Institute of Health Sciences

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    Exploring the role of NAD metabolism in response to mitochondrial respiratory chain inhibition
    Mukherjee, Piyali
    Mitochondrial Complex I deficiency has been reported in several diseases and strongly linked to patients with Parkinson ’s disease. However, there is poor mechanistic understanding of the pathways involved and no treatment regimen is currently available for mitochondrial complex I deficiency disorders. Rotenone is a potent inhibitor of mitochondrial ETC complex I. Several studies have indicated that rotenone-mediated cell death is associated with mitochondrial depolarization, DNA damage, and ROS generation that corroborates with similar observations in other mitochondrial complex I deficiency disorders but there lacks a comprehensive understanding of the cell death network induced by the deregulation of these pathways. Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that bridges mitochondrial energy production with metabolism. However, how NAD+ modulates cellular homeostasis in response to mitochondrial respiratory chain inhibition has not been comprehensively explored so far. This study focuses on understanding the events that lead to NAD+-dependent cell death following mitochondrial complex I inhibition. Our study revealed that early loss of endogenous NAD+ due to hyperactivation of PARP1 in the presence of rotenone may act as a ‘biological trigger’ of NADase Sarm1 activation in the presence of mitochondrial complex I inhibitor rotenone. This study demonstrated, replenishing NAD+ levels by PARP1 inhibitor, PJ34/Olaparib restored mitochondrial complex I activity, and early loss of NAD+, thereby preventing the activation of Sarm1. This conservation of NAD+ via PARP inhibition stimulated mitophagy and removal of damaged mitochondria, thereby preventing sustained ROS production. These cellular data were further validated in Drosophila melanogaster (w1118) where a significant reduction in rotenone-induced loss of locomotor abilities, reduced inflammatory response, restoration of dopaminergic neuronal loss, and reduced dSarm expression was observed in flies following PARP inhibition via the clinical inhibitor, Olaparib. Collectively, these observations not only uncover a novel regulation of cell death via endogenous NAD+ levels but also point towards an important understanding of how PARP inhibitors could be repurposed in the treatment of mitochondrial complex I deficiency disorders.
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    Microbial Signature Associated with the Development of Prostate and Oral cancers in Eastern Region of India
    Saha, Abhik
    The relationship between humans and microbes dates back to ancient times. Robert Koch's groundbreaking work on‘Pure Culture’ technique illuminated specific role of microbes in causing various human diseases. This technique, however, later met a challenge known as 'The Great Plate Count Anomaly' where many visible microbes under the microscope couldn't be cultivated in pure culture, leading to the concept of 'Uncultivable Microbes'. Advanced sequencing techniques, such as metagenomics sequencing, shotgun sequencing, whole genome sequencing and 16S rRNA amplicon-based sequencing emerged as powerful tools to explore the uncultivable microbial world. In this study, we aimed to uncover the integral connections of microbial communities with both prostate cancer (PCa) and oral squamous cell carcinoma (OSCC) development through utilizing uncultivated sequencing technology along with various bioinformatics analysis. Prostate and oral cancers pose significant health challenges globally as well as with respect to Indian patients. Meticulous analysis of commensal bacteria compositions in both benign prostatic hyperplasia (BPH) and PCa patients’ revealed Prevotella copri, Cupriavidus campinensis and Propionibacterium acnes dominated in diseased prostate lesions. While PCa samples exhibited elevated levels of Cupriavidus taiwanensis and Methylobacterium organophilum, BPH samples were enriched with Kocuria palustris and Cellvibrio mixtus. Several human tumor viruses like Epstein-Barr virus (EBV), hepatitis B virus (HBV) and high-risk human papillomavirus (HPV) strains HPV-16 and HPV-18 were also strongly associated with PCa development, correlating with its bacterial signature. OSCC represents the most common oral malignancy. In contrast to adjancent normal samples, malignant oral tissues showed decreased bacterial genera of Actinomyces, Sutterella, Stenotrophomonas, Anoxybacillus and Serratia along with increased bacterial genera of Prevotella, Corynebacterium, Pseudomonas, Deinococcus and Noviherbaspirillum. In addition, high-risk HPV-16 strain was significantly linked to OSCC progression. Collectively, these findings reveal the complex interaction of bacterial and viral signatures with PCa and OSCC development.