Melbourne Dental School - Research Publications
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ItemEosinophils in Oral Disease: A Narrative Review(MDPI, 2024-04)The prevalence of diseases characterised by eosinophilia is on the rise, emphasising the importance of understanding the role of eosinophils in these conditions. Eosinophils are a subset of granulocytes that contribute to the body's defence against bacterial, viral, and parasitic infections, but they are also implicated in haemostatic processes, including immunoregulation and allergic reactions. They contain cytoplasmic granules which can be selectively mobilised and secrete specific proteins, including chemokines, cytokines, enzymes, extracellular matrix, and growth factors. There are multiple biological and emerging functions of these specialised immune cells, including cancer surveillance, tissue remodelling and development. Several oral diseases, including oral cancer, are associated with either tissue or blood eosinophilia; however, their exact mechanism of action in the pathogenesis of these diseases remains unclear. This review presents a comprehensive synopsis of the most recent literature for both clinicians and scientists in relation to eosinophils and oral diseases and reveals a significant knowledge gap in this area of research.
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ItemTranscriptional regulation of glucose transporters in human oral squamous cell carcinoma cells(WILEY, 2022-09)The increased glucose uptake observed in cancer cells is mediated by glucose transporters (GLUTs), a class of transmembrane proteins that facilitate the transport of glucose and other substrates across the plasma membrane. Despite the important role of glucose in the pathophysiology of oral squamous cell carcinoma (OSCC), there is very limited data regarding the expression of GLUTs in normal or malignant cells from the oral mucosa. We analysed the messenger RNA (mRNA) expression of all 14 GLUTs in two OSCC (H357/H400) and one non-malignant oral keratinocyte (OKF6) cell line using a quantitative polymerase chain reaction. GLUT expression was evaluated at baseline and after treatment with two specific GLUT inhibitors, namely, BAY876 (GLUT1) and WZB117 (GLUT1, GLUT3 and GLUT4). Here, we show that GLUT1, GLUT3, GLUT4, GLUT5, GLUT6, GLUT8, GLUT12 and GLUT13 transcripts were measurably expressed in all cell lines while GLUT2, GLUT7, GLUT9, GLUT11 and GLUT14 were not expressed. GLUT10 was only found in H357. In the presence of BAY876 and WZB117, OSCC cells exhibited significant alterations in the transcriptional profile of GLUTs. In particular, we observed distinct proliferation-dependent changes of mRNAs to GLUT1, GLUT3, GLUT4, GLUT5 and GLUT6 in response to selective GLUT inhibitors. In summary, we documented for the first time the expression of GLUT5, GLUT6 and GLUT12 in normal and malignant oral keratinocytes. Whilst regulation of GLUT transcripts was cell line and inhibitor specific, GLUT3 was consistently upregulated in actively proliferating OSCC cell lines, but not in OKF6, regardless of the inhibitor used, suggesting that modulation of this transporter may act as one of the primary compensation mechanisms for OSCC cells upon inhibition of glucose uptake.
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ItemCharacterization of a novel dual murine model of chemotherapy-induced oral and intestinal mucositis(NATURE PORTFOLIO, 2023-01-25)Oral and intestinal mucositis are debilitating inflammatory diseases observed in cancer patients undergoing chemo-radiotherapy. These are devastating clinical conditions which often lead to treatment disruption affecting underlying malignancy management. Although alimentary tract mucositis involves the entire gastrointestinal tract, oral and intestinal mucositis are often studied independently utilizing distinct organ-specific pre-clinical models. This approach has however hindered the development of potentially effective whole-patient treatment strategies. We now characterize a murine model of alimentary tract mucositis using 5-Fluorouracil (5-FU). Mice were given 5-FU intravenously (50 mg/kg) or saline every 48 h for 2 weeks. Post initial injection, mice were monitored clinically for weight loss and diarrhea. The incidence and extent of oral mucositis was assessed macroscopically. Microscopical and histomorphometric analyses of the tongue and intestinal tissues were conducted at 3 interim time points during the experimental period. Repeated 5-FU treatment caused severe oral and intestinal atrophy, including morphological damage, accompanied by body weight loss and mild to moderate diarrhea in up to 77.8% of mice. Oral mucositis was clinically evident throughout the observation period in 88.98% of mice. Toluidine blue staining of the tongue revealed that the ulcer size peaked at day-14. In summary, we have developed a model reproducing the clinical and histologic features of both oral and intestinal mucositis, which may represent a useful in vivo pre-clinical model for the study of chemotherapy-induced alimentary tract mucositis and the development of preventative therapies.
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ItemSAR131675, a VEGRF3 Inhibitor, Modulates the Immune Response and Reduces the Growth of Colorectal Cancer Liver Metastasis(MDPI, 2022-06)Most patients with colorectal cancer (CRC) develop metastases, predominantly in the liver (CLM). Targeted therapies are being investigated to improve current CLM treatments. This study tested the effectiveness of SAR131675, a selective VEGFR-3 tyrosine kinase inhibitor, to inhibit CLM in a murine model. Following intrasplenic induction of CLM, mice were treated daily with SAR131675. Tumor growth and immune infiltrates into tumor and liver tissues were assessed at 10-, 16- and 22-days post tumor induction by stereology, IHC and flow cytometry. SAR151675 treatment significantly reduced tumor burden and F4/80+ macrophages in the liver tissues. Analysis of immune cell infiltrates in liver showed tissue that at day 22, had the proportion of CD45+ leukocytes significantly reduced, particularly myeloid cells. Analysis of myeloid cells (CD11b+ CD45+) indicated that the proportion of F4/80- Ly6Clow was significantly reduced, including a predominate PD-L1+ subset, while CD3+ T cells increased, particularly CD8+ PD1+, reflected by an increase in the CD8+:CD4+ T cell ratio. In the tumor tissue SAR11675 treatment reduced the predominant population of F4/80+ Ly6Clo and increased CD4+ T cells. These results suggest that SAR131675 alters the immune composition within tumor and the surrounding liver in the later stages of development, resulting in a less immunosuppressive environment. This immunomodulation effect may contribute to the suppression of tumor growth.
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ItemEnhancing proline-rich antimicrobial peptide action by homodimerization: influence of bifunctional linker(ROYAL SOC CHEMISTRY, 2022-02-23)Antimicrobial peptides (AMPs) are host defense peptides, and unlike conventional antibiotics, they possess potent broad spectrum activities and, induce little or no antimicrobial resistance. They are attractive lead molecules for rational development to improve their therapeutic index. Our current studies examined dimerization of the de novo designed proline-rich AMP (PrAMP), Chex1-Arg20 hydrazide, via C-terminal thiol addition to a series of bifunctional benzene or phenyl tethers to determine the effect of orientation of the peptides and linker length on antimicrobial activity. Antibacterial assays confirmed that dimerization per se significantly enhances Chex1-Arg20 hydrazide action. Greatest advantage was conferred using perfluoroaromatic linkers (tetrafluorobenzene and octofluorobiphenyl) with the resulting dimeric peptides 6 and 7 exhibiting potent action against Gram-negative bacteria, especially the World Health Organization's critical priority-listed multidrug-resistant (MDR)/extensively drug-resistant (XDR) Acinetobacter baumannii as well as preformed biofilms. Mode of action studies indicated these lead PrAMPs can interact with both outer and inner bacterial membranes to affect the membrane potential and stress response. Additionally, 6 and 7 possess potent immunomodulatory activity and neutralise inflammation via nitric oxide production in macrophages. Molecular dynamics simulations of adsorption and permeation mechanisms of the PrAMP on a mixed lipid membrane bilayer showed that a rigid, planar tethered dimer orientation, together with the presence of fluorine atoms that provide increased bacterial membrane interaction, is critical for enhanced dimer activity. These findings highlight the advantages of use of such bifunctional tethers to produce first-in-class, potent PrAMP dimers against MDR/XDR bacterial infections.
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ItemCommonly Prescribed Anticoagulants Exert Anticancer Effects in Oral Squamous Cell Carcinoma Cells In Vitro(MDPI, 2022-04)Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. With anticoagulant usage on the rise, it is important to elucidate their potential effects on tumour biology and interactions with chemotherapeutics. The aim of the present study was to investigate the effects of anticoagulants on OSCC cell lines and their interactions with the drug 5-fluorouracil (5-FU). Cell proliferation was assessed using an MTS in vitro assay in two human OSCC cell lines (H357/H400) and in normal oral keratinocytes (OKF6) treated with the 5-FU (0.2/1/5/10 μg/mL), conventional anticoagulants warfarin (1/5/10/20 μM) and heparin (5/20/80 U), as well as four new oral anticoagulants, dabigatran (5/10/20 μM), rivaroxaban (5/10/20 μM), apixaban (0.1/1/5 μg/mL), and edoxaban (5/10/20 μM). Cell migration was assessed at 3 h intervals up to18 h using a wound healing assay. Our results clearly demonstrate, for the first time, that commonly prescribed anticoagulants exert in vitro antiproliferative effects on OSCC cells. Furthermore, treatment with some anticoagulants reduced the migration of OSCC cell lines. Nevertheless, most of the anticoagulants tested reduced the effectiveness of the chemotherapeutic agent tested, 5-FU, highlighting potential flaws in the current pharmacological management of these patients. Our findings showed the need for the immediate translation of this research to preclinical animal models.
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ItemMilk-Derived Proteins and Peptides in Head and Neck Carcinoma Treatment(MDPI AG, 2022)Research investigating milk-derived proteins has brought to light the potential for their use as novel anticancer agents. This paper aims to systematically review studies examining the effectiveness of milk-derived proteins in the treatment of head and neck cancer. A systematic literature search of Medline, Evidence-Based Medicine, and Web of Science databases including papers published from all dates was completed. Inter-rater reliability was high during the title, abstract, and full-text screening phases. Inclusion criteria, exclusion criteria, and data extraction were based on the PICOS tool and research questions. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analysis criteria. Eligible in vitro and in vivo studies (n = 8/658) evaluated lactoferrin, α-lactalbumin, and its complexes, such as HAMLET, BAMLET and lactalbumin-oleic acid complexes, as well as lactoperoxidase, whey, and casein. Their effectiveness in the treatment of head and neck cancer cells lines found that these compounds can inhibit tumour growth modulate cancer gene expression, and have cytotoxic effects on cancer cells. However, the exact mechanisms by which these effects are achieved are not well understood. Systematically designed, large, optimally controlled, collaborative studies, both in vitro and in vivo, will be required to gain a better understanding of their potential role in the treatment of head and neck cancer.
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ItemReply to Astarita et al. Comment on "Celentano et al. Suitability of a Progenitor Cell-Enriching Device for In Vitro Applications. Coatings 2021, 11, 146"(MDPI, 2021-07)We would like to thank HBW representatives for their comments [...]