ORCID Profile
0000-0002-0489-2638
Current Organisations
Ehime University
,
University of Technology Sydney
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Publisher: Elsevier BV
Date: 03-2020
Publisher: Elsevier BV
Date: 11-2022
Publisher: MDPI AG
Date: 25-11-2014
Publisher: MDPI AG
Date: 17-11-2022
DOI: 10.3390/NU14224861
Abstract: Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic disease of the gastrointestinal (GI) tract its burden has significantly increased in recent decades, with 6.8 million cases of IBD reported in 2017 according to the Global Burden of Disease study [...]
Publisher: American Chemical Society (ACS)
Date: 03-10-2019
DOI: 10.1021/ACS.JMEDCHEM.9B01283
Abstract: Lysyl oxidase-like 2 (LOXL2) is a secreted enzyme that catalyzes the formation of cross-links in extracellular matrix proteins, namely, collagen and elastin, and is indicated in fibrotic diseases. Herein, we report the identification and subsequent optimization of a series of indole-based fluoroallylamine inhibitors of LOXL2. The result of this medicinal chemistry c aign is
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: Elsevier BV
Date: 05-2023
Publisher: Science Alert
Date: 15-10-2017
Publisher: American Physiological Society
Date: 12-10-2018
Publisher: American Physiological Society
Date: 04-2021
Abstract: HIF-1 plays an important role in epithelial restitution, selectively inducing integrins α6 and α2 to promote migration and proliferation, respectively. HIF-stabilizing prolyl-hydroxylase inhibitors accelerate intestinal mucosal healing by inducing epithelial integrin expression.
Publisher: Springer Science and Business Media LLC
Date: 14-03-2020
DOI: 10.1186/S12885-020-6686-X
Abstract: Colorectal cancer (CRC) is the most common cancer and a leading cause of death worldwide. Extracellular matrix (ECM) proteins regulate tumor growth and development in CRC. Elastin (ELN) is a component of ECM proteins involved in the tumor microenvironment. However, the role of ELN in CRC remains unclear. In this study, we analyzed ELN gene expression in tumors from CRC patients and adjacent non-tumor colon tissues and healthy controls from two existing microarray datasets. ELN protein was measured in human normal colon cells and colon cancer epithelial cells and tumor development was assessed in colon epithelial cells cultured in medium with or without ELN peptide on plates coated with ELN recombinant protein. Control plates were coated with PBS only. We found ELN gene expression was increased in tumors from CRC patients compared to adjacent non-tumor tissues and healthy controls. ELN protein was increased in cancer cells compared to normal colon epithelial cells. Transforming growth factor beta (TGF-β) was a key cytokine to induce production of ECM proteins, but it did not induce ELN expression in colon cancer cells. Matrix metalloproteinase 9 ( MMP9 ) gene expression was increased, but that of MMP12 (elastase) did not change between CRC patients and control. Tissue inhibitor of metalloproteinases 3 ( TIMP3 ) gene expression was decreased in colon tissues from CRC patients compared to healthy controls. However, MMP9, MMP12 and TIMP3 proteins were increased in colon cancer cells. ELN recombinant protein increased proliferation and wound healing in colon cancer epithelial cells. This had further increased in cancer cells incubated in plates coated with recombinant ELN coated plate and in culture media containing ELN peptide. A potential mechanism was that ELN induced epithelial mesenchymal transition with increased alpha-smooth muscle actin and vimentin proteins but decreased E-cadherin protein. Tumor necrosis factor alpha ( TNF ) mRNA was also increased in CRC patients compared to controls. ELN recombinant protein induced further increases in TNF protein in mouse bone marrow derived macrophages after lipopolysaccharide stimulation. These data suggest ELN regulates tumor development and the microenvironment in CRC.
Publisher: Wiley
Date: 21-06-2017
DOI: 10.1111/ALL.13212
Abstract: Asthma is an allergic airway disease (AAD) caused by aberrant immune responses to allergens. Protein phosphatase-2A (PP2A) is an abundant serine/threonine phosphatase with anti-inflammatory activity. The ubiquitin proteasome system (UPS) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed whether enhancing PP2A activity with fingolimod (FTY720) or 2-amino-4-(4-(heptyloxy) phenyl)-2-methylbutan-1-ol (AAL Acute AAD was induced in C57BL/6 mice by intraperitoneal sensitization with ovalbumin (OVA) in combination with intranasal (i.n) exposure to OVA. Chronic AAD was induced in mice with prolonged i.n exposure to crude house dust mite (HDM) extract. Mice were treated with vehicle, FTY720, AAL AAL These findings highlight the potential of combination therapies that enhance PP2A and inhibit proteasome activity as novel therapeutic strategies for asthma.
Publisher: American Society for Clinical Investigation
Date: 22-08-2019
Publisher: Science Alert
Date: 15-12-2016
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1186/S12931-020-01445-6
Abstract: Severe acute respiratory syndrome (SARS)-CoV-2-induced coronavirus disease-2019 (COVID-19) is a pandemic disease that affects 2.8 million people worldwide, with numbers increasing dramatically daily. However, there is no specific treatment for COVID-19 and much remains unknown about this disease. Angiotensin-converting enzyme (ACE)2 is a cellular receptor of SARS-CoV-2. It is cleaved by type II transmembrane serine protease (TMPRSS)2 and disintegrin and metallopeptidase domain (ADAM)17 to assist viral entry into host cells. Clinically, SARS-CoV-2 infection may result in acute lung injury and lung fibrosis, but the underlying mechanisms of COVID-19 induced lung fibrosis are not fully understood. The networks of ACE2 and its interacting molecules were identified using bioinformatic methods. Their gene and protein expressions were measured in human epithelial cells after 24 h SARS-CoV-2 infection, or in existing datasets of lung fibrosis patients. We confirmed the binding of SARS-CoV-2 and ACE2 by bioinformatic analysis. TMPRSS2, ADAM17, tissue inhibitor of metalloproteinase (TIMP)3, angiotensinogen (AGT), transformation growth factor beta (TGFB1), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF) A and fibronectin (FN) were interacted with ACE2, and the mRNA and protein of these molecules were expressed in lung epithelial cells. SARS-CoV-2 infection increased ACE2 , TGFB1 , CTGF and FN1 mRNA that were drivers of lung fibrosis. These changes were also found in lung tissues from lung fibrosis patients. Therefore, SARS-CoV-2 binds with ACE2 and activates fibrosis-related genes and processes to induce lung fibrosis.
Publisher: IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund
Date: 2022
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.CBI.2022.110048
Abstract: Mucus gel constitutes of heavily cross-linked mucin fibers forming a viscoelastic, dense porous network that coats all the exposed epithelia not covered with the skin. The layer provides protection to the underlying gastrointestinal, respiratory, and female reproductive tracts, in addition to the organs such as the surface of eye by trapping the pathogens, irritants, environmental fine particles, and potentially hazardous foreign matter. However, this property of mucus gel poses a substantial challenge for realizing the localized and sustained drug delivery across the mucosal surfaces. The mucus permeating particles that spare the protective properties of mucus gel improve the therapeutic potency of the drugs aimed at the management of diseases, including sexually transmitted infections, lung cancer, irritable bowel disease, degenerative eye diseases and infections, and cystic fibrosis. As such, the mucoadhesive materials conjugated with drug molecules display a prolonged retention time in the mucosal gel that imparts a sustained release of the deliberated drug molecules across the mucosa. The contemporarily developed mucus penetrating materials for drug delivery applications comprise of a finer size, appreciable hydrophilicity, and a neutral surface to escape the entrapment within the cross-inked mucus fibers. Pertaining to the mucus secretion as a first line of defence in respiratory tract in response to the invading physical, chemical, and biological pathogens, the development of mucus penetrating materials hold promise as a stalwart approach for revolutionizing the respiratory drug delivery paradigm. The present review provides an epigrammatic collation of the mucus penetrating/mucoadhesive materials for achieving a controlled/sustained release of the cargo pharmaceutics and drug molecules across the respiratory mucus barrier.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 11-2020
Publisher: Research Square Platform LLC
Date: 15-02-2021
DOI: 10.21203/RS.3.RS-189214/V1
Abstract: Background: High water demand accompanied with an unreliable piped water supply has forced urban residents to store water in containers. This situation potentially increases the number of breeding sites for mosquito vectors, such as Aedes. Method: This study aimed to test the hypothesis if piped water connection availability, tap water use, and highly stable tap water supply can help minimize the use of water storage containers as well as the presence of larvae and number of adult Aedes mosquitoes. We conducted a community-based entomological survey of 343 households from 36 neighborhoods or Rukun Tetangga in Makassar City, Indonesia. Our model based on the hypothesis was tested by piecewise structural equation modeling analysis. Results: A significant negative correlation was found between the stability of tap water supply and the number of water storage containers (−0.16, P 0.05). Of the two categories of water storage containers, the unintentional water storage containers demonstrated a significantly ( P 0.001) higher effect on larval prevalence than the intentional one. Further, both container categories have significant indirect effects on the number of adult mosquitoes mediated by larval presence. Conclusion: Improving water supply condition, particularly by assuring a stable tap water supply, could minimize the use of intentional water storage containers. Furthermore, a regular community-wide health education program that targets the elimination of unintentional water storage containers, which can be breeding grounds for Aedes larvae mosquitoes, is necessary.
Publisher: Oxford University Press (OUP)
Date: 17-08-2020
DOI: 10.1002/JLB.3MR0720-472RR
Abstract: The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, is one of the most well-characterized inflammasomes, activated by pathogen-associated molecular patterns and damage-associated molecular patterns, including from commensal or pathogenic bacterial and viral infections. The NLRP3 inflammasome promotes inflammatory cell recruitment and regulates immune responses in tissues such as the gastrointestinal tract and the lung, and is involved in many diseases that affect the gut and lung. Recently, the microbiome in the gut and the lung, and the crosstalk between these organs (gut–lung axis), has been identified as a potential mechanism that may influence disease in a bidirectional manner. In this review, we focus on themes presented in this area at the 2019 World Congress on Inflammation. We discuss recent evidence on how the microbiome can affect NLRP3 inflammasome responses in the gut and lung, the role of this inflammasome in regulating gut and lung inflammation in disease, and its potential role in the gut–lung axis. We highlight the exponential increase in our understanding of the NLRP3 inflammasome due to the synthesis of the NLRP3 inflammasome inhibitor, MCC950, and propose future studies that may further elucidate the roles of the NLRP3 inflammasome in gut and lung diseases.
Publisher: American Thoracic Society
Date: 10-2023
Publisher: Wiley
Date: 12-10-2017
DOI: 10.1111/RESP.12908
Abstract: COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD.
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: Wiley
Date: 2019
DOI: 10.1002/CTI2.1084
Abstract: Chronic obstructive pulmonary disease (COPD) is a progressive disease that causes significant mortality and morbidity worldwide and is primarily caused by the inhalation of cigarette smoke (CS). Lack of effective treatments for COPD means there is an urgent need to identify new therapeutic strategies for the underlying mechanisms of pathogenesis. Tristetraprolin (TTP) encoded by the Zfp36 gene is an anti‐inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD. Here, we identify a novel protective role for TTP in CS‐induced experimental COPD using Zfp36 aa/aa mice, a genetically modified mouse strain in which endogenous TTP cannot be phosphorylated, rendering it constitutively active as an mRNA‐destabilising factor. TTP wild‐type ( Zfp36 +/+ ) and Zfp36 aa/aa active C57BL/6J mice were exposed to CS for four days or eight weeks, and the impact on acute inflammatory responses or chronic features of COPD, respectively, was assessed. After four days of CS exposure, Zfp36 aa/aa mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild‐type controls. After eight weeks, Zfp36 aa/aa mice had reduced pulmonary inflammation, airway remodelling and emphysema‐like alveolar enlargement, and lung function was improved. We then used pharmacological treatments in vivo (protein phosphatase 2A activator, AAL (S) , and the proteasome inhibitor, bortezomib) to promote the activation and stabilisation of TTP and show that hallmark features of CS‐induced experimental COPD were ameliorated. Collectively, our study provides the first evidence for the therapeutic potential of inducing TTP as a treatment for COPD.
Publisher: Future Science Ltd
Date: 11-2020
Abstract: Aim: In the present study boswellic acids-loaded chitosan nanoparticles were synthesized using ionic gelation technique. The influence of independent variables were studied and optimized on dependent variables using central composite design. Methodology & results: The designed nanoparticles were observed spherical in shape with an average size of 67.5–187.2 nm and have also shown an excellent entrapment efficiency (80.06 ± 0.48). The cytotoxicity assay revealed enhanced cytotoxicity for drug-loaded nanoparticles in contrast to the free drug having an IC 50 value of 17.29 and 29.59 μM, respectively. Flow cytometry confirmed that treatment of cells with 40 μg/ml had arrested 22.75 ± 0.3% at SubG 0 phase of the cell cycle when compared with untreated A459 cells. The observed results justified the boswellic acids-loaded chitosan nanoparticles were effective due to greater cellular uptake, sustained intercellular drug retention and enhanced antiproliferative effect by inducing apoptosis.
Publisher: American Thoracic Society
Date: 15-09-2021
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.SCITOTENV.2015.05.137
Abstract: People living in slums can be considered left behind with regard to national successes in achieving Millennium Development Goals (MDGs). The objective of this study was to evaluate the living and working conditions of waste pickers and their children in a landfill slum located in the largest city in eastern Indonesia. A total of 113 people from the landfill slum and 1184 people from the general population participated in face-to-face interviews. Municipal solid waste (MSW) was analyzed for metals, metalloids and fecal indicator bacteria. Ambient air quality including particulate matter was measured in the landfill. Households in the landfill slum were 5.73 (p=0.04) times more likely to be below the international poverty line (MDG 1: Poverty) and 15.6 times (p<0.01) more likely to have no one in the household possessing a primary education (MDG 2: Universal Education), and 107 times (p<0.01) more likely not to have improved sanitation facilities (MDG 7: Environmental Sustainability) when compared to the general population. Diarrhea is one of the leading causes of death in children under five in Indonesia. Young children living in the landfill slum were 2.87 times (p=0.02) more likely to develop diarrhea than their general population counterparts. Other survey results and environmental measurements suggest that landfill slum children have additional adverse health effects (e.g. infections and poisoning). Poverty underlies several MDG issues that directly or indirectly affect child health. Therefore, eradicating extreme poverty will continue to be the most critical challenge for the MDGs beyond 2015.
Publisher: MDPI AG
Date: 15-03-2021
DOI: 10.3390/NU13030944
Abstract: It is unknown whether a healthy diet or unhealthy diet combined with specific supplements may jointly contribute to incidence of obesity and cardiovascular disease (CVD). We included 69,990 participants from the 45 and Up Study who completed both baseline (2006–2009) and follow-up (2012–2015) surveys. We found that compared to participants with a long-term healthy diet and no supplement consumption, those with a long-term healthy diet combined with multivitamins and minerals (MVM) or fish oil consumption were associated with a lower incidence of CVD (p 0.001) whilst those with an unhealthy diet and no MVM or fish oil consumption were associated with a higher risk of obesity (p 0.05). Compared to participants with a long-term healthy diet and no calcium consumption, the combination of a long-term healthy diet and calcium consumption was linked to a lower risk of CVD (IRR = 0.87, 95% CI: 0.78 0.96). In conclusion, a long-term healthy diet combined with MVM or fish oil was associated with a lower incidence of CVD. Participants who maintained a healthy diet and used calcium supplements were associated with a lower incidence of obesity. However, these associations were not found among those with an unhealthy diet, despite taking similar supplements.
Publisher: BMJ
Date: 07-11-2022
DOI: 10.1136/THORAX-2021-218555
Abstract: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma. We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo. MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity. Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma.
Publisher: European Respiratory Society (ERS)
Date: 07-2022
DOI: 10.1183/13993003.01431-2021
Abstract: COPD is the third leading cause of death worldwide. Cigarette smoke (CS)-induced chronic inflammation inducing airway remodelling, emphysema and impaired lung function is the primary cause. Effective therapies are urgently needed. Human chymase (hCMA)1 and its orthologue mCMA1/mouse mast cell protease (mMCP)5 are exocytosed from activated mast cells and have adverse roles in numerous disorders, but their role in COPD is unknown. We evaluated hCMA1 levels in lung tissues of COPD patients. We used mmcp5 -deficient ( −/− ) mice to evaluate this protease's role and potential for therapeutic targeting in CS-induced experimental COPD. In addition, we used ex vivo/in vitro studies to define mechanisms. The levels of hCMA1 mRNA and CMA1 + mast cells were increased in lung tissues from severe compared to early/mild COPD patients, non-COPD smokers and healthy controls. Degranulated mast cell numbers and mMCP5 protein were increased in lung tissues of wild-type mice with experimental COPD. mmcp5 −/− mice were protected against CS-induced inflammation and macrophage accumulation, airway remodelling, emphysema and impaired lung function in experimental COPD. CS extract challenge of co-cultures of mast cells from wild-type, but not mmcp5 −/− mice with wild-type lung macrophages increased in tumour necrosis factor (TNF)-α release. It also caused the release of CMA1 from human mast cells, and recombinant hCMA-1 induced TNF-α release from human macrophages. Treatment with CMA1 inhibitor potently suppressed these hallmark features of experimental COPD. CMA1/mMCP5 promotes the pathogenesis of COPD, in part, by inducing TNF-α expression and release from lung macrophages. Inhibiting hCMA1 may be a novel treatment for COPD.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Wiley
Date: 15-04-2020
Publisher: Wiley
Date: 28-06-2017
DOI: 10.1111/IMR.12543
Abstract: Severe, steroid-resistant asthma is clinically and economically important since affected in iduals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been h ered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma.
Publisher: Elsevier BV
Date: 09-2022
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: 05-2016
DOI: 10.1038/MI.2015.104
Abstract: Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM10-induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma.
Publisher: Future Science Ltd
Date: 05-2020
Publisher: Elsevier BV
Date: 03-2022
Publisher: Frontiers Media SA
Date: 13-12-2021
Abstract: Colorectal cancer (CRC) is the third most common diagnosed cancer worldwide, but there are no effective cures for it. Hyaluronan and proteoglycan link protein-1 (HAPLN1) is a component of the extracellular matrix (ECM) proteins and involved in the tumor environment in the colon. Transforming growth factor (TGF)-β is a key cytokine that regulates the deposition of ECM proteins in CRC. However, the role of HAPLN1 in TGF-β contributions to CRC remains unknown. We found that the mRNA expression of HAPLN1 was decreased in tumors from CRC patients compared with healthy controls and normal tissue adjacent to the tumor using two existing microarray datasets. This was validated at the protein level by tissue array from CRC patients ( n = 59). HAPLN1 protein levels were also reduced in human CRC epithelial cells after 24 h of TGF-β stimulation, and its protein expression correlated with type I collagen alpha-1 (COL1A1) in CRC. Transfection of HAPLN1 overexpression plasmids into these cells increased protein levels but reduced COL1A1 protein, tumor growth, and cancer cell migration. TGF-β stimulation increased Smad2/3, p-Smad2/3, Smad4, and E-adhesion proteins however, HAPLN1 overexpression restored these proteins to baseline levels in CRC epithelial cells after TGF-β stimulation. These findings suggest that HAPLN1 regulates the TGF-β signaling pathway to control collagen deposition via the TGF-β signaling pathway and mediates E-adhesion to control tumor growth. Thus, treatments that increase HAPLN1 levels may be a novel therapeutic option for CRC.
Publisher: Wiley
Date: 30-03-2020
DOI: 10.1002/PATH.5401
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.AJPATH.2018.03.016
Abstract: Inflammatory bowel disease (IBD) is associated with several immune-mediated extraintestinal manifestations. More than half of all IBD patients have some form of respiratory pathology, most commonly neutrophil-mediated diseases, such as bronchiectasis and chronic bronchitis. Using murine models of colitis, we aimed to identify the immune mechanisms driving pulmonary manifestations of IBD. We found increased neutrophil numbers in lung tissue associated with the pulmonary vasculature in both trinitrobenzenesulfonic acid- and dextran sulfate sodium-induced models of colitis. Analysis of systemic inflammation identified that neutrophilia was associated with bacteremia and pyrexia in animal models of colitis. We further identified IL-6 as a systemic mediator of neutrophil recruitment from the bone marrow of dextran sulfate sodium animals. Functional inhibition of IL-6 led to reduced systemic and pulmonary neutrophilia, but it did not attenuate established colitis pathology. These data suggest that systemic bacteremia and pyrexia drive IL-6 secretion, which is a critical driver for pulmonary manifestation of IBD. Targeting IL-6 may reduce neutrophil-associated extraintestinal manifestations in IBD patients.
Publisher: American Society for Clinical Investigation
Date: 16-06-2016
Publisher: Springer Science and Business Media LLC
Date: 07-07-2022
DOI: 10.1007/S11356-022-21454-W
Abstract: Asthma is a chronic inflammatory disease primarily characterized by inflammation and reversible bronchoconstriction. It is currently one of the leading causes of morbidity and mortality in the world. Oxidative stress further complicates the pathology of the disease. The current treatment strategies for asthma mainly involve the use of anti-inflammatory agents and bronchodilators. However, long-term usage of such medications is associated with severe adverse effects and complications. Hence, there is an urgent need to develop newer, novel, and safe treatment modalities for the management of asthma. This has therefore prompted further investigations and detailed research to identify and develop novel therapeutic interventions from potent untapped resources. This review focuses on the significance of oxidative stressors that are primarily derived from both mitochondrial and non-mitochondrial sources in initiating the clinical features of asthma. The review also discusses the biological scavenging system of the body and factors that may lead to its malfunction which could result in altered states. Furthermore, the review provides a detailed insight into the therapeutic role of nutraceuticals as an effective strategy to attenuate the deleterious effects of oxidative stress and may be used in the mitigation of the cardinal features of bronchial asthma.
Publisher: MDPI AG
Date: 20-10-2022
DOI: 10.3390/NU14204409
Abstract: COVID-19 induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a pandemic and it has led to more than 620 million patients with 6.56 million deaths globally. Males are more susceptible to COVID-19 infection and associated with a higher chance to develop severe COVID-19 than females. Aged people are at a high risk of COVID-19 infection, while young children have also increased cases. COVID-19 patients typically develop respiratory system pathologies, however symptoms in the gastrointestinal (GI) tract are also very common. Inflammatory cell recruitments and their secreted cytokines are found in the GI tract in COVID-19 patients. Microbiota changes are the key feature in COVID-19 patients with gut injury. Here, we review all current known mechanisms of COVID-19-induced gut injury, and the most acceptable one is that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptor on host cells in the GI tract. Interestingly, inflammatory bowel disease (IBD) is an inflammatory disorder, but the patients with IBD do not have the increased risk to develop COVID-19. There is currently no cure for COVID-19, but anti-viruses and monoclonal antibodies reduce viral load and shorten the recovery time of the disease. We summarize current therapeutics that target symptoms in the GI tract, including probiotics, ACE2 inhibitors and nutrients. These are promising therapeutic options for COVID-19-induced gut injury.
Publisher: Future Science Ltd
Date: 02-2022
Abstract: Chronic respiratory disorders affect millions of people worldwide. Pathophysiological changes to the normal airway wall structure, including changes in the composition and organization of its cellular and molecular constituents, are referred to as airway remodeling. The inadequacy of effective treatment strategies and scarcity of novel therapies available for the treatment and management of chronic respiratory diseases have given rise to a serious impediment in the clinical management of such diseases. The progress made in advanced drug delivery, has offered additional advantages to fight against the emerging complications of airway remodeling. This review aims to address the gaps in current knowledge about airway remodeling, the relationships between remodeling, inflammation, clinical phenotypes and the significance of using novel drug delivery methods.
Publisher: Elsevier BV
Date: 08-2022
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: Wiley
Date: 12-10-2016
DOI: 10.1111/BPH.13573
Publisher: European Respiratory Society (ERS)
Date: 17-03-2020
DOI: 10.1183/13993003.01340-2019
Abstract: Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma. We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild–moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV 1 ). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV 1 /forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules alent metal transporter 1 ( DMT1 ) and transferrin receptor 1 ( TFR1 ) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1 + macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo , including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses. Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
Publisher: American Thoracic Society
Date: 03-2018
No related grants have been discovered for Gang Liu.