ORCID Profile
0000-0002-6640-0846
Current Organisations
Duke-NUS Medical School
,
The University of Newcastle
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Publisher: American Physiological Society
Date: 09-2023
DOI: 10.1152/AJPLUNG.00232.2022
Abstract: Influenza A virus (IAV) infection during pregnancy with asthma is a major health concern leading to increased morbidity for both mother and baby. Using murine models, we show that IAV infection in pregnancy with allergic airway disease is associated with impaired global antiviral and antimicrobial responses, increased lung inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). Targeting specific β-defensins or microRNAs (miRNAs) may prove useful in future treatments for IAV infection during pregnancy.
Publisher: Frontiers Media SA
Date: 05-01-2022
DOI: 10.3389/FIMMU.2021.771136
Abstract: Allergic rhinitis (AR) is a common heterogeneous chronic disease with a high prevalence and a complex pathogenesis influenced by numerous factors, involving a combination of genetic and environmental factors. To gain insight into the pathogenesis of AR and to identity diagnostic biomarkers, we combined systems biology approach to analyze microbiome and serum composition. We collected inferior turbinate swabs and serum s les to study the microbiome and serum metabolome of 28 patients with allergic rhinitis and 15 healthy in iduals. We sequenced the V3 and V4 regions of the 16S rDNA gene from the upper respiratory s les. Metabolomics was used to examine serum s les. Finally, we combined differential microbiota and differential metabolites to find potential biomarkers. We found no significant differences in ersity between the disease and control groups, but changes in the structure of the microbiota. Compared to the HC group, the AR group showed a significantly higher abundance of 1 phylum ( Actinobacteria ) and 7 genera ( Klebsiella , Prevotella and Staphylococcus , etc. ) and a significantly lower abundance of 1 genus ( Pelomonas ). Serum metabolomics revealed 26 different metabolites (Prostaglandin D2, 20-Hydroxy-leukotriene B4 and Linoleic acid, etc. ) and 16 disrupted metabolic pathways (Linoleic acid metabolism, Arachidonic acid metabolism and Tryptophan metabolism, etc. ). The combined respiratory microbiome and serum metabolomics datasets showed a degree of correlation reflecting the influence of the microbiome on metabolic activity. Our results show that microbiome and metabolomics analyses provide important candidate biomarkers, and in particular, differential genera in the microbiome have also been validated by random forest prediction models. Differential microbes and differential metabolites have the potential to be used as biomarkers for the diagnosis of allergic rhinitis.
Publisher: Springer Science and Business Media LLC
Date: 22-09-2016
Publisher: eLife Sciences Publications, Ltd
Date: 27-06-2019
DOI: 10.7554/ELIFE.42448
Abstract: Although respiratory syncytial virus (RSV) is responsible for more human deaths each year than influenza, its pathogenic mechanisms are poorly understood. Here high-resolution quantitative imaging, bioenergetics measurements and mitochondrial membrane potential- and redox-sensitive dyes are used to define RSV’s impact on host mitochondria for the first time, delineating RSV-induced microtubule/dynein-dependent mitochondrial perinuclear clustering, and translocation towards the microtubule-organizing centre. These changes are concomitant with impaired mitochondrial respiration, loss of mitochondrial membrane potential and increased production of mitochondrial reactive oxygen species (ROS). Strikingly, agents that target microtubule integrity the dynein motor protein, or inhibit mitochondrial ROS production strongly suppresses RSV virus production, including in a mouse model with concomitantly reduced virus-induced lung inflammation. The results establish RSV’s unique ability to co-opt host cell mitochondria to facilitate viral infection, revealing the RSV-mitochondrial interface for the first time as a viable target for therapeutic intervention.
Publisher: Future Medicine Ltd
Date: 12-2020
Abstract: Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation underwent various physicochemical characterization experiments, an in vitro release study, molecular simulations and was evaluated for in vitro anti-inflammatory activity. Results: Results showed that Nio-Curc had a mean particle size of 284.93 ± 14.27 nm, zeta potential of -46.93 and encapsulation efficacy of 99.62%, which demonstrates optimized physicochemical characteristics. Curcumin release in vitro could be sustained for up to 24 h. Additionally, Nio-Curc effectively reduced mRNA transcript expression of pro-inflammatory markers IL-6, IL-8, IL-1β and TNF-α in immortalized human airway basal cell line (BCi-NS1.1). Conclusion: In this study, we have demonstrated that Nio-Curc mitigated the mRNA expression of pro-inflammatory markers in an in vitro study, which could be applied to treatment of asthma with further studies.
Publisher: Elsevier BV
Date: 2022
DOI: 10.2139/SSRN.4113979
Publisher: Elsevier BV
Date: 07-2021
Publisher: Elsevier BV
Date: 2021
Publisher: Public Library of Science (PLoS)
Date: 09-2017
Publisher: American Thoracic Society
Date: 05-2015
Publisher: Frontiers Media SA
Date: 06-02-2018
Publisher: Begell House
Date: 2019
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.CBI.2018.12.009
Abstract: 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.
Publisher: Wiley
Date: 17-11-2017
DOI: 10.1002/PATH.4979
Abstract: Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c
Publisher: Frontiers Media SA
Date: 04-07-2018
Publisher: eLife Sciences Publications, Ltd
Date: 29-04-2019
Publisher: American Thoracic Society
Date: 06-2011
Publisher: American Society for Clinical Investigation
Date: 22-08-2019
Publisher: Wiley
Date: 09-2021
DOI: 10.1111/RESP.14141
Abstract: Influenza virus (FLU), rhinovirus (RV) and respiratory syncytial virus (RSV) are the most common acute respiratory infections worldwide. Infection can cause severe health outcomes, while therapeutic options are limited, primarily relieving symptoms without attenuating the development of lesions or impaired lung function. We therefore examined the inflammatory response to these infections with the intent to identify common components that are critical drivers of immunopathogenesis and thus represent potential therapeutic targets. BALB/c mice were infected with FLU, RV or RSV, and lung function, airway inflammation and immunohistopathology were measured over a 10‐day period. Anti‐IL‐17A mAb was administered to determine the impact of attenuating this cytokine's function on the development and severity of disease. All three viruses induced severe airway constriction and inflammation at 2 days post‐infection (dpi). However, only FLU induced prolonged inflammation till 10 dpi. Increased IL‐17A expression was correlated with the alterations in lung function and its persistence. Neutralization of IL‐17A did not affect the viral replication but led to the resolution of airway hyperresponsiveness. Furthermore, anti‐IL‐17A treatment resulted in reduced infiltration of neutrophils (in RV‐ and FLU‐infected mice at 2 dpi) and lymphocytes (in RSV‐infected mice at 2 dpi and FLU‐infected mice at 10 dpi), and attenuated the severity of immunopathology. IL‐17A is a common pathogenic molecule regulating disease induced by three prevalent respiratory viruses. Targeting the IL‐17A pathway may provide a unified approach to the treatment of these respiratory infections alleviating both inflammation‐induced lesions and difficulties in breathing.
Publisher: Frontiers Media SA
Date: 25-02-2022
DOI: 10.3389/FIMMU.2022.805558
Abstract: 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.
Publisher: American Society for Clinical Investigation
Date: 06-04-2017
Publisher: Springer Science and Business Media LLC
Date: 20-11-2019
DOI: 10.1186/S12931-019-1225-5
Abstract: Respiratory virus-induced asthma exacerbations occur frequently during pregnancy and are associated with adverse outcomes for mother and child. Primary nasal epithelial cells (pNECs) provide a useful method to study immune responses in pregnancy. pNECs were obtained by nasal brushings from pregnant and non-pregnant women with and without asthma. pNECS were infected in vitro with major group Rhinovirus 43 (RV43) and seasonal influenza (H3N2). Following infection, pNECs showed measurable quantities of interferon (IFN)-λ, IL-1β, IL-8, IP-10 and MIP1-α. pNECs provide a safe and effective method for studying respiratory epithelial cell responses during pregnancy.
Publisher: Frontiers Media SA
Date: 12-04-2018
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Routledge
Date: 20-05-2018
Publisher: Cold Spring Harbor Laboratory
Date: 10-2020
DOI: 10.1101/2020.09.30.317818
Abstract: SARS-CoV-2 infection causes an inflammatory cytokine storm and acute lung injury. Currently there are no effective antiviral and/or anti-inflammatory therapies. Here we demonstrate that 2019 SARS-CoV-2 spike protein subunit 1 (CoV2-S1) induces high levels of NF-κB activations, production of pro-inflammatory cytokines and mild epithelial damage, in human bronchial epithelial cells. CoV2-S1-induced NF-κB activation requires S1 interaction with human ACE2 receptor and early activation of endoplasmic reticulum (ER) stress, and associated unfolded protein response (UPR), and MAP kinase signalling pathways. We developed an antagonistic peptide that inhibits S1-ACE2 interaction and CoV2-S1-induced productions of pro-inflammatory cytokines. The existing FDA-approved ER stress inhibitor, 4-phenylburic acid (4-PBA), and MAP kinase inhibitors, trametinib and ulixertinib, ameliorated CoV2-S1-induced inflammation and epithelial damage. These novel data highlight the potentials of peptide-based antivirals for novel ACE2-utilising CoVs, while repurposing existing drugs may be used as treatments to d en elevated inflammation and lung injury mediated by SARS-CoV-2.
Publisher: Bentham Science Publishers Ltd.
Date: 24-01-2018
DOI: 10.2174/2211738505666170808094635
Abstract: Vesicular systems like nanotechnology and liposomes are gaining tremendous 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. The objective of this paper is to review the recent literature on vesicular drug delivery systems containing curcumin. 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 involving curcumin which have been studied recently, targeting pulmonary diseases. 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 curcumin 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. This mini review, in this direction, tries to highlight the key research interventions employing vesicular systems of drug delivery with curcumin.
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1247
Publisher: Springer Science and Business Media LLC
Date: 22-05-2019
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-11-2021
DOI: 10.1126/SCITRANSLMED.AAV7223
Abstract: Inhibition of cigarette smoke–induced microRNA-21 suppresses chronic obstructive pulmonary disease through effects on a SATB1/S100A9/NF-κB axis.
Publisher: BMJ
Date: 11-09-2021
DOI: 10.1136/THORAXJNL-2020-215979
Abstract: The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype. Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma. Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone ( BiP, CANX, CALR ), ER-associated protein degradation ( EDEM1, DERL1) and ER stress-induced apoptosis ( DDIT3, PPP1R15A ) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs. Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma.
Publisher: Wiley
Date: 19-08-2019
DOI: 10.1111/IMCB.12284
Abstract: 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.
Publisher: Bentham Science Publishers Ltd.
Date: 02-12-2020
DOI: 10.2174/1871530320666200503053846
Abstract: The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its erse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.
Publisher: MDPI AG
Date: 02-02-2019
DOI: 10.3390/MOLECULES24030549
Abstract: Columbianadin (CBN) is one of the main bioactive constituents isolated from the root of Angelica pubescens. Although the anti-inflammatory activity of CBN has been reported, the underpinning mechanism of this remains unclear. In this study, we investigated the anti-inflammatory effect of CBN on lipopolysaccharide (LPS)-stimulated THP-1 cells and explored the possible underlying molecular mechanisms. The results showed that CBN suppressed LPS-mediated inflammatory response mainly through the inactivation of the NOD1 and NF- κ B p65 signaling pathways. Knockdown of NOD1 reduced the degree to which inflammatory cytokines decreased following CBN treatment, whereas forced expression of NOD1 and CBN treatment reduced NF- κ B p65 activation and the secretion of inflammatory cytokines. Furthermore, CBN significantly reduced cellular apoptosis by inhibiting the NOD1 pathway. Collectively, our results indicate that CBN suppressed the LPS-mediated inflammatory response by inhibiting NOD1/NF- κ B activation. Further investigations are required to determine the mechanisms of action of CBN in the inhibition of NOD signaling: However, CBN may be employed as a therapeutic agent for multiple inflammatory diseases.
Publisher: Wiley
Date: 17-01-2021
DOI: 10.1111/RESP.14003
Abstract: COVID‐19 is complicated by acute lung injury, and death in some in iduals. 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. 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. 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. 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.
Publisher: American Physiological Society
Date: 12-2020
DOI: 10.1152/AJPLUNG.00374.2020
Abstract: 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 erse 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.
Publisher: Wiley
Date: 20-12-2014
DOI: 10.1111/CEA.12218
Abstract: 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). 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. 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. Asthmatic pBECs had significantly reduced release of IL-6, CXCL-8 and IFN-λ 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-λ to infection. In contrast, in asthmatic pBECs where responses were already reduced, there was no further reduction in IL-6 and IFN-λ, although there was in CXCL-10. 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.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Research Square Platform LLC
Date: 09-2020
DOI: 10.21203/RS.3.RS-57848/V2
Abstract: The authors have withdrawn this preprint due to erroneous posting.
Publisher: Future Science Ltd
Date: 04-2018
Abstract: 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.
Publisher: Research Square Platform LLC
Date: 27-08-2020
DOI: 10.21203/RS.3.RS-57848/V1
Abstract: Toll-like receptor (TLR)7 is known for eliciting immunity against single-stranded RNA viruses. TLR7 was increased in both human and cigarette smoke (CS)-induced experimental chronic obstructive pulmonary disease (COPD). Severity of CS-induced emphysema and COPD was reduced in TLR7-deficient mice whilst inhalation of imiquimod (TLR7-agonist) induced emphysema in naïve mice. Imiquimod-induced emphysema was reduced in mice treated with mast cell stabilizer cromolyn or deficient in mast cell protease-6. Therapeutic treatment with anti-TLR7 monoclonal antibody suppressed CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells. We demonstrate an unexpected role for TLR7 in mediating emphysema and COPD through mast cell activity.
Publisher: Springer Science and Business Media LLC
Date: 24-03-2021
DOI: 10.1186/S13287-021-02244-6
Abstract: 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. 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. 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-κB and PI3K/AKT signaling was dependent on TRAF1. MSC-Exo can ameliorate SSRA by moderating inflammation, which is achieved by reshaping macrophage polarization via inhibition of TRAF1.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1038/S41385-019-0163-3
Abstract: 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-1β levels, bacterial load and PAFR protein expression in mouse lungs. Antagonism of PAFR decreased lung neutrophilia, TNF, and IL-1β 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.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.CBI.2020.108947
Abstract: Inflammatory responses play a remarkable role in the mechanisms of acute and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis and lung cancer. Currently, there is a resurgence in the use of drugs from natural sources for various ailments as potent therapeutics. Berberine, an alkaloid prominent in the Chinese traditional system of medicine has been reported to exert therapeutic properties in various diseases. Nevertheless, the number of studies focusing on the curative potential of berberine in inflammatory diseases involving the respiratory system is limited. In this review, we have attempted to discuss the reported anti-inflammatory properties of berberine that function through several pathways such as, the NF-κB, ERK1/2 and p38 MAPK pathways which affect several pro-inflammatory cytokines in the pathophysiological processes involved in chronic respiratory diseases. This review would serve to provide valuable information to researchers who work in this field and a new direction in the field of drug discovery with respect to respiratory diseases.
Publisher: Elsevier BV
Date: 03-2018
Publisher: American Thoracic Society
Date: 07-2016
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.COLSURFB.2018.08.027
Abstract: 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-1β (IL-1β) 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-1β 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.
Publisher: MDPI AG
Date: 08-04-2020
DOI: 10.3390/IJMS21072577
Abstract: Gastric ulcer (GU), a prevalent digestive disease, has a high incidence and is seriously harmful to human health. Finding a natural drug with a gastroprotective effect is needed. Ocotillol, the derivate of ocotillol-type saponins in the Panax genus, possesses good anti-inflammatory activity. The study aimed to investigate the gastroprotective effect of ocotillol on acetic acid-induced GU rats. The serum levels of endothelin-1 (ET-1) and nitric oxide (NO), the gastric mucosa levels of epidermal growth factor, superoxide dismutase and NO were assessed. Hematoxylin and eosin staining of gastric mucosa for pathological changes and immunohistochemical staining of ET-1, epidermal growth factor receptors and inducible nitric oxide synthase were evaluated. A UPLC-QTOF-MS-based serum metabolomics approach was applied to explore the latent mechanism. A total of 21 potential metabolites involved in 7 metabolic pathways were identified. The study helps us to understand the pathogenesis of GU and to provide a potential natural anti-ulcer agent.
Publisher: Public Library of Science (PLoS)
Date: 02-03-2012
Publisher: CRC Press
Date: 23-06-2014
DOI: 10.1201/B16778-5
Publisher: Frontiers Media SA
Date: 30-11-2018
Publisher: MDPI AG
Date: 28-08-2019
DOI: 10.3390/IJMS20174216
Abstract: The heterogeneity of asthma involves complex pathogenesis leading to confusion regarding the choice of therapeutic strategy. In the clinic, asthma is commonly classified as having either eosinophilic asthma (EA) or non-eosinophilic asthma (NEA) phenotypes. Microbiota colonizing in airways has been demonstrated to induce distinct phenotypes of asthma and the resistance to steroids. Rhodiola wallichiana var. cholaensis (RWC) has the potential to alleviate asthmatic inflammation according to recent studies, but its pharmacological mechanisms remain unclarified. In our study, murine asthmatic phenotypes were established and treated with RWC and/or dexamethasone (DEX). Combined treatment with RWC and DEX could improve spirometry and airway hyperresponsiveness (AHR) in asthmatic phenotypes, alleviate steroid resistance in NEA, and reduce the inflammatory infiltration of the both phenotypes. The combined treatment increased Th1, regulated the imbalance of Th2/Th1, and decreased the related cytokines in EA. As for NEA, the combined treatment reduced Th17 and promoted the accumulation of regulatory T cells (Tregs) in lung. A microbiome study based on 16S rDNA sequencing technique revealed the significantly changed structure of the lower airway microbiota after combined treatment in NEA, with 4 distinct genera and 2 species identified. OPLS-DA models of metabolomics analysis based on UPLC-Q/TOF-MS technique identified 34 differentiated metabolites and 8 perturbed metabolic pathways. A joint multiomics study predicted that the colonized microbiota in airways might be associated with susceptibility of asthma and steroid resistance, which involved systematic and pulmonary metabolic perturbation. In summary, the pharmacological network of RWC included the complicated interaction mechanisms of immune regulation, microbiota change, and metabolic perturbation.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.BIOPHA.2018.11.051
Abstract: 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 ex le 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.
Publisher: The Korean Academy of Asthma, Allergy and Clinical Immunology and The Korean Academy of Pediatric Al
Date: 2022
Publisher: eLife Sciences Publications, Ltd
Date: 17-01-2017
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1038/MI.2015.111
Abstract: 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.
Publisher: MDPI AG
Date: 14-12-2015
DOI: 10.3390/V7122961
Publisher: eLife Sciences Publications, Ltd
Date: 14-02-2017
DOI: 10.7554/ELIFE.20444
Abstract: Influenza virus infections have a significant impact on global human health. In iduals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.
Publisher: American Thoracic Society
Date: 21-08-2023
Start Date: 2020
End Date: 2024
Funder: National Natural Science Foundation of China
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: Hunter Medical Research Institute
View Funded ActivityStart Date: 2013
End Date: 2014
Funder: University of Newcastle Australia
View Funded ActivityStart Date: 2013
End Date: 2014
Funder: University of Newcastle Australia
View Funded Activity