Saudi Cultural Missions Theses & Dissertations
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Item Restricted Role of Retinoic Acid Receptor β Signalling in Alzheimer’s Disease(Saudi Digital Library, 2023-08-27) Almuallim, Hassan Yousef Othman; Corcoran, JonathanAlzheimer's disease, the most common form of Dementia, is characterized by a debilitating progression of memory impairment and cognitive decline. The distinct neuropathological hallmarks characterizing Alzheimer's disease revolve around the existence of senile plaques containing amyloid-β, as well as neurofibrillary tangles composed of tau protein, precipitating oxidative stress and neuroinflammation. The therapeutic options for Alzheimer’s disease are either symptomatic treatments or disease-modifying drugs, with the latter currently showing significant investment in targeting amyloid-β. Interestingly, DNA double-strand breaks play a role in increasing the secretion of amyloid-β, consequently triggering the aggregation of amyloid-β plaques. However, there are currently no therapeutic options available for Alzheimer’s disease that specifically target the induction of DNA repair. KCL286, a synthetic retinoic acid receptor beta agonist with promising results from a phase I clinical trial, has demonstrated its capacity to initiate DNA repair mechanisms in a nerve injury model. In this context, we embarked upon an investigation into the effects of KCL286 administration in Tg2576 mice, a transgenic strain characterized by human amyloid precursor protein overexpression and consequently amyloid-β accumulation. A three-month treatment significantly reduced the DNA damage response protein γH2AX, in particular the gene expression of γH2AX within the hippocampus. The inducing of DNA double-strand break repair corresponded with the clearance of amyloid-β deposits and reduction in inflammation. The study underscores the potential of stimulating the RARβ signalling pathway via the RARβ agonist KCL286, as it appears to induce DNA repair mechanism and amyloid-β clearance. This reinforces the drug’s promise as a prospective therapeutic candidate for Alzheimer's disease.22 0Item Restricted Effect of the inflammatory mediator TNF-α on colorectal cancer epithelial cells development and metastasis, role of dietary carcinogens and miRNA(ICL, 2023-05-01) Alotaibi, Aminah Ghazi; Gooderham, Nigel; Li, JiaColorectal cancer (CRC) is the third most common cancer world-wide and second leading cause of mortality. The majority of CRC cancer cases result from epigenetic and genetic alterations that promote development and metastasis of the disease. Exposure to environmental and dietary carcinogens are strongly associated with CRC. Also, inflammatory mediators are known as a major risk factor for CRC, however the underlying mechanisms are still understudied. Upregulation of pro-inflammatory mediators and dysregulation of miRNAs in the tumour microenvironment (TME) have been observed in CRC. Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine thought to play numerous roles in tumour progression including epigenetic gene regulation, activation of tumour promoting signalling pathways, thus presence of TNF- in CRC tumour microenvironment may be key to promoting CRC progression. I hypothesise that the presence of TNF- α in the TME could regulate miRNAs and enzyme expression to induce DNA damage caused by dietary carcinogens, thereby stimulating changes that promote CRC development and metastasis. The present study investigated this hypothesis through a mechanistic approach with in vitro cell line culture. Effects of TNF-α on phenotypic changes were observed and the potential involvement of miRNAs were determined. The results showed that TNF-α enhances dietary carcinogen-induced DNA damage through activation of JNK signalling pathway. Also, TNF-α induced metastatic phenotype cell proliferation and migration through miRNA regulation. Moreover TNF-α regulated expression of CYP450 enzymes through miRNA regulation, which can promote chemical carcinogen genotoxicity. Taken together, the data indicated that CRC progression and metastasis may be related to epigenetic and inflammatory mediators active at the tumour site. Understanding these molecular mechanisms could provide better prevention and therapeutic strategies.26 0