Medicine and Health Sciences Commons^™

Perivascular Macrophages In The Neonatal Macaque Brain Undergo Massive Necroptosis After Simian Immunodeficiency Virus Infection, Diana G. Bohannon, Yueying Wang, Colin H. Reinhart, Julian B. Hattler, Jiangtao Luo, Hamid R. Okhravi, Jianshui Zhang, Qingsheng Li, Marcelo J. Kuroda, Woong-Ki Kim

Nebraska Center for Virology: Faculty Publications

We previously showed that rhesus macaques neonatally infected with simian immunodeficiency virus (SIV) do not develop SIV encephalitis (SIVE) and maintain low brain viral loads despite having similar plasma viral loads compared to SIV-infected adults. We hypothesize that differences in myeloid cell populations that are the known target of SIV and HIV in the brain contribute to the lack of neonatal susceptibility to lentivirus-induced encephalitis. Using immunohistochemistry and immunofluorescence microscopy, we examined the frontal cortices from uninfected and SIV-infected infant and adult macaques (n = 8/ea) as well as adults with SIVE (n = 4) to determine differences in myeloid …

The Effect Of The Senolytic Abt-263 On Androgen Deprivation-Induced Senescent Prostate Tumor Cells, So Min Lee

Theses and Dissertations

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men. Although standard treatments such as androgen deprivation therapies (ADT) and antiandrogens have increased survival for many patients, most men placed on these therapies will develop castration-resistant disease (CRPC). Previous studies have shown that these treatments have limited cytotoxicity and instead promote cell growth arrest. Our current work demonstrates that prostate tumor cells grown in the absence of androgens by using charcoal-stripped serum undergo senescence-mediated or senescent-like growth arrest, based on the cellular expression of senescence-associated-beta-galactosidase (SA-β-Gal). Our studies further suggest that this senescence is transient and …

Caspases And Cancer: Connections Through Circular Dichroism Spectroscopy, Sarah M. Hethcox

Honors College Theses

While excessive cell death inevitably leads to negative effects, the endurance of damaged cells in the presence of death signals can be equally detrimental to health. Apoptosis, or programmed cell death, is a highly regulated process in which cues from within or from outside a cell can trigger an irreversible sequence of signals that carry out cell destruction known as the apoptotic cascade. A group of enzymes called caspases play a vital role in this cascade with some participating as initiators and others acting as effectors of protein cleavage and intracellular breakdown. Although it is normal for the activity of …

Till Death Do Us Part: The Marriage Of Autophagy And Apoptosis., Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Autophagy is a widely conserved catabolic process that is necessary for maintaining cellular homeostasis under normal physiological conditions and driving the cell to switch back to this status quo under times of starvation, hypoxia, and oxidative stress. The potential similarities and differences between basal autophagy and stimulus-induced autophagy are still largely unknown. Both act by clearing aberrant or unnecessary cytoplasmic material, such as misfolded proteins, supernumerary and defective organelles. The relationship between reactive oxygen species (ROS) and autophagy is complex. Cellular ROS is predominantly derived from mitochondria. Autophagy is triggered by this event, and by clearing the defective organelles effectively, …

Novel Insights Into The Contribution Of Cellular Senescence To Cancer Therapy: Reversibility, Dormancy And Senolysis., Tareq Saleh

Theses and Dissertations

Cellular senescence a specialized form of growth arrest that contributes to the pathogenesis of several aging-related disorders including cancer. While by definition tumor cells are considered immortalized, they can undergo senescence when exposed to conventional and targeted cancer therapy. Therapy-Induced Senescence (TIS) represents a fundamental response to therapy and impacts its outcomes. However, TIS has been considered a positive therapeutic goal since senescent tumor cells are expected to enter a state of permanent growth abrogation. In this work we examined the hypothesis that a subpopulation of senescent cells can re-acquire proliferative potential after a state of senescent dormancy, indicating that …

Parasympathetic Nerve Derived Exosomes Inhibit Hyperglycemia Induced Apoptosis In Cardiomyoblast Cells, Reetish K. Singla

Honors Undergraduate Theses

Diabetic cardiomyopathy involves both forms of cardiac cell cell death such as apoptosis and necrosis. However, this remains unknown whether hyperglycemia induced apoptosis in the cell culture system is inhibited by parasympathetic nerve derived exosomes. We isolated parasympathetic and sympathetic nerves and derived exosomes. We developed hyperglycemia induced apoptosis in H9c2 cells. H9c2 cells were divided into 4 groups: 1) Control, 2) H9c2+ Glucose 100 mmol, 3) H9c2+ Glucose +parasympathetic-exo, 4) H9c2+ Glucose+sympathetic-exo. We determined cell proliferation and viability with MTT assay kit and apoptosis with TUNEL staining and cell death detection ELISA kit. Data was further confirmed with pro-apoptotic …

Guidelines And Recommendations On Yeast Cell Death Nomenclature, Didac Carmona-Gutierrez, Maria Anna Bauer, Andreas Zimmermann, Andrés Aguilera, Nicanor Austriaco, Kathryn Ayscough, Rena Balzan, Shoshana Bar-Nun, Antonio Barrientos, Peter Belenky, Marc Blondel, Ralf J Braun, Michael Breitenbach, William C Burhans, Sabrina Büttner, Duccio Cavalieri, Michael Chang, Katrina F Cooper, Manuela Côrte-Real, Vítor Costa, Christophe Cullin, Ian Dawes, Jörn Dengjel, Martin B Dickman, Tobias Eisenberg, Birthe Fahrenkrog, Nicolas Fasel, Kai-Uwe Fröhlich, Ali Gargouri, Sergio Giannattasio, Paola Goffrini, Campbell W Gourlay, Chris M Grant, Michael T Greenwood, Nicoletta Guaragnella, Thomas Heger, Jürgen Heinisch, Eva Herker, Johannes M Herrmann, Sebastian Hofer, Antonio Jiménez-Ruiz, Helmut Jungwirth, Katharina Kainz, Dimitrios P Kontoyiannis, Paula Ludovico, Stéphen Manon, Enzo Martegani, Cristina Mazzoni, Lynn A Megeney, Chris Meisinger, Jens Nielsen, Thomas Nyström, Heinz D Osiewacz, Tiago F Outeiro, Hay-Oak Park, Tobias Pendl, Dina Petranovic, Stephane Picot, Peter Polčic, Ted Powers, Mark Ramsdale, Mark Rinnerthaler, Patrick Rockenfeller, Christoph Ruckenstuhl, Raffael Schaffrath, Maria Segovia, Fedor F Severin, Amir Sharon, Stephan J Sigrist, Cornelia Sommer-Ruck, Maria João Sousa, Johan M Thevelein, Karin Thevissen, Vladimir Titorenko, Michel B Toledano, Mick Tuite, F-Nora Vögtle, Benedikt Westermann, Joris Winderickx, Silke Wissing, Stefan Wölfl, Zhaojie J Zhang, Richard Y Zhao, Bing Zhou, Lorenzo Galluzzi, Guido Kroemer, Frank Madeo

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic …

The Role Of Mapk And Scf In The Destruction Of Med13 In Cyclin C Mediated Cell Death, David C Stieg, Stephen D Willis, Joseph Scuorzo, Mia Song, Vidyaramanan Ganesan, Randy Strich, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

In response to stress, the yeast¹ and mammalian² cyclin C translocate from the nucleus to the cytoplasm, where it associates with the GTPase Drp1/Dnm1 to drive mitochondrial fragmentation and apoptosis. Therefore, the decision to release cyclin C represents a key life or death decision. In unstressed cells, the cyclin C‐Cdk8 kinase regulates transcription by associating with the Mediator of RNA polymerase II. We previously reported that the Mediator component Med13 anchors cyclin C in the nucleus³. Loss of Med13 function leads to constitutive cytoplasmic localization of cyclin C, resulting in fragmented mitochondria, hypersensitivity to stress and …

Theaflavin-3, 3'-Digallate Induces Apoptosis And G2 Cell Cycle Arrest Through The Akt/Mdm2/P53 Pathway In Cisplatin-Resistant Ovarian Cancer A2780/Cp70 Cells, Youying Tu, Eunhye Kim, Ying Gao, Gary O. Rankin, Bo Li, Yi Charlie Chen

Pharmacology, Physiology and Toxicology

Ovarian cancer is the most lethal gynecological cancer among women worldwide. Adverse side effects and acquired resistance to conventional platinum based chemotherapy are major impediments in ovarian cancer treatment, and drive the development of more selective anticancer drugs that target cancer-specific defects. In this study, theaflavin-3, 3'-digallate (TF3), the major theaflavin monomer in black tea, exhibited a potent growth inhibitory effect on the cisplatinresistant ovarian cancer A2780/CP70 cells (IC50, 23.81 μM), and was less cytotoxic to a normal ovarian IOSE‑364 cells (IC50, 59.58 μM) than to the cancer cells. Flow cytometry analysis indicated that TF3 induced preferential apoptosis and G2 …

Notch1 Gain Of Function In Germ Cells Causes Failure Of Spermatogenesis In Male Mice, Zaohua Huang, Bryan Rivas, Alexander I. Agoulnik

HWCOM Faculty Publications

NOTCH1 is a member of the NOTCH receptor family, a group of single-pass trans-membrane receptors. NOTCH signaling is highly conserved in evolution and mediates communication between adjacent cells. NOTCH receptors have been implicated in cell fate determination, as well as maintenance and differentiation of stem cells. In the mammalian testis expression of NOTCH1 in somatic and germ cells has been demonstrated, however its role in spermatogenesis was not clear. To study the significance of NOTCH1 in germ cells, we applied a cre/loxP approach in mice to induce NOTCH1 gain- or loss-of function specifically in male germ cells. Using a Stra8-icre …

Immunologic Effects Of Gliotoxin In Rats: Mechanisms For Prevention Of Autoimmune Diabetes Mellitus, Honggang Liu, Susan H. Jackman, Henry Driscoll, Bryan Larsen

Susan H. Jackman

Various fungal products, such as gliotoxin (GT), have immunomodulating activity, a fact exploited previously by our group for prevention of autoimmune diabetes mellitus in BB/Wor rats. To understand better the immunologic effects in GT-treated rats, splenocytes from 65-day-old prediabetic diabetes-prone rats were phenotypically characterized after chronic treatment with GT. A parallel study examined the direct effects of GT on splenocyte preparations incubated with the mycotoxin. In vitro treatment of splenocytes with GT revealed relative decreases in CD4+ and increases in CD8+ T-cell subsets, whereas in vivo treatment with GT did not result in detectable alterations in relative CD4+ and CD8+ …

Immunologic Effects Of Gliotoxin In Rats: Mechanisms For Prevention Of Autoimmune Diabetes Mellitus, Honggang Liu, Susan H. Jackman, Henry Driscoll, Bryan Larsen

Henry Driscoll

Various fungal products, such as gliotoxin (GT), have immunomodulating activity, a fact exploited previously by our group for prevention of autoimmune diabetes mellitus in BB/Wor rats. To understand better the immunologic effects in GT-treated rats, splenocytes from 65-day-old prediabetic diabetes-prone rats were phenotypically characterized after chronic treatment with GT. A parallel study examined the direct effects of GT on splenocyte preparations incubated with the mycotoxin. In vitro treatment of splenocytes with GT revealed relative decreases in CD4+ and increases in CD8+ T-cell subsets, whereas in vivo treatment with GT did not result in detectable alterations in relative CD4+ and CD8+ …

The P53-Induced Siva-1 Plays A Significant Role In Cisplatin-Mediated Apoptosis, John L. Barkinge, Radhika Gudi, Hawkins Sarah, Fei Chu, Alip Borthakur, Bellur S. Prabhakar

Clinical & Translational Sciences

Background: The pro-apoptotic protein Siva-1 functions in both extrinsic and intrinsic cell death signaling; however, the exact contribution of the endogenous Siva-1 to DNA damage-induced apoptosis is unclear. Using cisplatin, a chemotherapeutic drug, to induce DNA damage and cell death, we determined the role of Siva-1.

Methods: Cisplatin treated HCT116 colorectal carcinoma cells (p53+/+ and -/-) were used in the study. With the help of recombinant lentivirus that can express siSiva (siRNA that specifi cally targets Siva-1), we also generated Siva-1 knockdown HCT116 cells. Apoptosis was determined by tetramethyl rhodamine methyl ester (TMRM) staining and propidium iodide (PI) staining.

Results: …

Inhibition Of Oncogene-Induced Inflammatory Chemokines Using A Farnesyltransferase Inhibitor., Katharine C Degeorge, Brent R Degeorge, James S Testa, Jay L Rothstein

Department of Microbiology and Immunology Faculty Papers

ABSTRACT: BACKGROUND: Farnesyltransferase inhibitors (FTI) are small molecule agents originally formulated to inhibit the oncogenic functions of Ras. Although subsequent analysis of FTI activity revealed wider effects on other pathways, the drug has been demonstrated to reduce Ras signaling by direct measurements. The purpose of the current study was to determine if FTI could be used to inhibit the inflammatory activities of a known Ras-activating human oncoprotein, RET/PTC3. RET/PTC3 is a fusion oncoprotein expressed in the thyroid epithelium of patients afflicted with thyroid autoimmune disease and/or differentiated thyroid carcinoma. Previous studies have demonstrated that RET/PTC3 signals through Ras and can …

Smc3 Knockdown Triggers Genomic Instability And P53-Dependent Apoptosis In Human And Zebrafish Cells., Giancarlo Ghiselli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: The structural maintenance of chromosome 3 (SMC3) protein is a constituent of a number of nuclear multimeric protein complexes that are involved in DNA recombination and repair in addition to chromosomal segregation. Overexpression of SMC3 activates a tumorigenic cascade through which mammalian cells acquire a transformed phenotype. This has led us to examine in depth how SMC3 level affects cell growth and genomic stability. In this paper the effect of SMC3 knockdown has been investigated. RESULTS: Mammalian cells that are SMC3 deficient fail to expand in a clonal population. In order to shed light on the underlying mechanism, experiments …

Immunologic Effects Of Gliotoxin In Rats: Mechanisms For Prevention Of Autoimmune Diabetes Mellitus, Honggang Liu, Susan H. Jackman, Henry Driscoll, Bryan Larsen

Biochemistry and Microbiology

Various fungal products, such as gliotoxin (GT), have immunomodulating activity, a fact exploited previously by our group for prevention of autoimmune diabetes mellitus in BB/Wor rats. To understand better the immunologic effects in GT-treated rats, splenocytes from 65-day-old prediabetic diabetes-prone rats were phenotypically characterized after chronic treatment with GT. A parallel study examined the direct effects of GT on splenocyte preparations incubated with the mycotoxin. In vitro treatment of splenocytes with GT revealed relative decreases in CD4+ and increases in CD8+ T-cell subsets, whereas in vivo treatment with GT did not result in detectable alterations in relative CD4+ and CD8+ …