past surgical history and the obstetrical prognosis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  11. Magnetic hyperthermia and pH-responsive effective drug delivery to the sub-cellular level of human breast cancer cells by modified CoFe2O4nanoparticles.

    Science.gov (United States)

    Oh, Yunok; Moorthy, Madhappan Santha; Manivasagan, Panchanathan; Bharathiraja, Subramaniyan; Oh, Junghwan

    2017-02-01

    Magnetic iron oxide nanoparticles (MNPs) have been extensively utilized in a wide range of biomedical applications including magnetic hyperthermia agent. To improve the efficiency of the MNPs in therapeutic applications, in this study, we have synthesized CoFe 2 O 4 nanoparticles and its surface was further functionalized with meso-2,3-dimercaptosuccinic acid (DMSA). The anticancer agent, Doxorubucin (DOX) was conjugated with CoFe 2 O 4 @DMSA nanoparticle to evaluate the combined effects of thermotherapy and chemotherapy. The drug delivery efficiency of the DOX loaded CoFe 2 O 4 @DMSA nanoparticles were examined based on magnetically triggered delivery of DOX into the subcellular level of cancer cells by using MDA-MB-231 cell line. The amine part of the DOX molecules were effectively attached through an electrostatic interactions and/or hydrogen bonding interactions with the carboxylic acid groups of the DMSA functionalities present onto the surface of the CoFe 2 O 4 nanoparticles. The DOX loaded CoFe 2 O 4 @DMSA nanoparticles can effectively uptake with cancer cells via typical endocytosis process. After endocytosis, DOX release from CoFe 2 O 4 nanoparticles was triggered by intracellular endosomal/lysosomal acidic environments and the localized heat can be generated under an alternating magnetic field (AMF). In the presence of AMF, the released DOX molecules were accumulated with high concentrations into the subcellular level at a desired sites and exhibited a synergistic effect of an enhanced cell cytotoxicity by the combined effects of thermal-chemotherapy. Importantly, pH- and thermal-responsive Dox-loaded CoFe 2 O 4 nanoparticles induced significant cellular apoptosis more efficiently mediated by active mitochondrial membrane and ROS generation than the free Dox. Thus, the Dox-loaded CoFe 2 O 4 @DMSA nanoparticles can be used as a potential therapeutic agent in cancer therapy by combining the thermo-chemotherapy techniques. Copyright © 2016. Published by

  12. Self-Assembled Cationic Biodegradable Nanoparticles from pH-Responsive Amino-Acid-Based Poly(Ester Urea Urethane)s and Their Application As a Drug Delivery Vehicle.

    Science.gov (United States)

    He, Mingyu; Potuck, Alicia; Kohn, Julie C; Fung, Katharina; Reinhart-King, Cynthia A; Chu, Chih-Chang

    2016-02-08

    The objective of this study is to develop a new family of biodegradable and biologically active copolymers and their subsequent self-assembled cationic nanoparticles as better delivery vehicles for anticancer drugs to achieve the synergism between the cytotoxicity effects of the loaded drugs and the macrophage inflammatory response of the delivery vehicle. This family of cationic nanoparticles was formulated from a new family of amphiphilic cationic Arginine-Leucine (Arg-Leu)-based poly(ester urea urethane) (Arg-Leu PEUU) synthesized from four building blocks (amino acids, diols, glycerol α-monoallyl ether, and 1,6 hexamethylene diisocyanate). The chemical, physical, and biological properties of Arg-Leu PEUU biomaterials can be tuned by controlling the feed ratio of the four building blocks. The Arg-Leu PEUU copolymers have weight-average molecular weights from 13.4 to 16.8 kDa and glass-transition temperatures from -3.4 to -4.6 °C. The self-assembled cationic nanoparticles (Arg-Leu PEUU NPs) were prepared using a facile dialysis method. Arg-Leu PEUU NPs have average diameters ranging from 187 to 272 nm, show good biocompatibility with 3T3 fibroblasts, and they support bovine aortic endothelial cell (BAEC) proliferation and adhesion. Arg-Leu PEUU NPs also enhanced the macrophages' production of tumor necrosis factor-α (TNF-α) and nitric oxide (NO), but produced relatively low levels of interleukin-10 (IL-10), and therefore, the antitumor activity of macrophages might be enhanced. Arg-Leu PEUU NPs were taken up by HeLa cells after 4 h of incubation. The in vitro hemolysis assay showed the cationic Arg-Leu PEUU NPs increased their chance of endosomal escape at a more acidic pH. Doxorubicin (DOX) was successfully incorporated into the Arg-Leu PEUU NPs, and the DOX-loaded Arg-Leu PEUU NPs exhibited a pH-dependent drug release profile with accelerated release kinetics in a mild acidic condition. The DOX-loaded 6-Arg-4-Leu-4 A/L-2/1 NPs showed higher HeLa cell

  13. Continuous software delivery

    OpenAIRE

    Krmavnar, Nina

    2015-01-01

    The main purpose of the thesis is the demonstration of one of the best possible approaches to an automated continuous delivery process as it relates to certain application types. In the introductory part, the main reason for choosing the subject is presented, along with a few examples of why nowadays - in order to keep pace with the competition - such an approach seems necessary. Following chapters discuss the basics of software delivery, starting with configuration and version control manage...

  14. Ontogeny, immunocytochemical localization, and biochemical properties of the pregnancy-associated uterine elastase/cathepsin-G protease inhibitor, antileukoproteinase (ALP): monospecific antibodies to a synthetic peptide recognize native ALP.

    Science.gov (United States)

    Simmen, R C; Michel, F J; Fliss, A E; Smith, L C; Fliss, M F

    1992-04-01

    Expression of the mRNA encoding the elastase/cathepsin-G protease inhibitor, antileukoproteinase (ALP), is highest in pig uterus during mid- and late pregnancy, suggesting a stage of pregnancy-dependent role for ALP in feto-maternal interactions. To elucidate a function for ALP in these events, immunogenic probes were developed to localize sites of ALP expression in the environment of the developing fetus. Monospecific antibodies raised against a 16-mer synthetic peptide corresponding to residues 21-36 (ALP 16P) of the deduced amino acid sequence of pig uterine ALP were generated by active immunization of sheep. ALP 16P conjugated to keyhole limpet hemocyanin elicited high titer antibodies that were specific to ALP. The antipeptide antibodies were used to characterize pig uterine ALP from allantoic fluids. Uterine ALP has an approximate mol wt of 14,000 and a pI of 8.2 and exhibits elastase inhibitor activity. Amino-terminal amino acid sequencing of uterine ALP indicated the sequence AENALKGGACPPRKIVQC, which has 44% identity with the corresponding region in human bronchial ALP. RIA for ALP, developed using ALP 16P as standard and iodinated tracer, demonstrated the presence of immunoreactive ALP in early, mid-, and late pregnant endometrium and myometrium, placenta, allantoic fluids, fetal cord blood, and fetal liver. ALP was undetectable in the maternal circulation. The ALP levels in endometrium, allantoic fluids, and fetal cord blood changed with the stage of pregnancy; however, ALP content in placenta, myometrium, and fetal liver, although different among tissues, remained invariant during gestation. By immunocytochemical analyses, ALP was localized in the glandular epithelium of the uterus, in placenta, and in fetal liver, consistent with the presence of immunoreactive ALP as measured by RIA. The localization of uterine ALP in placenta and its corresponding transport to fetal circulation provide strong evidence to support a physiological function for the

  15. Conscientious Objection and Reproductive Health Service Delivery ...

    African Journals Online (AJOL)

    HP

    Medical doctors are bound by ethics in their clinical practice – health service delivery. They often discharge their contractual responsibilities under the provisions of their professional ethical code and personal morality. Ethical principles in clinical care include i) Respect for patient's autonomy ii) Doing good (beneficence) ...

  16. Decentralisation in Uganda: Prospects for Improved Service Delivery

    African Journals Online (AJOL)

    seriane.camara

    In Uganda, Chile and Cote D'Ivoire, it was carried out for improving service delivery (Shah and Theresa 2004). In. Uganda, the Local Government Act (1997), a central part of the decentralisation policy, stipulates that most central government powers and responsibilities for public services planning and delivery should be ...

  17. Guidelines for Psychological Practice in Health Care Delivery Systems

    Science.gov (United States)

    American Psychologist, 2013

    2013-01-01

    Psychologists practice in an increasingly diverse range of health care delivery systems. The following guidelines are intended to assist psychologists, other health care providers, administrators in health care delivery systems, and the public to conceptualize the roles and responsibilities of psychologists in these diverse contexts. These…

  18. Advanced SLARette delivery machine

    International Nuclear Information System (INIS)

    Bodner, R.R.

    1995-01-01

    SLARette 1 equipment, comprising of a SLARette Delivery Machine, SLAR Tools, SLAR power supplies and SLAR Inspection Systems was designed, developed and manufactured to service fuel channels of CANDU 6 stations during the regular yearly station outages. The Mark 2 SLARette Delivery Machine uses a Push Tube system to provide the axial and rotary movements of the SLAR Tool. The Push Tubes are operated remotely but must be attached and removed manually. Since this operation is performed at the Reactor face, there is radiation dose involved for the workers. An Advanced SLARette Delivery Machine which incorporates a computer controlled telescoping Ram in the place of the Push Tubes has been recently designed and manufactured. Utilization of the Advanced SLARette Delivery Machine significantly reduces the amount of radiation dose picked up by the workers because the need to have workers at the face of the Reactor during the SLARette operation is greatly reduced. This paper describes the design, development and manufacturing process utilized to produce the Advanced SLARette Delivery Machine and the experience gained during the Gentilly-2 NGS Spring outage. (author)

  19. Global Delivery Models

    DEFF Research Database (Denmark)

    Manning, Stephan; Møller Larsen, Marcus; Bharati, Pratyush M.

    2015-01-01

    Global delivery models (GDMs) are transforming the global IT and business process outsourcing industry. GDMs are a new form of client-specific investment promoting service integration with clients by combining client proximity with time-zone spread for 24/7 service operations. We investigate...... antecedents and contingencies of setting up GDM structures. Based on comprehensive data we show that providers are likely to establish GDM location configurations when clients value access to globally distributed talent and speed of service delivery, in particular when services are highly commoditized....... Findings imply that coordination across time zones increasingly affects international operations in business-to-business and born-global industries....

  20. Cement composite delivery system.

    Science.gov (United States)

    Convery, F R; Devine, S D; Hollis, J M; Woo, S L

    1986-09-01

    Several new and innovative techniques have recently been introduced that purport to increase the strength of polymethyl methacrylate bone cement. One of these concepts is the use of carbon and polymer fibers to form a cement composite. Bone cement composites usually 1% fiber, are very difficult to use clinically. The composite is very sticky and viscous, which precludes effective hand packing or the use of conventional delivery systems. A new delivery system for very viscous materials is presented and examples of in vitro application are shown.

  1. Redefining continuing education delivery.

    Science.gov (United States)

    Carlton, K H

    1997-01-01

    Just as technology is transforming the delivery of education, the Internet and advanced telecommunication applications are changing the "face" of CE and the connotation of "lifelong learning." As late as the mid-1980s, a discussion of computer applications in nursing CE focused on the "timely" transition to microcomputers as tools for the enhancement of managerial tasks for increased productivity. Even as recently as 1990, there seemed to be "time" for those providers who were "slower to adopt innovation" to "catch up." Now, the CE provider who does not integrate the microcomputer and advanced telecommunications as an integral component of their delivery modalities may be outsourced rapidly by an educational or commercial competitive unit that is able to utilize the communication medium, mergers and partnerships, enterprise, and individual lifestyle and learning patterns that will epitomize the CE unit of the 21st century. As with the "re-engineering" of nursing education, the "re-engineered" delivery modalities of evolving CE entity might now best be conceptualized on a continuum from the traditional mode that time and place dependent to a mode of synchronous and asynchronous data and advanced telecommunication. Delivery methods will need to be selected according to the target populations, content, and situation. The health-care educational provider may discover, as in other industries, that a combination of distance and residential offerings will be the most successful medium for the delivery of CE to the progressively more "information and technologically savvy" lifelong learner of the 21st century. In addressing the dramatic effects of the information technology era on the refocused multimedia/interactive delivery method for student education, educators amply quoted Bob Dylan's phrase of the 1960s, "The times, they are a-changing." And so, we see that the times are also changing at an astronomical rate for the health-care educational provider as well as the

  2. Cesarean section and the manipulation of exact delivery time.

    Science.gov (United States)

    Fabbri, Daniele; Monfardini, Chiara; Castaldini, Ilaria; Protonotari, Adalgisa

    2016-07-01

    Physicians are often alleged responsible for the manipulation of delivery timing. We investigate this issue in a setting that negates the influence of financial incentives on physician's behavior. Working on a sample of women admitted at the onset of labor in a big public hospital in Italy we estimate a model for the exact time of delivery as driven by individual Indication to Cesarean Section (ICS) and covariates. We find that ICS does not affect the day of delivery but leads to a circadian rhythm in the likelihood of delivery. The pattern is consistent with the postponement of high ICS deliveries in the late night\\early morning shift. Our evidence hardly supports the manipulation of timing of births as driven by medical staff's "demand for leisure". Physicians seem to manipulate the exact timing of delivery to reduce exposure to risk factors extant during off-peak periods. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Newborn Analgesia Mediated by Oxytocin during Delivery

    Science.gov (United States)

    Mazzuca, Michel; Minlebaev, Marat; Shakirzyanova, Anastasia; Tyzio, Roman; Taccola, Giuliano; Janackova, Sona; Gataullina, Svetlana; Ben-Ari, Yehezkel; Giniatullin, Rashid; Khazipov, Rustem

    2011-01-01

    The mechanisms controlling pain in newborns during delivery are poorly understood. We explored the hypothesis that oxytocin, an essential hormone for labor and a powerful neuromodulator, exerts analgesic actions on newborns during delivery. Using a thermal tail-flick assay, we report that pain sensitivity is two-fold lower in rat pups immediately after birth than 2 days later. Oxytocin receptor antagonists strongly enhanced pain sensitivity in newborn, but not in 2-day-old rats, whereas oxytocin reduced pain at both ages suggesting an endogenous analgesia by oxytocin during delivery. Similar analgesic effects of oxytocin, measured as attenuation of pain-vocalization induced by electrical whisker pad stimulation, were also observed in decerebrated newborns. Oxytocin reduced GABA-evoked calcium responses and depolarizing GABA driving force in isolated neonatal trigeminal neurons suggesting that oxytocin effects are mediated by alterations of intracellular chloride. Unlike GABA signaling, oxytocin did not affect responses mediated by P2X3 and TRPV1 receptors. In keeping with a GABAergic mechanism, reduction of intracellular chloride by the diuretic NKCC1 chloride co-transporter antagonist bumetanide mimicked the analgesic actions of oxytocin and its effects on GABA responses in nociceptive neurons. Therefore, endogenous oxytocin exerts an analgesic action in newborn pups that involves a reduction of the depolarizing action of GABA on nociceptive neurons. Therefore, the same hormone that triggers delivery also acts as a natural pain killer revealing a novel facet of the protective actions of oxytocin in the fetus at birth. PMID:21519396

  4. Biomaterials for nanoparticle vaccine delivery systems.

    Science.gov (United States)

    Sahdev, Preety; Ochyl, Lukasz J; Moon, James J

    2014-10-01

    Subunit vaccination benefits from improved safety over attenuated or inactivated vaccines, but their limited capability to elicit long-lasting, concerted cellular and humoral immune responses is a major challenge. Recent studies have demonstrated that antigen delivery via nanoparticle formulations can significantly improve immunogenicity of vaccines due to either intrinsic immunostimulatory properties of the materials or by co-entrapment of molecular adjuvants such as Toll-like receptor agonists. These studies have collectively shown that nanoparticles designed to mimic biophysical and biochemical cues of pathogens offer new exciting opportunities to enhance activation of innate immunity and elicit potent cellular and humoral immune responses with minimal cytotoxicity. In this review, we present key research advances that were made within the last 5 years in the field of nanoparticle vaccine delivery systems. In particular, we focus on the impact of biomaterials composition, size, and surface charge of nanoparticles on modulation of particle biodistribution, delivery of antigens and immunostimulatory molecules, trafficking and targeting of antigen presenting cells, and overall immune responses in systemic and mucosal tissues. This review describes recent progresses in the design of nanoparticle vaccine delivery carriers, including liposomes, lipid-based particles, micelles and nanostructures composed of natural or synthetic polymers, and lipid-polymer hybrid nanoparticles.

  5. Healthcare Delivery Systems at Higher Educational Institutions in India

    Directory of Open Access Journals (Sweden)

    Rajiv Chintaman Yeravdekar

    2014-01-01

    Conclusions: The collective responses obtained could provide the basis for a policy formulation. The policy formulation in turn could be the basis of a national consensus for health care delivery systems operational at higher educational institutions in India.

  6. Biomedical materials, devices and drug delivery systems by radiation techniques

    International Nuclear Information System (INIS)

    Kaetsu, Isao.

    1996-01-01

    The study of radiation polymerization in a super-cooled state started in 1966 and has been applied to the immobilization of biofunctional materials since 1973. In the last twenty years, application has been concentrated on the immobilization of drugs and hormones for the purpose of drug delivery systems. Very recently, the author has proposed a concept of environmental signal responsive chemical delivery system, as a new generation of controlled release and delivery systems. The study and development of materials, devices and systems is described. The signal responsive delivery system consists of a sensor part and a controlled delivery part. Therefore, the use of immobilization techniques for the biochip sensor and the hydrogel actuator has been investigated. As a future goal, systems for brain research are to be designed and studied. (author)

  7. Transdermal delivery of ketorolac.

    Science.gov (United States)

    Amrish, Chandra; Kumar, Sharma Pramod

    2009-03-01

    A reservoir type transdermal patch for delivery of ketorolac, a potent analgesic agent was studied. The low permeability of skin is the rate-limiting step for delivery of most of the drugs. Studies were carried out to investigate the effect of permeation enhancers on the in vitro permeation of ketorolac across rat skin. The reservoir type transdermal patch was fabricated and the core was filled with gel system of a non ionic polymer HPMC (hydroxypropyl methyl cellulose) formulated in PBS (phosphate buffer saline) solution of pH of 5.4 along with isopropyl alcohol at 25% w/w concentration. Various permeation enhancers' viz. dimethyl sulphoxide, d-limonene, eucalyptus oil and transcutol (diethylene glycol monoethyl ether) were incorporated into the gel system. Permeation enhancement of ketorolac with different enhancers followed the order eucalyptus oil> transcutol> DMSO> d-limonene. Cyclic terpene containing eucalyptus oil was found to be the most promising chemical permeation enhancer for transdermal delivery of ketorolac. The increase in concentration of eucalyptus oil further enhanced drug permeation with maximum flux being achieved at 10% w/w of 66.38 microg/cm(2)/h. Further enhancement of permeation rate of ketorolac across skin was attained by application of abrading gel containing crushed apricot seed onto the skin. There was 5.16 times enhancement and flux of 93.10 microg/cm(2)/h was attained. A reservoir type transdermal patch for delivery of ketorolac thus appears to be feasible of delivering ketorolac across skin.

  8. Drug delivery and formulations.

    Science.gov (United States)

    Breitkreutz, Jörg; Boos, Joachim

    2011-01-01

    Paediatric drug delivery is a major challenge in drug development. Because of the heterogeneous nature of the patient group, ranging from newborns to adolescents, there is a need to use appropriate excipients, drug dosage forms and delivery devices for different age groups. So far, there is a lack of suitable and safe drug formulations for children, especially for the very young and seriously ill patients. The new EU legislation will enforce paediatric clinical trials and drug development. Current advances in paediatric drug delivery include interesting new concepts such as fast-dissolving drug formulations, including orodispersible tablets and oral thin strips (buccal wafers), and multiparticulate dosage forms based on mini-tabletting or pelletization technologies. Parenteral administration is likely to remain the first choice for children in the neonatal period and for emergency cases. Alternative routes of administration include transdermal, pulmonary and nasal drug delivery systems. A few products are already available on the market, but others still need further investigations and clinical proof of concept.

  9. Caesarean delivery: conflicting interests.

    Science.gov (United States)

    Osuna, Eduardo; Pérez Cárceles, Maria Dolores; Sánchez Ferrer, Maria Luisa; Machado, Francisco

    2015-12-01

    Within the maternal-fetal relationship, interests may sometimes diverge. In this paper, a pregnant woman's refusal to undergo a caesarean delivery, which was recommended both to save the life of the fetus and to minimize risks to her, is described. The legal aspects involved in the conflict between maternal autonomy and fetal well-being are analysed. The patient requested an abortion because of the poor condition of the fetus; however, according to Spanish legislation, the possibility of abortion was rejected as the pregnancy was in its 27th week. The woman still persisted in her refusal to accept a caesarian delivery. After the medical team sought guidance on the course to follow, the Duty Court authorized a caesarean delivery against the wishes of the patient. From a legal point of view, at stake were the freedom of the woman - expressed by the decision to reject a caesarean delivery - and the life of the unborn child. In clinical treatment, the interests of the fetus are generally aligned with those of the pregnant woman. When they are not, it is the pregnant woman's autonomy that should be respected, and coercion should form no part of treatment, contrary to the decision of this court. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  10. A Medical Delivery Device

    DEFF Research Database (Denmark)

    2010-01-01

    The present invention relates to a medical delivery device comprising at least two membrane electrode assembly units each of which comprises three layers: an upper and a lower electrode and a selective ionic conductive membrane provided there-between. At least one of the three layers are shared...

  11. Smart Drug Delivery Systems in Cancer Therapy.

    Science.gov (United States)

    Unsoy, Gozde; Gunduz, Ufuk

    2018-02-08

    Smart nanocarriers have been designed for tissue-specific targeted drug delivery, sustained or triggered drug release and co-delivery of synergistic drug combinations to develop safer and more efficient therapeutics. Advances in drug delivery systems provide reduced side effects, longer circulation half-life and improved pharmacokinetics. Smart drug delivery systems have been achieved successfully in the case of cancer. These nanocarriers can serve as an intelligent system by considering the differences of tumor microenvironment from healthy tissue, such as low pH, low oxygen level, or high enzymatic activity of matrix metalloproteinases. The performance of anti-cancer agents used in cancer diagnosis and therapy is improved by enhanced cellular internalization of smart nanocarriers and controlled drug release. Here, we review targeting, cellular internalization; controlled drug release and toxicity of smart drug delivery systems. We are also emphasizing the stimulus responsive controlled drug release from smart nanocarriers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome.

    Science.gov (United States)

    Maes, Michael; Twisk, Frank N M; Kubera, Marta; Ringel, Karl; Leunis, Jean-Claude; Geffard, Michel

    2012-02-01

    Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by a) systemic IgA/IgM responses against the lipopolysaccharides (LPS) of commensal bacteria; b) inflammation, e.g. increased plasma interleukin-(IL)1 and tumor necrosis factor (TNF)α; and c) activation of cell-mediated immunity (CMI), as demonstrated by increased neopterin. To study the relationships between the IgA/IgM responses to the LPS of microbiota, inflammation, CMI and the symptoms of ME/CFS we measured the IgA/IgM responses to the LPS of 6 different enterobacteria, serum IL-1, TNFα, neopterin, and elastase in 128 patients with ME/CFS and chronic fatigue (CF). Severity of symptoms was assessed by the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Serum IL-1, TNFα, neopterin and elastase are significantly higher in patients with ME/CFS than in CF patients. There are significant and positive associations between the IgA responses to LPS and serum IL-1, TNFα, neopterin and elastase. Patients with an abnormally high IgA response show increased serum IL-1, TNFα and neopterin levels, and higher ratings on irritable bowel syndrome (IBS) than subjects with a normal IgA response. Serum IL-1, TNFα and neopterin are significantly related to fatigue, a flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability. The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Self-nanoemulsifying drug delivery systems for oral insulin delivery

    DEFF Research Database (Denmark)

    Li, Ping; Tan, Angel; Prestidge, Clive A

    2014-01-01

    This study aims at evaluating the combination of self-nanoemulsifying drug delivery systems (SNEDDS) and enteric-coated capsules as a potential delivery strategy for oral delivery of insulin. The SNEDDS preconcentrates, loaded with insulin-phospholipid complex at different levels (0, 2.5 and 10% w...

  14. Advanced materials and processing for drug delivery: the past and the future.

    Science.gov (United States)

    Zhang, Ying; Chan, Hon Fai; Leong, Kam W

    2013-01-01

    Design and synthesis of efficient drug delivery systems are of vital importance for medicine and healthcare. Materials innovation and nanotechnology have synergistically fueled the advancement of drug delivery. Innovation in material chemistry allows the generation of biodegradable, biocompatible, environment-responsive, and targeted delivery systems. Nanotechnology enables control over size, shape and multi-functionality of particulate drug delivery systems. In this review, we focus on the materials innovation and processing of drug delivery systems and how these advances have shaped the past and may influence the future of drug delivery. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Prenatal counseling regarding cesarean delivery.

    Science.gov (United States)

    Leeman, Lawrence M

    2008-09-01

    In 1970, the cesarean delivery rate in the United States was 5.5% and women receiving prenatal care only required the knowledge that cesarean delivery was an uncommon solution to dire obstetric emergencies. In 2008, when almost one in three women deliver by cesarean, counseling on cesarean delivery must be part of each woman's prenatal care. The content of that discussion varies based on the woman's obstetric history and the anticipated mode of delivery.

  16. Drug delivery with living cells

    NARCIS (Netherlands)

    Fliervoet, Lies A L; Mastrobattista, Enrico

    2016-01-01

    The field of drug delivery has grown tremendously in the past few decades by developing a wide range of advanced drug delivery systems. An interesting category is cell-based drug delivery, which includes encapsulation of drugs inside cells or attached to the surface and subsequent transportation

  17. Pyomyositis after vaginal delivery.

    LENUS (Irish Health Repository)

    Gaughan, Eve

    2011-01-01

    Pyomyositis is a purulent infection of skeletal muscle that arises from haematogenous spread, usually with abscess formation. It can develop after a transient bacteraemia of any cause. This type of infection has never been reported before in the literature after vaginal delivery. A 34-year-old woman had progressive severe pain in the left buttock and thigh and weakness in the left lower limb day 1 post spontaneous vaginal delivery. MRI showed severe oedema of the left gluteus, iliacus, piriformis and adductor muscles of the left thigh and a small fluid collection at the left hip joint. She was diagnosed with pyomyositis. She had fever of 37.9°C immediately postpartum and her risk factors for bacteraemia were a mild IV cannula-associated cellulitis and labour itself. She required prolonged treatment with antibiotics before significant clinical improvement was noted.

  18. Supersaturating drug delivery systems

    DEFF Research Database (Denmark)

    Laitinen, Riikka; Löbmann, Korbinian; Grohganz, Holger

    2017-01-01

    Amorphous solid dispersions (ASDs) are probably the most common and important supersaturating drug delivery systems for the formulation of poorly water-soluble compounds. These delivery systems are able to achieve and maintain a sustained drug supersaturation which enables improvement...... of the bioavailability of poorly water-soluble drugs by increasing the driving force for drug absorption. However, ASDs often require a high weight percentage of carrier (usually a hydrophilic polymer) to ensure molecular mixing of the drug in the carrier and stabilization of the supersaturated state, often leading...... strategy for poorly-soluble drugs. While the current research on co-amorphous formulations is focused on preparation and characterization of these systems, more detailed research on their supersaturation and precipitation behavior and the effect of co-formers on nucleation and crystal growth inhibition...

  19. Social video content delivery

    CERN Document Server

    Wang, Zhi; Zhu, Wenwu

    2016-01-01

    This brief presents new architecture and strategies for distribution of social video content. A primary framework for socially-aware video delivery and a thorough overview of the possible approaches is provided. The book identifies the unique characteristics of socially-aware video access and social content propagation, revealing the design and integration of individual modules that are aimed at enhancing user experience in the social network context. The change in video content generation, propagation, and consumption for online social networks, has significantly challenged the traditional video delivery paradigm. Given the massive amount of user-generated content shared in online social networks, users are now engaged as active participants in the social ecosystem rather than as passive receivers of media content. This revolution is being driven further by the deep penetration of 3G/4G wireless networks and smart mobile devices that are seamlessly integrated with online social networking and media-sharing s...

  20. Mucoadhesive drug delivery systems

    Directory of Open Access Journals (Sweden)

    Rahamatullah Shaikh

    2011-01-01

    Full Text Available Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Over the past few decades, mucosal drug delivery has received a great deal of attention. Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The mucoadhesive ability of a dosage form is dependent upon a variety of factors, including the nature of the mucosal tissue and the physicochemical properties of the polymeric formulation. This review article aims to provide an overview of the various aspects of mucoadhesion, mucoadhesive materials, factors affecting mucoadhesion, evaluating methods, and finally various mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal.

  1. Polymer nanogels: a versatile nanoscopic drug delivery platform

    Science.gov (United States)

    Chacko, Reuben T.; Ventura, Judy; Zhuang, Jiaming; Thayumanavan, S.

    2012-01-01

    In this review we put the spotlight on crosslinked polymer nanogels, a promising platform that has the characteristics of an “ideal” drug delivery vehicle. Some of the key aspects of drug delivery vehicle design like stability, response to biologically relevant stimuli, passive targeting, active targeting, toxicity and ease of synthesis are discussed. We discuss several delivery systems in this light and highlight some examples of systems, which satisfy some or all of these design requirements. In particular, we point to the advantages that crosslinked polymeric systems bring to drug delivery. We review some of the synthetic methods of nanogel synthesis and conclude with the diverse applications in drug delivery where nanogels have been fruitfully employed. PMID:22342438

  2. Nonviral Delivery Systems For Cancer Gene Therapy: Strategies And Challenges.

    Science.gov (United States)

    Shim, Gayong; Kim, Dongyoon; Le, Quoc-Viet; Park, Gyu Thae; Kwon, Taekhyun; Oh, Yu-Kyoung

    2018-01-19

    Gene therapy has been receiving widespread attention due to its unique advantage in regulating the expression of specific target genes. In the field of cancer gene therapy, modulation of gene expression has been shown to decrease oncogenic factors in cancer cells or increase immune responses against cancer. Due to the macromolecular size and highly negative physicochemical features of plasmid DNA, efficient delivery systems are an essential ingredient for successful gene therapy. To date, a variety of nanostructures and materials have been studied as nonviral gene delivery systems. In this review, we will cover nonviral delivery strategies for cancer gene therapy, with a focus on target cancer genes and delivery materials. Moreover, we will address current challenges and perspectives for nonviral delivery-based cancer gene therapeutics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Advanced drug delivery approaches against periodontitis.

    Science.gov (United States)

    Joshi, Deeksha; Garg, Tarun; Goyal, Amit K; Rath, Goutam

    2016-01-01

    Periodontitis is an inflammatory disease of gums involving the degeneration of periodontal ligaments, creation of periodontal pocket and resorption of alveolar bone, resulting in the disruption of the support structure of teeth. According to WHO, 10-15% of the global population suffers from severe periodontitis. The disease results from the growth of a diverse microflora (especially anaerobes) in the pockets and release of toxins, enzymes and stimulation of body's immune response. Various local or systemic approaches were used for an effective treatment of periodontitis. Currently, controlled local drug delivery approach is more favorable as compared to systemic approach because it mainly focuses on improving the therapeutic outcomes by achieving factors like site-specific delivery, low dose requirement, bypass of first-pass metabolism, reduction in gastrointestinal side effects and decrease in dosing frequency. Overall it provides a safe and effective mode of treatment, which enhances patient compliance. Complete eradication of the organisms from the sites was not achieved by using various surgical and mechanical treatments. So a number of polymer-based delivery systems like fibers, films, chips, strips, microparticles, nanoparticles and nanofibers made from a variety of natural and synthetic materials have been successfully tested to deliver a variety of drugs. These systems are biocompatible and biodegradable, completely fill the pockets, and have strong retention on the target site due to excellent mucoadhesion properties. The review summarizes various available and recently developing targeted delivery devices for the treatment of periodontitis.

  4. Multifunctional Nanoparticles for Drug Delivery Applications Imaging, Targeting, and Delivery

    CERN Document Server

    Prud'homme, Robert

    2012-01-01

    This book clearly demonstrates the progression of nanoparticle therapeutics from basic research to applications. Unlike other books covering nanoparticles used in medical applications, Multifunctional Nanoparticles for Drug Delivery Applications presents the medical challenges that can be reduced or even overcome by recent advances in nanoscale drug delivery. Each chapter highlights recent progress in the design and engineering of select multifunctional nanoparticles with topics covering targeting, imaging, delivery, diagnostics, and therapy.

  5. Magnetic targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Timothy Wiedmann

    2009-10-01

    Full Text Available Lung cancer is the most common cause of death from cancer in both men and women. Treatment by intravenous or oral administration of chemotherapy agents results in serious and often treatment-limiting side effects. Delivery of drugs directly to the lung by inhalation of an aerosol holds the promise of achieving a higher concentration in the lung with lower blood levels. To further enhance the selective lung deposition, it may be possible to target deposition by using external magnetic fields to direct the delivery of drug coupled to magnetic particles. Moreover, alternating magnetic fields can be used to induce particle heating, which in turn controls the drug release rate with the appropriate thermal sensitive material.With this goal, superparamagetic nanoparticles (SPNP were prepared and characterized, and enhanced magnetic deposition was demonstrated in vitro and in vivo. SPNPs were also incorporated into a lipid-based/SPNP aerosol formulation, and drug release was shown to be controlled by thermal activation. Because of the inherent imaging potential of SPNPs, this use of nanotechnology offers the possibility of coupling the diagnosis of lung cancer to drug release, which perhaps will ultimately provide the “magic bullet” that Paul Ehrlich originally sought.

  6. [Operative vaginal deliveries training].

    Science.gov (United States)

    Dupuis, O

    2008-12-01

    The appropriate use of forceps, vacuums or spatulas facilitates the rapid delivery of foetuses faced with life-threatening situations. It also makes possible the relief of certain cases of prolonged second-stage labor. In France, operative vaginal delivery (OVD) accounts for approximately 10% of all births. OVD training aims to optimize maternal, as well as neonatal safety. It should enable trainees to indicate or contraindicate an OVD safely, as well as to choose the appropriate instrument, use it correctly, and master quality control principles. Traditional OVD training is confronted with both spatial and time-related limitations. Spatial constraints involve both the teacher and trainee who only have limited visual access to the pelvic canal, and the head of the foetus; the time constraint occurs whenever the OVD occurs in an emergency setting. These limitations have been further aggravated by new constraints: decreasing time dedicated to training (European safety rules prohibit work the day after night duty), increasing litigation, and constraints imposed by society. Training by means of simulation removes such limitations making it possible to both avoid exposing pregnant women to the hazards of traditional training, and adapt the training to the skills of each trainee. OVD training should include forceps, vacuums and the use of spatulas. The OVD skills of obstetricians should be audited regularly on both a personal and a confidential level. Such audits could be based on a method using a simulator. Prospective studies comparing traditional and simulation-based training should be encouraged.

  7. Document delivery services contrasting views

    CERN Document Server

    1999-01-01

    Design and maintain document delivery services that are ideal for academic patrons! In Document Delivery Services: Contrasting Views, you'll visit four university library systems to discover the considerations and challenges each library faced in bringing document delivery to its clientele. This book examines the questions about document delivery that are most pressing in the profession of library science. Despite their own unique experiences, you'll find common practices among all four?including planning, implementation of service, and evaluation of either user satisfaction and/or vendor per

  8. Intranasal delivery of antipsychotic drugs.

    Science.gov (United States)

    Katare, Yogesh K; Piazza, Justin E; Bhandari, Jayant; Daya, Ritesh P; Akilan, Kosalan; Simpson, Madeline J; Hoare, Todd; Mishra, Ram K

    2017-06-01

    Antipsychotic drugs are used to treat psychotic disorders that afflict millions globally and cause tremendous emotional, economic and healthcare burdens. However, the potential of intranasal delivery to improve brain-specific targeting remains unrealized. In this article, we review the mechanisms and methods used for brain targeting via the intranasal (IN) route as well as the potential advantages of improving this type of delivery. We extensively review experimental studies relevant to intranasal delivery of therapeutic agents for the treatment of psychosis and mental illnesses. We also review clinical studies in which intranasal delivery of peptides, like oxytocin (7 studies) and desmopressin (1), were used as an adjuvant to antipsychotic treatment with promising results. Experimental animal studies (17) investigating intranasal delivery of mainstream antipsychotic drugs have revealed successful targeting to the brain as suggested by pharmacokinetic parameters and behavioral effects. To improve delivery to the brain, nanotechnology-based carriers like nanoparticles and nanoemulsions have been used in several studies. However, human studies assessing intranasal delivery of mainstream antipsychotic drugs are lacking, and the potential toxicity of nanoformulations used in animal studies has not been explored. A brief discussion of future directions anticipates that if limitations of low aqueous solubility of antipsychotic drugs can be overcome and non-toxic formulations used, IN delivery (particularly targeting specific tissues within the brain) will gain more importance moving forward given the inherent benefits of IN delivery in comparison to other methods. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Thermoreversible gelation polymer as an embolic material for aneurysm treatment: a delivery device for dermal fibroblasts and basic fibroblast growing factor into experimental aneurysms in rats.

    Science.gov (United States)

    Dobashi, Hisashi; Akasaki, Yasuharu; Yuki, Ichiro; Arai, Takao; Ohashi, Hiroki; Murayama, Yuichi; Takao, Hiroyuki; Abe, Toshiaki

    2013-11-01

    This study evaluates whether thermoreversible gelation polymer (TGP) can be used as a delivery device to deploy dermal fibroblasts and cytokines into experimental aneurysms in rats. The right common iliac artery of rats was surgically ligated and an experimental aneurysm was created by applying exogenous elastase. Seven days later, two aneurysms were harvested and used as controls (Group A), two were embolized with pure TGP (Group B), two were embolized with TGP and basic fibroblast growth factor (bFGF) (Group C) and two were embolized with TGP loaded with rat dermal fibroblasts (Group D). The aneurysms were also embolized with TGP mixed with dermal fibroblasts and bFGF at different concentrations (10 ng/ml: Group E (n=2), 100 ng/ml: Group F (n=2), 1000 ng/ml: Group G (n=2)). Each aneurysm sample was harvested after 7 days and histologic analyses were performed. The most advanced thrombus organization in the aneurysm, such as prominent fibroblast proliferation and collagen deposition, was observed in Groups E, F and G, although there was no noticeable difference between the groups. Moderate thrombus organization was seen in Group D and minimal thrombus organization was seen in Groups B and C. TGP mixed with both dermal fibroblasts and bFGF induced the most advanced thrombus organization in the experimental aneurysms followed by TGP mixed only with dermal fibroblasts. TGP may be useful as a delivery device to deploy fibroblasts and cytokines into aneurysms.

  10. Document Delivery Services around the World

    Directory of Open Access Journals (Sweden)

    Ashrafosadat Foladi

    2008-04-01

    Full Text Available Given the importance of information access versus collection, the present study identified and investigated ten most important document delivery websites which had the highest frequency of citations in online directories and printed sources. The evaluation was based on the indicators and policies of Iranian Scientific Information and Documentation Center (IRANDOC. These included document diversity, document request mechanisms, document delivery options, response time, payment options, costs, and copy right clearance. The findings were then processed statistically using SPSS. It was found that based on document diversity BLDSC, LHL and DocDeliver are the frontrunners. On the account of subject comprehensiveness, Doc Deliver, BLDSC, Infotrieve, Ingenta, ISI and UMI are at the same level. All ten sites studied covered basic sciences. BL is strong with respect to diversity of document delivery options, payment options and response time. ISI is most suitable when diversity in request options is required. Ingenta is suitable when diversity in payment options are required. NTIS is in the lead when special documents such as technical reports are required, while UMI is most suitable for Dissertations and rare books

  11. Plasmon resonant liposomes for controlled drug delivery

    Science.gov (United States)

    Knights-Mitchell, Shellie S.; Romanowski, Marek

    2015-03-01

    Nanotechnology use in drug delivery promotes a reduction in systemic toxicity, improved pharmacokinetics, and better drug bioavailability. Liposomes continue to be extensively researched as drug delivery systems (DDS) with formulations such as Doxil® and Ambisome® approved by FDA and successfully marketed in the United States. However, the limited ability to precisely control release of active ingredients from these vesicles continues to challenge the broad implementation of this technology. Moreover, the full potential of the carrier to sequester drugs until it can reach its intended target has yet to be realized. Here, we describe a liposomal DDS that releases therapeutic doses of an anticancer drug in response to external stimulus. Earlier, we introduced degradable plasmon resonant liposomes. These constructs, obtained by reducing gold on the liposome surface, facilitate spatial and temporal release of drugs upon laser light illumination that ultimately induces an increase in temperature. In this work, plasmon resonant liposomes have been developed to stably encapsulate and retain doxorubicin at physiological conditions represented by isotonic saline at 37o C and pH 7.4. Subsequently, they are stimulated to release contents either by a 5o C increase in temperature or by laser illumination (760 nm and 88 mW/cm2 power density). Successful development of degradable plasmon resonant liposomes responsive to near-infrared light or moderate hyperthermia can provide a new delivery method for multiple lipophilic and hydrophilic drugs with pharmacokinetic profiles that limit clinical utility.

  12. Medical abortion service delivery.

    Science.gov (United States)

    Breitbart, V; Rogers, M K; Vanderhei, D

    2000-08-01

    Medical abortion with mifepristone and methotrexate regimens may be offered in a variety of American medical practice settings. In this article the new provider will find information on all aspects of the patient care delivery system for medical abortion, including physical space requirements, staffing and training, patient flow, cost, security, marketing, and quality assurance. Because of the limited published data available regarding logistic issues surrounding abortion care, the information in this article derives largely from the experiences of providers who have established medical abortion practices in their offices or clinics. Its goals are to help make the initial start-up phase briefer and more rewarding for new providers, to offer helpful guidelines for incorporation of medical abortion into practice, and to encourage more practitioners to see the benefits of adding this option to their practices.

  13. Secondary fuel delivery system

    Science.gov (United States)

    Parker, David M.; Cai, Weidong; Garan, Daniel W.; Harris, Arthur J.

    2010-02-23

    A secondary fuel delivery system for delivering a secondary stream of fuel and/or diluent to a secondary combustion zone located in the transition piece of a combustion engine, downstream of the engine primary combustion region is disclosed. The system includes a manifold formed integral to, and surrounding a portion of, the transition piece, a manifold inlet port, and a collection of injection nozzles. A flowsleeve augments fuel/diluent flow velocity and improves the system cooling effectiveness. Passive cooling elements, including effusion cooling holes located within the transition boundary and thermal-stress-dissipating gaps that resist thermal stress accumulation, provide supplemental heat dissipation in key areas. The system delivers a secondary fuel/diluent mixture to a secondary combustion zone located along the length of the transition piece, while reducing the impact of elevated vibration levels found within the transition piece and avoiding the heat dissipation difficulties often associated with traditional vibration reduction methods.

  14. Microneedle and mucosal delivery of influenza vaccines

    Science.gov (United States)

    Kang, Sang-Moo; Song, Jae-Min; Kim, Yeu-Chun

    2017-01-01

    In recent years with the threat of pandemic influenza and other public health needs, alternative vaccination methods other than intramuscular immunization have received great attention. The skin and mucosal surfaces are attractive sites probably because of both non-invasive access to the vaccine delivery and unique immunological responses. Intradermal vaccines using a microinjection system (BD Soluvia) and intranasal vaccines (FluMist) are licensed. As a new vaccination method, solid microneedles have been developed using a simple device that may be suitable for self-administration. Because coated micorneedle influenza vaccines are administered in the solid state, developing formulations maintaining the stability of influenza vaccines is an important issue to be considered. Marketable microneedle devices and clinical trials remain to be developed. Other alternative mucosal routes such as oral and intranasal delivery systems are also attractive for inducing cross protective mucosal immunity but effective non-live mucosal vaccines remain to be developed. PMID:22697052

  15. Polysaccharide-Based Micelles for Drug Delivery

    Directory of Open Access Journals (Sweden)

    Nan Zhang

    2013-05-01

    Full Text Available Delivery of hydrophobic molecules and proteins has been an issue due to poor bioavailability following administration. Thus, micelle carrier systems are being investigated to improve drug solubility and stability. Due to problems with toxicity and immunogenicity, natural polysaccharides are being explored as substitutes for synthetic polymers in the development of new micelle systems. By grafting hydrophobic moieties to the polysaccharide backbone, self-assembled micelles can be readily formed in aqueous solution. Many polysaccharides also possess inherent bioactivity that can facilitate mucoadhesion, enhanced targeting of specific tissues, and a reduction in the inflammatory response. Furthermore, the hydrophilic nature of some polysaccharides can be exploited to enhance circulatory stability. This review will highlight the advantages of polysaccharide use in the development of drug delivery systems and will provide an overview of the polysaccharide-based micelles that have been developed to date.

  16. Cationic Bolaamphiphiles for Gene Delivery

    Science.gov (United States)

    Tan, Amelia Li Min; Lim, Alisa Xue Ling; Zhu, Yiting; Yang, Yi Yan; Khan, Majad

    2014-05-01

    Advances in medical research have shed light on the genetic cause of many human diseases. Gene therapy is a promising approach which can be used to deliver therapeutic genes to treat genetic diseases at its most fundamental level. In general, nonviral vectors are preferred due to reduced risk of immune response, but they are also commonly associated with low transfection efficiency and high cytotoxicity. In contrast to viral vectors, nonviral vectors do not have a natural mechanism to overcome extra- and intracellular barriers when delivering the therapeutic gene into cell. Hence, its design has been increasingly complex to meet challenges faced in targeting of, penetration of and expression in a specific host cell in achieving more satisfactory transfection efficiency. Flexibility in design of the vector is desirable, to enable a careful and controlled manipulation of its properties and functions. This can be met by the use of bolaamphiphile, a special class of lipid. Unlike conventional lipids, bolaamphiphiles can form asymmetric complexes with the therapeutic gene. The advantage of having an asymmetric complex lies in the different purposes served by the interior and exterior of the complex. More effective gene encapsulation within the interior of the complex can be achieved without triggering greater aggregation of serum proteins with the exterior, potentially overcoming one of the great hurdles faced by conventional single-head cationic lipids. In this review, we will look into the physiochemical considerations as well as the biological aspects of a bolaamphiphile-based gene delivery system.

  17. Emerging Frontiers in Drug Delivery.

    Science.gov (United States)

    Tibbitt, Mark W; Dahlman, James E; Langer, Robert

    2016-01-27

    Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and materials advances that are enabling the field to overcome these hurdles for clinical impact.

  18. Hydrogen Delivery Technical Team Roadmap

    Energy Technology Data Exchange (ETDEWEB)

    None

    2013-06-01

    The mission of the Hydrogen Delivery Technical Team (HDTT) is to enable the development of hydrogen delivery technologies, which will allow for fuel cell competitiveness with gasoline and hybrid technologies by achieving an as-produced, delivered, and dispensed hydrogen cost of $2-$4 per gallon of gasoline equivalent of hydrogen.

  19. Silk-Based Biomaterials for Sustained Drug Delivery

    Science.gov (United States)

    Yucel, Tuna; Lovett, Michael L.; Kaplan, David L.

    2014-01-01

    Silk presents a rare combination of desirable properties for sustained drug delivery, including aqueous-based purification and processing options without chemical cross-linkers, compatibility with common sterilization methods, controllable and surface-mediated biodegradation into non-inflammatory by-products, biocompatibility, utility in drug stabilization, and robust mechanical properties. A versatile silk-based toolkit is currently available for sustained drug delivery formulations of small molecule through macromolecular drugs, with a promise to mitigate several drawbacks associated with other degradable sustained delivery technologies in the market. Silk-based formulations utilize silk’s well-defined nano- through microscale structural hierarchy, stimuli-responsive self-assembly pathways and crystal polymorphism, as well as sequence and genetic modification options towards targeted pharmaceutical outcomes. Furthermore, by manipulating the interactions between silk and drug molecules, near-zero order sustained release may be achieved through diffusion- and degradation-based release mechanisms. Because of these desirable properties, there has been increasing industrial interest in silk-based drug delivery systems currently at various stages of the developmental pipeline from pre-clinical to FDA-approved products. Here, we discuss the unique aspects of silk technology as a sustained drug delivery platform and highlight the current state of the art in silk-based drug delivery. We also offer a potential early development pathway for silk-based sustained delivery products. PMID:24910193

  20. Inhibiting the Th17/IL-17A-related inflammatory responses with digoxin confers protection against experimental abdominal aortic aneurysm.

    Science.gov (United States)

    Wei, Zhanjie; Wang, Yu; Zhang, Kailun; Liao, Yaohang; Ye, Ping; Wu, Jie; Wang, Yang; Li, Feifei; Yao, Yufeng; Zhou, Yanzhao; Liu, Jinping

    2014-11-01

    T helper 17 cells and interleukin-17A have been implicated in the progression of abdominal aortic aneurysm (AAA). Retinoic acid-related orphan receptor gamma thymus, the master transcription factor of T helper 17 cell differentiation, is selectively antagonized by digoxin. However, the effect of antagonizing retinoic acid-related orphan receptor gamma thymus on AAA has not been investigated. We used human aortic sample analysis and 2 different experimental AAA models: (a) Angiotensin II (Ang II)-induced ApoE(-/-) male mice (Ang II/APOE model) and (b) porcine pancreatic elastase perfusion C57BL/6 mice (porcine pancreatic elastase/C57 model). In the Ang II/APOE model, all mice (n=80) were divided into 4 groups: sham group (saline+0.5% dimethyl sulfoxide treatment), control group (Ang II+0.5% dimethyl sulfoxide treatment), low-dose group (Ang II+low-dose digoxin, 20 μg/d per mouse), and high-dose group (Ang II+high-dose digoxin, 40 μg/d per mouse). All treatments began on day 0 after surgery. Efficacy was determined via aortic diameter and systolic blood pressure measurements, histopathology and protein expression, and flow cytometry analysis when euthenized. Human aortic tissue analysis showed that both interleukin-17A and retinoic acid-related orphan receptor gamma thymus increased in AAA tissues. The low-dose and high-dose groups had AAA incidences of 60% and 35%, respectively, compared with 70% in the control group. The T helper 17- and interleukin-17A-related inflammatory responses were dose-dependently attenuated by digoxin treatment. Digoxin was also highly effective in the porcine pancreatic elastase/C57 model. Digoxin attenuates experimental AAA progression in a model-independent manner. Antagonizing retinoic acid-related orphan receptor gamma thymus activity by digoxin may become a novel strategy for nonsurgical AAA treatment. © 2014 American Heart Association, Inc.

  1. Electronic Nicotine Delivery Systems.

    Science.gov (United States)

    Walley, Susan C; Jenssen, Brian P

    2015-11-01

    Electronic nicotine delivery systems (ENDS) are rapidly growing in popularity among youth. ENDS are handheld devices that produce an aerosolized mixture from a solution typically containing concentrated nicotine, flavoring chemicals, and propylene glycol to be inhaled by the user. ENDS are marketed under a variety of names, most commonly electronic cigarettes and e-cigarettes. In 2014, more youth reported using ENDS than any other tobacco product. ENDS pose health risks to both users and nonusers. Nicotine, the major psychoactive ingredient in ENDS solutions, is both highly addictive and toxic. In addition to nicotine, other toxicants, carcinogens, and metal particles have been detected in solutions and aerosols of ENDS. Nonusers are involuntarily exposed to the emissions of these devices with secondhand and thirdhand aerosol. The concentrated and often flavored nicotine in ENDS solutions poses a poisoning risk for young children. Reports of acute nicotine toxicity from US poison control centers have been increasing, with at least 1 child death reported from unintentional exposure to a nicotine-containing ENDS solution. With flavors, design, and marketing that appeal to youth, ENDS threaten to renormalize and glamorize nicotine and tobacco product use. There is a critical need for ENDS regulation, legislative action, and counter promotion to protect youth. ENDS have the potential to addict a new generation of youth to nicotine and reverse more than 50 years of progress in tobacco control. Copyright © 2015 by the American Academy of Pediatrics.

  2. Drug delivery systems: Advanced technologies potentially applicable in personalized treatments.

    Science.gov (United States)

    Coelho, Jorge F; Ferreira, Paula C; Alves, Patricia; Cordeiro, Rosemeyre; Fonseca, Ana C; Góis, Joana R; Gil, Maria H

    2010-03-01

    Advanced drug delivery systems (DDS) present indubitable benefits for drug administration. Over the past three decades, new approaches have been suggested for the development of novel carriers for drug delivery. In this review, we describe general concepts and emerging research in this field based on multidisciplinary approaches aimed at creating personalized treatment for a broad range of highly prevalent diseases (e.g., cancer and diabetes). This review is composed of two parts. The first part provides an overview on currently available drug delivery technologies including a brief history on the development of these systems and some of the research strategies applied. The second part provides information about the most advanced drug delivery devices using stimuli-responsive polymers. Their synthesis using controlled-living radical polymerization strategy is described. In a near future it is predictable the appearance of new effective tailor-made DDS, resulting from knowledge of different interdisciplinary sciences, in a perspective of creating personalized medical solutions.

  3. Emerging Technologies of Polymeric Nanoparticles in Cancer Drug Delivery

    International Nuclear Information System (INIS)

    Brewer, E.; Coleman, J.; Lowman, A.

    2011-01-01

    Polymeric nanomaterials have the potential to improve upon present chemotherapy delivery methods. They successfully reduce side effects while increasing dosage, increase residence time in the body, offer a sustained and tunable release, and have the ability to deliver multiple drugs in one carrier. However, traditional nanomaterial formulations have not produced highly therapeutic formulations to date due to their passive delivery methods and lack of rapid drug release at their intended site. In this paper, we have focused on a few smart technologies that further enhance the benefits of typical nanomaterials. Temperature and pH-responsive drug delivery devices were reviewed as methods for triggering release of encapsulating drugs, while aptamer and ligand conjugation were discussed as methods for targeted and intracellular delivery, with emphases on in vitro and in vivo works for each method.

  4. Emerging Technologies of Polymeric Nanoparticles in Cancer Drug Delivery

    Directory of Open Access Journals (Sweden)

    Erik Brewer

    2011-01-01

    Full Text Available Polymeric nanomaterials have the potential to improve upon present chemotherapy delivery methods. They successfully reduce side effects while increasing dosage, increase residence time in the body, offer a sustained and tunable release, and have the ability to deliver multiple drugs in one carrier. However, traditional nanomaterial formulations have not produced highly therapeutic formulations to date due to their passive delivery methods and lack of rapid drug release at their intended site. In this paper, we have focused on a few “smart” technologies that further enhance the benefits of typical nanomaterials. Temperature and pH-responsive drug delivery devices were reviewed as methods for triggering release of encapsulating drugs, while aptamer and ligand conjugation were discussed as methods for targeted and intracellular delivery, with emphases on in vitro and in vivo works for each method.

  5. Filamentous bacteriophage fd as an antigen delivery system in vaccination.

    Science.gov (United States)

    Prisco, Antonella; De Berardinis, Piergiuseppe

    2012-01-01

    Peptides displayed on the surface of filamentous bacteriophage fd are able to induce humoral as well as cell-mediated immune responses, which makes phage particles an attractive antigen delivery system to design new vaccines. The immune response induced by phage-displayed peptides can be enhanced by targeting phage particles to the professional antigen presenting cells, utilizing a single-chain antibody fragment that binds dendritic cell receptor DEC-205. Here, we review recent advances in the use of filamentous phage fd as a platform for peptide vaccines, with a special focus on the use of phage fd as an antigen delivery platform for peptide vaccines in Alzheimer's Disease and cancer.

  6. Space age health care delivery

    Science.gov (United States)

    Jones, W. L.

    1977-01-01

    Space age health care delivery is being delivered to both NASA astronauts and employees with primary emphasis on preventive medicine. The program relies heavily on comprehensive health physical exams, health education, screening programs and physical fitness programs. Medical data from the program is stored in a computer bank so epidemiological significance can be established and better procedures can be obtained. Besides health care delivery to the NASA population, NASA is working with HEW on a telemedicine project STARPAHC, applying space technology to provide health care delivery to remotely located populations.

  7. Delivery systems for antimicrobial peptides

    DEFF Research Database (Denmark)

    Nordström, Randi; Malmsten, Martin

    2017-01-01

    on the identification such peptides, as well as on their optimization to reach potent antimicrobial and anti-inflammatory effects at simultaneously low toxicity against human cells. In comparison, delivery systems for antimicrobial peptides have attracted considerably less interest. However, such delivery systems......, or through achieving co-localization with intracellular pathogens. Here, an overview is provided of the current understanding of delivery systems for antimicrobial peptides, with special focus on AMP-carrier interactions, as well as consequences of these interactions for antimicrobial and related biological...

  8. Ceramic drug-delivery devices.

    Science.gov (United States)

    Lasserre, A; Bajpai, P K

    1998-01-01

    A variety of ceramics and delivery systems have been used to deliver chemicals, biologicals, and drugs at various rates for desired periods of time from different sites of implantation. In vitro and in vivo studies have shown that ceramics can successfully be used as drug-delivery devices. Matrices, inserts, reservoirs, cements, and particles have been used to deliver a large variety of therapeutic agents such as antibiotics, anticancer drugs, anticoagulants, analgesics, growth factors, hormones, steroids, and vaccines. In this article, the advantages and disadvantages of conventional drug-delivery systems and the different approaches used to deliver chemical and biological agents by means of ceramic systems will be reviewed.

  9. Evaluation of Aerosol Delivery of Nanosuspension for Pre-clinical Pulmonary Drug Delivery

    Directory of Open Access Journals (Sweden)

    Chiang Po-Chang

    2009-01-01

    Full Text Available Abstract Asthma and chronic obstructive pulmonary disease (COPD are pulmonary diseases that are characterized by inflammatory cell infiltration, cytokine production, and airway hyper-reactivity. Most of the effector cells responsible for these pathologies reside in the lungs. One of the most direct ways to deliver drugs to the target cells is via the trachea. In a pre-clinical setting, this can be achieved via intratracheal (IT, intranasal (IN, or aerosol delivery in the desired animal model. In this study, we pioneered the aerosol delivery of a nanosuspension formulation in a rodent model. The efficiency of different dosing techniques and formulations to target the lungs were compared, and fluticasone was used as the model compound. For the aerosol particle size determination, a ten-stage cascade impactor was used. The mass median aerodynamic diameter (MMAD was calculated based on the percent cumulative accumulation at each stage. Formulations with different particle size of fluticasone were made for evaluation. The compatibility of regular fluticasone suspension and nanosuspension for aerosol delivery was also investigated. The in vivo studies were conducted on mice with optimized setting. It was found that the aerosol delivery of fluticasone with nanosuspension was as efficient as intranasal (IN dosing, and was able to achieve dose dependent lung deposition.

  10. Lentiviral Delivery of Proteins for Genome Engineering.

    Science.gov (United States)

    Cai, Yujia; Mikkelsen, Jacob Giehm

    2016-01-01

    Viruses have evolved to traverse cellular barriers and travel to the nucleus by mechanisms that involve active transport through the cytoplasm and viral quirks to resist cellular restriction factors and innate immune responses. Virus-derived vector systems exploit the capacity of viruses to ferry genetic information into cells, and now - more than three decades after the discovery of HIV - lentiviral vectors based on HIV-1 have become instrumental in biomedical research and gene therapies that require genomic insertion of transgenes. By now, the efficacy of lentiviral gene delivery to stem cells, cells of the immune system including T cells, hepatic cells, and many other therapeutically relevant cell types is well established. Along with nucleic acids, HIV-1 virions carry the enzymatic tools that are essential for early steps of infection. Such capacity to package enzymes, even proteins of nonviral origin, has unveiled new ways of exploiting cellular intrusion of HIV-1. Based on early findings demonstrating the packaging of heterologous proteins into virus particles as part of the Gag and GagPol polypeptides, we have established lentiviral protein transduction for delivery of DNA transposases and designer nucleases. This strategy for delivering genome-engineering proteins facilitates high enzymatic activity within a short time frame and may potentially improve the safety of genome editing. Exploiting the full potential of lentiviral vectors, incorporation of foreign protein can be combined with the delivery of DNA transposons or a donor sequence for homology-directed repair in so-called 'all-in-one' lentiviral vectors. Here, we briefly describe intracellular restrictions that may affect lentiviral gene and protein delivery and review the current status of lentiviral particles as carriers of tool kits for genome engineering.

  11. Accumulation of a maize proteinase inhibitor in response to wounding and insect feeding, and characterization of its activity toward digestive proteinases of Spodoptera littoralis larvae.

    Science.gov (United States)

    Tamayo, M C; Rufat, M; Bravo, J M; San Segundo, B

    2000-06-01

    The mpi gene encodes a maize proteinase inhibitor (MPI) protein whose mRNA accumulates in response to mechanical wounding. In this study, mpi gene expression in response to different types of damage was investigated. In mechanically damaged leaves of maize (Zea mays L.), mpi mRNA accumulation was affected by the degree of damage inflicted on the leaf. Consecutive wounds resulted in higher levels of mpi transcripts. The MPI protein was expressed in Escherichia coli and purified. Polyclonal antibodies were then produced and used to study MPI accumulation in insect-wounded and mechanically wounded maize leaves. When larvae of the lepidopteran insect Spodoptera littoralis were fed on maize leaves, MPI accumulated in tissues adjacent to the wound site. The level of inhibitor accumulation was higher in leaves chewed by larvae than in leaves that had been damaged mechanically. Longer feeding periods also resulted in higher levels of MPI accumulation. Additionally, the inhibitory properties of MPI toward mammalian and insect digestive serine proteinases were determined. Contrary to the majority of the plant proteinase inhibitors described, MPI is an inhibitor of mammalian elastase that only weakly inhibits mammalian chymotrypsin. However, both elastase and chymotrypsin-like activities from the larval midgut of S. littoralis were effectively inhibited by MPI. We discuss these results with regard to the function and evolution of plant proteinase inhibitors. The availability of a plant proteinase inhibitor which is able to inhibit the two types of insect digestive proteinase, elastase and chymotrypsin, might be useful for engineering protection against lepidopteran insect pests in transgenic plants.

  12. Ultrasound mediated transdermal drug delivery.

    Science.gov (United States)

    Azagury, Aharon; Khoury, Luai; Enden, Giora; Kost, Joseph

    2014-06-01

    Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injections. However, the stratum corneum serves as a barrier that limits the penetration of substances to the skin. Application of ultrasound (US) irradiation to the skin increases its permeability (sonophoresis) and enables the delivery of various substances into and through the skin. This review presents the main findings in the field of sonophoresis in transdermal drug delivery as well as transdermal monitoring and the mathematical models associated with this field. Particular attention is paid to the proposed enhancement mechanisms and future trends in the fields of cutaneous vaccination and gene therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Continuous Delivery and Quality Monitoring

    CERN Multimedia

    CERN. Geneva

    2016-01-01

    After introducing Continuous Delivery, I will switch the topic and try to answer the question how much should we invest in quality and how to do it efficiently. My observations reveal that software quality is often considered as the slo...

  14. Oral delivery of anticancer drugs

    DEFF Research Database (Denmark)

    Thanki, Kaushik; Gangwal, Rahul P; Sangamwar, Abhay T

    2013-01-01

    The present report focuses on the various aspects of oral delivery of anticancer drugs. The significance of oral delivery in cancer therapeutics has been highlighted which principally includes improvement in quality of life of patients and reduced health care costs. Subsequently, the challenges...... incurred in the oral delivery of anticancer agents have been especially emphasized. Sincere efforts have been made to compile the various physicochemical properties of anticancer drugs from either literature or predicted in silico via GastroPlus™. The later section of the paper reviews various emerging...... trends to tackle the challenges associated with oral delivery of anticancer drugs. These invariably include efflux transporter based-, functional excipient- and nanocarrier based-approaches. The role of drug nanocrystals and various others such as polymer based- and lipid based...

  15. Extracellular vesicles for drug delivery

    NARCIS (Netherlands)

    Vader, Pieter; Mol, Emma A; Pasterkamp, Gerard; Schiffelers, Raymond M

    2016-01-01

    Extracellular vesicles (EVs) are cell-derived membrane vesicles, and represent an endogenous mechanism for intercellular communication. Since the discovery that EVs are capable of functionally transferring biological information, the potential use of EVs as drug delivery vehicles has gained

  16. Application of nanohydrogels in drug delivery systems: recent patents review.

    Science.gov (United States)

    Dalwadi, Chintan; Patel, Gayatri

    2015-01-01

    Nanohydrogel combines the advantages of hydrogel and nano particulate systems. Similar to the hydrogel and macrogel, nanohydrogel can protect the drug and control drug release by stimuli responsive conformation or biodegradable bond into the polymer networks. Nanohydrogel has drawn huge interest due to their potential applications, such as carrier in target-specific controlled drug delivery, absorbents, chemical/biological sensors, and bio-mimetic materials. Similar to the nanoparticles, stimuli responsive nanohydrogel can easily be delivered in the liquid form for parenteral drug delivery application. This review highlights the methods to prepare nanohydrogel based on natural and synthetic polymers for diverse applications in drug delivery. It also encompasses the drug loading and drug release mechanism of the nanohydrogel formulation and patents related to the composition and chemical methods for preparation of nanohydrogel formulation with current status in clinical trials.

  17. [French residents' training in instrumental deliveries: A national survey].

    Science.gov (United States)

    Saunier, C; Raimond, E; Dupont, A; Pelissier, A; Bonneau, S; Gabriel, R; Graesslin, O

    2016-11-01

    To evaluate French residents in Obstetrics and Gynaecology's training in instrumental deliveries in 2015. We conducted a national descriptive survey among 758 residents between December 2014 and January 2015. Respondents were invited by email to specify their University Hospital, their current university term, the number of instrumental deliveries performed by vacuum extractor, forceps or spatulas, and whether they made systematic ultrasound exams before performing the extraction. Response rate was 34.7 % (n=263). There were important differences between regions in terms of type of instruments used. Vacuum extractor was the most commonly used instrument for instrumental deliveries by French residents (56.9 %), more than forceps (25.2 %) and spatulas (17.9 %). At the end of the residency, all the residents had been trained in instrumental deliveries with at least two instruments. The training of difficult techniques as well as their perfect control is required for instrumental deliveries. Yet, we are forced to note that there are substantial differences in the French residents' training in instrumental deliveries depending on their region. So, teaching at least two techniques seems essential as well as improving the training capacities and standardizing practices. A greater systematization of the teaching of the mechanics and obstetric techniques might be a solution to be considered too. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. Microneedle-mediated delivery of viral vectored vaccines.

    Science.gov (United States)

    Zaric, Marija; Ibarzo Yus, Bárbara; Kalcheva, Petya Petrova; Klavinskis, Linda Sylvia

    2017-10-01

    Microneedle array platforms are a promising technology for vaccine delivery, due to their ease of administration with no sharp waste generated, small size, possibility of targeted delivery to the specified skin depth and efficacious delivery of different vaccine formulations, including viral vectors. Areas covered: Attributes and challenges of the most promising viral vector candidates that have advanced to the clinic and that have been leveraged for skin delivery by microneedles; The importance of understanding the immunobiology of antigen-presenting cells in the skin, in particular dendritic cells, in order to generate further improved skin vaccination strategies; recent studies where viral vectors expressing various antigens have been coupled with microneedle technology to examine their potential for improved vaccination. Expert opinion: Simple, economic and efficacious vaccine delivery methods are needed to improve health outcomes and manage possible outbreaks of new emerging viruses. Understanding what innate/inflammatory signals are required to induce both immediate and long-term responses remains a major hurdle in the development of the effective vaccines. One approach to meet these needs is microneedle-mediated viral vector vaccination. In order for this technology to fulfil this potential the industry must invest significantly to further develop its design, production, biosafety, delivery and large-scale manufacturing.

  19. Neonatal outcomes and operative vaginal delivery versus cesarean delivery.

    LENUS (Irish Health Repository)

    Contag, Stephen A

    2010-06-01

    We compared outcomes for neonates with forceps-assisted, vacuum-assisted, or cesarean delivery in the second stage of labor. This is a secondary analysis of a randomized trial in laboring, low-risk, nulliparous women at >or=36 weeks\\' gestation. Neonatal outcomes after use of forceps, vacuum, and cesarean were compared among women in the second stage of labor at station +1 or below (thirds scale) for failure of descent or nonreassuring fetal status. Nine hundred ninety women were included in this analysis: 549 (55%) with an indication for delivery of failure of descent and 441 (45%) for a nonreassuring fetal status. Umbilical cord gases were available for 87% of neonates. We found no differences in the base excess (P = 0.35 and 0.78 for failure of descent and nonreassuring fetal status) or frequencies of pH below 7.0 (P = 0.73 and 0.34 for failure of descent and nonreassuring fetal status) among the three delivery methods. Birth outcomes and umbilical cord blood gas values were similar for those neonates with a forceps-assisted, vacuum-assisted, or cesarean delivery in the second stage of labor. The occurrence of significant fetal acidemia was not different among the three delivery methods regardless of the indication.

  20. On the concavity of delivery games

    NARCIS (Netherlands)

    Hamers, H.J.M.

    1995-01-01

    Delivery games, introduced by Hamers, Borm, van de Leensel and Tijs (1994), are combinatorial optimization games that arise from delivery problems closely related to the Chinese postman problem (CPP). They showed that delivery games are not necessarily balanced. For delivery problems corresponding

  1. 38 CFR 21.4505 - Check delivery.

    Science.gov (United States)

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Check delivery. 21.4505...) VOCATIONAL REHABILITATION AND EDUCATION Education Loans § 21.4505 Check delivery. (a) General. Education... surviving spouse is enrolled for delivery by the educational institution. (b) Delivery and certification. (1...

  2. 18 CFR 157.211 - Delivery points.

    Science.gov (United States)

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Delivery points. 157... for Certain Transactions and Abandonment § 157.211 Delivery points. (a) Construction and operation—(1... delivery point, excluding the construction of certain delivery points subject to the prior notice...

  3. 19 CFR 10.101 - Immediate delivery.

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Immediate delivery. 10.101 Section 10.101 Customs... Importations § 10.101 Immediate delivery. (a) Shipments entitled to immediate delivery. Shipments consigned to... as shipments the immediate delivery of which is necessary within the purview of section 448(b...

  4. Decentralisation in Uganda: Prospects for Improved Service Delivery

    African Journals Online (AJOL)

    Since the 1980s, many Sub-Saharan African countries have been undergoing structural reforms with a view to promoting efficient service delivery. ... Financial decentralisation, on the other hand, attempted to assign responsibilities and taxes between the centre and local governments, to enable the transfer of grants and ...

  5. Maternal deaths from bleeding associated with caesarean delivery ...

    African Journals Online (AJOL)

    subcategory of haemorrhage-related maternal death, unlike the pattern in other countries. ... Maternal deaths associated with caesarean deliveries (CDs) have been increasing in South Africa over the past decade. The objective of this ..... haemorrhage, or delayed action in response to deteriorating vital signs. • There was ...

  6. Industrial Perspectives of Work Place Basics and Training Delivery Services.

    Science.gov (United States)

    Logan, Joyce; Byers, Charles

    1991-01-01

    Kentucky employers (249 of 800 surveyed) identified adaptability, teamwork, communication, and problem solving as entry-level and advancement skills. Over 50 percent did no preemployment testing. Responses indicated areas needing change: training focused on workplace basics, accessible training delivery, and preemployment assessment services. (SK)

  7. Waste feed delivery program systems engineering implementation plan

    International Nuclear Information System (INIS)

    O'Toole, S.M.; Hendel, B.J.

    1998-01-01

    This document defines the systems engineering processes and products planned by the Waste Feed Delivery Program to develop the necessary and sufficient systems to provide waste feed to the Privatization Contractor for Phase 1. It defines roles and responsibilities for the performance of the systems engineering processes and generation of products

  8. Dispensing apparatus for use in a cued food delivery task.

    Science.gov (United States)

    Deweese, Menton M; Claiborne, Kimberly N; Ng, Jennifer; Dirba, Danika D; Stewart, Hannah L; Schembre, Susan M; Versace, Francesco

    2015-01-01

    Neurobiological models of obesity postulate that obese individuals have difficulty regulating food intake partly because they attribute excessive salience to stimuli signaling food availability. Typically, human studies that investigate the relationship between brain responses to food-related stimuli and obesity present food cues without subsequent delivery of food. However, in order to identify the brain correlates of cue reactivity, we must record brain responses to food-related cues signaling food availability. Therefore, we have developed a dispensing apparatus for use in a cued-food delivery task in which event-related potentials (ERPs) to food-related images predicting food delivery and images not predicting food delivery can be recorded. Here, we describe a method where:•The experimental apparatus dispenses an edible item (i.e., a chocolate candy) which may or may not be eaten, or a non-edible control item (e.g., a plastic bead).•Deposit boxes are available to store uneaten candies and the non-edible control items.•The dispensing mechanism is capable of recording the exact timestamp when each delivery event occurs (e.g., release from the dispenser, arrival in the receptacle, storage in the deposit box).

  9. Dispensing apparatus for use in a cued food delivery task

    Science.gov (United States)

    Deweese, Menton M.; Claiborne, Kimberly N.; Ng, Jennifer; Dirba, Danika D.; Stewart, Hannah L.; Schembre, Susan M.; Versace, Francesco

    2015-01-01

    Neurobiological models of obesity postulate that obese individuals have difficulty regulating food intake partly because they attribute excessive salience to stimuli signaling food availability. Typically, human studies that investigate the relationship between brain responses to food-related stimuli and obesity present food cues without subsequent delivery of food. However, in order to identify the brain correlates of cue reactivity, we must record brain responses to food-related cues signaling food availability. Therefore, we have developed a dispensing apparatus for use in a cued-food delivery task in which event-related potentials (ERPs) to food-related images predicting food delivery and images not predicting food delivery can be recorded. Here, we describe a method where:•The experimental apparatus dispenses an edible item (i.e., a chocolate candy) which may or may not be eaten, or a non-edible control item (e.g., a plastic bead).•Deposit boxes are available to store uneaten candies and the non-edible control items.•The dispensing mechanism is capable of recording the exact timestamp when each delivery event occurs (e.g., release from the dispenser, arrival in the receptacle, storage in the deposit box). PMID:26870667

  10. 34 CFR 303.525 - Delivery of services in a timely manner.

    Science.gov (United States)

    2010-07-01

    ... 34 Education 2 2010-07-01 2010-07-01 false Delivery of services in a timely manner. 303.525... Matters § 303.525 Delivery of services in a timely manner. Each lead agency is responsible for the... SPECIAL EDUCATION AND REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION EARLY INTERVENTION PROGRAM FOR...

  11. Pulmonary delivery of an inulin-stabilized influenza subunit vaccine prepared by spray-freeze drying induces systemic, mucosal humoral as well as cell-mediated immune responses in BALB/c mice

    NARCIS (Netherlands)

    Amorij, J-P.; Saluja, V.; Petersen, A.H.; Hinrichs, W.L.J.; Huckriede, A.; Frijlink, H.W.

    2007-01-01

    In this study pulmonary vaccination with a new influenza subunit vaccine powder was evaluated. Vaccine powder was produced by spray-freeze drying (SFD) using the oligosaccharide inulin as stabilizer. Immune responses after pulmonary vaccination of BALB/c mice with vaccine powder were determined and

  12. Propulsion and Power Rapid Response Research and Development (R&D) Support. Delivery Order 0011: Advanced Propulsion Fuels Research and Development-Subtask: Framework and Guidance for Estimating Greenhouse Gas Footprints of Aviation Fuels

    Science.gov (United States)

    2009-04-01

    agricultural commodity markets, and the modeler must be confident their choice is relevant and comprehensively describes subsequent indirect land... Maize Ethanol: The Role of Market-Meditate Responses, GTAP Working Paper No. 55, http://ideas.repec.org/s/gta/workpp.html 4. USEPA (2009) Technical

  13. Bladder Injury During Cesarean Delivery

    Science.gov (United States)

    Tarney, Christopher M.

    2013-01-01

    Cesarean section is the most common surgery performed in the United States with over 30% of deliveries occurring via this route. This number is likely to increase given decreasing rates of vaginal birth after cesarean section (VBAC) and primary cesarean delivery on maternal request, which carries the inherent risk for intraoperative complications. Urologic injury is the most common injury at the time of either obstetric or gynecologic surgery, with the bladder being the most frequent organ damaged. Risk factors for bladder injury during cesarean section include previous cesarean delivery, adhesions, emergent cesarean delivery, and cesarean section performed at the time of the second stage of labor. Fortunately, most bladder injuries are recognized at the time of surgery, which is important, as quick recognition and repair are associated with a significant reduction in patient mortality. Although cesarean delivery is a cornerstone of obstetrics, there is a paucity of data in the literature either supporting or refuting specific techniques that are performed today. There is evidence to support double-layer closure of the hysterotomy, the routine use of adhesive barriers, and performing a Pfannenstiel skin incision versus a vertical midline subumbilical incision to decrease the risk for bladder injury during cesarean section. There is also no evidence that supports the creation of a bladder flap, although routinely performed during cesarean section, as a method to reduce the risk of bladder injury. Finally, more research is needed to determine if indwelling catheterization, exteriorization of the uterus, and methods to extend hysterotomy incision lead to bladder injury. PMID:24876830

  14. [Delivery of the IUGR fetus].

    Science.gov (United States)

    Perrotin, F; Simon, E G; Potin, J; Laffon, M

    2013-12-01

    The purpose of this paper is to review available data regarding the management of delivery in intra uterine growth retarded fetuses and try to get recommendations for clinical obstetrical practice. Bibliographic research performed by consulting PubMed database and recommendations from scientific societies with the following words: small for gestational age, intra-uterine growth restriction, fetal growth restriction, very low birth weight infants, as well as mode of delivery, induction of labor, cesarean section and operative delivery. The diagnosis of severe IUGR justifies the orientation of the patient to a referral centre with all necessary resources for very low birth weight or premature infants Administration of corticosteroids for fetal maturation (before 34 WG) and a possible neuroprotective treatment by with magnesium sulphate (before 32-33 WG) should be discussed. Although elective caesarean section is common, there is no current evidence supporting the use of systematic cesarean section, especially when the woman is in labor. Induction of labor, even with unfavorable cervix is possible under continuous FHR monitoring, in favorable obstetric situations and in the absence of severe fetal hemodynamic disturbances. Instrumental delivery and routine episiotomy are not recommended. For caesarean section under spinal anesthesia, an adequate anesthetic management must ensure the maintenance of basal blood pressure. Compared with appropriate for gestational age fetus, IUGR fetus is at increased risk of metabolic acidosis or perinatal asphyxia during delivery. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  15. Dispensing apparatus for use in a cued food delivery task

    OpenAIRE

    Deweese, Menton M.; Claiborne, Kimberly N.; Ng, Jennifer; Dirba, Danika D.; Stewart, Hannah L.; Schembre, Susan M.; Versace, Francesco

    2015-01-01

    Neurobiological models of obesity postulate that obese individuals have difficulty regulating food intake partly because they attribute excessive salience to stimuli signaling food availability. Typically, human studies that investigate the relationship between brain responses to food-related stimuli and obesity present food cues without subsequent delivery of food. However, in order to identify the brain correlates of cue reactivity, we must record brain responses to food-related cues signal...

  16. Mucosal delivery of vaccines: role of mucoadhesive/biodegradable polymers.

    Science.gov (United States)

    Garg, Neeraj K; Mangal, Sharad; Khambete, Hemant; Sharma, Pradeep K; Tyagi, Rajeev K

    2010-06-01

    Majority of infectious microorganism make their gateway to the host through mucosal surfaces, such as gastrointestinal tract, nasal and vaginal tract. Mucosal immune response structured as sIgA can effectively prevent the attachment and invasion of the microorganism from mucosal surface and thereby serves as an efficient tool against infectious disease. There has been an increased demand for the development of novel vaccine that leads to the induction of immune response in systemic circulation as well as at mucosal surfaces against infectious disease. Mucosal delivery of vaccine provides basis for induction of both mucosal as well as systemic immune responses against the infectious organisms. However, a variety of factors such as mucociliary clearance, presence of deteriorating enzymes, pH extremes (GIT), low permeation and metabolic degradation limit the mucosal delivery of vaccine. Numerous strategies have been explored in the meadow of mucosal vaccination for the purpose of efficient antigen delivery through mucosal route(s). Polymeric carrier(s) such as nanoparticles and microparticles loaded with the antigen can serve as the basis for creation of important formulations for improved vaccine. Biodegradable and mucoadhesive polymeric carrier(s) seems to be most promising candidate for mucosal vaccine delivery. Several polymers from natural and synthetic origin, such as polylactide-co-glycolide, chitosan, alginate, carbopol, gelatin etc., have been explored for the efficient mucosal vaccine delivery and significant results have been obtained. This review outlines the polymers used in mucosal vaccine delivery with special reference to mucoadhesive/biodegradable polymers. This article also covers the recent patent granted in the field on polymeric carrier mediated mucosal vaccination.

  17. Albumin-based drug delivery

    DEFF Research Database (Denmark)

    Larsen, Maja Thim; Kuhlmann, Matthias; Hvam, Michael Lykke

    2016-01-01

    The effectiveness of a drug is dependent on accumulation at the site of action at therapeutic levels, however, challenges such as rapid renal clearance, degradation or non-specific accumulation requires drug delivery enabling technologies. Albumin is a natural transport protein with multiple ligand...... binding sites, cellular receptor engagement, and a long circulatory half-life due to interaction with the recycling neonatal Fc receptor. Exploitation of these properties promotes albumin as an attractive candidate for half-life extension and targeted intracellular delivery of drugs attached by covalent...... conjugation, genetic fusions, association or ligand-mediated association. This review will give an overview of albumin-based products with focus on the natural biological properties and molecular interactions that can be harnessed for the design of a next-generation drug delivery platform....

  18. Polymer architecture and drug delivery.

    Science.gov (United States)

    Qiu, Li Yan; Bae, You Han

    2006-01-01

    Polymers occupy a major portion of materials used for controlled release formulations and drug-targeting systems because this class of materials presents seemingly endless diversity in topology and chemistry. This is a crucial advantage over other classes of materials to meet the ever-increasing requirements of new designs of drug delivery formulations. The polymer architecture (topology) describes the shape of a single polymer molecule. Every natural, seminatural, and synthetic polymer falls into one of categorized architectures: linear, graft, branched, cross-linked, block, star-shaped, and dendron/dendrimer topology. Although this topic spans a truly broad area in polymer science, this review introduces polymer architectures along with brief synthetic approaches for pharmaceutical scientists who are not familiar with polymer science, summarizes the characteristic properties of each architecture useful for drug delivery applications, and covers recent advances in drug delivery relevant to polymer architecture.

  19. The heritability of preterm delivery.

    Science.gov (United States)

    Ward, Kenneth; Argyle, VeeAnn; Meade, Mary; Nelson, Lesa

    2005-12-01

    To study the heritability of preterm delivery. Women who delivered a singleton infant at less than 36 weeks of gestation were asked about their family history. Twenty-eight families were identified in which the proband had at least five first- or second-degree relatives with preterm delivery. An extensive genealogy database (GenDB) was constructed using more than 9,000 genealogy sources in the public domain (records before 1929). GenDB documents the relationships between more than 17.5 million ancestors and 3.5 million descendants of approximately 10,000 individuals who moved to Utah in the mid 1800s. This database was searched for the names, birth dates, and birthplaces of the four grandparents for each of the 28 probands. Pairwise coefficients of kinship were determined for the 93 preterm delivery grandparents identified, and for sets of 100 individuals born in the 1920s who were randomly selected from the population database. Probands had a mean of 3.3 grandparents included in this database. The average coefficient of kinship for controls was 1.5 x 10(6) (standard deviation = 0.6 x 10(6)). This measure agrees with previous calculations for the Utah population. The coefficient of kinship for familial preterm delivery grandparents was more than 50 standard deviations higher (3.4 x 10(5) [P < .001]). This study confirms the familial nature of preterm delivery. On average, gravidae randomly selected from our population are 23rd degree relatives, while these preterm delivery probands are eighth-degree relatives. A genome-wide scan using these affected families is underway.

  20. External triggering and triggered targeting strategies for drug delivery

    Science.gov (United States)

    Wang, Yanfei; Kohane, Daniel S.

    2017-06-01

    Drug delivery systems that are externally triggered to release drugs and/or target tissues hold considerable promise for improving the treatment of many diseases by minimizing nonspecific toxicity and enhancing the efficacy of therapy. These drug delivery systems are constructed from materials that are sensitive to a wide range of external stimuli, including light, ultrasound, electrical and magnetic fields, and specific molecules. The responsiveness conferred by these materials allows the release of therapeutics to be triggered on demand and remotely by a physician or patient. In this Review, we describe the rationales for such systems and the types of stimuli that can be deployed, and provide an outlook for the field.

  1. Cesarean delivery on maternal request.

    Science.gov (United States)

    Viswanathan, Meera; Visco, Anthony G; Hartmann, Katherine; Wechter, Mary Ellen; Gartlehner, Gerald; Wu, Jennifer M; Palmieri, Rachel; Funk, Michele Jonsson; Lux, Linda; Swinson, Tammeka; Lohr, Kathleen N

    2006-03-01

    The RTI International-University of North Carolina at Chapel Hill Evidence-based Practice Center (RTI-UNC EPC) systematically reviewed the evidence on the trend and incidence of cesarean delivery (CD) in the United States and in other developed countries, maternal and infant outcomes of cesarean delivery on maternal request (CDMR) compared with planned vaginal delivery (PVD), factors affecting the magnitude of the benefits and harms of CDMR, and future research directions. We searched MEDLINE, Cochrane Collaboration resources, and Embase and identified 1,406 articles to examine against a priori inclusion criteria. We included studies published from 1990 to the present, written in English. Studies had to include comparison between the key reference group (CDMR or proxies) and PVD. A primary reviewer abstracted detailed data on key variables from included articles; a second senior reviewer confirmed accuracy. We identified 13 articles for trends and incidence of CD, 54 for maternal and infant outcomes, and 5 on modifiers of CDMR. The incidence of CDMR appears to be increasing. However, accurately assessing either its true incidence or trends over time is difficult because currently CDMR is neither a well-recognized clinical entity nor an accurately reported indication for diagnostic coding or reimbursement. Virtually no studies exist on CDMR, so the knowledge base rests chiefly on indirect evidence from proxies possessing unique and significant limitations. Furthermore, most studies compared outcomes by actual routes of delivery, resulting in great uncertainty as to their relevance to planned routes of delivery. Primary CDMR and planned vaginal delivery likely do differ with respect to individual outcomes for either mothers or infants. However, our comprehensive assessment, across many different outcomes, suggests that no major differences exist between primary CDMR and planned vaginal delivery, but the evidence is too weak to conclude definitively that differences

  2. Cesarean delivery and subsequent pregnancies.

    Science.gov (United States)

    Daltveit, Anne Kjersti; Tollånes, Mette Christophersen; Pihlstrøm, Hege; Irgens, Lorentz M

    2008-06-01

    To assess possible effects of a cesarean delivery on outcome in subsequent pregnancies. Using an historical cohort design, we analyzed 637,497 first and second births among women with two or more single births and 242,812 first, second, and third births among women with three or more single births registered in the population-based Medical Birth Registry of Norway between 1967 and 2003. Compared with a vaginal delivery at first birth, a cesarean delivery at first birth was followed, in a second pregnancy, by increased risks of preeclampsia (odds ratio [OR] 2.9 and corresponding 95% confidence interval [CI] 2.8-3.1), small for gestational age (OR 1.5; CI 1.4-1.5), placenta previa (OR 1.5; CI 1.3-1.8, placenta accreta (OR 1.9; CI 1.3-2.8), placental abruption (OR 2.0; CI 1.8-2.2), and uterine rupture (OR 37.4; CI 24.9-56.2). After excluding women with the actual complication at first birth, the corresponding ORs were, in general, lower: 1.7 (CI 1.6-1.8), 1.3 (CI 1.3-1.4), 1.4 (CI 1.2-1.7), 1.9 (CI 1.3-2.8), 1.7 (CI 1.6-1.9), and 37.2 (CI 24.7-55.9), respectively. Corresponding reduction in numbers of cesarean deliveries needed to prevent one case were 114, 56, 1,140, 3,706, 300, and 461. In third births, ORs after repeat cesarean delivery were similar to or lower than the ORs after one cesarean delivery; also here, the exclusion of women with the actual outcome in any of their previous pregnancies tended to reduce the ORs. Cesarean delivery was associated with an increased risk of complications in a subsequent pregnancy, but excess risks were reduced after excluding women with the actual complication in any of their previous births. To obtain less biased effects of cesarean delivery on subsequent pregnancies, it is important to account for obstetric history. II.

  3. Vaginal Birth After Cesarean Delivery: Deciding on a Trial of Labor After a Cesarean Delivery (TOLAC)

    Science.gov (United States)

    f AQ FREQUENTLY ASKED QUESTIONS FAQ070 LABOR, DELIVERY, AND POSTPARTUM CARE Vaginal Birth After Cesarean Delivery • What is a vaginal birth after cesarean delivery (VBAC)? • What is a trial of labor ...

  4. A real-time virtual delivery system for photon radiotherapy delivery monitoring

    Directory of Open Access Journals (Sweden)

    Feng Shi

    2014-03-01

    Full Text Available Purpose: Treatment delivery monitoring is important for radiotherapy, which enables catching dosimetric error at the earliest possible opportunity. This project develops a virtual delivery system to monitor the dose delivery process of photon radiotherapy in real-time using GPU-based Monte Carlo (MC method.Methods: The simulation process consists of 3 parallel CPU threads. A thread T1 is responsible for communication with a linac, which acquires a set of linac status parameters, e.g. gantry angles, MLC configurations, and beam MUs every 20 ms. Since linac vendors currently do not offer interface to acquire data in real time, we mimic this process by fetching information from a linac dynalog file at the set frequency. Instantaneous beam fluence map (FM is calculated based. A FM buffer is also created in T1 and the instantaneous FM is accumulated to it. This process continues, until a ready signal is received from thread T2 on which an in-house developed MC dose engine executes on GPU. At that moment, the accumulated FM is transferred to T2 for dose calculations, and the FM buffer in T1 is cleared. Once the dose calculation finishes, the resulting 3D dose distribution is directed to thread T3, which displays it in three orthogonal planes in color wash overlaid on the CT image. This process continues to monitor the 3D dose distribution in real-time.Results: An IMRT and a VMAT cases used in our patient-specific QA are studied. Maximum dose differences between our system and treatment planning system are 0.98% and 1.58% for the IMRT and VMAT cases, respectively. The update frequency is >10Hz and the relative uncertainty level is 2%.Conclusion: By embedding a GPU-based MC code in a novel data/work flow, it is possible to achieve real-time MC dose calculations to monitor delivery process.------------------------------Cite this article as: Shi F, Gu X, Graves YJ, Jiang S, Jia X. A real-time virtual delivery system for photon radiotherapy delivery

  5. Advances in buccal drug delivery.

    Science.gov (United States)

    Birudaraj, Raj; Mahalingam, Ravichandran; Li, Xiaoling; Jasti, Bhaskara R

    2005-01-01

    The buccal route offers an attractive alternative for systemic drug delivery of drugs because of better patient compliance, ease of dosage form removal in emergencies, robustness, and good accessibility. Use of buccal mucosa for drug absorption was first attempted by Sobrero in 1847, and since then much research was done to deliver drugs through this route. Today, research is more focused on the development of suitable delivery devices, permeation enhancement, and buccal delivery of drugs that undergo a first-pass effect, such as cardiovascular drugs, analgesics, and peptides. In addition, studies have been conducted on the development of controlled or slow release delivery systems for systemic and local therapy of diseases in the oral cavity. In this review, the anatomy and physiology of buccal mucosa, followed by discussion of recent literature on the buccal permeation enhancement, and pathways of enhancement for various molecules are detailed. In addition, bioadhesion theories from historic perspective and current status are discussed. The various dosage forms on the market and in different stages of development are also reviewed.

  6. Software Build and Delivery Systems

    Energy Technology Data Exchange (ETDEWEB)

    Robey, Robert W. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-07-10

    This presentation deals with the hierarchy of software build and delivery systems. One of the goals is to maximize the success rate of new users and developers when first trying your software. First impressions are important. Early successes are important. This also reduces critical documentation costs. This is a presentation focused on computer science and goes into detail about code documentation.

  7. Surfactant Delivery into the Lung

    Science.gov (United States)

    Grotberg, James; Filoche, Marcel

    2014-11-01

    We have developed a multiscale, compartmentalized model of surfactant and liquid delivery into the lung. Assuming liquid plug propagation, the airway compartment accounts for the plug's volume deposition (coating) on the airway wall, while the bifurcation compartment accounts for plug splitting from the parent airway to the two daughter airways. Generally the split is unequal due to gravity and geometry effects. Both the deposition ratio RD (deposition volume/airway volume), and the splitting ratio, RS, of the daughters volumes are solved independently from one another. Then they are used in a 3D airway network geometry to achieve the distribution of delivery into the lung. The airway geometry is selected for neonatal as well as adult applications, and can be advanced from symmetric, to stochastically asymmetric, to personalized. RD depends primarily on the capillary number, Ca, while RS depends on Ca, the Reynolds number, Re, the Bond number, Bo, the dose volume, VD, and the branch angles. The model predicts the distribution of coating on the airway walls and the remaining plug volume delivered to the alveolar region at the end of the tree. Using this model, we are able to simulate and test various delivery protocols, in order to optimize delivery and improve the respiratory function.

  8. Biomaterials for drug delivery patches.

    Science.gov (United States)

    Santos, Lúcia F; Correia, Ilídio J; Silva, A Sofia; Mano, João F

    2018-06-15

    The limited efficiency of conventional drugs has been instigated the development of new and more effective drug delivery systems (DDS). Transdermal DDS, are associated with numerous advantages such its painless application and less frequent replacement and greater flexibility of dosing, features that triggered the research and development of such devices. Such systems have been produced using either biopolymer; or synthetic polymers. Although the first ones are safer, biocompatible and present a controlled degradation by human enzymes or water, the second ones are the most currently available in the market due to their greater mechanical resistance and flexibility, and non-degradation over time. This review highlights the most recent advances (mainly in the last five years) of patches aimed for transdermal drug delivery, focusing on the different materials (natural, synthetic and blends) and latest designs for the development of such devices, emphasizing also their combination with drug carriers that enable enhanced drug solubility and a more controlled release of the drug over the time. The benefits and limitations of different patches formulations are considered with reference to their appliance to transdermal drug delivery. Furthermore, a record of the currently available patches on the market is given, featuring their most relevant characteristics. Finally, a list of most recent/ongoing clinical trials regarding the use of patches for skin disorders is detailed and critical insights on the current state of patches for transdermal drug delivery are also provided. Copyright © 2018. Published by Elsevier B.V.

  9. Document Delivery: Evaluating the Options.

    Science.gov (United States)

    Ward, Suzanne M.

    1997-01-01

    Discusses options available to libraries for document delivery. Topics include users' needs; cost; copyright compliance; traditional interlibrary loan; types of suppliers; selection criteria, including customer service; new developments in interlibrary loan, including outsourcing arrangements; and the need to evaluate suppliers. (LRW)

  10. Microcontainers for Intestinal Drug Delivery

    DEFF Research Database (Denmark)

    Tentor, Fabio; Mazzoni, Chiara; Keller, Stephan Sylvest

    Among all the drug administration routes, the oral one is the most preferred by the patients being less invasive, faster and easier. Oral drug delivery systems designed to target the intestine are produced by powder technology and capsule formulations. Those systems including micro- and nano...

  11. Antigen delivery systems for veterinary vaccine development. Viral-vector based delivery systems.

    Science.gov (United States)

    Brun, Alejandro; Albina, Emmanuel; Barret, Tom; Chapman, David A G; Czub, Markus; Dixon, Linda K; Keil, Günther M; Klonjkowski, Bernard; Le Potier, Marie-Frédérique; Libeau, Geneviève; Ortego, Javier; Richardson, Jennifer; Takamatsu, Haru-H

    2008-12-02

    The recent advances in molecular genetics, pathogenesis and immunology have provided an optimal framework for developing novel approaches in the rational design of vaccines effective against viral epizootic diseases. This paper reviews most of the viral-vector based antigen delivery systems (ADSs) recently developed for vaccine testing in veterinary species, including attenuated virus and DNA and RNA viral vectors. Besides their usefulness in vaccinology, these ADSs constitute invaluable tools to researchers for understanding the nature of protective responses in different species, opening the possibility of modulating or potentiating relevant immune mechanisms involved in protection.

  12. Preparing and evaluating delivery systems for proteins

    DEFF Research Database (Denmark)

    Jorgensen, L; Moeller, E H; van de Weert, M

    2006-01-01

    From a formulation perspective proteins are complex and therefore challenging molecules to develop drug delivery systems for. The success of a formulation depends on the ability of the protein to maintain the native structure and activity during preparation and delivery as well as during shipping...... and long-term storage of the formulation. Therefore, the development and evaluation of successful and promising drug delivery systems is essential. In the present review, some of the particulate drug delivery systems for parenteral delivery of protein are presented and discussed. The challenge...... for incorporation of protein in particulate delivery systems is exemplified by water-in-oil emulsions....

  13. Biomaterials for mRNA delivery.

    Science.gov (United States)

    Islam, Mohammad Ariful; Reesor, Emma K G; Xu, Yingjie; Zope, Harshal R; Zetter, Bruce R; Shi, Jinjun

    2015-12-01

    Messenger RNA (mRNA) has recently emerged with remarkable potential as an effective alternative to DNA-based therapies because of several unique advantages. mRNA does not require nuclear entry for transfection activity and has a negligible chance of integrating into the host genome which excludes the possibility of potentially detrimental genomic alternations. Chemical modification of mRNA has further enhanced its stability and decreased its activation of innate immune responses. Additionally, mRNA has been found to have rapid expression and predictable kinetics. Nevertheless, the ubiquitous application of mRNA remains challenging given its unfavorable attributes, such as large size, negative charge and susceptibility to enzymatic degradation. Further refinement of mRNA delivery modalities is therefore essential for its development as a therapeutic tool. This review provides an exclusive overview of current state-of-the-art biomaterials and nanotechnology platforms for mRNA delivery, and discusses future prospects to bring these exciting technologies into clinical practice.

  14. Mathematical modeling of drug delivery.

    Science.gov (United States)

    Siepmann, J; Siepmann, F

    2008-12-08

    Due to the significant advances in information technology mathematical modeling of drug delivery is a field of steadily increasing academic and industrial importance with an enormous future potential. The in silico optimization of novel drug delivery systems can be expected to significantly increase in accuracy and easiness of application. Analogous to other scientific disciplines, computer simulations are likely to become an integral part of future research and development in pharmaceutical technology. Mathematical programs can be expected to be routinely used to help optimizing the design of novel dosage forms. Good estimates for the required composition, geometry, dimensions and preparation procedure of various types of delivery systems will be available, taking into account the desired administration route, drug dose and release profile. Thus, the number of required experimental studies during product development can be significantly reduced, saving time and reducing costs. In addition, the quantitative analysis of the physical, chemical and potentially biological phenomena, which are involved in the control of drug release, offers another fundamental advantage: The underlying drug release mechanisms can be elucidated, which is not only of academic interest, but a pre-requisite for an efficient improvement of the safety of the pharmaco-treatments and for effective trouble-shooting during production. This article gives an overview on the current state of the art of mathematical modeling of drug delivery, including empirical/semi-empirical and mechanistic realistic models. Analytical as well as numerical solutions are described and various practical examples are given. One of the major challenges to be addressed in the future is the combination of mechanistic theories describing drug release out of the delivery systems with mathematical models quantifying the subsequent drug transport within the human body in a realistic way. Ideally, the effects of the design

  15. Oral transmucosal delivery of naratriptan.

    Science.gov (United States)

    Sattar, Mohammed; Lane, Majella E

    2016-11-30

    Naratriptan (NAR) is currently used as the hydrochloride salt (NAR.HCl) for the treatment of migraine and is available in tablet dosage forms for oral administration. Buccal drug delivery offers a num