- •Preface
- •Contents
- •Contributors
- •1.1 Introduction
- •1.2 Pathogenesis of AMD
- •1.2.1 Oxidative Damage
- •1.2.2 Lipofuscin Accumulation
- •1.2.4 Complement Mutations
- •1.2.5 Mitochondrial Damage
- •1.2.6 DICER 1
- •1.3 Treatment
- •1.3.1 Antioxidants
- •1.3.2 Visual Cycle Modulators
- •1.3.4 Neurotrophic Agents
- •1.3.5 Antiangiogenic Agents
- •1.3.5.1 Intracellular Angiogenic Factor Production
- •1.3.5.2 Extracellular Angiogenic Factors
- •1.3.6 Endothelial Cell Receptor Binding
- •1.3.7 Endothelial Cell Activation
- •1.3.8 Endothelial Cell Proliferation
- •1.3.9 Endothelial Cell Directional Migration
- •1.3.10 Extracellular Matrix Remodeling
- •1.3.11 Tube Formation
- •1.3.11.1 Loop Formation (Arteriovenous Differentiation)
- •1.3.11.2 Vascular Stabilization
- •1.4 Combination Therapy
- •1.5 Conclusions
- •References
- •2.1 Introduction
- •2.1.1 Complement Pathways
- •2.1.2 Oxidative Stress
- •2.3.1 The Mouse CNV Model
- •2.3.2 RPE Monolayers
- •2.3.3 Concept
- •2.5 Summary and Outlook
- •References
- •3.1 Introduction
- •3.2.1 Advanced Glycation End Products
- •3.2.2 Carboxyethylpyrrole
- •3.2.3 Oxidation Products of Lipofuscin
- •3.3 Summary and Conclusions
- •References
- •4.1 Introduction
- •4.2 Oxidative Stress and AMD
- •4.2.1 Basic Concepts on Oxidative Stress
- •4.2.2 Oxidative Stress in AMD
- •4.3 Malondialdehyde in AMD
- •4.3.1 Lipid Peroxidation and Malondialdehyde
- •4.3.2 Materials and Methods
- •4.3.2.1 RPE Cell Culture
- •4.3.2.2 Patients
- •4.3.2.3 MDA Assay
- •4.3.3 MDA Levels in Cultured RPE Cells and in Patients with AMD
- •4.4 Summary and Conclusions
- •References
- •5.1 Introduction
- •5.2 The Origin and Housing of RPE Lipofuscin
- •5.3 Bisretinoid Constituents of RPE Lipofuscin
- •5.3.1 A2E, Isomers and Precursors
- •5.3.4 Photooxidized Forms of Bisretinoid Pigments
- •5.4 Photoreactivity of RPE Lipofuscin
- •5.5 Photooxidation of RPE Bisretinoids
- •5.6 Bisretinoid Photodegradation
- •5.7 Potential for Cell and Tissue Damage
- •5.9 A Role for Antioxidants
- •5.10 Conclusions
- •References
- •6.1 Introduction
- •6.1.1 RPE Lipofuscin Accumulation with Age and Relation to AMD
- •6.1.2 Known Chromophores Found in RPE Lipofuscin and the Mechanism of Damage
- •6.1.3 Formation of Higher Molecular Weight Material
- •6.1.4 Current Studies and Possible Structures of Higher Molecular Weight Products
- •6.1.4.1 Lipofuscin Extracts
- •6.1.4.3 Esters and Aldehydes
- •6.2 Conclusions
- •References
- •7.2 DHA in Photoreceptor Cells
- •7.3 Neuroprotectin D1 Synthesis is an Early Response to Oxidative Stress in RPE Cells
- •7.5 Neurotrophins Trigger the Synthesis and Polarized Secretion of Neuroprotectin D1 from Human RPE Cells
- •7.6 Photoreceptor Outer Segment Phagocytosis Induces RPE Cell Survival Signaling with Associated Synthesis of NPD1 During Oxidative Stress
- •References
- •8.1 Introduction
- •8.2.1 Subcellular Localization
- •8.2.2 Expression Levels in the Retina
- •8.4.3 Regulation of RDH12 Expression and Activity During Chronic and Acute Stress
- •8.5 RDH12 and Leber Congenital Amaurosis
- •8.5.1 Inactivating Mutations of RDH12
- •8.5.2 Loss of Which RDH12 Function Induces LCA?
- •8.6 Summary and Conclusions
- •References
- •9.1 Introduction
- •9.2 GSH Metabolism: General Principles
- •9.2.2 Role of Mitochondrial GSH in Protection
- •9.2.3 GSH as a ROS Scavenger
- •9.2.4 GSH Distribution in the Retina and RPE in Health and Disease
- •9.5 Future Perspectives
- •References
- •10.1 Introduction
- •10.2 Mitochondria
- •10.2.1 Mitochondrial Biogenesis and Maintenance
- •10.2.2 Mitochondrial Removal and Degradation
- •10.3 Mitochondria and Reactive Oxygen Species
- •10.3.1 Reactive Oxygen and Nitrogen Species (ROS and RNS)
- •10.3.2 Mitochondria are a Major Source of Intracellular ROS
- •10.3.3 Other Sources of ROS in the Retina
- •10.4 The Mitochondrial Genome
- •10.4.1 Susceptibility of Mitochondrial DNA to Oxidative Stress
- •10.4.2 Mitochondrial DNA Damage
- •10.4.3 Mitochondrial DNA Repair Pathways
- •10.4.4 The Mitochondrial Base Excision Repair (mtBER) Pathway
- •10.4.6 Other Mitochondrial DNA Repair Pathways
- •10.4.6.2 Mismatch Repair (MMR)
- •10.4.6.3 Translesion Synthesis (TLS) and Damage Tolerance
- •10.4.6.4 Nucleotide Excision Repair (NER)
- •10.4.7 Intramitochondrial Localization of DNA Repair Proteins
- •10.4.8 mtDNA Damage Sensing and Signaling
- •10.4.9 Import of Nuclear Encoded DNA Repair Enzymes into the Mitochondria
- •10.5 Mitochondrial DNA Damage/Repair in the Retina and RPE
- •10.5.1 Mitochondrial DNA Damage/Repair in the RPE
- •10.5.2 DNA Repair and the Adaptive Response in the RPE
- •10.6 Pathologies Associated with Mitochondrial Dysfunction and Oxidative Stress in the Retina
- •10.6.2 Diabetic Retinopathy
- •10.6.3 Glaucoma
- •10.6.4 Uveitis
- •10.7 Pathologies Associated with Inherited Mitochondrial Disorders
- •10.8 Potential Therapeutic Options for Targeting Mitochondrial DNA Damage
- •10.8.1 Mitochondrial Biogenesis
- •10.8.2 Enhancing mtDNA Repair
- •10.8.3 Antioxidants
- •10.8.4 Autophagy
- •10.9 Conclusion
- •References
- •11.1 Introduction
- •11.2 ER Function in Normal Physiology
- •11.2.1 Major Roles of Rough ER (RER) and Smooth ER (SER)
- •11.2.2 ER and Oxidative Protein Folding
- •11.2.3 ER Resident Proteins
- •11.2.4 Potential Threat to ER Function in RPE
- •11.3 ER Response to Oxidative Stress in RPE
- •11.3.2 Initiation of UPR to Alleviate ER Burden
- •11.4 Chronic ER Stress and Oxidative Stress in the Vicious Cycle of Apoptosis Induction
- •11.5 Future Perspectives
- •References
- •12.1 Introduction
- •12.2 Iron Homeostasis
- •12.2.1 General Iron Homeostasis
- •12.2.2 Iron Import into the Retina
- •12.2.2.1 Transferrin Mediated Transport
- •12.2.2.3 Dexras
- •12.2.3 Iron Storage
- •12.2.3.1 Ferritin
- •12.2.3.2 Mitochondrial Ferritin
- •12.2.4 Iron Export
- •12.2.4.1 Ceruloplasmin
- •12.2.4.2 Hephaestin
- •12.2.4.3 Ferroportin and Hepcidin
- •12.3 Disruption of Iron Homeostasis and Oxidative Damage
- •12.4 Retinal Disorders Resulting from Abnormal Retinal Iron Metabolism
- •12.4.2 Aceruloplasminemia
- •12.4.3 Hemochromatosis
- •12.4.4 Friedreich’s Ataxia
- •12.4.6 Siderosis
- •12.4.7 Subretinal Hemorrhage
- •12.5 Potential Therapeutics
- •References
- •13.1 Vascular Endothelial Growth Factor and Its Functions in the Retina
- •13.1.1 VEGF Isoforms
- •13.1.2 VEGF Functions
- •13.1.3 Cells Secreting VEGF in the Retina
- •13.1.3.1 Retinal Pigment Epithelium
- •13.1.3.2 Müller Cells
- •13.1.3.3 Astrocytes
- •13.1.3.4 Pericytes
- •13.1.4 VEGF Receptors and VEGF Induced Signal Transduction
- •13.1.4.1 VEGF Receptors
- •VEGFR-1
- •VEGFR-2
- •Neuropilin
- •Heparan Sulfate Proteoglycan
- •13.2 Regulation of VEGF Expression
- •13.2.1 Transcriptional Regulation
- •13.2.2 Translational Regulation
- •13.2.3 Hypoxia Induced VEGF Regulation
- •13.2.4 Posttranslational Regulation
- •13.2.5 Autocrine VEGF Regulation
- •13.2.6 Pathological VEGF Production
- •13.2.6.1 Hyperglycemia
- •13.2.6.2 Oxidative Stress
- •13.2.6.3 Cytokines
- •13.2.6.4 Endoplasmic Reticulum
- •13.2.6.5 Additional Factors
- •13.3.1 Pegaptanib
- •13.3.2 Bevacizumab and Ranibizumab
- •13.3.4 siRNA
- •13.3.5 Small Molecule Tryrosine Kinase Inhibitors
- •13.3.6 Other Inhibitors
- •13.4.2 Interaction of VEGF Antagonists with Antiangiogenic VEGFxxxb
- •13.5 Conclusion
- •References
- •14.1 Introduction
- •14.2 NADPH Oxidase and Redox Signaling
- •14.3 Expression of NADPH Oxidase Subunit p22phox in the Retina
- •14.4 NADPH Oxidase and Choroidal Neovascularization
- •14.5 Implication and Therapeutic Potential of NADPH Oxidase in Development of CNV
- •14.6 Summary and Future Perspective
- •References
- •15.1 Introduction
- •15.2 Aging
- •15.3 Deposition and Formation of Oxidized LDL
- •15.6 Treatments for AMD
- •15.7 Conclusions
- •References
- •16.1 Introduction
- •16.2 HGF and Its Receptor (MET)
- •16.2.1 Production and Secretion of HGF
- •16.2.2 MET and Biological Effects of HGF
- •16.2.3 Signaling Pathways of HGF
- •16.2.4 HGF and MET in Disease States
- •16.4 HGF Protects RPE Cells from Oxidative Stress
- •16.4.1 HGF and RPE Cells
- •16.4.2 HGF Promotes Cell Survival
- •16.4.3 HGF Protects Cells from Oxidative Stress
- •16.4.4 HGF Protects RPE Cells from Hydrogen Peroxide
- •16.4.5 HGF Protects RPE Cells Against Ceramide Damage
- •16.4.6 HGF Protects RPE Cells from Glutathione Depletion
- •References
- •17.1 Introduction
- •17.2.1 Fundoscopy
- •17.2.2 Histology
- •17.2.3 Ultrastructure
- •17.3.1 Lipofuscin (A2E)
- •17.3.3 HtrA2/Omi
- •References
- •18.1 Introduction
- •18.2 Systemic Markers of Oxidative Stress
- •18.2.1 Redox Status
- •18.2.2 DNA Damage
- •18.2.4 Lipid Peroxidation
- •18.3 Defenses Against Oxidative Stress
- •18.3.1 Antioxidants
- •18.3.2 Antioxidant Enzymes
- •18.4 Oxidative Stress and Genetics
- •18.4.1 Antioxidant Enzyme Polymorphisms
- •18.5 Environmental Exposures and Oxidative Stress
- •18.5.1 Smoking
- •18.5.2 Light Exposure
- •18.6 AMD Treatments and Oxidative Stress
- •18.8 Summary and Conclusions
- •References
- •19.1 Characteristics of Cerium Oxide Nanoparticles
- •19.3 Mechanism of Nanoceria Uptake, Internalization, and Localization in the Cell
- •19.4 Biological Effect, Functional Mechanism, and Applications
- •19.4.1 Bacteria
- •19.4.2 Plants
- •19.4.3 Medical Usage
- •19.4.3.1 Radioprotectants
- •19.4.3.2 Burn Treatment
- •19.4.4 Medical Imaging
- •19.5 Stability of Nanoceria Under storage Conditions and Its Longevity in the Cell In Vivo
- •19.6 Oxidative Damage Results in Neurodegeneration
- •19.7.1 Prolong Cellular Life Span
- •19.7.2 Cardioprotection
- •19.8 Treatment of Ocular Disorders
- •19.8.1 Methodology
- •19.8.2 Prevention of Light Damage and Rescue of Retinal Function
- •19.8.3 Treatment of Degenerative Ocular Diseases
- •19.8.4 Treatment of Ocular Neovascular Diseases
- •19.9 Toxicity and Environmental Impacts
- •19.10 Conclusion and Future Directions
- •References
- •20.1 Introduction
- •20.2 Retinal Progenitor Cells (RPCs) Are Multipotential
- •20.4 Therapeutic Strategies for Repair and Regeneration of Retinal Cells: Repair of the RPE
- •20.5 Challenges for RPE Stem Cell Therapy
- •20.6 Characterization of RPE-Like Cells Derived from BMDCs
- •20.7 BMDCs Differentiate into Retinal Cells
- •20.8 Summary and Future of Cell Therapy for Dysfunctional RPE
- •References
- •21.1 Introduction
- •21.2 Carotenoids in Retinal Diseases
- •21.4 Polyphenols or Phenolic Esters in Retinopathies
- •21.4.1 Caffeic Acid Phenethyl Ester
- •21.4.2 Catechin
- •21.4.3 Curcumin
- •21.4.4 Proanthocyanidin
- •21.4.5 Resveratrol
- •21.5.2 Sulforaphane
- •21.6 Vitamins in Retinopathies
- •21.6.1 Vitamin A
- •21.7 Perspectives
- •References
- •22.1 Introduction
- •22.1.1 Neuroprotection as a Strategy for Retinal Degenerative Disease
- •22.2.2 Putative Mechanisms of CNS Neuroprotection
- •22.3.9 Conclusion
- •22.4 Mechanisms of Retinal Protection
- •22.4.1 Insights from In Vitro Models
- •22.5.1 Background to the Disease and the Associated Preclinical Data
- •22.5.2 Overview of the Clinical Development Program
- •References
- •23.1 Introduction
- •23.2 Pathogenesis
- •23.4 Pegaptanib
- •23.5 Bevacizumab
- •23.6 Ranibizumab
- •23.7.1 Ranibizumab
- •23.7.2 Bevacizumab
- •23.8 Comparison of AMD Treatment Trials (CATT)
- •23.9 Management of Nonresponders
- •23.11 Conclusion
- •References
- •24.1 Introduction
- •24.2 Rationale for Combination Therapy
- •24.3 Supporting Evidence for Combination Therapy
- •24.4 Currently Applied Combination Therapies
- •24.5 Challenges for Combination Therapy
- •References
- •25.1 Human Endothelial Progenitor Cells
- •25.3 Function of EPCs
- •25.3.1 EPCs in Vascular Repair and Neovascularization
- •25.4 EPCs in Diabetes
- •25.4.1 EPC as a Biomarker in Diabetes
- •25.4.1.1 EPC Dysfunction in Diabetes
- •25.4.1.2 Oxidative Stress and EPC Dysfunction in Diabetes
- •25.4.1.3 Therapeutic Angiogenesis by EPCs in Diabetic Retinopathy
- •25.5 Conclusion
- •References
- •26.1 Introduction
- •26.1.1 Nitric Oxide
- •26.1.2 Nitric Oxide Regulation
- •26.1.3 Nitric Oxide in Normal and Pathophysiological Conditions
- •26.2 Retinal Vascular Diseases: The Role of iNOS
- •26.2.1 Nitric Oxide in Diabetic Retinopathy
- •26.2.2 iNOS in Diabetic Retinopathy
- •26.2.2.2 iNOS and Leukocyte Adhesion to Retinal Vessels
- •26.2.2.3 iNOS and Retinal Cell Death
- •26.2.3 Proliferative Retinal Diseases
- •26.2.3.1 iNOS and Proliferative Retinal Diseases
- •26.2.3.2 iNOS and Ocular Neovascularization in Retinal Vascular Diseases
- •26.3 Conclusions
- •References
- •27.1 Introduction
- •27.2 Animal Model
- •27.2.1 LHP Preparation and Injection Procedure
- •27.2.2 Acridine Orange Digital Fluorography
- •27.3 Experimental Results
- •27.3.1 Leukocyte Rolling
- •27.3.2 Accumulated Leukocytes in the Retinal Microcirculation
- •27.3.3 Diameter of Major Retinal Vessels
- •27.3.4 SOD Treatment
- •27.4 Discussion
- •27.5 Conclusions
- •References
- •28.1 Introduction
- •28.1.2 Metabolism and Balance in Generation and Quenching of ROS
- •28.2 Role of Oxygen Concentration on Generation of ROS in the Developing Retina
- •28.3.1 Perinatal Considerations
- •28.3.2 Neonatal Considerations
- •28.3.2.1 Polyunsaturated Fatty Acids in Retina and Brain
- •28.3.2.2 Increased Oxidation
- •28.3.2.3 Reduced Antioxidant Enzyme Systems
- •28.3.3 Environmental Stimuli
- •28.3.3.1 Light
- •28.3.3.2 Oxygen Changes in Development and Prematurity
- •28.3.3.3 Nutrition
- •28.3.3.4 Effect of Blood Transfusions on Oxidative Stress in Prematurity
- •28.4 Evidence from Animal Models
- •28.4.1 Background
- •28.4.2 Effects of Hypoxia on Bioenergetic Oxygen Sensor Mechanisms and Related to ROP
- •28.4.2.2 NADPH Oxidase
- •28.4.2.3 Cytochrome p450 Monooxygenases (CYP)
- •28.4.2.4 eNOS
- •28.4.2.5 Heme Oxygenase
- •28.4.2.6 Metabolic Effects of Hypoxia
- •28.4.3 Laboratory Evidence of Antioxidants on Animal Models of ROP
- •28.5 Clinical Studies of Antioxidants on ROP
- •28.6 Genetics
- •28.7 Summary
- •References
- •29.1 Introduction
- •29.1.1 Oxidative Stress in Glaucoma
- •29.1.2 Oxidative Stress in Diabetic Retinopathy
- •29.1.3 Oxidative Stress in Age Related Macular Degeneration
- •29.1.4 Vascular Endothelial Growth Factor
- •29.1.5 VEGF Mediated Neuroprotection
- •29.1.6 Mechanisms of VEGF Protection Against Oxidative Stress
- •References
- •30.1 Introduction
- •30.1.1 Oxidation and Oxidative Stress
- •30.1.2 Reactive Oxygen Intermediates
- •30.1.3 ROIs and Cellular Retinal Damage
- •30.1.4 Light, Cellular Retinal Damage and AMD
- •30.1.5 Carotenoids
- •30.1.6 Chemistry of Carotenoids: Basic Structural Components
- •30.2 Building Blocks
- •30.3 The Polyene Backbone
- •30.5 Terminal Groups
- •30.5.1 Source of Macular Carotenoids
- •30.5.2 Macular Carotenoids: The Origins of Macular Pigment
- •30.5.3 The Functions of the Macular Carotenoids as Macular Pigment for AMD
- •30.6 Antioxidant Properties
- •30.6.1 The Functions of the Macular Carotenoids as Macular Pigment for Visual Performance
- •References
- •31.1 Introduction
- •31.2 Composition and Distribution
- •31.3 Selective Uptake and Deposition Process of MP
- •31.4 Measurements
- •31.4.1 Heterochromatic Flicker Photometry
- •31.4.4 Resonance Raman Spectroscopy
- •31.5 Antioxidant Mechanism of MP and Its Relation to Retinal Health and Disease
- •31.5.1 Oxidative Stress in Human Retina and the Antioxidant Mechanism of MP
- •31.5.2 MP in Human Eye Health and Disease
- •31.5.2.2 MacTel
- •31.5.2.3 Acuity
- •31.6 Ocular Carotenoid Supplementation Studies
- •31.7 Conclusion
- •References
- •Index
- •About the Authors
404 |
X. Cai et al. |
19.4.2Plants
Aged rice seeds treated by cerium nitrates enhanced the activities of enzymes associated with reduction of oxidative stress, thus increasing the respiration rate. They were added in fertilizers and increased harvest [42]. Supplementation of 0.5Ð10 mM cerium nitrate to the culture medium signiÞcantly increased the height, the dry weight and average number of ßower bolting [43]. Using 7 nm CeO2 nanoparticles to treat corn, tomato, cucumber, and alfalfa seeds signiÞcantly reduced germination rate but root growth and shoot elongation were signiÞcantly promoted. Furthermore, X-ray absorption spectroscopy (XAS) revealed that the nanoparticles were within root seedlings. ICP-OES (inductively coupled plasma-optical emission spectroscopy) demonstrated that nanoparticles remained in the same oxidation state (+4) after uptake by roots [44].
19.4.3Medical Usage
19.4.3.1Radioprotectants
Radiation is one of the commonly used strategies for cancer treatment. It is unique and efÞcient in killing the cancer cells, but new free radicals are produced during radiation treatment and are harmful to the normal cells near the treated site [34]. Amifostine is currently the only free radical scavenger for clinical applications to protect normal cells against radiation, but one major disadvantage of amifostine is its very short half-life in serum [34]. Radiation at a dose of 10 Gy to an immortalized normal breast epithelial cell line, CRL8798, and human breast carcinoma cell, MCF-7, caused 40Ð50% of cell death when cell viability was measured at 24 and 48 h. If the cells were pretreated with 10 nM CNPs 24 h prior to irradiation, CRL8798 cells were almost completely protected, whereas there was no statistically signiÞcant protection for MCF-7 cells. CNP concentrations ranging from 0 to 5 mM did not have signiÞcant toxic effects on CRL8798 cells, while a slight effect on MCF-7 cells was induced when concentrations were higher than 50 nM [34]. This suggests that CNPs can act as effective radioprotectants for normal tissues. Their long-term retention suggests that CNPs will be better than amifostine for protection of normal cells during radiation therapy [34]. In mouse models, nanoceria prevent high dose radiation-induced pneumonitis [45]. Dextran-coated cerium oxide nanoparticles (DNC) have been shown to be unable to regenerate at pH 4.0 and maintain a relatively high amount of Ce4+ for 10 days after H2O2 addition [21]. Lung (A-549) and breast cancer (BT-474) cells have been shown to upregulate glycolytic activity and lactic acid production which results in an acidic microenviroment [46]. Treatment with DNC before administering H2O2 and other biological relevant radicals produces no protection of the cancer cells but long-term cytoprotection to nontransformed surrounding normal cells [21].
