2023 |
Vanders RL, Gomez HM, Hsu AC, Daly K, Wark PAB, Horvat JC, Hansbro PM, 'Inflammatory and antiviral responses to influenza A virus infection are dysregulated in pregnant mice with allergic airway disease.', Am J Physiol Lung Cell Mol Physiol, 325 L385-L398 (2023) [C1]
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2023 |
Girkin JLN, Bryant NE, Loo S-L, Hsu A, Kanwal A, Williams TC, et al., 'Upper Respiratory Tract OC43 Infection Model for Investigating Airway Immune-Modifying Therapies.', Am J Respir Cell Mol Biol, 69 614-622 (2023) [C1]
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2023 |
Gu Y, Hsu AC-Y, Zuo X, Guo X, Zhou Z, Jiang S, et al., 'Chronic exposure to low-level lipopolysaccharide dampens influenza-mediated inflammatory response via A20 and PPAR network', FRONTIERS IN IMMUNOLOGY, 14 (2023) [C1]
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2023 |
Liu G, Haw TJ, Starkey MR, Philp AM, Pavlidis S, Nalkurthi C, et al., 'TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase.', Nat Commun, 14 7349 (2023) [C1]
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2023 |
Yousefi M, Lee WS, Chan WOY, He W, Mah MG, Yong CL, et al., 'Betacoronaviruses SARS-CoV-2 and HCoV-OC43 infections in IGROV-1 cell line require aryl hydrocarbon receptor', EMERGING MICROBES & INFECTIONS, 12 (2023) [C1]
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2022 |
Yuan Y, Wang C, Wang G, Guo X, Jiang S, Zuo X, et al., 'Airway Microbiome and Serum Metabolomics Analysis Identify Differential Candidate Biomarkers in Allergic Rhinitis', FRONTIERS IN IMMUNOLOGY, 12 (2022) [C1]
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2022 |
Pathinayake PS, Waters DW, Nichol KS, Brown AC, Reid AT, Hsu AC-Y, et al., 'Endoplasmic reticulum-unfolded protein response signalling is altered in severe eosinophilic and neutrophilic asthma', THORAX, 77 443-451 (2022) [C1]
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2022 |
Liu Y, Zhang X, Zhang L, Oliver BG, Wang HG, Liu ZP, et al., 'Sputum Metabolomic Profiling Reveals Metabolic Pathways and Signatures Associated With Inflammatory Phenotypes in Patients With Asthma', ALLERGY ASTHMA & IMMUNOLOGY RESEARCH, 14 393-411 (2022) [C1]
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2022 |
Liu X, Li X, Chen L, Hsu ACY, Asquith KL, Liu C, et al., 'Proteomic Analysis Reveals a Novel Therapeutic Strategy Using Fludarabine for Steroid-Resistant Asthma Exacerbation', Frontiers in Immunology, 13 (2022) [C1]
Virus-induced asthma exacerbation is a health burden worldwide and lacks effective treatment. To better understand the disease pathogenesis and find novel therapeutic targets, we ... [more]
Virus-induced asthma exacerbation is a health burden worldwide and lacks effective treatment. To better understand the disease pathogenesis and find novel therapeutic targets, we established a mouse model of steroid (dexamethasone (DEX)) resistant asthma exacerbation using ovalbumin (OVA) and influenza virus (FLU) infection. Using liquid chromatography-tandem mass spectrometry (LC-MC/MS), we performed a shotgun proteomics assay coupled with label-free quantification to define all dysregulated proteins in the lung proteome of asthmatic mice. Compared to control, 71, 89, and 30 proteins were found significantly upregulated by at least two-fold (p-value = 0.05) in OVA-, OVA/FLU-, and OVA/FLU/DEX-treated mice, respectively. We then applied a Z-score transformed hierarchical clustering analysis and Ingenuity Pathway Analysis (IPA) to highlight the key inflammation pathways underlying the disease. Within all these upregulated proteins, 64 proteins were uniquely highly expressed in OVA/FLU mice compared to OVA mice; and 11 proteins were DEX-refractory. IPA assay revealed two of the most enriched pathways associated with these over-expressed protein clusters were those associated with MHC class I (MHC-I) antigen-presentation and interferon (IFN) signaling. Within these pathways, signal-transducer-and-activator-of-transcription-1 (STAT1) protein was identified as the most significantly changed protein contributing to the pathogenesis of exacerbation and the underlying steroid resistance based on the label-free quantification; and this was further confirmed by both Parallel Reaction Monitoring (PRM) proteomics assay and western blots. Further, the pharmacological drug Fludarabine decreased STAT1 expression, restored the responsiveness of OVA/FLU mice to DEX and markedly suppressed disease severity. Taken together, this study describes the proteomic profile underpinning molecular mechanisms of FLU-induced asthma exacerbation and identifies STAT1 as a potential therapeutic target, more importantly, we provided a novel therapeutic strategy that may be clinically translated into practice.
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2022 |
Wang GQ, Gu Y, Wang C, Wang F, Hsu AC-Y, 'A Game of Infection - Song of Respiratory Viruses and Interferons.', Frontiers in cellular and infection microbiology, 12 937460 (2022) [C1]
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2021 |
Liu J, Liu Y, Yu H, Zhang Y, Hsu ACY, Zhang M, et al., 'Design, synthesis and biological evaluation of novel pyxinol derivatives with anti-heart failure activity', Biomedicine and Pharmacotherapy, 133 (2021) [C1]
Heart failure (HF) is an important and leading cause of substantial morbidity and mortality globally. The angiotensin-converting enzymatic (ACE) is the causative source for conges... [more]
Heart failure (HF) is an important and leading cause of substantial morbidity and mortality globally. The angiotensin-converting enzymatic (ACE) is the causative source for congestive heart failure. Natural products and its derivatives play a vital role in drug discovery and development owing to their efficacy and low toxicity. Pyxinol is a potent natural agent for cardiovascular disease. Thus we investigated the effect on ACE and HF of pyxinol derivatives. We designed and synthesized 32 novel fatty acid ester derivatives of pyxinol via esterification. Among them, compounds 2e (IC50=105 nM) and 3b (IC50=114 nM) displayed excellent ACE inhibitory activity in vitro, and exhibited non-toxic to H9c2 cells. The interactions between ACE and compounds were predicted by molecular docking respectively. In verapamil-induced zebrafish HF model, the activity assay showed that these two derivatives could improve cardiovascular physiological indexes including heart beats, venous congestion, heart dilation, cardiac output, ejection fraction and fractional shortening in a dose-dependent manner. A UPLC-QTOF-MS-based serum metabolomics approach was applied to explore the latent mechanism. A total of 25 differentiated metabolites and 8 perturbed metabolic pathways were identified. These results indicated that pyxinol fatty acid ester derivatives 2e and 3b might be considered as potent drug candidates against heart failure and deserved further research and development.
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2021 |
Yuan YL, Zhang X, Liu L, Wang G, Chen-Yu Hsu A, Huang D, Oliver BG, 'Total IgE Variability Is Associated with Future Asthma Exacerbations: A 1-Year Prospective Cohort Study', Journal of Allergy and Clinical Immunology: In Practice, 9 2812-2824 (2021) [C1]
Background: Few prospective studies have investigated the relationship between IgE variability and risk for asthma exacerbations (AEs). Objective: To explore the relationship betw... [more]
Background: Few prospective studies have investigated the relationship between IgE variability and risk for asthma exacerbations (AEs). Objective: To explore the relationship between IgE variability and AEs. Methods: Recruited patients with stable asthma underwent two serum total IgE tests within a month (at screening [baseline IgE] and at 1 month) to obtain the coefficient of variation (CV) of base 10 log-transformed IgE. Patients with IgE CV were divided into IgE CV-high and IgE CV-low cohorts based on the CV median and were observed within 12 months, during which the association between IgE variability and AEs was explored using a negative binomial regression model. Results: The IgE CV levels obtained from 340 patients classified patients into two groups (n = 170 for the IgE CV-high and IgE CV-low groups, respectively) based on the serum total IgE CV median of 2.12% (quartiles 1 and 3: 0.98% and 3.91%, respectively). The IgE CV-high patients exhibited worse asthma control and lung function and more marked airway inflammation, and received more intensive medication use compared with IgE CV-low patients. The IgE CV-high patients exhibited increased rates of moderate-to-severe (adjusted rate ratio = 2.88; 95% confidence interval, 1.65-5.03; P < .001) and severe (adjusted rate ratio = 2.16; 95% confidence interval, 1.08-4.32; P = .029) AEs during the follow-up year compared with IgE CV-low patients. Furthermore, sputum IL-6 partially mediated the associations between IgE CV with moderate-to-severe and severe AEs. Conclusions: Variability in total serum IgE levels is an easily obtained and practical measure for predicting AEs. Future studies are needed to investigate whether IgE variability can be used to guide precision medicine in asthma.
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2021 |
Chong WC, Shastri MD, Peterson GM, Patel RP, Pathinayake PS, Dua K, et al., 'The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders', Clinical and Translational Immunology, 10 (2021) [C1]
Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, pa... [more]
Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders.
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2021 |
Dong B, Wang C, Zhang J, Zhang J, Gu Y, Guo X, et al., 'Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization', Stem Cell Research and Therapy, 12 (2021) [C1]
Background: Severe, steroid-resistant asthma (SSRA) is a serious clinical problem in asthma management. Affected patients have severe clinical symptoms, worsened quality of life, ... [more]
Background: Severe, steroid-resistant asthma (SSRA) is a serious clinical problem in asthma management. Affected patients have severe clinical symptoms, worsened quality of life, and do not respond to steroid, a mainstay steroid treatment of asthma. Thus, effective therapies are urgently needed. Exosomes derived from mesenchymal stem cell (MSC-Exo) has become attractive candidates for the lung inflammatory diseases through its immunomodulatory effects. In this study, we explored the therapeutic effects of MSC-Exo in SSRA and identified the therapeutic mechanism of MSC-Exo. Method: Exosomes from human umbilical cord mesenchymal stem cell¿(hUCMSC)¿were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis and flow cytometry analysis. Effects of MSC-Exo on airway hyper responsiveness (AHR), inflammation, histopathology, and macrophage polarization in SSRA in mice were evaluated. Systematic depletion of macrophages determined the role of macrophages in the therapeutic effect of SSRA in mice. LPS-stimulated RAW 264.7 cell model was constructed to determine the underlying mechanism of MSC-Exo on macrophage polarization. qRT-PCR, Western blotting, immunofluorescence, and flow cytometry were performed to evaluate the expression of M1 or M2 markers. Tandem mass tags (TMT)-labeled quantitative proteomics were applied to explore the central protein during the regulation effect of MSC-Exo on macrophage polarization. Knockdown and overexpression of TRAF1 were used to further clarify the role of the central protein on macrophage polarization. Result: We successfully isolated and characterized exosomes from hUCMSCs. We verified that the intratracheal administration of MSC-Exo reversed AHR, histopathology changes, and inflammation in SSRA mice. Systematic depletion of macrophages weakened the therapeutic effect of MSC-Exo. We found that MSC-Exo treatment inhibited M1 polarization and promoted M2 polarization in LPS-stimulated RAW 264.7 cells. Subsequently, tumor necrosis factor receptor-associated factor 1 (TRAF1) was determined as the central protein which may be closely related to the regulation of macrophage polarization from TMT-labeled quantitative proteomics analysis. Knockdown and overexpression of TRAF1 demonstrated that the effect of MSC-Exo treatment on macrophage polarization, NF-¿B and PI3K/AKT signaling was dependent on TRAF1. Conclusion: MSC-Exo can ameliorate SSRA by moderating inflammation, which is achieved by reshaping macrophage polarization via inhibition of TRAF1.
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2021 |
Pathinayake PS, Hsu AC-Y, Wark PAB, 'PAT in the ER for Transmembrane Protein Folding (vol 46, pg 1007, 2020)', TRENDS IN BIOCHEMICAL SCIENCES, 46 344-344 (2021)
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2021 |
Wark PAB, Pathinayake PS, Kaiko G, Nichol K, Ali A, Chen L, et al., 'ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma', Respirology, 26 442-451 (2021) [C1]
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 protea... [more]
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 COVID-19 complications.
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2021 |
Kim RY, Sunkara KP, Bracke KR, Jarnicki AG, Donovan C, Hsu AC, et al., 'microRNA-21-mediated SATB1/S100A9/NF-kappa B axis promotes chronic obstructive pulmonary disease pathogenesis', SCIENCE TRANSLATIONAL MEDICINE, 13 (2021) [C1]
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2021 |
Wadhwa R, Paudel KR, Chin LH, Hon CM, Madheswaran T, Gupta G, et al., 'Anti-inflammatory and anticancer activities of Naringenin-loaded liquid crystalline nanoparticles in vitro', JOURNAL OF FOOD BIOCHEMISTRY, 45 (2021) [C1]
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2021 |
Liu X, Nguyen TH, Sokulsky L, Li X, Netto KG, Hsu AC-Y, et al., 'IL-17A is a common and critical driver of impaired lung function and immunopathology induced by influenza virus, rhinovirus and respiratory syncytial virus', RESPIROLOGY, 26 1049-1059 (2021) [C1]
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2020 |
Wang C, Yuan Y, Pan H, Hsu AC-Y, Chen J, Liu J, et al., 'Protective Effect of Ocotillol, the Derivate of Ocotillol-Type Saponins in Panax Genus, against Acetic Acid-Induced Gastric Ulcer in Rats Based on Untargeted Metabolomics', INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21 (2020) [C1]
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2020 |
Pathinayake PS, Hsu AC-Y, Wark PAB, 'PAT in the ER for Transmembrane Protein Folding', TRENDS IN BIOCHEMICAL SCIENCES, 45 1007-1008 (2020)
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2020 |
Jin-Ying WYW, Yin Ng Z, Mehta M, Shukla SD, Panneerselvam J, Madheswaran T, et al., 'Curcumin-loaded niosomes downregulate mRNA expression of pro-inflammatory markers involved in asthma: An in vitro study', Nanomedicine, 15 2955-2970 (2020) [C1]
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 ... [more]
Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation underwent various physicochemical characterization experiments, an in vitro release study, molecular simulations and was evaluated for in vitro anti-inflammatory activity. Results: Results showed that Nio-Curc had a mean particle size of 284.93 ± 14.27 nm, zeta potential of -46.93 and encapsulation efficacy of 99.62%, which demonstrates optimized physicochemical characteristics. Curcumin release in vitro could be sustained for up to 24 h. Additionally, Nio-Curc effectively reduced mRNA transcript expression of pro-inflammatory markers; IL-6, IL-8, IL-1ß and TNF-a in immortalized human airway basal cell line (BCi-NS1.1). Conclusion: In this study, we have demonstrated that Nio-Curc mitigated the mRNA expression of pro-inflammatory markers in an in vitro study, which could be applied to treatment of asthma with further studies.
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2020 |
Guan X, Yuan Y, Wang G, Zheng R, Zhang J, Dong B, et al., 'Ginsenoside Rg3 ameliorates acute exacerbation of COPD by suppressing neutrophil migration', INTERNATIONAL IMMUNOPHARMACOLOGY, 83 (2020) [C1]
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2020 |
Loo SL, Wark PAB, Esneau C, Nichol KS, Hsu ACY, Bartlett NW, 'Human coronaviruses 229E and OC43 replicate and induce distinct antiviral responses in differentiated primary human bronchial epithelial cells', American Journal of Physiology - Lung Cellular and Molecular Physiology, 319 L926-L931 (2020) [C1]
The recurrent emergence of novel, pathogenic coronaviruses (CoVs) severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1; 2002), Middle East respiratory syndrome (MERS)-CoV (... [more]
The recurrent emergence of novel, pathogenic coronaviruses (CoVs) severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1; 2002), Middle East respiratory syndrome (MERS)-CoV (2012), and most recently SARS-CoV-2 (2019) has highlighted the need for physiologically informative airway epithelial cell infection models for studying immunity to CoVs and development of antiviral therapies. To address this, we developed an in vitro infection model for two human coronaviruses; alphacoronavirus 229E-CoV (229E) and betacoronavirus OC43-CoV (OC43) in differentiated primary human bronchial epithelial cells (pBECs). Primary BECs from healthy subjects were grown at air-liquid interface (ALI) and infected with 229E or OC43, and replication kinetics and time-course expression of innate immune mediators were assessed. OC43 and 229E-CoVs replicated in differentiated pBECs but displayed distinct replication kinetics: 229E replicated rapidly with viral load peaking at 24 h postinfection, while OC43 replication was slower peaking at 96 h after infection. This was associated with diverse antiviral response profiles defined by increased expression of type I/III interferons and interferon-stimulated genes (ISGs) by 229E compared with no innate immune activation with OC43 infection. Understanding the host-virus interaction for previously established coronaviruses will give insight into pathogenic mechanisms underpinning SARS-CoV-2-induced respiratory disease and other future coronaviruses that may arise from zoonotic sources.
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2020 |
Yong DOC, Saker SR, Chellappan DK, Madheswaran T, Panneerselvam J, Choudhury H, et al., 'Molecular and immunological mechanisms underlying the various pharmacological properties of the potent bioflavonoid, rutin', Endocrine, Metabolic and Immune Disorders - Drug Targets, 20 1590-1596 (2020) [C1]
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 ... [more]
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 anti-diabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.
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2020 |
Chan Y, Ng SW, Chellappan DK, Madheswaran T, Zeeshan F, Kumar P, et al., 'Celastrol-loaded liquid crystalline nanoparticles as an anti-inflammatory intervention for the treatment of asthma', INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS, 70 754-763 (2020) [C1]
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2020 |
Tew XN, Lau NJX, Chellappan DK, Madheswaran T, Zeeshan F, Tambuwala MM, et al., 'Immunological axis of berberine in managing inflammation underlying chronic respiratory inflammatory diseases', CHEMICO-BIOLOGICAL INTERACTIONS, 317 (2020) [C1]
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2020 |
Chin LH, Hon CM, Chellappan DK, Chellian J, Madheswaran T, Zeeshan F, et al., 'Molecular mechanisms of action of naringenin in chronic airway diseases', European Journal of Pharmacology, 879 (2020) [C1]
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2019 |
Hayman TJ, Hsu AC, Kolesnik TB, Dagley LF, Willemsen J, Tate MD, et al., 'RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses', Immunology and Cell Biology, 97 840-852 (2019) [C1]
The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascade... [more]
The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid¿inducible gene-I (RIG-I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN-stimulated genes. Ubiquitination of RIG-I by the E3 ligases tripartite motif-containing 25 (TRIM25) and Riplet is thought to be requisite for RIG-I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG-I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG-I agonists. This is in contrast to deletion of either Rig-i or Riplet, which completely abrogated RIG-I-dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG-I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in¿vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG-I signaling in viral infections and will inform future studies in the field.
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2019 |
Zhang C, Chen-Yu Hsu A, Pan H, Gu Y, Zuo X, Dong B, et al., 'Columbianadin suppresses lipopolysaccharide (LPS)-induced inflammation and apoptosis through the NOD1 pathway', Molecules, 24 1-12 (2019) [C1]
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Nova |
2019 |
Dua K, Malyla V, Singhvi G, Wadhwa R, Krishna RV, Shukla SD, et al., 'Increasing complexity and interactions of oxidative stress in chronic respiratory diseases: An emerging need for novel drug delivery systems', Chemico-Biological Interactions, 299 168-178 (2019) [C1]
Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonary disease (COPD), inf... [more]
Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonary disease (COPD), infections and lung cancer. Even though there are various existing anti-inflammatory therapies, which are not enough to control the inflammation caused due to various contributing factors such as anti-inflammatory genes and antioxidant enzymes. This leads to an urgent need of novel drug delivery systems to combat the oxidative stress. This review gives a brief insight into the biological factors involved in causing oxidative stress, one of the emerging hallmark feature in CRDs and particularly, highlighting recent trends in various novel drug delivery carriers including microparticles, microemulsions, microspheres, nanoparticles, liposomes, dendrimers, solid lipid nanocarriers etc which can help in combating the oxidative stress in CRDs and ultimately reducing the disease burden and improving the quality of life with CRDs patients. These carriers improve the pharmacokinetics and bioavailability to the target site. However, there is an urgent need for translational studies to validate the drug delivery carriers for clinical administration in the pulmonary clinic.
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2019 |
Liu L, Zhang X, Liu Y, Zhang L, Zheng J, Wang J, et al., 'Chitinase-like protein YKL-40 correlates with inflammatory phenotypes, anti-asthma responsiveness and future exacerbations', Respiratory Research, 20 1-12 (2019) [C1]
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Nova |
2019 |
Gu Y, Hsu ACY, Pang Z, Pan H, Zuo X, Wang G, et al., 'Role of the Innate Cytokine Storm Induced by the Influenza A Virus', Viral Immunology, 32 244-251 (2019) [C1]
Influenza A viruses (IAVs) can be classified into dozens of subtypes based on their hemagglutinin (HA) and neuraminidase (NA) proteins. To date, 18 HA subtypes and 11 NA subtypes ... [more]
Influenza A viruses (IAVs) can be classified into dozens of subtypes based on their hemagglutinin (HA) and neuraminidase (NA) proteins. To date, 18 HA subtypes and 11 NA subtypes of IAVs that spread in animals and humans have been found. Following infection, the IAV first induces the innate immune system, which can rapidly recruit innate immune cells and cytokines to the site of infection. Influenza-induced cytokine storms have been associated with uncontrolled proinflammatory responses, which may lead to significant immunopathy and severe disease. Cytokine storms are complicated by several types of cytokines and chemokines that have various activities. In addition to their direct effects, their crossregulation causes cytokine networks to form; these networks determine the outcome of viral infections. In this review, we focus on cytokine storms and their signaling pathways that are triggered by the different subtypes of IAV.
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Nova |
2019 |
Hu MJ, Schulze KE, Ghildyal R, Henstridge DC, Kolanowski JL, New EJ, et al., 'Respiratory syncytial virus co-opts host mitochondrial function to favour infectious virus production', eLife, 8 1-30 (2019) [C1]
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Nova |
2019 |
Yong DOC, Saker SR, Wadhwa R, Chellappan DK, Madheswaran T, Panneerselvam J, et al., 'Preparation, characterization and in-vitro efficacy of quercetin loaded liquid crystalline nanoparticles for the treatment of asthma', JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY, 54 (2019) [C1]
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Nova |
2019 |
Zhu H, Liu J, Lin H, Zhang Y, Yang N, Zhou B, et al., 'UPLC-QTOF-MS-guided isolation of anti-COPD ginsenosides from wild ginseng', RSC Advances, 9 38658-38668 (2019) [C1]
Four previously undescribed ginsenosides, along with five known analogues were isolated from wild ginseng by a UPLC-QTOF-MS-guided fractionation procedure. Their structures were e... [more]
Four previously undescribed ginsenosides, along with five known analogues were isolated from wild ginseng by a UPLC-QTOF-MS-guided fractionation procedure. Their structures were elucidated on the basis of spectroscopic and spectrometric data (1D and 2D NMR, HR-ESI-MS). The isolated compounds could significantly inhibit the cigarette smoke extract (CSE)-induced inflammatory reaction in A549 cells. The HDAC2 pathway might be involved in the protective effect against the CSE-mediated inflammatory response in A549 cells.
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Nova |
2019 |
Liu G, Cooley MA, Jarnicki AG, Borghuis T, Nair PM, Tjin G, et al., 'Fibulin-1c regulates transforming growth factor-beta activation in pulmonary tissue fibrosis', JCI INSIGHT, 4 (2019) [C1]
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Nova |
2019 |
Pang Z, Ran N, Yuan Y, Wang C, Wang G, Lin H, et al., 'Phenotype-Specific Therapeutic Effect of Rhodiola wallichiana var. cholaensis Combined with Dexamethasone on Experimental Murine Asthma and Its Comprehensive Pharmacological Mechanism', International journal of molecular sciences, 20 (2019) [C1]
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Nova |
2019 |
Wang G, Pang Z, Chen-Yu Hsu A, Guan X, Ran N, Yuan Y, et al., 'Combined treatment with SB203580 and dexamethasone suppresses non-typeable Haemophilus influenzae-induced Th17 inflammation response in murine allergic asthma', European Journal of Pharmacology, 862 (2019) [C1]
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Nova |
2019 |
Ng SW, Chan Y, Chellappan DK, Madheswaran T, Zeeshan F, Chan YL, et al., 'Molecular modulators of celastrol as the keystones for its diverse pharmacological activities', Biomedicine and Pharmacotherapy, 109 1785-1792 (2019) [C1]
In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their ... [more]
In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.
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Nova |
2019 |
Soon L, Ng PQ, Chellian J, Madheswaran T, Panneerselvam J, Gupta G, et al., 'Therapeutic potential of artemisia vulgaris: An insight into underlying immunological mechanisms', Journal of Environmental Pathology, Toxicology and Oncology, 38 205-216 (2019) [C1]
Artemisia vulgaris is a traditional Chinese herb believed to have a wide range of healing properties; it is traditionally used to treat numerous health ailments. The plant is comm... [more]
Artemisia vulgaris is a traditional Chinese herb believed to have a wide range of healing properties; it is traditionally used to treat numerous health ailments. The plant is commonly called mugwort or riverside wormwood. The plant is edible, and in addition to its medicinal properties, it is also used as a culinary herb in Asian cooking in the form of a vegetable or in soup. The plant has garnered the attention of researchers in the past few decades, and several research studies have investigated its biological effects, including antioxidant, anti-inflammatory, anticancer, hypolipidemic, and antimicrobial properties. In this review, various studies on these biological effects are discussed along with the tests conducted, compounds involved, and proposed mechanisms of action. This review will be of interest to the researchers working in the field of herbal medicine, pharmacology, medical sciences, and immunology.
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Nova |
2019 |
Liu G, Mateer SW, Hsu A, Goggins BJ, Tay H, Mathe A, et al., 'Platelet activating factor receptor regulates colitis-induced pulmonary inflammation through the NLRP3 inflammasome', Mucosal Immunology, 12 862-873 (2019) [C1]
Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, which occurs in up to 50% of IBD patient... [more]
Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, which occurs in up to 50% of IBD patients. In animal models of colitis, pulmonary inflammation is driven by neutrophilic infiltrations, primarily in response to the systemic bacteraemia and increased bacterial load in the lungs. Platelet activating factor receptor (PAFR) plays a critical role in regulating pulmonary responses to infection in conditions, such as chronic obstructive pulmonary disease and asthma. We investigated the role of PAFR in pulmonary EIMs of IBD, using dextran sulfate sodium (DSS) and anti-CD40 murine models of colitis. Both models induced neutrophilic inflammation, with increased TNF and IL-1ß levels, bacterial load and PAFR protein expression in mouse lungs. Antagonism of PAFR decreased lung neutrophilia, TNF, and IL-1ß in an NLRP3 inflammasome-dependent manner. Lipopolysaccharide from phosphorylcholine (ChoP)-positive bacteria induced NLRP3 and caspase-1 proteins in human alveolar epithelial cells, however antagonism of PAFR prevented NLRP3 activation by ChoP. Amoxicillin reduced bacterial populations in the lungs and reduced NLRP3 inflammasome protein levels, but did not reduce PAFR. These data suggest a role for PAFR in microbial pattern recognition and NLRP3 inflammasome signaling in the lung.
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Nova |
2019 |
Vanders RL, Hsu A, Gibson PG, Murphy VE, Wark PAB, 'Nasal epithelial cells to assess in vitro immune responses to respiratory virus infection in pregnant women with asthma', RESPIRATORY RESEARCH, 20 (2019) [C1]
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Nova |
2018 |
Zhang HP, Wang L, Wang Z, Xu XR, Zhou XM, Liu G, et al., 'Chinese herbal medicine formula for acute asthma: A multi-center, randomized, double-blind, proof-of-concept trial', Respiratory Medicine, 140 42-49 (2018) [C1]
Background: Despite advances in asthma management, exacerbations constitute a significant health economic burden. Objective: To observe the efficacy and safety of Chinese herbal m... [more]
Background: Despite advances in asthma management, exacerbations constitute a significant health economic burden. Objective: To observe the efficacy and safety of Chinese herbal medicine formula entitled PingchuanYiqi (PCYQ) granule, on acute asthma and to explore its possible mechanism. Materials and methods: This proof-of-concept study consisted of a randomized, double-blind, placebo-controlled trial in patients with acute asthma (n = 300). Participants with acute mild-to-moderate asthma recruited from seven centers in China were randomly assigned to receive PCYQ or placebo. The primary outcomes were PEF (L/min) and total asthma symptom scores. Furthermore, a panel of cytokines including serum IL-4, IL-5, IL-6, IL-8, IL-1ß, IL-17A, IFN-a, IFN-ß, IFN-¿, CRP, CCL-5, IP-10, and PGD2 levels was detected using ELISA. Results: The PCYQ (n = 139) significantly improved the morning PEF on day 4 (349.73 ± 93.92 vs. 313.56 ± 92.91 L/min, P = 0.004) and day 7 (360.42 ± 94.39 vs. 329.52 ± 95.97 L/min, P = 0.023), and the evening PEF on day 4 (352.65 ± 95.47 vs. 320.58 ± 95.30 L/min, P = 0.012) and day 7 (360.42 ± 94.39 vs. 336.86 ± 95.59 L/min, P = 0.029) in comparison with the placebo (n = 143). The PCYQ also improved the clinical symptoms scores and reduced the puffs of short-acting ß2-agonist (all P < 0.05). Furthermore, the PCYQ statistically reduced IL-5, IL-8, IL-1ß and PGD2 in serum. Conclusion: The PCYQ as the Chinese herbal medicine formula significantly improves lung function and symptoms of acute asthma, and reduces SABA dosage possibly via decrease of inflammatory biomarkers such as IL-5, IL-8, IL-1ß and PGD2. Trial registration: ISRCTN61674768 (http://www.isrctn.com/).
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Nova |
2018 |
Smed-Sorensen A, Oh DY, Oshiumi H, Hsu AC-Y, 'Emerging Viruses: Host Immunity and Novel Therapeutic Interventions', FRONTIERS IN IMMUNOLOGY, 9 (2018) [C1]
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Nova |
2018 |
Ng ZY, Wong JY, Panneerselvam J, Madheswaran T, Kumar P, Pillay V, et al., 'Assessing the potential of liposomes loaded with curcumin as a therapeutic intervention in asthma', Colloids and Surfaces B: Biointerfaces, 172 51-59 (2018) [C1]
Curcumin a component of turmeric, which is derived from Curcuma longa is used as a colouring agent and as a dietary spice for centuries. Extensive studies have been done on the an... [more]
Curcumin a component of turmeric, which is derived from Curcuma longa is used as a colouring agent and as a dietary spice for centuries. Extensive studies have been done on the anti-inflammatory activity of curcumin along with its molecular mechanism involving different signalling pathways. However, the physicochemical and biological properties such as poor solubility and rapid metabolism of curcumin have led to low bioavailability and hence limits its application. Current therapies for asthma such as bronchodilators and inhaled corticosteroids (ICS) are aimed at controlling disease symptoms and prevent asthma exacerbation. However, this approach requires lifetime therapy and is associated with a constellation of side effects. This creates a clear unmet medical need and there is an urgent demand for new and more-effective treatments. The present study is aimed to formulate liposomes containing curcumin and evaluate for its anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation on BCi-NS1.1 cell line. Curcumin and salbutamol liposomes were formulated using lipid hydration method. The prepared liposomes were characterized in terms of particle size, zeta potential, encapsulation efficiency and in-vitro release profile. The liposomes were tested on BCI-NS1.1 cell line to evaluate its anti-inflammatory properties. The various pro-inflammatory markers studied were Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-1ß (IL-1ß) and Tumour Necrosis Factor-a (TNF-a). Additionally, molecular mechanics simulations were used to elucidate the positioning, energy minimization, and aqueous dispersion of the liposomal architecture involving lecithin and curcumin. The prepared curcumin formulation showed an average size and zeta potential of 271.3 ± 3.06 nm and -61.0 mV, respectively. The drug encapsulation efficiency of liposomal curcumin is 81.1%. Both curcumin-loaded liposomes formulation (1 µg/mL, 5 µg/mL) resulted in significant (p < 0.05) reduction in the level of pro-inflammatory marker expression such as IL-6, IL-8, IL-1ß and TNF-a compared to positive control group. Liposomal curcumin with the dose of 1 µg/mL reduced the inflammatory markers more effectively compared to that of 5 µg/mL. Liposomal curcumin could be a promising intervention for asthma therapy showing their efficacy in suppressing the important pro-inflammatory markers involved in the pathogenesis of asthma.
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Nova |
2018 |
Hsu A, 'Influenza Virus: A Master Tactician in Innate Immune Evasion and Novel Therapeutic Interventions', Frontiers in Immunology, 9 (2018) [C1]
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Nova |
2018 |
Tan DBA, Teo T-H, Setiawan AM, Ong NE, Zimmermann M, Hsu AC-Y, et al., 'Impaired Th1 responses in patients with acute exacerbations of COPD are improved with PD-1 blockade', CLINICAL IMMUNOLOGY, 188 64-66 (2018)
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2018 |
Pathinayake PS, Hsu AC-Y, Waters DW, Hansbro PM, Wood LG, Wark PAB, 'Understanding the Unfolded Protein Response in the Pathogenesis of Asthma', FRONTIERS IN IMMUNOLOGY, 9 (2018) [C1]
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Nova |
2018 |
Chellappan DK, Ng ZY, Wong JY, Hsu A, Wark P, Hansbro N, et al., 'Immunological axis of curcumin-loaded vesicular drug delivery systems', Future Medicinal Chemistry, 10 839-844 (2018) [C1]
Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Suc... [more]
Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Such systems use particles at a nanoscale range, bringing about their intended use through a range of complex mechanisms. Apart from delivering drug substances into target tissues, these vesicular systems also effectively overcome problems like insolubility and unequal drug distribution. Several mechanisms are explored lately by different workers, and interest over vesicular curcumin has been renewed in the past decade. This commentary discusses several immunological targets in which curcumin is employed in a vesicular form.
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Nova |
2018 |
Thi HN, Liu X, Su ZZ, Hsu AC-Y, Foster PS, Yang M, 'Potential Role of MicroRNAs in the Regulation of Antiviral Responses to influenza infection', FRONTIERS IN IMMUNOLOGY, 9 (2018) [C1]
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Nova |
2017 |
Chellappan DK, Hansbro PM, Dua K, Hsu A, Gupta G, Ng ZY, et al., 'Vesicular Systems Containing Curcumin and Their Applications in Respiratory Disorders A Mini Review', Pharmaceutical Nanotechnology, 5 250-254 (2017)
Background: Vesicular systems like nanotechnology and liposomes are gaining tremen-dous attention lately in the field of respiratory diseases. These formulations enhance bioavaila... [more]
Background: Vesicular systems like nanotechnology and liposomes are gaining tremen-dous attention lately in the field of respiratory diseases. These formulations enhance bioavailability of the drug candidate, which could be achieved through a novel drug delivery mechanism. Moreover, the therapeutic potential achieved through these systems is highly controllable over long durations of time providing better efficacy and patient compliance. Objective: The objective of this paper is to review the recent literature on vesicular drug delivery systems containing curcumin. Methods: We have collated and summarized various recent attempts made to develop different controlled release drug delivery systems containing curcumin which would be of great interest for herbal, formulation and biological scientists. There are several vesicular nanotechnological techniques involv-ing curcumin which have been studied recently, targeting pulmonary diseases. Results: Different vesicular systems containing curcumin are being studied for their therapeutic potential in different respiratory diseases. There has been a renewed interest in formulations containing cur-cumin recently, primarily owing to the broad spectrum therapeutic potential of this miracle substance. Various types of formulations, containing curcumin, targeting different bodily systems have recently emerged and, nevertheless, the search for newer frontiers with this drug goes on. Conclusion: This mini review, in this direction, tries to highlight the key research interventions em-ploying vesicular systems of drug delivery with curcumin.
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2017 |
Conickx G, Mestdagh P, Cobos FA, Verhamme FM, Maes T, Vanaudenaerde BM, et al., 'MicroRNA profiling reveals a role for MicroRNA-218-5p in the pathogenesis of chronic obstructive pulmonary disease', American Journal of Respiratory and Critical Care Medicine, 195 43-56 (2017) [C1]
Rationale: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. Objectives: To identify dysregulated miRNAs in lung tissue of patients wi... [more]
Rationale: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. Objectives: To identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD). Methods: We performed miRNA and mRNA profiling using high throughput stem-loop reverse-transcriptase quantitative polymerase chain reaction and mRNA microarray, respectively, on lung tissue of 30 patients (screening cohort) encompassing 8 never-smokers, 10 smokers without airflow limitation, and 12 smokers with COPD. Differential expression of miRNA-218-5p (miR-218-5p) was validated by reverse-transcriptase quantitative polymerase chain reaction in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells. Localization of miR-218-5p was assessed by in situ hybridization. In vitro and in vivo perturbation of miR-218-5p combined with RNA sequencing and gene set enrichment analysis was used to elucidate its functional role in COPD pathogenesis. Measurements and Main Results: Several miRNAs were differentially expressed among the different patient groups. Interestingly, miR-218-5p was significantly down-regulated in smokers without airflow limitation and in patients with COPD compared with never-smokers. Decreased pulmonary expression of miR-218-5p was validated in an independent validation cohort, in cigarette smoke-exposed mice, and in human bronchial epithelial cells. Importantly, expression of miR-218-5p strongly correlated with airway obstruction. Furthermore, cellular localization of miR-218-5p in human and murine lung revealed highest expression of miR-218-5p in the bronchial airway epithelium. Perturbation experiments with a miR-218-5p mimic or inhibitor demonstrated a protective role of miR-218-5p in cigarette smoke-induced inflammation and COPD. Conclusions: We highlight a role for miR-218-5p in the pathogenesis of COPD.
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Nova |
2017 |
Huff RD, Hsu ACY, Nichol KS, Jones B, Knight DA, Wark PAB, et al., 'Regulation of xanthine dehydrogensase gene expression and uric acid production in human airway epithelial cells', PLoS ONE, 12 1-17 (2017) [C1]
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Nova |
2017 |
Liu G, Cooley MA, Nair PM, Donovan C, Hsu AC, Jarnicki AG, et al., 'Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c', JOURNAL OF PATHOLOGY, 243 510-523 (2017) [C1]
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Nova |
2017 |
Kedzierski L, Tate MD, Hsu AC, Kolesnik TB, Linossi EM, Dagley L, et al., 'Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling', eLife, 6 1-27 (2017) [C1]
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Nova |
2017 |
Hsu AC-Y, Dua K, Starkey MR, Haw T-J, Nair PM, Nichol K, et al., 'MicroRNA-125a and -b inhibit A20 and MAVS to promote inflammation and impair antiviral response in COPD', JCI INSIGHT, 2 (2017) [C1]
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Nova |
2016 |
Haw TJ, Starkey MR, Nair PM, Pavlidis S, Liu G, Nguyen DH, et al., 'A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease', Mucosal Immunology, 9 859-872 (2016) [C1]
Chronic obstructive pulmonary disease (COPD) is a life-Threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective ... [more]
Chronic obstructive pulmonary disease (COPD) is a life-Threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-Type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL + CD11b + monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.
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Nova |
2016 |
Hsu ACY, Parsons K, Moheimani F, Knight DA, Hansbro PM, Fujita T, Wark PA, 'Impaired antiviral stress granule and IFN-ß enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium', American Journal of Respiratory Cell and Molecular Biology, 55 117-127 (2016) [C1]
Chronic obstructive pulmonary disease (COPD) is a serious lung disease that progressively worsens lung function. Those affected are highly susceptible to influenza virus infection... [more]
Chronic obstructive pulmonary disease (COPD) is a serious lung disease that progressively worsens lung function. Those affected are highly susceptible to influenza virus infections that result in exacerbations with exaggerated symptoms with increased mortality. The mechanisms underpinning this increased susceptibility to infection in COPD are unclear. In this study, we show that primary bronchial epithelial cells (pBECs) from subjects with COPD have impaired induction of type I IFN (IFN-ß) and lead to heightened viral replication after influenza viral infection. COPD pBECs have reduced protein levels of protein kinase (PK) R and decreased formation of PKR-mediated antiviral stress granules, which are critical in initiating type I IFNinductions. In addition, reduced protein expression of p300 resulted in decreased activation of IFN regulatory factor 3 and subsequent formation of IFN-ß enhanceosome in COPD pBECs. The decreased p300 induction was the result of enhanced levels of microRNA (miR)-132. Ectopic expression of PKR or miR-132 antagomiR alone failed to restore IFN-ß induction, whereas cotreatment increased antiviral stress granule formation, induction of p300, and IFN-ß in COPD pBECs. This study reveals that decreased induction of both PKR and p300 proteins contribute to impaired induction of IFN-ß in COPD pBECs upon influenza infection.
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Nova |
2016 |
Gang L, Hsu A, Cooley MA, Jarnicki AG, Nair PM, Haw TJ, et al., 'Fibulin-1 regulates the pathogenesis of tissue remodeling in respiratory diseases', Journal of Clinical Investigation Insight, 1 (2016) [C1]
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Nova |
2016 |
Moheimani F, Hsu AC-Y, Reid AT, Williams T, Kicic A, Stick SM, et al., 'The genetic and epigenetic landscapes of the epithelium in asthma', RESPIRATORY RESEARCH, 17 (2016) [C1]
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Nova |
2015 |
Pathinayake PS, Hsu A, wark PA, 'Innate Immunity and Immune Evasion by Enterovirus 71', Viruses, 7 (2015) [C1]
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Nova |
2015 |
Hsu ACY, Starkey MR, Hanish I, Parsons K, Haw TJ, Howland LJ, et al., 'Targeting PI3K-p110a suppresses influenza virus infection in chronic obstructive pulmonary disease', American Journal of Respiratory and Critical Care Medicine, 191 1012-1023 (2015) [C1]
Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which ... [more]
Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations. Objectives: To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD and the potential for therapeutic targeting. Methods: We used a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke-induced experimental COPD, and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors. Measurements and Main Results: COPDpBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity, reduced retinoic acid-inducible gene-I, and IFN/cytokine and chemokine responses. Increased PI3K-p110a levels and activity inCOPDpBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110a inhibitors, or exogenous IFN-b restored protective antiviral responses, suppressed infection, and improved lung function. Conclusions: The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which are mediated by increased PI3K-p110a activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and/or treat influenza.
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Nova |
2014 |
Parsons KS, Hsu AC, Wark PAB, 'TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection', Clinical and Experimental Allergy, 44 91-101 (2014) [C1]
Summary: Background: Rhinoviruses (RV) are the most common acute triggers of asthma, and airway epithelial cells are the primary site of infection. Asthmatic bronchial epithelial ... [more]
Summary: Background: Rhinoviruses (RV) are the most common acute triggers of asthma, and airway epithelial cells are the primary site of infection. Asthmatic bronchial epithelial cells (BECs) have been found to have impaired innate immune responses to RV. RV entry and replication is recognized by pathogen recognition receptors (PRRs), specifically toll-like receptor (TLR)3 and the RNA helicases; retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Objective: Our aim was to assess the relative importance of these PRRs in primary bronchial epithelial cells (pBEC) from healthy controls and asthmatics following RV infection and determine whether deficient innate immune responses in asthmatic pBECs were due to abnormal signalling via these PRRs. Methods: The expression patterns and roles of TLR3 and MDA5 were investigated using siRNA knock-down, with subsequent RV1B infection in pBECs from each patient group. We also used BX795, a specific inhibitor of TBK1 and IKKi. Results: Asthmatic pBECs had significantly reduced release of IL-6, CXCL-8 and IFN-¿ in response to RV1B infection compared with healthy pBECs. In healthy pBECs, siMDA5, siTLR3 and BX795 all reduced release of IL-6, CXCL-10 and IFN-¿ to infection. In contrast, in asthmatic pBECs where responses were already reduced, there was no further reduction in IL-6 and IFN-¿, although there was in CXCL-10. Conclusion and Clinical Relevance: Impaired antiviral responses in asthmatic pBECs are not due to deficient expression of PRRs; MDA5 and TLR3, but an inability to later activate types I and III interferon immune responses to RV infection, potentially increasing susceptibility to the effects of RV infection. © 2013 John Wiley & Sons Ltd.
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Nova |
2013 |
Baines KJ, Hsu AC-Y, Tooze M, Gunawardhana LP, Gibson PG, Wark PAB, 'Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD', RESPIRATORY RESEARCH, 14 (2013) [C1]
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Nova |
2012 |
Hsu A, See HV, Hansbro PM, Wark PA, 'Innate immunity to influenza in chronic airways diseases', Respirology, 17 1166-1175 (2012) [C1]
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Nova |
2012 |
Hsu A, Parsons KS, Barr I, Lowther S, Middleton D, Hansbro PM, Wark PA, 'Critical role of constitutive type I interferon response in bronchial epithelial cell to influenza infection', PLoS One, 7 (2012) [C1]
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Nova |
2011 |
Hsu A, Barr I, Hansbro PM, Wark PA, 'Human influenza is more effective than Avian influenza at antiviral suppression in airway cells', American Journal of Respiratory Cell and Molecular Biology, 44 906-913 (2011) [C1]
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Nova |
1995 |
IANCU TC, SHILOH H, RAJA KB, SIMPSON RJ, PETERS TJ, PERL DP, et al., 'THE HYPOTRANSFERRINAEMIC MOUSE - ULTRASTRUCTURAL AND LASER MICROPROBE ANALYSIS OBSERVATIONS', JOURNAL OF PATHOLOGY, 177 83-94 (1995)
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