Medicine and Health Sciences Commons^™

Autophagy And Apoptosis: Current Challenges Of Treatment And Drug Resistance In Multiple Myeloma., Omar S Al-Odat, Daniel A Guirguis, Nicole K Schmalbach, Gabriella Yao, Tulin Budak-Alpdogan, Subash C. Jonnalagadda, Manoj K Pandey

Cooper Medical School of Rowan University Faculty Scholarship

Over the past two decades, the natural history of multiple myeloma (MM) has evolved dramatically, owing primarily to novel agents targeting MM in the bone marrow microenvironment (BMM) pathways. However, the mechanisms of resistance acquisition remain a mystery and are poorly understood. Autophagy and apoptosis are tightly controlled processes and play a critical role in the cell growth, development, and survival of MM. Genetic instability and abnormalities are two hallmarks of MM. During MM progression, plasma malignant cells become genetically unstable and activate various signaling pathways, resulting in the overexpression of abnormal proteins that disrupt autophagy and apoptosis biological processes. …

Mitochondrial Autophagy In Ischemic Aged Livers, Jae-Sung Kim, William C Chapman, Yiing Lin

2020-Current year OA Pubs

Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury.

Principles Of Dormancy Evident In High-Grade Serous Ovarian Cancer, Trevor G. Shepherd, Frederick A. Dick

Paediatrics Publications

In cancer, dormancy refers to a clinical state in which microscopic residual disease becomes non-proliferative and is largely refractory to chemotherapy. Dormancy was first described in breast cancer where disease can remain undetected for decades, ultimately leading to relapse and clinical presentation of the original malignancy. A long latency period can be explained by withdrawal from cell proliferation (cellular dormancy), or a balance between proliferation and cell death that retains low levels of residual disease (tumor mass dormancy). Research into cellular dormancy has revealed features that define this state. They include arrest of cell proliferation, altered cellular metabolism, and unique …

Caspase-8 Inactivation Drives Autophagy-Dependent Inflammasome Activation In Myeloid Cells., Yung-Hsuan Wu, Shu-Ting Mo, I-Ting Chen, Fu-Yi Hsieh, Shie-Liang Hsieh, Jianke Zhang, Ming-Zong Lai

Department of Microbiology and Immunology Faculty Papers

Caspase-8 activity controls the switch from cell death to pyroptosis when apoptosis and necroptosis are blocked, yet how caspase-8 inactivation induces inflammasome assembly remains unclear. We show that caspase-8 inhibition via IETD treatment in Toll-like receptor (TLR)-primed Fadd-/-Ripk3-/- myeloid cells promoted interleukin-1β (IL-1β) and IL-18 production through inflammasome activation. Caspase-8, caspase-1/11, and functional GSDMD, but not NLRP3 or RIPK1 activity, proved essential for IETD-triggered inflammasome activation. Autophagy became prominent in IETD-treated Fadd-/-Ripk3-/- macrophages, and inhibiting it attenuated IETD-induced cell death and IL-1β/IL-18 production. In contrast, inhibiting GSDMD or autophagy did not prevent IETD-induced septic …

Promotion Of A Synthetic Degradation Of Activated Stat6 By Parp-1 Inhibition: Roles Of Poly(Adp-Ribosyl)Ation, Calpains And Autophagy, Jeffrey Wang, Mohamed A. Ghonim, Salome V. Ibba, Hanh H. Luu, Yucel Aydin, Peter A. Greer, A. Hamid Boulares

School of Medicine Faculty Publications

Background: We reported that PARP-1 regulates genes whose products are crucial for asthma, in part, by controlling STAT6 integrity speculatively through a calpain-dependent mechanism. We wished to decipher the PARP-1/STAT6 relationship in the context of intracellular trafficking and promoter occupancy of the transcription factor on target genes, its integrity in the presence of calpains, and its connection to autophagy. Methods: This study was conducted using primary splenocytes or fibroblasts derived from wild-type or PARP-1−/− mice and Jurkat T cells to mimic Th2 inflammation. Results: We show that the role for PARP-1 in expression of IL-4-induced genes (e.g. gata-3) in splenocytes …

A Protocol To Induce Systemic Autophagy And Increase Energy Metabolism In Mice Using Pegylated Arginine Deiminase, Yiming Zhang, Brian J. Debosch

2020-Current year OA Pubs

Obesity is a prevalent metabolic disorder worldwide. Here, we describe a comprehensive protocol using pegylated arginine deiminase (ADI-EPG 20) to apply the concept that arginine depletion induces systemic autophagy to drive whole-body energy metabolism and weight loss in mice. We detail the steps for cohort setup, mouse husbandry, and treatment and provide expected results under these conditions. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2022a, 2022b).

The Effects Of Autophagy And Proteasomes On Tgfβ Signalling And Emt, Charles Brandon Trelford

Electronic Thesis and Dissertation Repository

Transforming growth factor-β (TGFβ) signalling regulates growth, proliferation, immunity, and development. Although TGFβ typically antagonizes tumour formation, tumour cells often acquire mutations within the TGFβ signalling pathway that activate epithelial-mesenchymal transition (EMT). During EMT, epithelial tumour cells lose epithelial-like properties and acquire mesenchymal-like characteristics, which allows tumour cells to detach from the primary tumour and establish metastatic colonies. In addition to EMT, TGFβ augments tumourigenesis by increasing the degradation of damaged macromolecules and organelles via autophagy. Autophagy contributes to radiotherapy and chemotherapy resistance by mitigating the damages inflicted on tumour cells. Currently, there is a growing interest in the relationship …

Antiaging Mechanism Of Natural Compounds: Effects On Autophagy And Oxidative Stress., Elizabeth Taylor, Yujin Kim, Kaleb Zhang, Lenne Chau, Bao Chieu Nguyen, Srujana Rayalam, Xinyu Wang

PCOM Scholarly Papers

Aging is a natural biological process that manifests as the progressive loss of function in cells, tissues, and organs. Because mechanisms that are meant to promote cellular longevity tend to decrease in effectiveness with age, it is no surprise that aging presents as a major risk factor for many diseases such as cardiovascular disease, neurodegenerative disorders, cancer, and diabetes. Oxidative stress, an imbalance between the intracellular antioxidant and overproduction of reactive oxygen species, is known to promote the aging process. Autophagy, a major pathway for protein turnover, is considered as one of the hallmarks of aging. Given the progressive physiologic …

Activation Of Autophagic Flux Maintains Mitochondrial Homeostasis During Cardiac Ischemia/Reperfusion Injury, Lihao He, Sumanth D Prabhu, Et Al

2020-Current year OA Pubs

Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing peptide, Tat-Beclin 1 (TB), reduces infarct size when administered at the time of reperfusion. However, since SAHA affects multiple pathways in addition to inducing autophagy, whether autophagic flux induced by TB maintains mitochondrial homeostasis during ischemia/reperfusion (I/R) injury is unknown. We tested whether the augmentation of autophagic flux by TB has cardioprotection by preserving mitochondrial homeostasis both …

Effect Of Injury Mechanism And Severity On The Molecular Pathophysiology Of Traumatic Brain Injury, Brandon Mcdonald

Department of Agricultural and Biological Systems Engineering: Dissertations, Theses, and Student Research

Traumatic brain injury (TBI) mechanism and severity are heterogenous clinically, resulting in a multitude of physical, cognitive, and behavioral deficits. However, approximately 80% suffer from milder injuries. Thus, examining pathophysiological changes associated with mild TBI is imperative for improving clinical translation and evaluating the efficacy of potential therapeutic strategies. Through this work, we developed models of TBI, ranging in both injury mechanism and severity, using an electromagnetic controlled cortical impact (CCI) device. First, we characterized and optimized a closed head, mild TBI model (DTBI) to determine the clinical translatability and practicality of producing repeated mild injuries. Interestingly, we determined that …

Endothelial Autophagy In Coronary Microvascular Dysfunction And Cardiovascular Disease, Fujie Zhao, Ganesh Satyanarayana, Zheng Zhang, Jianli Zhao, Xin-Liang Ma, Yajing Wang

Department of Emergency Medicine Faculty Papers

Coronary microvascular dysfunction (CMD) refers to a subset of structural and/or functional disorders of coronary microcirculation that lead to impaired coronary blood flow and eventually myocardial ischemia. Amid the growing knowledge of the pathophysiological mechanisms and the development of advanced tools for assessment, CMD has emerged as a prevalent cause of a broad spectrum of cardiovascular diseases (CVDs), including obstructive and nonobstructive coronary artery disease, diabetic cardiomyopathy, and heart failure with preserved ejection fraction. Of note, the endothelium exerts vital functions in regulating coronary microvascular and cardiac function. Importantly, insufficient or uncontrolled activation of endothelial autophagy facilitates the pathogenesis of …

Human Macrophages Exhibit Gm-Csf Dependent Restriction Of Mycobacterium Tuberculosis Infection Via Regulating Their Self-Survival, Differentiation And Metabolism, Abhishek Mishra, Vipul K. Singh, Chinnaswamy Jagannath, Margaret Sunitha Selvaraj, Selvakumar Subbian, Blanca I. Restrepo, Marie-Claire Gauduin, Arshad Khan

School of Medicine Publications and Presentations

GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of M. tuberculosis infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed …

Genome-Wide Transcript And Protein Analysis Highlights The Role Of Protein Homeostasis In The Aging Mouse Heart., Isabela Gerdes Gyuricza, Joel M Chick, Gregory R Keele, Andrew Deighan, Steven C. Munger, Ron Korstanje, Steven P Gygi, Gary Churchill

Faculty Research 2022

Investigation of the molecular mechanisms of aging in the human heart is challenging because of confounding factors, such as diet and medications, as well as limited access to tissues from healthy aging individuals. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyze transcriptome and proteome data from 185 genetically diverse male and female mice at ages 6, 12, and 18 mo to characterize molecular changes that occur in the …

Diurnal Regulation Of Exercise-Induced Myocardial Signaling And Transcription, Charli Aguilar

UNLV Theses, Dissertations, Professional Papers, and Capstones

Introduction: Exercise is well known for its many benefits on the body and most notably the heart. Recent emphasis, and significant resources, have been dedicated to elucidating the molecular mechanisms through which exercise exerts its pluripotent beneficial effects on health and the prevention of disease. A continuous evolution in this field has sought to modulate and optimize exercise in various ways to maximize the benefits. In recent years, a growing appreciation for the impact of circadian rhythms has gained traction and their influence on many essential biological functions have been integrated into exercise physiology (i.e. - chrono-exercise), as well as …

The Role Of Mtorc1 In Autophagy As It Relates To Cancer, Olivia Robinson

Senior Honors Theses

The mammalian target of rapamycin complex 1, mTORC1, is composed of several subunit proteins with many cellular responsibilities including participation in a complex cell signaling cascade leading to autophagy, which is the regulated degradation of cell components. mTORC1 is frequently mutated or dysregulated within human cancer. Normally, mTORC1 functions to provide efficient regulation of autophagy according to intracellular levels of growth factors, amino acids, nutrients, oxygen levels, and more that can either inhibit mTORC1 and upregulate autophagy or activate mTORC1 and downregulate autophagy. A better understanding of mTORC1 is imperative to preparing cancer therapy treatments. Various cancerous tissue types require …

Mitophagy-Mediated Regulation Of Ros Homeostasis During Hsc Activation Contributes To Cell Fate, Amber Lynne Smith

Theses and Dissertations (ETD)

The ability of hematopoietic stem cells to self-renew and differentiate is required for the maintenance of all blood lineages under basal physiologic conditions and in response to inflammatory stress. The degradative capacity of the autophagy-lysosomal system is a determinant of hematopoietic stem cell (HSC) activation status with low autophagy predicting activation of HSCs, and autophagy deficiency causing the spontaneous loss of quiescence and HSC exhaustion. Although an increase in mitochondrial activity has been suggested as the cause of HSC depletion in autophagy-defective models, the contribution of mitophagy to HSC function remains to be elucidated. Here, we capitalized on the observation …

Arsenic Toxicity On Metabolism And Autophagy In Adipose And Muscle Tissues, Seung-Hyun Ro, Jiyoung Bae, Yura Jang, Jacob Myers, Soonkyu Chung, Jiujiu Yu, Sathish Kumar Natarajan, Rodrigo Franco, Hyun-Seob Song

Department of Microbiology and Immunology Faculty Papers

Arsenic, a naturally occurring metalloid derived from the environment, has been studied worldwide for its causative effects in various cancers. However, the effects of arsenic toxicity on the development and progression of metabolic syndrome, including obesity and diabetes, has received less attention. Many studies suggest that metabolic dysfunction and autophagy dysregulation of adipose and muscle tissues are closely related to the development of metabolic disease. In the USA, arsenic contamination has been reported in some ground water, soil and grain samples in major agricultural regions, but the effects on adipose and muscle tissue metabolism and autophagy have not been investigated …

Suppression Of Pi3k Signaling Is Linked To Autophagy Activation And The Spatiotemporal Induction Of The Lens Organelle Free Zone, Rifah Gheyas, Ramon Ortega-Alvarez, Daniel Chauss, Marc Kantorow, A. Menko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The terminal steps of lens cell differentiation require elimination of all organelles to create a central Organelle Free Zone (OFZ) that is required for lens function of focusing images on the retina. Previous studies show that the spatiotemporal elimination of these organelles during development is autophagy-dependent. We now show that the inhibition of PI3K signaling in lens organ culture results in the premature induction of autophagy within 24 h, including a significant increase in LAMP1+ lysosomes, and the removal of lens organelles from the center of the lens. Specific inhibition of just the PI3K/Akt signaling axis was directly linked to …

Increased Drp1 Promotes Autophagy And Escc Progression By Mtdna Stress Mediated Cgas-Sting Pathway., Yujia Li, Hui Chen, Qi Yang, Lixin Wan, Jing Zhao, Yuanyuan Wu, Jiaxin Wang, Yating Yang, Menglan Niu, Hongliang Liu, Junqi Liu, Hushan Yang, Shaogui Wan, Yanming Wang, Dengke Bao

Department of Medical Oncology Faculty Papers

Background: Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC).

Methods: Immunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. …

Selective Elimination Of Pluripotent Stem Cells By Pikfyve Specific Inhibitors., Arup R Chakraborty, Alex Vassilev, Sushil K Jaiswal, Constandina E O'Connell, John F Ahrens, Barbara S Mallon, Martin Pera, Melvin L Depamphilis

Faculty Research 2022

Inhibition of PIKfyve phosphoinositide kinase selectively kills autophagy-dependent cancer cells by disrupting lysosome homeostasis. Here, we show that PIKfyve inhibitors can also selectively eliminate pluripotent embryonal carcinoma cells (ECCs), embryonic stem cells, and induced pluripotent stem cells under conditions where differentiated cells remain viable. PIKfyve inhibitors prevented lysosome fission, induced autophagosome accumulation, and reduced cell proliferation in both pluripotent and differentiated cells, but they induced death only in pluripotent cells. The ability of PIKfyve inhibitors to distinguish between pluripotent and differentiated cells was confirmed with xenografts derived from ECCs. Pretreatment of ECCs with the PIKfyve specific inhibitor WX8 suppressed their …

The Role Of Decorin Proteoglycan In Mitophagy., Thomas Neill, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Proteoglycans are emerging as critical regulators of intracellular catabolism. This rise in prominence has transformed our basic understanding and alerted us to the existence of non-canonical pathways, independent of nutrient deprivation, that potently control the autophagy downstream of a cell surface receptor. As a member of the small leucine-rich proteoglycan gene family, decorin has single-handedly pioneered the connection between extracellular matrix signaling and autophagy regulation. Soluble decorin evokes protracted endothelial cell autophagy via Peg3 and breast carcinoma cell mitophagy via mitostatin by interacting with VEGFR2 or the MET receptor tyrosine kinase, respectively. In this paper, we give a mechanistic perspective …

Does Data-Independent Acquisition Data Contain Hidden Gems? A Case Study Related To Alzheimer's Disease, Evan E Hubbard, Randall J Bateman, Richard J Perrin, Et Al.

2020-Current year OA Pubs

One of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant …

Ferritinophagy And Α-Synuclein: Pharmacological Targeting Of Autophagy To Restore Iron Regulation In Parkinson’S Disease, Matthew K. Boag, Angus Roberts, Vladimir N. Uversky, Linlin Ma, Des R. Richardson, Dean L. Pountney

Molecular Medicine Faculty Publications

A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution of α-synuclein aggregation, iron accumulation, and mitochondrial dysfunction plague nigral neurons, yet the events underlying iron accumulation are poorly understood. Elevated intracellular iron concentrations up-regulate ferritin expression, an iron storage protein that provides cytoprotection against redox stress. The lysosomal degradation pathway, autophagy, can release iron from ferritin stores to facilitate its trafficking in a process termed ferritinophagy. Aggregated …

Mammalian Target Of Rapamycin Cell Signaling Pathway In Phosphatase And Tensin Homolog Induced Kinase 1 Knockout Rat Model Of Familial Parkinson's Disease, Martha Helena Mortell

Theses and Dissertations--Medical Sciences

More than 10 million people are living with Parkinson’s disease (PD), one million of which are people in the United States. PD is the second most common age-related neurodegenerative disorder, after Alzheimer’s disease, and is characterized by the accumulation of a-synuclein aggregates and the degeneration of dopaminergic neurons. The loss of endogenous dopamine in PD brain accounts for the motor decline presented clinically in PD patients. Etiological factors of PD include oxidative damage and inflammation, although the detailed mechanisms remain unknown. Risk factors for PD include gender, age, environmental factors, and gene mutations.

The current thesis research employed phosphatase and …