Medicine and Health Sciences Commons^™

An Essential Role For Monocyte Chemoattractant Protein-1 In Alcoholic Liver Injury: Regulation Of Proinflammatory Cytokines And Hepatic Steatosis In Mice, Pranoti Mandrekar, Aditya Ambade, Arlene Lim, Gyongyi Szabo, Donna Catalano

Gyongyi Szabo

The importance of chemokines in alcoholic liver injury has been implicated. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated in patients with alcoholic liver disease is not yet understood. Here, we evaluated the pathophysiological significance of MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), in alcoholic liver injury. The Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1-deficient knockout (KO) mice for 6 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. MCP-1 was increased in Kupffer cells (KCs) as …

Mitochondrial Fission Induces Glycolytic Reprogramming In Cancer-Associated Myofibroblasts, Driving Stromal Lactate Production, And Early Tumor Growth., Carmela Guido, Diana Whitaker-Menezes, Zhao Lin, Richard G Pestell, Anthony Howell, Teresa A Zimmers, Mathew C Casimiro, Saveria Aquila, Sebastiano Ando', Ubaldo E Martinez-Outschoorn, Federica Sotgia, Michael P Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Recent studies have suggested that cancer cells behave as metabolic parasites, by inducing oxidative stress in adjacent normal fibroblasts. More specifically, oncogenic mutations in cancer cells lead to ROS production and the "secretion" of hydrogen peroxide species. Oxidative stress in stromal fibroblasts then induces their metabolic conversion into cancer-associated fibroblasts. Such oxidative stress drives the onset of autophagy, mitophagy, and aerobic glycolysis in fibroblasts, resulting in the local production of high-energy mitochondrial fuels (such as L-lactate, ketone bodies, and glutamine). These recycled nutrients are then transferred to cancer cells, where they are efficiently burned via oxidative mitochondrial metabolism (OXPHOS). We …

Two-Compartment Tumor Metabolism: Autophagy In The Tumor Microenvironment And Oxidative Mitochondrial Metabolism (Oxphos) In Cancer Cells., Ahmed F Salem, Diana Whitaker-Menezes, Zhao Lin, Ubaldo E. Martinez-Outshoorn, Herbert B Tanowitz, Mazhar Salim Al-Zoubi, Anthony Howell, Richard Pestell, Federica Sotgia, Michael P. Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Previously, we proposed a new paradigm to explain the compartment-specific role of autophagy in tumor metabolism. In this model, autophagy and mitochondrial dysfunction in the tumor stroma promotes cellular catabolism, which results in the production of recycled nutrients. These chemical building blocks and high-energy "fuels" would then drive the anabolic growth of tumors, via autophagy resistance and oxidative mitochondrial metabolism in cancer cells. We have termed this new form of stromal-epithelial metabolic coupling: "two-compartment tumor metabolism." Here, we stringently tested this energy-transfer hypothesis, by genetically creating (1) constitutively autophagic fibroblasts, with mitochondrial dysfunction or (2) autophagy-resistant cancer cells, with increased …

Ctgf Drives Autophagy, Glycolysis And Senescence In Cancer-Associated Fibroblasts Via Hif1 Activation, Metabolically Promoting Tumor Growth., Claudia Capparelli, Diana Whitaker-Menezes, Carmela Guido, Renee Balliet, Timothy G Pestell, Anthony Howell, Sharon Sneddon, Richard Pestell, Ubaldo E. Martinez-Outshoorn, Michael P. Lisanti, Federica Sotgia

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Previous studies have demonstrated that loss of caveolin-1 (Cav-1) in stromal cells drives the activation of the TGF-β signaling, with increased transcription of TGF-β target genes, such as connective tissue growth factor (CTGF). In addition, loss of stromal Cav-1 results in the metabolic reprogramming of cancer-associated fibroblasts, with the induction of autophagy and glycolysis. However, it remains unknown if activation of the TGF-β / CTGF pathway regulates the metabolism of cancer-associated fibroblasts. Therefore, we investigated whether CTGF modulates metabolism in the tumor microenvironment. For this purpose, CTGF was overexpressed in normal human fibroblasts or MDA-MB-231 breast cancer cells. Overexpression of …

Effect Of Oxidative Stress On Protein Tyrosine Phosphatase 1b In Scleroderma Dermal Fibroblasts., Pei-Suen Tsou, Nadine N. Talia, Adam J. Pinney, Ann Kendzicky, Sonsoles Piera-Velazquez, Sergio A. Jimenez, James R. Seibold, Kristine Phillips, Alisa E Koch

Department of Dermatology and Cutaneous Biology Faculty Papers

OBJECTIVE: Platelet-derived growth factor (PDGF) and its receptor, PDGFR, promote fibrosis in systemic sclerosis (SSc; scleroderma) dermal fibroblasts, and such cells in scleroderma skin lesions produce excessive reactive oxygen species (ROS). PDGFR is phosphorylated upon PDGF stimulation, and is dephosphorylated by protein tyrosine phosphatases (PTPs), including PTP1B. This study was undertaken to determine whether the thiol-sensitive PTP1B is affected by ROS in SSc dermal fibroblasts, thereby enhancing the phosphorylation of PDGFR and synthesis of type I collagen. This study also sought to investigate the effect of a thiol antioxidant, N-acetylcysteine (NAC), in SSc.

METHODS: Fibroblasts were isolated from the skin …

Distribution, Elimination, And Biopersistence To 90 Days Of A Systemically Introduced 30 Nm Ceria-Engineered Nanomaterial In Rats, Robert A. Yokel, Tu C. Au, Robert Macphail, Sarita S. Hardas, D. Allan Butterfield, Rukhsana Sultana, Michael Goodman, Michael T. Tseng, Mo Dan, Hamed Haghnazar, Jason M. Unrine, Uschi M. Graham, Peng Wu, Eric A. Grulke

Pharmaceutical Sciences Faculty Publications

Nanoceria is used as a catalyst in diesel fuel, as an abrasive in printed circuit manufacture, and is being pursued as an antioxidant therapeutic. Our objective is to extend previous findings showing that there were no reductions of cerium in organs of the mononuclear phagocyte (reticuloendothelial) system up to 30 days after a single nanoscale ceria administration. An ~5% aqueous dispersion of citrate-stabilized 30 nm ceria, synthesized and characterized in-house, or vehicle, was iv infused into rats terminated 1, 7, 30, or 90 days later. Cageside observations were obtained daily, body weight weekly. Daily urinary and fecal cerium outputs were …

Reactive Oxygen Species And Mitochondrial Sensitivity To Oxidative Stress Determine Induction Of Cancer Cell Death By P21, Ionica Masgras, Samantha Carrera, Petra J. De Verdier, Paul Brennan, Aneela Majid, Wan Makhtar, Eugene Tulchinsky, George D. Jones, Igor Roninson, Salvador Macip

Faculty Publications

p21(Waf1/Cip1/Sdi1) is a cyclin-dependent kinase inhibitor that mediates cell cycle arrest. Prolonged p21 up-regulation induces a senescent phenotype in normal and cancer cells, accompanied by an increase in intracellular reactive oxygen species (ROS). However, it has been shown recently that p21 expression can also lead to cell death in certain models. The mechanisms involved in this process are not fully understood. Here, we describe an induction of apoptosis by p21 in sarcoma cell lines that is p53-independent and can be ameliorated with antioxidants. Similar levels of p21 and ROS caused senescence in the absence of significant death in other cancer …

The Graded Redefined Assessment Of Strength Sensibility And Prehension: Reliability And Validity., Sukhvinder Kalsi-Ryan, Dorcas Beaton, Armin Curt, Susan Duff, Milos R Popovic, Claudia Rudhe, Michael G Fehlings, Mary C Verrier

Department of Physical Therapy Faculty Papers

Abstract With the advent of new interventions targeted at both acute and chronic spinal cord injury (SCI), it is critical that techniques and protocols are developed that reliably evaluate changes in upper limb impairment/function. The Graded Redefined Assessment of Strength Sensibility and Prehension (GRASSP) protocol, which includes five subtests, is a quantitative clinical upper limb impairment measure designed for use in acute and chronic cervical SCI. The objectives of this study were to: (1) establish the inter-rater and test-retest reliability, and (2) establish the construct and concurrent validity with the International Standards of Neurological Classification of Spinal Cord Injury (ISNCSCI), …

Bmi-1 Absence Causes Premature Brain Degeneration, Guangliang Cao, Minxia Gu, Min Zhu, Junying Gao, Ying Yin, Charles Marshall, Ming Xiao, Jiong Ding, Dengshun Miao

Physical Therapy Faculty Publications

Bmi-1, a polycomb transcriptional repressor, is implicated in cell cycle regulation and cell senescence. Its absence results in generalized astrogliosis and epilepsy during the postnatal development, but the underlying mechanisms are poorly understood. Here, we demonstrate the occurrence of oxidative stress in the brain of four-week-old Bmi-1 null mice. The mice showed various hallmarks of neurodegeneration including synaptic loss, axonal demyelination, reactive gliosis and brain mitochondrial damage. Moreover, astroglial glutamate transporters and glutamine synthetase decreased in the Bmi-1 null hippocampus, which might contribute to the sporadic epileptic-like seizures in these mice. These results indicate that Bmi-1 is required for maintaining …

Dna Damage And Oxidative Stress Induced-P53 Activity In Astrocytes Causes Growth Arrest, Sarah A. Humphrey

Electronic Thesis and Dissertation Repository

An increasing body of evidence suggests that astrocytes play a key role in modulating neuronal fate during acute and chronic neurodegenerative conditions. Following CNS injury, an upregulation of p53 has been noted in both neurons and reactive astrocytes. p53 is an extremely important protein in determining cell fate decisions and its activation can result in the transcriptional induction of target genes that regulate apoptosis, autophagy, senescence and cell-cycle arrest. We found that p53 is upregulated in primary cortical astrocytes following oxidative stress and DNA damage and that this upregulation results in the p53-dependent transcriptional induction of several target genes involved …

Conformational Altered P53 As An Early Marker Of Oxidative Stress In Alzheimer's Disease, Laura Buizza, Giovanna Cenini, Cristina Lanni, Giulia Ferrari-Toninelli, Chiara Prandelli, Stefano Govoni, Erica Buoso, Marco Racchi, Maria Barcikowska, Maria Styczynska, Aleksandra Szybinska, D. Allan Butterfield, Maurizio Memo, Daniela Uberti

Sanders-Brown Center on Aging Faculty Publications

In order to study oxidative stress in peripheral cells of Alzheimer's disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut …

A Mechanistic Study Of S-Adenosyl-L-Methionine Protection Against Acetaminophen Hepatotoxicity, James Michael Brown

Theses, Dissertations and Capstones

Acetaminophen (APAP) toxicity remains the leading cause of drug induced liver failure in the United States. The current therapy for APAP toxicity is N-acetylcysteine (NAC). NAC must be administered within eight hours of APAP overdose for maximum efficacy. That, coupled with the fact that APAP toxicity may not be overtly evident, makes an alternative therapeutic intervention worth exploring. Previous work by our laboratory has demonstrated that S-adenosyl-L-methionine (SAMe) prevents APAP toxicity when given following APAP overdose in C57Bl/6 mice at a level comparable to NAC. The focus of the current work was to examine the mechanistic aspects of this protection …

Glutamate Receptor-Mediated Taurine Release From The Hippocampus During Oxidative Stress, Brian Christopher Tucker

Browse all Theses and Dissertations

Oxidative stress is an important result of cerebral ischemia and has been directly linked to hippocampal swelling and cytotoxic brain edema in vitro. Swollen brain cells activate volume regulatory mechanisms including a significant efflux of the endogenous sulfonic amino acid taurine via volume-regulated anion channels (VRACs). Studies in brain slice preparations also suggest that the excitatory amino acid glutamate plays an important role in both brain tissue swelling and in cell volume regulation. We examined relationships between oxidative stress, glutamate receptor activation, cell swelling, and volume regulation in acutely prepared slices of rat hippocampus. Our results indicate that the release …