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    Study the effect of phytochemicals phenethyl isothiocyanate (PEITC) and Quercetin on mitochondrial biogenesis in cancer and normal cell lines
    (Central University of Punjab, 2018) Thakur, Anchal; Chander, Harish
    Phytochemicals are plant-derived chemicals generally are biologically active compounds and mediate positive health benefits by targeting genes or metabolic pathways of a cell. The phytochemicals examined can be classified into main categories, such as carotenoids and polyphenols, which include phenolic acids, flavonoids and stilbenes / lignans. Quercetin is isolated from the Tridax procumbens (Linn.). Its anti-cancer activity has been well documented in vitro and in vivo. It could be pro-apoptotic as well as anti-apoptotic depending upon its concentration of it and time of exposure. Isothiocyanates are cruciferous derived phytochemicals. PEITC majorly isolated from Nasturtium officinale (watercress) has shown to mediate its anti-cancer activity through ROS-mediated pathway. It is a basic leucine zipper protein involved in protection against oxidative damage triggered by stress like injury or inflammation through regulation of the expression of anti- oxidant proteins. Under oxidative stress, inactivation of Kelch-like ECH-associated protein 1 (Keap1) occurs which is a cytosolic repressor protein that binds to Nrf2. This results in Nrf2-Keap1 complex dissociation, and hence, promoting the translocation of Nrf2 to the v nucleus where it binds to ARE (anti-oxidant response element), and induce the transcription of anti-oxidative proteins. Quercetin and PEITC treatment to the cancer cells led to decreased mitochondrial biogenesis as the NRF-2 levels diminishes as the concentration of the drug increases. The anti-oxidant levels are getting down in the cancer cells leading to ROS accumulation in the cancer cells leading ultimately to the death. Quercetin and PEITC treatment to the normal HBL-100 cells induced the mitochondrial biogenesis by increasing NRF-2 levels as the concentration of the drug increases. Confocal microscopy results also proved that treatment of quercetin or PEITC or the combination of both drugs was found to be effective in cancer cells as the mitochondria size and shape got decreased interpreted through the intensity of green dye. To conclude our study, it has been shown that quercetin and PEITC lead to increased mitochondrial biogenesis in normal cells whereas decreased mitochondrial biogenesis in cancer cells.
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    Oxidative Stress Events and Neuronal Dysfunction in Alzheimer’s Disease: Focus on APE1/Ref-1-Mediated Survival Strategies
    (Springer, 2014) Kaur, Navrattan; Sarkar, Bibekananda; Mittal, Sunil; Dhiman, Monisha; Taglialatela, Gulio; Perez-polo, Regino J.; Mantha, Anil K.
    Alzheimer’s disease (AD) is an important public health problem which affects millions of people worldwide. The major pathological hallmarks associated with AD are the accumulation of amyloid beta (Aβ) in senile plaques and neurofibrillary tangles (NFT) made up of hyperphosphorylated tau proteins. New findings suggest that oligomeric Aβ is a more toxic species than fibrillar Aβ relevant to AD pathology. Although the molecular mechanism(s) underlying the disease is not identified completely, various factors have been implicated in the development of AD. Accumulating evidences point towards the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of AD and recognise them as an early event in AD development. Ageing is considered the greatest risk factor for AD and is linked to oxidative stress which causes accumulation of somatic mutations in mitochondrial DNA (mtDNA) over time and leads to genome instability and mitochondrial dysfunction. Recent studies on AD patients and transgenic mouse models suggest that amyloid precursor protein (APP) and Aβ localise to mitochondria, interact with mitochondrial proteins, disrupt electron transport chain (ETC), increases reactive oxygen species (ROS) level, impair axonal mitochondrial trafficking, thus leading to synaptic damage and cognitive decline associated with AD. It is not known whether accumulation of Aβ is the cause or outcome of declining mitochondrial function in AD. In order to counteract oxidative stress and maintain genome integrity, various DNA repair pathways exist, base excision repair (BER) pathway being the predominant pathway for repairing oxidised base lesions in neuronal cells. APE1 is the central enzyme of the BER pathway, having both repair and redox activities and shown to enhance neuronal survival after oxidative stress. Newer studies are revealing the role of APE1 in maintenance of mitochondrial genome repair and function. In this scenario, antioxidant-based therapy, which could reduce oxidative stress and modulate the activities of APE1, can serve as effective treatment providing neuroprotection in AD. This book chapter summarises some recent developments in understanding the pathogenesis of AD linking Aβ-induced oxidative stress, mitochondrial dysfunction, role of APE1 and phytochemicals toward AD therapeutics.