Medicine and Health Sciences Commons^™

Synergistic Effects Of Nanosecond Pulsed Plasma And Electric Field On Inactivation Of Pancreatic Cancer Cells In Vitro, Edwin A. Oshin, Zobia Minhas, Ruben M. L. Colunga Biancatelli, John D. Catravas, Richard Heller, Siqi Guo, Chunqi Jiang

Bioelectrics Publications

Nanosecond pulsed atmospheric pressure plasma jets (ns-APPJs) produce reactive plasma species, including charged particles and reactive oxygen and nitrogen species (RONS), which can induce oxidative stress in biological cells. Nanosecond pulsed electric field (nsPEF) has also been found to cause permeabilization of cell membranes and induce apoptosis or cell death. Combining the treatment of ns-APPJ and nsPEF may enhance the effectiveness of cancer cell inactivation with only moderate doses of both treatments. Employing ns-APPJ powered by 9 kV, 200 ns pulses at 2 kHz and 60-nsPEF of 50 kV/cm at 1 Hz, the synergistic effects on pancreatic cancer cells (Pan02) …

Dihydroethidium-Derived Fluorescence In Electrically Stressed Cells Indicates Intracellular Microenvironment Modifications Independent Of Ros, Esin B. Sözer, Iurii Semenov, P. Thomas Vernier

Bioelectrics Publications

Intracellular reactive oxygen species (ROS) generation is widely suggested as a trigger for biological consequences of electric field exposures, such as those in electroporation applications. ROS are linked with membrane barrier function degradation, genetic damage, and complex events like immunological cell death. Dihydroethidium (DHE) is commonly used to monitor ROS in cells. DHE is linked to intracellular ROS by a primary oxidation product, Ethidium (Eth⁺), that shows increased fluorescence upon binding to polynucleotides. We observed changes in DHE-derived fluorescence in Chinese hamster ovary (CHO) cells post 300-ns electric pulse exposures, comparing them to tert-butyl-hydroperoxide (t-BHP) induced oxidative stress. …

Usp1 Expression Driven By Ews::Fli1 Dually Promotes Ewing Sarcoma Cell Survival By Mitigating The Replication Stress Response And Stabilizing Survivin, Halle Mallard

Theses & Dissertations

Ewing sarcoma (EWS) is a malignant pediatric bone cancer. EWS express a fusion oncogene resulting from the reciprocal translocation of EWSR1 an ETS transcription factor. In most EWS tumors, this occurs with FLI1, creating the EWS::FLI1 fusion oncogene which encodes an aberrant transcription factor. Independent of its transcriptional activity, EWS::FLI1 deregulates other cellular processes driving oncogenesis. For cases with a single, localized tumor, roughly 80% of patients remain event-free after five years. Disease dissemination is a problem – about 25% of patients have metastatic disease at diagnosis. Long-term survival for these patients is less than 40%. Presently, no second line …

Ccdc50 Promotes Tumor Growth Through Regulation Of Lysosome Homeostasis, Penghui Jia, Tian Tian, Zibo Li, Yicheng Wang, Yuxin Lin, Weijie Zeng, Yu Ye, Miao He, Xiangrong Ni, Ji'an Pan, Xiaonan Dong, Jian Huang, Chun-Mei Li, Deyin Guo, Panpan Hou

Student and Faculty Publications

The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 …

Immunepotent Crp Enhances Cyclophosphamide-Induced Cytotoxicity Through A Caspase Independent But Ros Dependent Mechanism In Triple Negative-Breast Cancer Cells, Ana L. Rivera, A. C. Martínez-Torres, C. Rodríguez-Padilla

Research Symposium

Background: Breast cancer (BC) is one of the leading causes of cancer death worldwide. Cyclophosphamide (CYP) remains a mainstay in cancer therapy mainly in the triple negative breast cancer subtype (TNBC) in spite of harmful adverse effects and cell death-resistances. To face this, combination of chemotherapies and immunotherapies has been proposed. IMMUNEPOTENT CRP (ICRP) is an immunotherapy that has cytotoxic effects in several cancer cells without affecting peripheral blood mononuclear cells (PBMC) and CD3+ cells, beside improving clinical parameters of chemotherapy-treated patients. The aim of this study was to evaluate the mechanism of cytotoxicity induced by ICRP in combination with …

Pathobiology Of Myocardial Ischemia And Reperfusion Injury: Models, Modes, Molecular Mechanisms, Modulation, And Clinical Applications, L Maximilian Buja

Student and Faculty Publications

This review presents an integrated approach to the analysis of myocardial ischemia and reperfusion injury and the modulating influence of myocardial conditioning during the evolution of acute myocardial infarction (AMI) and other clinical settings. Experimental studies have involved a spectrum of in vitro, ex vivo, and in vivo models, and guidelines have been developed for the conduct of rigorous preclinical studies and for the identification of various forms of cell injury and death in evolving AMI. AMI in vivo is dominated by oncosis (cell injury with swelling) leading to necroptosis and final necrosis of ischemic cardiomyocytes (CMCs), without or with …

Slc7a11 Expression Level Dictates Differential Responses To Oxidative Stress In Cancer Cells, Yuelong Yan, Hongqi Teng, Qinglei Hang, Lavanya Kondiparthi, Guang Lei, Amber Horbath, Xiaoguang Liu, Chao Mao, Shiqi Wu, Li Zhuang, M James You, Masha V Poyurovsky, Li Ma, Kellen Olszewski, Boyi Gan

Student and Faculty Publications

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show …

Ultra-Low Intensity Post-Pulse Affects Cellular Responses Caused By Nanosecond Pulsed Electric Fields, Kamal Asadipour, Carol Zhou, Vincent Yi, Stephen J. Beebe, Shu Xiao

Electrical & Computer Engineering Faculty Publications

High-intensity nanosecond pulse electric fields (nsPEF) can preferentially induce various effects, most notably regulated cell death and tumor elimination. These effects have almost exclusively been shown to be associated with nsPEF waveforms defined by pulse duration, rise time, amplitude (electric field), and pulse number. Other factors, such as low-intensity post-pulse waveform, have been completely overlooked. In this study, we show that post-pulse waveforms can alter the cell responses produced by the primary pulse waveform and can even elicit unique cellular responses, despite the primary pulse waveform being nearly identical. We employed two commonly used pulse generator designs, namely the Blumlein …

Epc-Exs Improve Astrocyte Survival And Oxidative Stress Through Different Uptaking Pathways In Diabetic Hypoxia Condition, Manasi Suchit Halurkar, Jinju Wang, Shuzhen Chen, Ji Chen Bihl

Pharmacology and Toxicology Faculty Publications

Background: Hyperglycemia contributes to cardiovascular complications in patients with type 2 diabetes. We confirmed that high glucose (HG) induces endothelial dysfunction and cerebral ischemic injury is enlarged in diabetic mice. Stem cell-released exosomes have been shown to protect the brain from ischemic stroke. We have previously shown that endothelial progenitor cells (EPCs)-released exosomes (EPC-EXs) can protect endothelial cells from hypoxia/reoxygenation (H/R) and HG-induced injury. Here, we aim to investigate the effects of EPC-EXs on astrocytes under H/R and HG-induced injury and whether miR-126 enriched EPC-EXs (miR126-EPC-EXs) have enhanced efficacy. Methods: EPC-EX uptake and co-localization were measured by fluorescent microscopy using …

Induced Cytotoxicity In Crebbp/Ep300mut Head And Neck Squamous Cell Carcinoma, Thomaia Pamplin

Dissertations & Theses (Open Access)

INDUCED CYOTOXICTY IN CREBBP/EP300mut HEAD AND NECK SQUAMOUS CELL CARCINOMA

Thomaia Pamplin

Advisor: Curtis Pickering, Ph.D.

Background: Head and neck squamous cell carcinoma HNSCC is the most common malignancy in the head and neck. Most cases are found in advanced stages and depending on the location can be treated with surgical resection and/or radiation (XRT), chemotherapy, or chemoradiation. Our lab groups have identified that HNSCC with a mutation in its CREBBP/EP300 genes can be sensitized to XRT when the histone acetyltransferase activity of CREBBP/EP300 is inhibited. This radiosensitization manifests in the form of increased cell death for …

Lysosomal Zn 2+ Release Triggers Rapid, Mitochondria-Mediated, Non-Apoptotic Cell Death In Metastatic Melanoma, Wanlu Du, Mingxue Gu, Meiqin Hu, Timothy Nold, Prateeksunder Pinchi, Wei Chen, Michael Ryan, Ahmed Bannaga, Haoxing Xu

Medical Student Research Symposium

During tumor progression, lysosome function is often maladaptively upregulated to match the high energy demand required for cancer cell hyper-proliferation and invasion. Here, we report that mucolipin TRP channel 1 (TRPML1), a lysosomal Ca2+ and Zn2+ release channel that regulates multiple aspects of lysosome function, is dramatically upregulated in metastatic melanoma cells compared with normal cells. TRPML-specific synthetic agonists (ML-SAs) are sufficient to induce rapid (within hours) lysosomal Zn2+-dependent necrotic cell death in metastatic melanoma cells while completely sparing normal cells. ML-SA-caused mitochondria swelling and dysfunction lead to cellular ATP depletion. While pharmacological inhibition or genetic silencing of TRPML1 in …

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 …

Focused Ultrasound Stimulation Of Microbubbles In Combination With Radiotherapy For Acute Damage Of Breast Cancer Xenograft Model, Deepa Sharma, Farah Hussein, Niki Law, Golnaz Farhat, Christine Tarapacki, Lakshmanan Sannachi, Anoja Giles, Gregory J. Czarnota

Publications and Scholarship

Objective: Several studies have focused on the use of ultrasound-stimulated microbubbles (USMB) to induce vascular damage in order to enhance tumor response to radiation. Methods: In this study, power Doppler imaging was used along with immunohisto- chemistry to investigate the effects of combining radiation therapy (XRT) and USMB using an ultrasound-guided focused ultrasound (FUS) therapy system in a breast cancer xenograft model. Specifically, MDA-MB-231 breast cancer xenograft tumors were induced in severe combined immuno-deficient female mice. The mice were treated with FUS alone, ultrasound and microbubbles (FUS + MB) alone, 8 Gy XRT alone, or a combined treatment consisting of …

Cell Death Induced In Glioblastoma Cells By Plasma-Activated-Liquids (Pal) Is Primarily Mediated By Membrane Lipid Peroxidation And Not Ros Influx, Sebnem Gunes, Zhonglei He, Evanthia Tsoukou, Sing Wei Ng, Daniela Boehm, Beatriz Pinheiro, Paula Bourke, Renee Malone, Patrick J. Cullen, Wenxin Wang, James Curtin

Articles

Since first identified in 1879, plasma, the fourth state of matter, has been developed and utilised in many fields. Nonthermal atmospheric plasma, also known as cold plasma, can be applied to liquids, where plasma reactive species such as reactive Oxygen and Nitrogen species and their effects can be retained and mediated through plasma-activated liquids (PAL). In the medical field, PAL is considered promising for wound treatment, sterilisation and cancer therapy due to its rich and relatively long-lived reactive species components. This study sought to identify any potential antagonistic effect between antioxidative intracellularly accumulated platinum nanoparticles (PtNPs) and PAL. We found …

Electroporation And Cell Killing By Milli- To Nanosecond Pulses And Avoiding Neuromuscular Stimulation In Cancer Ablation, Emily Gudvangen, Vitalii Kim, Vitalij Novickij, Federico Battista, Andrei G. Pakhomov

Bioelectrics Publications

Ablation therapies aim at eradication of tumors with minimal impact on surrounding healthy tissues. Conventional pulsed electric field (PEF) treatments cause pain and muscle contractions far beyond the ablation area. The ongoing quest is to identify PEF parameters efficient at ablation but not at stimulation. We measured electroporation and cell killing thresholds for 150 ns–1 ms PEF, uni- and bipolar, delivered in 10- to 300-pulse trains at up to 1 MHz rates. Monolayers of murine colon carcinoma cells exposed to PEF were stained with YO-PRO-1 dye to detect electroporation. In 2–4 h, dead cells were labeled with propidium. Electroporation and …

Zebrafish Paralogs Brd2a And Brd2b Are Needed For Proper Circulatory, Excretory And Central Nervous System Formation And Act As Genetic Antagonists During Development, Gregory L Branigan, Kelly S Olsen, Isabella Burda, Matthew W Haemmerle, Jason Ho, Alexandra Venuto, Nicholas D D'Antonio, Ian E Briggs, Angela J Dibenedetto

Department of Biochemistry and Molecular Biology Faculty Papers

Brd2 belongs to the BET family of epigenetic transcriptional co-regulators that act as adaptor-scaffolds for the assembly of chromatin-modifying complexes and other factors at target gene promoters. Brd2 is a protooncogene and candidate gene for juvenile myoclonic epilepsy in humans, a homeobox gene regulator in Drosophila, and a maternal-zygotic factor and cell death modulator that is necessary for normal development of the vertebrate central nervous system (CNS). As two copies of Brd2 exist in zebrafish, we use antisense morpholino knockdown to probe the role of paralog Brd2b, as a comparative study to Brd2a, the ortholog of human Brd2. A deficiency …

Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness, Pratyusha Mandal, Lynsey Nagrani, Liliana Hernandez, Anita Louise Mccormick, Christopher Dillon, Heather Koehler, Linda Roback, Emad S Alnemri, Douglas Green, Edward Mocarski

Department of Biochemistry and Molecular Biology Faculty Papers

Programmed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.5-encoded viral mitochon-drial inhibitor of apoptosis (vMIA), a BAX suppressor that functions in concert with M41.1-encoded viral inhibitor of BAK oligomerization (vIBO), (ii) M36-encoded viral inhibitor of caspase-8 activation (vICA), and (iii) M45-encoded viral inhibitor of RIP/RHIM activation (vIRA). Following infection of bone marrow-derived macrophages, the virus initially …

Co-Targeting Plk1 And Dnmt3a In Advanced Prostate Cancer, Zhuangzhuang Zhang, Lijun Cheng, Qiongsi Zhang, Yifan Kong, Daheng He, Kunyu Li, Matthew Rea, Jianlin Wang, Ruixin Wang, Jinghui Liu, Zhiguo Li, Chongli Yuan, Enze Liu, Yvonne N. Fondufe-Mittendorf, Lang Li, Tao Han, Chi Wang, Xiaoqi Liu

Toxicology and Cancer Biology Faculty Publications

Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network-based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein-protein interactions to identify novel co-targets for PCa treatment. The results show that polo-like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)-related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 …

Cardiac Inflammation, Oxidative Stress, Nrf2 Expression, And Coagulation Events In Mice With Experimental Chronic Kidney Disease, Abderrahim Nemmar, Suhail Al-Salam, Sumaya Beegam, Nur Elena Zaaba, Javed Yasin, Naserddine Hamadi, Badreldin H. Ali

All Works

Chronic kidney disease (CKD) is known to be associated with cardiovascular dysfunction. Dietary adenine intake in mice is also known to induce CKD. However, in this experimental model, the mechanisms underlying the cardiotoxicity and coagulation disturbances are not fully understood. Here, we evaluated cardiac inflammation, oxidative stress, DNA damage, and coagulation events in mice with adenine (0.2% w/w in feed for 4 weeks)-induced CKD. Control mice were fed with normal chow for the same duration. Adenine increased water intake, urine output, relative kidney weight, the plasma concentrations of urea and creatinine, and the urinary concentrations of kidney injury molecule-1 and …

Ursolic Acid Inhibits Collective Cell Migration And Promotes Jnk-Dependent Lysosomal Associated Cell Death In Gioblastoma Multiforme Cells, Gillian Conway, Diamante Zizyte, Julie Mondala, Zhonglei He, Lorna Lynam, Mathilde Lecourt, Orla L. Howe, James Curtin

Articles

Ursolic acid (UA) is a bioactive compound which has demonstrated therapeutic efficacy in a variety of cancer cell lines. UA activates various signalling pathways in Glioblastoma multiforme (GBM) and offers a promising starting point in drug discovery; however, understanding the relationship between cell death and migration has yet to be elucidated. UA induces a dose dependent cytotoxic response demonstrated by flow cytometry and biochemical cytotoxicity assays. Inhibitor and fluorescent probe studies demonstrate that UA induces a caspase independent, JNK dependent, mechanism of cell death. Migration studies established that UA inhibits GBM collective cell migration in a time dependent manner that …

Characterizing The Role Of Necroptosis Of Airway Epithelial Cells In The Immune Response To Respiratory Pathogens, Ashleigh Nichole Riegler

All ETDs from UAB

Necroptosis, a programmed form of lytic cell death, is initiated by various viral and bacterial pathogens through irreparable ion dysregulation and energy depletion. This cellular damage results in the activation of the cellular kinases RIPK1 and RIPK3, consecutively, and the activation and membrane targeting of MLKL, the latter responsible for lysis. Here we have demonstrated that necroptosis of airway epithelial cells is key in the development of the adaptive immune response to asymptomatic colonization by Streptococcus pneumoniae (Spn). Briefly, necroptotic deficient animals or wildtype animals colonized with Spn lacking the necroptosis-triggering pneumolysin toxin, failed to recruit CD11c+ leukocytes to the …

Kidney Injury Molecule-1 Mediated Phagocytosis And Its Therapeutic Application In Ameliorating Renal Transplant Ischemia Reperfusion Injury, Ji Yun Lee

Electronic Thesis and Dissertation Repository

Renal transplantation is a life-saving procedure for patients with end-stage renal disease. Persistent graft inflammation and fibrosis due to injury from repeated insults - both alloantigen-dependent and -independent - lead to chronic allograft dysfunction and long-term graft loss. Ischemia-reperfusion injury (IRI) to the graft is an inescapable consequence of transplantation and can result in significant delayed graft function (DGF). Tissue damage and graft dysfunction resulting from transplant-associated IRI have been correlated with acute rejection and long-term graft loss. During IRI, dying renal proximal tubular epithelial cells (TECs) release pro-inflammatory mediators, worsening tissue damage and further potentiating injury by initiating an …

Phosphorylation Of Cyclophilin D At Serine 191 Regulates Mitochondrial Permeability Transition Pore Opening And Cell Death After Ischemia-Reperfusion, Stephen Hurst, Fabrice Gonnot, Maya Dia, Claire Crola Da Silva, Ludovic Gomez, Shey-Shing Sheu

Department of Medicine Faculty Papers

The mitochondrial permeability transition pore (mPTP) plays a critical role in the pathogenesis of cardiovascular diseases, including ischemia/reperfusion injury. Although the pore structure is still unresolved, the mechanism through which cyclophilin D (CypD) regulates mPTP opening is the subject of intensive studies. While post-translational modifications of CypD have been shown to modulate pore opening, specific phosphorylation sites of CypD have not yet been identified. We hypothesized here that phosphorylation of CypD on a serine residue controls mPTP opening and subsequent cell death at reperfusion. We combined in silico analysis with in vitro and genetic manipulations to determine potential CypD phosphorylation …

Boosting Cellular Nad+ Concentration With Nicotinamide Mononucleotide Prevents Doxorubicin-Induced Cardiotoxicity, Rebecca Dang

Electronic Thesis and Dissertation Repository

Doxorubicin (DOX) is a powerful chemotherapy that functions by interfering with cancer cells’ growth. However, the use of DOX is limited due to its detrimental side effects that can lead to serious cardiovascular complications. Our goal is to determine if nicotinamide mononucleotide (NMN) and histone acetyltransferase (HAT) inhibitors can protect against DOX-induced cardiotoxicity. Our findings revealed that DOX reduced NAD⁺ concentration and induced damage to H9c2 cells as evidenced by higher caspase-3 activity and lactate dehydrogenase release. Pre-incubation with NMN increased NAD⁺ concentration and attenuated DOX-induced damage. There was higher cell viability in the NMN pre-incubated group compared …

A Rapid Absorbance-Based Growth Assay To Screen The Toxicity Of Oligomer Aβ42 And Protect Against Cell Death In Yeast, Prashant Bharadwaj, Ralph Martins

Research outputs 2014 to 2021

Multiple lines of evidence show that soluble oligomer forms of amyloid β protein (Aβ42) are the most neurotoxic species in the brain and correlates with the degree of neuronal loss and cognitive deficit in Alzheimer's disease. Although many studies have used mammalian cells to investigate oligomer Aβ42 toxicity, the use of more simple eukaryotic cellular systems offers advantages for large-scale screening studies. We have previously established and validated budding yeast, Saccharomyces cerevisiae to be a simple and a robust model to study the toxicity of Aβ. Using colony counting based methods, oligomeric Aβ42 was shown to induce dose-dependent cell death …

Cadm1 Is A Twist1-Regulated Suppressor Of Invasion And Survival., Edward J. Hartsough, Michele B. Weiss, Shea A. Heilman, Timothy J. Purwin, Curtis H Kugel, Sheera R. Rosenbaum, Dan A. Erkes, Manoela Tiago, Kim Hookim, Inna Chervoneva, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Metastatic cancer remains a clinical challenge; however, patients diagnosed prior to metastatic dissemination have a good prognosis. The transcription factor, TWIST1 has been implicated in enhancing the migration and invasion steps within the metastatic cascade, but the range of TWIST1-regulated targets is poorly described. In this study, we performed expression profiling to identify the TWIST1-regulated transcriptome of melanoma cells. Gene ontology pathway analysis revealed that TWIST1 and epithelial to mesenchymal transition (EMT) were inversely correlated with levels of cell adhesion molecule 1 (CADM1). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrated that TWIST1 physically interacts with the CADM1 promoter, suggesting …

Iron-Dependent Cleavage Of Ribosomal Rna During Oxidative Stress In The Yeast Saccharomyces Cerevisiae, Jessica A Zinskie, Arnab Ghosh, Brandon M Trainor, Daniel Shedlovskiy, Dimitri G Pestov, Natalia Shcherbik

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Stress-induced strand breaks in rRNA have been observed in many organisms, but the mechanisms by which they originate are not well-understood. Here we show that a chemical rather than an enzymatic mechanism initiates rRNA cleavages during oxidative stress in yeast (Saccharomyces cerevisiae). We used cells lacking the mitochondrial glutaredoxin Grx5 to demonstrate that oxidant-induced cleavage formation in 25S rRNA correlates with intracellular iron levels. Sequestering free iron by chemical or genetic means decreased the extent of rRNA degradation and relieved the hypersensitivity of grx5Δ cells to the oxidants. Importantly, subjecting purified ribosomes to an in vitro iron/ascorbate …

Modeling The Dynamics Of Human Liver Failure Post Liver Resection, Babita Verma, Pushpavanam Subramaniam, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Liver resection is an important clinical intervention to treat liver disease. Following liver resection, patients exhibit a wide range of outcomes including normal recovery, suppressed recovery, or liver failure, depending on the regenerative capacity of the remnant liver. The objective of this work is to study the distinct patient outcomes post hepatectomy and determine the processes that are accountable for liver failure. Our model based approach shows that cell death is one of the important processes but not the sole controlling process responsible for liver failure. Additionally, our simulations showed wide variation in the timescale of liver failure that is …

Acetic Acid Induces Sch9p-Dependent Translocation Of Isc1p From The Endoplasmic Reticulum Into Mitochondria, António Rego, Katrina F Cooper, Justin Snider, Yusuf A Hannun, Vítor Costa, Manuela Côrte-Real, Susana R Chaves

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Changes in sphingolipid metabolism have been linked to modulation of cell fate in both yeast and mammalian cells. We previously assessed the role of sphingolipids in cell death regulation using a well characterized yeast model of acetic acid-induced regulated cell death, finding that Isc1p, inositol phosphosphingolipid phospholipase C, plays a pro-death role in this process. Indeed, isc1∆ mutants exhibited a higher resistance to acetic acid associated with reduced mitochondrial alterations. Here, we show that Isc1p is regulated by Sch9p under acetic acid stress, since both single and double mutants lacking Isc1p or/and Sch9p have the same resistant phenotype, and SCH9 …

Binge Alcohol Exposure Causes Neurobehavioral Deficits And Gsk3Β Activation In The Hippocampus Of Adolescent Rats, Zhe Ji, Lin Yuan, Xiong Lu, Hanqing Ding, Jia Luo, Zun-Ji Ke

Pharmacology and Nutritional Sciences Faculty Publications

Heavy alcohol exposure causes profound damage to the adolescent brain, particularly the hippocampus, which underlie some behavioral deficits. However, the underlying molecular mechanisms remain inconclusive. The current study sought to determine whether binge alcohol exposure affects the hippocampus-related behaviors and key signaling proteins that may mediate alcohol neurotoxicity in adolescent rats. Alcohol exposure reduced the number of both NeuN-positive and doublecortin-positive cells in the hippocampus. Alcohol also induced neurodegeneration which was confirmed by ultrastructural analysis by electronic microscopy and was accompanied with the activation of microglia. Binge alcohol exposure impaired spatial learning and memory which was evaluated by the Morris …