Saudi Cultural Missions Theses & Dissertations
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Item Restricted The Modulation Effect of Inflammatory Cytokines on T cell Proliferation in Hypertension(University of Glasgow, 2024-05) Alsheikh, Eman; Marta, Czesnikiewicz-Guzik; Tomasz, GuzikHypertension is a common medical condition with very serious target organ consequences, increasing the risk of heart disease, stroke, and severe health complications. Despite the identification of various mechanisms (vascular, renal, and central mechanism) contributing to the pathogenesis of hypertension, the majority of cases lack a clear aetiology. Emerging evidence has established a significant association between hypertension and immune responses, particularly involving adaptive immune cells and inflammatory cytokines. Immunosuppressive drugs and cytokine inhibitors have shown potential in mitigating hypertension, suggesting a crucial role of the immune system in this condition. Given the central role of T lymphocytes in the adaptive immune response, this study hypothesises that, in the context of hypertension, inflammatory cytokines can modulate T cell activation independently of antigen stimulation. To test this hypothesis, total T cells were isolated from the spleens and PBMCs of normotensive and hypertensive mice and exposed to a range of cytokines, including TNF-α, IL-6, IL-15, IFN-γ, IL-7, IL-1β, IL-17A, IL-2, and IL-12, using different stimulation protocols. Aiming to understand the effects of these cytokines on T cell proliferation, differentiation, and the expression of activation markers such as CD69. Our findings highlight the varying abilities of cytokines to sustain T cell viability, with IL 7, IL-15, and IL-6 demonstrating a tendency for greater efficacy compared to other cytokines. In addition, IL-7 and IL-15 significantly impact T cell proliferation, notably affecting the CD8+ T cell population. However, despite these effects, no significant difference was detected between normotensive and hypertensive T cells in response to IL-7 and IL-15. This suggests that while these cytokines are potent in driving T cell proliferation, their influence is not specifically heightened in the context of hypertension. In GSEA and KEGG analyses, the Ca2+ signalling pathway was distinctively activated in response to IL-7 and IL-15 in Ang II induced hypertension. Conclusion: These data imply that most studied cytokines linked to hypertension pathology do not substantially affect normotensive or hypertensive T cells in a murine model. However, T cell proliferation was elevated in both Sham and Ang II mice in response to IL-15 and IL-7. Together, the data presented in this thesis warrant further investigations into the role of cytokines in hypertension and may point to IL-15 or IL-7 as biological targets for antihypertension therapy.43 0Item Restricted The effect of senolytics on cardiac remodelling and repair after injury induced by isoproterenol(King's College London, 2024-04) Altuwaijri, Ahmed; Ellison-Hughes, GeorginaSenescent cells accumulate during ageing and contribute to tissue deterioration, including in the heart. Senescent cells negatively affect an organ's microenvironment by refusing to die and producing a pro-inflammatory senescence-associated secretory phenotype (SASP). Genetic or pharmacologic clearance of senescent cells by senolytics has been shown to improve cardiac recovery and remodelling in aged mice. Moreover, senolytics have improved cardiac recovery after cardiac injury and in heart failure models in aged and young adult mice. Isoproterenol (ISO) has been widely used to induce cardiac injury in rodents, but it is unknown if ISO induces senescence and whether increased senescent cells in the heart contribute to cardiac deterioration and pathophysiology. This PhD aimed to first establish a cardiac injury model which led to increased senescence in the hearts of young adult mice by ISO. Second, to investigate the effects of the senolytics, dasatanib+quercetin (D+Q) on cardiac recovery and remodelling after ISO-injury in young adult and aged mice. To establish the dose of ISO that induced senescence with cardiac injury, ISO 150 mg/kg or 100 mg/kg was subcutaneously administered to ~12-week-old male mice (n=3 per group) for six consecutive days. Echocardiography was conducted from baseline to day 7. On day 7 after ISO, hearts were excised in order to analyse cardiac injury and cellular senescence. Results indicated that 100 mg/kg and 150 mg/kg ISO induced injury mainly in the apex of the heart. However, SA-β-gal staining was evident only in the apex of the ISO 150 mg/kg group. Therefore, ISO 150 mg/kg was chosen over the ISO 100 mg/kg dose. To establish the timeline of increased senescence after ISO-injury, 150 mg/kg ISO was subcutaneously administered to ~12-week-old male mice (n= 3-9 per group) for six consecutive days. Echocardiography was conducted at baseline, day 7 and 14 following ISO administration. Mice were sacrificed and hearts were excised for analysis of cardiac injury and senescence on days 7, 10 and 14. ISO 150 mg/kg successfully induced cardiac injury and senescence that lasted for 14 days. The peak of senescence was observed on day 10 following ISO. Next, ISO 150 mg/kg was subcutaneously administered to ~12-week-old male mice for six consecutive days. On day 10 after ISO, D+Q (5 mg/kg, 50 mg/kg) were administered by oral gavage for five consecutive days. Echocardiography was performed at baseline, day 7 post-ISO, and day 28 after the last D+Q dose. The hearts were excised on day 28 following the last D+Q dose to investigate cardiac injury and cellular senescence. Young adult mice treated with D+Q showed better cardiac recovery and remodelling after ISO injury. D+Q enhanced cardiac function, reduced hypertrophy, and reduced senescence markers. However, levels of collagen and DNA damage were unaffected by D+Q treatment. Aged male mice had four cycles of D+Q (5 mg/kg, 50 mg/kg) via oral gavage. Each cycle was composed of 3 days on and 12 days off. After that, aged mice hearts were injured by subcutaneous injection of 50 mg/kg ISO for six consecutive days. Echocardiography was performed at baseline, 24 hours after D+Q, and 28 days after the last ISO dose. The hearts were excised on day 28 following the last ISO dose to investigate cardiac injury, cellular senescence and remodelling. D+Q did not enhance cardiac function in the aged mice before ISO injury. However, D+Q improved cardiac recovery and survival after ISO injury. In the ISO-injured aged mice, D+Q enhanced cardiac function, reduced hypertrophy, reduced fibrosis, reduced DNA damage and senescence markers, and increased cardiomyocyte DNA synthesis. Clearance of the senescent cells and their SASP factors by D+Q senolytics improved cardiac function and recovery after ISO injury in aged and young adult male mice. These findings encourage the use of senolytics as a potential adjunct therapy for cardiac injury and deterioration with ageing. Senolytics could be used to improve the microenvironment of the heart so that it is more resilient to damage and can recover more effectively.24 0Item Restricted Enhancing Chemical Adherence Testing through Pharmacokinetics and Pharmacogenetics Insights and Mass Spectrometry Advancements.(University of Leicester, 0024-05-18) Alghamdi, Randah; Gupta, PankajThis thesis addresses the pressing issue of medication non-adherence with a focus on hypertension. Non-adherence is common and significantly elevates the risk of hospitalisation and mortality. The study investigates chemical adherence tests to assess medication adherence, employing liquid chromatography with tandem mass spectrometry (LC-MS/MS) as a robust method. The introduction highlights the complexities of adherence measurement and outlines potential limitations, including the influence of pharmacokinetics (PK) and pharmacogenetics on medication detection and the time-consuming nature of chemical adherence testing (CAT) processes. The central hypothesis underpinning this research is that the pharmacokinetics and pharmacogenetics of antihypertensive medications do not significantly affect medication detection or, consequently, the results of CAT by LC-MS/MS. This hypothesis is explored through a series of specific aims, including establishing PK parameters for the 20 most commonly prescribed antihypertensive medications through a comprehensive literature review. Additionally, the study aims to determine whether these PK parameters have any bearing on the outcomes of CAT using LC-MS/MS. A systematic review is conducted to identify genetic polymorphisms related to the effects of cardiovascular medications within the Biology Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) cohort, and the subsequent investigation focuses on the association between genetic polymorphisms and medication detection rates in the same cohort. Furthermore, the study strives to develop and partial validate an improved and more efficient CAT method for quantitating various cardiometabolic medications using LC-QQTO MS, a crucial step in ensuring accurate adherence assessments. The findings of this research reveal several critical insights. Chapter 3, which reviews the PK parameters of commonly prescribed antihypertensive medications, demonstrates no significant correlation between these parameters and adherence scores. This observation holds for multiple parameters, including bioavailability, urine excretion, clearance, volume of distribution (VD), half-life, peak time, and peak concentrations. Logistic regression analysis confirms that PK parameters do not predict non-adherence, even when considering additional factors such as age, sex, the number of medications, and creatinine levels. In Chapter 4, the systematic review uncovers various genetic polymorphisms associated with cardiovascular medication effects in the BIOSTAT-CHF cohort. However, these genetic variations do not exhibit a substantial correlation with non-adherence to prescribed cardiovascular drugs and encompass a wide range of effects, including PK influences, adverse drug reactions, metabolic responses, therapeutic outcomes, and risk-related impacts. Additionally, a non-directed genome wide association study (GWAS) showed weak associations with some potential polymorphisms, but none met the usual threshold of significance. Chapter 5 focuses on the development and partial validation of LC-QTOF-MS methods for the quantitation of cardiometabolic medications. Due to the distinct challenges posed by the COVID-19 pandemic, the objective was modified to conduct a partial validation assessment. The analysis time was reduced by 10 times from the previous method. The optimization of conditions for both positive and negative modes of LC-QTOF-MS is detailed, covering parameters such as capillary voltage, energy settings, and mobile phase selection. The validation results underscore the importance of tailored approaches for different pharmaceutical compounds, emphasising the significance of meticulous method development and validation in pharmaceutical analysis. In conclusion, this thesis proves the central hypothesis that the pharmacokinetics and pharmacogenetics of antihypertensive medications do not significantly affect medication detection and, therefore, do not influence the outcomes of CAT by LC-MS/MS. These findings offer valuable insights into improving medication adherence assessment and management in cardiometabolic diseases, highlighting the need for a multifaceted approach that considers pharmacokinetics and pharmacogenetics. Notably, my thesis had to adapt to the challenges posed by the COVID-19 crisis. The research shifted its focus from the initial plan of conducting PK profiles of antihypertensive medications in healthy volunteers to the plan of undertaking a systematic review of genetic polymorphisms associated with various effects of cardiovascular medications within the BIOSTAT-CHF cohort study.10 0Item Restricted The Role of the Built Environment in Physical Activity Changes and Cardiometabolic Outcomes Among Lifestyle Modification Intervention Participants(University of Pittsburgh, 2023-06-28) Bu Saad, Mohammed; Rockette-Wagner, BonnyINTRODUCTION: More novel approaches to improve health outcomes for at-risk individuals are needed as type 2 diabetes grows. Neighborhood walkability and physical activity (PA) have been found to be related in adult population research. However, whether walkability influences people's ability to change their lifestyle behaviors and improve their cardiometabolic outcomes as a result of a lifestyle intervention is unknown. METHODS: We examined the association between neighborhood walkability and the six-month changes in (1) physical activity and (2) cardiometabolic outcomes among individuals at risk of diabetes using two cohorts of participants (n=390) who were enrolled in DPP-based community lifestyle interventions (DPP-GLB). In addition, for participants (n=221) undergoing a DPP-based online lifestyle intervention in primary care settings (OCELOT study), we examined participants’ success in (3) meeting a step counts/day equivalent of the program PA goal and the role of neighborhood walkability in PA achievement at 12 months post-intervention. Regression analyses were applied (1: linear; 2: linear and logistic; and 3: logistic). RESULTS: For DPP-GLB participants, self-reported baseline PA levels were positively associated with greater neighborhood walkability. Over 6 months of intervention neighborhood walkability was inversely associated with PA change. Living in a car-dependent neighborhood versus walkable neighborhood was associated with a statistically significant greater increase in self-reported PA, leading to reduced differences in PA levels across neighborhood walkability categories. Neighborhood walkability was also inversely related to improvements in insulin and blood glucose, but positively associated with blood pressure improvements. In the OCELOT cohort, pedometer-measured PA goal achievement did not differ across the study arms (VLM-S: standard coaching; VLM-M: modulated coaching; OGR: control arm). Regarding PA goal achievement by neighborhood walkability, participants living in walkable neighborhoods (Very Walkable and Walker's Paradise) were more likely to meet the PA goal than those living in car-dependent neighborhoods. CONCLUSIONS: This dissertation provides valuable evidence regarding the association between neighborhood walkability and PA goal achievement and changes in cardiometabolic outcomes among adults at risk for or with T2DM while participating in a lifestyle intervention. These results suggest that prevention programs should incorporate contextual factors of participants' neighborhoods in their program materials and start considering multi-level intervention approaches.21 0