Browsing by Author "Upamalika, S.W.A.M."

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    Increased Reactive Oxygen Species Induced by Toxic Heavy Metals as an Initiator of CKDu
    (Uva Wellassa University of Sri Lanka, 2018) Upamalika, S.W.A.M.; Wannige, C.T.
    For more than two decades, many people in the North Central Province of Sri Lanka are affected by chronic kidney disease of uncertain etiology (CKDu) . The main risk factors of this disease are identified as heavy metals (arsenic, cadmium and lead), pesticide exposure, heat stress and dehydration, fluoride content and hardness of water. To identify molecular mechanisms of renal injury by these factors, we carried out a comprehensive literature survey. According to literature, heavy metals like arsenic initiate toxicity through generation of excessive Reactive oxygen species via two mechanisms. The first mechanism is inducing enzyme complexes to increase reactive oxygen species formation. The second mechanism is via inhibiting antioxidant enzymes. To take an insight into which mechanism has the highest impact, we regenerated an existing mathematical model of redox system in the body. Since experimental data show an increase of superoxide level with heavy metal exposure, we increased superoxide concentration ten times in the simulation. Further, to simulate the inhibition of enzymes, enzyme levels were decreased ten times. Both changes increased reactive oxygen species levels such as hydroxyl ion and lipid peroxidation. In addition, increasing the superoxide level showed high impact rather than decreasing the antioxidant enzymes levels. The reason for increase of superoxide could be the ability of heavy metals to interact in activation of enzyme complexes such as NADPH oxidase, mitochondrial transport chain enzyme complexes I and III. The reason for depletion of antioxidants like Glutathione and antioxidant enzymes such as Superoxide dismutase and Catalase would be the ability of heavy metals to complex with thiol groups in these molecules. The outcome of both mechanisms was an accumulation of higher amount of reactive oxygen species inside the cell. These reactive oxygen species induced oxidative stress activates cellular pathways which lead to cellular toxicity.
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    Sensitivity Analysis of a Redox System Model to Understand the Initiation of Chronic Kidney Disease of Unknown Etiology Progression
    (Uva Wellassa University of Sri Lanka, 2020) Upamalika, S.W.A.M.; Wannige, C.T.; Vidanagamachchi, S.M.
    Identification of the most significant parameter set in a mathematical model is very important to understand the model behavior. Sensitivity analysis is carried out to accomplish this purpose. Chronic Kidney Disease of unknown etiology has been identified as a disease with very high death rates in many tropical countries around the world including Sri Lanka, India, Egypt, and some Mesoamerican countries. Heavy metal exposure is one of the identified evidential factors of this disease progression. Oxidative stress is the main pathological mechanism that leads the kidney tubular cells to cell death pathways with heavy metal exposure. Oxidative stress is raised due to the unbalanced production of reactive oxygen species inside the cells. In this study, a sensitivity analysis was carried out on an existing mathematical model of the Redox system of the body to identify the parameters which are significant in controlling the process of reactive oxygen generation. After simulating the existing mathematical model, a sensitivity analysis was carried out including a local sensitivity analysis which gives the individual effect followed by a global sensitivity analysis which gives the group effect of parameter perturbations. According to the study, five parameters out of sixteen parameters in the mathematical model were identified from the local sensitivity analysis as the most sensitive parameters. Global sensitivity analysis was used to rank them according to the P values of the KS test. A constant was identified which is related to superoxide variation in the system has the highest sensitivity. Also, most of the identified sensitive parameters are correlated with enzyme driven reactions. According to the researchers' perspective, heavy metal exposure also affects the enzymes in the redox system of the body. Therefore, when modeling heavy metal toxicity we can conclude that much consideration should be given to those reactions correlated with enzymes. Keywords: CKDu, Oxidative stress, Mathematical modeling, Sensitivity analysis, Parameters