947 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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Wadhwa, R, Dua, K, Adcock, IM, Horvat, JC, Kim, RY, Hansbro, PM, Wadhwa, R, Dua, K, Adcock, IM, Horvat, JC, Kim, RY, and Hansbro, PM
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- 2019
3. Cord blood granulocyte levels are associated with severe bronchiolitis in the first year of life
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Gabriela Martins Costa Gomes, Carla Rebeca Da Silva Sena, Vanessa E Murphy, Philip M Hansbro, Malcolm R Starkey, Peter G Gibson, Joerg Mattes, and Adam M Collison
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bronchiolitis ,cord blood ,eosinophil ,neutrophil ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Objectives Bronchiolitis is a leading cause of infant hospitalisation in the first year of life, and it preferentially affects infants born to mothers with asthma. Here, we evaluate cord blood granulocytes in infants born to mothers with asthma participating in the Breathing for Life Trial (BLT), to investigate early life determinants of bronchiolitis hospitalisation within the first year of life. Methods Cord blood from 89 participants was collected into EDTA tubes and processed within 6 h of birth. Cells were stained in whole cord blood for eosinophils (CD45+, CD193+, CD16−), and neutrophils (CD45+, CD193−, CD16+). Medical records were reviewed for bronchiolitis hospitalisation in the first 12 months of life. Statistical analyses were conducted using Stata IC16.1. Results Logistic regression adjusted for caesarean section, gestational age, maternal smoking during pregnancy, foetal heart deceleration during labour, and season of birth revealed an association between cord blood eosinophil levels and bronchiolitis hospitalisation in the first 12 months of life with an Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC) curve of 0.943 (aOR = 1.35, P = 0.011). Neutrophils were associated with the risk of bronchiolitis hospitalisation in a univariable logistic regression (OR = 0.93, P = 0.029); however, there was no statistical significance in the adjusted model. Conclusions Higher eosinophil numbers in cord blood were associated with bronchiolitis hospitalisation in the first 12 months in a cohort of infants born to asthmatic mothers. This suggests that susceptibility to bronchiolitis in later life is influenced by the immune cell profile prior to viral infection.
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- 2024
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4. Interferon-epsilon is a novel regulator of NK cell responses in the uterus
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Jemma R Mayall, Jay C Horvat, Niamh E Mangan, Anne Chevalier, Huw McCarthy, Daniel Hampsey, Chantal Donovan, Alexandra C Brown, Antony Y Matthews, Nicole A de Weerd, Eveline D de Geus, Malcolm R Starkey, Richard Y Kim, Katie Daly, Bridie J Goggins, Simon Keely, Steven Maltby, Rennay Baldwin, Paul S Foster, Michael J Boyle, Pradeep S Tanwar, Nicholas D Huntington, Paul J Hertzog, and Philip M Hansbro
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Interferon-Epsilon ,Type I Interferon ,Natural Killer Cell ,Female Reproductive Tract ,Chlamydia Infection ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract The uterus is a unique mucosal site where immune responses are balanced to be permissive of a fetus, yet protective against infections. Regulation of natural killer (NK) cell responses in the uterus during infection is critical, yet no studies have identified uterine-specific factors that control NK cell responses in this immune-privileged site. We show that the constitutive expression of IFNε in the uterus plays a crucial role in promoting the accumulation, activation, and IFNγ production of NK cells in uterine tissue during Chlamydia infection. Uterine epithelial IFNε primes NK cell responses indirectly by increasing IL-15 production by local immune cells and directly by promoting the accumulation of a pre-pro-like NK cell progenitor population and activation of NK cells in the uterus. These findings demonstrate the unique features of this uterine-specific type I IFN and the mechanisms that underpin its major role in orchestrating innate immune cell protection against uterine infection.
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- 2024
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5. Characterization and inhibition of inflammasome responses in severe and non-severe asthma
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Jay C. Horvat, Richard Y. Kim, Natasha Weaver, Christopher Augood, Alexandra C. Brown, Chantal Donovan, Pierrick Dupre, Lakshitha Gunawardhana, Jemma R. Mayall, Nicole G. Hansbro, Avril A. B. Robertson, Luke A. J. O’Neill, Matthew A. Cooper, Elizabeth G. Holliday, Philip M. Hansbro, and Peter G. Gibson
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Asthma ,Severe asthma ,NLRP3 inflammasome ,IL-1β ,Inflammasome inhibition ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Increased airway NLRP3 inflammasome-mediated IL-1β responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown. Objective To investigate the activation and inhibition of inflammasome-mediated IL-1β responses in immune cells from patients with asthma. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1β release were assessed. Results PBMCs from patients with non-severe or severe asthma produced more IL-1β in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1β in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1β release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1β release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1β release from PBMCs from all groups. Conclusion An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease.
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- 2023
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6. TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase
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Gang Liu, Tatt Jhong Haw, Malcolm R. Starkey, Ashleigh M. Philp, Stelios Pavlidis, Christina Nalkurthi, Prema M. Nair, Henry M. Gomez, Irwan Hanish, Alan CY. Hsu, Elinor Hortle, Sophie Pickles, Joselyn Rojas-Quintero, Raul San Jose Estepar, Jacqueline E. Marshall, Richard Y. Kim, Adam M. Collison, Joerg Mattes, Sobia Idrees, Alen Faiz, Nicole G. Hansbro, Ryutaro Fukui, Yusuke Murakami, Hong Sheng Cheng, Nguan Soon Tan, Sanjay H. Chotirmall, Jay C. Horvat, Paul S. Foster, Brian GG. Oliver, Francesca Polverino, Antonio Ieni, Francesco Monaco, Gaetano Caramori, Sukhwinder S. Sohal, Ken R. Bracke, Peter A. Wark, Ian M. Adcock, Kensuke Miyake, Don D. Sin, and Philip M. Hansbro
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Science - Abstract
Abstract Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.
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- 2023
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7. “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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- 2019
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8. How different viruses perturb host cellular machinery via short linear motifs
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Sobia Idrees, Keshav Raj Paudel, Tayyaba Sadaf, and Philip M. Hansbro
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virus ,protein-protein interaction ,short linear motifs ,mimicry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Biology (General) ,QH301-705.5 - Abstract
The virus interacts with its hosts by developing protein-protein interactions. Most viruses employ protein interactions to imitate the host protein: A viral protein with the same amino acid sequence or structure as the host protein attaches to the host protein's binding partner and interferes with the host protein's pathways. Being opportunistic, viruses have evolved to manipulate host cellular mechanisms by mimicking short linear motifs. In this review, we shed light on the current understanding of mimicry via short linear motifs and focus on viral mimicry by genetically different viral subtypes by providing recent examples of mimicry evidence and how high-throughput methods can be a reliable source to study SLiM-mediated viral mimicry.
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- 2023
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9. Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection
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Tomalika R. Ullah, Matt D. Johansen, Katherine R. Balka, Rebecca L. Ambrose, Linden J. Gearing, James Roest, Julian P. Vivian, Sunil Sapkota, W. Samantha N. Jayasekara, Daniel S. Wenholz, Vina R. Aldilla, Jun Zeng, Stefan Miemczyk, Duc H. Nguyen, Nicole G. Hansbro, Rajan Venkatraman, Jung Hee Kang, Ee Shan Pang, Belinda J. Thomas, Arwaf S. Alharbi, Refaya Rezwan, Meredith O’Keeffe, William A. Donald, Julia I. Ellyard, Wilson Wong, Naresh Kumar, Benjamin T. Kile, Carola G. Vinuesa, Graham E. Kelly, Olivier F. Laczka, Philip M. Hansbro, Dominic De Nardo, and Michael P. Gantier
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Science - Abstract
Abstract TANK-binding kinase 1 (TBK1) is a key signalling component in the production of type-I interferons, which have essential antiviral activities, including against SARS-CoV-2. TBK1, and its homologue IκB kinase-ε (IKKε), can also induce pro-inflammatory responses that contribute to pathogen clearance. While initially protective, sustained engagement of type-I interferons is associated with damaging hyper-inflammation found in severe COVID-19 patients. The contribution of TBK1/IKKε signalling to these responses is unknown. Here we find that the small molecule idronoxil inhibits TBK1/IKKε signalling through destabilisation of TBK1/IKKε protein complexes. Treatment with idronoxil, or the small molecule inhibitor MRT67307, suppresses TBK1/IKKε signalling and attenuates cellular and molecular lung inflammation in SARS-CoV-2-challenged mice. Our findings additionally demonstrate that engagement of STING is not the major driver of these inflammatory responses and establish a critical role for TBK1/IKKε signalling in SARS-CoV-2 hyper-inflammation.
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- 2023
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10. Distinct Effects of Respiratory Viral Infection Models on miR-149-5p, IL-6 and p63 Expression in BEAS-2B and A549 Epithelial Cells
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Nafeesa Shahdab, Christopher Ward, Philip M. Hansbro, Stephen Cummings, John S. Young, and Fatemeh Moheimani
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miR-149-5p ,epithelial cells ,IL-6 ,p63 ,poly (I:C) ,SARS-CoV-2 spike protein ,Cytology ,QH573-671 - Abstract
Respiratory viruses cause airway inflammation, resulting in epithelial injury and repair. miRNAs, including miR-149-5p, regulate different pathological conditions. We aimed to determine how miR-149-5p functions in regulating pro-inflammatory IL-6 and p63, key regulators of airway epithelial wound repair, in response to viral proteins in bronchial (BEAS-2B) and alveolar (A549) epithelial cells. BEAS-2B or A549 cells were incubated with poly (I:C, 0.5 µg/mL) for 48 h or SARS-CoV-2 spike protein-1 or 2 subunit (S1 or S2, 1 μg/mL) for 24 h. miR-149-5p was suppressed in BEAS-2B challenged with poly (I:C), correlating with IL-6 and p63 upregulation. miR-149-5p was down-regulated in A549 stimulated with poly (I:C); IL-6 expression increased, but p63 protein levels were undetectable. miR-149-5p remained unchanged in cells exposed to S1 or S2, while S1 transfection increased IL-6 expression in BEAS-2B cells. Ectopic over-expression of miR-149-5p in BEAS-2B cells suppressed IL-6 and p63 mRNA levels and inhibited poly (I:C)-induced IL-6 and p63 mRNA expressions. miR-149-5p directly suppressed IL-6 mRNA in BEAS-2B cells. Hence, BEAS-2B cells respond differently to poly (I:C), S1 or S2 compared to A549 cells. Thus, miR-149-5p dysregulation may be involved in poly (I:C)-stimulated but not S1- or S2-stimulated increased IL-6 production and p63 expression in BEAS-2B cells.
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- 2024
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11. 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 A. B. Wark
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Medicine ,Science - Abstract
Abstract 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, 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. 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 infection. CRpBECs differentiated in PneumaCult were smaller and had a lower TEER and cilia beat frequency compared to BEGM media. PneumaCult media cultures exhibited 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. 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
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12. Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon
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Tristram A. J. Ryan, Alexander Hooftman, Aisling M. Rehill, Matt D. Johansen, Eóin C. O’ Brien, Juliana E. Toller-Kawahisa, Mieszko M. Wilk, Emily A. Day, Hauke J. Weiss, Pourya Sarvari, Emilio G. Vozza, Fabian Schramm, Christian G. Peace, Alessia Zotta, Stefan Miemczyk, Christina Nalkurthi, Nicole G. Hansbro, Gavin McManus, Laura O’Doherty, Siobhan Gargan, Aideen Long, Jean Dunne, Clíona Ní Cheallaigh, Niall Conlon, Michael Carty, Padraic G. Fallon, Kingston H. G. Mills, Emma M. Creagh, James S. O’ Donnell, Paul J. Hertzog, Philip M. Hansbro, Rachel M. McLoughlin, Małgorzata Wygrecka, Roger J. S. Preston, Zbigniew Zasłona, and Luke A. J. O’Neill
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Science - Abstract
Abstract Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
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- 2023
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13. SARS‐CoV‐2‐infected human airway epithelial cell cultures uniquely lack interferon and immediate early gene responses caused by other coronaviruses
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Ying Wang, Melissa Thaler, Clarisse Salgado‐Benvindo, Nathan Ly, Anouk A Leijs, Dennis K Ninaber, Philip M Hansbro, Fia Boedijono, Martijn J vanHemert, Pieter S Hiemstra, Anne M van derDoes, and Alen Faiz
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coronavirus ,immediate early genes ,primary airway epithelial cells ,RNA sequencing ,SARS‐CoV‐2 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Objectives Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a member of a class of highly pathogenic coronaviruses. The large family of coronaviruses, however, also includes members that cause only mild symptoms, like human coronavirus‐229E (HCoV‐229E) or OC43 (HCoV‐OC43). Unravelling how molecular (and cellular) pathophysiology differs between highly and low pathogenic coronaviruses is important for the development of therapeutic strategies. Methods Here, we analysed the transcriptome of primary human bronchial epithelial cells (PBEC), differentiated at the air–liquid interface (ALI) after infection with SARS‐CoV‐2, SARS‐CoV, Middle East Respiratory Syndrome (MERS)‐CoV and HCoV‐229E using bulk RNA sequencing. Results ALI‐PBEC were efficiently infected by all viruses, and SARS‐CoV, MERS‐CoV and HCoV‐229E infection resulted in a largely similar transcriptional response. The response to SARS‐CoV‐2 infection differed markedly as it uniquely lacked the increase in expression of immediate early genes, including FOS, FOSB and NR4A1 that was observed with all other coronaviruses. This finding was further confirmed in publicly available experimental and clinical datasets. Interfering with NR4A1 signalling in Calu‐3 lung epithelial cells resulted in a 100‐fold reduction in extracellular RNA copies of SARS‐CoV‐2 and MERS‐CoV, suggesting an involvement in virus replication. Furthermore, a lack in induction of interferon‐related gene expression characterised the main difference between the highly pathogenic coronaviruses and low pathogenic viruses HCoV‐229E and HCoV‐OC43. Conclusion Our results demonstrate a previously unknown suppression of a host response gene set by SARS‐CoV‐2 and confirm a difference in interferon‐related gene expression between highly pathogenic and low pathogenic coronaviruses.
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- 2024
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14. Gut microbiota from patients with COVID-19 cause alterations in mice that resemble post-COVID symptoms
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Viviani Mendes de Almeida, Daiane F. Engel, Mayra F. Ricci, Clênio Silva Cruz, Ícaro Santos Lopes, Daniele Almeida Alves, Mirna d’ Auriol, João Magalhães, Elayne C. Machado, Victor M. Rocha, Toniana G. Carvalho, Larisse S. B. Lacerda, Jordane C. Pimenta, Mariana Aganetti, Giuliana S. Zuccoli, Bradley J. Smith, Victor C. Carregari, Erika da Silva Rosa, Izabela Galvão, Geovanni Dantas Cassali, Cristiana C. Garcia, Mauro Martins Teixeira, Leiliane C. André, Fabiola Mara Ribeiro, Flaviano S. Martins, Rafael Simone Saia, Vivian Vasconcelos Costa, Daniel Martins-de-Souza, Philip M. Hansbro, João Trindade Marques, Eric R. G. R. Aguiar, and Angélica T. Vieira
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COVID-19 ,SARS-CoV-2 ,post-COVID ,microbiota ,inflammation ,antimicrobial-resistance ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
ABSTRACTLong-term sequelae of coronavirus disease (COVID)-19 are frequent and of major concern. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the host gut microbiota, which is linked to disease severity in patients with COVID-19. Here, we report that the gut microbiota of post-COVID subjects had a remarkable predominance of Enterobacteriaceae strains with an antibiotic-resistant phenotype compared to healthy controls. Additionally, short-chain fatty acid (SCFA) levels were reduced in feces. Fecal transplantation from post-COVID subjects to germ-free mice led to lung inflammation and worse outcomes during pulmonary infection by multidrug-resistant Klebsiella pneumoniae. transplanted mice also exhibited poor cognitive performance. Overall, we show prolonged impacts of SARS-CoV-2 infection on the gut microbiota that persist after subjects have cleared the virus. Together, these data demonstrate that the gut microbiota can directly contribute to post-COVID sequelae, suggesting that it may be a potential therapeutic target.
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- 2023
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15. A unique role for IL-13 in inducing esophageal eosinophilia through MID-1 and STAT6
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Jason L. N. Girkin, Leon A. Sokulsky, Malcolm R. Starkey, Philip M. Hansbro, Paul S. Foster, Adam M. Collison, and Joerg Mattes
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eosinophils ,eosinophilic esophagitis ,allergy ,interleukin 13 (IL-13) ,midline 1 (Mid1) ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionEosinophilic esophagitis (EoE) is associated with allergen-driven inflammation of the esophagus and an upregulated Th2 cytokine signature. Recombinant interleukin (IL)-13 (rIL-13) administration to mice induces some of the hallmark features of EoE, including increased eotaxin expression and eosinophil recruitment. Inflammation in EoE has previously been shown to depend on the expression of TRAIL and MID-1, which reduced protein phosphatase 2A (PP2A) activity. The relationship between IL-13 and TRAIL signalling in esophageal eosinophilia is currently unknown.ObjectiveTo investigate the interaction between IL-13-driven eosinophil infiltration and TRAIL or MID-1 in the esophagus.MethodWe administered rIL-13 to wild type (WT), TRAIL-deficient (Tnsf10−/−) or STAT6-deficient (STAT6−/−) mice and targeted MID-1 with small interfering RNA.ResultsrIL-13 administration to mice increased TRAIL and MID-1 expression in the esophagus while reducing PP2A activity. TRAIL deficient, but not STAT6 deficient mice demonstrated increased MID-1 expression and PP2A reduction upon IL-13 challenge which correlated with eosinophil infiltration into the esophagus. Silencing MID-1 expression with siRNA completely ablated IL-13 induced eosinophil infiltration of the esophagus, restored PP2A activity, and reduced eotaxin-1 expression.ConclusionIL-13-driven eosinophil infiltration of the esophagus induced eosinophilia and eotaxin-1 expression in a STAT6-dependent and MID-1-dependent manner. This study highlights a novel mechanism employed by IL-13 to perpetuate eosinophil infiltration.
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- 2023
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16. '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
17. 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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COVID-19 ,SARS-CoV-2 ,ARDS ,Biomarkers ,Cytokines ,Chemokines ,Therapeutics. Pharmacology ,RM1-950 - Abstract
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
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18. Broadly neutralizing SARS-CoV-2 antibodies through epitope-based selection from convalescent patients
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Romain Rouet, Jake Y. Henry, Matt D. Johansen, Meghna Sobti, Harikrishnan Balachandran, David B. Langley, Gregory J. Walker, Helen Lenthall, Jennifer Jackson, Stephanie Ubiparipovic, Ohan Mazigi, Peter Schofield, Deborah L. Burnett, Simon H. J. Brown, Marianne Martinello, Bernard Hudson, Nicole Gilroy, Jeffrey J. Post, Anthony Kelleher, Hans-Martin Jäck, Christopher C. Goodnow, Stuart G. Turville, William D. Rawlinson, Rowena A. Bull, Alastair G. Stewart, Philip M. Hansbro, and Daniel Christ
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Science - Abstract
Here, Rouet et al. present a strategy for the identification of broadly neutralising antibodies against SARS-CoV-2 receptor binding domain from peripheral blood mononuclear cells of convalescent patients, which enabled the identification of a new class 6 epitope.
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- 2023
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19. Exploring Viral–Host Protein Interactions as Antiviral Therapies: A Computational Perspective
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Sobia Idrees, Hao Chen, Nisha Panth, Keshav Raj Paudel, and Philip M. Hansbro
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protein–protein interactions ,viral–host interactions ,antiviral therapies ,Biology (General) ,QH301-705.5 - Abstract
The interactions between human and viral proteins are pivotal in viral infection and host immune responses. These interactions traverse different stages of the viral life cycle, encompassing initial entry into host cells, replication, and the eventual deployment of immune evasion strategies. As viruses exploit host cellular machinery for their replication and survival, targeting key protein–protein interactions offer a strategic approach for developing antiviral drugs. This review discusses how viruses interact with host proteins to develop viral–host interactions. In addition, we also highlight valuable resources that aid in identifying new interactions, incorporating high-throughput methods, and computational approaches, ultimately helping to understand how these tools can be effectively utilized to study viral–host interactions.
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- 2024
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20. Pre-clinical lung squamous cell carcinoma mouse models to identify novel biomarkers and therapeutic interventions
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Priyanka Sahu, Chantal Donovan, Keshav Raj Paudel, Sophie Pickles, Vrushali Chimankar, Richard Y. Kim, Jay C. Horvart, Kamal Dua, Antonio Ieni, Francesco Nucera, Helle Bielefeldt-Ohmann, Sarah Mazilli, Gaetano Caramori, J. Guy Lyons, and Philip M. Hansbro
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lung cancer ,squamous cell carcinoma ,animal models ,risk factors ,genetic and epigenetic alterations ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Primary lung carcinoma or lung cancer (LC) is classified into small-cell or non-small-cell (NSCLC) lung carcinoma. Lung squamous cell carcinoma (LSCC) is the second most common subtype of NSCLC responsible for 30% of all LCs, and its survival remains low with only 24% of patients living for five years or longer post-diagnosis primarily due to the advanced stage of tumors at the time of diagnosis. The pathogenesis of LSCC is still poorly understood and has hampered the development of effective diagnostics and therapies. This review highlights the known risk factors, genetic and epigenetic alterations, miRNA biomarkers linked to the development and diagnosis of LSCC and the lack of therapeutic strategies to target specifically LSCC. We will also discuss existing animal models of LSCC including carcinogen induced, transgenic and xenograft mouse models, and their advantages and limitations along with the chemopreventive studies and molecular studies conducted using them. The importance of developing new and improved mouse models will also be discussed that will provide further insights into the initiation and progression of LSCC, and enable the identification of new biomarkers and therapeutic targets.
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- 2023
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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
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Science - Abstract
Current vaccines against SARS-CoV-2 reduce mortality but are less effective in preventing infection. Here the authors show that intranasal vaccination with a subunit vaccine including an TLR2-stimulating adjuvant induces strong neutralising antibody and T-cell responses against SARS-CoV-2 in the lungs that protect against infection.
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- 2022
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22. Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation
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Ilaria Salvato, Luca Ricciardi, Jessica Dal Col, Annunziata Nigro, Giorgio Giurato, Domenico Memoli, Assunta Sellitto, Erwin Pavel Lamparelli, Maria Assunta Crescenzi, Monica Vitale, Alessandro Vatrella, Francesco Nucera, Paola Brun, Federico Caicci, Paola Dama, Thomas Stiff, Leandro Castellano, Sobia Idrees, Matt D. Johansen, Alen Faiz, Peter A. Wark, Philip M. Hansbro, Ian M. Adcock, Gaetano Caramori, and Cristiana Stellato
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airway epithelium ,AU-rich element factor 1 (AUF-1) ,cell senescence ,chronic inflammation ,chronic obstructive pulmonary disease ,inflammaging ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionThe RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss.ResultsRNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3’-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets’ steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression.DiscussionLoss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells.
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- 2023
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23. Systemic alterations in neutrophils and their precursors in early-stage chronic obstructive pulmonary disease
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Theodore S. Kapellos, Kevin Baßler, Wataru Fujii, Christina Nalkurthi, Anna C. Schaar, Lorenzo Bonaguro, Tal Pecht, Izabela Galvao, Shobhit Agrawal, Adem Saglam, Erica Dudkin, Amit Frishberg, Elena de Domenico, Arik Horne, Chantal Donovan, Richard Y. Kim, David Gallego-Ortega, Tessa E. Gillett, Meshal Ansari, Jonas Schulte-Schrepping, Nina Offermann, Ignazio Antignano, Burcu Sivri, Wenying Lu, Mathew S. Eapen, Martina van Uelft, Collins Osei-Sarpong, Maarten van den Berge, Hylke C. Donker, Harry J.M. Groen, Sukhwinder S. Sohal, Johanna Klein, Tina Schreiber, Andreas Feißt, Ali Önder Yildirim, Herbert B. Schiller, Martijn C. Nawijn, Matthias Becker, Kristian Händler, Marc Beyer, Melania Capasso, Thomas Ulas, Jan Hasenauer, Carmen Pizarro, Fabian J. Theis, Philip M. Hansbro, Dirk Skowasch, and Joachim L. Schultze
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CP: Immunology ,Biology (General) ,QH301-705.5 - Abstract
Summary: Systemic inflammation is established as part of late-stage severe lung disease, but molecular, functional, and phenotypic changes in peripheral immune cells in early disease stages remain ill defined. Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small-airway inflammation, emphysema, and severe breathing difficulties. Using single-cell analyses we demonstrate that blood neutrophils are already increased in early-stage COPD, and changes in molecular and functional neutrophil states correlate with lung function decline. Assessing neutrophils and their bone marrow precursors in a murine cigarette smoke exposure model identified similar molecular changes in blood neutrophils and precursor populations that also occur in the blood and lung. Our study shows that systemic molecular alterations in neutrophils and their precursors are part of early-stage COPD, a finding to be further explored for potential therapeutic targets and biomarkers for early diagnosis and patient stratification.
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- 2023
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24. The diagnostic potential of oxidative stress biomarkers for preeclampsia: systematic review and meta-analysis
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Dinara Afrose, Hao Chen, Amali Ranashinghe, Chia-chi Liu, Annemarie Henessy, Philip M. Hansbro, and Lana McClements
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Preeclampsia ,Oxidative stress ,Heavy metals ,Biomarkers ,MDA ,IMA ,Medicine ,Physiology ,QP1-981 - Abstract
Highlights Biomarkers of oxidative stress are related to the pathogenesis of preeclampsia and might be indicative of evolving preeclampsia and utilized for timely diagnosis and management of preeclampsia. Systematic review and meta-analysis were conducted to evaluate the diagnostic accuracy of oxidative stress markers based on their diagnostic sensitivities and specificities. Clinically relevant positive predictive values (PPVs) and negative predictive values (NPVs) were determined for each biomarker. IMA, UA, and MDA were associated with 3.38, 3.05, and 2.37 odds ratios for preeclampsia onset. IMA exhibited the most promising diagnostic potential with an average PPV of 0.852 and NPV of 0.811, respectively. Minor heterogeneity was reported for these biomarkers (Higgins’ I 2 = 0–15.879%). These oxidative stress markers should be further explored in larger cohorts for preeclampsia diagnosis.
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- 2022
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25. Toll-like receptors, innate immune system, and lung diseases
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Vyoma K. Patel, Keshav R. Paudel, Shakti D. Shukla, Gang Liu, Brian G. Oliver, Philip M. Hansbro, and Kamal Dua
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toll-like receptors ,respiratory diseases ,innate immunity ,covid ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Biology (General) ,QH301-705.5 - Published
- 2022
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26. Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies
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Neha Chopra, Spiro Menounos, Jaesung P. Choi, Philip M. Hansbro, Ashish D. Diwan, and Abhirup Das
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blood-spinal cord barrier (BSCB) ,spinal cord injury (SCI) ,amyotrophic lateral sclerosis (ALS) ,degenerative cervical myelopathy (DCM) ,peripheral nerve injury (PNI) ,ischemia reperfusion injury (IRI) ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause–effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it.
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- 2021
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27. A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection
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Claudio Counoupas, Matt D. Johansen, Alberto O. Stella, Duc H. Nguyen, Angela L. Ferguson, Anupriya Aggarwal, Nayan D. Bhattacharyya, Alice Grey, Owen Hutchings, Karishma Patel, Rezwan Siddiquee, Erica L. Stewart, Carl G. Feng, Nicole G. Hansbro, Umaimainthan Palendira, Megan C. Steain, Bernadette M. Saunders, Jason K. K. Low, Joel P. Mackay, Anthony D. Kelleher, Warwick J. Britton, Stuart G. Turville, Philip M. Hansbro, and James A. Triccas
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Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
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
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28. Key role of dysregulated airway epithelium in response to respiratory viral infections in asthma
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Fatemeh Moheimani, Nafeesa Shahdab, Stephen Cummings, Philip M. Hansbro, and Christopher Ward
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Medicine - Published
- 2022
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29. Editorial: Advanced therapeutic delivery for the management of chronic respiratory diseases
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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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drug delivery ,chronic respiratory disease ,pulmonary medicine ,therapeutic delivery ,drug discovery ,Medicine (General) ,R5-920 - Published
- 2022
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30. Publisher Correction: Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon
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Tristram A. J. Ryan, Alexander Hooftman, Aisling M. Rehill, Matt D. Johansen, Eóin C. O’ Brien, Juliana E. Toller-Kawahisa, Mieszko M. Wilk, Emily A. Day, Hauke J. Weiss, Pourya Sarvari, Emilio G. Vozza, Fabian Schramm, Christian G. Peace, Alessia Zotta, Stefan Miemczyk, Christina Nalkurthi, Nicole G. Hansbro, Gavin McManus, Laura O’Doherty, Siobhan Gargan, Aideen Long, Jean Dunne, Clíona Ní Cheallaigh, Niall Conlon, Michael Carty, Padraic G. Fallon, Kingston H. G. Mills, Emma M. Creagh, James S. O’ Donnell, Paul J. Hertzog, Philip M. Hansbro, Rachel M. McLoughlin, Małgorzata Wygrecka, Roger J. S. Preston, Zbigniew Zasłona, and Luke A. J. O’Neill
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Science - Published
- 2023
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31. Biomedical applications of metallic nanoparticles in cancer: Current status and future perspectives
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Rubiya Khursheed, Kamal Dua, Sukriti Vishwas, Monica Gulati, Niraj Kumar Jha, Ghalib Mohammed Aldhafeeri, Fayez Ghadeer Alanazi, Bey Hing Goh, Gaurav Gupta, Keshav Raj Paudel, Philip M. Hansbro, Dinesh Kumar Chellappan, and Sachin Kumar Singh
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Cancer ,Nanotechnology ,Drug delivery ,Metallic nanoparticles ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The current advancements in nanotechnology are as an outcome of the development of engineered nanoparticles. Various metallic nanoparticles have been extensively explored for various biomedical applications. They attract lot of attention in biomedical field due to their significant inert nature, and nanoscale structures, with size similar to many biological molecules. Their intrinsic characteristics which include electronic, optical, physicochemical and, surface plasmon resonance, that can be changed by altering certain particle characteristics such as size, shape, environment, aspect ratio, ease of synthesis and functionalization properties have led to numerous applications in various fields of biomedicine. These include targeted drug delivery, sensing, photothermal and photodynamic therapy, imaging, as well as the modulation of two or three applications. The current article also discusses about the various properties of metallic nanoparticles and their applications in cancer imaging and therapeutics. The associated bottlenecks related to their clinical translation are also discussed.
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- 2022
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32. No smoke without fire: the impact of cigarette smoking on the immune control of tuberculosis
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Diana H. Quan, Alexander J. Kwong, Philip M. Hansbro, and Warwick J. Britton
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Diseases of the respiratory system ,RC705-779 - Abstract
Cigarette smoke (CS) exposure is a key risk factor for both active and latent tuberculosis (TB). It is associated with delayed diagnosis, more severe disease progression, unfavourable treatment outcomes and relapse after treatment. Critically, CS exposure is common in heavily populated areas with a high burden of TB, such as China, India and the Russian Federation. It is therefore prudent to evaluate interventions for TB while taking into account the immunological impacts of CS exposure. This review is a mechanistic examination of how CS exposure impairs innate barrier defences, as well as alveolar macrophage, neutrophil, dendritic cell and T-cell functions, in the context of TB infection and disease.
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- 2022
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33. Activation of the AIM2 Receptor in Circulating Cells of Post-COVID-19 Patients With Signs of Lung Fibrosis Is Associated With the Release of IL-1α, IFN-α and TGF-β
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Chiara Colarusso, Michela Terlizzi, Angelantonio Maglio, Antonio Molino, Claudio Candia, Carolina Vitale, Philip M. Hansbro, Alessandro Vatrella, Aldo Pinto, and Rosalinda Sorrentino
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SARS–CoV–2 ,AIM2 inflammasome ,post-COVID-19 ,cytokines ,post-COVID-19 lung fibrosis ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Severe acute respiratory syndrome-coronavirus-2 (SARS‐CoV‐2), responsible for COVID-19, has caused a global pandemic. Observational studies revealed a condition, herein called as Long-COVID syndrome (PC), that affects both moderately and severely infected patients, reducing quality-of-life. The mechanism/s underlying the onset of fibrotic-like changes in PC are still not well defined. The goal of this study was to understand the involvement of the Absent in melanoma-2 (AIM2) inflammasome in PC-associated lung fibrosis-like changes revealed by chest CT scans. Peripheral blood mononuclear cells (PBMCs) obtained from PC patients who did not develop signs of lung fibrosis were not responsive to AIM2 activation by Poly dA:dT. In sharp contrast, PBMCs from PC patients with signs of lung fibrosis were highly responsive to AIM2 activation, which induced the release of IL-1α, IFN-α and TGF-β. The recognition of Poly dA:dT was not due to the activation of cyclic GMP-AMP (cGAMP) synthase, a stimulator of interferon response (cGAS-STING) pathways, implying a role for AIM2 in PC conditions. The release of IFN-α was caspase-1- and caspase-4-dependent when AIM2 was triggered. Instead, the release of pro-inflammatory IL-1α and pro-fibrogenic TGF-β were inflammasome independent because the inhibition of caspase-1 and caspase-4 did not alter the levels of the two cytokines. Moreover, the responsiveness of AIM2 correlated with higher expression of the receptor in circulating CD14+ cells in PBMCs from patients with signs of lung fibrosis.
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- 2022
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34. Australia as a global sink for the genetic diversity of avian influenza A virus
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Michelle Wille, Victoria Grillo, Silvia Ban de Gouvea Pedroso, Graham W. Burgess, Allison Crawley, Celia Dickason, Philip M. Hansbro, Md. Ahasanul Hoque, Paul F. Horwood, Peter D. Kirkland, Nina Yu-Hsin Kung, Stacey E. Lynch, Sue Martin, Michaela McArthur, Kim O’Riley, Andrew J. Read, Simone Warner, Bethany J. Hoye, Simeon Lisovski, Trent Leen, Aeron C. Hurt, Jeff Butler, Ivano Broz, Kelly R. Davies, Patrick Mileto, Matthew J. Neave, Vicky Stevens, Andrew C. Breed, Tommy T. Y. Lam, Edward C. Holmes, Marcel Klaassen, and Frank Y. K. Wong
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Most of our understanding of the ecology and evolution of avian influenza A virus (AIV) in wild birds is derived from studies conducted in the northern hemisphere on waterfowl, with a substantial bias towards dabbling ducks. However, relevant environmental conditions and patterns of avian migration and reproduction are substantially different in the southern hemisphere. Through the sequencing and analysis of 333 unique AIV genomes collected from wild birds collected over 15 years we show that Australia is a global sink for AIV diversity and not integrally linked with the Eurasian gene pool. Rather, AIV are infrequently introduced to Australia, followed by decades of isolated circulation and eventual extinction. The number of co-circulating viral lineages varies per subtype. AIV haemagglutinin (HA) subtypes that are rarely identified at duck-centric study sites (H8-12) had more detected introductions and contemporary co-circulating lineages in Australia. Combined with a lack of duck migration beyond the Australian-Papuan region, these findings suggest introductions by long-distance migratory shorebirds. In addition, on the available data we found no evidence of directional or consistent patterns in virus movement across the Australian continent. This feature corresponds to patterns of bird movement, whereby waterfowl have nomadic and erratic rainfall-dependant distributions rather than consistent intra-continental migratory routes. Finally, we detected high levels of virus gene segment reassortment, with a high diversity of AIV genome constellations across years and locations. These data, in addition to those from other studies in Africa and South America, clearly show that patterns of AIV dynamics in the Southern Hemisphere are distinct from those in the temperate north. Author summary A result of the ever-growing poultry industry is a dramatic global increase in the incidence of high pathogenicity avian influenza virus outbreaks. In contrast, wild birds are believed to be the main reservoir for low pathogenic avian influenza A virus. Due to intensive research and surveillance of AIV in waterfowl in the Northern Hemisphere, we have a better understanding of AIV ecology and evolution in that region compared to the Southern Hemisphere, which are characterised by different patterns of avian migration and ecological conditions. We analysed 333 unique AIV genomes collected from wild birds in Australia to understand how Australia fits into global AIV dynamics and how viruses are maintained and dispersed within the continent of Australia. We show that the Southern Hemisphere experiences differing evolutionary dynamics to those seen in Northern Hemisphere with Australia representing a global sink for AIV.
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- 2022
35. Pathophysiological Correlation between Cigarette Smoking and Amyotrophic Lateral Sclerosis
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Spiro Menounos, Philip M. Hansbro, Ashish D. Diwan, and Abhirup Das
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amyotrophic lateral sclerosis (ALS) ,motor neuron degeneration ,cigarette smoking ,oxidative stress ,neuroinflammation ,immunometabolism ,Neurosciences. Biological psychiatry. Neuropsychiatry ,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.
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- 2021
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36. Mitochondria-Targeted Antioxidants as a Therapeutic Strategy for Chronic Obstructive Pulmonary Disease
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Lauren H. Fairley, Shatarupa Das, Vivek Dharwal, Nadia Amorim, Karl J. Hegarty, Ridhima Wadhwa, Guntipally Mounika, and Philip M. Hansbro
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antioxidants ,mitochondria ,COPD ,lung ,ROS ,pulmonary disease ,Therapeutics. Pharmacology ,RM1-950 - 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.
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- 2023
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37. Exploring the Remarkable Chemotherapeutic Potential of Polyphenolic Antioxidants in Battling Various Forms of Cancer
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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
flavonoids ,antioxidant ,anticancer ,nanotechnology ,combination therapy ,Organic chemistry ,QD241-441 - 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.
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- 2023
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38. Nanoformulations-Based Metronomic Chemotherapy: Mechanism, Challenges, Recent Advances, and Future Perspectives
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Vijay Kumar Panthi, Kamal Dua, Sachin Kumar Singh, Gaurav Gupta, Philip M. Hansbro, and Keshav Raj Paudel
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nanoformulations ,cancers ,metronomic chemotherapy ,clinical study ,Pharmacy and materia medica ,RS1-441 - 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.
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- 2023
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39. The Pandemic and Your Skin—Direct and Indirect Impact of COVID-19
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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, and Yousuf Mohammed
- Subjects
COVID-19 ,skin manifestations ,immunological response ,PPEs ,Chemistry ,QD1-999 - Abstract
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.
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- 2023
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40. Extracellular Vesicles Released from Cancer Cells Promote Tumorigenesis by Inducing Epithelial to Mesenchymal Transition via β-Catenin Signaling
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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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lung cancer ,extracellular vesicles ,tumorigenesis ,β-catenin signaling ,biomarkers ,EMT ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - 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.
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- 2023
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41. Exposure to the gut microbiota from cigarette smoke-exposed mice exacerbates cigarette smoke extract-induced inflammation in zebrafish larvae
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Simone Morris, Kathryn Wright, Vamshikrishna Malyla, Warwick J. Britton, Philip M. Hansbro, Pradeep Manuneedhi Cholan, and Stefan H. Oehlers
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Zebrafish ,Cigarette smoke ,Enterocolitis ,Microbiota ,Specialties of internal medicine ,RC581-951 - Abstract
Cigarette smoke (CS)-induced inflammation leads to a range of diseases including chronic obstructive pulmonary disease and cancer. The gut microbiota is a major modifying environmental factor that determine the severity of cigarette smoke-induced pathology. Microbiomes and metabolites from CS-exposed mice exacerbate lung inflammation via the gut-lung axis of shared mucosal immunity in mice but these systems are expensive to establish and analyse. Zebrafish embryos and larvae have been used to model the effects of cigarette smoking on a range of physiological processes and offer an amenable platform for screening modifiers of cigarette smoke-induced pathologies with key features of low cost and rapid visual readouts. Here we exposed zebrafish larvae to cigarette smoke extract (CSE) and characterised a CSE-induced leukocytic inflammatory phenotype with increased neutrophilic and macrophage inflammation in the gut. The CSE-induced phenotype was exacerbated by co-exposure to microbiota from the faeces of CS-exposed mice, but not control mice. Microbiota could be recovered from the gut of zebrafish and studied in isolation in a screening setting. This demonstrates the utility of the zebrafish-CSE exposure platform for identifying environmental modifiers of cigarette smoking-associated pathology and demonstrates that the CS-exposed mouse gut microbiota potentiates the inflammatory effects of CSE across host species.
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- 2021
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42. Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease
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Kate L. Bowerman, Saima Firdous Rehman, Annalicia Vaughan, Nancy Lachner, Kurtis F. Budden, Richard Y. Kim, David L. A. Wood, Shaan L. Gellatly, Shakti D. Shukla, Lisa G. Wood, Ian A. Yang, Peter A. Wark, Philip Hugenholtz, and Philip M. Hansbro
- Subjects
Science - Abstract
Chronic obstructive pulmonary disease (COPD) is a progressing disease, with lung but not gut microbiota implicated in its etiology. Here the authors compare the stool from patients with COPD and healthy controls to find specific gut bacteria and metabolites associated with active disease, thereby hinting at a potential role for the gut microbiome in COPD.
- Published
- 2020
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43. SARS-CoV-2 induces transcriptional signatures in human lung epithelial cells that promote lung fibrosis
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Jincheng Xu, Xiaoyue Xu, Lina Jiang, Kamal Dua, Philip M. Hansbro, and Gang Liu
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Coronavirus ,SARS-CoV-2 ,Angiotensin-converting enzyme 2 ,Lung fibrosis ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Severe acute respiratory syndrome (SARS)-CoV-2-induced coronavirus disease-2019 (COVID-19) is a pandemic disease that affects > 2.8 million people worldwide, with numbers increasing dramatically daily. However, there is no specific treatment for COVID-19 and much remains unknown about this disease. Angiotensin-converting enzyme (ACE)2 is a cellular receptor of SARS-CoV-2. It is cleaved by type II transmembrane serine protease (TMPRSS)2 and disintegrin and metallopeptidase domain (ADAM)17 to assist viral entry into host cells. Clinically, SARS-CoV-2 infection may result in acute lung injury and lung fibrosis, but the underlying mechanisms of COVID-19 induced lung fibrosis are not fully understood. Methods The networks of ACE2 and its interacting molecules were identified using bioinformatic methods. Their gene and protein expressions were measured in human epithelial cells after 24 h SARS-CoV-2 infection, or in existing datasets of lung fibrosis patients. Results We confirmed the binding of SARS-CoV-2 and ACE2 by bioinformatic analysis. TMPRSS2, ADAM17, tissue inhibitor of metalloproteinase (TIMP)3, angiotensinogen (AGT), transformation growth factor beta (TGFB1), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF) A and fibronectin (FN) were interacted with ACE2, and the mRNA and protein of these molecules were expressed in lung epithelial cells. SARS-CoV-2 infection increased ACE2, TGFB1, CTGF and FN1 mRNA that were drivers of lung fibrosis. These changes were also found in lung tissues from lung fibrosis patients. Conclusions Therefore, SARS-CoV-2 binds with ACE2 and activates fibrosis-related genes and processes to induce lung fibrosis.
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- 2020
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44. Elastin is a key factor of tumor development in colorectal cancer
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Jinzhi Li, Xiaoyue Xu, Yanyan Jiang, Nicole G. Hansbro, Philip M. Hansbro, Jincheng Xu, and Gang Liu
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Colorectal cancer ,Extracellular matrix protein ,Elastin, epithelial-mesenchymal transition ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Colorectal cancer (CRC) is the most common cancer and a leading cause of death worldwide. Extracellular matrix (ECM) proteins regulate tumor growth and development in CRC. Elastin (ELN) is a component of ECM proteins involved in the tumor microenvironment. However, the role of ELN in CRC remains unclear. Methods In this study, we analyzed ELN gene expression in tumors from CRC patients and adjacent non-tumor colon tissues and healthy controls from two existing microarray datasets. ELN protein was measured in human normal colon cells and colon cancer epithelial cells and tumor development was assessed in colon epithelial cells cultured in medium with or without ELN peptide on plates coated with ELN recombinant protein. Control plates were coated with PBS only. Results We found ELN gene expression was increased in tumors from CRC patients compared to adjacent non-tumor tissues and healthy controls. ELN protein was increased in cancer cells compared to normal colon epithelial cells. Transforming growth factor beta (TGF-β) was a key cytokine to induce production of ECM proteins, but it did not induce ELN expression in colon cancer cells. Matrix metalloproteinase 9 (MMP9) gene expression was increased, but that of MMP12 (elastase) did not change between CRC patients and control. Tissue inhibitor of metalloproteinases 3 (TIMP3) gene expression was decreased in colon tissues from CRC patients compared to healthy controls. However, MMP9, MMP12 and TIMP3 proteins were increased in colon cancer cells. ELN recombinant protein increased proliferation and wound healing in colon cancer epithelial cells. This had further increased in cancer cells incubated in plates coated with recombinant ELN coated plate and in culture media containing ELN peptide. A potential mechanism was that ELN induced epithelial mesenchymal transition with increased alpha-smooth muscle actin and vimentin proteins but decreased E-cadherin protein. Tumor necrosis factor alpha (TNF) mRNA was also increased in CRC patients compared to controls. ELN recombinant protein induced further increases in TNF protein in mouse bone marrow derived macrophages after lipopolysaccharide stimulation. Conclusions These data suggest ELN regulates tumor development and the microenvironment in CRC.
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- 2020
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45. Loss of Hyaluronan and Proteoglycan Link Protein-1 Induces Tumorigenesis in Colorectal Cancer
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Yao Wang, Xiaoyue Xu, Jacqueline E. Marshall, Muxue Gong, Yang Zhao, Kamal Dua, Philip M. Hansbro, Jincheng Xu, and Gang Liu
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HAPLN1 ,extracellular matrix protein ,microenvironment ,TGF-β ,CRC ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Colorectal cancer (CRC) is the third most common diagnosed cancer worldwide, but there are no effective cures for it. Hyaluronan and proteoglycan link protein-1 (HAPLN1) is a component of the extracellular matrix (ECM) proteins and involved in the tumor environment in the colon. Transforming growth factor (TGF)-β is a key cytokine that regulates the deposition of ECM proteins in CRC. However, the role of HAPLN1 in TGF-β contributions to CRC remains unknown. We found that the mRNA expression of HAPLN1 was decreased in tumors from CRC patients compared with healthy controls and normal tissue adjacent to the tumor using two existing microarray datasets. This was validated at the protein level by tissue array from CRC patients (n = 59). HAPLN1 protein levels were also reduced in human CRC epithelial cells after 24 h of TGF-β stimulation, and its protein expression correlated with type I collagen alpha-1 (COL1A1) in CRC. Transfection of HAPLN1 overexpression plasmids into these cells increased protein levels but reduced COL1A1 protein, tumor growth, and cancer cell migration. TGF-β stimulation increased Smad2/3, p-Smad2/3, Smad4, and E-adhesion proteins; however, HAPLN1 overexpression restored these proteins to baseline levels in CRC epithelial cells after TGF-β stimulation. These findings suggest that HAPLN1 regulates the TGF-β signaling pathway to control collagen deposition via the TGF-β signaling pathway and mediates E-adhesion to control tumor growth. Thus, treatments that increase HAPLN1 levels may be a novel therapeutic option for CRC.
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- 2021
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46. Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages
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Marcia A Munoz, Emma K Fletcher, Oliver P Skinner, Julie Jurczyluk, Esther Kristianto, Mark P Hodson, Shuting Sun, Frank H Ebetino, David R Croucher, Philip M Hansbro, Jacqueline R Center, and Michael J Rogers
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osteoporosis ,pneumonia ,bisphosphonate ,prenylation ,alveolar macrophage ,inflammasome ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.
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- 2021
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47. Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation
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Mohamed F. AlAjmi, Shama Khan, Arunabh Choudhury, Taj Mohammad, Saba Noor, Afzal Hussain, Wenying Lu, Mathew Suji Eapen, Vrushali Chimankar, Philip M Hansbro, Sukhwinder Singh Sohal, Abdelbaset Mohamed Elasbali, and Md. Imtaiyaz Hassan
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serum/glucocorticoid regulated kinase 1 ,deleterious mutations ,single amino acid substitutions ,molecular dynamics simulation ,essential dynamics ,Biology (General) ,QH301-705.5 - Abstract
Serum and glucocorticoid-regulated kinase 1 (SGK1) is a Ser/Thr protein kinase involved in regulating cell survival, growth, proliferation, and migration. Its elevated expression and dysfunction are reported in breast, prostate, hepatocellular, lung adenoma, and renal carcinomas. We have analyzed the SGK1 mutations to explore their impact at the sequence and structure level by utilizing state-of-the-art computational approaches. Several pathogenic and destabilizing mutations were identified based on their impact on SGK1 and analyzed in detail. Three amino acid substitutions, K127M, T256A, and Y298A, in the kinase domain of SGK1 were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic (MD) simulations for 200 ns. MD results indicate substantial conformational alterations in SGK1, thus its functional loss, particularly upon T256A mutation. This study provides meaningful insights into SGK1 dysfunction upon mutation, leading to disease progression, including cancer, and neurodegeneration.
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- 2021
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48. Probiotic Bifidobacterium longum subsp. longum Protects against Cigarette Smoke-Induced Inflammation in Mice
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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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probiotic ,Bifidobacterium ,cigarette smoke ,COPD ,inflammation ,SCFA ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Bifidobacterium are prominent gut commensals that produce the short-chain fatty acid (SCFA) acetate, and they are often used as probiotics. Connections between the gut and the lung, termed the gut–lung axis, are regulated by the microbiome. The gut–lung axis is increasingly implicated in cigarette smoke-induced diseases, and cigarette smoke exposure has been associated with depletion of Bifidobacterium species. In this study, we assessed the impact of acetate-producing Bifidobacterium longum subsp. longum (WT) and a mutant strain with an impaired acetate production capacity (MUT) on cigarette smoke-induced inflammation. The mice were treated with WT or MUT B. longum subsp. longum and exposed to cigarette smoke for 8 weeks before assessments of lung inflammation, lung tissue gene expression and cecal SCFAs were performed. Both strains of B. longum subsp. longum reduced lung inflammation, inflammatory cytokine expression and adhesion factor expression and alleviated cigarette smoke-induced depletion in caecum butyrate. Thus, the probiotic administration of B. longum subsp. longum, irrespective of its acetate-producing capacity, alleviated cigarette smoke-induced inflammation and the depletion of cecal butyrate levels.
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- 2022
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49. 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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berberine ,liquid crystalline nanoparticles ,inflammation ,oxidative stress ,macrophages ,LPS ,Chemistry ,QD1-999 - 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
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50. The FBXW7‐NOTCH interactome: A ubiquitin proteasomal system‐induced crosstalk modulating oncogenic transformation in human tissues
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Rohan Kar, Saurabh Kumar Jha, Shreesh Ojha, Ankur Sharma, Sunny Dholpuria, Venkata Sita Rama Raju, Parteek Prasher, Dinesh Kumar Chellappan, Gaurav Gupta, Sachin KumarSingh, Keshav Raj Paudel, Philip M. Hansbro, Sandeep KumarSingh, Janne Ruokolainen, Kavindra Kumar Kesari, Kamal Dua, and Niraj Kumar Jha
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cancer ,diagnostic markers ,E3 ligase ,FBXW7 ,mutation ,NOTCH ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Ubiquitin ligases or E3 ligases are well programmed to regulate molecular interactions that operate at a post‐translational level. Skp, Cullin, F‐box containing complex (or SCF complex) is a multidomain E3 ligase known to mediate the degradation of a wide range of proteins through the proteasomal pathway. The three‐dimensional domain architecture of SCF family proteins suggests that it operates through a novel and adaptable “super‐enzymatic” process that might respond to targeted therapeutic modalities in cancer. Recent findings Several F‐box containing proteins have been characterized either as tumor suppressors (FBXW8, FBXL3, FBXW8, FBXL3, FBXO1, FBXO4, and FBXO18) or as oncogenes (FBXO5, FBXO9, and SKP2). Besides, F‐box members like βTrcP1 and βTrcP2, the ones with context‐dependent functionality, have also been studied and reported. FBXW7 is a well‐studied F‐box protein and is a tumor suppressor. FBXW7 regulates the activity of a range of substrates, such as c‐Myc, cyclin E, mTOR, c‐Jun, NOTCH, myeloid cell leukemia sequence‐1 (MCL1), AURKA, NOTCH through the well‐known ubiquitin‐proteasome system (UPS)‐mediated degradation pathway. NOTCH signaling is a primitive pathway that plays a crucial role in maintaining normal tissue homeostasis. FBXW7 regulates NOTCH protein activity by controlling its half‐life, thereby maintaining optimum protein levels in tissue. However, aberrations in the FBXW7 or NOTCH expression levels can lead to poor prognosis and detrimental outcomes in patients. Therefore, the FBXW7‐NOTCH axis has been a subject of intense study and research over the years, especially around the interactome's role in driving cancer development and progression. Several studies have reported the effect of FBXW7 and NOTCH mutations on normal tissue behavior. The current review attempts to critically analyze these mutations prognostic value in a wide range of tumors. Furthermore, the review summarizes the recent findings pertaining to the FBXW7 and NOTCH interactome and its involvement in phosphorylation‐related events, cell cycle, proliferation, apoptosis, and metastasis. Conclusion The review concludes by positioning FBXW7 as an effective diagnostic marker in tumors and by listing out recent advancements made in cancer therapeutics in identifying protocols targeting the FBXW7‐NOTCH aberrations in tumors.
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- 2021
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