Saudi Cultural Missions Theses & Dissertations
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Item Restricted Identification of Novel Modulators of Airway Proliferation and Differentiation(University College of London, 2024-08-29) AlKayid, Ghidran; Ishii, YukiThe human lung’s airway epithelium, compromising of pseudostratified cells, is essential for maintaining respiratory function. These cells proliferate and differentiate into diverse cell types necessary for a functional epithelium. However, the regulatory mechanisms controlling their proliferation, self-renewal, and differentiation are not fully understood, this presents a significant opportunity to develop targeted therapeutic strategies to enhance airway tissue repair and regeneration. To explore this, High- throughput screening methods have identified, a promising compound. One candidate is Leflunomide, inhibits a potential therapeutic agent. Leflunomide exerts its effects by inhibiting dihydroorotate dehydrogenase. This study investigated in vitro the effects of Leflunomide on the expression of Wnt-pathway associated genes LEF1, AXIN2, c- myc, and cyclin D1 in HBECs obtained from various donors. Primary HBECs cultures were optimised, and gene expression analysis was conducted using Quantitative PCR with normalisation to the housekeeping genes RSP13 and GAPDH. Fold changes in gene expression were determined using the 2-∆∆CT method. Leflunomide treatment showed a notable increase in AXIN2 gene expression in the HBEC cell line, suggesting activation of the Wnt signalling pathway. However, other genes, including LEF1, c-myc, and cyclinD1, did not show significant expression changes across different donor cell lines. This suggests that while Leflunomide may influence certain aspects of the Wnt-pathway, its effects are selective rather than broad. Further in vivo studies are needed to fully understand the therapeutic potential of Leflunomide and to evaluate its ability to effectively promote airway epithelial repair by modulating the Wnt pathway, supporting its repurposing for the treatment of airway dysfunction diseases.19 0Item Restricted The impact of macrophage migration inhibitory factor inhibition on acute myeloid leukaemia(University of Westminster, 2024-05) Aljuhani, Talah; Saia, MarcoAcute myeloid leukaemia (AML) is one of the most aggressive and challenging malignancies that is characterised by rapid blast cell proliferation in the bone marrow and peripheral blood. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is overexpressed in various types of solid tumours. Despite considerable evidence regarding the function of MIF in different tumours and cancers, limited research has been conducted on its role in AML. This study aimed to explore MIF’s role in AML, specifically in relation to cell proliferation, cell cycle, and apoptosis. Additionally, the effects of a 50 µM ISO-1 MIF inhibitor on restricting AML cell growth by inhibiting MIF were assessed. Herein, THP-1 cells demonstrated high surface CD44 and CXCR4 receptor expression and low surface CD74 and CXCR2 receptor expression, suggesting the contribution of CD44 and CXCR4 receptors in MIF activation, thereby AML development. Additionally, the cell proliferation rate was decreased, the apoptotic cell count was increased, the percentage of treated cells in the pre-G0-G1 phase was increased, and the percentages of cells in the G0-G1, S, and G2-M phases were decreased. This suggests an impact of the ISO-1 inhibitor on decreasing AML proliferation, inducing apoptosis, and regulating the cell cycle. These results can have a positive impact on understanding MIF’s role in AML pathogenesis and improving AML treatment efficiency using potential therapeutic targets that can have a considerable impact on the survival rate and health outcomes of patients.10 0Item Restricted NOVEL IN SILICO-DESIGNED SMYD3 INHIBITORS ELIMINATE UNRESTRAINED PROLIFERATION OF BREAST CARCINOMA CELLS(Saudi Digital Library, 2023-10-03) Alshiraihi, Ilham Mohammed; Brown, MarkSMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. Elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation. In this study, we used in silico screening to identify potential small molecule inhibitors of SMYD3 and tested the ability of these inhibitors to reduce its methyltransferase activity in vitro. Using breast cancer cell lines that overexpress SMYD3 and normal breast epithelial cell lines, we have confirmed the ability of one of these inhibitors, Inhibitor-4, to reduce cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting normal cell behavior. Our results provide a proof of concept for the in silico design of small molecule enzyme inhibitors and for the use of such an inhibitor to target SMYD3 for the treatment of cancer.14 0Item Restricted Modulation of Autistic-Related Factors in Hippocampal Neurons: Role of Oxytocin(2023-04-24) Alfaifi, Hassan; Castejon, AnaBackground: Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with dysregulation of several cellular processes. Accumulating evidence links ASD to the abnormality of cellular growth and programmed cell death (apoptosis). According to many postmortem and animal studies, abnormalities of several apoptotic signaling pathways have been linked to the induction of ASD, such as the ERK and p53 signaling pathways. Besides, the participation of neuroinflammation and oxidative stress in ASD induction and perpetuation has been identified. It has been reported that the levels of ROS and interleukin-1β are abnormally increased in neuronal brain cells in individuals with ASD. Therefore, agents that can improve cellular growth, regulate apoptosis, and reduce oxidative stress and neuroinflammation, like the neuropeptide oxytocin (OXT), may be effective in managing ASD. Objective: Our main goal was to investigate the effects of OXT on autistic-related factors, including cellular growth, oxidative stress, and neuroinflammation, as well as the intracellular signaling pathways involved in these effects. Methodology: We evaluated the effect of OXT on cell growth and death by performing cell counting (hemocytometer), MTT assay, and Bresto blue assay in hippocampal neurons (mHippoE-2). The proliferative effect mechanisms were evaluated using western blotting and MTT assay. In the survival experiments, viability was assessed by MTT assay in cells incubated in the presence or absence of OXT 1000 nM and/or 1000nM OXTA with oxidative stress inducers (H2O2, DMNQ, and CPT) and neuroinflammatory inducer (LPS). The mechanisms of the protective effect were evaluated using western blotting, ELISA. Also, we used the DCFDA kit to evaluate the antioxidant effect of OXT. Moreover, we employed the immunocytochemistry technique to assess the effect of 1000 nM OXT and/or 1000 nM OXTA against the induced morphological alterations. v Results: This study revealed that OXT significantly induced cell growth in hippocampal neurons (mHippoE-2). The OXTA (L-371,257) significantly reduced cell growth. The proliferative effect of OXT is mediated through MEK/ERK signaling pathway. In addition, treatment with 1000 nM OXT significantly reduced the reduction in cell viability induced by oxidative stress inducers (H2O2, CPT, and DMNQ) but not inflammatory inducer (LPS). In addition, OXT significantly reduced ROS generation when the cells were exposed to H2O2 and DMNQ but not CPT. The western blotting technique demonstrated that OXT significantly reduced the protein levels of p53-caspase 3 and increased the levels of Mdm2 induced by H2O2 and DMNQ, but not CPT. Our morphological studies showed that OXT countered the reduction in cellular projection length induced by H2O2, CPT, and DMNQ. Furthermore, OXT significantly reduced the protein levels of PI3K and p-AKT but not the NLRP3-caspase 1 signaling pathway. Conclusion: Our results indicate that OXT has a proliferative effect by activating the ERK signaling pathway. Furthermore, we revealed that the protective effect of OXT was mediated through the modulation of oxidative stress and mitochondrial apoptosis pathway. Moreover, OXT decreased the levels of some inflammatory-mediated proteins. On the other hand, these effects were lacking in the presence of OXTA. These results will contribute to a better understanding of OXT’s potential role in autistic-related factors associated with cell loss, oxidative stress, and neuroinflammation.6 0