472 results on '"Philip M Hansbro"'
Search Results
2. 'Cellular mechanisms underlying steroid-resistant asthma.' Ridhima Wadhwa, Kamal Dua, Ian M. Adcock, Jay C. Horvat, Richard Y. Kim and Philip M. Hansbro. Eur Respir Rev 2019; 28: 190021
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Richard Kim and Philip Hansbro
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Pulmonary and Respiratory Medicine - Published
- 2019
3. Antiviral Responses of Tissue-resident CD49a+ Lung Natural Killer Cells Are Dysregulated in Chronic Obstructive Pulmonary Disease
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Grace E. Cooper, Jemma Mayall, Chantal Donovan, Tatt J. Haw, Kurtis F. Budden, Nicole G. Hansbro, Evy E. Blomme, Tania Maes, Chia Wei Kong, Jay C. Horvat, Salim I. Khakoo, Tom M. A. Wilkinson, Philip M. Hansbro, and Karl J. Staples
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Pulmonary and Respiratory Medicine ,Critical Care and Intensive Care Medicine - Published
- 2023
4. Targeting the mitochondria in chronic respiratory diseases
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Dinesh Kumar Chellappan, Keshav Raj Paudel, Nian Wan Tan, Ka Seng Cheong, Samantha Sert Qi Khoo, Su Min Seow, Jestin Chellian, Mayuren Candasamy, Vyoma K. Patel, Poonam Arora, Pankaj Kumar Singh, Sachin Kumar Singh, Gaurav Gupta, Brian G. Oliver, Philip M. Hansbro, and Kamal Dua
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Pulmonary Disease, Chronic Obstructive ,0604 Genetics ,Biochemistry & Molecular Biology ,Lung Neoplasms ,Humans ,Molecular Medicine ,Cell Biology ,Lung ,Molecular Biology ,Asthma ,Mitochondria - Abstract
Mitochondria are one of the basic essential components for eukaryotic life survival. It is also the source of respiratory ATP. Recently published studies have demonstrated that mitochondria may have more roles to play aside from energy production. There is an increasing body of evidence which suggest that mitochondrial activities involved in normal and pathological states contribute to significant impact to the lung airway morphology and epithelial function in respiratory diseases such as asthma, COPD, and lung cancer. This review summarizes the pathophysiological pathways involved in asthma, COPD, lung cancer and highlights potential treatment strategies that target the malfunctioning mitochondria in such ailments. Mitochondria are responsive to environmental stimuli such as infection, tobacco smoke, and inflammation, which are essential in the pathogenesis of respiratory diseases. They may affect mitochondrial shape, protein production and ultimately cause dysfunction. The impairment of mitochondrial function has downstream impact on the cytosolic components, calcium control, response towards oxidative stress, regulation of genes and proteins and metabolic activities. Several novel compounds and alternative medicines that target mitochondria in asthma and chronic lung diseases have been discussed here. Moreover, mitochondrial enzymes or proteins that may serve as excellent therapeutic targets in COPD are also covered. The role of mitochondria in respiratory diseases is gaining much attention and mitochondria-based treatment strategies and personalized medicine targeting the mitochondria may materialize in the near future. Nevertheless, more in-depth studies are urgently needed to validate the advantages and efficacy of drugs that affect mitochondria in pathological states.
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- 2022
5. Vitamin D—A prominent immunomodulator to prevent<scp>COVID</scp>‐19 infection
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Sumel Ashique, Kirti Gupta, Gaurav Gupta, Neeraj Mishra, Sachin Kumar Singh, Sheetu Wadhwa, Monica Gulati, Harish Dureja, Flavia Zacconi, Brian G. Oliver, Keshav Raj Paudel, Philip M. Hansbro, Dinesh Kumar Chellappan, and Kamal Dua
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Rheumatology - Abstract
COVID-19 remains a life-threatening infectious disease worldwide. Several bio-active agents have been tested and evaluated in an effort to contain this disease. Unfortunately, none of the therapies have been successful, owing to their safety concerns and the presence of various adverse effects. Various countries have developed vaccines as a preventive measure; however, they have not been widely accepted as effective strategies. The virus has proven to be exceedingly contagious and lethal, so finding an effective treatment strategy has been a top priority in medical research. The significance of vitamin D in influencing many components of the innate and adaptive immune systems is examined in this study. This review aims to summarize the research on the use of vitamin D for COVID-19 treatment and prevention. Vitamin D supplementation has now become an efficient option to boost the immune response for all ages in preventing the spread of infection. Vitamin D is an immunomodulator that treats infected lung tissue by improving innate and adaptive immune responses and downregulating the inflammatory cascades. The preventive action exerted by vitamin D supplementation (at a specific dose) has been accepted by several observational research investigations and clinical trials on the avoidance of viral and acute respiratory dysfunctions. To assess the existing consensus about vitamin D supplementation as a strategy to treat and prevent the development and progression of COVID-19 disease, this review intends to synthesize the evidence around vitamin D in relation to COVID-19 infection.
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- 2022
6. Comparison of Commercially Available Differentiation Media on Cell Morphology, Function, and Anti-Viral Responses in Conditionally Reprogrammed Human Bronchial Epithelial Cells
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Nikhil T Awatade, Andrew T Reid, Kristy S Nichol, Kurtis F Budden, Punnam Chander Veerati, Prabuddha S Pathinayake, Christopher L Grainge, Philip M Hansbro, and Peter AB Wark
- Abstract
Introduction: Primary air liquid interface (ALI) cultures of bronchial epithelial cells are used extensively to model airway responses. A recent advance is the development of conditional reprogramming that enhances proliferative capability. Several different media and protocols are utilized, yeteven subtle differences may influence cellular responses. We compared the morphology and functional responses, including innate immune responses to rhinovirus infection in conditionally reprogrammed primary bronchial epithelial cells (pBECs) differentiated using two commonly used culture media. Methods: pBECs collected from healthy donors (n = 5) were CR using g-irradiated 3T3 fibroblasts and Rho Kinase inhibitor. CRpBECs were differentiated at ALI in either PneumaCult™ (PN-ALI) or Bronchial Epithelial Growth Medium (BEGM)-based differentiation media (BEBM:DMEM, 50:50, Lonza™) - (AB-ALI) for 28 days. Transepithelial electrical resistance (TEER), immunofluorescence, histology, cilia activity, ion channel function, and expression of cell markers were analyzed. Viral RNA was assessed by RT-qPCR and anti-viral proteins quantified by LEGENDplex™ following Rhinovirus-A1b (RVA1b) infection. Results: CRpBECs differentiated in PneumaCult™ were smaller and had a lower TEER and cilia beat frequency (CBF) compared to BEGM media. PneumaCult™ media cultures exhibited significantly increased FOXJ1 expression, more ciliated cells with a larger active area, increased intracellular mucins, and increased calcium-activated chloride channel current. However, there were no significant changes in viral RNA or host antiviral responses. Conclusion: There are distinct structural and functional differences in pBECs cultured in the two commonly used ALI differentiation media. Such factors need to be taken into consideration when designing CRpBECs ALI experiments for specific research questions.
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- 2023
7. Boswellic Acids: A Critical Appraisal of Their Therapeutic and Nutritional Benefits in Chronic Inflammatory Diseases
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Harish Dureja, Neeta solanki, Gaurav Gupta, Dinesh Kumar Chellappan, Sachin Kumar Singh, Monica Gulati, Keshav Raj Paudel, Philip M Hansbro, Kamal Dua, Suraj Bhan, and Manisha saini
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Endocrinology, Diabetes and Metabolism ,Immunology and Allergy - Abstract
Background: In the last few decades, it has been largely perceived that the factors affecting the immune system and its varying pathways lead to the pathological progression of inflammation and inflammatory conditions. Chronic inflammation also contributes to common diseases, such as diabetes mellitus, ischemic heart disease, cancer, chronic renal inflammatory disease, non-alcoholic fatty hepatic disease, autoimmune diseases and neurodegenerative diseases. Objective: Interestingly, plant sources and secondary metabolites from plants have been increasingly employed in managing acute and chronic inflammatory diseases for centuries. Boswellic acids are pentacyclic triterpenoidal moieties obtained from the oleo gum resin of different Boswellia species. Methods: Detailed data was collected revealing the anti-inflammatory potential of Boswellic acids through various databases. Result: These are pharmacologically active agents that possess promising anti-inflammatory, anti-arthritic, antirheumatic, anti-diarrheal, anti-hyperlipidemic, anti-asthmatic, anti-cancer, and anti-microbial effects. Conclusion: Boswellic acids have been in use since ancient times primarily to treat acute and chronic inflammatory diseases. This review discusses the various mechanisms underlying the inflammatory process and the necessity of such natural products as a medication to treat inflammatory diseases. In addition, a discussion has also been extended to understand the primary targets involved in inflammation. The review further explores the therapeutic potential of boswellic acids in chronic inflammatory diseases by analyzing numerous reported scientific studies.
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- 2023
8. Cigarette smoking induces lung cancer tumorigenesis via upregulation of the WNT/β-catenin signaling pathway
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Vamshikrishna Malyla, Keshav Raj Paudel, Gabriele De Rubis, Nicole G. Hansbro, Philip M. Hansbro, and Kamal Dua
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0601 Biochemistry and Cell Biology, 1115 Pharmacology and Pharmaceutical Sciences ,General Medicine ,Pharmacology & Pharmacy ,General Pharmacology, Toxicology and Pharmaceutics ,General Biochemistry, Genetics and Molecular Biology - Published
- 2023
9. Advanced models for respiratory disease and drug studies
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Jesus Shrestha, Keshav Raj Paudel, Hojjatollah Nazari, Vivek Dharwal, Sajad Razavi Bazaz, Matt D. Johansen, Kamal Dua, Philip M. Hansbro, and Majid Ebrahimi Warkiani
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Pharmacology ,Medicinal & Biomolecular Chemistry ,Drug Discovery ,Molecular Medicine ,0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, 1115 Pharmacology and Pharmaceutical Sciences - Abstract
The global burden of respiratory diseases is enormous, with many millions of people suffering and dying prematurely every year. The global COVID-19 pandemic witnessed recently, along with increased air pollution and wildfire events, increases the urgency of identifying the most effective therapeutic measures to combat these diseases even further. Despite increasing expenditure and extensive collaborative efforts to identify and develop the most effective and safe treatments, the failure rates of drugs evaluated in human clinical trials are high. To reverse these trends and minimize the cost of drug development, ineffective drug candidates must be eliminated as early as possible by employing new, efficient, and accurate preclinical screening approaches. Animal models have been the mainstay of pulmonary research as they recapitulate the complex physiological processes, Multiorgan interplay, disease phenotypes of disease, and the pharmacokinetic behavior of drugs. Recently, the use of advanced culture technologies such as organoids and lung-on-a-chip models has gained increasing attention because of their potential to reproduce human diseased states and physiology, with clinically relevant responses to drugs and toxins. This review provides an overview of different animal models for studying respiratory diseases and evaluating drugs. We also highlight recent progress in cell culture technologies to advance integrated models and discuss current challenges and present future perspectives.
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- 2023
10. Comparison of commercially available differentiation media on morphology, function, and virus-host interaction in conditionally reprogrammed human bronchial epithelial cells
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Nikhil T Awatade, Andrew T Reid, Kristy S Nichol, Kurtis F Budden, Punnam C Veerati, Prabuddha S Pathinayake, Christopher L Grainge, Philip M Hansbro, and Peter AB Wark
- Abstract
IntroductionPrimary air liquid interface (ALI) cultures of bronchial epithelial cells are used extensively to model airway responses. A recent advance is the development of conditional reprogramming that enhances proliferative capability. Several different media and protocols are utilized, yet even subtle differences may influence cellular responses. We compared the morphology and functional responses, including innate immune responses to rhinovirus infection in conditionally reprogrammed primary bronchial epithelial cells (pBECs) differentiated using two commonly used culture media.MethodspBECs from healthy participants (n = 5) were CR using γ-irradiated 3T3 fibroblasts and Rho Kinase inhibitor. CRpBECs were differentiated at ALI in either PneumaCult™ (PN-ALI) or Bronchial Epithelial Growth Medium (BEGM)-based differentiation media (BEBM:DMEM, 50:50, Lonza™) - (AB-ALI) for 28 days. Transepithelial electrical resistance (TEER), immunofluorescence, histology, cilia activity, ion channel function, and expression of cell markers were analyzed. Viral load was assessed by RT-qPCR and anti-viral factors quantified by Legendplex following Rhinovirus-A1b (RVA1b) infection.ResultsCRpBECs differentiated in PneumaCult™ were smaller and had a lower TEER and cilia beat frequency (CBF) compared to BEGM media. PneumaCult™ media cultures exhibited significantly increasedFOXJ1expression, more ciliated cells with a larger active area, increased intracellular mucins, and increased calcium-activated chloride channel current. However, there were no significant changes in viral RNA or host antiviral responses.ConclusionThere are distinct structural and functional differences in CRpBECs cultured in the two commonly used ALI differentiation media. Such factors need to be taken into consideration when designing and comparing CRpBECs ALI experiments.
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- 2023
11. Cellular and molecular features of COVID-19 associated ARDS: therapeutic relevance
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Gaetano Scaramuzzo, Francesco Nucera, Alessio Asmundo, Roberto Messina, Matilde Mari, Federica Montanaro, Matt D. Johansen, Francesco Monaco, Guido Fadda, Giovanni Tuccari, Nicole G. Hansbro, Philip M. Hansbro, Trevor T. Hansel, Ian M. Adcock, Antonio David, Paul Kirkham, Gaetano Caramori, Carlo Alberto Volta, and Savino Spadaro
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1103 Clinical Sciences, 1115 Pharmacology and Pharmaceutical Sciences ,Clinical Biochemistry ,Immunology ,Cell Biology - Abstract
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can be asymptomatic or cause a disease (COVID-19) characterized by different levels of severity. The main cause of severe COVID-19 and death is represented by acute (or acute on chronic) respiratory failure and acute respiratory distress syndrome (ARDS), often requiring hospital admission and ventilator support.The molecular pathogenesis of COVID-19-related ARDS (by now termed c-ARDS) is still poorly understood. In this review we will discuss the genetic susceptibility to COVID-19, the pathogenesis and the local and systemic biomarkers correlated with c-ARDS and the therapeutic options that target the cell signalling pathways of c-ARDS.
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- 2023
12. Generation of cardio-protective antibodies after pneumococcal polysaccharide vaccine: Early results from a randomised controlled trial
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Shu Ren, Philip M. Hansbro, Wichat Srikusalanukul, Jay C. Horvat, Tegan Hunter, Alexandra C. Brown, Roseanne Peel, Jack Faulkner, Tiffany-Jane Evans, Shu Chuen Li, David Newby, Alexis Hure, Walter P. Abhayaratna, Sotirios Tsimikas, Ayelet Gonen, Joseph L. Witztum, John Attia, Walter Abhayaratna, Catherine D'Este, Andrew Tonkin, Ingrid Hopper, Amanda Thrift, Christopher Levi, Jonathan Sturm, David Durrheim, Joseph Hung, Tom Briffa, Derek Chew, Phil Anderson, Lynelle Moon, and Mark McEvoy
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Pneumococcal Vaccines ,Streptococcus pneumoniae ,Immunoglobulin M ,Immunoglobulin G ,Australia ,Humans ,Atherosclerosis ,Cardiology and Cardiovascular Medicine ,Biomarkers - Abstract
Observational studies have demonstrated that the pneumococcal polysaccharide vaccine (PPV) is associated with reduced risk of cardiovascular events. This may be mediated through IgM antibodies to OxLDL, which have previously been associated with cardioprotective effects. The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE) is a double-blind, randomised controlled trial (RCT) of PPV in preventing ischaemic events. Participants received PPV or placebo once at baseline and are being followed-up for incident fatal and non-fatal myocardial infarction or stroke over 6 years.A subgroup of participants at one centre (Canberra; n = 1,001) were evaluated at 1 month and 2 years post immunisation for changes in surrogate markers of atherosclerosis, as pre-specified secondary outcomes: high-sensitive C-reactive protein (CRP), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT). In addition, 100 participants were randomly selected in each of the intervention and control groups for measurement of anti-pneumococcal antibodies (IgG, IgG2, IgM) as well as anti-OxLDL antibodies (IgG and IgM to CuOxLDL, MDA-LDL, and PC-KLH).Concentrations of anti-pneumococcal IgG and IgG2 increased and remained high at 2 years in the PPV group compared to the placebo group, while IgM increased and then declined, but remained detectable, at 2 years. There were statistically significant increases in all anti-OxLDL IgM antibodies at 1 month, which were no longer detectable at 2 years; there was no increase in anti-OxLDL IgG antibodies. There were no significant changes in CRP, PWV or CIMT between the treatment groups at the 2-year follow-up.PPV engenders a long-lasting increase in anti-pneumococcal IgG, and to a lesser extent, IgM titres, as well as a transient increase in anti-OxLDL IgM antibodies. However, there were no detectable changes in surrogate markers of atherosclerosis at the 2-year follow-up. Long-term, prospective follow-up of clinical outcomes is continuing to assess if PPV reduces CVD events.
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- 2022
13. Aim2 suppresses cigarette smoke‐induced neutrophil recruitment, neutrophil caspase‐1 activation and anti‐Ly6G‐mediated neutrophil depletion
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Chantal Donovan, Richard Y Kim, Izabela Galvao, Andrew G Jarnicki, Alexandra C Brown, Bernadette Jones‐Freeman, Henry M Gomez, Ridhima Wadhwa, Elinor Hortle, Ranjith Jayaraman, Haroon Khan, Sophie Pickles, Priyanka Sahu, Vrushali Chimankar, Xiaofan Tu, Md Khadem Ali, Jemma R Mayall, Duc H Nguyen, Kurtis F Budden, Vinod Kumar, Kate Schroder, Avril AB Robertson, Matthew A Cooper, Peter AB Wark, Brian G Oliver, Jay C Horvat, and Philip M Hansbro
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DNA-Binding Proteins ,Mice, Inbred C57BL ,Mice ,Neutrophil Infiltration ,Neutrophils ,Caspase 1 ,Immunology ,Animals ,0601 Biochemistry and Cell Biology, 1107 Immunology ,Immunology and Allergy ,Cell Biology ,Cigarette Smoking - Abstract
Increased inflammasome responses are strongly implicated in inflammatory diseases; however, their specific roles are incompletely understood. Therefore, we sought to examine the roles of nucleotide-binding oligomerization domain-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) and absent in melanoma-2 (AIM2) inflammasomes in cigarette smoke-induced inflammation in a model of experimental chronic obstructive pulmonary disease (COPD). We targeted NLRP3 with the inhibitor MCC950 given prophylactically or therapeutically and examined Aim2
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- 2022
14. The science of matcha: Bioactive compounds, analytical techniques and biological properties
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Bhakta Prasad Gaire, Tarun Belwal, Philip M. Hansbro, Niraj Kumar Jha, Keshav Raj Paudel, Latita Subedi, Sachin Kumar Singh, Anjana Adhikari-Devkota, Yuki Kurauchi, Kengo Hori, Hari Prasad Devkota, Kamal Dua, and Dinesh Kumar Chellappan
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chemistry.chemical_compound ,Nutraceutical ,chemistry ,Biological property ,Food products ,Chemical constituents ,Camellia sinensis ,Food science ,Biology ,Green tea ,Theanine ,Food Science ,Biotechnology - Abstract
Background The interest in the plant-derived healthy foods, nutraceuticals, functional foods and food supplements is increasing in recent times as potential agents in maintenance of health and the prevention and treatment of diseases. Matcha tea powder is obtained from the leaves of tea plant (Camellia sinensis (L.) Kuntze) grown under specific condition using about 90% shade. As compared to green tea, a hot water extract of tea leaves, matcha is consumed as a powder of whole leaves. Matcha powder is reported to have higher content of some bioactive components such as catechins, theanine and caffeine. In recent years, there is an increased market demand and consumption of matcha as a drink and as a component in various beverages, snacks and other food products. Scope and approach In this review, the available scientific information of the chemical constituents and their analysis and biological activities were critically analyzed. These results may help to understand current status of research on matcha and the gaps which help to guide future research related to evidence based product formulations. Key findings and conclusions Various studies have reported the difference in bioactive compounds in matcha as compared to green tea and other tea formulations. The content and composition were mostly affected by the cultivation and processing techniques. Analysis of marketed samples in various countries have shown the variable content of the bioactive compounds. Thus, there is a need for proper standardization for maintaining the quality. Matcha as a whole, its extract and compounds have shown promising biological activities in in vitro and animal studies. However, comparatively only a few clinical studies are performed, which need future attention. There should also be more detailed studies regarding matcha-containing food products' formulation, quality control and biological activities.
- Published
- 2021
15. A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection
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Matt D. Johansen, Bernadette M. Saunders, Jason Low, Erica L. Stewart, Alice Grey, Rezwan Siddiquee, Joel P. Mackay, Anupriya Aggarwal, Nayan D. Bhattacharyya, Umaimainthan Palendira, Stuart Turville, Anthony D. Kelleher, Megan Steain, James A. Triccas, Carl G. Feng, Warwick J. Britton, Owen Hutchings, Angela Ferguson, Alberto Ospina Stella, Duc H. Nguyen, Philip M. Hansbro, Nicole G. Hansbro, K. Patel, and Claudio Counoupas
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Protein vaccines ,medicine.medical_treatment ,viruses ,Immunology ,Article ,Virus ,Antigen ,Immunity ,Medicine ,Pharmacology (medical) ,RC254-282 ,Pharmacology ,Heterologous vaccine ,biology ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC581-607 ,Experimental models of disease ,Vaccination ,Infectious Diseases ,Cytokine ,biology.protein ,Antibody ,Immunologic diseases. Allergy ,business ,Tuberculosis vaccines - Abstract
Global control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guérin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilised, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralising antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralised B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.
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- 2021
16. Rapid separation of bacteria from primary nasal samples using inertial microfluidics
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Jesus Shrestha, Sajad Razavi Bazaz, Lin Ding, Steven Vasilescu, Sobia Idrees, Bill Söderström, Philip M. Hansbro, Maliheh Ghadiri, and Majid Ebrahimi Warkiani
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Bacteria ,Microfluidics ,Biomedical Engineering ,Humans ,Bioengineering ,General Chemistry ,Sequence Analysis, DNA ,Cell Separation ,Biochemistry ,03 Chemical Sciences, 09 Engineering ,Analytical Chemistry - Abstract
Microbial populations play a crucial role in human health and the development of many diseases. These diseases often arise from the explosive proliferation of opportunistic bacteria, such as those in the nasal cavity. Recently, there have been increases in the prevalence of these opportunistic pathogens displaying antibiotic resistance. Thus, the study of the nasal microbiota and its bacterial diversity is critical in understanding pathogenesis and developing microbial-based therapies for well-known and emerging diseases. However, the isolation and analysis of these populations for clinical study complicates the already challenging task of identifying and profiling potentially harmful bacteria. Existing methods are limited by low sample throughput, expensive labeling, and low recovery of bacteria with ineffective removal of cells and debris. In this study, we propose a novel microfluidic channel with a zigzag configuration for enhanced isolation and detection of bacteria from human clinical nasal swabs. This microfluidic zigzag channel separates the bacteria from epithelial cells and debris by size differential focusing. As such, pure bacterial cell fractions devoid of large contaminating debris or epithelial cells are obtained. DNA sequencing performed on the separated bacteria defines the diversity and species present. This novel method of bacterial separation is simple, robust, rapid, and cost-effective and has the potential to be used for the rapid identification of bacterial cell populations from clinical samples.
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- 2022
17. Phytantriol-Based Berberine-Loaded Liquid Crystalline Nanoparticles Attenuate Inflammation and Oxidative Stress in Lipopolysaccharide-Induced RAW264.7 Macrophages
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Abdullah M. Alnuqaydan, Abdulmajeed G. Almutary, Mohd Azam, Bikash Manandhar, Gabriele De Rubis, Thiagarajan Madheswaran, Keshav Raj Paudel, Philip M. Hansbro, Dinesh Kumar Chellappan, and Kamal Dua
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0912 Materials Engineering, 1007 Nanotechnology ,berberine ,liquid crystalline nanoparticles ,inflammation ,oxidative stress ,macrophages ,LPS ,advanced drug delivery ,chronic inflammatory diseases ,General Chemical Engineering ,General Materials Science - Abstract
Inflammation and oxidative stress are interrelated processes that represent the underlying causes of several chronic inflammatory diseases that include asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), allergies, diabetes, and cardiovascular diseases. Macrophages are key initiators of inflammatory processes in the body. When triggered by a stimulus such as bacterial lipopolysaccharides (LPS), these cells secrete inflammatory cytokines namely TNF-α that orchestrate the cellular inflammatory process. Simultaneously, pro-inflammatory stimuli induce the upregulation of inducible nitric oxide synthase (iNOS) which catalyzes the generation of high levels of nitric oxide (NO). This, together with high concentrations of reactive oxygen species (ROS) produced by macrophages, mediate oxidative stress which, in turn, exacerbates inflammation in a feedback loop, resulting in the pathogenesis of several chronic inflammatory diseases. Berberine is a phytochemical embedded with potent in vitro anti-inflammatory and antioxidant properties, whose therapeutic application is hindered by poor solubility and bioavailability. For this reason, large doses of berberine need to be administered to achieve the desired pharmacological effect, which may result in toxicity. Encapsulation of such a drug in liquid crystalline nanoparticles (LCNs) represents a viable strategy to overcome these limitations. We encapsulated berberine in phytantriol-based LCNs (BP-LCNs) and tested the antioxidant and anti-inflammatory activities of BP-LCNs in vitro on LPS-induced mouse RAW264.7 macrophages. BP-LCNs showed potent anti-inflammatory and antioxidant activities, with significant reduction in the gene expressions of TNF-α and iNOS, followed by concomitant reduction of ROS and NO production at a concentration of 2.5 µM, which is lower than the concentration of free berberine concentration required to achieve similar effects as reported elsewhere. Furthermore, we provide evidence for the suitability for BP-LCNs both as an antioxidant and as an anti-inflammatory agent with potential application in the therapy of chronic inflammatory diseases.
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- 2022
18. Probiotic
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Kurtis F, Budden, Shaan L, Gellatly, Annalicia, Vaughan, Nadia, Amorim, Jay C, Horvat, Nicole G, Hansbro, David L A, Wood, Philip, Hugenholtz, Paul G, Dennis, Peter A B, Wark, and Philip M, Hansbro
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- 2022
19. T-helper 22 cells develop as a distinct lineage from Th17 cells during bacterial infection and phenotypic stability is regulated by T-bet
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Alyssa J. Lochrin, Richard Kim, Philip M. Hansbro, Maximilian Plank, Steven Maltby, Jemma R. Mayall, Kelly L. Asquith, Hock L. Tay, Paul S. Foster, Gabrielle T. Belz, Simon Keely, Jay C. Horvat, Jessica L. Barnes, Gerard E. Kaiko, and Lorena R Sabino
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0301 basic medicine ,Genetically modified mouse ,Lineage (genetic) ,Immunology ,Regulator ,Interleukin ,Inflammation ,Biology ,Phenotype ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,Immunology and Allergy ,medicine.symptom ,Transcription factor ,Homeostasis ,030215 immunology - Abstract
CD4+ T-helper 22 (Th22) cells are a phenotypically distinct lymphocyte subset that produces high levels of interleukin (IL)-22 without co-production of IL-17A. However, the developmental origin and lineage classification of Th22 cells, their interrelationship to Th17 cells, and potential for plasticity at sites of infection and inflammation remain largely undefined. An improved understanding of the mechanisms underpinning the outgrowth of Th22 cells will provide insights into their regulation during homeostasis, infection, and disease. To address this knowledge gap we generated 'IL-17A-fate-mapping IL-17A/IL-22 reporter transgenic mice' and show that Th22 cells develop in the gastrointestinal tract and lung during bacterial infection without transitioning via an Il17a-expressing intermediate, although in some compartments alternative transition pathways exist. Th22-cell development was not dependent on T-bet; however, this transcription factor functioned as a promiscuous T-cell-intrinsic regulator of IL-17A and IL-22 production, in addition to regulating the outgrowth, phenotypic stability, and plasticity of Th22 cells. Thus, we demonstrate that at sites of mucosal bacterial infection Th22 cells develop as a distinct lineage independently of Th17 cells; though both lineages exhibit bidirectional phenotypic flexibility within infected tissues and their draining lymph nodes, and that T-bet plays a critical regulatory role in Th22-cell function and identity.
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- 2021
20. Gasping for Sulfide: A Critical Appraisal of Hydrogen Sulfide in Lung Disease and Accelerated Aging
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Peter A. B. Wark, Matthew Whiteman, Roberta Torregrossa, Dario Pacitti, Haroon Khan, Chris J. Scotton, Vinod Kumar, and Philip M. Hansbro
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Lung Diseases ,inorganic chemicals ,0301 basic medicine ,Biochemistry & Molecular Biology ,Aging ,congenital, hereditary, and neonatal diseases and abnormalities ,Sulfide ,Physiology ,Hydrogen sulfide ,Clinical Biochemistry ,Cystathionine beta-Synthase ,Inflammation ,Sulfides ,Mitochondrion ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 1115 Pharmacology and Pharmaceutical Sciences ,medicine ,Humans ,Hydrogen Sulfide ,Molecular Biology ,General Environmental Science ,chemistry.chemical_classification ,030102 biochemistry & molecular biology ,Cystathionine gamma-Lyase ,Cell Biology ,equipment and supplies ,Accelerated aging ,humanities ,respiratory tract diseases ,Cell biology ,030104 developmental biology ,chemistry ,Lung disease ,General Earth and Planetary Sciences ,medicine.symptom - Abstract
Hydrogen sulfide (H2S) is a gaseous signaling molecule involved in a plethora of physiological and pathological processes. It is primarily synthesized by cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase as a metabolite of the transsulfuration pathway. H2S has been shown to exert beneficial roles in lung disease acting as an anti-inflammatory and antiviral and to ameliorate cell metabolism and protect from oxidative stress. H2S interacts with transcription factors, ion channels, and a multitude of proteins via post-translational modifications through S-persulfidation ("sulfhydration"). Perturbation of endogenous H2S synthesis and/or levels have been implicated in the development of accelerated lung aging and diseases, including asthma, chronic obstructive pulmonary disease, and fibrosis. Furthermore, evidence indicates that persulfidation is decreased with aging. Here, we review the use of H2S as a biomarker of lung pathologies and discuss the potential of using H2S-generating molecules and synthesis inhibitors to treat respiratory diseases. Furthermore, we provide a critical appraisal of methods of detection used to quantify H2S concentration in biological samples and discuss the challenges of characterizing physiological and pathological levels. Considerations and caveats of using H2S delivery molecules, the choice of generating molecules, and concentrations are also reviewed. Antioxid. Redox Signal. 35, 551-579.
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- 2021
21. Mucosal TLR2-activating protein-based vaccination induces potent pulmonary immunity and protection against SARS-CoV-2 in mice
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Anneliese S. Ashhurst, Matt D. Johansen, Joshua W. C. Maxwell, Skye Stockdale, Caroline L. Ashley, Anupriya Aggarwal, Rezwan Siddiquee, Stefan Miemczyk, Duc H. Nguyen, Joel P. Mackay, Claudio Counoupas, Scott N. Byrne, Stuart Turville, Megan Steain, James A. Triccas, Philip M. Hansbro, Richard J. Payne, and Warwick J. Britton
- Subjects
Multidisciplinary ,COVID-19 Vaccines ,SARS-CoV-2 ,Vaccination ,General Physics and Astronomy ,COVID-19 ,Viral Vaccines ,General Chemistry ,Antibodies, Viral ,Antibodies, Neutralizing ,General Biochemistry, Genetics and Molecular Biology ,Toll-Like Receptor 2 ,Mice ,Spike Glycoprotein, Coronavirus ,Humans ,Animals ,Lung ,Immunity, Mucosal - Abstract
Current vaccines against SARS-CoV-2 substantially reduce mortality, but protection against infection is less effective. Enhancing immunity in the respiratory tract, via mucosal vaccination, may provide protection against infection and minimise viral spread. Here, we report testing of a subunit vaccine in mice, consisting of SARS-CoV-2 Spike protein with a TLR2-stimulating adjuvant (Pam2Cys), delivered to mice parenterally or mucosally. Both routes of vaccination induce substantial neutralising antibody (nAb) titres, however, mucosal vaccination uniquely generates anti-Spike IgA, increases nAb in the serum and airways, and increases lung CD4+ T-cell responses. TLR2 is expressed by respiratory epithelia and immune cells. Using TLR2 deficient chimeric mice, we determine that TLR2 expression in either compartment facilitates early innate responses to mucosal vaccination. By contrast, TLR2 on hematopoietic cells is essential for optimal lung-localised, antigen-specific responses. In K18-hACE2 mice, vaccination provides complete protection against disease and sterilising lung immunity against SARS-CoV-2, with a short-term non-specific protective effect from mucosal Pam2Cys alone. These data support mucosal vaccination as a strategy to improve protection in the respiratory tract against SARS-CoV-2 and other respiratory viruses.
- Published
- 2022
22. Anti-Viral Responses of Tissue-Resident CD49a+ Lung NK Cells Are Dysregulated in COPD
- Author
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Grace E, Cooper, Jemma, Mayall, Chantal, Donovan, Tatt J, Haw, Kurtis F, Budden, Nicole G, Hansbro, Evy E, Blomme, Tania, Maes, Chia Wei, Kong, Jay C, Horvat, Salim I, Khakoo, Tom M A, Wilkinson, Philip M, Hansbro, and Karl J, Staples
- Abstract
Tissue-resident natural killer cells have been identified in numerous organs, but little is known about their functional contribution to respiratory immunity, in particular during chronic lung diseases such as COPD.To investigate the phenotype and antiviral responses of trNK cells in murine cigarette smoke-induced experimental COPD and in human lung parenchyma from COPD donors.Mice were exposed to cigarette smoke for 10 weeks to induce COPD-like lung disease. Lung tissue resident NK cell phenotypes and function were analysed by flow cytometry in both murine and human disease with and without challenge with influenza A virus.In the mouse lung CD49a+CD49b+EOMES+ and CD49a+CD49b-EOMESlo NK cell populations had a distinct phenotype compared with CD49a- circulating NK cells. CD49a+ NK cells were more extensively altered earlier in disease onset than circulating NK cells and increased proportions of CD49a+ NK cells correlated with worsening disease in both murine and human COPD. Furthermore, the presence of lung disease delayed both circulating and tissue-resident NK cell functional responses to influenza infection. CD49a+ NK cells markedly increased their NKG2D, CD103 and CD69 expression in experimental COPD following influenza infection, and human CD49a+ NK cells were hyperactive to ex vivo influenza infection in COPD donors.Collectively, these results demonstrate that tissue-resident NK cell function is altered in cigarette smoke-induced disease and suggests that smoke exposure may aberrantly prime tissue-resident NK cell responsiveness to viral infection. This may contribute to excess inflammation during viral exacerbations of COPD.
- Published
- 2022
23. More New Zealand Storm Petrels Fregetta maoriana off Gau Island, Fiji, in May 2022
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Robert L. Flood, Mike Danzenbaker, Philip M. Hansbro, Colin Rogers, Hiroyuki Tanoi, and Shoko Tanoi
- Subjects
Animal Science and Zoology ,Ecology, Evolution, Behavior and Systematics - Published
- 2022
24. Nutraceuticals and COVID-19: A mechanistic approach toward attenuating the disease complications
- Author
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Keshav Raj Paudel, Vyoma Patel, Sukriti Vishwas, Saurabh Gupta, Sumit Sharma, Yinghan Chan, Niraj Kumar Jha, Jesus Shrestha, Mohammad Imran, Nisha Panth, Shakti Dhar Shukla, Saurav Kumar Jha, Hari Prasad Devkota, Majid Ebrahimi Warkiani, Sachin Kumar Singh, Md Khadem Ali, Gaurav Gupta, Dinesh Kumar Chellappan, Philip M. Hansbro, and Kamal Dua
- Subjects
Pharmacology ,Biophysics ,Cell Biology ,Food Science - Abstract
Nutraceuticals have emerged as potential compounds to attenuate the COVID-19 complications. Precisely, these food additives strengthen the overall COVID treatment and enhance the immunity of a person. Such compounds have been used at a large scale, in almost every household due to their better affordability and easy access. Therefore, current research is focused on developing newer advanced formulations from potential drug candidates including nutraceuticals with desirable properties viz, affordability, ease of availability, ease of administration, stability under room temperature, and potentially longer shelf-lives. As such, various nutraceutical-based products such as compounds could be promising agents for effectively managing COVID-19 symptoms and complications. Most importantly, regular consumption of such nutraceuticals has been shown to boost the immune system and prevent viral infections. Nutraceuticals such as vitamins, amino acids, flavonoids like curcumin, and probiotics have been studied for their role in the prevention of COVID-19 symptoms such as fever, pain, malaise, and dry cough. In this review, we have critically reviewed the potential of various nutraceutical-based therapeutics for the management of COVID-19. We searched the information relevant to our topic from search engines such as PubMed and Scopus using COVID-19, nutraceuticals, probiotics, and vitamins as a keyword. Any scientific literature published in a language other than English was excluded. PRACTICAL APPLICATIONS: Nutraceuticals possess both nutritional values and medicinal properties. They can aid in the prevention and treatment of diseases, as well as promote physical health and the immune system, normalizing body functions, and improving longevity. Recently, nutraceuticals such as probiotics, vitamins, polyunsaturated fatty acids, trace minerals, and medicinal plants have attracted considerable attention and are widely regarded as potential alternatives to current therapeutic options for the effective management of various diseases, including COVID-19.
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- 2022
25. RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD
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Hannelore P. Van Eeckhoutte, Chantal Donovan, Richard Y. Kim, Thomas M. Conlon, Meshal Ansari, Haroon Khan, Ranjith Jayaraman, Nicole G. Hansbro, Yves Dondelinger, Tom Delanghe, Allison M. Beal, Brad Geddes, John Bertin, Tom Vanden Berghe, Joyceline De Volder, Tania Maes, Peter Vandenabeele, Bart M. Vanaudenaerde, Dieter Deforce, Sonja Škevin, Filip Van Nieuwerburgh, Fien M. Verhamme, Guy F. Joos, Sobia Idrees, Herbert B. Schiller, Ali Önder Yildirim, Alen Faiz, Mathieu J.M. Bertrand, Guy G. Brusselle, Philip M. Hansbro, and Ken R. Bracke
- Subjects
Pulmonary and Respiratory Medicine ,11 Medical and Health Sciences, 1116 Medical Physiology ,Respiratory System - Abstract
BackgroundReceptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of COPD pathogenesis. We aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD.MethodsWe assessedRIPK1expression in single-cell RNA sequencing (RNA-seq) data from human and mouse lungs, and validated RIPK1 levels in lung tissue of COPD patientsviaimmunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, usingRipk1S25D/S25Dkinase-deficient mice and the RIPK1 kinase inhibitor GSK′547.ResultsRIPK1expression increased in alveolar type 1 (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients compared with never-smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increasedRipk1expression similarly in AT2 cells, and further in alveolar macrophages and T-cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS exposure, as well as airway remodelling, emphysema, and apoptotic and necroptotic cell death upon chronic CS exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-seq on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition.ConclusionsRIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach.
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- 2022
26. Stinging Nettle (
- Author
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Hari Prasad, Devkota, Keshav Raj, Paudel, Shristi, Khanal, Ananda, Baral, Nisha, Panth, Anjana, Adhikari-Devkota, Niraj Kumar, Jha, Niranjan, Das, Sachin Kumar, Singh, Dinesh Kumar, Chellappan, Kamal, Dua, and Philip M, Hansbro
- Subjects
Plant Leaves ,Plant Extracts ,Anti-Inflammatory Agents ,Urtica dioica ,Urticaceae - Abstract
Stinging nettle (
- Published
- 2022
27. A kNGR Peptide-Tethered Lipid–Polymer Hybrid Nanocarrier-Based Synergistic Approach for Effective Tumor Therapy: Development, Characterization, Ex-Vivo, and In-Vivo Assessment
- Author
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Madhu Gupta, Vikas Sharma, Kalicharan Sharma, Anoop Kumar, Ajay Sharma, Imran Kazmi, Fahad A. Al-Abbasi, Sami I. Alzarea, Obaid Afzal, Abdulmalik Saleh Alfawaz Altamimi, Sachin Kumar Singh, Gaurav Gupta, Keshav Raj Paudel, Philip M. Hansbro, and Kamal Dua
- Subjects
kNGR peptide ,hybrid nanoparticles ,targeted therapy ,intracellular delivery ,polymer-lipid CD13 receptor ,Pharmaceutical Science ,1115 Pharmacology and Pharmaceutical Sciences - Abstract
The present study aims to design, develop and characterize kNGR (Asn-Gly-Arg) peptide-conjugated lipid–polymer-based nanoparticles for the target-specific delivery of anticancer bioactive(s), i.e., Paclitaxel (PTX). The kNGR-PEG-DSPE conjugate was synthesized and characterized by using spectral analysis. The dual-targeted PLGA–lecithin–PEG core-shell nanoparticles (PLNs-kNGR-NPs) were synthesized using a modified nanoprecipitation process, and their physiological properties were determined. The results support that, compared to other NPs, PLNs-kNGR-NPs are highly cytotoxic, owing to higher apoptosis and intracellular uptake. The significance of rational nanoparticle design for synergistic treatment is shown by the higher tumor volume inhibition percentage rate (59.7%), compared to other designed formulations in Balb/c mice in the HT-1080 tumor-induced model. The overall results indicate that the PLNs-kNGR-NPs-based hybrid lipid–polymer nanoparticles present the highest therapeutic efficacy against solid tumor overexpressing the CD13 receptors.
- Published
- 2022
28. Editorial: Advanced therapeutic delivery for the management of chronic respiratory diseases
- Author
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Keshav Raj Paudel, Dinesh Kumar Chellappan, Ronan MacLoughlin, Terezinha de Jesus Andreoli Pinto, Kamal Dua, and Philip M. Hansbro
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General Medicine - Published
- 2022
29. Key role of dysregulated airway epithelium in response to respiratory viral infections in asthma
- Author
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Fatemeh Moheimani, Nafeesa Shahdab, Stephen Cummings, Philip M. Hansbro, and Christopher Ward
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Pulmonary and Respiratory Medicine - Abstract
A differentiated air-liquid interface model shows that the airway epithelium plays a key role in response to respiratory viral infections in people with asthma https://bit.ly/3yDgiX1.
- Published
- 2022
30. Recent advances in lung-on-a-chip models
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Isabella Francis, Jesus Shrestha, Keshav Raj Paudel, Philip M. Hansbro, Majid Ebrahimi Warkiani, and Suvash C. Saha
- Subjects
Pharmacology ,Lab-On-A-Chip Devices ,Medicinal & Biomolecular Chemistry ,Respiratory Tract Diseases ,Drug Discovery ,Cell Culture Techniques ,0601 Biochemistry and Cell Biology, 1115 Pharmacology and Pharmaceutical Sciences ,Animals ,Lung - Abstract
With the global burden of respiratory diseases, rapid identification of the best therapeutic measures to combat these diseases is essential. Animal models and 2D cell culture models do not replicate the findings observed in vivo. To gain deeper insight into lung pathology and physiology, 3D and advanced lung-on-a-chip models have been developed recently. Lung-on-a-chip models more accurately simulate the lung's microenvironment and functions in vivo, resulting in more-accurate assessments of drug safety and effectiveness. This review discusses the transition from 2D to 3D models and the recent advances in lung-on-a-chip platforms, their implementation and the numerous challenges faced. Finally, a general overview of this platform and its potential applications in respiratory disease research and drug discovery is highlighted.
- Published
- 2022
31. Smoking induces shifts in cellular composition and transcriptome within the bronchial mucus barrier
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Senani N. H. Rathnayake, Benedikt Ditz, Jos van Nijnatten, Tayyaba Sadaf, Philip M. Hansbro, Corry A. Brandsma, Wim Timens, Annemarie van Schadewijk, Peter S. Hiemstra, Nick H. T. ten Hacken, Brian Oliver, Huib A. M. Kerstjens, Maarten van den Berge, Alen Faiz, Groningen Research Institute for Asthma and COPD (GRIAC), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
- Subjects
Pulmonary and Respiratory Medicine ,goblet cell ,bronchial mucus barrier ,Respiratory System ,cellular deconvolution ,gene expression ,11 Medical and Health Sciences ,smoking - Abstract
Background and Objective: Smoking disturbs the bronchial-mucus-barrier. This study assesses the cellular composition and gene expression shifts of the bronchial-mucus-barrier with smoking to understand the mechanism of mucosal damage by cigarette smoke exposure. We explore whether single-cell-RNA-sequencing (scRNA-seq) based cellular deconvolution (CD) can predict cell-type composition in RNA-seq data.Methods: RNA-seq data of bronchial biopsies from three cohorts were analysed using CD. The cohorts included 56 participants with chronic obstructive pulmonary disease [COPD] (38 smokers; 18 ex-smokers), 77 participants without COPD (40 never-smokers; 37 smokers) and 16 participants who stopped smoking for 1 year (11 COPD and 5 non-COPD-smokers). Differential gene expression was used to investigate gene expression shifts. The CD-derived goblet cell ratios were validated by correlating with staining-derived goblet cell ratios from the COPD cohort. Statistics were done in the R software (false discovery rate p-value < 0.05).Results: Both CD methods indicate a shift in bronchial-mucus-barrier cell composition towards goblet cells in COPD and non-COPD-smokers compared to ex- and never-smokers. It shows that the effect was reversible within a year of smoking cessation. A reduction of ciliated and basal cells was observed with current smoking, which resolved following smoking cessation. The expression of mucin and sodium channel (ENaC) genes, but not chloride channel genes, were altered in COPD and current smokers compared to never smokers or ex-smokers. The goblet cell-derived staining scores correlate with CD-derived goblet cell ratios.Conclusion: Smoking alters bronchial-mucus-barrier cell composition, transcriptome and increases mucus production. This effect is partly reversible within a year of smoking cessation. CD methodology can predict goblet-cell percentages from RNA-seq.
- Published
- 2022
32. Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined with Single-Cell RNA Sequencing
- Author
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Matt D. Johansen, Rashad M. Mahbub, Sobia Idrees, Duc H. Nguyen, Stefan Miemczyk, Prabuddha Pathinayake, Kristy Nichol, Nicole G. Hansbro, Linden J. Gearing, Paul J. Hertzog, David Gallego-Ortega, Warwick J. Britton, Bernadette M. Saunders, Peter A. Wark, Alen Faiz, and Philip M. Hansbro
- Subjects
COVID-19 ,COPD ,single-cell RNA sequenzing ,interferon ,protease ,Pulmonary and Respiratory Medicine ,SARS-CoV-2 ,Sequence Analysis, RNA ,Respiratory System ,Epithelial Cells ,Critical Care and Intensive Care Medicine ,Pulmonary Disease, Chronic Obstructive ,Cytokines ,Humans ,11 Medical and Health Sciences ,Serpins ,Peptide Hydrolases - Abstract
Rationale: Patients with chronic obstructive pulmonary disease (COPD) develop more severe coronavirus disease (COVID-19); however, it is unclear whether they are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and what mechanisms are responsible for severe disease. Objectives: To determine whether SARS-CoV-2 inoculated primary bronchial epithelial cells (pBECs) from patients with COPD support greater infection and elucidate the effects and mechanisms involved. Methods: We performed single-cell RNA sequencing analysis on differentiated pBECs from healthy subjects and patients with COPD 7 days after SARS-CoV-2 inoculation. We correlated changes with viral titers, proinflammatory responses, and IFN production. Measurements and Main Results: Single-cell RNA sequencing revealed that COPD pBECs had 24-fold greater infection than healthy cells, which was supported by plaque assays. Club/goblet and basal cells were the predominant populations infected and expressed mRNAs involved in viral replication. Proteases involved in SARS-CoV-2 entry/infection (TMPRSS2 and CTSB) were increased, and protease inhibitors (serpins) were downregulated more so in COPD. Inflammatory cytokines linked to COPD exacerbations and severe COVID-19 were increased, whereas IFN responses were blunted. Coexpression analysis revealed a prominent population of club/goblet cells with high type 1/2 IFN responses that were important drivers of immune responses to infection in both healthy and COPD pBECs. Therapeutic inhibition of proteases and inflammatory imbalances reduced viral titers and cytokine responses, particularly in COPD pBECs. Conclusions: COPD pBECs are more susceptible to SARS-CoV-2 infection because of increases in coreceptor expression and protease imbalances and have greater inflammatory responses. A prominent cluster of IFN-responsive club/goblet cells emerges during infection, which may be important drivers of immunity. Therapeutic interventions suppress SARS-CoV-2 replication and consequent inflammation.
- Published
- 2022
33. Therapeutic targeting of the respiratory microbiome
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Sanjay H. Chotirmall, Debby Bogaert, James D. Chalmers, Michael J. Cox, Philip M. Hansbro, Yvonne J. Huang, Philip L. Molyneaux, David N. O’Dwyer, Alexa A. Pragman, Geraint B. Rogers, Leopoldo N. Segal, and Robert P. Dickson
- Subjects
Pulmonary and Respiratory Medicine ,16S ,metagenomics ,Microbiota ,Respiratory System ,microbiology ,Humans ,microbiome ,Critical Care and Intensive Care Medicine ,11 Medical and Health Sciences ,host-microbe interactions - Abstract
The last decade of research has revolutionized our understanding of respiratory microbiology, revealing that the lungs and airways contain diverse and dynamic microbial communities in health and disease. This “respiratory ecosystem”—a densely interconnected environment of microbial and host interactions—represents a tremendous and under-appreciated source of biological and clinical heterogeneity across patients with acute and chronic lung disease. Unlike other major sources of heterogeneity, such as comorbidities and host genetics, the respiratory microbiome is readily modifiable by clinical interventions, and therefore represents an untapped opportunity for therapeutic manipulation. As a potential “treatable trait” in efforts to subphenotype patients and deliver precision medicine, the respiratory microbiome is a promising therapeutic target. In this Pulmonary Perspective, we identify and discuss multiple challenges, both conceptual and practical, that must be overcome before the respiratory microbiome can be effectively modulated as a therapeutic target. Barriers include: 1) the need to identify specific microbiologic and ecologic “targets” for therapeutic modulation; 2) the need for an improved understanding of the efficacy and persistence of response to respiratory microbiome-modulating interventions; 3) the need for clinicians to be able to access, understand and utilize microbiome data for sub-phenotyping patients, and 4) specific concerns in special populations (including children, patients with chronic lung disease, and critically ill patients). By delineating these barriers, we identify opportunities for prospective research to advance our understanding of the respiratory microbiome, its role in human respiratory disease, and its genuine potential as a therapeutic target.
- Published
- 2022
34. Pathophysiological Correlation between Cigarette Smoking and Amyotrophic Lateral Sclerosis
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Abhirup Das, Spiro Menounos, Philip M. Hansbro, and Ashish D. Diwan
- Subjects
0301 basic medicine ,amyotrophic lateral sclerosis (ALS) ,motor neuron degeneration ,immunometabolism ,cigarette smoking ,Neurosciences. Biological psychiatry. Neuropsychiatry ,medicine.disease_cause ,neuroinflammation ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,oxidative stress ,Microbiome ,Epigenetics ,Amyotrophic lateral sclerosis ,Neuroinflammation ,1109 Neurosciences, 1701 Psychology, 1702 Cognitive Sciences ,Neurology & Neurosurgery ,business.industry ,medicine.disease ,Pathophysiology ,030104 developmental biology ,Environmental Risk Factor ,business ,Neuroscience ,030217 neurology & neurosurgery ,Oxidative stress ,RC321-571 - Abstract
Cigarette smoke (CS) has been consistently demonstrated to be an environmental risk factor for amyotrophic lateral sclerosis (ALS), although the molecular pathogenic mechanisms involved are yet to be elucidated. Here, we propose different mechanisms by which CS exposure can cause sporadic ALS pathogenesis. Oxidative stress and neuroinflammation are widely implicated in ALS pathogenesis, with blood–spinal cord barrier disruption also recognised to be involved in the disease process. In addition, immunometabolic, epigenetic and microbiome alterations have been implicated in ALS recently. Identification of the underlying pathophysiological mechanisms that underpin CS-associated ALS will drive future research to be conducted into new targets for treatment.
- Published
- 2021
35. Mitochondria-Targeted Antioxidants as a Therapeutic Strategy for Chronic Obstructive Pulmonary Disease
- Author
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Lauren H. Fairley, Shatarupa Das, Vivek Dharwal, Nadia Amorim, Karl J. Hegarty, Ridhima Wadhwa, Guntipally Mounika, and Philip M. Hansbro
- Subjects
Physiology ,Clinical Biochemistry ,Cell Biology ,Molecular Biology ,Biochemistry - Abstract
Oxidative stress is a major hallmark of COPD, contributing to inflammatory signaling, corticosteroid resistance, DNA damage, and accelerated lung aging and cellular senescence. Evidence suggests that oxidative damage is not solely due to exogenous exposure to inhaled irritants, but also endogenous sources of oxidants in the form of reactive oxygen species (ROS). Mitochondria, the major producers of ROS, exhibit impaired structure and function in COPD, resulting in reduced oxidative capacity and excessive ROS production. Antioxidants have been shown to protect against ROS-induced oxidative damage in COPD, by reducing ROS levels, reducing inflammation, and protecting against the development of emphysema. However, currently available antioxidants are not routinely used in the management of COPD, suggesting the need for more effective antioxidant agents. In recent years, a number of mitochondria-targeted antioxidant (MTA) compounds have been developed that are capable of crossing the mitochondria lipid bilayer, offering a more targeted approach to reducing ROS at its source. In particular, MTAs have been shown to illicit greater protective effects compared to non-targeted, cellular antioxidants by further reducing apoptosis and offering greater protection against mtDNA damage, suggesting they are promising therapeutic agents for the treatment of COPD. Here, we review evidence for the therapeutic potential of MTAs as a treatment for chronic lung disease and discuss current challenges and future directions.
- Published
- 2023
36. Exploring the Remarkable Chemotherapeutic Potential of Polyphenolic Antioxidants in Battling Various Forms of Cancer
- Author
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Mohammad Imran, Areeba Insaf, Nazeer Hasan, Vrushabh V. Sugandhi, Deumaya Shrestha, Keshav Raj Paudel, Saurav Kumar Jha, Philip M. Hansbro, Kamal Dua, Hari Prasad Devkota, and Yousuf Mohammed
- Subjects
Chemistry (miscellaneous) ,Organic Chemistry ,Drug Discovery ,Molecular Medicine ,Pharmaceutical Science ,0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 0307 Theoretical and Computational Chemistry ,Physical and Theoretical Chemistry ,Analytical Chemistry - Abstract
Plant-derived compounds, specifically antioxidants, have played an important role in scavenging the free radicals present under diseased conditions. The persistent generation of free radicals in the body leads to inflammation and can result in even more severe diseases such as cancer. Notably, the antioxidant potential of various plant-derived compounds prevents and deregulates the formation of radicals by initiating their decomposition. There is a vast literature demonstrating antioxidant compounds’ anti-inflammatory, anti-diabetic, and anti-cancer potential. This review describes the molecular mechanism of various flavonoids, such as quercetin, kaempferol, naringenin, epicatechin, and epicatechin gallate, against different cancers. Additionally, the pharmaceutical application of these flavonoids against different cancers using nanotechnologies such as polymeric, lipid-based nanoparticles (solid–lipid and liquid–lipid), liposomes, and metallic nanocarriers is addressed. Finally, combination therapies in which these flavonoids are employed along with other anti-cancer agents are described, indicating the effective therapies for the management of various malignancies.
- Published
- 2023
37. Nanoformulations-Based Metronomic Chemotherapy: Mechanism, Challenges, Recent Advances, and Future Perspectives
- Author
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Vijay Kumar Panthi, Kamal Dua, Sachin Kumar Singh, Gaurav Gupta, Philip M. Hansbro, and Keshav Raj Paudel
- Subjects
Pharmaceutical Science - Abstract
Cancer-related death is a significant health and economic burden worldwide, and some conventional chemotherapy is associated with limited effectiveness in completely curing various cancers, severe adverse effects, and destruction of healthy cells. To overcome the complications associated with conventional treatment, metronomic chemotherapy (MCT) is extensively suggested. In this review, we aim to highlight the importance of MCT over conventional chemotherapeutic approach with emphasis on nanoformulations-based MCT, their mechanism, challenges, recent advances, and future perspectives. Nanoformulations-based MCT revealed remarkable antitumor activity in both preclinical and clinical settings. For example, the metronomic scheduling of oxaliplatin-loaded nanoemulsion and polyethylene glycol-coated stealth nanoparticles incorporating paclitaxel were proven very effective in tumor-bearing mice and rats, respectively. Additionally, several clinical studies have demonstrated the benefit of MCT with acceptable tolerance. Moreover, metronomic might be a promising treatment strategy for improving cancer care in low- and middle-income nations. However, an appropriate alternative to a metronomic regimen for an individual ailment, suitable combinational delivery and scheduling, and predictive biomarkers are certain parts that remain unanswered. Further clinical-based comparative research studies are mandatory to be performed before entailing this treatment modality in clinical practice as alternative maintenance therapy or in place of transferring to therapeutic management.
- Published
- 2023
38. Tackling the cytokine storm using advanced drug delivery in allergic airway disease
- Author
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Vyoma K. Patel, Sukriti Vishwas, Rajan Kumar, Gabriele De Rubis, Shakti D. Shukla, Keshav Raj Paudel, Bikash Manandhar, Thakur Gurjeet Singh, Dinesh Kumar Chellappan, Monica Gulati, Indu Pal Kaur, Venkata Sita Rama Raju Allam, Philip M. Hansbro, Brian G. Oliver, Ronan MacLoughlin, Sachin Kumar Singh, and Kamal Dua
- Subjects
Pharmaceutical Science ,Pharmacology & Pharmacy ,1115 Pharmacology and Pharmaceutical Sciences - Published
- 2023
39. The Pandemic and Your Skin—Direct and Indirect Impact of COVID-19
- Author
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Mohammad Imran, Xuping Jin, Masood Ali, Pronalis Tapfumaneyi, Pauline Lelasseur, Laure Carlo, Axelle Jude, Alice Le Bourg, Bhavesh Panchal, Arianna Dick, Keshav Raj Paudel, Philip M. Hansbro, Yousuf Mohammed, University of Queensland [Brisbane], Rhodes University, Grahamstown, Université de Rennes - Faculté de Médecine (UR Médecine), Université de Rennes (UR), Royal Melbourne Institute of Technology University (RMIT University), University of Technology Sydney (UTS), and MI is supported by the Research Training Program Scholarship, The University of Queensland, and PMH is funded by a Fellowship and grants from the National Health and Medical Research Council (NHMRC) of Australia (1175134) and by UTS.
- Subjects
skin manifestations ,PPEs ,immunological response ,Aging ,[SDV]Life Sciences [q-bio] ,COVID-19 ,Pharmaceutical Science ,Chemical Engineering (miscellaneous) ,Surgery ,Dermatology ,0305 Organic Chemistry - Abstract
International audience; Apart from well-known respiratory symptoms, less frequent symptoms also appear as a direct result of COVID-19 infection, or as indirect effects of the recommended quarantine and related lifestyle changes. The impact of the COVID-19 pandemic on human skin is predominantly focused on in this article. Cutaneous manifestations, including redness, chilblain-like symptoms (COVID toes), hives or urticaria rash, water blisters, and fishing net-like red-blue patterns on the skin, may appear as accompanying or as systemic COVID-19 symptoms with potential lesions at different skin sites. These symptoms were related to skin phototypes and vitamin D deficiency. Moreover, Black, Asian, and minority ethnic origin patients are found to be more sensitive to COVID-19 infection than Caucasians because of vitamin D deficiency. The region of population with lighter skin phototypes have a significantly higher chance to develop cutaneous manifestations than population with dark skin. In addition, adverse effects, such as skin barrier damage and irritation, may also occur due to extensive personal protective equipment usage (e.g., masks, protective suits, and a few others) and predominately alcohol-based sanitizers. This manuscript covers various aspects of COVID-19 and its clinical skin manifestations.
- Published
- 2023
40. Extracellular Vesicles Released from Cancer Cells Promote Tumorigenesis by Inducing Epithelial to Mesenchymal Transition via β-Catenin Signaling
- Author
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Vamshikrishna Malyla, Keshav Raj Paudel, Gabriele De Rubis, Nicole G. Hansbro, Philip M. Hansbro, and Kamal Dua
- Subjects
β-catenin signaling ,Chemical Physics ,Organic Chemistry ,EMT ,biomarkers ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences ,lung cancer ,tumorigenesis ,Physical and Theoretical Chemistry ,extracellular vesicles ,Molecular Biology ,Spectroscopy - Abstract
Lung cancer is the leading cause of cancer-related deaths globally, in part due to a lack of early diagnostic tools and effective pharmacological interventions. Extracellular vesicles (EVs) are lipid-based membrane-bound particles released from all living cells in both physiological and pathological states. To understand the effects of lung-cancer-derived EVs on healthy cells, we isolated and characterized EVs derived from A549 lung adenocarcinoma cells and transferred them to healthy human bronchial epithelial cells (16HBe14o). We found that A549-derived EVs carry oncogenic proteins involved in the pathway of epithelial to mesenchymal transition (EMT) that are regulated by β-catenin. The exposure of 16HBe14o cells to A549-derived EVs resulted in a significant increase in cell proliferation, migration, and invasion via upregulating EMT markers such as E-Cadherin, Snail, and Vimentin and cell adhesion molecules such as CEACAM-5, ICAM-1, and VCAM-1, with concomitant downregulation of EpCAM. Our study suggests a role for cancer-cell-derived EVs to induce tumorigenesis in adjacent healthy cells by promoting EMT via β-catenin signaling.
- Published
- 2023
41. Mitochondrial dysfunctions associated with chronic respiratory diseases and their targeted therapies: an update
- Author
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Keshav Raj Paudel, Niraj Kumar Jha, Ronan MacLoughlin, Philip M. Hansbro, Brian G. Oliver, Kamal Dua, Vivek Dharwal, and Dinesh Kumar Chellappan
- Subjects
Lung Diseases ,Pharmacology ,business.industry ,Inflammation ,Mitochondrion ,Bioinformatics ,Mitochondria ,Benzodiazepines ,Oxidative Stress ,Adenosine Triphosphate ,Glyburide ,Drug Discovery ,Humans ,Molecular Medicine ,Medicine ,Respiratory system ,medicine.symptom ,Reactive Oxygen Species ,business - Published
- 2021
42. <scp>ACE2</scp> expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma
- Author
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Thomas Iosifidis, Nathan W. Bartlett, Kristy Nichol, Wenying Lu, Philip M. Hansbro, Ayesha Ali, Erika N. Sutanto, Mathew Suji Eapen, Kevin Looi, Peter A. B. Wark, Luke W. Garratt, Christopher Oldmeadow, Sukhwinder Singh Sohal, Stephen M. Stick, Anthony Kicic, Punnam Chander Veerati, Prabuddha S. Pathinayake, Alan Hsu, Andrew T. Reid, Ling Chen, and Gerard E. Kaiko
- Subjects
Male ,coronavirus disease, COVID‐19 ,Pulmonary and Respiratory Medicine ,Proteases ,Respiratory System ,ACE2 ,Comorbidity ,Peptidyl-Dipeptidase A ,Lung injury ,SARS‐CoV‐2 ,03 medical and health sciences ,0302 clinical medicine ,angiotensin‐converting enzyme 2 ,Gene expression ,Humans ,Medicine ,030212 general & internal medicine ,Furin ,ComputingMilieux_MISCELLANEOUS ,11 Medical and Health Sciences ,Asthma ,COPD ,biology ,SARS-CoV-2 ,business.industry ,Australia ,Editorials ,COVID-19 ,Epithelial Cells ,Middle Aged ,medicine.disease ,respiratory tract diseases ,3. Good health ,Editorial ,Gene Expression Regulation ,030228 respiratory system ,Immunology ,Cohort ,biology.protein ,Immunohistochemistry ,Female ,viral infection ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Background and objective: COVID-19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter AEC. We determined what factors are associated with ACE2 expression particularly in patients with asthma and COPD. Methods: We obtained lower AEC from 145 people from two independent cohorts, aged 2–89 years, Newcastle (n = 115) and Perth (n = 30), Australia. The Newcastle cohort was enriched with people with asthma (n= 37) and COPD (n = 38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry was assessed by qPCR, and protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AEC. Results: Increased gene expression of ACE2 was associated with older age (P = 0.03) and male sex (P = 0.03), but not with pack-years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma patients (P = 0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in patients with asthma (P = 0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface, was increased (P = 0.02). ACE2 protein expression was also reduced in endobronchial biopsies from asthma patients. Conclusion: Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over-represented in those with COVID19 complications.
- Published
- 2021
43. Differences in pulmonary group 2 innate lymphoid cells are dependent on mouse age, sex and strain
- Author
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Malcolm R. Starkey, Svenja Loering, Paul S. Foster, Philip M. Hansbro, Guy J. M. Cameron, Nirmal Prasad Bhatt, and Gabrielle T. Belz
- Subjects
Male ,0301 basic medicine ,Immunology ,Biology ,Flow cytometry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,medicine ,Animals ,Immunology and Allergy ,Lymphocytes ,Respiratory system ,skin and connective tissue diseases ,Lung ,Interleukin 5 ,Mice, Inbred BALB C ,medicine.diagnostic_test ,Innate lymphoid cell ,Interleukin ,Cell Biology ,respiratory system ,Immunity, Innate ,Mice, Inbred C57BL ,body regions ,030104 developmental biology ,medicine.anatomical_structure ,Interleukin 13 ,Female ,030215 immunology - Abstract
Innate lymphoid cells (ILCs) are resident in the lung and are involved in both the maintenance of homeostasis and the pathogenesis of respiratory diseases. In this study, murine lung ILCs were characterized using flow cytometry and the impact of mouse age, sex and strain were assessed. Lung ILCs were found as early as postnatal day 4 and numbers peaked at 2 weeks, and then decreased as the lung matured. During postnatal lung development, ILC expressed differential amounts of group 2 ILC (ILC2)-associated cell surface antigens including ST2, CD90.2 and ICOS. Using Il5venus Il13td-tomato dual reporter mice, neonates were found to have increased constitutive interleukin (IL)-13 expression compared with adult mice. Neonates and adults had similar ratios of IL-5+ CD45+ leukocytes; however, these cells were mostly composed of ILCs in neonates and T cells in adults. Sex-specific differences in ILC numbers were also observed, with females having greater numbers of lung ILCs than males in both neonatal and adult mice. Female lung ILCs also expressed higher levels of ICOS and decreased KLRG1. Mouse strain also impacted on lung ILCs with BALB/c mice having more ILCs in the lung and increased expression of ST2 and ICOS compared with C57BL/6J mice. Collectively, these data show that lung ILC numbers, cell surface antigen expression, IL-5 and IL-13 levels differed between neonatal and adult lung ILCs. In addition, cell surface antigens commonly used for ILC2 quantification, such as ST2, CD90.2 and ICOS, differ depending on age, sex and strain and these are important considerations for consistent universal identification of lung ILC2s.
- Published
- 2021
44. Beyond the Obvious: Smoking and Respiratory Infection Implications on Alzheimer's Disease
- Author
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Gaurav Gupta, Parteek Prasher, Krishna P. Sunkara, Philip M. Hansbro, Dinesh Kumar Chellappan, Kamal Dua, Murtaza M. Tambuwala, Shakti D. Shukla, Rohit Goyal, Alaa A. A. Aljabali, Ridhima Wadhwa, Keshav Raj Paudel, Meenu Mehta, and Nisha Panth
- Subjects
Neurotoxins ,Population ,1109 Neurosciences, 1115 Pharmacology and Pharmaceutical Sciences ,Plaque, Amyloid ,Disease ,medicine.disease_cause ,Tobacco smoke ,Amyloid beta-Protein Precursor ,Alzheimer Disease ,Risk Factors ,medicine ,Animals ,Humans ,education ,Respiratory Tract Infections ,Neuroinflammation ,Neurons ,Pharmacology ,education.field_of_study ,Neurology & Neurosurgery ,Amyloid beta-Peptides ,Lung ,business.industry ,General Neuroscience ,Smoking ,Brain ,Respiratory infection ,Review article ,Oxidative Stress ,medicine.anatomical_structure ,Immunology ,business ,Oxidative stress - Abstract
Tobacco smoke is not only a leading cause for chronic obstructive pulmonary disease, cardiovascular disorders, and lung and oral cancers, but also causes neurological disorders such as Alzheimer ’s disease. Tobacco smoke consists of more than 4500 toxic chemicals, which form free radicals and can cross blood-brain barrier resulting in oxidative stress, an extracellular amyloid plaque from the aggregation of amyloid β (Aβ) peptide deposition in the brain. Further, respiratory infections such as Chlamydia pneumoniae, respiratory syncytial virus have also been involved in the induction and development of the disease. The necessary information collated on this review has been gathered from various literature published from 1995 to 2019. The review article sheds light on the role of smoking and respiratory infections in causing oxidative stress and neuroinflammation, resulting in Alzheimer's disease (AD). This review will be of interest to scientists and researchers from biological and medical science disciplines, including microbiology, pharmaceutical sciences and the translational researchers, etc. The increasing understanding of the relationship between chronic lung disease and neurological disease is two-fold. First, this would help to identify the risk factors and possible therapeutic interventions to reduce the development and progression of both diseases. Second, this would help to reduce the probable risk of development of AD in the population prone to chronic lung diseases.
- Published
- 2020
45. Molecular and Immunological Mechanisms Underlying the Various Pharmacological Properties of the Potent Bioflavonoid, Rutin
- Author
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Hira Choudhury, Trudi Collet, Alan Hsu, Philip M. Hansbro, David Ong Cherk Yong, Manisha Pandey, Gaurav Gupta, Thiagarajan Madheswaran, Farrukh Zeeshan, Dinesh Kumar Chellappan, Yik Lung Chan, Sanggetha Raja Saker, Jithendra Panneerselvam, Nicole G. Hansbro, Brian G. Oliver, Kamal Dua, and Peter A. B. Wark
- Subjects
0301 basic medicine ,Rutin ,Endocrinology, Diabetes and Metabolism ,Anti-Inflammatory Agents ,030209 endocrinology & metabolism ,Pharmacology ,Biology ,Antioxidants ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Molecular level ,Anti-Allergic Agents ,Animals ,Humans ,Hypoglycemic Agents ,Immunology and Allergy ,Medicinal plants ,Antineoplastic Agents, Phytogenic ,Oxidative Stress ,Safety profile ,030104 developmental biology ,chemistry ,Bioflavonoid ,Anti allergy ,Inflammation Mediators ,Reactive Oxygen Species ,Large group ,Signalling pathways ,Signal Transduction - Abstract
The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its diverse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.
- Published
- 2020
46. Curcumin-loaded niosomes downregulate mRNA expression of pro-inflammatory markers involved in asthma: an in vitro study
- Author
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Philip M. Hansbro, Meenu Mehta, Zhao Yin Ng, Viness Pillay, Jin-Ying Wong, Mary Bebawy, Thiagarajan Madheswaran, Gaurav Gupta, Dinesh Kumar Chellappan, Shakti D. Shukla, Pradeep Kumar, Kamal Dua, Peter A. B. Wark, Nicole G. Hansbro, Jithendra Panneerselvam, Alan Hsu, and Poonam Negi
- Subjects
0303 health sciences ,Messenger RNA ,Chemistry ,Mrna expression ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Development ,Pharmacology ,medicine.disease ,In vitro ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,Curcumin ,medicine ,In vitro study ,General Materials Science ,Niosome ,030304 developmental biology ,Asthma - Abstract
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-1β and TNF-α 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.
- Published
- 2020
47. Emerging concepts and directed therapeutics for the management of asthma: regulating the regulators
- Author
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Madhur D. Shastri, Murtaza M. Tambuwala, Philip M. Hansbro, Dinesh Kumar Chellappan, Wai Chin Chong, Gregory M. Peterson, Shakti D. Shukla, Malik Q. Mahmood, Rahul P. Patel, Nicole G. Hansbro, and Kamal Dua
- Subjects
0301 basic medicine ,Pharmacology ,medicine.medical_specialty ,Allergy ,business.industry ,Immunology ,Provocation test ,Disease ,medicine.disease ,respiratory tract diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Targeted drug delivery ,medicine ,Pharmacology (medical) ,Airway Remodelling ,Intensive care medicine ,business ,Myofibroblast ,030217 neurology & neurosurgery ,Asthma - Abstract
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.
- Published
- 2020
48. Antiproliferative effects of boswellic acid-loaded chitosan nanoparticles on human lung cancer cell line A549
- Author
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Gaurav Gupta, Saurabh Satija, Harish Dureja, Philip M. Hansbro, Dinesh Kumar Chellappan, Murtaza M. Tambuwala, Gang Liu, Keshav Raj Paudel, Kamal Dua, Nicole G. Hansbro, Meenu Mehta, Alaa A. A. Aljabali, and Neeta Solanki
- Subjects
Cell Survival ,Medicinal & Biomolecular Chemistry ,Molecular Conformation ,Nanoparticle ,Antineoplastic Agents ,01 natural sciences ,0304 Medicinal and Biomolecular Chemistry, 1115 Pharmacology and Pharmaceutical Sciences ,Chitosan ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Particle Size ,Lung cancer ,Cell Proliferation ,030304 developmental biology ,Pharmacology ,Drug Carriers ,0303 health sciences ,Dose-Response Relationship, Drug ,Human lung cancer ,Cell Cycle ,Chitosan nanoparticles ,medicine.disease ,Triterpenes ,0104 chemical sciences ,Bioavailability ,010404 medicinal & biomolecular chemistry ,chemistry ,A549 Cells ,Cell culture ,Nanoparticles ,Molecular Medicine ,Boswellic acid ,Drug Screening Assays, Antitumor ,Nuclear chemistry - Abstract
Aim: In the present study boswellic acids-loaded chitosan nanoparticles were synthesized using ionic gelation technique. The influence of independent variables were studied and optimized on dependent variables using central composite design. Methodology & results: The designed nanoparticles were observed spherical in shape with an average size of 67.5–187.2 nm and have also shown an excellent entrapment efficiency (80.06 ± 0.48). The cytotoxicity assay revealed enhanced cytotoxicity for drug-loaded nanoparticles in contrast to the free drug having an IC50value of 17.29 and 29.59 μM, respectively. Flow cytometry confirmed that treatment of cells with 40 μg/ml had arrested 22.75 ± 0.3% at SubG0phase of the cell cycle when compared with untreated A459 cells. The observed results justified the boswellic acids-loaded chitosan nanoparticles were effective due to greater cellular uptake, sustained intercellular drug retention and enhanced antiproliferative effect by inducing apoptosis.
- Published
- 2020
49. Single cell RNA-seq identifies inflammation-induced loss of CFTR-expressing airway ionocytes in non-eosinophilic asthma
- Author
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Ling Chen, Gabriela Araujo Hoefel, Prabuddha S. Pathinayake, Andrew Reid, Coady Kelly, Tan HuiYing, Richard Y Kim, Philip M Hansbro, Steven L Brody, Paul S Foster, Jay C Horvat, Carlos Riveros, Peter AB Wark, and Gerard E Kaiko
- Subjects
respiratory system ,respiratory tract diseases - Abstract
Asthma is the most common chronic airways disease worldwide and the severe treatment resistant subtype of asthma is responsible for the majority of disease burden. Asthma is heterogeneous in nature and can be classified according to airway infiltrates as eosinophilic or non-eosinophilic (sometimes referred to as Type 2 low), which is further divided into paucigranulocytic (low levels of granulocytes), or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in airway tissue, sputum, and bronchoalveolar lavage. Severe non-eosinophilic asthma currently has fewer effective treatment options and many of these patients fail to qualify for newer biologic monoclonal therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is a key protein whose function is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease (COPD) and has proven a valuable therapeutic target. Using human bronchial epithelial cells (hBECs) isolated differentiated at air-liquid interface we demonstrated a reduced function of the CFTR in non-eosinophilic asthma. Characterization of the cell and molecular differences in airway epithelial cells between severe asthma subtypes using single cell RNA-sequencing (scRNAseq) revealed that airway epithelial cells from non-eosinophilic asthma, and in particular neutrophilic asthma patients, fail to differentiate into CFTR-expressing ionocytes compared with eosinophilic asthma or healthy donors. We identified a novel ionocyte transcriptional signature, which was present in both bronchial and tracheal airway epithelial samples indicating conserved anatomical gene regulation. Using protein markers and immunofluorescent quantification loss of ionocytes was confirmed in non-eosinophilic asthma hBECs. Similarly, ioncytes were also diminished in the airways of a murine model of neutrophilic-dominant but not eosinophilic allergen asthma models. Furthermore, treatment of hBECs from healthy donors with a neutrophilic asthma-like inflammatory cytokine mixture, but not IL-13, led to loss of ionocytes primarily due to IFN-γ. Inflammation-induced loss of CFTR-expressing ionocytes in airway cells from non-eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target for this difficult-to-treat disease.
- Published
- 2022
50. Dressing multifunctional nanoparticles with natural cell-derived membranes for superior chemotherapy
- Author
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Mohammad Imran, Keshav Raj Paudel, Saurav Kumar Jha, Philip M Hansbro, Kamal Dua, and Yousuf Mohammed
- Subjects
Drug Delivery Systems ,Biomimetic Materials ,Cell Membrane ,Biomedical Engineering ,Medicine (miscellaneous) ,Nanoparticles ,General Materials Science ,Bioengineering ,Multifunctional Nanoparticles ,Development ,Bandages - Published
- 2022
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