104 results found
Monnery BD, Wright M, Cavill R, et al., 2017, Cytotoxicity of polycations: Relationship of molecular weight and the hydrolytic theory of the mechanism of toxicity, International Journal of Pharmaceutics, Vol: 521, Pages: 249-258, ISSN: 0378-5173
The mechanism of polycation cytotoxicity and the relationship to polymer molecular weight is poorly understood. To gain an insight into this important phenomenon a range of newly synthesised uniform (near monodisperse) linear polyethylenimines, commercially available poly(l-lysine)s and two commonly used PEI-based transfectants (broad 22 kDa linear and 25 kDa branched) were tested for their cytotoxicity against the A549 human lung carcinoma cell line. Cell membrane damage assays (LDH release) and cell viability assays (MTT) showed a strong relationship to dose and polymer molecular weight, and increasing incubation times revealed that even supposedly “non-toxic” low molecular weight polymers still damage cell membranes. The newly proposed mechanism of cell membrane damage is acid catalysed hydrolysis of lipidic phosphoester bonds, which was supported by observations of the hydrolysis of DOPC liposomes.
Armstrong-James DPH, 2016, Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death, American Journal of Respiratory and Critical Care Medicine, Vol: 194, Pages: 1127-1139, ISSN: 1535-4970
Rationale: Pulmonary aspergillosis is a lethal mold infection in the immunocompromised host. Understanding initial control of infection and how this is altered in the immunocompromised host are key goals for comprehension of the pathogenesis of pulmonary aspergillosis.Objectives: To characterize the outcome of human macrophage infection with Aspergillus fumigatus and how this is altered in transplant recipients on calcineurin inhibitor immunosuppressants.Methods: We defined the outcome of human macrophage infection with A. fumigatus, as well as the impact of calcineurin inhibitors, through a combination of single-cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies.Measurements and Main Results: Macrophage phagocytosis of A. fumigatus enabled control of 90% of fungal germination. However, fungal germination in the late phagosome led to macrophage necrosis. During programmed necroptosis, we observed frequent cell–cell transfer of A. fumigatus between macrophages, which assists subsequent control of germination in recipient macrophages. Lateral transfer occurred through actin-dependent exocytosis of the late endosome in a vasodilator-stimulated phosphoprotein envelope. Its relevance to the control of fungal germination was also shown by direct visualization in our zebrafish aspergillosis model in vivo. The calcineurin inhibitor FK506 (tacrolimus) reduced cell death and lateral transfer in vitro by 50%. This resulted in uncontrolled fungal germination in macrophages and also resulted in hyphal escape.Conclusions: These observations identify programmed, necrosis-dependent lateral transfer of A. fumigatus between macrophages as an important host strategy for controlling fungal germination. This process is critically dependent on calcineurin. Our studies provide fundamental insights into the pathogenesis of pulmonary aspergillosis in the immunocompromised host.
Czaplewski L, Bax R, Clokie M, et al., 2016, Alternatives to antibiotics-a pipeline portfolio review, LANCET INFECTIOUS DISEASES, Vol: 16, Pages: 239-251, ISSN: 1473-3099
Shaunak S, 2015, Perspective: Dendrimer drugs for infection and inflammation, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 468, Pages: 435-441, ISSN: 0006-291X
Shah A, Kannambath S, Herbst S, et al., 2015, 'THE KISS OF DEATH' - CALCINEURIN INHIBITORS PREVENT ACTIN-DEPENDENT LATERAL TRANSFER OF ASPERGILLUS FUMIGATUS IN NECROPTOTIC HUMAN MACROPHAGES, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A48-A48, ISSN: 0040-6376
Singanayagam A, Lamb L, Makinde JE, et al., 2015, Systemic cytokine storm in severe eosinophilic dermatitis, QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, Vol: 108, Pages: 907-908, ISSN: 1460-2725
Islam D, Lombardini E, Ruamsap N, et al., 2015, Controlling the cytokine storm in severe bacterial diarrhoea with an oral Toll-like receptor 4 antagonist, Immunology, Vol: 147, Pages: 178-189, ISSN: 0019-2805
Shigella dysenteriae causes the most severe of all infectious diarrheas and colitis. We infected rhesus macaques orally and also treated them orally with a small and non-absorbable polypropyletherimine dendrimer glucosamine (DG) that is a Toll Like Receptor-4 antagonist. Antibiotics were not given for this life threatening infection. Six days later, the clinical score for diarrhea, mucus and blood was 54% lower, colon IL-8 and IL-6 were both 77% lower, and colon neutrophil infiltration was 75% less. Strikingly, vasculitis did not occur and tissue fibrin thrombi were reduced by 67%. There was no clinical toxicity or adverse effect of DG on systemic immunity. This is the first report in nonhuman primates of the therapeutic efficacy of a small and orally bioavailable TLR antagonist in severe infection. Our results show that an oral TLR4 antagonist can enable controlled resolution of the infection-related-inflammatory response and can also prevent neutrophil-mediated gut wall necrosis in severe infectious diarrheas.
Shirkhani K, Teo I, Armstrong-James D, et al., 2015, Nebulised amphotericin B-polymethacrylic acid nanoparticle prophylaxis prevents invasive aspergillosis, NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE, Vol: 11, Pages: 1217-1226, ISSN: 1549-9634
Monnery BD, Shaunak S, Thanou M, et al., 2015, Improved Synthesis of Linear Poly(ethylenimine) via Low-Temperature Polymerization of 2-Isopropyl-2-oxazoline in Chlorobenzene, MACROMOLECULES, Vol: 48, Pages: 3197-3206, ISSN: 0024-9297
Shah A, Abdolrasouli A, Soresi S, et al., 2015, The Utility of Novel Multi-Stage Testing for the Diagnosis of Pulmonary Aspergillosis in a Cohort of Lung Transplant Recipients, 35th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation, Publisher: ELSEVIER SCIENCE INC, Pages: S306-S306, ISSN: 1053-2498
Herbst S, Shah A, Moya MM, et al., 2015, Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus, EMBO Molecular Medicine, Vol: 7, Pages: 240-258, ISSN: 1757-4676
Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF‐κB for TNF‐α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin‐1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9‐dependent and Bruton's tyrosine kinase‐dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF‐κB for TNF‐α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant‐related invasive aspergillosis.
Beecham AH, Patsopoulos NA, Xifara DK, et al., 2013, Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis, NATURE GENETICS, Vol: 45, Pages: 1353-+, ISSN: 1061-4036
Shah A, Herbst S, Kannambath S, et al., 2013, CALCINEURIN INHIBITORS IMPAIR THE HOST INNATE IMMUNE RESPONSE TO INVASIVE ASPERGILLOSIS LIKELY DUE TO A CALCINEURIN-DEPENDANT DEFECT IN FUNGAL KILLING IN ALVEOLAR MACROPHAGES, JOURNAL OF INFECTION, Vol: 67, Pages: 343-344, ISSN: 0163-4453
Herbst S, Shah A, Carby M, et al., 2013, A new and clinically relevant murine model of solid-organ transplant aspergillosis, DISEASE MODELS & MECHANISMS, Vol: 6, Pages: 643-651, ISSN: 1754-8403
Armstrong-James D, Teo I, Herbst S, et al., 2012, Renal Allograft Recipients Fail to Increase Interferon-γ During Invasive Fungal Diseases, AMERICAN JOURNAL OF TRANSPLANTATION, Vol: 12, Pages: 3437-3440, ISSN: 1600-6135
Teo I, Toms SM, Marteyn B, et al., 2012, Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers, EMBO MOLECULAR MEDICINE, Vol: 4, Pages: 866-881, ISSN: 1757-4676
Morris TC, Moore LSP, Shaunak S, 2012, MOBILE PHONES: UNHELPFUL APPS Doctors taking a pulse using their mobile phone can spread MRSA, BRITISH MEDICAL JOURNAL, Vol: 344, ISSN: 0959-535X
Barata T, Teo I, Lalwani S, et al., 2011, Computational design principles for bioactive dendrimer based constructs as antagonists of the TLR4-MD-2-LPS complex, BIOMATERIALS, Vol: 32, Pages: 8702-8711, ISSN: 0142-9612
Corware K, Harris D, Teo I, et al., 2011, Accelerated healing of cutaneous leishmaniasis in non-healing BALB/c mice using water soluble amphotericin B-polymethacrylic acid, BIOMATERIALS, Vol: 32, Pages: 8029-8039, ISSN: 0142-9612
Barata TS, Brocchini S, Teo I, et al., 2011, From sequence to 3D structure of hyperbranched molecules: application to surface modified PAMAM dendrimers, JOURNAL OF MOLECULAR MODELING, Vol: 17, Pages: 2741-2749, ISSN: 1610-2940
Monnery B, Shaunak S, Thanou M, et al., 2011, Monodisperse 1-PEI: A route to the optimum polymer transfectant?, Publisher: MARY ANN LIEBERT INC, Pages: A90-A91, ISSN: 1043-0342
Barata TS, Shaunak S, Teo I, et al., 2011, Structural studies of biologically active glycosylated polyamidoamine (PAMAM) dendrimers, JOURNAL OF MOLECULAR MODELING, Vol: 17, Pages: 2051-2060, ISSN: 1610-2940
Barata TS, Teo I, Brocchini S, et al., 2011, Partially Glycosylated Dendrimers Block MD-2 and Prevent TLR4-MD-2-LPS Complex Mediated Cytokine Responses, PLOS COMPUTATIONAL BIOLOGY, Vol: 7, ISSN: 1553-734X
Karina C, Matthew R, Ian T, et al., 2010, A COST-EFFECTIVE CURE FOR CUTANEOUS LEISHMANIASIS, JOURNAL OF INFECTION, Vol: 61, Pages: 522-523, ISSN: 0163-4453
Corware KD, Rogers M, Teo I, et al., 2010, An amphotericin B-based drug for treating experimental Leishmania major infection, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 104, Pages: 749-750
There is an urgent need for a non-toxic and low-cost treatment for cutaneous leishmaniasis. We synthesised and tested in vivo an amphotericin B-poly(methacrylic acid) drug (AmB-PMA) that had previously shown in-vitro activity against Leishmania major and L. donovani parasites. Efficacy was determined using L. major footpad infection in 30 non-healing BALB/c mice. Three subcutaneous injections of AmB-PMA at days 7, 14 and 21 post-infection resulted in a reduction of ∼80% in lesion size by day 35 post-infection in 18 treated mice compared with six untreated controls, and complete healing of lesions by day 50 with no lesion relapse seen at day 80 post-infection in six treated mice. Healing was associated with decreased IL-10 (P=0.002) and increased IFN-γ (P=0.005) in the footpad.
Barata TS, Brocchini S, Teo I, et al., 2010, Structural Studies on Glycosylated PAMAM Dendrimers, JOURNAL OF PHARMACY AND PHARMACOLOGY, Vol: 62, Pages: 1371-1372, ISSN: 0022-3573
Armstrong-James D, Teo IA, Shrivastava S, et al., 2010, Exogenous Interferon-γ Immunotherapy for Invasive Fungal Infections in Kidney Transplant Patients, AMERICAN JOURNAL OF TRANSPLANTATION, Vol: 10, Pages: 1796-1803, ISSN: 1600-6135
Lalwani S, Chouai A, Perez LM, et al., 2009, Mimicking PAMAM Dendrimers with Amphoteric, Hybrid Triazine Dendrimers: A Comparison of Dispersity and Stability, MACROMOLECULES, Vol: 42, Pages: 6723-6732, ISSN: 0024-9297
Lalwani S, Venditto VJ, Chouai A, et al., 2009, Electrophoretic Behavior of Anionic Triazine and PAMAM Dendrimers: Methods for Improving Resolution and Assessing Purity Using Capillary Electrophoresis, MACROMOLECULES, Vol: 42, Pages: 3152-3161, ISSN: 0024-9297
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