ORCID Profile
0000-0001-8577-8628
Current Organisation
Mater Research Institute The University of Queensland
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Publisher: Springer Science and Business Media LLC
Date: 02-11-2014
DOI: 10.1038/NM.3705
Abstract: In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.
Publisher: Frontiers Media SA
Date: 14-06-2022
DOI: 10.3389/FCIMB.2022.856962
Abstract: The mucosal surfaces that form the boundary between the external environment and the underlying tissue are protected by a mucus barrier. Mucin glycoproteins, both secreted and cell surface mucins, are the major components of the barrier. They can exclude pathogens and toxins while hosting the commensal bacteria. In this review, we highlight the dynamic function of the mucins and mucus during infection, how this mucosal barrier is regulated, and how pathogens have evolved mechanisms to evade this defence system.
Publisher: Informa UK Limited
Date: 07-2020
DOI: 10.2147/DMSO.S251567
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.TIPS.2021.08.005
Abstract: Macromolecular therapeutics of biological origin, also known as biologics, have become one of the fastest-growing classes of drugs for management of a range of chronic and acute conditions. The majority of approved biologics are administered via the parenteral route and are thus expensive, have low patient compliance, and have high systemic toxicity. Therefore, tremendous efforts have been devoted to the development of carriers for oral delivery of biologics. This review evaluates key chemical (e.g. pH and enzymes) and physiological challenges to oral biologics delivery. We review the conventional formulation strategies and their limitations, followed by a detailed account of the progress on the use of nanocarriers used for oral biologics delivery, covering organic and inorganic nanocarriers. Lastly, we discuss limitations and opportunities presented by these emerging nanomaterials in oral biologics delivery.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.BIOCEL.2012.10.011
Abstract: The body's mucosal surfaces are protected from pathogens and physical and chemical attack by the gel-like extracellular matrix, mucus. The framework of this barrier is provided by polymeric, gel-forming mucins. These enormous O-linked glycoproteins are synthesised, stored and secreted by goblet cells that are also the source of other protective factors. Immune regulation of goblet cells during the course of infection impacts on mucin production and properties and ultimately upon barrier function. The barrier function of mucins in protection of the host is well accepted as an important aspect of innate defence. However, it is becoming increasingly clear that mucins have a much more direct role in combating pathogens and parasites and are an important part of the coordinated immune response to infection. Of particular relevance to this review is the finding that mucins are essential anti-parasitic effector molecules. The current understanding of the roles of these multifunctional glycoproteins, and other goblet cell products, in mucosal defence against intestinal dwelling nematodes is discussed.
Publisher: Springer Science and Business Media LLC
Date: 04-08-2017
Publisher: Elsevier BV
Date: 07-2021
Publisher: Public Library of Science (PLoS)
Date: 16-08-2018
Publisher: eLife Sciences Publications, Ltd
Date: 22-07-2020
DOI: 10.7554/ELIFE.56907
Abstract: Diabetes mellitus is a known susceptibility factor for severe influenza virus infections. However, the mechanisms that underlie this susceptibility remain incompletely understood. Here, the effects of high glucose levels on influenza severity were investigated using an in vitro model of the pulmonary epithelial-endothelial barrier as well as an in vivo murine model of type II diabetes. In vitro we show that high glucose conditions prior to IAV infection increased virus-induced barrier damage. This was associated with an increased pro-inflammatory response in endothelial cells and the subsequent damage of the epithelial junctional complex. These results were subsequently validated in vivo . This study provides the first evidence that hyperglycaemia may increase influenza severity by damaging the pulmonary epithelial-endothelial barrier and increasing pulmonary oedema. These data suggest that maintaining long-term glucose control in in iduals with diabetes is paramount in reducing the morbidity and mortality associated with influenza virus infections.
Publisher: Wiley
Date: 27-06-2014
DOI: 10.1002/ART.38638
Abstract: Spondyloarthritides (SpA) occur in 1% of the population and include ankylosing spondylitis (AS) and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis, and IBD. Genetic studies implicate interleukin-23 (IL-23) receptor signaling in the development of SpA and IBD, and IL-23 overexpression in mice is sufficient for enthesitis, driven by entheseal-resident T cells. However, in genetically prone in iduals, it is not clear where IL-23 is produced and how it drives the SpA syndrome, including IBD or subclinical gut inflammation of AS. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We undertook this study to determine the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP-70(W163C)-mutant (SKG) mice injected intraperitoneally with β-1,3-glucan (curdlan). Eight weeks after curdlan injection in wild-type or IL-17A(-/-) SKG or BALB/c mice, pathology was scored in tissue sections. Mice were treated with anti-IL-23 or anti-IL-22. Cytokine production and endoplasmic reticulum (ER) stress were determined in affected organs. In curdlan-treated SKG mice, arthritis, enthesitis, and ileitis were IL-23 dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-23 was induced in the ileum, where it lified ER stress, goblet cell dysfunction, and proinflammatory cytokine production. IL-17A was pathogenic, while IL-22 was protective against ileitis. IL-22+CD3- innate-like cells were increased in lamina propria mononuclear cells of ileitis-resistant BALB/c mice, which developed ileitis after curdlan injection and anti-IL-22. In response to systemic β-1,3-glucan, intestinal IL-23 provokes local mucosal dysregulation and cytokines driving the SpA syndrome, including IL-17/IL-22-dependent enthesitis. Innate IL-22 production promotes ileal tolerance.
Publisher: Wiley
Date: 21-12-2012
DOI: 10.1111/J.1440-1746.2011.06909.X
Abstract: The gastrointestinal tract is protected by a mucus barrier with both secreted and cell-surface mucins contributing to the exclusion of luminal microbes and toxins. Alterations in the structure and/or quantity of mucins alter the barrier function of mucus and could play roles in initiating and maintaining mucosal inflammation in inflammatory bowel diseases (IBD), and in driving cancer development in the intestine. The aim of this review is to focus on the roles of the mucins in IBD. The polymorphisms of mucin genes that have been associated with susceptibility to IBD, and alterations in mucin expression as well as factors that regulate production of the mucins in IBD, are summarized. Data from animal models of intestinal inflammation, which support the importance of mucins in IBD and cancer development, are also discussed.
Publisher: MDPI AG
Date: 11-04-2019
DOI: 10.3390/NU11040815
Abstract: The positive effects of dietary fibre on gut barrier function and inflammation have not been completely elucidated. Mice studies show gut barrier disruption and diet-induced insulin resistance can be alleviated by cytokine interleukin-22 (IL-22). However, little is known about IL-22 in humans and its association with gut-beneficial nutrients like fibre. We investigated whether fibre intake was associated with circulating levels of IL-22 in 48 participants with metabolic syndrome (MetS). Bivariate analysis was used to explore associations between circulating IL-22, fibre intake, MetS factors, body composition, and cardiorespiratory fitness (peak oxygen uptake, V ˙ O2peak). Hierarchical multiple regression (HMR) was used to test the independent association of fibre intake with circulating IL-22, adjusting for variables correlated with IL-22. Circulating IL-22 was positively associated with fibre intake (rs = 0.393, p 0.006). The HMR-adjusted model explained 40% of circulating IL-22 variability, and fibre intake significantly improved the prediction model by 8.4% (p 0.022). Participants with fibre intake above median intake of 21.5 g/day had a significantly higher circulating IL-22 than the lower intake group (308.3 ± 454.4 vs. 69.0 ± 106.4 pg/mL, p 0.019). Fibre intake is independently associated with increased circulating IL-22 in in iduals with MetS. Findings warrant further investigations to evaluate whether changes in dietary fibre intake alter circulating IL-22, and its effects on health outcomes.
Publisher: Frontiers Media SA
Date: 24-07-2020
Publisher: Wiley
Date: 26-09-2014
DOI: 10.1002/ART.38773
Abstract: The spondyloarthritides share genetic susceptibility, interleukin-23 (IL-23) dependence, and the involvement of microbiota. The aim of the current study was to elucidate how host genetics influence gut microbiota and the relationship between microbiota and organ inflammation in spondyloarthritides. BALB/c ZAP-70(W163C) -mutant (SKG) mice, Toll-like receptor 4 (TLR-4)-deficient SKG mice, and wild-type BALB/c mice were housed under specific pathogen-free conditions. SKG and wild-type BALB/c mice were maintained under germ-free conditions, and some of these mice were recolonized with altered Schaedler flora. All of the mice were injected intraperitoneally with microbial β-1,3-glucan (curdlan). Arthritis, spondylitis, and ileitis were assessed histologically. Microbiome composition was analyzed in serial fecal s les obtained from mice that were co-housed beginning at the time of weaning, using 454 pyrosequencing. Infiltrating cells and cytokines in the peritoneal cavity were measured by flow cytometry and enzyme-linked immunosorbent assay. Cytokine, endoplasmic reticulum (ER) stress marker, and tight junction protein transcription was measured by quantitative real-time polymerase chain reaction. Microbiota content and response to curdlan varied according to whether T cell receptor signal strength was normal or was impaired due to the ZAP-70(W163C) mutation. Curdlan triggered acute inflammation regardless of the presence of the SKG allele or microbiota. However, no or limited microbiota content attenuated the severity of arthritis. In contrast, ileal IL-23 expression, ER stress, lymph node IL-17A production, goblet cell loss, and ileitis development were microbiota-dependent. Ileitis but not arthritis was suppressed by microbiota transfer upon co-housing SKG mice with wild-type BALB/c mice, as well as by TLR-4 deficiency. The interaction between immunogenetic background and host microbiota leads to an IL-23-dependent loss of mucosal function, triggering ileitis in response to curdlan.
Publisher: MDPI AG
Date: 19-08-2019
DOI: 10.3390/PHARMACEUTICS11080418
Abstract: Type 2 diabetes makes up approximately 85% of all diabetic cases and it is linked to approximately one-third of all hospitalisations. Newer therapies with long-acting biologics such as glucagon-like peptide-1 (GLP-1) analogues have been promising in managing the disease, but they cannot reverse the pathology of the disease. Additionally, their parenteral administration is often associated with high healthcare costs, risk of infections, and poor patient adherence associated with phobia of needles. Oral delivery of these compounds would significantly improve patient compliance however, poor enzymatic stability and low permeability across the gastrointestinal tract makes this task challenging. In the present work, large pore dendritic silica nanoparticles (DSNPs) with a pore size of ~10 nm were prepared, functionalized, and optimized in order to achieve high peptide loading and improve intestinal permeation of exenatide, a GLP-1 analogue. Compared to the loading capacity of the most popular, Mobil Composition of Matter No. 41 (MCM-41) with small pores, DSNPs showed significantly high loading owing to their large and dendritic pore structure. Among the tested DSNPs, pristine and phosphonate-modified DSNPs (PDSNPs) displayed remarkable loading of 40 and 35% w/w, respectively. Furthermore, particles successfully coated with positively charged chitosan reduced the burst release of exenatide at both pH 1.2 and 6.8. Compared with free exenatide, both chitosan-coated and uncoated PDSNPs enhanced exenatide transport through the Caco-2 monolayer by 1.7 fold. Interestingly, when a triple co-culture model of intestinal permeation was used, chitosan-coated PDSNPs performed better compared to both PDSNPs and free exenatide, which corroborated our hypothesis behind using chitosan to interact with mucus and improve permeation. These results indicate the emerging role of large pore silica nanoparticles as promising platforms for oral delivery of biologics such as exenatide.
Publisher: Public Library of Science (PLoS)
Date: 13-02-2017
Publisher: Wiley
Date: 2018
DOI: 10.1002/CTI2.1035
Publisher: Bioscientifica
Date: 17-11-2015
DOI: 10.1530/JME-15-0232
Abstract: The inability of pancreatic β-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on β-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in β-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic β-cell defects in rare forms of diabetes, in T2D β-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to β-cell stress in diabetes and our discovery that interleukin 22 protects β-cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that β-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control.
Publisher: Wiley
Date: 2018
DOI: 10.1002/CTI2.1014
Publisher: MDPI AG
Date: 15-07-2019
DOI: 10.3390/IJMS20143468
Abstract: The interleukin (IL)-20 subfamily of cytokines consists of IL-19, IL-20, IL-22, IL-24, and IL-26, and the expression of IL-20, IL-22, and IL-24 is reported to be higher in the colon of patients with ulcerative colitis. Although the receptors for these cytokines are highly expressed in the colon epithelium, their effects on epithelial renewal are not clearly understood. This study evaluated the effects of IL-20, IL-22, and IL-24 in epithelial renewal using the LS174T human colon cancer epithelial cell line. LS174T cells were treated with IL-20, IL-22, and IL-24 (25, 50, and 100 ng/mL) and a live-cell imaging system was used to evaluate the effects on cell proliferation. Following treatment, the signaling pathways contributing to cell proliferation were investigated through Western blotting in LS174T cells and downstream transcriptional changes through qRT-PCR in LS174T cells, and RNA-Seq in primary murine intestinal epithelial cells. Our results demonstrated that only IL-22 promoted LS174T cell proliferation, mediated via extracellular-signal-regulated kinase (ERK)1/2-mediated downstream regulation of p90RSK, c-Jun, and transcriptional changes of TRIM15 and STOM. IL-22 also promoted expression of ERK1/2-independent genes such as DDR2, LCN2, and LRG1, which are known to be involved in cell proliferation and migration. This study suggests that IL-22 induces cell proliferation in highly proliferative cells such as intestinal epithelial cells.
Publisher: Elsevier BV
Date: 05-2010
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1038/MI.2016.132
Publisher: Rockefeller University Press
Date: 18-04-2011
DOI: 10.1084/JEM.20102057
Abstract: De novo expression of Muc5ac, a mucin not normally expressed in the intestinal tract, is induced in the cecum of mice resistant to Trichuris muris infection. In this study, we investigated the role of Muc5ac, which is detected shortly before worm expulsion and is associated with the production of interleukin-13 (IL-13), in resistance to this nematode. Muc5ac-deficient mice were incapable of expelling T. muris from the intestine and harbored long-term chronic infections, despite developing strong TH2 responses. Muc5ac-deficient mice had elevated levels of IL-13 and, surprisingly, an increase in the TH1 cytokine IFN-γ. Because TH1 inflammation is thought to favor chronic nematode infection, IFN-γ was neutralized in vivo, resulting in an even stronger TH2-type immune response. Nevertheless, despite a more robust TH2 effector response, the Muc5ac-deficient mice remained highly susceptible to chronic T. muris infection. Importantly, human MUC5AC had a direct detrimental effect on nematode vitality. Moreover, the absence of Muc5ac caused a significant delay in the expulsion of two other gut-dwelling nematodes (Trichinella spiralis and Nippostrongylus brasiliensis). Thus, for the first time, we identify a single mucin, Muc5ac, as a direct and critical mediator of resistance during intestinal nematode infection.
Publisher: American Thoracic Society
Date: 02-2022
Publisher: BMJ
Date: 17-04-2014
Publisher: Springer Science and Business Media LLC
Date: 19-08-2019
DOI: 10.1038/S41388-019-0951-Y
Abstract: Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced β-catenin signaling, have more tumor-infiltrating CD103
Publisher: Informa UK Limited
Date: 2021
Publisher: Oxford University Press (OUP)
Date: 05-2015
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1053/J.GASTRO.2012.10.043
Abstract: Protein misfolding and endoplasmic reticulum (ER) stress have been observed in intestinal secretory cells from patients with inflammatory bowel diseases and induce intestinal inflammation in mice. However, it is not clear how immune factors affect ER stress and therefore disease symptoms. We analyzed the effects of interleukin (IL)-10 on ER stress in intestinal tissues in wild-type C57BL/6, Winnie, IL-10(-/-), and Winnie × IL-10(+/-) mice. In Winnie mice, misfolding of the intestinal mucin Muc2 initiates ER stress and inflammation. We also analyzed the effects of different inhibitors of IL-10 signaling and the N-glycosylation inhibitor tunicamycin in cultured human LS174T goblet cells. Administration of neutralizing antibodies against IL-10 or its receptor (IL-10R1) to Winnie mice rapidly exacerbated ER stress and intestinal inflammation compared with mice given vehicle (controls). Antibodies against IL-10 also increased accumulation of misfolded Muc2 in the ER of goblet cells of Winnie mice and increased T-cell production of inflammatory cytokines. Winnie × IL-10(+/-) mice and IL-10(-/-) mice with a single Winnie allele each developed more severe inflammation than Winnie mice or IL-10(-/-) mice. Administration of tunicamycin to wild-type mice caused intestinal ER stress, which increased when IL-10R1 was blocked. In LS174T cells, induction of ER stress with tunicamycin and misfolding of MUC2 were reduced by administration of IL-10 this reduction required STAT1 and STAT3. In LS174T cells incubated with tunicamycin, IL-10 up-regulated genes involved in MUC2 folding and in ER-associated degradation and maintained correct folding of MUC2, its transport from the ER, and its O-glycosylation and secretion. IL-10 prevents protein misfolding and ER stress by maintaining mucin production in goblet cells and helps the intestine preserve the mucus barrier.
Publisher: Elsevier BV
Date: 2020
Publisher: MDPI AG
Date: 22-12-2022
DOI: 10.3390/IJMS24010174
Abstract: The cytokine Interleukin (IL)-20 belongs to the IL-10 superfamily. IL-20 levels are reported to increase in the intestines of Ulcerative Colitis (UC) patients, however not much is known about its effects on intestinal epithelial cells. Here, we investigated the influence of IL-20 on intestinal epithelial cell lines and primary intestinal organoid cultures. By using chemical-induced (dextran sodium sulphate DSS) colitis and a spontaneous model of colitis (Winnie mice), we assess whether recombinant IL-20 treatment is beneficial in reducing/improving pathology. Following stimulation with IL-20, intestinal primary organoids from wild-type and Winnie mice increased the expression of ERK1/2. However, this was lost when cells were differentiated into secretory goblet cells. Importantly, IL-20 treatment significantly reduced endoplasmic reticulum (ER) stress, as measured by spliced-XBP1 in epithelial cells, and this effect was lost in the goblet cells. IL-20 treatment in vivo in the DSS and Winnie models had minimal effects on pathology, but a decrease in macrophage activation was noted. Taken together, these data suggest a possible, but subtle role of IL-20 on epithelial cells in vivo. The therapeutic potential of IL-20 could be harnessed by the development of a targeted therapy or combination therapy to improve the healing of the mucosal barrier.
Publisher: Informa UK Limited
Date: 22-12-2017
Publisher: Wiley
Date: 14-12-2010
Publisher: Public Library of Science (PLoS)
Date: 11-10-2012
Publisher: Humana Press
Date: 16-12-2012
DOI: 10.1007/978-1-61779-513-8_18
Abstract: Most mammalian pathogens and parasites infect their hosts via the mucosal surfaces. The first barrier they encounter in all mucosal tissues is a layer of viscous mucus which can be modulated by immune responses to the pathogen or parasite. The major macromolecular constituents of mucus are secreted mucin glycoproteins which give mucus its viscous properties. Underneath the mucus layer, the mucosal epithelial cells have a cell surface glycocalyx that is rich in transmembrane mucin glycoproteins. Both the cell surface and secreted mucins present a vast array of potential binding sites for pathogens and parasites and both forms of mucins are involved in protecting the host from infection. However, many pathogens and parasites have evolved mechanisms to subvert the mucin barrier. Thus, studying mucin interactions with pathogens and parasites is critical to understanding host-pathogen interactions at the mucosal surfaces. In this chapter, we describe methods for studying the interactions between mucins and pathogens and parasites, methods for studying the degradation of mucins by pathogens and parasites, and in vitro and in vivo methods for exploring the functional significance of the mucins in host defence from infection.
Publisher: Frontiers Media SA
Date: 06-07-2021
DOI: 10.3389/FCIMB.2021.691823
Abstract: Type 2 diabetes (T2D) is a well-known risk factor for tuberculosis (TB), but little is known about pre-diabetes and the relative contribution of impaired glucose tolerance vs. obesity towards susceptibility to TB. Here, we developed a preclinical model of pre-diabetes and TB. Mice fed a high fat diet (HFD) for 12 weeks presented with impaired glucose tolerance and hyperinsulinemia compared to mice fed normal chow diet (NCD). Infection with M. tuberculosis (Mtb) H 37 R v after the onset of dysglycemia was associated with significantly increased lung pathology, lower concentrations of TNF-α, IFN-γ, IFN-β and IL-10 and a trend towards higher bacterial burden at 3 weeks post infection. To determine whether the increased susceptibility of pre-diabetic mice to TB is reversible and is associated with dysglycemia or increased body fat mass, we performed a diet reversal experiment. Pre-diabetic mice were fed a NCD for 10 additional weeks (HFD/NCD) at which point glucose tolerance was restored, but body fat mass remained higher compared to control mice that consumed NCD throughout the entire experiment (NCD/NCD). Upon Mtb infection HFD/NCD mice had significantly lower bacterial burden compared to NCD/NCD mice and this was accompanied by restored IFN-γ responses. Our findings demonstrate that pre-diabetes increases susceptibility to TB, but a high body mass index without dysglycemia is protective. This murine model offers the opportunity to further study the underlying immunological, metabolic and endocrine mechanisms of this association.
Publisher: Elsevier BV
Date: 2022
Publisher: Rockefeller University Press
Date: 11-09-2023
DOI: 10.1084/JEM.20230106
Location: United Kingdom of Great Britain and Northern Ireland
Location: Australia
No related grants have been discovered for Sumaira Hasnain.