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4th International Conference on Oxidative/Nitrosative Stress and Disease

4th International Conference on Oxidative/Nitrosative Stress and Disease

Wednesday, October 28, 2009 - Friday, October 30, 2009

The New York Academy of Sciences

Presented By

Presented by the UMDNJ, the New York Academy of Sciences, NIOSH, and Rutgers University.


The aim of the conference is to provide an open forum for the discussion of recent advances related to the cellular and molecular mechanisms mediating the generation of reactive oxygen and nitrogen species and their role in the pathogenesis of human disease, with a particular focus on the respiratory and cardiovascular systems. The conference will bring together basic and clinical scientists in the field with unique approaches and research efforts. The overall goal is to facilitate collaborative studies that will lead to new insights into the pathogenesis of cardiopulmonary diseases characterized by excessive oxidative and nitrosative stress and may suggest innovative directions for therapeutic intervention.

Accreditation Statement

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of UMDNJ-Center for Continuing and Outreach Education and The New York Academy of Sciences. UMDNJ-Center for Continuing and Outreach Education is accredited by the ACCME to provide continuing medical education for physicians.

Designation Statement

UMDNJ-Center for Continuing and Outreach Education designates the educational activity for a maximum of 17.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Presented by


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*Presentation times are subject to change.

Day 1: Wednesday, October 28

8:00 AM

Registration and Poster Set-up

8:45 AM

Welcome and Introductory Remarks

SESSION I: Inflammation, Lung Cancer and Fibroproliferative Diseases: Roles of Reactive Oxygen/Nitrogen Species

9:00 AM

Reactive Oxygen/Nitrogen Species in Lung Cancer and Fibrosis
Val Vallyathan, PhD, NIOSH/CDC and
Neelam Azad, PhD, Hampton University

9:30 AM

Role of Reactive Oxidant Species in Environmental Lung Disease
William N. Rom, MD, MPH New York University School of Medicine

10:00 AM

Cell Signaling and Inflammatory Pathways in Asbestos-Related Diseases
Brooke T. Mossman, PhD, University of Vermont

10:30 AM

Coffee Break and Poster Viewing

11:00 AM

The Role of iNOS-Mediated DNA Damage in Lung Carcinogenesis
Yusuke Hiraku, MD, PhD, Mie University Graduate School of Medicine

11:30 AM

Regulation of Apoptosis through Cysteine Oxidation: Implications for Fibrotic Lung Disease
Yvonne Janssen-Heininger, PhD, University of Vermont

12:00 PM

Inhibition of Inflammation and Carcinogenesis by Tocopherols
Chung S. Yang, PhD, Rutgers University

Data Blitz Session I

12:30 PM

Nitric Oxide Regulates Lung Carcinoma Cell Anoikis through S-Nitrosylation and Inhibition of Proteasomal Degradation Of Caveolin-1
Yon Rojanasakul, PhD, West Virginia University
12:45 PM

Role of Asymmetric Dimethylarginine in Enhanced iNOS Expression And Lung Inflammation
Sandra M. Wells, PhD, University of Nebraska Medical Center
1:00 PM

Lunch and Poster Session I

SESSION II: Reactive Oxygen and Reactive Nitrogen Species: Signaling and Detection

2:30 PM

Signaling by Reactive Oxygen Species and Aldehydes
Henry Jay Forman, PhD, University of California, Merced

3:00 PM

S-nitrosylation and Denitrosylation of Proteins in Health and Disease
Jonathan Stamler, MD, Duke University

3:30 PM

Nitric Oxide - A Molecular "Switch" in Redox Signaling
Bruce A. Freeman, PhD, University of Pittsburgh

4:00 PM

Coffee Break and Poster Viewing

4:30 PM

NO-Modification of Biomolecules in the Lung Lining: Inflammatory Implications
Andrew J. Gow, PhD, Rutgers University

5:00 PM

Pathophysiological Functions of Reactive Nitrogen Species in Vascular Disorders
Harry Ischiropoulos, PhD, Children's Hospital of Philadelphia

5:30 PM

Panel Discussion:
Clinical implications for the data presented in Sessions I and II

6:30 PMNetworking Reception

7:30 PM

Breakdown of Poster Session I

Day 2: Thursday, October 29

8:00 AM

Registration and Poster Session II Set-up

SESSION III: Oxygen Radicals and Cardiopulmonary Pathology

8:30 AM

Oxidative Stress: Acute and Progressive Lung Injury
Peter A. Ward, MD, University of Michigan

9:00 AM

Macrophages, Reactive Oxygen/Nitrogen Species and Lung Injury
Debra L. Laskin, PhD, Rutgers University

9:30 AM

VEGFR2 Redox Signaling in Endothelial Dysfunction in Response to Cigarette Smoke Exposure
Irfan Rahman, PhD, University of Rochester

10:00 AM

Coffee Break and Poster Viewing

10:30 AM

Nitric Oxide and Zinc Homeostasis in Pulmonary Endothelium
Bruce R. Pitt, PhD, University of Pittsburgh Graduate School of Public Health

11:00 AM

Reactive Species Regulation of Ion Channels in the Lung
Sadis Matalon, PhD, The University of Alabama at Birmingham

11:30 AM

Oxidative Stress Effects on Airways and Lungs
Kian Fan Chung, MD, Imperial College, London

12:00 PM

Role of Flavin-Dependent Oxidoreductases in Mediating Redox Cycling Of Chemotherapeutic Agents
Jeffrey D. Laskin, PhD, UMDNJ-Robert Wood Johnson Medical School

Data Blitz Session II

12:15 PM

Beneficial Effects of L-Arginine in Arginase-Nos Paradox and Nitrosative Stress in Murine Model Of Asthma
Tanveer Ahmad, Institute of Genomics and Integrative Biology
12:45 PM

TRPA1 is a Major Oxidant Receptor in Murine Sensory Neurons
Bret F. Bessac, PhD, Yale University School of Medicine

12:45 PM
Lunch and Poster Session II

SESSION IV: Cardiopulmonary Disease: Role of Reactive Oxygen and Nitrogen Species

2:30 PM

The Effects of Exercise Training on Endothelial Function and Nitric Oxide Bioavailability in Peripheral Arterial Disease: Diabetes is Different!
Jason David Allen, PhD, Duke University

3:00 PM

Acute Effects of Motor Vehicle Traffic-Related Exposures on Measures of Oxidative Stress
Robert Laumbach, MD, MPH, UMDNJ-Robert Wood Johnson Medical School

3:30 PM

Genetic Mechanisms of Susceptibility to Oxidant-Induced Lung Disease
Steven R. Kleeberger, PhD, National Institutes of Health/National Institute of Environmental Health Sciences

4:00 PM

Coffee Break and Poster Viewing

4:30 PM

Role of NADPH In the Generation of Reactive Oxygen Species by Catalase
Diane E. Heck, PhD, New York Medical College

4:45 PM

Oxidant-Redox Regulation of Pulmonary Vascular Responses to Hypoxia and Nitric Oxide-cGMP Signaling
Michael S. Wolin, PhD, New York Medical College

5:00 PM

The Role of Oxidative Stress in the Pathogenesis and Treatment of Asthma
Allen Dozor, MD, New York Medical College

5:15 PM

Panel Discussion:
Clinical implications for the data presented in Sessions III and IV

6:15 PM

Breakdown of Poster Session II

Day 3: Friday, October 30

8:00 AM


SESSION V: Role of Oxidants in Nanotoxicology: Screening Tests to Evaluate the Safety of Nanoparticles Prior to Medical Application

8:30 AM

Nanotoxicology as a Predictive Science: Use of a Hierarchical Oxidative Stress Paradigm for Evaluation of Safety
André E. Nel, MD, PhD, University of California, Los Angeles

9:00 AM

Use of Oxidative Lipidomics and Signaling by Oxidized Lipids in Safety Screening of Nanoparticles
Valerian E. Kagan, PhD, University of Pittsburgh

9:30 AM

Carbon Nanotubes
Ken Donaldson, PhD, University of Edinburgh

10:00 AM

Coffee Break

10:30 AM

Nanoparticles and the CNS: Dosimetry, Biokinetics, and Effects
Gunter Oberdörster, DVM, PhD, University of Rochester

11:00 AM

Pulmonary Toxicity of Single Walled Carbon Nanotubes In Vivo: Relevance to Occupational Exposures
Anna A. Shvedova, PhD, NIOSH, CDC

Data Blitz Session III

11:30 AM

Oxidative Stress in Genetic Obesity and Hypertension: Shrob Rats
Paul Ernsberger, PhD, Case Western Reserve University

11:45 AM

Oxidative/Nitrosative(O/N) Stress Triggers Diabetes in Streptozotocin-Rats and Prevented by C-Ptio - or Supplements in Human Diabetic Retinopathy
Knox Van Dyke, PhD, West Virginia University Medical Center

12:00 PM

Detection of Hydrogen Sulfide in Plasma and Knee-Joint Synovial Fluid from Rheumatoid Arthritis Patients: Relation to Clinical and Laboratory Measures of Inflammation
Matt Whiteman, PhD, Peninsula Medical School

12:15 PM


SESSION VI: Prevention of Oxygen/Nitrogen Radical Disease

1:30 PM

Vascular Inflammation and Oxidative Stress in Atherosclerosis and Aging: Ameliorating Effects of Alpha-Lipoic Acid
Balz Frei, PhD, Oregon State University

2:00 PM

Oxidant Stress and Airway Disease
David Peden, MD, The University of North Carolina at Chapel Hill

2:30 PM

Genes Related to Oxidative Stress and Susceptibility to Air Pollution
Joel Schwartz, PhD, Harvard University

3:00 PM

Coffee Break

3:30 PM

Changes in Indicators of Pulmonary Oxidative and Nitrosative Stress Following Drastic Changes in Air Pollution during the Beijing HEART Study
Howard M. Kipen, MD, UMDNJ-Robert Wood Johnson Medical School

4:00 PM

The Future of Antioxidants and the Future of Biomarkers
Barry Halliwell, PhD, National University of Singapore

4:30 PM

Reducing Health Affects Associated with Ambient Pollution Through Antioxidant Supplementation
Fernando Holguin, MD, Children's Hospital of Pittsburgh

5:00 PM

Panel Discussion:
Clinical implications for the data presented in Sessions V and VI

6:00 PM

Closing Remarks

6:15 PMMeeting Concludes


Debra L. Laskin, PhD

Rutgers University

Howard Kipen, MD

UMDNJ-Robert Wood Johnson Medical School

Val Vallyathan, PhD


Vince Castranova, PhD


Andrew J. Gow, PhD

Rutgers University

Jeffrey D. Laskin, PhD

UMDNJ-Robert Wood Johnson Medical School

Diane E. Heck, PhD

New York Medical College


Jason David Allen

Duke University

Neelam Azad, PhD

Hampton University

Kian Fan Chung, MD

Imperial College

Allen Dozor, MD

New York Medical College

Ken Donaldson, PhD

University of Edinburgh

Henry Jay Forman, PhD

University of California, Merced

Bruce A. Freeman, PhD

University of Pittsburgh

Balz Frei, PhD

Oregon State University

Barry Halliwell, PhD

National University of Singapore

Yusuke Hiraku, MD, PhD

Mie University Graduate School of Medicine

Fernando Holguin, MD

Children's Hospital of Pittsburgh

Harry Ischiropoulos, PhD

Children's Hospital of Philadelphia

Yvonne Janssen-Heininger, PhD

University of Vermont

Valerian E. Kagan, PhD

University of Pittsburgh

Steven R. Kleeberger, PhD

National Institutes of Health/National Institute of Environmental Health Sciences

Robert Laumbach, MD, MPH

UMDNJ-Robert Wood Johnson Medical School

Sadis Matalon, PhD

The University of Alabama at Birmingham

Brooke T. Mossman, PhD

University of Vermont College of Medicine

André E. Nel, MD, PhD

University of California, Los Angeles

Gunter Oberdörster, DVM, PhD

University of Rochester

David Peden, MD

The University of North Carolina at Chapel Hill

Bruce R. Pitt, PhD

University of Pittsburgh Graduate School of Public Health

Irfan Rahman, PhD

University of Rochester

William N. Rom, MD, MPH

New York University School of Medicine

Joel Schwartz, PhD

Harvard University

Anna A. Shvedova, PhD


Jonathan Stamler, MD

Duke University

Peter A. Ward, MD

University of Michigan Medical School

Michael S. Wolin

New York Medical College

Chung S. Yang, PhD

Rutgers University


For opportunities to support this event, please contact Sonya Dougal at or 212.298.8682.

Presented by
  • National Institute for Occupational Safety and Health/Centers for Disease Control and Prevention

Academy Friends

University of Medicine and Dentistry of NJ/Rutgers University
   • Environmental and Occupational Health Sciences Institute
   • National Institute Arthritis and Musculoskeletal and Skin Disease-UMDNJ-Rutgers University
     CounterAct Center of Excellence

Department of Pathology, West Virginia University

The Society of Toxicology

National Institute of Environmental Health Sciences

The Company of Biologists, publishers of the journals, Development, Journal of Cell Science, and Disease Models & Mechanisms

This event is funded in part by the Life TechnologiesTM Foundation.

Invitrogen is an exhibitor of this event.

Leica Microsystems, Inc. is an exhibitor of this event.

This conference has been endorsed by the American Thoracic Society.

The project described is supported by Award Number R13HL097539 from the National Heart, Lung, And Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health.

This conference has been endorsed by the American Thoracic Society.

Media Partners

Day 1: October 28, 2009

SESSION I: Inflammation, Lung Cancer and Fibroproliferative Diseases: Roles of Reactive Oxygen/Nitrogen Species

Reactive Oxygen/Nitrogen Species in Lung Cancer

Neelam Azad, PhD1, Anand Iyer, PhD1, Val Vallyathan, PhD2, Yon Rojanasakul, PhD3
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia. 2Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia. 3Department of Pharmaceutical and Pharmacological Sciences, School of Pharmacy, West Virginia University, Morgantown, WV

Lung cancer is the leading cause of cancer mortality worldwide. Reactive oxygen/nitrogen species (ROS/RNS) are known to be the key players in lung inflammation and cancer as increased ROS/RNS production leads to genetic mutations, predisposing individuals to cancer. Individuals are constantly exposed to increased levels of ROS/RNS generated from various carcinogens. Hexavalent chromium [Cr(VI)] compounds are redox cycling environmental carcinogens strongly associated with the incidence of lung cancer. Generation of reactive species and dysregulation of apoptosis have been implicated in Cr(VI)-induced lung carcinogenesis; however, the underlying mechanisms are largely unknown. In our study, we observed that ROS, specifically superoxide anion (·O2‾), mediated Cr(VI)-induced apoptosis of human lung epithelial cells. Cr(VI)-induced apoptosis mainly through the mitochondrial death pathway via caspase-9 activation, which was negatively regulated by the mitochondrial anti-apoptotic protein Bcl-2. Specifically, ·O2‾ induced apoptosis by downregulating and degrading Bcl-2 protein through the ubiquitin-proteasomal pathway. Consequently, overexpression of Bcl-2 blocked Cr(VI)-induced apoptosis, whereas Cr(VI)-induced nitric oxide (NO) production was involved in the stabilization of Bcl-2. This mechanism involved NO-mediated S-nitrosylation of Bcl-2, which prevented its ubiquitination and subsequent proteasomal degradation. Therefore, NO was found to exert an anti-apoptotic effect in response to Cr(VI) exposure. The mechanism of Cr(VI)-induced apoptosis resistance was verified in an in vitro model that facilitated mechanistic studies of Cr(VI)-induced carcinogenesis. Long-term exposure to Cr(VI) led to the malignant transformation of non-tumorigenic human lung epithelial cells. Cr(VI)-transformed cells exhibited loss of contact inhibition, colony formation, and increased rates of cell invasion, migration and proliferation as compared to passage-matched control cells. Cr(VI)-transformed cells showed decreased apoptosis and ROS production. The mechanism by which these cells evaded apoptosis involved NO-mediated S-nitrosylation and stabilization of Bcl-2 protein. Taken together, this study establishes an important in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis, and elucidates a novel mechanism of apoptosis-resistant and malignant transformation of non-tumorigenic lung cells in response to a human carcinogen. The study also reveals a novel mechanism linking ·O2‾ and NO with Bcl-2 stability providing a new dimension to reactive species-mediated Bcl-2 stability, apoptotic cell death and cancer development.

Role of Reactive Oxidant Species in Environmental Lung Disease

William N. Rom MD, MPH, Division of Pulmonary and Critical Care Medicine, NYU School of Medicine, New York, NY

ROS contribute to inflammation and injury of the lower respiratory tract after inhalation of particulates that lead to fibrosis and/or cancer. The technique of bronchoalveolar lavage in humans has recovered alveolar macrophages (AMs) in dust diseases that release increased amounts of ROS. Peptide growth factors (PDGF, IGF-I) from AMs and matrix metalloproteinases contribute to the inflammation. Other cells are important: eosinophils cause acute eosinophilic pneumonia due to WTC dust; eosinophils from TPE release very high ROS leading to fibrosis, and neutrophils releasing elastase cause focal emphysema in CWP. Key to the fibrosing process is Transforming Growth Factor-β from myofibroblasts. Myofibroblasts develop from progenitor cells in the basal layers of the airway epithelium and migrate into the interstitium releasing excess amounts of collagen. Progenitor cells activate embryonic signaling pathways through Hedgehog that can be tagged with Gli1-lacZ to identify key players in the ROS-inflammation-fibrosis process.

Cell Signaling and Inflammatory Pathways in Asbestos-Related Diseases

Arti Shukla, PhD, Jedd M. Hillegass, PhD, Maximilian B. MacPherson, BSc, Stacie L. Beuschel, BSc, Sherrill A. Lathrop, BSc, Nicholas H. Heintz, PhD, Brooke T. Mossman, PhD, Department of Pathology, University of Vermont College of Medicine, Burlington, VT

Exposure to asbestos fibers is associated with the development of pulmonary fibrosis, lung cancers and mesotheliomas. Several years ago we questioned the conclusion that asbestos was primarily a DNA- damaging or genotoxic carcinogen, suggesting instead that the initial interaction of asbestos fibers at the plasma membrane triggered multiple signaling cascades that are linked to transcription factors (AP-1, NF-κB, CREB, etc.) governing abnormal cell proliferation and inflammation. Many of these signaling pathways are initiated by elaboration of oxidants both extracellularly and intracellularly. Recently we have shown that asbestos fibers stimulate NADPH oxidases in human macrophages, a key cell in early responses to asbestos, that leads to activation of the inflammasome (Dostert et al, Science 320:674-677). We addressed the hypothesis that NADPH oxidases were over-expressed after exposures to asbestos and in human mesothelioma cells, leading to activation of extracellular-signal regulated kinases (ERKs 1 and 2) critical to the development of asbestos injury, inflammation and mesotheliomas. In RNA interference experiments, human mesothelioma cells (kindly provided by Dr. Harvey I. Pass, NYU) were stably transfected with either shERK1 or shERK2 before characterization in vitro and injection into a mouse xenograft model. We show that ERK2 is causally linked to both asbestos toxicity and the development of mesotheliomas. Microarray experiments on shERK1, shERK2 and shControl mesothelioma lines reveal unique cell death and oxidant/antioxidant genes regulated by ERKs. These studies link ERK mechanistically to the development of inflammation and mesothelioma. (This work is supported by P01 grants from NCI and NHLBI and a training grant from the NIEHS.)

The Role of iNOS-Mediated DNA Damage in Inflammation-Related Carcinogenesis

Shosuke Kawanishi, PhD1, Yusuke Hiraku, MD, PhD2, Takamichi Ichinose, PhD3, Mariko Murata, MD, PhD2
1Suzuka University of Medical Science, Suzuka, Mie, Japan, 2Mie University Graduate School of Medicine, Mie, Japan, 3Oita University of Nursing and Health Sciences, Oita, Japan

Chronic infection and inflammation considerably contribute to environmental carcinogenesis. Chronic inflammation has been estimated to account for approximately 25 % of human cancers. The International Agency for Research on Cancer (IARC) has estimated that approximately 18 % of cancer cases worldwide is attributable to infectious diseases. Moreover, not only infectious diseases but also various physical, chemical and immunological factors participate in inflammation-related carcinogenesis. Under inflammatory condition, reactive oxygen and nitrogen species are generated from inflammatory and epithelial cells and may play an important role in inflammation-related carcinogenesis by causing DNA damage. Nitric oxide (NO) is generated through the expression of inducible nitric oxide synthase (iNOS) and interacts with superoxide (O2•-) to form highly reactive peroxynitrite (ONOO-), which reacts with guanine to produce 8-nitroguanine, a mutagenic DNA lesion.

We performed immunohistochemical analysis to examine 8-nitroguanine formation in various clinical specimens and animal models of cancer-prone infectious diseases induced by the liver fluke Opisthorchis viverrini, Helicobacter pylori, hepatitis C virus, human papillomavirus (HPV) and Epstein-Barr virus (EBV). We demonstrated that 8-nitroguanine formation was observed at the sites of carcinogenesis and increased during tumor development. 8-Nitroguanine formation in cervical biopsy specimens of HPV-induced cervical intraepithelial neoplasia was increased with its grade. 8-Nitroguanine formation in cancer cells of patients with EBV-mediated nasopharyngeal carcinoma was significantly stronger than that in biopsy specimens of nasopharyngitis patients. We have also reported that strong 8-nitroguanine formation was closely associated with a poor prognosis in patients with soft tissue tumor.

Asbestos fibers are potent carcinogens causing lung cancer and malignant mesothelioma in humans. We found that 8-nitroguanine was formed particularly in the nucleus of bronchial epithelial cells in the lung tissues of mice intratracheally administered asbestos fibers. Interestingly, quantitative image analysis revealed that crocidolite induced 8-nitrogunaine formation to a significantly greater extent than chrysotile in consistency with their carcinogenic potentials. iNOS expression was also observed in the bronchial epithelial cells and its immunoreactivity was correlated with that of 8-nitrogunaine. On the basis of these findings, we have proposed that 8-nitroguanine could be a potential biomarker to evaluate the risk of inflammation-related carcinogenesis and the prognosis of cancer patients.

Regulation of Apoptosis through Cysteine Oxidation: Implications for Fibrotic Lung Disease

Yvonne MW Janssen-Heininger, PhD1, Vikas Anathy, PhD1, Scott Aesif, PhD1, Jos van der Velden, PhD1, Amy S. Guala1, Jessica N. Reiss1, Elle Roberson1, Ralph C. Budd2, Niki L. Reynaert, PhD3
Department of Pathology1 and Medicine2 University of Vermont, Burlington VT, and Department of Respiratory Medicine3 Maastricht University Medical Center, Maastricht, the Netherlands

Tissue fibrosis is believed to be a manifestation of dysregulated repair following injury, in association with impaired re-epithelialization, and aberrant myofibroblast activation and proliferation. Numerous pathways have been linked to the pathogenesis of fibrotic lung disease, including the death receptor, Fas which contributes to apoptosis of lung epithelial cells. A redox imbalance also has been implicated in disease pathogenesis, although mechanistic details whereby oxidative changes intersect with pro-fibrotic signaling pathways remain elusive. Oxidation of cysteines in proteins, which encompass S-nitrosylation, S-glutathionylation (PSSG), among others are known to act as regulatory events that affect protein structure and function. The overall goal of the research that will be discussed was to determine whether cysteine oxidation events, notably protein S-glutathionylation (PSSG) are important in FasL-induced apoptosis. We recently demonstrated that Fas Ligand (FasL)-induced death of lung epithelial cells is accelerated following S-glutathionylation of the death receptor Fas (Fas-SSG) itself at cysteine 294. Fas-SSG occurs following caspase-8 induced degradation of glutaredoxin, 1, which under physiological conditions acts to decompose PSSG. Fas-SSG promotes its recruitment into lipid rafts, oligomerization, and Death Inducing Signaling Complex formation, leading to feed forward amplification of caspase 8 activation and apoptosis. Ablation of glutaredoxin 1, via SiRNA or gene ablation augments FasL-induced Fas-SSG and sensitizes epithelial cells to apoptosis, while conversely overexpression of glutaredoxin-1 attenuates Fas-SSG, and protects against apoptosis. Using glutaredoxin-1 mediated cysteine derivatization in situ, I will demonstrate evidence that protein S-glutathionylation is increased in two independent mouse models of fibrosis, and in patients with idiopathic pulmonary fibrosis. Lastly, the impact of modulation of glutaredoxin-1 in mouse models will be presented in order to demonstrate the functional significance of protein-S-glutathionylation in fibrogenesis. Funded by NIH R01 HL079331 and R03 HL095404.

Inhibition of Inflammation and Carcinogenesis in the Lung and Colon by Tocopherols

Chung S. Yang, PhD, Guang Xun Li, PhD, Gang Lu, PhD, and Jihyeung Ju, PhD, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ

Tocopherols, which exist in α, β, γ, and δ forms, are antioxidative nutrients known as vitamin E. Although α-tocopherol (α-T) is the major form of vitamin E found in the blood and tissues, γ- and δ-T have been suggested to have stronger anti-inflammatory activities. A robust cancer preventive activity of these tocopherols has not been demonstrated previously. In the present study, using a tocopherol mixture that is rich in γ-T (γ-TmT, which contains 57% γ-T), we demonstrated the inhibition of inflammation as well as of cancer formation and growth in the lung and colon in animal models. When given in the diet at 0.3%, γ-TmT inhibited lung tumorigenesis in the A/J mice, induced by the tobacco carcinogen NNK or NNK plus benzo[a]pyrene (a ubiquitous environmental carcinogen). Dietary 0.3% γ-TmT also inhibited the growth of human lung cancer H1299 cells in xenograft tumors in NCr-nu/nu mice. In both experimental systems, γ-TmT decreased the levels of 8-hydroxydeoxyguanosine (a product of DNA oxidation), γ-H2AX (an indicator of DNA repair caused by DNA double-strand breakage), and nitrotyrosine in tumors. The plasma levels of prostaglandin E2 and leukotriene B4 were also decreased by γ-TmT treatment in mice. More evident anti-inflammatory activity was demonstrated in mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS), as indicated by the inflammatory index and biochemical markers. The anti-inflammatory activity of pure γ-T and δ-T was also demonstrated in this model. Inhibition of colon carcinogenesis (reduction of adenocarcinoma and adenoma formation by ~80%) was observed when 0.3% γ-TmT diet was initiated either before or after AOM/DSS treatment. These results demonstrate the anti-oxidative, anti-inflammatory, and anti-carcinogenic activities of a mixture of γ-T-rich tocopherols (supported by NIH grant CA122474 and CA120915).

SESSION II: Reactive Oxygen and Reactive Nitrogen Species: Signaling and Detection

Signaling by Reactive Oxygen Species and Aldehydes

Henry Jay Forman, PhD, School of Natural Sciences, University of California, Merced, Merced, CA

Signaling by H2O2, α,β-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (HNE) and related chemical species is thought to differ from signaling by other second messengers because the oxidants and other electrophiles can readily undergo non-enzymatic reactions and are therefore classified as “reactive.” Although there are some significant differences in the chemistry of these reactive species from classic second messengers, such as cyclic AMP, there are significant similarities between signaling by H2O2 and classic second messengers in terms of the kinetics and regulation of their production and degradation, and effect on signaling pathways including reversibility of action. HNE can form reversible adducts with proteins but its involvement in signaling appears to be less similar to that of the classic second messengers and more like other post-translational signaling, such as farnesylation or ubiquitination.The chemistry of cysteine provides a common factor that underlies signaling by H2O2 and HNE. Nonetheless, as H2O2 and HNE are rapidly metabolized in vivo and have very different physical properties, spatial considerations are also important in their actions. Therefore, the locations of sources of H2O2 and α,β-unsaturated aldehydes, the NADPH oxidases, mitochondria, membrane lipids, and redox cycling toxicants, as well as their targets are key factors. The activation of the JNK pathway by HNE and endogenously generated H2O2 illustrates these principles.

S-nitrosylation and Denitrosylation of Proteins in Health and Disease

Jonathan S. Stamler, MD, Duke University, Durham, NC

S-nitrosylation and denitrosylation, the covalent attachment and removal of NO groups from the thiol side chain of cysteine, have emerged as important mechanisms for dynamic, posttranslational regulation of most or all classes of protein. S-nitrosylation thereby conveys a large part of the ubiquitous influence of NO on cellular signal transduction, and provides a prototypic example of redox-based physiological regulation. Accumulating evidence suggests that alterations in S-nitrosylation-regulated signaling contribute to human disease.

Nitric Oxide - A Molecular "Switch" in Redox Signaling

Bruce A. Freeman, PhD, Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA

Over the last 50 years, the posttranslational modification (PTM) of proteins has emerged as a central mechanism for cells to regulate metabolism, growth, differentiation, cell-cell interactions, and immune responses. By influencing protein structure and function, PTM leads to a multiplication of proteome diversity. Redox-dependent PTMs, mediated by environmental and endogenously-generated reactive species, exert both cell signaling and toxicological actions in organisms. PTMs induced by the electrophilic byproducts of redox reactions most frequently occur at protein thiols, with other nucleophilic amino acids serving as less favorable targets. Advances in mass spectrometry and affinity chemistry strategies have improved the detection of electrophile-induced protein modifications both in vitro and in vivo, revealing a high degree of amino acid and protein selectivity of electrophilic PTM. Some PTMs that are induced by electrophilic products of redox reactions appear to modulate physiological signaling pathways that have evolved to act as sensors of oxidative conditions. The identification of these biological targets of electrophiles has motivated further study of the functional impact of various PTM reactions on specific signaling pathways and how this might impact organisms. We also now appreciate that nitric oxide profoundly stimulates the post-translational modification of proteins via the formation of multiple reactive byproducts. This presentation will describe the formation, signaling actions and potential therapeutic uses of electrophilic fatty acid derivatives stemming from these reactions.

NO-Modification of Biomolecules in the Lung Lining: Inflammatory Implications

Andrew Gow, PhD, Rutgers University, Piscataway, NJ

The biological chemistry of Nitric Oxide (NO) is complex in that there are multiple reactive targets and its reactivity is flux rate dependent. However, this very complexity undoubtedly lies at the heart of how NO is capable of controlling such a wide range of biological processes. Nowhere is this more apparent than in the lung where NO controls a wide range of functions ranging from bronchial and vascular tone, to innate immunity and development; and there are multiple reactive targets. These reactive targets allow for the generation of novel NO-modified biomolecules such as S-nitrosylated Surfactant Protein D and nitrated lipids. We have investigated the capability of NO-modified biomolecules to activate cellular signaling pathways in both epithelial and monocytic cells. Our results indicate that these compounds are capable of eliciting a variety of responses and thus may provide a mechanism for the multifarious nature of NO. Specifically, we have begun to investigate how such NO-modifications are involved in a NOS-mediated lung injury model, intratracheal bleomycin administration. Our observations within this model indicate demonstrate the importance of NO-modified biomolecules in mediating lung injury and repair.

Pathophysiological Functions of Reactive Nitrogen Species in Vascular Disorders

Harry Ischiropoulos, PhD, Departments of Pediatrics and Pharmacology, The Children's Hospital of Philadelphia Research Institute and The University of Pennsylvania Philadelphia, PA

Over the last decade basic and translational medicine discoveries have implicated alterations in nitric oxide (NO) metabolism in atherothrombotic diseases. Specifically, we have employed mass-spectrometry-based proteomic approaches to identify site specific NO-mediated oxidative modifications to protein targets of pathobiological relevance to atherothrombotic vascular diseases. Published and new data will be presented relating to the functional consequences of fibrinogen modifications by NO-derived oxidants in animal models of atherosclerosis and in humans. Protein tyrosine nitration also results in the induction of immune responses in humans and animal models. Recent studies have indicated the presence of circulating immunoglobulins that specifically recognize the modified nitrated tyrosine residues in proteins. Preliminary data have indicated that the levels of these specific circulating immunoglobulins are strong predictors of angiographic evidence of coronary artery disease, as well as its acute adverse complications including incident risks for experiencing myocardial infarction, stroke or death. The data suggest that nitrated fibrinogen and immunoglobulins to nitrated proteins may represent two novel prognostic parameters for identifying individuals at increased risk for subsequent adverse cardiac outcomes.

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