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Full-Text Articles in Medicine and Health Sciences
Activation Of Ampk To Diminish Sepsis-Induced Lung Injury, Nathaniel Bone
Activation Of Ampk To Diminish Sepsis-Induced Lung Injury, Nathaniel Bone
All ETDs from UAB
Sepsis is the most frequent cause of death of hospitalized patients in modern ICUs. Severe infection, trauma, hemorrhage, burns, and surgery are significant causes of multi-organ injury and immune dysfunction that in turn primes for a high risk of secondary lung infections. In addition to detrimental inflammation, sepsis is linked to loss of metabolic plasticity due to mitochondrial dysfunction in immune cells and lung tissue. In particular, mitochondrial failure in lungs of critically ill septic patients is correlated with high mortality rates. We proposed that AMP-activated protein kinase (AMPK) activation, a major bioenergetic sensor and metabolic regulator, is a plausible …
Post-Transcriptional Regulation Of Autophagy By The 5’-3’ Mrna Decay Pathway In Saccharomyces Cerevisiae, Matthew Weaver
Post-Transcriptional Regulation Of Autophagy By The 5’-3’ Mrna Decay Pathway In Saccharomyces Cerevisiae, Matthew Weaver
All ETDs from UAB
The process of bulk degradation of cytoplasmic contents, called macroautophagy or simply autophagy, is a heavily conserved cellular process from yeast to humans. In yeast, it involves more than 30 different autophagy related genes (ATG) that coordinate the process of building a double membrane vesicle, called the autophagosome, that fuses with the vacuole to allow degradation and recycling of its contents. This process can also be selective, involving the recruitment of the autophagic machinery to specific organelles. In this work, we used RNA sequencing (RNA-seq) to identify a subset of ATG genes that are heavily upregulated in response to nitrogen …
Autophagy In Mitochondrial Quality Control And Proteotoxicity In Neurons, Matthew Redmann
Autophagy In Mitochondrial Quality Control And Proteotoxicity In Neurons, Matthew Redmann
All ETDs from UAB
Parkinson’s disease (PD) is the 2nd most common neurodegenerative disorder with aging as a significant risk factor. Sharing with aging brains, postmortem PD brains exhibit cellular deficits including autophagic dysfunction, mitochondrial dysfunction, and intracellular protein aggregates of alpha-synuclein. This dissertation will focus on the interplay between these key disease features. To that end, we coupled primary cortical neuronal cultures from either rats or mice with Seahorse extracellular flux, metabolomics and biochemical techniques. Autophagy is an important cell recycling program responsible for the clearance of damaged proteins and organelles. Bafilomycin A1 and chloroquine are compounds that inhibit autophagy by targeting the …
Changes In Gene Expression During Nitrogen Starvation Are Mediated By Targeted Degradation Of Translation And Mrna Decay Factors In Saccharomyces Cerevisiae, Shane Patrick Kelly
Changes In Gene Expression During Nitrogen Starvation Are Mediated By Targeted Degradation Of Translation And Mrna Decay Factors In Saccharomyces Cerevisiae, Shane Patrick Kelly
All ETDs from UAB
Autophagy is the cellular mechanism of recruitment and decay of cytoplasmic molecules, proteins, and organelles that are obsolete for a particular growth condition. Autophagic degradation is distinct from proteasomal degradation by the formation of a de-novo double membrane which engulfs its cargo to be delivered for degradation to the yeast vacuole. Once thought to be only a general phenomenon of bulk decay, several autophagic pathways have demonstrated selectivity. In the following work we show that during nitrogen starvation (a potent inducer of autophagy) in the yeast Saccharomyces cerevisiae, a subset of translation factors are degraded selectively and rapidly. We go …
Linking Adiponectin And Autophagy In The Regulation Of Breast Cancer Metastatic Potential, Emily Libby
Linking Adiponectin And Autophagy In The Regulation Of Breast Cancer Metastatic Potential, Emily Libby
All ETDs from UAB
Curative approaches for metastatic breast cancer remain elusive. Adiponectin is the most abundant of the adipocyte-secreted adipokines, and there is recent interest in development of adiponectin-based therapies for this disease. Yet, while multiple epidemiological studies have indicated that low levels of circulating plasma adiponectin portend poorer prognosis, recent work has reported that elevated adiponectin expression in breast tissue correlates with advanced disease. Further, isoform-specific roles of this molecule are not well understood. Thus, the overarching purpose of this work was to elucidate how adiponectin isoforms contribute to the microenvironmental regulation of the early steps of breast cancer metastasis. We show …
Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson
Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson
All ETDs from UAB
Neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and Huntington's disease are all characterized by metabolic dysfunction, increased oxidative damage to proteins and organelles, formation of proteinaceous inclusions, decreased autophagic and proteasomal function, and eventual neuronal and glial cell death. While our understanding of the mechanisms that underlie many of these pathologies is constantly growing, their exact cause, onset, interplay and progression still remain unclear. The gap between the description of disease pathologies and understanding the fundamental mechanisms of disease pathogenesis, progression and potential therapeutics to mitigate disease progression is still large. Based on the observation that altered glucose utilization, …
Mitochondrial Dysfunction In Response To Neurotoxins And The Role Of Mitophagy, Samantha Giordano
Mitochondrial Dysfunction In Response To Neurotoxins And The Role Of Mitophagy, Samantha Giordano
All ETDs from UAB
Parkinson's disease (PD) is the second most common neurodegenerative disorder. Two major factors in both familial and sporadic PD are mitochondrial dysfunction and insufficient autophagy. My thesis research focuses on the interplay between these activities in PD. To investigate the common and differential effects of PD-inducing neurotoxins on mitochondrial bioenergetics and their relationships to cell survival, we used an in vitro culture system, differentiated dopaminergic SH-SY5Y neuroblastoma cells. We found that the neurotoxins rotenone, 1-methyl-4- phenylyridinium (MPP+) and 6-hydroxydopamine (6-OHDA), decreased mitochondrial respiration and induced cell death in these cells. The extent and characteristics of mitochondrial dysfunction in response to …
The Role Of The Autophagy-Lysosome Pathway In In Vitro Models Of Neurodegeneration, Burton Mader
The Role Of The Autophagy-Lysosome Pathway In In Vitro Models Of Neurodegeneration, Burton Mader
All ETDs from UAB
Recent studies have provided strong evidence that alterations in protein degradation pathways, such as the autophagy-lysosome pathway (ALP), may contribute to neuronal dysfunction and death which lead to clinical symptoms diagnosed with various neurodegenerative diseases. Parkinson's disease (PD) is characterized by neuromuscular abnormalities resulting from the pathological loss of substantia nigra dopaminergic neurons and widespread detection of Lewy bodies, intracellular protein inclusions composed primarily of α-synuclein. Additionally, altered gene function regulating the expression of α-synuclein has been directly linked to the PD pathogenesis. Autophagy is an intracellular degradation process that when altered can lead to the accumulation neurotoxic proteins such …
Sulindac Sulfide Amide As A Novel Agent For The Prevention And Treatment Of Lung Cancer, Evrim Gurpinar
Sulindac Sulfide Amide As A Novel Agent For The Prevention And Treatment Of Lung Cancer, Evrim Gurpinar
All ETDs from UAB
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from cyclooxygenase (COX) inhibition limit their use in cancer prevention. We recently described a N,N-dimethylethyl amine derivative of SS, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth inhibitory activity. Here, we studied the basis for the growth inhibitory effects of SSA on human lung adenocarcinoma cell lines and evaluated its preclinical pharmacology. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2-5 μ compared with 44-52 …
Regulation Of Cell Death By Autophagy In Glial Neoplasms, Latika R. Kohli
Regulation Of Cell Death By Autophagy In Glial Neoplasms, Latika R. Kohli
All ETDs from UAB
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive malignancies of the peripheral nervous system. The majority of MPNSTs arise in patients of the autosomal dominant genetic disorder neurofibromatosis type I (NF1) although they also arise sporadically. In the absence of any effective chemotherapeutic options and with surgery constituting the mainstay of treatment, MPNST patients face an extremely poor prognosis. This underscores the need to develop novel therapeutic strategies against this tumor type. It is well accepted that the crosstalk between autophagy and apoptosis can be exploited to derive maximal therapeutic benefit, especially through combinatorial therapies. However, this interaction is extremely …
Mitochondrial Morphology And Function In Neuronal Cells Under Stress, Lonnie Schneider
Mitochondrial Morphology And Function In Neuronal Cells Under Stress, Lonnie Schneider
All ETDs from UAB
Neurodegenerative disease encompasses a wide range of conditions and pathologies that can manifest at any age depending on the etiology. A major factor in both early onset and age-related neurodegeneration is mitochondrial dysfunction. To investigate how mitochondrial bioenergetics is affected by cellular stress, we used an in vitro culture system to examine mitochondrial function in response to oxidative stress. We also studied an in vivo model of neuronal ceroid lipofuscinosis to determine the impact of deficient autophagy-lysosomal activity on mitochondrial morphology, composition and function. In vitro we found that retinoic acid-induced differentiation of dopaminergic neuroblastoma SH-SY5Y cells exhibited increased mitochondrial …
Modulation Of Alpha-Synuclein Metabolism And Toxicity By Cathepsin D, Donna Marlana Crabtree
Modulation Of Alpha-Synuclein Metabolism And Toxicity By Cathepsin D, Donna Marlana Crabtree
All ETDs from UAB
Parkinson's disease (PD) is the most commonly occurring neurodegenerative movement disorder, and aberrant accumulation of the protein α-synuclein is thought to be a major contributing factor in disease development. Dysfunction of the autophagy lysosome pathway (ALP) has been implicated in PD pathogenesis. Our lab and others have shown that the lysosomal enzyme cathepsin D (CD) is an important regulator of α-synuclein degradation. The primary focus of this thesis is probing the structure/function dynamic that exists between α-synuclein and CD. We have found that lentiviral-mediated over expression of wild type CD (wtCD) leads to subtle alterations in the ALP in a …
Regulation Of Neuronal Death By The Autophagy Lysosomal Pathway: Implications For Parkinson Disease, Violetta N. Pivtoraiko
Regulation Of Neuronal Death By The Autophagy Lysosomal Pathway: Implications For Parkinson Disease, Violetta N. Pivtoraiko
All ETDs from UAB
Parkinson Disease (PD) is the second most common age-related neurodegenerative disorder and is characterized pathologically by the loss of dopaminergic (DA) neurons in the stubstantia nigra pars compacta (SNpc). Mitochondrial dysfunction, increased oxidative stress, and accumulation of aggregated α-synuclein (α-syn), an intracellular protein involved in synaptic function, are all pathological hallmarks of PD have been implicated in PD pathogenesis. However, it is debated whether α-syn aggregates themselves are responsible for neurodegeneration in PD, cellular pathways involved in degradation of α-syn aggregates are believed to promote neuron survival. The autophagy lysosomal pathway (ALP), a physiological mechanism for recycling of intracellular components, …
Protein Modifications And The Response To Oxidized Lipids In Cardiovascular Cells, Ashlee Higdon
Protein Modifications And The Response To Oxidized Lipids In Cardiovascular Cells, Ashlee Higdon
All ETDs from UAB
Free radical catalyzed oxidation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid is increased in cardiovascular disease states, including atherosclerosis and heart failure. Oxidized lipids have been extensively studied and found to recapitulate several key steps in atherogenesis. However, clinical trials with antioxidants such as alpha-tocopherol have been less promising than originally predicted. Now appreciated as more than just biomarkers of disease, lipid peroxidation products have been shown to have roles in pathogenesis as well as physiology. Of particular interest are reactive lipid species that possess electrophilic carbonyls enabling them to act in a receptor-independent manner. To date, the …
Role Of Heme Oxygenase-1 In Acute Kidney Injury, Subhashini Bolisetty
Role Of Heme Oxygenase-1 In Acute Kidney Injury, Subhashini Bolisetty
All ETDs from UAB
Acute kidney injury (AKI), defined as the rapid loss of kidney function, is often seen in the setting of multiple organ failure in critically ill patients. Lack of established therapeutic approaches to overcome AKI has lead to unacceptably high incidence of morbidity and mortality in these patients. The molecular mechanisms that lead to AKI often have oxidative stress as a common pathogenic event. The kidney responds by prompt induction of its own anti-oxidant machinery including the highly inducible, anti-inflammatory and anti-apoptotic gene-heme oxygenase-1 (HO-1). This microsomal enzyme degrades pro-oxidant heme, which is released from heme proteins. The cytoprotective properties of …
Role Of 14-3-3&Tau In Autophagy And Role Of Edd In P53 Regulation, Shiyun Ling
Role Of 14-3-3&Tau In Autophagy And Role Of Edd In P53 Regulation, Shiyun Ling
All ETDs from UAB
Unrestricted cell proliferation and suppression of cell death are two essential events for tumor development. My dissertation research involves two proteins, 14-3-3 &tau and EDD which are involved in diverse pathways related to these two fields in recent studies. Previous study demonstrates that 14-3-3ô regulates p21 degradation. Up-regulation of 14-3-3ô is seen in breast cancer and is correlated with the down-regulation of p21 in breast cancer. Amplification or overexpression of EDD was observed in breast cancer and ovarian cancers. Illustrating the new roles of these two proteins in proliferation and cell death will advance our knowledge in tumorigenesis and help …