Implication of Oxysterols and Phytosterols in Aging and Human Diseases (Advances in Experimental Medicine and Biology, 1440)

This book provides basic knowledge of the biology, chemistry, and function of oxysterols and its derivatives as well as of phytosterols in numerous human diseases. The book is divided into six sections and begins with an introduction to the biological and chemical properties of oxysterols and its derivatives as well as phytosterols, their synthesis, and the methods currently used for their detection in various biospecimens. The following section discusses in detail the various effects of oxysterols on numerous human diseases, including infectious diseases, inflammatory and autoimmune diseases, atherosclerosis, and cancer, as well as neurological and neuropsychiatric disorders. Importantly, the potential of oxysterols as biomarkers for some of these diseases is also highlighted. The book concludes with an outlook on the pharmacological and nutritional effects of oxysterols and phytosterols and their potential use by the food, and pharmaceutical industries. Aiming to provide an in-depth overview of the biological and the chemical properties of oxysterols and phytosterols and their implications for human health, this book will be of interest to basic and clinical scientists, as well as to anyone working in the food or pharmaceutical industry who is exploring the potential of oxysterols and phytosterols. Preface References Contents About the Editor Part I: Chemical Characteristics 1: The Structure of Oxysterols Determines Their Behavior at Phase Boundaries: Implications for Model Membranes and Structure-A... 1.1 Model Techniques for Investigation of Oxysterols ́ Activity on Membrane Level 1.2 Characteristics of Pure Oxysterols at Phase Boundary 1.3 Interactions of Oxysterols with Selected Components of Cell Membranes 1.4 Investigation of Oxysterols Activity in Biomimetic Systems 1.4.1 Disturbing of Cholesterol Homeostasis 1.4.2 Influence on Lipid Rafts 1.4.3 Oxysterols in Neurodegeneration 1.4.4 Oxysterols Effect on Erythrocytes 1.4.5 Beneficiary Effects of Oxysterols 1.4.6 Investigation of Oxysterols Transport Between Membrane Leaflets References 2: Association of ABCG5 and ABCG8 Transporters with Sitosterolemia 2.1 Introduction 2.2 Sterol Transport 2.3 ABC Transporters 2.4 Main Diseases Related to ABC Transporters 2.5 ABCG5/G8 Transporter 2.5.1 ABCG5/G8 Transporter Genes 2.5.2 Characteristics of the ABCG5/G8 Transporter Structure 2.5.3 Observations on ABCG5/G8 Mutations 2.5.4 Function and Regulation of ABCG5/G8 2.6 Sitosterolemia References Part II: Bio- and Chemical- Synthesis, and Analytical Methods 3: Chemical and Biochemical Features of Spinasterol and Schottenol 3.1 Introduction 3.2 Δ7 Sterols Occurrence 3.3 Δ7 Sterols Chemistry 3.4 Δ7-Sterols Characterization 3.5 Spinasterol and Schottenol (Also Named Dihydrospinasterol) Characterization 3.6 Conclusion References 4: LC-MS Approaches for Oxysterols in Various Biosamples 4.1 Introduction Autoxidation 4.2 LC-MS of Oxysterols 4.2.1 How Are Oxysterols Separated? 4.2.2 How Are Oxysterols Transferred to the Mass Spectrometer? 4.3 Sample Cleanup Before LC-MS Analysis 4.4 Sample Preparation of Various Biosamples for LC-MS Analysis 4.4.1 Plasma and Serum 4.4.1.1 Analysis Without Derivatization 4.4.1.2 Analysis with EADSA Derivatization 4.4.1.3 Other Derivatization Approaches 4.4.2 Cultured Cells 4.4.3 Tissue 4.4.3.1 Brain Tissue 4.4.3.2 Breast Cancer Tissue 4.4.4 Exosomes 4.4.5 Organoids 4.5 Conclusion References 5: Mass Spectrometry Imaging of Cholesterol and Oxysterols 5.1 Introduction 5.2 MALDI-MSI and DESI-MSI of Cholesterol and Its Precursors 5.3 MSI of Sterols Exploiting Chemical Derivatization 5.4 Secondary Ion Mass Spectrometry (SIMS): MSI 5.5 Potential Use of MSI to Study the Involvement of Sterols in Disease 5.6 Conclusion References Part III: Implication in Aging and Human Diseases 6: Oxysterols in Central and Peripheral Synaptic Communication 6.1 Oxysterols Connected to Synaptic Transmission 6.2 24-Hydroxycholesterol as Endogenous Modulator of Neurotransmission in Central and Peripheral Synapses: The Role of NMDA Re... 6.2.1 Effects and Targets of 24-Hydroxycholesterol in Synapses of CNS 6.2.1.1 Synaptic Effects of CYP46A1 Modulation 6.2.1.2 Discovery of Glutamate NMDA Receptors as a Target for 24-Hydroxycholesterol 6.2.1.3 Using 24-HC and Its Analogs for Correction of NMDA Receptor Hypofunction 6.2.1.4 Inhibition of 24-Hydroxycholesterol Production as Strategy to Overcome Consequences of NMDA Receptor Hyperactivation 6.2.2 A Possible Neurohumoral Action of 24-Hydroxycholesterol on Peripheral Neurotransmission 6.2.2.1 The Role of NMDA Receptors and Nitric Oxide Synthases in Transduction of 24-Hydroxycholesterol Signal in Neuromuscular... 6.2.2.2 A Possible Role of 24-Hydroxycholesterol/Nitric Oxide Link in Amyotrophic Lateral Sclerosis 6.2.2.3 Nuclear Liver X Receptor as Target of 24-Hydroxycholesterol in Neuromuscular Junctions 6.2.2.4 Effects of 24-Hydroxycholesterol on beta-Adrenergic Signaling: A Possible Implication in Neurocardiac Coupling 6.3 The Role of 25-Hydroxycholesterol in Mediating the Effects of Inflammation on Synaptic Transmission 6.3.1 GABA and Glutamate NMDA Receptors as Targets of 25-Hydroxycholesterol in CNS 6.3.2 Role of 25-Hydroxycholesterol in Modulation of Structural and Functional Properties of Neuromuscular Junctions: A Contri... 6.4 27-Hydroxycholesterol, a ``Message ́ ́ from Periphery to Brain 6.5 Synaptic Action of Products of Cholesterol Oxidase Activity and Free Radical-Derived Oxysterols 6.5.1 Amyloid beta Peptide as Endogenous Cholesterol Oxidase 6.5.2 Effects of Non-enzymatically Generated Oxysterols on Neurotransmission-Related Targets 6.5.3 The Peripheral Synapses Under the Influence of Cholesterol Oxidase and Non-enzymatically Generated Oxysterols 6.6 Conclusion References 7: Oxysterols in Infectious Diseases 7.1 Introduction 7.2 The Role of Oxysterols in Respiratory Infections 7.2.1 Oxysterols in the Immune Response to Tuberculosis 7.2.2 Oxysterols in the Immune Response to SARS-CoV-2 and Influenza Infection 7.2.3 Antiviral Activity of Oxysterols in Cell Systems 7.3 The Role of Oxysterols in Infections of the Gastrointestinal Tract and Liver 7.3.1 Oxysterols and Viral Pathogens of the Gastrointestinal Tract 7.3.2 Role of Oxysterols in Hepatitis Virus Infection 7.3.3 Oxysterols and Bacterial Pathogens of the Gastrointestinal Tract 7.4 Implications of Oxysterols for Other Viruses and Cell Types 7.4.1 Herpesvirus Family 7.4.1.1 Herpes Simplex Virus 1 7.4.1.2 Varicella Zoster Virus 7.4.1.3 Murine Gamma Herpes Virus 7.4.1.4 Mouse Cytomegalovirus 7.4.1.5 Kaposi Sarcoma Herpesvirus 7.4.1.6 Epstein-Barr Virus 7.4.2 Human Immunodeficiency Virus 7.4.3 Zika Virus 7.4.4 Lassa Virus 7.5 Emerging Cellular Mechanisms of Oxysterols in Host Defence 7.5.1 Oxysterols Enhance Host Cell Resistance via Reduction of Membrane Accessible Cholesterol 7.5.1.1 A Brief Primer on Intracellular Cholesterol Trafficking and Accessible Cholesterol 7.5.1.2 Antagonism of Cholesterol-Dependent Cytolysins and Other Bacterial Exotoxins 7.5.1.3 Inhibition of Transcellular Pathogen Spread 7.5.1.4 Inhibition of Viral Fusion 7.5.2 Oxysterols Modulate Membrane-Dependent Immune Signalling 7.5.3 Mixed Effects of Oxysterols on Inflammasome Activation and IL-1beta Induction 7.5.4 Emerging Roles for 25-OHC in Efferocytosis 7.6 Conclusions References 8: The Cholesterol-5,6-Epoxide Hydrolase: A Metabolic Checkpoint in Several Diseases 8.1 Introduction 8.2 The ChEH Enzyme 8.3 5,6-ECs Formation and Stability 8.4 ChEH Substrates 8.5 Subcellular Localization, Tissue Distribution and Regulation of ChEH 8.6 Biological Functions of the ChEH 8.6.1 Biological Properties of CT and Its Metabolites 8.6.2 Biological Properties of 5,6β-EC and Its Metabolites 8.6.3 Biological Properties of 5,6α-EC and Its Metabolites 8.7 Regulation of ChEH 8.8 Conclusion References 9: Impact of Oxysterols in Age-Related Disorders and Strategies to Alleviate Adverse Effects 9.1 Introduction 9.2 Biogenesis and Associated Signaling Pathways of Oxysterols 9.2.1 Formation of Oxysterols by Auto-oxidation 9.2.2 Formation of Oxysterols by Enzyme Action 9.3 Major Classification of Oxysterols and Their Derivatives Implicated in Diseases 9.3.1 7-α Hydroxycholesterol 9.3.2 7-β Hydroxycholesterol 9.3.3 7-Ketocholesterol 9.3.4 25-Hydroxycholesterol 9.3.5 27-Hydroxycholesterol 9.3.6 5α, 6α-Epoxycholesterol 9.3.7 Cholesterol 3β, 5α, 6β Triol 9.3.8 5β, 6β-Epoxycholesterol 9.3.9 Cholesterol 3β, 5α, 6α Triol 9.4 Potential Role of Oxysterols in Age-Related Disorders 9.4.1 Cardiovascular Disorders 9.4.2 Brain Disorders 9.4.3 Eye-Related Disorders 9.4.4 Bone Disorders 9.4.5 Pancreatic Disorders 9.4.6 Cancer 9.5 Strategies for Mitigation of Oxysterol-Mediated Cytotoxicity 9.5.1 Natural Cytoprotective Molecules and Oils Against Oxysterols 9.5.2 Synthetic Cytoprotective Molecules Against Oxysterols 9.5.3 Biodegradation of Oxysterols 9.6 Future Prospects and Conclusion References 10: Enzymatically Formed Oxysterols and Cell Death 10.1 Enzymatically Formed Oxysterols 10.2 The Role of Oxysterols in Cholesterol Homeostasis 10.3 24S-OHC 10.3.1 24S-OHC and Brain Disorder 10.3.2 24S-OHC-Induced Neuronal Cell Death 10.3.3 24S-OHC-Induced Cell Death in Other Cell Types 10.3.4 Protective or Damage-Promoting Effects of 24S-OHC Against Other Cytotoxic Stimulations 10.4 25-OHC 10.4.1 25-OHC and Related Diseases 10.4.2 25-OHC-Induced Cell Death 10.5 27-OHC 10.5.1 27-OHC and Related Diseases 10.5.2 27-OHC-Induced Cell Death 10.6 Concluding Remarks References 11: Oxysterols in Vascular Cells and Role in Atherosclerosis 11.1 Introduction 11.2 Oxysterols in Atherosclerotic Plaque and in Serum from Patients with CVD 11.2.1 Levels of Oxysterols in Atheroma Plaque and Plasma of Atherosclerotic Subjects 11.2.2 In Vitro and In Vivo Formation of Oxysterols 11.3 Biological Effects of Oxysterols in Atherogenesis and Plaque Progression 11.3.1 Oxysterols and Foam Cell Formation 11.3.2 Oxysterol and Apoptosis/Autophagy/Oxyautophagy 11.3.3 Oxysterols and Inflammation 11.4 Mechanisms of Oxysterol Efflux 11.5 Conclusions References 12: Implication of Oxysterols and Phytosterols in Aging and Human Diseases 12.1 Oxysterols: Origin and Formation of Oxysterols 12.1.1 Neurodegenerative Diseases 12.1.1.1 Demyelinating Diseases 12.1.1.2 Non-demyelinating Diseases 12.1.2 Intestinal Diseases 12.1.3 Oxysterols in Cancer 12.1.4 Oxysterols in Cardiovascular Diseases 12.1.4.1 Atherosclerosis and Vascular Aging 12.1.4.2 Stroke 12.2 Phytosterols, Their Origin and Functions 12.2.1 Neurodegenerative Diseases 12.2.2 Intestinal Inflammation 12.2.3 Cancers 12.2.4 Atherosclerosis and Cardiovascular Diseases 12.2.5 Phytosterolemia 12.3 Conclusion References 13: Sterols in Inflammatory Diseases: Implications and Clinical Utility 13.1 The First and Foremost: Cholesterol 13.1.1 History of Cholesterol Research 13.2 Plant-Based Sterols in Inflammation and Inflammatory Diseases 13.2.1 Inflammation and Phytosterols 13.2.2 CVDs and Phytosterols 13.2.3 Hepatic and Intestinal Inflammatory Diseases and Phytosterols 13.2.4 Cancer and Phytosterols 13.3 Clinical Utility of Sterols in Humans 13.3.1 Beta-Sitosterol, Campesterol, and Stigmasterol 13.3.2 Clinical Use and Implications 13.3.3 Conclusion References 14: Role of Oxysterols in Ocular Degeneration Mechanisms and Involvement of P2X7 Receptor 14.1 Ocular Degeneration 14.1.1 Cataract 14.1.2 Glaucoma 14.1.3 Macular Degeneration 14.1.4 Diabetic Retinopathy 14.2 Oxysterols in Ocular Degeneration 14.2.1 Oxysterols 14.2.2 Oxysterols and Cataracts 14.2.3 Oxysterols and Glaucoma 14.2.4 Oxysterols and AMD 14.2.5 Oxysterols and Diabetic Retinopathy 14.3 The P2X7 Receptor and Ocular Degeneration 14.3.1 The P2X7 Receptor 14.3.2 P2X7 Activation and Ocular Degeneration 14.3.3 P2X7 Activation and Oxysterols 14.4 Conclusion References 15: 24S-Hydroxycholesterol in Neuropsychiatric Diseases: Schizophrenia, Autism Spectrum Disorder, and Bipolar Disorder 15.1 Introduction 15.2 NPDs Associated with High Levels of 24S-OHC 15.2.1 Schizophrenia 15.2.2 Autism Spectrum Disorder 15.3 NPD Associated with Low Levels of 24S-OHC 15.3.1 Bipolar Disorder 15.4 Pharmacologic Targeting of 24S-OHC Levels 15.4.1 Pharmacological Inhibition of CYP46A1 15.4.2 Pharmacologic Activation of CYP46A1 15.5 Conclusion References Part IV: Biomarkers, Therapeutic and Industrial Applications 16: Oxysterols as Biomarkers of Aging and Disease 16.1 Introduction 16.2 Oxysterols and Ageing 16.3 Oxysterols in Neurodegenerative Diseases 16.4 Oxysterols in Cardiovascular Diseases 16.4.1 Atherosclerosis 16.4.2 Coronary Artery Diseases (CAD) 16.4.3 Heart Failure 16.5 Oxysterols and Cancer 16.5.1 Oxysterols and Breast Cancer 16.5.2 Oxysterols and Gastrointestinal Tract Malignancies 16.5.2.1 Hepatocellular Carcinoma 16.5.2.2 Colorectal Cancer 16.5.2.3 Pancreatic and Bile Duct Cancer 16.5.3 Oxysterols and Lung Cancer 16.5.4 Oxysterols and Prostate Cancer 16.5.5 Oxysterols as Antineoplastic Agents 16.6 Oxysterol and Metabolic Diseases 16.7 Oxysterols and Degenerative Diseases of the Eye 16.7.1 Age-Related Macular Degeneration (AMD) 16.7.2 Glaucoma 16.8 Conclusion References 17: The Diagnostic Use of the Plasma Quantification of 24S-Hydroxycholesterol and Other Oxysterols in Neurodegenerative Disease 17.1 Cholesterol 17.2 Brain Cholesterol 17.3 Brain Cholesterol Transport 17.4 Turnover of Brain Cholesterol and Conversion into 24S-Hydroxycholesterol 17.5 Plasma Oxysterols in Neurodegenerative Diseases 17.6 Other Oxysterols 17.7 Conclusion References 18: Oxy- and Phytosterols as Biomarkers: Current Status and Future Perspectives 18.1 Oxysterol Analytics Causes Challenges in Their Use as Biomarkers 18.2 Prospects in the Use of Oxysterols as Cardiovascular Biomarkers 18.3 Do Oxysterols Hold Promise for the Diagnostics of Neurological Diseases? 18.3.1 Alzheimer ́s Disease (AD) 18.3.2 Multiple Sclerosis (MuS), Parkinson ́s Disease (PD), and Huntington ́s Disease (HD) 18.3.3 Niemann-Pick C Disease (NPC) and Spastic Paraplegia Type 5 (SPG5) 18.3.4 Amyotrophic Lateral Sclerosis (ALS) 18.3.5 Smith-Lemli-Opitz Syndrome (SLOS) 18.4 Oxysterols as Biomarkers for Cancer: Future Perspectives 18.4.1 Breast Cancer (BC) 18.4.2 Other Cancers 18.5 Conclusions on Oxysterols as Biomarkers 18.6 Phytosterols 18.6.1 Phytosterols and Phytostanols and Their Presence in Food 18.6.2 Phytosterol and Phytostanol Metabolisms in Humans 18.6.3 Cholesterol Homeostasis and High Cholesterol Absorption 18.7 Phytosterols as Serum Biomarkers of Cholesterol Absorption 18.7.1 The Definition of a Biomarker 18.7.2 Serum Phytosterols and Cholesterol Absorption 18.7.3 Do the Serum Sitosterol, Campesterol, and Cholestanol Ratios to Cholesterol Fulfill the NIH Definitions for a Biomarker? 18.7.4 The Caveats Related to the Use of Phytosterols as Serum Biomarkers of Cholesterol Absorption 18.8 Future Perspectives of Phytosterols as Serum Biomarkers of Cholesterol Absorption References Part V: Pharmacological Applications 19: Therapeutic Applications of Oxysterols and Derivatives in Age-Related Diseases, Infectious and Inflammatory Diseases, and ... 19.1 Oxysterols: From Key Players in Various Diseases to Therapeutic Applications 19.2 Pharmacological Interest of Oxysterols and Derivatives in Age-Related Diseases 19.2.1 Eye Diseases 19.2.1.1 Cataract 19.2.1.2 Age-Related Macular Degeneration 19.2.2 Alzheimer ́s Disease 19.2.3 Osteoporosis 19.3 Oxysterols and Derivatives in the Pathophysiology and Treatment of Infectious Diseases 19.4 Oxysterols and Derivatives in Inflammatory Diseases and Immunotherapy 19.5 Oxysterols and Derivatives in Cancer: Focus on New Therapeutic Tools and Concept of Metabolic Therapy 19.5.1 Breast Cancer 19.5.2 Glioblastoma 19.5.3 Myeloma 19.5.4 Non-Small Cell Lung Cancer 19.5.5 Prostate Cancer 19.5.6 Other Types of Cancers 19.6 Conclusion and Perspectives References Part VI: Industrial Aspects 20: Current and New Insights on Delivery Systems for Plant Sterols in Food 20.1 Introduction 20.2 PS Characteristics 20.2.1 Biological Effects 20.2.2 Main Industrial Sources 20.2.3 Physical and Chemical Properties 20.2.4 Industrial Chemical Modifications for Food Applications 20.3 Theoretical Aspects of Delivery Systems 20.3.1 Emulsions 20.3.2 Liposomes 20.3.3 Solid Lipid Nanoparticles and Nanostructured Lipid Carriers 20.3.4 Gels 20.3.5 Complex Coacervation 20.3.6 Inclusion Complexation: Cyclodextrins 20.3.7 Other Techniques for Encapsulation: Powdered Forms 20.3.8 Characterization of Delivery Systems 20.3.8.1 Size 20.3.8.2 Electrical Characteristics 20.3.8.3 Physical State 20.4 Current Delivery Systems for PS Encapsulation 20.4.1 Encapsulation Efficiency and Stability 20.4.2 Encapsulated PS Bioaccessibility 20.5 Conclusions and Future Perspectives for Industrial PS Encapsulation References 21: In Vitro Evaluation of the Effects of 7-Ketocholesterol and 7β-Hydroxycholesterol on the Peroxisomal Status: Prevention of... 21.1 Introduction 21.2 Evaluation of the Effects of 7-Ketocholesterol and 7β-Hydroxycholesterol on the Peroxisomal Status 21.2.1 Effects of 7-Ketocholesterol and 7β-Hydroxycholesterol on the Peroxisomal Topography and Morphology 21.2.2 Effects of 7-Ketocholesterol and 7β-Hydroxycholesterol on the Peroxisomal Mass 21.2.3 Effects of 7-Ketocholesterol and 7β-Hydroxycholesterol on the Peroxisomal Activity 21.2.4 Impact of 7KC and 7β-Hydroxycholesterol on the Expression of Peroxisomal Genes Associated with Peroxisomal Biogenesis, ... 21.3 Prevention of 7-Ketocholesterol- and 7β-Hydroxycholesterol-Induced Peroxisomal Changes: Interest of Nutrients (ω3 Fatty A... 21.4 Conclusions References 22: Phytosterols: Potential Therapeutic Effects and Challenges in Food Industry 22.1 Introduction 22.2 Bioavailability of Phytosterols 22.3 Therapeutic Effects of Phytosterols 22.3.1 Anti-Leishmania Effects 22.3.2 Cholesterol Control and Cardiovascular Disease Prevention 22.3.3 Anticancer Effects 22.4 Enrichment of Phytosterols in Food Matrices in Food Industry 22.5 Conclusions References Advances in Experimental Medicine and Biology provides a platform for scientific contributions in the main disciplines of the biomedicine and the life sciences. 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