Saudi Cultural Missions Theses & Dissertations
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Item Restricted The role of Salmonella Typhimurium and microbiome-derived metabolites in tumour regression(University of Glasgow, 2024-01-15) Alfaqeer, Najla Qalit; Wall, Donal M.Cancer is a significant global health challenge, being the second leading cause of death worldwide with nearly 10 million deaths attributed in 2020, a rate of one in six deaths worldwide. Despite the variety of cancer treatments available, most existing treatments are not sufficiently effective to prevent progression of the disease, and many treatment options linked to unpleasant and intolerable long-term or short-term side effects. While surgery, chemotherapy, and radiotherapy form the backbone of most common treatment options, recent advances including targeted immunotherapy and hormonal therapy are improving outcomes and offer opportunities to reduce side effects. In this study, we have considered whether bacteria and bacterial-derived metabolites, offer any potential as therapies in cancer treatment. The first part of this study aimed to investigate the capacity of S. Typhimurium strains to selectively target and kill cancer cells. To this end, we evaluated the anti-tumour properties of several strains of S. Typhimurium, aiming to identify the strain with the highest activity for further optimization and use in cancer therapy. In terms of motility, virulence, and anti-tumour efficacy, the wild-type strain SL1344 and its attenuated SL7207 (SL1344∆aroA), SL1344ΔsipB, SL1344ΔavrA, SL1344ΔsipA, and VV341 strains were evaluated in vitro using a 3D spheroid melanoma model. After infection, three mutant strains, SL1344, ΔavrA, ΔsipA, and VV341, in addition to the double mutant strain ΔaroA/ΔavrA, were highly invasive and suppressed tumour growth, with SL1344 and ΔsipA restricting tumour growth by almost 36% and VV341and ΔavrA by 76%. Interestingly the highest reduction in tumour growth, approximately 89%, was observed when the tissue was infected by the double deletion mutant ΔaroA/ΔavrA. These results demonstrate that attenuated S. Typhimurium possess anti-tumour activity, which could be further improved to allow these bacteria to be used therapeutically individually or synergetically with other therapies. The second part of this study focused on the interaction between microbiome metabolites and cancer. Specifically, we examined two microbiome-derived metabolites produced by bacteria of the Lachnospiraceae family. These compounds 4-(trimethylammonio) pentanoate (4-TMAP), and 3-methyl-4-(trimethylammonio) butanoate (3M-4-TMAB) are thought to interfere with fatty acid β oxidation pathway within the mitochondria. Using these metabolites to induce mitochondrial dysfunction and block fatty acid oxidation, offers an opportunity to suppress tumour growth and prevent cancer progression. To test our hypothesis, three cancer cell lines were selected, which are highly dependent on fatty acid oxidation for progression and metastasis: breast cancer (BT549), prostate cancer (PC-3) and the melanoma cell line B16F10 which has previously been used to evaluate anti-cancer activity in Salmonella. We evaluated the tumour suppressive activity of the metabolites, 4-TMAP and 3M-4-TMAB separately and in combination with conventional tumour drug treatments (Docetaxel and MCL-1 inhibitor) using cell viability and the ability of cancer cells to proliferate and produce colonies, as readouts for efficacy. This showed that the metabolites some suppressed efficacy on cell viability when used as individual agents compared with the conventional drug treatments Docetaxel and Mcl-1 inhibitor (which were very efficacious showing a dramatic reduction of viability by 50% and 48% by Docetaxel and MCL-1 respectively). Furthermore, the sensitivity of tumour colony formation to metabolites varied between cell lines. However, 4-TMAP provided the highest inhibition percentage (41 %) in BT549 and B16F10 cells, while 3M-4-TMAB showed the highest inhibition (40 %) in PC-3 cells. In terms of cell metastasis evaluation, our results demonstrated that 4-TMAP and 3M-4-TMAB suppress tumour growth and cell migration of BT549 and B16F10 cells but did not prevent PC-3 migration. Our results, which examined the influence of metabolites on ATP production in the absence of glucose, showed an approximately 45% inhibition with 3M-4-TMAB in all cell lines. Finally, a metabolomics analysis study of the impact of treatment of the breast cancer cell line BT549 with 3M-4-TMAB and 4 TMAP demonstrated downregulation of several compounds related to carnitine compared to control. However, it was challenging using this data to determine the specific pathways affected by these treatments. In contrast, RNA-Seq data generated from the same cell line treated with the same metabolites revealed differential gene expression in genes that were mostly related to immune activity. Interestingly, CXCL1, a gene implicated in promoting tumour progression and metastasis, was downregulated after 3M-4TMAB treatment. Collectively, our results highlight a potential therapeutic application for targeting tumours with two different approaches; utilizing S. Typhimurium attenuated strains on melanoma and metabolites derived from Lachnospiracea family on three different cancer cell lines BT-549, PC-3, and B16F10.21 0Item Restricted Part 1: Studies on the Microbial Community profile of Two Caves in Greece and Slovakia. Part 2: Studies on the effect of Geographical and environmental factors on tea metabolites profile.(Saudi Digital Library, 2023-11-06) Almutari, Saleh; Kumaresan, Deepak; Di, WuThis comprehensive study delves into two distinct, yet interconnected realms of scientific inquiry: the microbiology of cave ecosystems and the metabolomics of tea. The first part of the study focuses on the microbial diversity in cave ecosystems, specifically in Crete (Greece) and Slovakia. Utilizing advanced techniques such as Oxford Nanopore Technologies for DNA sequencing and MicrobiomeAnalyst for data analysis, the research uncovers the complex microbial communities within these caves. Key findings include the dominance of certain microbial families like Sphingomonadaceae and the variation in microbial diversity between different cave locations. The study highlights the significant role of these microorganisms in cave ecosystems and sheds light on their potential biotechnological applications. The second part of the research investigates the impact of environmental and geographic factors on the metabolome profile of tea. Employing methods such as Liquid Chromatography-Mass Spectrometry (LC-MS) and Geographical Information Systems (GIS), the study examines how factors like altitude, soil composition, and climate affect the metabolite composition of tea. The results reveal distinct metabolomic fingerprints for teas from different geographic locations, underscoring the influence of environmental conditions on tea's flavor, aroma, and health benefits. The study contributes valuable insights into the metabolomics of tea and its implications for the tea industry, conservation, and health research. Overall, this dual-focused study bridges the gap between microbial ecology and plant metabolomics, offering a holistic view of the biological diversity in both subterranean and agricultural environments.14 0Item Restricted Assessing metabolic profiling for personalised nutrition(Saudi Digital Library, 2023-09-27) Alqarni, Lina; Frost, GaryBackground: Non-communicable diseases (NCDs) are the main causes of mortality and morbidity, globally and in the UK. Dietary changes, such as increasing intake of fibre, fruits and vegetables and reducing intake of saturated fat, free sugar and salt, have shown positive impacts on the risk factors associated with NCDs. However, there are concerns about the effectiveness of general dietary advice, due to the ineffectiveness in motivating people to change their eating habits or differences in individual biological responses to dietary intakes. Personalised dietary advice is proposed as an effective approach when considering the differences in individual response to diet and can be a more proactive intervention when it comes to encouraging people to change their eating habits. Recent advances have been made in the development of a new methodology that uses metabolic profiling and multivariate mathematical modelling to provide objective, accurate information about an individual's dietary patterns based on urine composition, which can be used to design personalised nutritional interventions. The aim of the thesis is to assess the feasibility of translating the metabolic profiling strategy into clinic to improve the nutritional management in the prevention of NCDs, including cardiovascular disease (CVD), by objectively assessing dietary habits and monitoring the compliance to dietary recommendations in order to provide personalised nutritional advice. Methods: Data from a previous pilot study was used to investigate concordance between metabolic profiling and traditional methods on long term dietary assessment in order to assess accurate dietary intakes. In a highly controlled environment, a randomised inpatient crossover clinical trial was conducted to assess the impact of dietary interventions on urinary metabolic profiles and clinical parameters in order to build a new mathematical model, particularly for people at risk of CVD. A dietary protocol was developed to facilitate personalised dietary counselling in alignment with public and patient involvement. A randomised pilot clinical trial was conducted to assess the feasibility of providing metabolically personalised dietary advice in clinic to help people at risk of CVD to change their dietary habits within their own environment using the new mathematical model and dietary protocol. Results: Findings from the pilot study showed poor agreement between the DASH score and the urinary dietary patterns score in overall data and subgroups. There were discrepancies in the concordance between the classifications of the dietary adherence of the urinary biomarkers and their related dietary intakes. In the randomised inpatient trial, two distinct isoenergetic dietary interventions with different compliance levels to NICE dietary guidelines were designed. Significant differences in the dietary intakes between the interventions (Diet1 vs Diet2) were reflected in the urinary metabolic profiles of participants; the RM-MCCV-PLS-DA model shows clear separation in the global urinary metabolic profiles of the two dietary patterns. A robust model has been developed using the global urinary metabolic profile associated with distinct dietary patterns. A dietary protocol has been developed to facilitate personalised dietary counselling and this was in alignment with public and patient involvement (PPI). PPI has positively impacted our dietary intervention design, researchers, dietitians, and participants at risk of CVD who involved in PPI activities. Finally, the randomised pilot clinical trial shows the feasibility of using metabolic profiling in clinic to personalise dietary advice for people at risk of CVD. Conclusion: A metabolic profiling strategy is promising and feasible and can objectively provide information about dietary adherence. In addition, it can be applied in conjunction with traditional dietary assessment methods to obtain further details about individual diets. However, some considerations need to be taken when applying urinary metabolic profiles in personalise nutrition and further research is needed to enhance the application of urinary metabolic profile.10 0