Saudi Cultural Missions Theses & Dissertations
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Item Restricted Characterisation of novel Markers role in Senescence and targeting them to eliminate senescent cells(University of Leicester, 2024-04-22) Albati, Amal Abdulah; Macip, SalvadorAgeing is a deterioration of organ function that increases the susceptibility for diseases. This deterioration is due to an impairment of cellular homeostasis occurred in response to the nine hallmarks of senescence is considered one of these hallmarks, which was observed first by Leonard Hayflicks and Paul Moorhead which defined as a cell cycle arrest in response to genetic or environmental stresses such as UV radiation, oncogene stress, telomere attrition and DNA damage. Senescent cells are metabolically active cells characterized by an irreversible cell cycle arrest and resistance to apoptosis. Senescence has two opposite impacts on organisms, as it has a beneficial effect such as tissue repair, wound healing and tumor suppression. However, accumulation of senescent cells has a detrimental effect found to enhance ageing and age-related pathologies such as Alzheimer disease, diabetes, fibrosis and cancer. Therefore, clearance of senescent cells could ameliorate the symptoms of ageing and age-related diseases thus increasing the healthspan and lifespan of organisms. However, there is no yet specific marker used to detect and eliminate senescent cells. Consequently, it is important to find a marker or combination of markers that are specifically identify senescent cells and use them as therapeutic tool to target and eliminate the accumulation of senescent cells. Here, we illustrated that Ibrutinib, a clinically approved chemical inhibitor of BTK, decreased the accumulation of senescent cells in vivo, leading to extended lifespan and mitigating age related decline in physical fitness. Besides, Ibrutinib demonstrated a pivotal role in maintaining heart function with age by effectively reducing the accumulation of senescent cells. Additionally, we examined three potential markers of senescence identified by proteomic screening, evaluating their expression levels with age and after Ibrutinib treatment. Specifically, we sought to understand the impact of ibrutinib on these markers with age by comparing treated mice to untreated counterparts and young controls in mouse tissues. Moreover, we assessed the binding of RGD peptide to integrin αVβ3, a protein identified by proteomic screening as expressed more in senescent cells. The investigation aimed to determine the potential utility of the RGD peptide as a drug delivery tool for future applications.27 0Item Restricted The Relationship between Depression, Stress-Related Neurobiology, and Incident Heart Failure: Understanding the Neurobiological Mechanisms Underlying Exercise as a Preventive Measure(Saudi Digital Library, 2023-04) Alhamam, Abdulaziz Arif Abdulaziz; Tawakol, AhmedBackground: Depression is associated with risk of developing heart failure (HF). Also, higher stress-related neural activity (SNA) associates with subsequent risk of cardiovascular disease. We investigated whether depression predicts subsequent HF through heightened SNA. Methods: Individuals (N=102,028; median age 57 years; 42.6% male) enrolled in the Mass General Brigham Biobank were identified to study the association of depression and incident HF, subset of 1,227 who underwent clinically indicated 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging were retrospectively identified. SNA was measured using validated methods, as amygdalar metabolic activity corrected for regulatory brain (i.e., medial prefrontal cortical) activity. Depression and subsequent development of HF was determined via medical record review using International Classification of Diseases 10 (ICD-10) codes. Survival analyses using Cox and Kaplan-Meier models were performed. Results: Over a median follow-up period of 3.5 (IQR 2.0-5.0) years, 2,631 (2.6%) individuals developed HF (717 Heart failure with reduced ejection fraction (HFrEF), 1,214 Heart failure with preserved ejection fraction (HFpEF)). Individuals with subsequent HF (versus no HF) had higher baseline SNA (mean Z-score 0.19 ± 1.07 versus -0.08 ± 0.99; p=0.005, adjusted for age and sex). SNA associated with subsequent HF when divided into tertiles (Figure 2B) and as a continuous measure (standardized HR [95% CI]: 1.40 [1.13-1.74], p=0.002, adjusted for age, sex, hypertension, hyperlipidemia, diabetes, and smoking). The association between depression and HF subtype was stronger for HFpEF (1.46 [1.28-1.65], p<0.001) than for HFrEF (1.09 [0.92 -1.3], p=0.32). Conclusion: In this retrospective study of individuals with depression have higher risk of incident HF through heightened SNA with a somewhat stronger association for HFpEF. Understanding the link between depression and subsequent HF may provide important insights into better HF prevention and management strategies.16 0