Role of AMPK in the Cytotoxic Effects of Anti-Tumour Agent, Dp44mT, in Pancreatic Cancer

Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor, that maintains cellular energy homeostasis under stress. Due to its central role in regulating multiple metabolic mechanisms within the cell, AMPK dysregulation is associated with cancer. Furthermore, iron’s ability to participate in pathways involving the generation of energy, suggest that AMPK phosphorylation and subsequent downstream effects could be critical to completely understand the emerging role of iron in interconnecting metabolic mechanisms. Hence, this thesis aimed to examine the role of AMPK, in the anti-tumour activity of the metal chelator, di-2-pyridylketone-4,4-dimethyl-3-thosemicarbazone (Dp44mT). We demonstrated that Dp44mT, decreases ATP via the suppression of energy generating pathways, glycolysis and mitochondrial respiration, resulting in the activation of the AMPK pathway. This response aims to rescue the loss of metal ions via chelation and the induction of cytotoxic damage mediated by redox cycling of the Dp44mT-metal ion complex. Furthermore, this thesis also elucidated the role of AMPK in Dp44mT-meidated autophagy and apoptosis. Additionally, Dp44mT can also initiate autophagy in an AMPK-independent manner, via Beclin-1. This thesis also demonstrated the crucial role of AMPK in lysosomal biogenesis and stability. Overall, the results presented within this thesis comprehensively elucidate the molecular response of AMPK in the highly complex, multifactorial, anti-tumour activity of Dp44mT. It was established that the activation of the AMPK pathway in response to Dp44mT acts as a rescue response against the oxidative and cytotoxic effects of this anti-tumour agent to prolong cell survival. This provides important clues to the potential role of possible synergistic combinations of Dp44mT with potent AMPK inhibitors for the effective treatment of cancer

Effect of Surface Temperature on Energy Consumption in a Calibrated Building: A Case Study of Delhi

Rapid urbanization and associated land-use changes in cities cause an increase in the demand for electricity by altering the local climate. The present study aims to examine the variations in total energy and cooling energy demand in a calibrated building energy model, caused by urban heat island formation over Delhi. The study used Sentinel-2A multispectral imagery for land use and land cover (LULC) of mapping of Delhi, and Moderate Resolution Imaging Spectroradiometer (MODIS) imagery for land surface temperature (LST) mapping during March 2018. It was observed that regions with dense built-up areas (i.e., with built-up area greater than 90%) had a higher annual land surface temperature (LST), i.e., 293.5 K and urban heat island intensity (UHII) ranging from 0.9 K–5.9 K. In contrast, lower annual values of LST (290K) and UHII (0.0–0.4 K) were observed in regions with high vegetation cover (53%). Statistical analysis reveals that a negative correlation exists between vegetation and nighttime LST, which is further confirmed by linear regression analysis. Energy simulations were performed on a calibrated building model placed at three different sites, identified on the basis of land use and land cover percentage and annual LST. Simulation results showed that the site located in the central part of Delhi displayed higher annual energy consumption (255.21 MWh/y) compared to the site located in the rural periphery (235.69 MWh/y). For all the three sites, the maximum electricity consumption was observed in the summer season, while the minimum was seen in the winter season. The study indicates that UHI formation leads to increased energy consumption in buildings, and thus UHI mitigation measures hold great potential for energy saving in a large city like Delhi

Iron Metabolism and Autophagy: A Poorly Explored Relationship that has Important Consequences for Health and Disease

Autophagy is an important cell survival pathway which is up-regulated under stress conditions.1) It is a well regulated catabolic process and enables the cell to recycle its constituents and organelles for re-use.1) Autophagy has been implicated to play an important role in a variety of disorders such as cancer and protein aggregatory neurodegenerative diseases e.g., Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.2) Iron is a critical metal required for normal cellular functioning.3) A very tightly regulated balance of iron levels is required for the normal physiological functioning of the cell.3) Both an excess and deficiency of iron can lead to cellular stress, and thereby, alters the autophagic status within the cell. Thus, it is important to completely understand how iron can affect the autophagic pathway and its potential implications under physiological as well as pathological conditions