4,662 research outputs found

    Ruthenium metallotherapeutics: a targeted approach to combatting multidrug resistant pathogens

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    The discovery of antibiotics revolutionised healthcare practice. However due to overuse, inappropriate use, widespread prophylaxis therapy and the lack of new developments, the threat of antimicrobial resistance is now a major global threat to health. By 2050, it is estimated that mortality due to antimicrobial resistant infections will exceed 10 million people per annum, superseding cancer as the leading cause of global mortality. The use of drug repurposing to identify potential therapies which combat antimicrobial resistance is one potential solution. Metals have been used as antimicrobial agents throughout the history of medicine for a broad range of applications, including the use of Silver as an antimicrobial agent which dates back to antiquity. More recently, Ruthenium metallotherapeutic complexes have been shown to exhibit highly active antimicrobial properties by targeting a range of bacterial species, and in contrast to traditional antibiotics, these compounds are thought to elicit antibacterial activity at multiple sites within the bacterial cell, which may reduce the possibility of resistance evolution. This study aimed to evaluate the antimicrobial activity of a series of Ruthenium metallotherapeutic complexes against multidrug-resistant bacterial pathogens, with a focus on use within wound care applications. Antimicrobial susceptibility assays identified two lead candidates, Hexaammineruthenium (III) chloride and [Chlorido(η6-p-cymene)(N-(4-chlorophenyl)pyridine-2-carbothioamide) ruthenium (II)] chloride which demonstrated activity against Pseudomonas aeruginosa and Staphylococcus aureus respectively with MIC values ranging between 4 μg mL-1 and 16 μg mL-1. Furthermore, Hexaammineruthenium (III) chloride demonstrated antibiofilm activity in both a time and concentration-dependent manner. Synergy studies combining lead complexes with antibiotics demonstrated the potential for use as resistance breakers. Subsequent in vitro infection modelling using scratch assays with skin cell lines, coupled with a 3D full thickness skin wound infection model was used to determine potential applied applications of Hexaammineruthenium (III) chloride for use as topical antimicrobial agent against P. aeruginosa infections. Antimicrobial mechanistic studies demonstrated that Hexaammineruthenium (III) chloride targeted the bacterial cell ultrastructure of P. aeruginosa strain PAO1 as cell perturbations were observed when treated cells were analysed by scanning electron microscopy. Furthermore, exposure of P. aeruginosa PAO1 to Hexaammineruthenium (III) chloride also resulted in a concentration dependent membrane depolarisation, which further supported the antimicrobial mechanistic role. Finally, global changes in gene expression following exposure of P. aeruginosa strain PAO1 to Hexaammineruthenium (III) chloride were explored by RNA sequencing. Genes involved in ribosome function, cofactor biosynthesis and membrane fusion were downregulated, which provided a further insight into the wider mechanisms of antibacterial activity. The research conducted in the present study indicated the potential use of Hexaammineruthenium (III) chloride (and derivatives) as a potential treatment option for chronic wounds infected with P. aeruginosa, which could be applied as either a direct treatment or used within antimicrobial wound care applications

    The evolution of nutritional care in children and young people with acute lymphoblastic leukaemia: a narrative review

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    This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: Data sharing is not applicable to this article as no new data were created or analysed in this study.Background: Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy in the world. Advances in treatment protocols have resulted in survival rates of >80% in most high‐income countries (HIC); however, children and young people (CYP) with ALL continue to face significant nutrition‐related challenges during treatment. Methods: This narrative review outlines the changing landscape of treatment and survivorship for CYP with ALL and the advances in nutrition knowledge that call for changes to clinical nutrition practice. Results: The incidence of ALL has remained stable in HIC; however, there have been significant advances in survival over the past 30 years. Overweight and obesity are increasingly prevalent in CYP with ALL at diagnosis, during treatment and in survivorship. Coupled with poor diet quality, high‐energy and saturated fat intakes, altered eating behaviours and inactivity, this necessitates the need for a shift in nutrition intervention. Undernutrition remains a concern for CYP with high‐risk treatment protocols where oral or enteral nutrition support remains a cornerstone of maintaining nutrition status. Conclusions: With improved treatment protocols and high survival rates, a shift to focusing on diet quality, prevention of excessive weight gain and obesity during treatment and survivorship is necessary

    Medicinal cannabis as a potential treatment for chronic pain and anxiety

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    Since its legalisation in Australia in 2016, the most common indications for which medicinal cannabis is prescribed are chronic pain and anxiety. This thesis aimed to explore the real-world use of cannabis for these indications, and the potential of translating this evidence into a clinical trial setting. The effectiveness and tolerability of medicinal cannabis for chronic pain, with a subset analysis on arthritis was explored using data from the CA Clinics Observational Study (CACOS). The chronic pain patients and arthritis subset reported significantly reduced pain intensity, with dry mouth, somnolence, and fatigue the most common AEs reported. The incidence of AEs in this cohort, and the association that these may have with concomitant medicines, cannabis constituents, and dose was also reported. Each patient was taking a median of six concomitant medications. Patients taking a gabapentinoid were more likely to report dizziness, and those taking a tricyclic antidepressant were more likely to report somnolence and anxiety. Next in this thesis clinical trial protocols were developed, the first to examine the efficacy of a transdermal CBD cream on patients with osteoarthritis. The second protocol follows a review on aromatase inhibitor associated-arthralgia, and proposes an oral CBD-extract to improve joint pain and health-related quality of life (HRQoL). Finally, use of cannabis for anxiety was reviewed and the effectiveness and tolerability of cannabis for anxiety, including post-traumatic stress disorder (PTSD) was explored using CACOS data. Significantly reduced anxiety was observed in patients with unspecified anxiety and PTSD, and the most common AEs reported were dry mouth, somnolence, and fatigue. The observed improvements in various HRQoL outcomes in both the chronic pain and anxiety cohorts, and the possible safety concerns raised in this thesis supports ongoing exploration of medicinal cannabis in clinical trial settings

    Effects of vascular endothelial growth factor receptor-1 inhibition on vasculogenic mimicry and the metabolic profile of breast cancer cells in vitro

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    Thesis (PhD (Physiology))--University of Pretoria, 2023.Female breast cancer is the leading diagnosed cancer globally and the fifth leading cause of cancer mortality worldwide. The ability of breast cancer cells to form vessel-like structures through vasculogenic mimicry (VM) contributes to cancer progression. Vasculogenic mimicry provides a route for the transportation of blood and nutrients, which sustains the growth and survival of breast tumours. Thus, in patients with breast cancer, VM is associated with high tumour grade, metastasis, and poor prognosis. The steps involved in VM include the proliferation and migration of cancer cells, their invasion of the extracellular matrix, and finally, the formation of tube-like structures. The vascular endothelial growth factor receptor-1 (VEGFR-1) signalling pathway is involved in VM, and targeting VEGFR-1 might have clinical relevance and warrants consideration when designing targeted therapies for breast cancer. Vascular endothelial growth factor receptor-1 is also associated with the metabolic adaptation of cancer cells, as observed in cancer patients who show a correlation between vascular endothelial growth factor A/VEGFR-1 expression and serum lactic acid levels. Indeed, VEGFR-1 promotes the Warburg effect associated with an enhanced acidic environment, which also induces the degradation and remodelling of the extracellular microenvironment. Therefore, the aim of the study was to investigate the effects of VEGFR-1 inhibition on the steps associated with VM, namely, cell growth, migration, invasion, and metabolism in breast cancer cells in vitro using VEGFR-1 inhibitors (ZM 306416 and sunitinib malate). Human breast cancer cell lines, MCF-10A, MCF-7, and MDA-MB 231 cells were maintained in an incubator at a temperature of 370C and in a humidified atmosphere containing 5% CO2. The effect of VEGFR-1 inhibition on cell viability was measured using the crystal violet assay on MCF-10A (a non-cancerous breast cell line), and breast cancer cell lines, MCF-7 and MDA-MB-231. For subsequent experiments, MDA-MB-231 cells were used as a model of investigation because profound effects (being highly responsive to the drugs of investigation) were observed with this cell line. Light microscopy was employed to study cell morphology. The effect of VEGFR-1 inhibition on cell migration and invasion was assessed using the scratch assay and the Boyden chamber, respectively. The optimisation of liquid chromatography with the tandem mass spectrometry method for the simultaneous assay of metabolites in cell culture preparations was determined. Lastly, the effects of treatment on the metabolic profile of breast cells were assessed using liquid chromatography with tandem mass spectrometry, enzyme-linked immunosorbent assay, and a pH meter/electrode. The results demonstrated that sunitinib malate had great efficacy and potency than ZM 306416, as sunitinib malate is a multi-kinase inhibitor. Overall, inhibiting VEGFR-1 reduces cell growth and alters breast cancer cell morphology. In addition, inhibiting the VEGFR-1 signalling pathway attenuates migration and invasion possibly by reducing ATP formation and the extracellular fluid acidity. Optimisation of mass spectrometry in terms of achieving mass ratio and ionisation mode of analytes (glucose-6-phosphate, fructose-6-phosphate, pyruvate, lactate, and glutamate) was achieved, however the optimisation of liquid chromatography was challenging, although it was discovered that analytes of interest in this study should be analysed using the Luna NH2 column to achieve retention and high separation. This study has formed the basis for further investigation of VEGFR-1 targeting in reducing VM and altering metabolic patterns in breast cancer to improve the treatment of this disease.PhysiologyPhD (Physiology)Unrestricte
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