ORCID Profile
0000-0003-0567-8382
Current Organisation
Queensland University of Technology
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Atmospheric Aerosols | Infectious Agents | Atmospheric Sciences | Engineering Systems Design | Tissue engineering | Biofabrication | Biomedical engineering | Microfluidics and nanofluidics | Public Health and Health Services | Environmental Chemistry (incl. Atmospheric Chemistry) | Environmental Engineering Design | Environmental and Occupational Health and Safety |
ANZSRC Socio-Economic Objective (SEO)
Disease Distribution and Transmission (incl. Surveillance and Response) | Urban and Industrial Air Quality | Climate and Climate Change not elsewhere classified | Commercial Building Management and Services | Environmental Health | Environmentally Sustainable Transport not elsewhere classified | Health Protection and/or Disaster Response
Related Links
Publications
In situ detection of Australian gill-associated virus with a yellow head virus gene probe
Publisher: Elsevier BV
Date: 02-2002
Human Metapneumovirus Impairs Apoptosis of Nasal Epithelial Cells in Asthma via HSP70
Publisher: S. Karger AG
Date: 11-10-2017
DOI: 10.1159/000449101
Abstract: Asthmatics are highly susceptible to respiratory viral infections, possibly due to impaired innate immunity. However, the exact mechanisms of susceptibility are likely to differ amongst viruses. Therefore, we infected primary nasal epithelial cells (NECs) from adults with mild-to-moderate asthma, with respiratory syncytial virus (RSV) or human metapneumovirus (hMPV) in vitro and investigated the antiviral response. NECs from these asthmatics supported elevated hMPV but not RSV infection, compared to non-asthmatic controls. This correlated with reduced apoptosis and reduced activation of caspase-9 and caspase-3/7 in response to hMPV, but not RSV. The expression of heat shock protein 70 (HSP70), a known inhibitor of caspase activation and subsequent apoptosis, was lified in response to hMPV infection. Chemical inhibition of HSP70 function restored caspase activation and reduced hMPV infection in NECs from asthmatic subjects. There was no impairment in the production of IFN by NECs from asthmatics in response to either hMPV or RSV, demonstrating that increased infection of asthmatic airway cells by hMPV is IFN-independent. This study demonstrates, for the first time, a mechanism for elevated hMPV infection in airway epithelial cells from adult asthmatics and identifies HSP70 as a potential target for antiviral and asthma therapies.
Correction to: 2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales
Publisher: Springer Science and Business Media LLC
Date: 17-11-2021
A synergistic combination of Phyllanthus emblica and Alpinia galanga against H 2 O 2 -induced oxidative stress and lipid peroxidation in human ECV304 cells
Publisher: Elsevier BV
Date: 04-2018
Specific Interaction between eEF1A and HIV RT Is Critical for HIV-1 Reverse Transcription and a Potential Anti-HIV Target.
Publisher: Public Library of Science (PLoS)
Date: 12-2015
Anticancer activity of arborinine from Glycosmis parva leaf extract in human cervical cancer cells
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.BBRC.2018.04.175
Abstract: Glycosmis parva is a small shrub found in Thailand. Ethyl acetate (EtOAc) extract from its leaves has been shown to exert anticancer effects in vitro however, the compound responsible for this activity has not been isolated and characterized. In this study, we demonstrate that arborinine, a major acridone alkaloid in the EtOAc fraction, decreased proliferation and was strongly cytotoxic to HeLa cervical cancer cells without significantly affecting normal cells. The compound also inhibited tumor spheroid growth much more potently than chemotherapeutic drugs bleomycin, gemcitabine, and cisplatin. In addition, unlike cisplatin, arborinine activated caspase-dependent apoptosis without inducing DNA damage response. We further show that arborinine strongly suppressed cancer cell migration by downregulating expression of key regulators of epithelial-mesenchymal transition. Taken together, our data provide important insights into the molecular mechanism of arborinine's anticancer activity, supporting its potential use for treating cervical cancer.
Ethanolic Fenugreek Extract: Its Molecular Mechanisms against Skin Aging and the Enhanced Functions by Nanoencapsulation
Publisher: MDPI AG
Date: 20-02-2022
DOI: 10.3390/PH15020254
Abstract: Fenugreek, or Trigonella foenum-graecum L. (family Leguminosae) seeds, are typically used as food supplements to increase postnatal lactation. Fenugreek extract displays antioxidative and anti-inflammatory properties, but its mechanisms against skin aging have not been exploited. In this research, we are the first to define an in vitro collagenase inhibitory activity of fenugreek extract (IC50 = 0.57 ± 0.02 mg/mL), which is 2.6 times more potent than vitamin C (IC50 = 1.46 mg/mL). Nanoencapsulation has been applied to improve the extract stability, and subsequently enhanced its bioactivities. Liponiosome encapsulating fenugreek extract (LNF) was prepared using a high-speed homogenizer, resulting in homogeneous spherical nanoparticles with sizes in the range of 174.7 ± 49.2 nm, 0.26 ± 0.04 in PdI, and 46.6 ± 7.4% of entrapment efficiency. LNF formulation significantly facilitated a sustained release and significantly enhanced skin penetration over the extracts, suggesting a potential use of LNF for transdermal delivery. The formulated LNF was highly stable, not toxic to human fibroblast, and was able to enhance cell viability, collagen production, and inhibit MMP1, MMP9, IL-6, and IL-8 secretions compared to the extract in the co-cultured skin model. Therefore, ethanolic fenugreek extract and its developed LNF display molecular mechanisms against skin aging and could potentially be used as an innovative ingredient for the prevention of skin aging.
Alpha and Lambda Interferon Together Mediate Suppression of CD4 T Cells Induced by Respiratory Syncytial Virus
Publisher: American Society for Microbiology
Date: 15-05-2006
DOI: 10.1128/JVI.80.10.5032-5040.2006
Abstract: The mechanism by which respiratory syncytial virus (RSV) suppresses T-cell proliferation to itself and other antigens is poorly understood. We used monocyte-derived dendritic cells (MDDC) and CD4 T cells and measured [ 3 H]thymidine incorporation to determine the factors responsible for RSV-induced T-cell suppression. These two cell types were sufficient for RSV-induced suppression of T-cell proliferation in response to cytomegalovirus or Staphylococcus enterotoxin B. Suppressive activity was transferable with supernatants from RSV-infected MDDC and was not due to transfer of live virus or RSV F (fusion) protein. Supernatants from RSV-infected MDDC, but not MDDC exposed to UV-killed RSV or mock conditions, contained alpha interferon (IFN-α median, 43 pg/ml) and IFN-λ (approximately 1 to 20 ng/ml). Neutralization of IFN-α with monoclonal antibody (MAb) against one of its receptor chains, IFNAR2, or of IFN-λ with MAb against either of its receptor chains, IFN-λR1 (interleukin 28R [IL-28R]) or IL-10R2, had a modest effect. In contrast, blocking the two receptors together markedly reduced or completely blocked the RSV-induced suppression of CD4 T-cell proliferation. Defining the mechanism of RSV-induced suppression may guide vaccine design and provide insight into previously uncharacterized human T-cell responses and activities of interferons.
Susceptibility of an Airborne Common Cold Virus to Relative Humidity
Publisher: American Chemical Society (ACS)
Date: 17-12-2021
Taxonomy of the order Mononegavirales: update 2019
Publisher: Springer Science and Business Media LLC
Date: 14-05-2019
Crinamine Induces Apoptosis and Inhibits Proliferation, Migration, and Angiogenesis in Cervical Cancer SiHa Cells
Publisher: MDPI AG
Date: 16-09-2019
DOI: 10.3390/BIOM9090494
Abstract: Crinum asiaticum is a perennial herb widely distributed in many warmer regions, including Thailand, and is well-known for its medicinal and ornamental values. Crinum alkaloids contain numerous compounds, such as crinamine. Even though its mechanism of action is still unknown, crinamine was previously shown to possess anticancer activity. In this study, we demonstrate that crinamine was more cytotoxic to cervical cancer cells than normal cells. It also inhibited anchorage-independent tumor spheroid growth more effectively than existing chemotherapeutic drugs carboplatin and 5-fluorouracil or the CDK9 inhibitor FIT-039. Additionally, unlike cisplatin, crinamine induced apoptosis without promoting DNA double-strand breaks. It suppressed cervical cancer cell migration by inhibiting the expression of positive regulators of epithelial-mesenchymal transition SNAI1 and VIM. Importantly, crinamine also exerted anti-angiogenic activities by inhibiting secretion of VEGF-A protein in cervical cancer cells and blood vessel development in zebrafish embryos. Gene expression analysis revealed that its mechanism of action might be attributed, in part, to downregulation of cancer-related genes, such as AKT1, BCL2L1, CCND1, CDK4, PLK1, and RHOA. Our findings provide a first insight into crinamine's anticancer activity, highlighting its potential use as an alternative bioactive compound for cervical cancer chemoprevention and therapy.
RSV Infection Promotes Necroptosis and HMGB1 Release by Airway Epithelial Cells
Publisher: American Thoracic Society
Date: 06-2020
Opinion to address the personal protective equipment shortage in the global community during the COVID-19 outbreak
Publisher: Elsevier BV
Date: 06-2020
IRF-3, IRF-7, and IPS-1 Promote Host Defense against Acute Human Metapneumovirus Infection in Neonatal Mice
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.AJPATH.2014.02.026
Abstract: Human metapneumovirus (hMPV) is a leading cause of respiratory tract disease in children and is associated with acute bronchiolitis, pneumonia, and asthma exacerbations, yet the mechanisms by which the host immune response to hMPV is regulated are poorly understood. By using gene-deleted neonatal mice, we examined the contributions of the innate receptor signaling molecules interferon (IFN)-β promoter stimulator 1 (IPS-1), IFN regulatory factor (IRF) 3, and IRF7. Viral load in the lungs was markedly greater in IPS-1(-/-) > IRF3/7(-/-) > IRF3(-/-), but not IRF7(-/-), mice compared with wild-type mice. IFN-β and IFN-λ2/3 (IL-28A/B) production was attenuated in the bronchoalveolar lavage fluid in all factor-deficient mice compared with wild-type mice at 1 day after infection, although IFN-λ2/3 was greater in IRF3/7(-/-) mice at 5 days after infection. IRF7(-/-) and IRF3/7(-/-) mice presented with airway eosinophilia, whereas only IRF3/7(-/-) mice developed an exaggerated type 1 and 17 helper T-cell response, characterized by natural killer T-cell and neutrophilic inflammation. Despite having the highest viral load, IPS-1(-/-) mice did not develop a proinflammatory cytokine or granulocytic response to hMPV infection. Our findings demonstrate that IFN-β, but not IFN-λ2/3, produced via an IPS-1-IRF3 signaling pathway, is important for hMPV clearance. In the absence of a robust type I IFN-α/β response, targeting the IPS-1 signaling pathway may limit the overexuberant inflammatory response that occurs as a consequence of viral persistence.
2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales
Publisher: Springer Science and Business Media LLC
Date: 31-08-2021
Codon stabilization analysis of the 248 temperature sensitive mutation for increased phenotypic stability of respiratory syncytial virus vaccine candidates
Publisher: Elsevier BV
Date: 09-2009
Suppression of the Induction of Alpha, Beta, and Gamma Interferons by the NS1 and NS2 Proteins of Human Respiratory Syncytial Virus in Human Epithelial Cells and Macrophages
Publisher: American Society for Microbiology
Date: 15-04-2004
DOI: 10.1128/JVI.78.8.4363-4369.2004
Abstract: Wild-type human respiratory syncytial virus (HRSV) is a poor inducer of alpha/beta interferons (IFN-α/β). However, recombinant HRSV lacking the NS1 and NS2 genes (ΔNS1/2) induced high levels of IFN-α and -β in human pulmonary epithelial cells (A549) as well as in macrophages derived from primary human peripheral blood monocytes. Results with NS1 and NS2 single- and double-gene-deletion viruses indicated that the two proteins function independently as well as coordinately to achieve the full inhibitory effect, with NS1 having a greater independent role. The relative contributions of the in idual NS proteins were the converse of that recently described for bovine RSV (J. F. Valarcher, J. Furze, S. Wyld, R. Cook, K. K. Conzelmann, and G. Taylor, J. Virol. 77:8426-8439, 2003). This pattern of inhibition by HRSV NS1 and NS2 also extended to the newly described antiviral cytokines IFN-λ1, -2 and -3.
The Impact of Early-Life Exposure to Air-borne Environmental Insults on the Function of the Airway Epithelium in Asthma
Publisher: Ubiquity Press, Ltd.
Date: 17-06-2016
DOI: 10.1016/J.AOGH.2016.01.007
Abstract: The airway epithelium is both a physical barrier protecting the airways from environmental insults and a significant component of the innate immune response. There is growing evidence that exposure of the airway epithelium to environmental insults in early life may lead to permanent changes in structure and function that underlie the development of asthma. Here we review the current published evidence concerning the link between asthma and epithelial damage within the airways and identify gaps in knowledge for future studies.
Human respiratory syncytial virus non-structural protein NS1 modifies miR-24 expression via transforming growth factor-β
Publisher: Microbiology Society
Date: 11-2015
DOI: 10.1099/JGV.0.000261
Genetic recombination during coinfection of two mutants of human respiratory syncytial virus
Publisher: American Society for Microbiology
Date: 15-10-2003
DOI: 10.1128/JVI.77.20.11201-11211.2003
Abstract: Recombination between coinfecting viruses had not been documented previously for a nonsegmented negative-strand RNA virus (mononegavirus). We investigated the potential of intermolecular recombination by respiratory syncytial virus (RSV) by coinfecting HEp-2 cells with two recombinant RSV (rRSV) mutants lacking either the G gene (ΔG/HEK) or the NS1 and NS2 genes (ΔNS1/2). These viruses replicate inefficiently and form pinpoint plaques in HEp-2 cells. Therefore, potential recombined viruses with a growth and/or plaque formation advantage should easily be identified and differentiated from the two parental viruses. Further identification of potential recombinants was aided by the inclusion of point mutation markers in the F and L genes of ΔG/HEK and the design of reverse transcription-PCR (RT-PCR) primers capable of detecting these markers. Independent coinfections and control single infections by these two rRSV mutants were performed. In one of six coinfections, an RSV variant was identified that produced plaques slightly larger than those of wild-type RSV in HEp-2 cells. RT-PCR and sequencing provided evidence that this variant was a recombined RSV (rec-RSV). The rec-RSV appeared to have been generated by a polymerase jump from the ΔG/HEK genome to that of ΔNS1/2 and back again in the vicinity of the SH-G-F genes. This apparently involved nonhomologous and homologous recombination events, respectively. The recombined genome was identical to that of the ΔG/HEK mutant except that all but the first 12 nucleotides of the SH gene were deleted and replaced by an insert consisting of the last 91 nucleotides of the G gene and its downstream intergenic region. This insert could have come only from the coinfecting ΔNS1/2 virus. This resulted in the formation of a short chimeric SH:G gene. Northern and Western blot analysis confirmed that the rec-RSV did not express the normal SH and G mRNAs and proteins but did express the aberrant SH:G mRNA. This provides an experimental demonstration of intermolecular recombination yielding a viable, helper-independent mononegavirus. However, the isolation of only a single rec-RSV under these optimized conditions supports the idea that RSV recombination is rare indeed.
Innate Immunity in the Middle Ear Mucosa
Publisher: Frontiers Media SA
Date: 29-10-2021
DOI: 10.3389/FCIMB.2021.764772
Abstract: Otitis media (OM) encompasses a spectrum of clinical presentations ranging from the readily identifiable Acute OM (AOM), which is characterised by otalgia and fever, to chronic otitis media with effusion (COME) where impaired hearing due to middle ear effusion may be the only clinical symptom. Chronic suppurative OM (CSOM) presents as a more severe form of OM, involving perforation of the tympanic membrane. The pathogenesis of OM in these varied clinical presentations is unclear but activation of the innate inflammatory responses to viral and/or bacterial infection of the upper respiratory tract performs an integral role. This localised inflammatory response can persist even after pathogens are cleared from the middle ear, eustachian tubes and, in the case of respiratory viruses, even the nasal compartment. Children prone to OM may experience an over exuberant inflammatory response that underlies the development of chronic forms of OM and their sequelae, including hearing impairment. Treatments for chronic effusive forms of OM are limited, with current therapeutic guidelines recommending a “watch and wait” strategy rather than active treatment with antibiotics, corticosteroids or other anti-inflammatory drugs. Overall, there is a clear need for more targeted and effective treatments that either prevent or reduce the hyper-inflammatory response associated with chronic forms of OM. Improved treatment options rely upon an in-depth understanding of OM pathogenesis, particularly the role of the host innate immune response during acute OM. In this paper, we review the current literature regarding the innate immune response within the middle ear to bacterial and viral otopathogens alone, and as co-infections. This is an important consideration, as the role of respiratory viruses as primary pathogens in OM is not yet fully understood. Furthermore, increased reporting from PCR-based diagnostics, indicates that viral/bacterial co-infections in the middle ear are more common than bacterial infections alone. Increasingly, the mechanisms by which viral/bacterial co-infections may drive or maintain complex innate immune responses and inflammation during OM as a chronic response require investigation. Improved understanding of the pathogenesis of chronic OM, including host innate immune response within the middle ear is vital for development of improved diagnostic and treatment options for our children.
Copd is associated with elevated ifn-β production by bronchial epithelial cells infected with rsv or hmpv
Publisher: MDPI AG
Date: 14-05-2021
DOI: 10.3390/V13050911
Abstract: IFN treatment may be a viable option for treating COPD exacerbations based on evidence of IFN deficiency in COPD. However, in vitro studies have used primarily influenza and rhinoviruses to investigate IFN responses. This study aims to investigate the susceptibility to infection and IFN response of primary bronchial epithelial cells (BECs) from COPD donors to infection with RSV and hMPV. BECs from five COPD and five healthy donors were used to establish both submerged monolayer and well-differentiated (WD) cultures. Two isolates of both RSV and hMPV were used to infect cells. COPD was not associated with elevated susceptibility to infection and there was no evidence of an intrinsic defect in IFN production in either cell model to either virus. Conversely, COPD was associated with significantly elevated IFN-β production in response to both viruses in both cell models. Only in WD-BECs infected with RSV was elevated IFN-β associated with reduced viral shedding. The role of elevated epithelial cell IFN-β production in the pathogenesis of COPD is not clear and warrants further investigation. Viruses vary in the responses that they induce in BECs, and so conclusions regarding antiviral responses associated with disease cannot be made based on single viral infections.
Hendra virus: An emerging paramyxovirus in Australia
Publisher: Elsevier BV
Date: 10-2012
Formulation, physical, in vitro and ex vivo evaluation of nanomedicine-based chemosterilant for non-surgical castration of male animals
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.THERIOGENOLOGY.2017.12.014
Abstract: The overpopulation of free-roaming companion animals has become the global crisis. The development and application of a suitable, effective, non-surgical approach for animal sterilization would have an enormous advantage over the current surgical method. The main purpose of this study was to develop and evaluate a novel nanomedicine-based chemosterilant for non-surgical castration of male companion animals. In this study, we first sought to investigate the testicular toxicity of different apoptosis-inducing agents. We next synthesized and characterized nano-sized particles which encapsulated the most potent testicular toxicants and evaluated in vitro sterilant properties. Our result showed that doxorubicin exhibited the highest cytotoxic activity against mouse spermatogenic cells. We therefore synthesized and characterized doxorubicin-encapsulated nanoemulsion. The negatively charged particle of doxorubicin-encapsulated nanoemulsion exhibited the anti-proliferative activity towards spermatogetic cells. Apoptosis studies revealed activation of Caspases 3 and 7 as well as annexin V expression. In addition, doxorubicin-encapsulated nanoemulsion exhibited anti-inflammatory activity in lipopolysaccharide-stimulated macrophages. Cell death was observed following treatment of isolated and cultured rat seminiferous tubules with doxorubicin-encapsulated nanoemulsion. In conclusion, nanoemulsion can be a potential carrier for prolonged release and to enhance activity of doxorubicin that may have utility in non-surgical castration of male animals.
Binding of the eukaryotic translation elongation factor 1A with the 5’UTR of HIV-1 genomic RNA is important for reverse transcription
Publisher: Springer Science and Business Media LLC
Date: 06-08-2015
Targeting the P2Y
Publisher: American Thoracic Society
Date: 02-2022
Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.JACI.2013.02.041
Abstract: Respiratory tract viruses are a major environmental risk factor for both the inception and exacerbations of asthma. Genetic defects in Toll-like receptor (TLR) 7-mediated signaling, impaired type I interferon responses, or both have been reported in asthmatic patients, although their contribution to the onset and exacerbation of asthma remains poorly understood. We sought to determine whether Pneumovirus infection in the absence of TLR7 predisposes to bronchiolitis and the inception of asthma. Wild-type and TLR7-deficient (TLR7(-/-)) mice were inoculated with the rodent-specific pathogen pneumonia virus of mice at 1 (primary), 7 (secondary), and 13 (tertiary) weeks of age, and pathologic features of bronchiolitis or asthma were assessed. In some experiments infected mice were exposed to low-dose cockroach antigen. TLR7 deficiency increased viral load in the airway epithelium, which became sloughed and necrotic, and promoted an IFN-α/β(low), IL-12p70(low), IL-1β(high), IL-25(high), and IL-33(high) cytokine microenvironment that was associated with the recruitment of type 2 innate lymphoid cells/nuocytes and increased TH2-type cytokine production. Viral challenge of TLR7(-/-) mice induced all of the cardinal pathophysiologic features of asthma, including tissue eosinophilia, mast cell hyperplasia, IgE production, airway smooth muscle alterations, and airways hyperreactivity in a memory CD4(+) T cell-dependent manner. Importantly, infections with pneumonia virus of mice promoted allergic sensitization to inhaled cockroach antigen in the absence but not the presence of TLR7. TLR7 gene defects and Pneumovirus infection interact to establish an aberrant adaptive response that might underlie virus-induced asthma exacerbations in later life.
Taxonomy of the order Mononegavirales: second update 2018
Publisher: Springer Science and Business Media LLC
Date: 20-01-2019
Surface modification of gold nanoparticles with neuron-targeted exosome for enhanced blood–brain barrier penetration
Publisher: Springer Science and Business Media LLC
Date: 04-06-2019
DOI: 10.1038/S41598-019-44569-6
Abstract: Gold nanoparticles (AuNPs) have been extensively used as nanomaterials for theranostic applications due to their multifunctional characteristics in therapeutics, imaging, and surface modification. In this study, the unique functionalities of exosome-derived membranes were combined with synthetic AuNPs for targeted delivery to brain cells. Here, we report the surface modification of AuNPs with brain-targeted exosomes derived from genetically engineered mammalian cells by using the mechanical method or extrusion to create these novel nanomaterials. The unique targeting properties of the AuNPs after fabrication with the brain-targeted exosomes was demonstrated by their binding to brain cells under laminar flow conditions as well as their enhanced transport across the blood brain barrier. In a further demonstration of their ability to target brain cells, in vivo bioluminescence imaging revealed that targeted-exosome coated AuNPs accumulated in the mouse brain after intravenous injection. The surface modification of synthetic AuNPs with the brain-targeted exosome demonstrated in this work represents a highly novel and effective strategy to provide efficient brain targeting and shows promise for the future in using modified AuNPs to penetrate the brain.
Antiviral and Antibacterial Nanostructured Surfaces with Excellent Mechanical Properties for Hospital Applications
Publisher: American Chemical Society (ACS)
Date: 07-05-2020
The Discovery of a Highly Selective 5,6,7,8‐Tetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4(3H)‐one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson’s Disease Model
Publisher: Wiley
Date: 13-11-2014
Abstract: Sirtuins, NAD(+) -dependent histone deacetylases (HDACs), have recently emerged as potential therapeutic targets for the treatment of a variety of diseases. The discovery of potent and isoform-selective inhibitors of this enzyme family should provide chemical tools to help determine the roles of these targets and validate their therapeutic value. Herein, we report the discovery of a novel class of highly selective SIRT2 inhibitors, identified by pharmacophore screening. We report the identification and validation of 3-((2-methoxynaphthalen-1-yl)methyl)-7-((pyridin-3-ylmethyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (ICL-SIRT078), a substrate-competitive SIRT2 inhibitor with a Ki value of 0.62 ± 0.15 μM and more than 50-fold selectivity against SIRT1, 3 and 5. Treatment of MCF-7 breast cancer cells with ICL-SIRT078 results in hyperacetylation of α-tubulin, an established SIRT2 biomarker, at doses comparable with the biochemical IC50 data, while suppressing MCF-7 proliferation at higher concentrations. In concordance with the recent reports that suggest SIRT2 inhibition is a potential strategy for the treatment of Parkinson's disease, we find that compound ICL-SIRT078 has a significant neuroprotective effect in a lactacystin-induced model of Parkinsonian neuronal cell death in the N27 cell line. These results encourage further investigation into the effects of ICL-SIRT078, or an optimised derivative thereof, as a candidate neuroprotective agent in in vivo models of Parkinson's disease.
Prevalence of Neutralising Antibodies to HCoV-NL63 in Healthy Adults in Australia
Publisher: MDPI AG
Date: 16-08-2021
DOI: 10.3390/V13081618
Abstract: The COVID-19 pandemic has highlighted the importance of understanding the immune response to seasonal human coronavirus (HCoV) infections such as HCoV-NL63, how existing neutralising antibodies to HCoV may modulate responses to SARS-CoV-2 infection, and the utility of seasonal HCoV as human challenge models. Therefore, in this study we quantified HCoV-NL63 neutralising antibody titres in a healthy adult population using plasma from 100 blood donors in Australia. A microneutralisation assay was performed with plasma diluted from 1:10 to 1:160 and tested with the HCoV-NL63 Amsterdam-1 strain. Neutralising antibodies were detected in 71% of the plasma s les, with a median geometric mean titre of 14. This titre was similar to those reported in convalescent sera taken from in iduals 3–7 months following asymptomatic SARS-CoV-2 infection, and 2–3 years post-infection from symptomatic SARS-CoV-1 patients. HCoV-NL63 neutralising antibody titres decreased with increasing age (R2 = 0.042, p = 0.038), but did not differ by sex. Overall, this study demonstrates that neutralising antibody to HCoV-NL63 is detectable in approximately 71% of the healthy adult population of Australia. Similar titres did not impede the use of another seasonal human coronavirus (HCoV-229E) in a human challenge model, thus, HCoV-NL63 may be useful as a human challenge model for more pathogenic coronaviruses.
Low Genetic Diversity of Hepatitis B Virus Surface Gene amongst Australian Blood Donors
Publisher: MDPI AG
Date: 30-06-2021
DOI: 10.3390/V13071275
Abstract: Variants in the small surface gene of hepatitis B virus (HBV), which codes for viral surface antigen (HBsAg), can affect the efficacy of HBsAg screening assays and can be associated with occult HBV infection (OBI). This study aimed to characterise the molecular ersity of the HBV small surface gene from HBV-reactive Australian blood donors. HBV isolates from 16 HBsAg-positive Australian blood donors’ plasma were sequenced and genotyped by phylogenies of viral coding genes and/or whole genomes. An analysis of the genetic ersity of eight HBV small surface genes from our 16 s les was conducted and compared with HBV sequences from NCBI of 164 international (non-Australian) blood donors. Genotypes A–D were identified in our s les. The region of HBV small surface gene that contained the sequence encoding the ‘a’ determinant had a greater genetic ersity than the remaining part of the gene. No escape mutants or OBI-related variants were observed in our s les. Variant call analysis revealed two s les with a nucleotide deletion leading to truncation of polymerase and/or large/middle surface amino acid sequences. Overall, we found that HBV small surface gene sequences from Australian donors demonstrated a lower level of genetic ersity than those from non-Australian donor population included in the study.
The eukaryotic elongation factor 1A is critical for genome replication of the paramyxovirus respiratory syncytial virus.
Publisher: Public Library of Science (PLoS)
Date: 05-12-2014
RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma
Publisher: eLife Sciences Publications, Ltd
Date: 18-01-2017
DOI: 10.7554/ELIFE.21199
Abstract: Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of in iduals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.
SiRNA against the G gene of human metapneumovirus
Publisher: Springer Science and Business Media LLC
Date: 10-07-2012
Abstract: Human metapneumovirus (hMPV) is a significant viral respiratory pathogen of infants and children, the elderly and immunocompromised in iduals. Disease associated with hMPV infection resembles that of human respiratory syncytial virus (RSV) and includes bronchiolitis and pneumonia. The glycosylated G attachment protein of hMPV is required for viral entry in vivo and has also been identified as an inhibitor of innate immune responses. We designed and validated two siRNA molecules against the G gene using A549 cells and demonstrated consistent 88-92% knock-down for one siRNA molecule, which was used in subsequent experiments. Significant reduction of G mRNA in A549 cells infected with hMPV did not result in a reduction in viral growth, nor did it significantly increase the production of type I interferon (α/β) in response to infection. However, there was a moderate increase in IFN-β mRNA expression in response to infection in siG-transfected cells compared to untransfected and si-mismatch-transfected cells. Expression of G by recombinant adenovirus did not affect type I IFN expression. G has been previously described as a type I interferon antagonist, although our findings suggest it may not be a significant antagonist.
Thermoresponsive Bacteriophage Nanocarrier as a Gene Delivery Vector Targeted to the Gastrointestinal Tract
Publisher: Elsevier BV
Date: 09-2018
The Absence of Interferon-β Promotor Stimulator-1 (IPS-1) Predisposes to Bronchiolitis and Asthma-like Pathology in Response to Pneumoviral Infection in Mice
Publisher: Springer Science and Business Media LLC
Date: 24-05-2017
DOI: 10.1038/S41598-017-02564-9
Abstract: Respiratory syncytial virus (RSV)-bronchiolitis is a major cause of infant morbidity and mortality and a risk factor for subsequent asthma. We showed previously that toll-like receptor (TLR)7 in plasmacytoid dendritic cells (pDCs) is critical for protection against bronchiolitis and asthma in mice infected with pneumonia virus of mice (PVM), the mouse homolog of RSV. This lack of redundancy was unexpected as interferon-β promotor stimulator-1 (IPS-1) signalling, downstream of RIG-I-like receptor (RLR) and not TLR7 activation, contributes to host defence in hRSV-inoculated adult mice. To further clarify the role of IPS-1 signalling, we inoculated IPS-1 −/− and WT mice with PVM in early-life, and again in later-life, to model the association between bronchiolitis and asthma. IPS-1 deficiency predisposed to severe PVM bronchiolitis, characterised by neutrophilic inflammation and necroptotic airway epithelial cell death, high mobility group box 1 (HMGB1) and IL-33 release, and downstream type-2 inflammation. Secondary infection induced an eosinophilic asthma-like pathophysiology in IPS-1 −/− but not WT mice. Mechanistically, we identified that IPS-1 is necessary for pDC recruitment, IFN-α production and viral control. Our findings suggest that TLR7 and RLR signalling work collaboratively to optimally control the host response to pneumovirus infection thereby protecting against viral bronchiolitis and subsequent asthma.
The gene encoding the nucleocapsid protein of Gill-associated nidovirus of Penaeus monodon prawns is located upstream of the glycoprotein gene
Publisher: American Society for Microbiology
Date: 15-08-2004
DOI: 10.1128/JVI.78.16.8935-8941.2004
Abstract: The ORF2 gene of Gill-associated virus (GAV) of Penaeus monodon prawns resides 93 nucleotides downstream of the ORF1a-ORF1b gene and encodes a 144-amino-acid hydrophilic polypeptide (15,998 Da pI, 9.75) containing 20 basic (14%) and 13 acidic (9%) residues and 19 prolines (13%). Antiserum to a synthetic ORF2 peptide or an Escherichia coli -expressed glutathione S -transferase-ORF2 fusion protein detected a 20-kDa protein in infected lymphoid organ and gill tissues in Western blots. The GAV ORF2 fusion protein antiserum also cross-reacted with the p20 nucleoprotein in virions of the closely related Yellow head virus . By immuno-gold electron microscopy, it was observed that the ORF2 peptide antibody localized to tubular GAV nucleocapsids, often at the ends or at lateral cross sections. As GAV appears to contain only two structural protein genes (ORF2 and ORF3), these data indicate that GAV differs from vertebrate nidoviruses in that the gene encoding the nucleocapsid protein is located upstream of the gene encoding the virion glycoproteins.
Chronic IL-33 expression predisposes to virus-induced asthma exacerbations by increasing type 2 inflammation and dampening antiviral immunity
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.JACI.2017.07.051
Abstract: Rhinovirus infection triggers acute asthma exacerbations. IL-33 is an instructive cytokine of type 2 inflammation whose expression is associated with viral load during experimental rhinovirus infection of asthmatic patients. We sought to determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and in vitro human primary airway epithelial cells (AECs). Mice were exposed to pneumonia virus of mice and cockroach extract in early and later life and then challenged with rhinovirus to model disease onset, progression, and chronicity. Interventions included anti-IL-33 or dexamethasone at various stages of disease. AECs were obtained from asthmatic patients and healthy subjects and treated with anti-IL-33 after rhinovirus infection. Anti-IL-33 decreased type 2 inflammation in all phases of disease however, the ability to prevent airway smooth muscle growth was lost after the progression phase. After the chronic phase, IL-33 levels were persistently high, and rhinovirus challenge exacerbated the type 2 inflammatory response. Treatment with anti-IL-33 or dexamethasone diminished exacerbation severity, and anti-IL-33, but not dexamethasone, promoted antiviral interferon expression and decreased viral load. Rhinovirus replication was higher and IFN-λ levels were lower in AECs from asthmatic patients compared with those from healthy subjects. Anti-IL-33 decreased rhinovirus replication and increased IFN-λ levels at the gene and protein levels. Anti-IL-33 or dexamethasone suppressed the magnitude of type 2 inflammation during a rhinovirus-induced acute exacerbation however, only anti-IL-33 boosted antiviral immunity and decreased viral replication. The latter phenotype was replicated in rhinovirus-infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defense.
Alterations of mineralized matrix by lead exposure in osteoblast (MC3T3-E1) culture
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.TOXLET.2018.10.008
Abstract: The present study investigated the effect of lead (Pb) on bone ultrastructure and chemistry using an in vitro bone model. MC3T3-E1 preosteoblasts were differentiated and treated with lead acetate at 0.4, 2, 10, and 50 μM. No abnormalities in either cell growth or bone nodule formation were observed with the treated dose of lead acetate. However, Pb treatments could significantly increase Pb accumulation in differentiated osteoblast cultures and upregulate expression of Divalent metal transporter 1 (Dmt1) in a dose dependent manner. Pb treatments also altered the expression of osteogenic genes, including secreted phosphoprotein 1, osteocalcin, type I collagen, and osteoprotegerin. Moreover, in mineralized osteoblast cultures, Pb was found to be mainly deposited as Pb salts and oxides, respectively. Ultrastructure analysis revealed Pb localizing with calcium and phosphorus in the mineralized matrix. In mineralizing osteoblast cells, Pb was found in the intracellular calcified vesicles which is one of the bone mineralization mechanisms. Pb was also present in mineral deposits with various shapes and sizes, such as small and large globular or needle-like mineral deposits representing early to mature stages of mineral deposits. Furthermore, Pb was found more in the globular deposits than the needle shaped mineral crystals. Taken together, our observations revealed how Pb incorporates into bone tissue, and showed a close association with bone apatite.
Liposomal Formulations of a Polyleucine–Antigen Conjugate as Therapeutic Vaccines against Cervical Cancer
Publisher: MDPI AG
Date: 10-02-2023
DOI: 10.3390/PHARMACEUTICS15020602
Abstract: Human papilloma virus (HPV) is responsible for all cases of cervical cancer. While prophylactic vaccines are available, the development of peptide-based vaccines as a therapeutic strategy is still under investigation. In comparison with the traditional and currently used treatment strategies of chemotherapy and surgery, vaccination against HPV is a promising therapeutic option with fewer side effects. A peptide derived from the HPV-16 E7 protein, called 8Qm, in combination with adjuvants showed promise as a therapeutic vaccine. Here, the ability of polymerized natural amino acids to act as a self-adjuvating delivery system as a therapeutic vaccine was investigated for the first time. Thus, 8Qm was conjugated to polyleucine by standard solid-phase peptide synthesis and self-assembled into nanoparticles or incorporated in liposomes. The liposome bearing the 8Qm conjugate significantly increased mice survival and decreased tumor growth after a single immunization. Further, these liposomes eradicated seven-day-old well-established tumors in mice. Dendritic cell (DC)-targeting moieties were introduced to further enhance vaccine efficacy, and the newly designed liposomal vaccine was tested in mice bearing 11-day-old tumors. Interestingly, these DCs-targeting moieties did not significantly improve vaccine efficacy, whereas the simple liposomal formulation of 8Qm-polyleucine conjugate was still effective in tumor eradication. In summary, a peptide-based anticancer vaccine was developed that stimulated strong cellular immune responses without the help of a classical adjuvant.
Sirtuin1 (SIRT1) in the acetylation of downstream target proteins
Publisher: Springer New York
Date: 2016
DOI: 10.1007/978-1-4939-3667-0_12
Abstract: Acetylation has been shown to be an important posttranslational modification (PTM) of both histone and nonhistone proteins with particular implications in cell signaling and transcriptional regulation of gene expression. Many studies have already demonstrated that SIRT1 is able to deacetylate histones and lead to gene silencing. It can also regulate the function of tumor suppressors including FOXO proteins and p53 by deacetylation. Here, we describe three experimental approaches for studying the modulation of the acetylation status of some of the known downstream targets of SIRT1.
The Human Respiratory Syncytial Virus Nonstructural Protein 1 Regulates Type I and Type II Interferon Pathways
Publisher: Elsevier BV
Date: 05-2012
Plasmacytoid Dendritic Cells Promote Host Defense against Acute Pneumovirus Infection via the TLR7–MyD88-Dependent Signaling Pathway
Publisher: The American Association of Immunologists
Date: 15-05-2011
Abstract: Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants. In human infants, plasmacytoid dendritic cells (pDC) are recruited to the nasal compartment during infection and initiate host defense through the secretion of type I IFN, IL-12, and IL-6. However, RSV-infected pDC are refractory to TLR7-mediated activation. In this study, we used the rodent-specific pathogen, pneumonia virus of mice (PVM), to determine the contribution of pDC and TLR7 signaling to the development of the innate inflammatory and early adaptive immune response. In wild-type, but not TLR7- or MyD88-deficient mice, PVM inoculation led to a marked infiltration of pDC and increased expression of type I, II, and III IFNs. The delayed induction of IFNs in the absence of TLR7 or MyD88 was associated with a diminished innate inflammatory response and augmented virus recovery from lung tissue. In the absence of TLR7, PVM-specific CD8+ T cell cytokine production was abrogated. The adoptive transfer of TLR7-sufficient, but not TLR7-deficient pDC to TLR7 gene-deleted mice recapitulated the antiviral responses observed in wild-type mice and promoted virus clearance. In summary, TLR7-mediated signaling by pDC is required for appropriate innate responses to acute pneumovirus infection. It is conceivable that as-yet–unidentified defects in the TLR7 signaling pathway may be associated with elevated levels of RSV-associated morbidity and mortality among otherwise healthy human infants.
HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling
Publisher: Public Library of Science (PLoS)
Date: 13-07-2020
A Mutant Tat Protein Inhibits HIV-1 Reverse Transcription by Targeting the Reverse Transcription Complex
Publisher: American Society for Microbiology
Date: 05-2015
DOI: 10.1128/JVI.03440-14
Abstract: Previously, we reported that a mutant of Tat referred to as Nullbasic inhibits HIV-1 reverse transcription although the mechanism of action is unknown. Here we show that Nullbasic is a reverse transcriptase (RT) binding protein that targets the reverse transcription complex rather than directly inhibiting RT activity. An interaction between Nullbasic and RT was observed by using coimmunoprecipitation and pulldown assays, and a direct interaction was measured by using a biolayer interferometry assay. Mixtures of recombinant 6×His-RT and Nullbasic-FLAG-V5-6×His at molar ratios of up to 1:20,000 did not inhibit RT activity in standard homopolymer primer template assays. An analysis of virus made by cells that coexpressed Nullbasic showed that Nullbasic copurified with virus particles, indicating that it was a virion protein. In addition, analysis of reverse transcription complexes (RTCs) isolated from cells infected with wild type or Nullbasic-treated HIV-1 showed that Nullbasic reduced the levels of viral DNA in RTC fractions. In addition, a shift in the distribution of viral DNA and CAp24 to less-dense non-RTC fractions was observed, indicating that RTC activity from Nullbasic-treated virus was impaired. Further analysis showed that viral cores isolated from Nullbasic-treated HIV undergo increased disassembly in vitro compared to untreated HIV-1. To our knowledge, this is the first description of an antiviral protein that inhibits reverse transcription by targeting the RTC and affecting core stability. IMPORTANCE HIV-1 infection is treated by using combinations of antiretroviral drugs that target independent steps of virus replication. A newly described antiviral protein called Nullbasic can also inhibit a combination of different steps in virus replication (transcription, reverse transcription, and Rev-mediated viral mRNA transport), although the precise mechanism of action is unknown. This study shows that Nullbasic can inhibit reverse transcription by binding to the viral enzyme called reverse transcriptase, which results in accelerated uncoating of the viral core and instability of the viral apparatus called the reverse transcription complex (RTC). This unique antiviral activity may inform development of other RTC inhibitors, as well as providing a unique investigative tool for dissecting the RTC cellular composition.
DC-SIGN and L-SIGN Are Attachment Factors That Promote Infection of Target Cells by Human Metapneumovirus in the Presence or Absence of Cellular Glycosaminoglycans.
Publisher: American Society for Microbiology
Date: 09-2016
DOI: 10.1128/JVI.00537-16
Abstract: It is well established that glycosaminoglycans (GAGs) function as attachment factors for human metapneumovirus (HMPV), concentrating virions at the cell surface to promote interaction with other receptors for virus entry and infection. There is increasing evidence to suggest that multiple receptors may exhibit the capacity to promote infectious entry of HMPV into host cells however, definitive identification of specific transmembrane receptors for HMPV attachment and entry is complicated by the widespread expression of cell surface GAGs. pgsA745 Chinese hamster ovary (CHO) cells are deficient in the expression of cell surface GAGs and resistant to HMPV infection. Here, we demonstrate that the expression of the Ca 2+ -dependent C-type lectin receptor (CLR) DC-SIGN (CD209L) or L-SIGN (CD209L) rendered pgsA745 cells permissive to HMPV infection. Unlike infection of parental CHO cells, HMPV infection of pgsA745 cells expressing DC-SIGN or L-SIGN was dynamin dependent and inhibited by mannan but not by pretreatment with bacterial heparinase. Parental CHO cells expressing DC-SIGN/L-SIGN also showed enhanced susceptibility to dynamin-dependent HMPV infection, confirming that CLRs can promote HMPV infection in the presence or absence of GAGs. Comparison of pgsA745 cells expressing wild-type and endocytosis-defective mutants of DC-SIGN/L-SIGN indicated that the endocytic function of CLRs was not essential but could contribute to HMPV infection of GAG-deficient cells. Together, these studies confirm a role for CLRs as attachment factors and entry receptors for HMPV infection. Moreover, they define an experimental system that can be exploited to identify transmembrane receptors and entry pathways where permissivity to HMPV infection can be rescued following the expression of a single cell surface receptor. IMPORTANCE On the surface of CHO cells, glycosaminoglycans (GAGs) function as the major attachment factor for human metapneumoviruses (HMPV), promoting dynamin-independent infection. Consistent with this, GAG-deficient pgaA745 CHO cells are resistant to HMPV. However, expression of DC-SIGN or L-SIGN rendered pgsA745 cells permissive to dynamin-dependent infection by HMPV, although the endocytic function of DC-SIGN/L-SIGN was not essential for, but could contribute to, enhanced infection. These studies provide direct evidence implicating DC-SIGN/L-SIGN as an alternate attachment factor for HMPV attachment, promoting dynamin-dependent infection via other unknown receptors in the absence of GAGs. Moreover, we describe a unique experimental system for the assessment of putative attachment and entry receptors for HMPV.
Utility of Three Nebulizers in Investigating the Infectivity of Airborne Viruses
Publisher: American Society for Microbiology
Date: 27-07-2021
DOI: 10.1128/AEM.00497-21
Abstract: Viral respiratory tract infections cause millions of lost days of work and physician visits globally, accounting for significant morbidity and mortality. Respiratory droplets and droplet nuclei from infected hosts are the potential carriers of such viruses within indoor environments.
Human Metapneumovirus Infection in Chronic Obstructive Pulmonary Disease: Impact of Glucocorticosteroids and Interferon
Publisher: Oxford University Press (OUP)
Date: 04-04-2017
Abstract: Human metapneumovirus (hMPV) infection is implicated in exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Research into the pathogenesis of infection is restricted to animal models, and information about hMPV replication and inflammatory and immune responses in human disease is limited. Human primary bronchial epithelial cells (PBECs) from healthy and asthmatic subjects and those with COPD were infected with hMPV, with or without glucocorticosteroid (GCS) exposure. Viral replication, inflammatory and immune responses, and apoptosis were analyzed. We also determined whether adjuvant interferon (IFN) can blunt hMPV infection in vitro and in a murine model. hMPV infected human PBECs and viral replication was enhanced in cells from patients with COPD. The virus induced gene expression of IFN-stimulated gene 56 (ISG56) and IFN-β, as well as IFN-γ-inducible protein 10 (IP-10) and regulated on activation, normal T cell expressed and secreted (RANTES), and more so in cells from patients with COPD. GCS exposure enhanced hMPV replication despite increased IFN expression. Augmented virus replication associated with GCS was mediated by reduced apoptosis via induction of antiapoptotic genes. Adjuvant IFN treatment suppressed hMPV replication in PBECs and reduced hMPV viral titers and inflammation in vivo. hMPV infects human PBECs, eliciting innate and inflammatory responses. Replication is enhanced by GCS and adjuvant IFN is an effective treatment, restricting virus replication and proinflammatory consequences of hMPV infections.
The eukaryotic translation elongation factor 1A regulation of actin stress fibers is important for infectious RSV production.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2018
The Development of Surface-Modified Liposomes as an Intranasal Delivery System for Group A Streptococcus Vaccines
Publisher: MDPI AG
Date: 30-01-2023
Abstract: Intranasal vaccine administration can overcome the disadvantages of injectable vaccines and present greater efficiency for mass immunization. However, the development of intranasal vaccines is challenged by poor mucosal immunogenicity of antigens and the limited availability of mucosal adjuvants. Here, we examined a number of self-adjuvanting liposomal systems for intranasal delivery of lipopeptide vaccine against group A Streptococcus (GAS). Among them, two liposome formulations bearing lipidated cell-penetrating peptide KALA and a new lipidated chitosan derivative (oleoyl-quaternized chitosan, OTMC) stimulated high systemic antibody titers in outbred mice. The antibodies were fully functional and were able to kill GAS bacteria. Importantly, OTMC was far more effective at stimulating antibody production than the classical immune-stimulating trimethyl chitosan formulation. In a simple physical mixture, OTMC also enhanced the immune responses of the tested vaccine, without the need for a liposome delivery system. The adjuvanting capacity of OTMC was further confirmed by its ability to stimulate cytokine production by dendritic cells. Thus, we discovered a new immune stimulant with promising properties for mucosal vaccine development.
Enhancing the Productivity and Stability of Superoxide Dismutase from Saccharomyces cerevisiae TBRC657 and Its Application as a Free Radical Scavenger
Publisher: MDPI AG
Date: 06-04-2022
DOI: 10.3390/FERMENTATION8040169
Abstract: Superoxide dismutase (SOD) is crucial antioxidant enzyme that plays a role in protecting cells against harmful reactive oxygen species (ROS) which are generated inside cells. Due to its functionality, SOD is used in many applications. In this study, Saccharomyces cerevisiae TBRC657 was selected as the SOD producer due to its high SOD production. After investigating an optimized medium, the major components were found to be molasses and yeast extract, which improved SOD production up to 3.97-fold compared to a synthetic medium. In addition, the optimized medium did not require any induction, which makes it suitable for applications in large-scale production. The SOD formulation was found to increase the stability of the conformational structure and prolong shelf-life. The results show that 1.0% (w/w) trehalose was the best additive, in giving the highest melting temperature by the DSF method and maintaining its activity at more than 80% after storage for 6 months. The obtained SOD was investigated for its cytotoxicity and ROS elimination against fibroblast cells. The results indicate that the SOD enhanced the proliferation and controlled ROS level inside the cells. Thus, the SOD obtained from S. cerevisiae TBRC657 cultured in the optimized medium could be a candidate for use as a ROS scavenger, which can be applied in many industries.
Pediatric nasal epithelial cells are less permissive to SARS-CoV-2 replication compared to adult cells
Publisher: Cold Spring Harbor Laboratory
Date: 08-03-2021
DOI: 10.1101/2021.03.08.434300
Abstract: Children typically experience more mild symptoms of COVID-19 when compared to adults. There is a strong body of evidence that children are also less susceptible to SARS-CoV-2 infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remains to be determined. Here, we use primary nasal epithelial cells from children and adults, differentiated at an air-liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the nasal epithelial cells of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the nasal epithelial cells of children. Importantly, the Delta variant also replicated to significantly lower titres in the nasal epithelial cells of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.
FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL
Publisher: American Association for Cancer Research (AACR)
Date: 12-2015
DOI: 10.1158/1541-7786.MCR-15-0127
Abstract: Glucocorticoids are widely used to treat B acute lymphoblastic leukemia (B-ALL) however, the molecular mechanism underlying glucocorticoid response and resistance is unclear. In this study, the role and regulation of FOXO3a in mediating the dexamethasone response in B-ALL were investigated. The results show that FOXO3a mediates the cytotoxic function of dexamethasone. In response to dexamethasone, it was found that FOXO3a translocates into the nucleus, where it induces the expression of downstream targets, including p27Kip1 and Bim, important for proliferative arrest and cell death in the sensitive RS4 and SUP-B15 B-ALL cells. FOXO3a activation by dexamethasone is mediated partially through the suppression of the PI3K/Akt signaling cascade. Furthermore, two posttranslational modifications were uncovered, phosphorylation on Ser-7 and acetylation on Lys-242/5, that associated with FOXO3a activation by dexamethasone. Immunoblot analysis showed that the phosphorylation on Ser-7 of FOXO3a is associated with p38/JNK activation, whereas the acetylation on Lys-242/5 is correlated with the downregulation of SIRT1/2/6 and the induction of the acetyltransferase CBP 300. Collectively, these results indicate that FOXO3a is essential for dexamethasone response in B-ALL cells, and its nuclear translocation and activation is associated with its phosphorylation on Ser-7 and acetylation on Lys-242/245. These posttranslational events can be exploited as biomarkers for B-ALL diagnosis and as drug targets for B-ALL treatment, particularly for overcoming the glucocorticoid resistance. Implications: FOXO3a and its posttranslational regulation are essential for dexamethasone response, and targeting FOXO3a and sirtuins may enhance the dexamethasone-induced cytotoxicity in B-ALL cells. Mol Cancer Res 13(12) 1578–90. ©2015 AACR.
Erratum: Suppression of the induction of alpha, beta, and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages (Journal of Virology (2004) 78, 8 (4363-4369))
Publisher: American Society for Microbiology
Date: 15-06-2004
Mutation of the elongin C binding domain of human respiratory syncytial virus non-structural protein 1 (NS1) results in degradation of NS1 and attenuation of the virus
Publisher: Springer Science and Business Media LLC
Date: 22-05-2011
Abstract: Human respiratory syncytial virus (RSV) is an important cause of lower respiratory tract disease in the paediatic population, immunocompromised in iduals and the elderly worldwide. However, despite global efforts over the past several decades there are no commercially available vaccines. RSV encodes 2 non-structural proteins, NS1 and NS2, that are type I interferon antagonists. RSV restricts type I interferon signaling and the expression of antiviral genes by degrading STAT2. It has been proposed that NS1 binds to elongin C to form a ubiquitin ligase (E3) complex that targets STAT2 for ubiquitination and proteosomal degradation. Here, we have engineered a live recombinant RSV in which the 3 consensus amino acids of the NS1 elongin C binding domain have been replaced with alanine (NS1F-ELCmut). Mutation of this region of NS1 resulted in attenuation of RSV replication in A549 cells to levels similar to that observed when the NS1 gene is completely deleted (ΔNS1). This mutation also resulted in moderate attenuation in Vero cells. Attenuation was correlated to intracellular degradation of the mutated NS1 protein. Time course analysis showed that mutant NS1 protein accumulated in cytoplasmic bodies that contained the lysosomal marker LAMP1. However lack of cleavage of LC3 suggested that autophagy was not involved. Induction of IFN-β mRNA expression also was observed in association with the degradation of NS1 protein and attenuation of viral growth. These results indicate that the elongin C binding region of NS1 is crucial for survival of the protein and that disruption of this region results in the degradation of NS1 and restriction of RSV replication.
PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN-
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-05-2018
DOI: 10.1126/SCITRANSLMED.AAO0052
Abstract: Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal s les from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon-λ (IFN-λ) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN-λ production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.
Gonadotropin-releasing hormone-modified chitosan as a safe and efficient gene delivery vector for spermatogonia cells
Publisher: Wiley
Date: 11-2018
DOI: 10.1111/RDA.13346
Abstract: The use of male gonadal tissue as a site for the local delivery of DNA is an interesting concept. Previously, we reported synthesis, physiochemical and biological properties of gonadotropin-releasing hormone (GnRH)-conjugated chitosan as a carrier for DNA delivery to GnRH receptor-overexpressing cells. In this study, the application of modified chitosan as a potential vector for gene delivery to testicular cells was carried out. Transfection efficiency was investigated in mouse-derived spermatogonia cells (GC-1 cells) using green fluorescent protein as a reporter gene. GnRH-conjugated chitosan exhibited higher transfection activity and specificity compared to the unmodified chitosan. Furthermore, the GnRH-modified chitosan showed less cytotoxicity. In conclusion, we have developed and successfully tested the GnRH-modified chitosan for delivery of a transgene of interest to spermatogonia cells in vitro. Such vector could be useful in particular for testis-mediated gene transfer.
Antiviral Nanostructured Surfaces Reduce the Viability of SARS-CoV-2
Publisher: American Chemical Society (ACS)
Date: 31-08-2020
Two-Dimensional Channel Coding Scheme for MCTF-Based Scalable Video Coding
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2007
Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-κB, and proinflammatory cytokines
Publisher: American Society for Microbiology
Date: 05-2005
DOI: 10.1128/JVI.79.9.5353-5362.2005
Abstract: Human respiratory syncytial virus (HRSV) is the leading cause of serious pediatric acute respiratory tract infections, and a better understanding is needed of the host response to HRSV and its attenuated vaccine derivatives. It has been shown previously that HRSV nonstructural proteins 1 and 2 (NS1 and NS2) inhibit the induction of alpha/beta interferon (IFN-α/β) in A549 cells and human macrophages. Two principal transcription factors for the early IFN-β and -α1 response are interferon regulatory factor 3 (IRF-3) and nuclear factor κB (NF-κB). At early times postinfection, wild-type HRSV and the NS1/NS2 deletion mutants were very similar in the ability to activate IRF-3. However, once NS1 and NS2 were expressed significantly, they acted cooperatively to suppress activation and nuclear translocation of IRF-3. Since these viruses differed greatly in the induction of IFN-α/β, NF-κB activation was evaluated in Vero cells, which lack the structural genes for IFN-α/β and would preclude confounding effects of IFN-α/β. This showed that deletion of the NS2 gene sharply reduced the ability of HRSV to induce activation of NF-κB. Since recombinant HRSVs from which the NS1 or NS2 genes have been deleted are being developed as vaccine candidates, we investigated whether the changes in activation of host transcription factors and increased IFN-α/β production had an effect on the epithelial production of proinflammatory factors. Viruses lacking NS1 and/or NS2 stimulated modestly lower production of RANTES (Regulated on Activation Normal T-cell Expressed and Secreted), interleukin 8, and tumor necrosis factor alpha compared to wild-type recombinant RSV, supporting their use as attenuated vaccine candidates.
Humidity-dependent survival of an airborne influenza a virus: Practical implications for controlling airborne viruses
Publisher: American Chemical Society (ACS)
Date: 20-04-2021
2022 taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales
Publisher: Springer Science and Business Media LLC
Date: 28-11-2022
DOI: 10.1007/S00705-022-05546-Z
Abstract: In March 2022, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by two new families (bunyaviral Discoviridae and Tulasviridae), 41 new genera, and 98 new species. Three hundred forty-nine species were renamed and/or moved. The accidentally misspelled names of seven species were corrected. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.
Viral and host factors determine innate immune responses in airway epithelial cells from children with wheeze and atopy
Publisher: BMJ
Date: 07-05-2014
Abalone Collagen Extracts Potentiate Stem Cell Properties of Human Epidermal Keratinocytes
Publisher: MDPI AG
Date: 20-07-2019
DOI: 10.3390/MD17070424
Abstract: Stem cell activities in human tissues are critical for tissue integrity and function. Maintaining keratinocyte stem cells (KSCs) stemness helps sustain healthy skin by supporting keratinocyte renewal, involving the formation of epidermal barriers. In this study, abalone collagen (AC) extracts with molecular weights of 3 kDa (AC 1) and 300 kDa (AC 2) were compared to the epidermal growth factor (EGF) for their effects on cell proliferation, cell migration (wound healing), spheroid formation, and the expression level of stem cell markers on human keratinocytes (HaCaT cells). Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell proliferation was quantified by ATP and DNA content analysis and Sulforhodamine B (SRB) assays. Cell migration assay was determined using the scratch wound healing test. Spheroid formation was evaluated and the expression level of stem cell markers was investigated by western blot analysis. The results showed that AC 1 at the concentration of 100 µg/mL could stimulate HaCaT cell proliferation, migration, spheroid formation, and the expression level of stem cell markers (keratin 19, β-catenin, ALDH1A1) compared to the control. In conclusion, a smaller molecular weight of abalone collagen extract exhibits a better effect on keratinocytes proliferation, migration, and stemness, which could be a potential active ingredient in cosmeceutical products.
Nanocarrier-mediated delivery of α-mangostin for non-surgical castration of male animals
Publisher: Springer Science and Business Media LLC
Date: 24-11-2017
DOI: 10.1038/S41598-017-16563-3
Abstract: The overpopulation of abandoned and stray companion animals has become a global crisis. The main purpose of this study was to develop a novel nanomedicine-based antifertility compound for non-surgical castration of male animals. Mangosteen ( Garcinia mangostana L) pericarp extract has been shown to exhibit anti-fertility property. α-mangostin (AM)-loaded nanostructured lipid carrier (AM-NLC) was developed to improve male germ cell apoptosis. This study was conducted to investigate physicochemical properties of AM-NLC and determine the biological effects of AM-NLC on spermatogonia cells and testicular explants obtained from castrated testes. AM-NLC was produced through a hot homogenization technique. The negatively charged particle of AM-NLC was nano-sized with a narrow dispersity. AM-NLC exhibited antiproliferative activity towards spermatogonium cells. It induced apoptosis in the cells. In addition, AM-NLC exhibited anti-inflammatory activities in lipopolysaccharide-activated macrophages. Abnormal anatomy of seminiferous tubule was noted following treatment of testicular explant with AM-NLC. This nanomedicine-based sterilant would be a promising platform that may have utility in non-surgical castration of male animals by intra-testicular injection.
Gill-associated virus of Penaeus monodon prawns: an invertebrate virus with ORF1a and ORF1b genes related to arteri- and coronaviruses
Publisher: Microbiology Society
Date: 06-2000
DOI: 10.1099/0022-1317-81-6-1473
Abstract: A 20089 nucleotide (nt) sequence was determined for the 5' end of the (+)-ssRNA genome of gill-associated virus (GAV), a yellow head-like virus infecting Penaeus monodon prawns. Clones were generated from a approximately 22 kb dsRNA purified from lymphoid organ total RNA of GAV-infected prawns. The region contains a single gene comprising two long overlapping open reading frames, ORF1a and ORF1b, of 4060 and 2646 amino acids, respectively. The ORFs are structurally related to the ORF1a and ORF1ab polyproteins of coronaviruses and arteriviruses. The 99 nt overlap between ORF1a and ORF1b contains a putative AAAUUUU 'slippery' sequence associated with -1 ribosomal frameshifting. A 131 nt stem-loop with the potential to form a complex pseudoknot resides 3 nt downstream of this sequence. Although different to the G/UUUAAAC frameshift sites and 'H-type' pseudoknots of nidoviruses, in vitro transcription/translation analysis demonstrated that the GAV element also facilitates read-through of the ORF1a/1b junction. As in coronaviruses, GAV ORF1a encodes a 3C-like cysteine protease domain located between two hydrophobic regions. However, its sequence suggests some structural relationship to the chymotrypsin-like serine proteases of arteriviruses. ORF1b encodes homologues of the 'SDD' polymerase, which among (+)-RNA viruses is unique to nidoviruses, as well as metal-ion-binding and helicase domains. The presence of a dsRNA replicative intermediate and ORF1a and ORF1ab polyproteins translated by a-1 frameshift suggests that GAV represents the first invertebrate member of the Order NIDOVIRALES:
Cell-based assay for characterizing cell adhesion properties of active targeted nanoparticles under static and flow condition using an integrated flow chamber
Publisher: Elsevier BV
Date: 06-2018
Differential neutrophil activation in viral infections: EnhancedTLR ‐7/8‐mediatedCXCL 8 release in asthma
Publisher: Wiley
Date: 18-10-2015
DOI: 10.1111/RESP.12657
Ancestral area reconstruction of sars-cov-2 indicates multiple sources of entry into Australia
Publisher: Bentham Science Publishers Ltd.
Date: 02-11-2021
DOI: 10.2174/1875036202114010013
Abstract: The ongoing COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). International travels to Australia during the early stages of the pandemic prior to border closure provided avenues for this virus to spread into Australia. Studies of SARS-CoV-2 biogeographical distribution can contribute to the understanding of the viral original sources to Australia. This study aimed to investigate the clonality and ancestral sources of Australian SARS-CoV-2 isolates using phylogenetic methods. We retrieved 1,346 complete genomes from Australia along with 153 genomes from other countries from the GISAID and NCBI nucleotide databases as of the 14 th May 2020. A representative dataset of 270 Australian and international sequences were resulted from performance of nucleotide redundancy reduction by CD-HIT. We then constructed a median-joining network by Network 10.1.0.0, and phylogenies by IQ-Tree, BEAST and FastTree. The Bayesian statistical dispersal-vicariance analysis (S-DIVA) and Bayesian interference for discrete areas (BayArea) built in RASP were used to reconstruct ancestral ranges over the phylogenetic trees. Two major clusters, from Europe and from Asia, were observed on the network of 183 haplotypes with distinct nucleotide variations. Analysis of ancestral area reconstruction over the phylogenies indicated most Australian SARS-CoV-2 sequences were disseminated from Europe and East Asia-Southeast Asia. The finding is genetic evidence for the geographic origins of the Australian SARS-CoV-2 sequences. Most Australian sequences were genetically similar to those from Europe and East Asia-Southeast Asia, which were also suggested as two main sources of introduction of SARS-CoV-2 to Australia.
Cationic liposome of hen egg white lysozyme for enhanced its stability, activity and accessibility in gastro-intestinal tract
Publisher: Elsevier BV
Date: 06-2023
In silico Analysis of Genetic Diversity of Human Hepatitis B Virus in Southeast Asia, Australia and New Zealand
Publisher: MDPI AG
Date: 09-04-2020
DOI: 10.3390/V12040427
Abstract: The extent of whole genome ersity amongst hepatitis B virus (HBV) genotypes is not well described. This study aimed to update the current distribution of HBV types and to investigate mutation rates and nucleotide ersity between genotypes in Southeast Asia, Australia and New Zealand. We retrieved 930 human HBV complete genomes from these regions from the NCBI nucleotide database for genotyping, detection of potential recombination, serotype prediction, mutation identification and comparative genome analyses. Overall, HBV genotypes B (44.1%) and C (46.2%) together with predicted serotypes adr (36%), adw2 (29%) and ayw1 (19.9%) were the most commonly circulating HBV types in the studied region. The three HBV variants identified most frequently were p.V5L, c.1896G A and double mutation c.1762A T/c.1764G A, while genotypes B and C had the widest range of mutation types. The study also highlighted the distinct nucleotide ersity of HBV genotypes for whole genome and along the genome length. Therefore, this study provided a robust update to HBV currently circulating in Southeast Asia, Australia and New Zealand as well as an insight into the association of HBV genetic hypervariability and prevalence of well reported mutations.
Antimicrobial Activity Enhancers: Towards Smart Delivery of Antimicrobial Agents
Publisher: MDPI AG
Date: 18-03-2022
DOI: 10.3390/ANTIBIOTICS11030412
Abstract: The development of effective treatments against infectious diseases is an extensive and ongoing process due to the rapid adaptation of bacteria to antibiotic-based therapies. However, appropriately designed activity enhancers, including antibiotic delivery systems, can increase the effectiveness of current antibiotics, overcoming antimicrobial resistance and decreasing the chance of contributing to further bacterial resistance. The activity/delivery enhancers improve drug absorption, allow targeted antibiotic delivery, improve their tissue and biofilm penetration and reduce side effects. This review provides insights into various antibiotic activity enhancers, including polymer, lipid, and silver-based systems, designed to reduce the adverse effects of antibiotics and improve formulation stability and efficacy against multidrug-resistant bacteria.
A HIV-1 Tat mutant protein disrupts HIV-1 Rev function by targeting the DEAD-box RNA helicase DDX1
Publisher: Springer Science and Business Media LLC
Date: 12-2014
2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales
Publisher: Springer Science and Business Media LLC
Date: 04-09-2020
The role of respiratory droplet physicochemistry in limiting and promoting the airborne transmission of human coronaviruses: A critical review
Publisher: Elsevier BV
Date: 05-2021
Eight Indole Alkaloids from the Roots of Maerua siamensis and Their Nitric Oxide Inhibitory Effects
Publisher: MDPI AG
Date: 04-11-2022
DOI: 10.3390/MOLECULES27217558
Abstract: Maerua siamensis (Capparaceae) roots are used for treating pain and inflammation in traditional Thai medicine. Eight new indole alkaloids, named maeruanitriles A and B, maeroximes A–C, and maeruabisindoles A–C, were isolated from them. Spectroscopic methods and computational analysis were applied to determine the structure of the isolated compounds. Maeroximes A–C possesses an unusual O-methyloxime moiety. The bisindole alkaloid maeruabisindoles A and B possess a rare azete ring, whereas maeruabisindole C is the first indolo[3,2-b]carbazole derivative found in this plant family. Five compounds [maeruanitriles A and B, maeroxime C, maeruabisindoles B, and C] displayed anti-inflammatory activity by inhibiting nitric oxide (NO) production in the lipopolysaccharide-induced RAW 264.7 cells. Maeruabisindole B was the most active inhibitor of NO production, with an IC50 of 31.1 ± 1.8 μM compared to indomethacin (IC50 = 150.0 ± 16.0 μM) as the positive control.
Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JACI.2016.02.039
Abstract: Frequent viral lower respiratory infections in early life are an independent risk factor for asthma onset. This risk and the development of persistent asthma are significantly greater in children who later become sensitized. We sought to elucidate the pathogenic processes that underlie the synergistic interplay between allergen exposures and viral infections. Mice were inoculated with a murine-specific Pneumovirus species (pneumonia virus of mice [PVM]) and exposed to low-dose cockroach extract (CRE) in early and later life, and airway inflammation, remodeling, and hyperreactivity assessed. Mice were treated with anti-IL-33 or apyrase to neutralize or block IL-33 release. PVM infection or CRE exposure alone did not induce disease, whereas PVM/CRE coexposure acted synergistically to induce the hallmark features of asthma. CRE exposure during viral infection in early life induced a biphasic IL-33 response and impaired IFN-α and IFN-λ production, which in turn increased epithelial viral burden, airway smooth muscle growth, and type 2 inflammation. These features were ameliorated when CRE-induced IL-33 release was blocked or neutralized, whereas substitution of CRE with exogenous IL-33 recapitulated the phenotype observed in PVM/CRE-coexposed mice. Mechanistically, IL-33 downregulated viperin and interferon regulatory factor 7 gene expression and rapidly degraded IL-1 receptor-associated kinase 1 expression in plasmacytoid dendritic cells both in vivo and in vitro, leading to Toll-like receptor 7 hyporesponsiveness and impaired IFN-α production. We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.
Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a–mediated T reg expansion
Publisher: Rockefeller University Press
Date: 22-12-2017
DOI: 10.1084/JEM.20170298
Abstract: Respiratory syncytial virus–bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.
Computer-Aided Virtual Screening and In Vitro Validation of Biomimetic Tyrosinase Inhibitory Peptides from Abalone Peptidome
Publisher: MDPI AG
Date: 05-02-2023
DOI: 10.3390/IJMS24043154
Abstract: Hyperpigmentation is a medical and cosmetic problem caused by an excess accumulation of melanin or the overexpression of the enzyme tyrosinase, leading to several skin disorders, i.e., freckles, melasma, and skin cancer. Tyrosinase is a key enzyme in melanogenesis and thus a target for reducing melanin production. Although abalone is a good source of bioactive peptides that have been used for several properties including depigmentation, the available information on the anti-tyrosinase property of abalone peptides remains insufficient. This study investigated the anti-tyrosinase properties of Haliotis ersicolor tyrosinase inhibitory peptides (hdTIPs) based on mushroom tyrosinase, cellular tyrosinase, and melanin content assays. The binding conformation between peptides and tyrosinase was also examined by molecular docking and dynamics study. KNN1 showed a high potent inhibitory effect on mushroom tyrosinase with an IC50 of 70.83 μM. Moreover, our selected hdTIPs could inhibit melanin production through the reductions in tyrosinase activity and reactive oxygen species (ROS) levels by enhancing the antioxidative enzymes. RF1 showed the highest activity on both cellular tyrosinase inhibition and ROS reduction. leading to the lower melanin content in B16F10 murine melanoma cells. Accordingly, it can be assumed that our selected peptides exhibited high potential in medical cosmetology applications.
Development of Tea Seed Oil Nanostructured Lipid Carriers and In Vitro Studies on Their Applications in Inducing Human Hair Growth
Publisher: MDPI AG
Date: 04-05-2022
DOI: 10.3390/PHARMACEUTICS14050984
Abstract: Synthetic drugs used to treat hair loss cause many side-effects. Natural tea seed oil possesses many activities that can suppress hair loss. However, it is oily and sticky in direct application. In this study, tea seed oil loaded nanostructured lipid carriers (NLC) using Tween 80 (NLC-T), Varisoft 442 (NLC-V), and a combination of both surfactants (NLC-C) was developed. The obtained nanoformulations showed spherical particles in the size range 130–430 nm. Particle size and size distribution of NLC-C and NLC-T after storage at 4, 25, and 40 °C for 90 days were unchanged, indicating their excellent stability. The pH of NLC-T, NLC-V, and NLC-C throughout 90 days remained at 3, 4, and 3.7, respectively. NLC-C showed significantly greater nontoxicity and growth-stimulating effect on human follicle dermal papilla (HFDP) cells than the intact oil. NLC-T and NLC-V could not stimulate cell growth and showed high cytotoxicity. NLC-C showed melting point at 52 ± 0.02 °C and its entrapment efficiency was 96.26 ± 2.26%. The prepared hair serum containing NLC-C showed better spreading throughout the formulation than that containing the intact oil. Using 5% NLC-C showed a 78.8% reduction in firmness of the hair serum while enhancing diffusion efficiency by reducing shear forces up to 81.4%. In conclusion, the developed NLC-C of tea seed oil is an effective alternative in stimulating hair growth. Hair serum containing NLC-C obviously reduces sticky, oily, and greasy feeling after use.
Related Organisations
National Institute Of Allergy And Infectious Diseases
Location: United States of America
Commonwealth Scientific And Industrial Research Organisation
Location: Australia
Related Funding Activities
Discovery Projects - Grant ID: DP230100721
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View Funded ActivityLinkage Projects - Grant ID: LP200301123
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View Funded ActivityDiscovery Projects - Grant ID: DP170102733
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