2021 |
Pinkerton JW, Kim RY, Koeninger L, Armbruster NS, Hansbro NG, Brown AC, et al., 'Human ß-defensin-2 suppresses key features of asthma in murine models of allergic airways disease.', Clin Exp Allergy, 51 120-131 (2021)
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2020 |
Mehta M, Chellappan DK, Wich PR, Hansbro NG, Hansbro PM, Dua K, 'miRNA nanotherapeutics: potential and challenges in respiratory disorders', FUTURE MEDICINAL CHEMISTRY, 12 987-990 (2020)
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2020 |
Yong DOC, Saker SR, Chellappan DK, Madheswaran T, Panneerselvam J, Choudhury H, et al., 'Molecular and Immunological Mechanisms Underlying the Various Pharmacological Properties of the Potent Bioflavonoid, Rutin.', Endocr Metab Immune Disord Drug Targets, 20 1590-1596 (2020)
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2020 |
Jin-Ying WYW, Yin Ng Z, Mehta M, Shukla SD, Panneerselvam J, Madheswaran T, et al., 'Curcumin-loaded niosomes downregulate mRNA expression of pro-inflammatory markers involved in asthma: An in vitro study', Nanomedicine, 15 2955-2970 (2020) [C1]
© 2020 Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation und... [more]
© 2020 Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation underwent various physicochemical characterization experiments, an in vitro release study, molecular simulations and was evaluated for in vitro anti-inflammatory activity. Results: Results showed that Nio-Curc had a mean particle size of 284.93 ± 14.27 nm, zeta potential of -46.93 and encapsulation efficacy of 99.62%, which demonstrates optimized physicochemical characteristics. Curcumin release in vitro could be sustained for up to 24 h. Additionally, Nio-Curc effectively reduced mRNA transcript expression of pro-inflammatory markers; IL-6, IL-8, IL-1ß and TNF-a in immortalized human airway basal cell line (BCi-NS1.1). Conclusion: In this study, we have demonstrated that Nio-Curc mitigated the mRNA expression of pro-inflammatory markers in an in vitro study, which could be applied to treatment of asthma with further studies.
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2020 |
Shastri MD, Chong WC, Dua K, Peterson GM, Patel RP, Mahmood MQ, et al., 'Emerging concepts and directed therapeutics for the management of asthma: regulating the regulators', Inflammopharmacology, (2020)
© 2020, Springer Nature Switzerland AG. Asthma is a common, heterogeneous and serious disease, its prevalence has steadily risen in most parts of the world, and the condition is o... [more]
© 2020, Springer Nature Switzerland AG. Asthma is a common, heterogeneous and serious disease, its prevalence has steadily risen in most parts of the world, and the condition is often inadequately controlled in many patients. Hence, there is a major need for new therapeutic approaches. Mild-to-moderate asthma is considered a T-helper cell type-2-mediated inflammatory disorder that develops due to abnormal immune responses to otherwise innocuous allergens. Prolonged exposure to allergens and persistent inflammation results in myofibroblast infiltration and airway remodelling with mucus hypersecretion, airway smooth muscle hypertrophy, and excess collagen deposition. The airways become hyper-responsive to provocation resulting in the characteristic wheezing and obstructed airflow experienced by patients. Extensive research has progressed the understanding of the underlying mechanisms and the development of new treatments for the management of asthma. Here, we review the basis of the disease, covering new areas such as the role of vascularisation and microRNAs, as well as associated potential therapeutic interventions utilising reports from animal and human studies. We also cover novel drug delivery strategies that are being developed to enhance therapeutic efficacy and patient compliance. Potential avenues to explore to improve the future of asthma management are highlighted.
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2020 |
Solanki N, Mehta M, Chellappan DK, Gupta G, Hansbro NG, Tambuwala MM, et al., 'Antiproliferative effects of boswellic acids-loaded chitosan nanoparticles on human lung cancer cell line A549.', Future medicinal chemistry, 12 2019-2034 (2020) [C1]
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2020 |
Khatak S, Mehta M, Awasthi R, Paudel KR, Singh SK, Gulati M, et al., 'Solid lipid nanoparticles containing anti-tubercular drugs attenuate the Mycobacterium marinum infection', Tuberculosis, 125 1-10 (2020) [C1]
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2020 |
Chan Y, Ng SW, Chellappan DK, Madheswaran T, Zeeshan F, Kumar P, et al., 'Celastrol-loaded liquid crystalline nanoparticles as an anti-inflammatory intervention for the treatment of asthma', INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS, (2020)
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2020 |
Li J, Xu X, Jiang Y, Hansbro NG, Hansbro PM, Xu J, Liu G, 'Elastin is a key factor of tumor development in colorectal cancer', BMC CANCER, 20 (2020) [C1]
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2020 |
Prasher P, Sharma M, Mehta M, Paudel KR, Satija S, Chellappan DK, et al., 'Plants derived therapeutic strategies targeting chronic respiratory diseases: Chemical and immunological perspective', Chemico-Biological Interactions, 325 (2020) [C1]
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2020 |
Schanin J, Gebremeskel S, Korver W, Falahati R, Butuci M, Haw TJ, et al., 'A monoclonal antibody to Siglec-8 suppresses non-allergic airway inflammation and inhibits IgE-independent mast cell activation', Mucosal Immunology, (2020)
© 2020, The Author(s). In addition to their well characterized role in mediating IgE-dependent allergic diseases, aberrant accumulation and activation of mast cells (MCs) is assoc... [more]
© 2020, The Author(s). In addition to their well characterized role in mediating IgE-dependent allergic diseases, aberrant accumulation and activation of mast cells (MCs) is associated with many non-allergic inflammatory diseases, whereby their activation is likely triggered by non-IgE stimuli (e.g., IL-33). Siglec-8 is an inhibitory receptor expressed on MCs and eosinophils that has been shown to inhibit IgE-mediated MC responses and reduce allergic inflammation upon ligation with a monoclonal antibody (mAb). Herein, we evaluated the effects of an anti-Siglec-8 mAb (anti-S8) in non-allergic disease models of experimental cigarette-smoke-induced chronic obstructive pulmonary disease and bleomycin-induced lung injury in Siglec-8 transgenic mice. Therapeutic treatment with anti-S8 inhibited MC activation and reduced recruitment of immune cells, airway inflammation, and lung fibrosis. Similarly, using a model of MC-dependent, IL-33-induced inflammation, anti-S8 treatment suppressed neutrophil influx, and cytokine production through MC inhibition. Transcriptomic profiling of MCs further demonstrated anti-S8-mediated downregulation of MC signaling pathways induced by IL-33, including TNF signaling via NF-¿B. Collectively, these findings demonstrate that ligating Siglec-8 with an antibody reduces non-allergic inflammation and inhibits IgE-independent MC activation, supporting the evaluation of an anti-Siglec-8 mAb as a therapeutic approach in both allergic and non-allergic inflammatory diseases in which MCs play a role.
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2020 |
Johansen MD, Irving A, Montagutelli X, Tate MD, Rudloff I, Nold MF, et al., 'Animal and translational models of SARS-CoV-2 infection and COVID-19.', Mucosal Immunol, 13 877-891 (2020)
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2020 |
Paudel KR, Dharwal V, Patel VK, Galvao I, Wadhwa R, Malyla V, et al., 'Role of Lung Microbiome in Innate Immune Response Associated With Chronic Lung Diseases', Frontiers in Medicine, 7 (2020)
© Copyright © 2020 Paudel, Dharwal, Patel, Galvao, Wadhwa, Malyla, Shen, Budden, Hansbro, Vaughan, Yang, Kohonen-Corish, Bebawy, Dua and Hansbro. Respiratory diseases such as asth... [more]
© Copyright © 2020 Paudel, Dharwal, Patel, Galvao, Wadhwa, Malyla, Shen, Budden, Hansbro, Vaughan, Yang, Kohonen-Corish, Bebawy, Dua and Hansbro. Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis, and lung cancer, pose a huge socio-economic burden on society and are one of the leading causes of death worldwide. In the past, culture-dependent techniques could not detect bacteria in the lungs, therefore the lungs were considered a sterile environment. However, the development of culture-independent techniques, particularly 16S rRNA sequencing, allowed for the detection of commensal microbes in the lung and with further investigation, their roles in disease have since emerged. In healthy individuals, the predominant commensal microbes are of phylum Firmicutes and Bacteroidetes, including those of the genera Veillonella and Prevotella. In contrast, pathogenic microbes (Haemophilus, Streptococcus, Klebsiella, Pseudomonas) are often associated with lung diseases. There is growing evidence that microbial metabolites, structural components, and toxins from pathogenic and opportunistic bacteria have the capacity to stimulate both innate and adaptive immune responses, and therefore can contribute to the pathogenesis of lung diseases. Here we review the multiple mechanisms that are altered by pathogenic microbiomes in asthma, COPD, lung cancer, and lung fibrosis. Furthermore, we focus on the recent exciting advancements in therapies that can be used to restore altered microbiomes in the lungs.
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2019 |
Dua K, Malyla V, Singhvi G, Wadhwa R, Krishna RV, Shukla SD, et al., 'Increasing complexity and interactions of oxidative stress in chronic respiratory diseases: An emerging need for novel drug delivery systems', Chemico-Biological Interactions, 299 168-178 (2019) [C1]
© 2018 Elsevier B.V. Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonar... [more]
© 2018 Elsevier B.V. Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonary disease (COPD), infections and lung cancer. Even though there are various existing anti-inflammatory therapies, which are not enough to control the inflammation caused due to various contributing factors such as anti-inflammatory genes and antioxidant enzymes. This leads to an urgent need of novel drug delivery systems to combat the oxidative stress. This review gives a brief insight into the biological factors involved in causing oxidative stress, one of the emerging hallmark feature in CRDs and particularly, highlighting recent trends in various novel drug delivery carriers including microparticles, microemulsions, microspheres, nanoparticles, liposomes, dendrimers, solid lipid nanocarriers etc which can help in combating the oxidative stress in CRDs and ultimately reducing the disease burden and improving the quality of life with CRDs patients. These carriers improve the pharmacokinetics and bioavailability to the target site. However, there is an urgent need for translational studies to validate the drug delivery carriers for clinical administration in the pulmonary clinic.
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2019 |
Hadjigol S, Netto KG, Maltby S, Tay HL, Nguyen TH, Hansbro NG, et al., 'Lipopolysaccharide induces steroid-resistant exacerbations in a mouse model of allergic airway disease collectively through IL-13 and pulmonary macrophage activation', CLINICAL AND EXPERIMENTAL ALLERGY, 50 82-94 (2019)
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2019 |
Shukla SD, Shastri MD, Chong WC, Dua K, Budden KF, Mahmood MQ, et al., 'Microbiome-focused asthma management strategies', Current Opinion in Pharmacology, 46 143-149 (2019) [C1]
© 2019 Elsevier Ltd Asthma is a common, heterogeneous and serious disease with high prevalence globally. Poorly controlled, steroid-resistant asthma is particularly important as t... [more]
© 2019 Elsevier Ltd Asthma is a common, heterogeneous and serious disease with high prevalence globally. Poorly controlled, steroid-resistant asthma is particularly important as there are no effective therapies and it exerts substantial healthcare and societal burden. The role of microbiomes, particularly in chronic diseases has generated considerable interest in recent times. Existing evidence clearly demonstrates an association between asthma initiation and the microbiome, both respiratory and gastro-intestinal, although its¿ roles are poorly understood when assessing the asthma progression or heterogeneity (i.e. phenotypes/endotypes) across different geographical locations. Moreover, modulating microbiomes could be preventive and/or therapeutic in patients with asthma warrants urgent attention. Here, we review recent advances in assessing the role of microbiomes in asthma and present the challenges associated with the potential therapeutic utility of modifying microbiomes in management.
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2019 |
Liu G, Cooley MA, Jarnicki AG, Borghuis T, Nair PM, Tjin G, et al., 'Fibulin-1c regulates transforming growth factor-beta activation in pulmonary tissue fibrosis', JCI INSIGHT, 4 (2019) [C1]
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2019 |
Ng SW, Chan Y, Chellappan DK, Madheswaran T, Zeeshan F, Chan YL, et al., 'Molecular modulators of celastrol as the keystones for its diverse pharmacological activities', Biomedicine and Pharmacotherapy, 109 1785-1792 (2019) [C1]
© 2018 The Authors In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is a... [more]
© 2018 The Authors In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.
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2019 |
Starkey MR, Plank MW, Casolari P, Papi A, Pavlidis S, Guo Y, et al., 'IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis', EUROPEAN RESPIRATORY JOURNAL, 54 (2019) [C1]
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2019 |
Soon L, Ng PQ, Chellian J, Madheswaran T, Panneerselvam J, Gupta G, et al., 'Therapeutic potential of artemisia vulgaris: An insight into underlying immunological mechanisms', Journal of Environmental Pathology, Toxicology and Oncology, 38 205-216 (2019) [C1]
© 2019 by Begell House, Inc. Artemisia vulgaris is a traditional Chinese herb believed to have a wide range of healing properties; it is traditionally used to treat numerous healt... [more]
© 2019 by Begell House, Inc. Artemisia vulgaris is a traditional Chinese herb believed to have a wide range of healing properties; it is traditionally used to treat numerous health ailments. The plant is commonly called mugwort or riverside wormwood. The plant is edible, and in addition to its medicinal properties, it is also used as a culinary herb in Asian cooking in the form of a vegetable or in soup. The plant has garnered the attention of researchers in the past few decades, and several research studies have investigated its biological effects, including antioxidant, anti-inflammatory, anticancer, hypolipidemic, and antimicrobial properties. In this review, various studies on these biological effects are discussed along with the tests conducted, compounds involved, and proposed mechanisms of action. This review will be of interest to the researchers working in the field of herbal medicine, pharmacology, medical sciences, and immunology.
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2018 |
Shastri MD, Shukla SD, Chong WC, Dua K, Peterson GM, Patel RP, et al., 'Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis', OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 2018 (2018) [C1]
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2018 |
Dua K, Hansbro NG, Foster PS, Hansbro PM, 'Targeting MicroRNAs: Promising Future Therapeutics in the Treatment of Allergic Airway Disease', CRITICAL REVIEWS IN EUKARYOTIC GENE EXPRESSION, 28 125-127 (2018)
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2018 |
Ng ZY, Wong JY, Panneerselvam J, Madheswaran T, Kumar P, Pillay V, et al., 'Assessing the potential of liposomes loaded with curcumin as a therapeutic intervention in asthma', Colloids and Surfaces B: Biointerfaces, 172 51-59 (2018) [C1]
© 2018 Elsevier B.V. Curcumin a component of turmeric, which is derived from Curcuma longa is used as a colouring agent and as a dietary spice for centuries. Extensive studies hav... [more]
© 2018 Elsevier B.V. Curcumin a component of turmeric, which is derived from Curcuma longa is used as a colouring agent and as a dietary spice for centuries. Extensive studies have been done on the anti-inflammatory activity of curcumin along with its molecular mechanism involving different signalling pathways. However, the physicochemical and biological properties such as poor solubility and rapid metabolism of curcumin have led to low bioavailability and hence limits its application. Current therapies for asthma such as bronchodilators and inhaled corticosteroids (ICS) are aimed at controlling disease symptoms and prevent asthma exacerbation. However, this approach requires lifetime therapy and is associated with a constellation of side effects. This creates a clear unmet medical need and there is an urgent demand for new and more-effective treatments. The present study is aimed to formulate liposomes containing curcumin and evaluate for its anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation on BCi-NS1.1 cell line. Curcumin and salbutamol liposomes were formulated using lipid hydration method. The prepared liposomes were characterized in terms of particle size, zeta potential, encapsulation efficiency and in-vitro release profile. The liposomes were tested on BCI-NS1.1 cell line to evaluate its anti-inflammatory properties. The various pro-inflammatory markers studied were Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-1ß (IL-1ß) and Tumour Necrosis Factor-a (TNF-a). Additionally, molecular mechanics simulations were used to elucidate the positioning, energy minimization, and aqueous dispersion of the liposomal architecture involving lecithin and curcumin. The prepared curcumin formulation showed an average size and zeta potential of 271.3 ± 3.06 nm and -61.0 mV, respectively. The drug encapsulation efficiency of liposomal curcumin is 81.1%. Both curcumin-loaded liposomes formulation (1 µg/mL, 5 µg/mL) resulted in significant (p < 0.05) reduction in the level of pro-inflammatory marker expression such as IL-6, IL-8, IL-1ß and TNF-a compared to positive control group. Liposomal curcumin with the dose of 1 µg/mL reduced the inflammatory markers more effectively compared to that of 5 µg/mL. Liposomal curcumin could be a promising intervention for asthma therapy showing their efficacy in suppressing the important pro-inflammatory markers involved in the pathogenesis of asthma.
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2018 |
Chellappan DK, Ng ZY, Wong JY, Hsu A, Wark P, Hansbro N, et al., 'Immunological axis of curcumin-loaded vesicular drug delivery systems', Future Medicinal Chemistry, 10 839-844 (2018) [C1]
© 2018 Newlands Press. Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immu... [more]
© 2018 Newlands Press. Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Such systems use particles at a nanoscale range, bringing about their intended use through a range of complex mechanisms. Apart from delivering drug substances into target tissues, these vesicular systems also effectively overcome problems like insolubility and unequal drug distribution. Several mechanisms are explored lately by different workers, and interest over vesicular curcumin has been renewed in the past decade. This commentary discusses several immunological targets in which curcumin is employed in a vesicular form.
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2017 |
Foster PS, Maltby S, Rosenberg HF, Tay HL, Hogan SP, Collison AM, et al., 'Modeling T
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd In this review, we highlight experiments conducted in our laboratories that have elucidated functional... [more]
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4+ T-helper type-2 lymphocytes (TH2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical TH2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of TH2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote TH2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of TH2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches.
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2017 |
Hansbro PM, Kim RY, Starkey MR, Donovan C, Dua K, Mayall JR, et al., 'Mechanisms and treatments for severe, steroid-resistant allergic airway disease and asthma', Immunological Reviews, 278 41-62 (2017) [C1]
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Severe, steroid-resistant asthma is clinically and economically important since affected individuals d... [more]
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Severe, steroid-resistant asthma is clinically and economically important since affected individuals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been hampered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma.
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2017 |
Nair PM, Starkey MR, Haw TJ, Liu G, Horvat JC, Morris JC, et al., 'Targeting PP2A and proteasome activity ameliorates features of allergic airway disease in mice', Allergy: European Journal of Allergy and Clinical Immunology, 72 1891-1903 (2017) [C1]
© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Background: Asthma is an allergic airway disease (AAD) caused by aberrant immune responses to alle... [more]
© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Background: Asthma is an allergic airway disease (AAD) caused by aberrant immune responses to allergens. Protein phosphatase-2A (PP2A) is an abundant serine/threonine phosphatase with anti-inflammatory activity. The ubiquitin proteasome system (UPS) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed whether enhancing PP2A activity with fingolimod (FTY720) or 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-1-ol (AAL (S) ), or inhibiting proteasome activity with bortezomib (BORT), could suppress experimental AAD. Methods: Acute AAD was induced in C57BL/6 mice by intraperitoneal sensitization with ovalbumin (OVA) in combination with intranasal (i.n) exposure to OVA. Chronic AAD was induced in mice with prolonged i.n exposure to crude house dust mite (HDM) extract. Mice were treated with vehicle, FTY720, AAL (S) , BORT or AAL (S) +BORT and hallmark features of AAD assessed. Results: AAL (S) reduced the severity of acute AAD by suppressing tissue eosinophils and inflammation, mucus-secreting cell (MSC) numbers, type 2-associated cytokines (interleukin (IL)-33, thymic stromal lymphopoietin, IL-5 and IL-13), serum immunoglobulin (Ig)E and airway hyper-responsiveness (AHR). FTY720 only suppressed tissue inflammation and IgE. BORT reduced bronchoalveolar lavage fluid (BALF) and tissue eosinophils and inflammation, IL-5, IL-13 and AHR. Combined treatment with AAL (S) +BORT had complementary effects and suppressed BALF and tissue eosinophils and inflammation, MSC numbers, reduced the production of type 2 cytokines and AHR. AAL (S) , BORT and AAL (S) +BORT also reduced airway remodelling in chronic AAD. Conclusion: These findings highlight the potential of combination therapies that enhance PP2A and inhibit proteasome activity as novel therapeutic strategies for asthma.
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2017 |
Dua K, Hansbro NG, Hansbro PM, 'STEROID RESISTANCE AND CONCOMITANT RESPIRATORY INFECTIONS: A CHALLENGING BATTLE IN PULMONARY CLINIC', EXCLI JOURNAL, 16 981-985 (2017)
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2017 |
Kim RY, Horvat JC, Pinkerton JW, Starkey MR, Essilfie AT, Mayall JR, et al., 'MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase mediated suppression of histone deacetylase 2', Journal of Allergy and Clinical Immunology, 139 519-532 (2017) [C1]
© 2016 American Academy of Allergy, Asthma & Immunology Background Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently req... [more]
© 2016 American Academy of Allergy, Asthma & Immunology Background Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The¿mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease. Objective We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches. Methods Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory¿tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated. Results Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21¿specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens. Conclusion We identify a previously unrecognized role for an¿miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma.
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2017 |
Liu G, Cooley MA, Nair PM, Donovan C, Hsu AC, Jarnicki AG, et al., 'Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c', JOURNAL OF PATHOLOGY, 243 510-523 (2017) [C1]
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2017 |
Dua K, Hansbro NG, Foster PS, Hansbro PM, 'MicroRNAs as therapeutics for future drug delivery systems in treatment of lung diseases', Drug Delivery and Translational Research, 7 168-178 (2017) [C1]
© 2016, Controlled Release Society. The rapid advancement in the area of microRNAs (miRNAs) from discovery to their translation into therapeutic moieties reflects their significan... [more]
© 2016, Controlled Release Society. The rapid advancement in the area of microRNAs (miRNAs) from discovery to their translation into therapeutic moieties reflects their significance as important regulators in the management of disease pathology. The miRNAs can potentially be a new class of drugs in the near future for the treatment of various lung diseases, but it lacks the current knowledge how these identified therapeutic moieties can be designed into an effective, patient complaint and targeted drug delivery system. miRNAs have characteristic features like small size and low molecular weight which makes them easily translated into an effective drug delivery system. In this review, we have summarised the concept of miRNAs and different approaches which can be employed to deliver miRNAs effectively and safely to the target cells including the challenges associated with their development in particular emphasis on pulmonary diseases. Such approaches will be of interest for both the biological and formulation scientists to understand and explore the new vistas in the area of miRNA delivery for pulmonary inflammatory diseases.
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2017 |
Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, et al., 'Role for NLRP3 inflammasome-mediated, IL-1ß-dependent responses in severe, steroid-resistant asthma', American Journal of Respiratory and Critical Care Medicine, 196 283-297 (2017) [C1]
© 2017 by the American Thoracic Society. Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pat... [more]
© 2017 by the American Thoracic Society. Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1ß responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma. Objectives: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1ß in severe, steroid-resistant asthma. Methods: We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1ß responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1ß responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1ß antibody. Roles for IL-1ß-induced neutrophilic inflammation were examined using IL-1ß and anti-Ly6G. Measurements and Main Results: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1ß responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1ß expression. Treatment with anti-IL-1ß, Ac- YVAD-cho, and MCC950 suppressed IL-1ß responses and the important steroid-resistant features of disease in mice, whereas IL-1ß administration recapitulated these features. Neutrophil depletion suppressed IL-1ß-induced steroid-resistant airway hyperresponsiveness. Conclusions: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.
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2016 |
Thorburn AN, Tseng H-Y, Donovan C, Hansbro NG, Jarnicki AG, Foster PS, et al., 'TLR2, TLR4 AND MyD88 Mediate Allergic Airway Disease (AAD) and Streptococcus pneumoniae-Induced Suppression of AAD.', PLoS One, 11 e0156402 (2016) [C1]
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2014 |
Maltby S, Hansbro NG, Tay HL, Stewart J, Plank M, Donges B, et al., 'Production and differentiation of myeloid cells driven by proinflammatory cytokines in response to acute pneumovirus infection in mice.', J Immunol, 193 4072-4082 (2014) [C1]
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2014 |
Grafton KT, Moir LM, Black JL, Hansbro NG, Hansbro PM, Burgess JK, Oliver BG, 'LF-15 & T7, synthetic peptides derived from tumstatin, attenuate aspects of airway remodelling in a murine model of chronic OVA-induced allergic airway disease', PLoS ONE, 9 (2014) [C1]
Background: Tumstatin is a segment of the collagen-IV protein that is markedly reduced in the airways of asthmatics. Tumstatin can play an important role in the development of air... [more]
Background: Tumstatin is a segment of the collagen-IV protein that is markedly reduced in the airways of asthmatics. Tumstatin can play an important role in the development of airway remodelling associated with asthma due to its antiangiogenic properties. This study assessed the anti-angiogenic properties of smaller peptides derived from tumstatin, which contain the interface tumstatin uses to interact with the aVb3 integrin. Methods: Primary human lung endothelial cells were exposed to the LF-15, T3 and T7 tumstatin-derived peptides and assessed for cell viability and tube formation in vitro. The impact of the anti-angiogenic properties on airways hyperresponsiveness (AHR) was then examined using a murine model of chronic OVA-induced allergic airways disease. Results: The LF-15 and T7 peptides significantly reduced endothelial cell viability and attenuated tube formation in vitro. Mice exposed to OVA+ LF-15 or OVA+T7 also had reduced total lung vascularity and AHR was attenuated compared to mice exposed to OVA alone. T3 peptides reduced cell viability but had no effect on any other parameters. Conclusion: The LF-15 and T7 peptides may be appropriate candidates for use as novel pharmacotherapies due to their small size and anti-angiogenic properties observed in vitro and in vivo. © 2014 Grafton et al.
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2013 |
Eftekhari P, Hajizadeh S, Reza Raoufy M, Reza Masjedi M, Yang M, Hansbro N, et al., 'Preventive effect of N-acetylcysteine in a mouse model of steroid resistant acute exacerbation of asthma', EXCLI Journal, 12 184-192 (2013) [C1]
Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acety... [more]
Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acetylcysteine (NAC) on the airway hyper-responsiveness (AHR) and the accumulation of inflammatory cells in the airways in an animal model of steroid resistant acute exacerbation of asthma. Systemically sensitized Balb/C mice were exposed to Ovalbumin aerosol on days 13, 14, 15 and 16, followed by intratracheal lipopolysaccharide (LPS) to induce acute exacerbation. NAC (intraperitoneal, 320 mg/kg 30 min before and 12 hours after each challenge) reduced hyperresponsiveness with/out dexamethasone. LPS application caused neutrophilia in bronchoalveolar lavage fluid (BALF) and eosinophil count was higher than respective control in BALF as well as neutrophils after dexamethasone treatment. NAC significantly decreased neutrophil and eosinophil count in BALF as well as inflammatory cytokines (IL-13 and IL-5).We concluded that addition of NAC to asthma therapy has beneficial preventive effects in an animal model of steroid resistant acute exacerbation of asthma.
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2013 |
Beckett EL, Stevens RL, Jarnicki AG, Kim RY, Hanish I, Hansbro NG, et al., 'A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis', The Journal of Allergy and Clinical Immunology, 131 752-762 (2013) [C1]
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2013 |
Simpson JL, McDonald VM, Baines KJ, Oreo KM, Wang F, Hansbro PM, Gibson PG, 'Influence of Age, Past Smoking, and Disease Severity on TLR2, Neutrophilic Inflammation, and MMP-9 Levels in COPD', MEDIATORS OF INFLAMMATION, 2013 (2013) [C1]
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2013 |
Collison A, Siegle JS, Hansbro NG, Kwok C-T, Herbert C, Mattes J, et al., 'Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma', DISEASE MODELS & MECHANISMS, 6 993-1000 (2013) [C1]
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2013 |
Herbert C, Siegle JS, Shadie AM, Nikolaysen S, Garthwaite L, Hansbro NG, et al., 'Development of asthmatic inflammation in mice following early-life exposure to ambient environmental particulates and chronic allergen challenge', DMM Disease Models and Mechanisms, 6 479-488 (2013) [C1]
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2011 |
Siegle JS, Hansbro NG, Dong C, Angkasekwinai P, Foster PS, Kumar RK, 'Blocking induction of T helper type 2 responses prevents development of disease in a model of childhood asthma', Clinical and Experimental Immunology, 165 19-28 (2011) [C1]
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2011 |
Davidson SK, Kaiko GE, Loh Z, Lalwani A, Zhang V, Spann K, et al., 'Plasmacytoid Dendritic Cells promote host defense against Acute Pneumovirus infection via the TLR7-MyD88-Dependent signaling pathway', Journal of Immunology, 186 5938-5948 (2011) [C1]
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2010 |
Lau JY, Oliver BG, Baraket M, Beckett EL, Hansbro NG, Moir LM, et al., 'Fibulin-1 Is increased in asthma - A novel mediator of airway remodeling?', Plos One, 5 1-13 (2010) [C1]
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2010 |
Burgess JK, Boustany S, Moir LM, Weckmann M, Lau JY, Grafton K, et al., 'Reduction of tumstatin in asthmatic airways contributes to angiogenesis, inflammation, and hyperresponsiveness', American Journal of Respiratory and Critical Care Medicine, 181 106-115 (2010) [C1]
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2010 |
Siegle JS, Hansbro NG, Herbert C, Rosenberg HF, Domachowske JB, Asquith KL, et al., 'Early-life viral infection and allergen exposure interact to induce an asthmatic phenotype in mice', Respiratory Research, 11 1-15 (2010) [C1]
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2009 |
Phipps S, Hansbro NG, Lam CE, Foo A, Matthaei KI, Foster PS, 'Allergic sensitization is enhanced in early life through toll-like receptor 7 activation', Clinical and Experimental Allergy, 39 1920-1928 (2009) [C1]
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2008 |
Ito K, Herbert C, Siegle JS, Vuppusetty C, Hansbro NG, Thomas PS, et al., 'Steroid-resistant neutrophilic inflammation in a mouse model of an acute exacerbation of asthma', American Journal of Respiratory Cell and Molecular Biology, 39 543-550 (2008) [C1]
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2008 |
Su Y-C, Rolph MS, Hansbro NG, Mackay CR, Sewell WA, 'Granulocyte-macrophage colony-stimulating factor is required for bronchial eosinophilia in a murine model of allergic airway inflammation', Journal of Immunology, 180 2600-2607 (2008) [C1]
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2008 |
Hansbro NG, Horvat JC, Wark PA, Hansbro PM, 'Understanding the mechanisms of viral induced asthma: New therapeutic directions', Pharmacology & Therapeutics, 117 313-353 (2008) [C1]
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2007 |
Horvat JC, Beagley KW, Wade MA, Preston JA, Hansbro NG, Hickey DK, et al., 'Neonatal chlamydial infection induces mixed T-cell responses that drive allergic airway disease', American Journal of Respiratory and Critical Care Medicine, 176 556-564 (2007) [C1]
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2007 |
Weckmann M, Collison A, Simpson JL, Kopp MV, Wark PA, Smyth MJ, et al., 'Critical link between TRAIL and CCL20 for the activation of T(H)2 cells and the expression of allergic airway disease', Nature Medicine, 13 1308-1315 (2007) [C1]
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2006 |
Siegle JS, Hansbro NG, Herbert C, Yang M, Foster PS, Kumar RK, 'Airway hyperreactivity in exacerbation of chronic asthma is independent of elosinophilic inflammation', American Journal of Respiratory Cell and Molecular Biology, 35 565-570 (2006) [C1]
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2004 |
Hansbro NG, Beagley LG, Christiansen D, Loveland BE, Johansson ES, Beagley KW, et al., 'Novel role for decay-accelerating factor in Coxsackievirus A21-mediated cell infectivity', Journal of Virology, 78 12677-12682 (2004) [C1]
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2004 |
Hansbro NG, Johansson ES, Au GG, Lindberg A, Barry RD, Shafren DR, 'Enterovirus capsid interactions with decay-accelerating factor mediate lytic cell infection', Journal of Virology, 78 1431-1439 (2004) [C1]
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2004 |
Shafren DR, Au GG, Nguyen T, Barry RD, Hansbro NG, Harvey ES, et al., 'Systemic therapy of malignant human melanoma tumors by a common cold-producing enterovirus, Coxsackievirus A21', Clinical Cancer Research, 10 53-60 (2004) [C1]
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2000 |
Hansbro NG, Clulow J, Man SY, Jones RC, 'pH and bicarbonate in the ductuli efferentes testis of the rat', INTERNATIONAL JOURNAL OF ANDROLOGY, 23 46-50 (2000) [C1]
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