Pharmacoepigenetics

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Translational Epigenetics Series
PHARMACOEPIGENETICS
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Contributors
Preface
1
The Epigenetic Machinery in the Life Cycle and Pharmacoepigenetics
	Introduction
	The Epigenetic Machinery
		DNA Methylation
		DNA Demethylation
			Ten-Eleven Translocation (TET) Proteins
			AID/APOBEC Family Cytidine Deaminases
			BER (Base Excision Repair) Glycosylases
		Chromatin Remodeling and Histone Modifications
			Chromatin
				Genome-Wide Chromatin Conformation, Spatial Organization, and 3D Genomics
			Histones
			Posttranslational Modifications
				Histone Methylation-Demethylation
				Histone Acetylation
				Histone Deacetylation
					Sirtuins
				Histone Acylation
				Histone Propionylation
				N-Glycosylation and O-GlcNAcylation
				Ubiquitination-Deubiquitination
				SUMOylation
				Histone Phosphorylation-Dephosphorylation
				Histone Chaperonization
				Glutathionylation
				Poly ADP-Ribosylation
				Oxidative Stress
			Other Posttranslational Changes
			Noncoding RNAs
				miRNAs
				circRNAs
				RNA Methylation
			Other Operational Elements of the Epigenetic Machinery
				DNA Replication Regulators
				N6-Adenine DNA Methylation
				Transcription Factors
				Transcriptional Repression
				Polycomb Group Proteins: Polycomb Repressive Complex 2 (PRC2)
				BET (Bromodomain and Extraterminal Domain) Proteins
				UHRF1
				Plant Homeodomain (PHD) Fingers
				HDACs
				Chromatin-Remodeling Factors
				Heterochromatin and Gene Silencing
				MEN1
				NPC, HOXA, and Nup93
				CCR4
				HP1
				TORC1
				WDR5
				Nudt21
				Trithorax-Group Proteins
				SUUR Protein
				Kap123
				SET Complex
				Histone Code Reader Spin1
				Proteasome
				Lipid Mediators
				Transposable Elements
				Intragenic Enhancers
				Genomic Regulatory Regions
	Singular Epigenetic Phenomena
		Aneuploidy
		X Chromosome Inactivation
		Meiotic Silencing
		RNA Splicing
		Copy Number Variation (CNV)
		The Epigenetic Clock
		Epigenetic Reprogramming Memory
		Transgenerational Epigenetic Inheritance
		DNA Repair Pathways and Genomic Instability
		Antibody Maturation
		Sexual Dimorphism
		Heritable RNAi
		Genomic Imprinting
	Evolution
	Population Epigenetics
	Fertility and Gestation
		In Vitro Fertilization and Assisted Reproduction Technology
	Placenta
	Lactation
	Development
	Maturation, Aging, and Longevity
		Telomeres
	Epigenetic Mendelian Disorders
	Pharmacoepigenetics Network
	Conclusions
	References
2
Pharmacoepigenetics: Basic Principles for Personalized Medicine
	Introduction: Personalized or Precision Medicine?
	Pharmacogenomics: The Core Discipline of Personalized Medicine
	Pharmacoepigenetics: An Additional Layer of Regulatory and Environmental Exposure Information Affecting Individual D ...
	Pharmacoepigenetics in Personalized/Precision Medicine
		Epigenetic Biomarkers of Drug Response
			DNA Methylation Markers
			MicroRNA Markers
		Epigenetic Drugs
	Epigenetic Tools in Personalized Cell Therapy
	Conclusions and Perspectives
	References
3
Epigenetic Mechanisms in the Regulation of Drug Metabolism and Transport
	Introduction
	Epigenetic Mechanisms
		DNA Methylation
		Chromatin Remodeling
		Noncoding RNAs
	Epigenetic Regulation of Genes Associated With Drug Metabolism and Transport (Pharmacoepigenetics)
		Epigenetic Modifications of Genes Encoding Phase I Drug-Metabolizing Enzymes
			Epigenetic Regulation During Sexual Differentiation
			Epigenetic Regulation During Development in Healthy and Cancer Cells
			Toxicoepigenetics Affecting Genes of Phase I Drug-Metabolizing Enzymes
		Epigenetic Modifications of Genes Encoding Phase II Drug-Metabolizing Enzymes
		Epigenetic Modifications of Genes Encoding Drug Transporters
		Epigenetic Modifications Involving Nuclear Receptors and Transcription Factors
	Epigenetics of Drug Resistance
		Drug Resistance Mediated by DNA Methylation in Transporter Genes
		Drug Resistance Mediated by Other Genes
		Drug Resistance Mediated by Chromatin Remodeling
		Drug Resistance Mediated by miRNAs
	Conclusions and Future Directions
	References
4
MicroRNA-Dependent Gene Regulation of the Human Cytochrome P450
	Introduction
	Molecular Mechanisms for the Regulation of CYP Expression by miRNAs
	Methods for Investigating the Regulation of CYP Expression by miRNAs
		In Silico Predictions of miRNA-CYP Regulatory Interactions
		Techniques for Characterizing miRNA-CYP mRNA Regulatory Interactions In Vitro
		Strategies for Characterizing miRNA-CYP mRNA Regulatory Interactions In Vivo
	Clinical Implications
		miRNAs as Biomarkers for CYP-Dependent Drug Efficacy
		miRNAs as Biomarkers for CYP-Dependent Drug Safety
		miRNA-Based Therapies Involving CYP Expression
	Conclusions
	References
5
Pathoepigenetics: The Role of Epigenetic Biomarkers in Disease Pathogenesis
	Introduction
	Cardiovascular Disorders
	Atherosclerosis
	Hypertension
	Venous Thromboembolism
	Cancer
		Breast Cancer
		Colorectal Cancer
		Hepatocellular Carcinoma
		Gastric Cancer
		Urogenital Carcinoma
		Prostate Cancer
		Ovarian Cancer
		Cervical Cancer
		Head and Neck Squamous Cell Carcinoma
		Lung Cancer
		Melanoma
		Esophageal Squamous Cell Carcinoma
		Myelodysplastic Syndromes
		Leukemia
		Lymphoma
		Multiple Myeloma
		Other Modalities of Cancer
			Oral Carcinoma
			Testicular Teratoma
			Bladder Cancer
			Neuroendocrine Tumors
			Parathyroid Carcinoma
			Cholangiocarcinoma
			Pancreatic Cancer
			Pheochromocytomas and Paragangliomas
			Pituitary Tumors
			Ewing Sarcoma
			Osteosarcoma
			Chondrosarcoma
			Polycystic Ovary Syndrome
	Metabolic Disorders
		Lipid Metabolism
		Obesity
		Diabetes
			Diabetic Retinopathy
			Diabetic Vasculopathy
			Gestational Diabetes
		Malnutrition and Starvation
		Metabolic Syndrome
	Immunological and Inflammatory Disorders
		Asthma
		Rheumatoid Arthritis
		Gout
		Systemic Lupus Erythematosus
		Psoriasis
		Inflammatory Bowel Disease
		Allergy
		Atopic Dermatitis
	Other Pathoepigenetic Disorders
		Bronchopulmonary Dysplasia
		Bone Disease
		Wilson Disease
		Kawasaki Disease
		Glaucoma
		Dyskeratosis Congenita
		Organ Fibrosis
		Liver Fibrosis
		Alcoholic Liver Disease
		Vitamin D Deficiency
		Autoimmune Disorders
		IgA Nephropathy and Henoch-Schönlein Purpura
		Systemic Sclerosis
		Infectious Disease
		Thyroid Disorders
		Pseudohypoparathyroidism
		Preeclampsia
		Preterm Birth
		Periodontitis
		Ulcerative Colitis
		Chronic Obstructive Pulmonary Disease
		Neural Tube Defects
		High Altitude-Associated Disorders
		Bruxism
		Rare Syndromes
			Mayer-Rokitansky-Küster-Hauser Syndrome
			Silver-Russell Syndrome
			Lipodystrophic Syndromes
			Scleroderma
		Organ Transplantation-Related Allograft Injury
	Gut Microbiome
	Pluripotent Stem Cells
	Epigenetic Biomarkers
	Conclusions
	References
6
Pharmacoepigenetic Processors: Epigenetic Drugs, Drug Resistance, Toxicoepigenetics, and Nutriepigenetics
	Introduction
	Pharmacoepigenetics Apparatus
		Pathogenic Genes
		Mechanistic Genes
		Metabolic Genes
		Transporter Genes
	Epigenetic Drugs
		Classification of Epigenetic Drugs
		DNA Methyltransferase Inhibitors
			Azacitidine
			5-Aza-2-Deoxycytidine (5-aza-dC) (Decitabine)
			5-Aza-2,2-Difluorodeoxycytidine (NUC013) and 3,5-Di-Trimethylsilyl-2,2-Difluoro-5-Azadeoxycytidine (NUC041)
			Guadecitabine (SGI-110)
			2-Amino-4-Halopyridine-C-Nucleosides (dXP) and Oligodeoxyribonucleotides (ODNs)
			Genipin
			Genistein
			Luteolin and Fisetin
			(-)-Epigallocatechin-3-Gallate (EGCG), Gallic acid, and Fermented Oolong Tea
			Zebularine
			DNMT-G9a Dual Inhibitors
			Maleimide Derivatives of RG108
			DNMT3A Inhibitors
		Histone Deacetylase (HDAC) Inhibitors
			Hydroxamic Acids
			Suberoylanilide Hydroxamic Acid (SAHA) (Vorinostat)
			Sodium Butyrate
			Trichostatin (TSA)
			Mocetinostat
			Belinostat
			Panobinostat
			Valproic Acid
			JSL-1
			RGFP966
			Pazopanib Hybrids
			m-Carboxycinnamic Acid Bishydroxamide
			Sirtuin Inhibitors
			Spirohydantoins and 1,2,4-Triazole-3-Carboxamide Derivatives
			α,β-Unsaturated Carboxylic Acid and Urea-Based Derivatives
			Carbamates
			N-Substituted 7-Aminoheptanohydroxamic Acid-Based HDAC Inhibitors
			Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors
			Abexinostat
			Polyoxometalates (PC-320)
			Macrocyclic Nonribosomal Peptide HDAC Inhibitors
			Chidamide
			Cd[l-Proline]2
			Tetrahydroisoquinoline-Based HDAC Inhibitor
			Dithienylethenes and Fulgimides
			Isatin/o-Phenylenediamine-Based HDAC Inhibitors
			Benzodiazepine Derivatives
			7-Ureido-N-Hydroxyheptanamide Derivative (CKD5)
			Phenylpyrrole-Based Derivatives
			Resveratrol
			2-[18F]Fluoroethyltriazolesuberohydroxamine Acid
			Dual/Hybrid Inhibitors
			Triple Inhibitors
		Histone Acetyltransferase (HAT) Inhibitors
		Histone Methyltransferase Inhibitors
			S-Adenosylmethionine (SAM)
			SMYD2 Inhibitors
			SET7/9 Inhibitors
			Polycomb Repressive Complex 2 (PRC2) Inhibitors
			EZH2 Inhibitors
			PKMT SUV420H1 and SUV420H2 Inhibitors
			PRMT Inhibitors
			CARM1 Inhibitors
			DOT1L Inhibitors
			Histone Lysine Methyltransferases G9a Inhibitors
			Trimethyllysine Analogs
			Verticillin A
			Difluorinated Propanediones
		Histone Demethylase Inhibitors
			Lysine-Specific Demethylase 1 (LSD1) Inhibitors
			KDM1 Inhibitors
			KDM3 Inhibitors (JMJD3 Histone Demethylase Inhibitors)
			KDM4 Inhibitors
			KDM5 Inhibitors
			KDM6 Inhibitors
			Tranylcypromine Derivatives
			Plant Homeodomain (PDH) Inhibitors
			PHF8 Inhibitors
		Bromodomain Inhibitors
	Other Pharmacoepigenetics-Related Products
		Polycomb Group Protein BMI-1 Inhibitor PTC-209
		All-Trans Retinoic Acid (ATRA)
		Engrailed 1 Interference Peptides (EN1-iPeps)
		TET2 Disruptors
		GCN5 Inhibitors
		RRx-001
		Crambescidin 800
		Ginkgolic Acid
		Corosolic Acid
		Puerarin
		Terrein
		Naringenin
		Eriocitrin
		Berberine
		Thymoquinone
		Vitamin E Phosphate Nucleoside Prodrugs
		Matrine
		Taxifolin
		3,3-Diindolylmethane
		Hydrogen Sulfide
		N-Acetylcysteine
		CPUK02 (15-Oxosteviol Benzyl Ester)
		Silibinin
		Dihydroartemisinin
		miRNA/UHRF1 Pathway Modulators
		1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidine-4-yl) Urea (TPPU)
		Suxiao Jiuxin
		trans-2-Phenylcyclopropylamine (2-PCPA)
		Ivermectin
		Senataxin
		Nanaomycin A
		Strigolactone Analogs
		Betaine
		d-2-Hydroxyglutarate
		β-Hydroxybutyrate
		Astaxanthin and Fucoxanthin Carotenoids
		Plant Alkaloids
		Spindlin1 Inhibitors
		Organoruthenium Compounds
	lncRNAs, miRNAs, and Derived Technologies
	Pharmacogenetics of Epigenetic Drugs
	Pharmacoepigenetic Effects of Selected Therapeutic Interventions
		Anticancer Strategies
			Aurora Kinase A Oncogene-H3K9 Combined Inhibition
			p38α Inhibitors and Taxanes
			Bortezomib
			Sorafenib
			Imatinib
			Ibrutinib
			Doxorubicin
			Methotrexate
			Polo-Like Kinase 4 (PLK4) Inhibitors
			Baicalin
			Sulforaphane
			Withaferin A
			α-Lipoic Acid
			PLK1 Inhibitors
			Proteasome Inhibitors
			Selenium Compounds
			Epigenetic Silencing of O-6-Methylguanine-DNA Methyltransferase
			Cancer Immunotherapy
			Synergistic and Multimodal Strategies
				Liver Cancer
				Pancreatic Cancer
				Myeloproliferative Neoplasms and Myeloid Leukemia
				Thyroid Cancer
				Lymphoma
				Acute Lymphocytic Leukemia
				Urothelial Carcinoma
				Sarcoma
				Prostate Cancer
				Breast Cancer
				Melanoma
				Glioma
				Colorectal Cancer
				Renal Carcinoma
				Other Neoplasms
		Immunosuppressants
			Rapamycin
			Tacrolimus and Mycophenolic Acid
		β2-Adrenoreceptor Agonists (Formoterol) and Glucocorticoids
		Nonsteroidal Antiinflammatory Drugs (NSAIDs)
		Paracetamol
		Aspirin
		Psychotropic Drugs
		Acetylcholinesterase Inhibitors
		Morphine
		5-HT2CR Antagonist SB243213/5-HT2CR Inverse Agonist SB206553
		Statins
		Telmisartan and Esculetin
		Metformin
		Allopurinol
		Antiprogeroid Treatments
		Granulocyte Colony-Stimulating Factor
		α-Oxoglutarate
		Melatonin
		Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2)-Driven Histone Crotonylation
		Antisense Oligonucleotides
		Plasmids
		Programmable Epigenetic Editors
		Nanoparticles
		Stem Cell Therapy
		CRISPR-Related Personalized Therapy
	Drug Resistance
		Glioma and Glioblastoma
		Lung Cancer
		Breast Cancer
		Bladder Cancer
		Prostate Cancer
		Chronic Myeloid Leukemia
		Acute Myeloid Leukemia
		Acute Lymphoblastic Leukemia
		Lymphoma
		Multiple Myeloma
		Pancreatic Carcinoma
		Colorectal Cancer
		Tongue Carcinoma
		Hepatocellular Carcinoma
		Osteosarcoma
		Esophageal Carcinoma
		Renal Cancer
		Melanoma
		Coronary Artery Disease
	Pharmacoepigenetic Predictors of Drug Efficacy and Safety
		Bevacizumab
		Trastuzumab
		Platinum
		Cisplatin
	Toxicoepigenetics
		Drugs
			Morphine
			Heroin
			Cocaine
			Amphetamines
			3,4-Methylenedioxymethamphetamine (MDMA)
			Phencyclidine
			Cannabis and Delta9-Tetrahydrocannabinol (THC)
			Glucocorticoids
			Oral Contraceptives
			Estradiol-17β
			Experimental Hepatotoxicants: Clofibrate and Phenobarbital
			Oxytetracycline
			Permethrin
			Antiepileptic Drugs
			Tetanus Vaccination
		Metals
			Arsenic and Related Compounds
			Lead
			Mercury
			Chromium
			Nickel
			Cadmium
			Titanium and Zirconium
		Phthalates
		Pesticides
		Herbicides
		Fungicides
		Dioxin
		N,N-Diethyl-m-Toluamide (DEET) and Fluocyanobenpyrazole (Fipronil)
		Furan
		Sarin
		Perfluorooctyl Sulfonate
		1-Trichloromethyl-1,2,3,4-Tetrahydro-β-Carboline
		Benzene and Fuel-Related Pollutants
		Sulfur Mustard
		Endocrine-Disrupting Compounds (EDCs)
			Bisphenol A (BPA)
		Polychlorinated Biphenyls (PCBs)
		Polybrominated Diphenyl Ethers
		Polycyclic Aromatic Hydrocarbons (PAHs)
		Organophosphate (OP) Flame Retardants
		1,3-Butadiene
		Vinyl Chloride Monomer
		Crude Oil
		Asbestos
		Tobacco and Cigarette Smoking
		Alcohol
		Ochratoxin A
		Air Pollution and Particulate Matter
		Ionizing Radiation
		Laser Irradiation
		Low-Frequency Magnetic Fields
	Nutriepigenetics
		Maternal Diet
			Body Weight and Lipid Metabolism
			Brain Maturation and Function
		Enteral Feeding
		Vitamin B
		Vitamin C
		Vitamin D
		Folic Acid
		Methionine
		Niacin
		Antioxidants
		Manganese
		Zinc
		Omega-3 Polyunsaturated Fatty Acids
		Hybrid Palm Oil
		Buttermilk and Krill Oil
		Olive Oil
		Hydroxytyrosol
		Polyphenols
		Brassica Derivatives
		Coffee
		Sucrose
		Fruit vs Juice
		Mediterranean Diet
		Western-Style Dyslipidemic Diet
		Dietary Fiber
		Astragalus Polysaccharides
		Epigenetic Nutraceuticals
		Age-Related Changes
		Caloric Restriction
		Chemopreventive Nutriepigenetics
	Conclusions
	References
7
Pharmacoepigenetics of Novel Nucleoside DNA Methyltransferase Inhibitors
	Introduction
	Approved DNMT Inhibitors
		5-Aza-2-Deoxycytidine (Decitabine)
		5-Azacytidine
	DNMT Inhibitors in Clinical Development
		Guadecitabine
		5-Fluoro-2-Deoxycytidine
		4-Thio-2-Deoxycytidine
	DNMT Inhibitors in Preclinical Development
		5-Aza-2,2-Difluoro-2-Deoxycytidine
		3,5-Di-Trimethylsilyl-2,2-Difluoro-5-Aza-2-Deoxycytidine
		5,6-Dihydro-5-Aza-2-Deoxycytidine
		Pyrimidin-2-One β-D-Ribofuranoside (Zebularine)
		5-Azacytidine-5-Elaidate
	Conclusion
	Acknowledgments
	References
8
Pharmacoepigenetics: Novel Mechanistic Insights in Drug Discovery and Development Targeting Chromatin-Modifyin ...
	Introduction
	Epigenetic Mechanisms
		Epigenetics in Cancer
		Histone Modification
		Histone Acetyltransferases
		Histone Deacetylases
		Histone Modification Leads to Cancer
		Molecular-Targeted Therapies for Histone Deacetylase
		Histone Deacetylase Enzymes as a New and Emerging Target for Cancer Treatment
	Histone Deacetylase Inhibitors
		Classification of Histone Deacetylase Inhibitors
		Histone Deacetylase Inhibitor Mechanisms of Action
		Histone Deacetylase Inhibitors in Clinical Trials
	Designing Pharmacophore-Based HDAC Inhibitors
	Peptide-Based Macrocyclic Histone Deacetylase Inhibitors
	Pharmacophore-Based Design and Development of Inhibitors Targeting Chromatin-Modifying Enzymes
	Conclusion
	References
9
Pharmacoepigenetics of EZH2 Inhibitors
	Polycomb Group Proteins
	EZH2
	Regulation of EZH2 From Transcription to Translation
	PRC2-Mediated EZH2 Targets
	EZH2 Targets Outside PRC2
	Common EZH2 Mutations
	Viral Interactions and EZH2
	Categories of EZH2 Inhibitors
		S-Adenosyl-l-Homocysteine Hydrolase Inhibitors
		S-Adenosylmethionine (SAM)-Competitive Inhibiting Compounds
		Inhibitors That Disrupt PRC2 Stability
	References
10
Regulators of Histone Acetylation: Bromodomain Inhibitors
	Introduction
	BET Family Proteins
		Features of BET Family Proteins and Potential Value as Therapeutic Targets
		Discovery of BET Bromodomain Inhibitors
		Kac-Binding Site Structure
		Kac Recognition Motifs for BET Bromodomain Inhibitors
		BET Bromodomain Inhibitors as Candidate Therapeutic Agents
	Polypharmacology
		Polypharmacological Agents Targeting Multiple Proteins
			Dual Kinase/BET Inhibitors
			Dual HDAC/BET Inhibitors
		Polypharmacological Agents Targeting Multiple Functional Mechanisms
			Inducers of BET Degradation
	Non-BET Bromodomain Inhibitors
	Conclusions and Prospects
	References
11
Bromodomain Inhibition and Its Application to Human Disease
	The Role of Histones in Chromatin-Signaling Pathways
		Histones and Their Posttranslational Modifications
		Installation and Removal of Histone Modifications
		Drugging Epigenetic Writers and Erasers
	Bromodomains and Their Inhibitors
		Structure and Functions of Bromodomains
		The Discovery of Bromodomain Inhibitors
		Inhibitors of BET Bromodomains
		Inducing Proteolysis With BET Inhibitors
		Bivalent BET Inhibitors
		Inhibitors Targeting Other BRD Families
	BET Bromodomain Inhibition in Pathological Contexts
		BET Inhibitors in Cancer
		BET Inhibitors in Inflammation
		BET Inhibitors in Cardiovascular Diseases
	Bromodomain Inhibition and Protozoal Infections
		Bromodomains in Parasitic Protozoa
		Inhibiting Bromodomains of Parasitic Protozoa
	Bromodomain Inhibition and Fungal Infections
		Fungal BET Bromodomains
		Inhibition of Fungal BET Bromodomains
	Bromodomain Inhibition and Viral Infections
	Future Directions
	Acknowledgments
	References
12
Epigenetic Drug Discovery for Cancer
	Introduction
	Bromodomain (BRD) Proteins and Their Interaction With Small-Molecule Inhibitors in Cancer
	Histone Acetyltransferases and Their Interaction With Small-Molecule Inhibitors in Cancer
	Histone Deacetylases and Their Interaction With Small-Molecule Inhibitors in Cancer
	Sirtuins and Their Interaction With Small-Molecule Activators/Inhibitors in Cancer
	References
13
Pharmacoepigenetics of Histone Deacetylase Inhibitors in Cancer
	Introduction
	Histone Acetylation and Deacetylation
	Histone Deacetylases
		Class I
		Class II
		Class III
		Class IV
	Histone Deacetylase Inhibitors
		Hydroxamic Acids
		Short Chain Fatty (Aliphatic) Acids
		Cyclic Peptides
		Benzamides
		Sirtuin Inhibitors
	Histone Deacetylase Inhibitors: Mechanism of Action
		Damage and Repair of DNA
		Alteration in Gene Expression
		Interruption of Cell Growth
		Induction of Apoptosis
		Disorder of Mitosis
		Reactive Oxygen Species (ROS) Reduction-Oxidation Changes
		Activation of HDAC6 and Target Proteins
		Antiangiogenesis
		Antimetastatic Effect
		Glucose Metabolism
		Induction of Autophagy
	Conclusion
	References
14
Pharmacoepigenetics of LSD1 Inhibitors in Cancer
	Introduction
	LSD1-Mediated Demethylation of Histone Lysines
	The Development of LSD1 Inhibitors for Cancer Therapy
		Irreversible Inhibitors
		Reversible Inhibitors
			Natural Products
			Nonnatural Inhibitors
	Conclusions
	References
15
Pharmacoepigenetic Considerations for the Treatment of Breast Cancer
	Breast Cancer
		Classification
		Interindividual Variability in Treatment Response
	Pharmacoepigenetics of Breast Cancer
		miRNA
		DNA Methylation
		Histone Modifications
	Role of Circulating Pharmacoepigenetic Biomarkers
	Epidrugs in Breast Cancer
	Conclusion
	References
16
Pharmacoepigenetics of Acute Myeloid Leukemia
	Introduction
	Epigenetic Mechanisms in AML
		Histone Acetylation and Methylation
		DNA Methylation and Hydroxymethylation
	Epigenetic Modifiers in AML Therapy
		Histone Deacetylase (HDAC) Inhibitors
		Bromodomain Inhibitors
		DOT1L Inhibitors
		Lysine-Specific Demethylase (LSD1) Inhibitors
		DNMT Inhibitors
		Isocitrate Dehydrogenase (IDH) Inhibitors
	Epigenetic Modifiers as Primers of Induction Therapy of AML
	Epigenetic Modifiers as Primers of AML Immunotherapy
		Basis for Immunotherapy of AML
		Rationales for Epigenetic Priming in Immunotherapy
	Concluding Remarks
	References
17
Therapeutic Potential of Pharmacoepigenetics in Cholangiocarcinoma
	Introduction
	Personalizing Epigenetic Therapy in Cholangiocarcinoma
		Epigenomic Heterogeneity in CCA
		CCA Patient Stratification for Epigenome-Targeted Therapies
	Contextualizing Epigenetic Therapy in Cholangiocarcinoma
		New Mechanisms for Old Pathways: Oncogenes and Tumor Suppressors in CCA
		Differentiation Therapy in CCA
		Immune Modulation in CCA
		Preventative Management in CCA
		Modulation of Metastasis in CCA
		Chemosensitization in CCA
	Conclusions and Future Directions
	References
18
Pharmacoepigenetics in Type 2 Diabetes Mellitus
	Overview of Type 2 Diabetes (T2D): Prevalence, Diagnosis, and Clinical Management
	Pharmacogenomics of T2D
	Common Epigenetic Modifications in T2D
		DNA Methylation and T2D
		miRNAs and T2D
		Histone Modifications and T2D
	Epigenetic Modifications and Interindividual Variation in Response to Antidiabetic Drugs
	Conclusions: Implications for Treatment Strategies and Precision Medicine
	References
19
Pharmacoepigenetics of Immunological Disorders
	Pharmacoepigenetics and Autoimmune Diseases
		Chromatin and Chromatin-Modifying Enzymes
		Histone Acetylation as a Therapeutic Target
		Histone Methylation Enzymes and Their Inhibitors
		DNA Methylation and Demethylation Enzymes and Their Inhibitors
		Inhibitors of DNA Methylation and Demethylation
		Pharmacology of Autoimmune Diseases Based on DNA Methylation and Chromatin Structure
	Pharmacoepigenetics and Immunodeficiency
		Epigenetic and Primary Immunodeficiencies
		Methylation Disorder: ICF Syndrome
		Kabuki Syndrome as a Histone/Chromatin-Related Disease
		Transcriptional Defects of CD19: A Potentially Dysfunctional Epigenetic Modification in CVID
		MicroRNA Disorders
		Defects in INO80: Chromatin and Histone Modification Disorder
		miRNA-155 Defects and CVID
		Pharmacoepigenetics in the Treatment of CVID
	Pharmacoepigenetics and Hypersensitivity
		Epigenetic Regulation of Allergic Diseases
		The Role of Pharmacoepigenetics in the Treatment of Hypersensitivity
	Conclusion and Prospectus
	Acknowledgments
	References
20
Pharmacoepigenetics of Rheumatic Disorders
	Introduction
	Epigenomics in Rheumatic Diseases
		Rheumatoid Arthritis
		Ankylosing Spondylitis
		Osteoarthritis
	Epigenetics and Response to Therapy
		Methotrexate
		Anti-TNF
		HDAC Inhibitors
	Conclusions
	References
21
Pharmacoepigenetics of Systemic Lupus Erythematosus
	Introduction
	DNA Methylation and DNA Hydroxymethylation
	Histone Modifications
	Noncoding RNAs Shape the Epigenome
	Environmental Factors and Behavior
	Future Directions
	Conclusions
	References
22
Epigenetics and Pharmacoepigenetics of Neurodevelopmental and Neuropsychiatric Disorders
	Introduction
	Neuropsychopharmacology and the Epigenetic Conundrum in CNS Disorders
	Brain Development
		Epigenetics of Neurogenesis and Neocortical Development
		Epigenetic Mechanisms in the Development of Other Cerebral Structures
		Glial Cells
		Interneurons
		Somatosensory Systems
		RNA Modifications
		Influence of Prenatal Environment on Brain Development and Transgenerational Effects
		Gut Microbiota-Brain Interactions
	Memory and Learning
	Stressful Events
		Mental Stress
		Social Stress
		Traumatic Stress
			Posttraumatic Stress Disorder
		Nutritional Stress
	Behavior
	Neurodevelopmental Disorders
		Intellectual Disability
		Fragile X Syndrome
		Imprinting Disorders
			Angelman Syndrome
			Prader-Willi Syndrome
		Rett Syndrome
		Usher Syndrome
		Cornelia de Lange Syndrome
		Temple-Baraitser and Zimmermann-Laband Syndromes
		Rubinstein-Taybi Syndrome
		Autism Spectrum Disorder
		Attention Deficit Hyperactivity Disorder
		Down Syndrome
		Turner Syndrome
		Cerebral Palsy
		Claes-Jensen Syndrome
		Sturge-Weber Syndrome
		Tuberous Sclerosis
		Silver-Russell Syndrome
		Facioscapulohumeral Muscular Dystrophy
		Grange Syndrome and Fibromuscular Dysplasia
		Congenital Myotonic Dystrophy
		Limb-Girdle Muscular Dystrophy
		Neurofibromatosis
		Neurofibromatosis-Noonan Syndrome
		Noonan Syndrome
		Friedreich's Ataxia
		Duchenne Muscular Dystrophy
		Emery-Dreifuss Muscular Dystrophy
		Double Cortex Syndrome
		Myoclonus-Dystonia
		Lesch-Nyhan disease
		Aicardi Syndrome
		Kabuki Syndrome
		CHARGE Syndrome
		Kleefstra Syndrome
		Autosomal-Dominant Cerebellar Ataxia, Deafness, and Narcolepsy
		Pitt-Hopkins Syndrome
		Sotos Syndrome
		Immunodeficiency, Centromere instability and Facial Anomalies Syndrome (ICF1)
		Hereditary SWI/SNF Complex Deficiency Syndromes
		Perlman Syndrome
		Weaver Syndrome
		Alpha Thalassemia/Mental Retardation X-Linked Syndrome
		Neural Tube Defects
		Moyamoya Disease
		Adrenoleukodystrophy
		Idiopathic Central Precocious Puberty
		Xeroderma Pigmentosum
		Lysosomal Storage Disorders
		Loeys-Dietz Syndrome
		Orofacial Cleft
		Craniosynostosis
		Zika Virus Infection
	Mood Disorders
		Major Depressive Disorder
		Bipolar Disorder
		Pharmacoepigenetics of Antidepressant Drugs
	Anxiety Disorders
	Psychosis and Schizophrenia
		Pharmacoepigenetics of Neuroleptic Drugs
	Personality Disorders
	Substance Use Disorders
		Alcohol Use Disorder
			Fetal Alcohol Spectrum Disorder
			Pharmacoepigenetics of Alcohol Dependence
		Drug Addiction
	Eating Disorders
	Sleep Disorders
	Epilepsy
	Brain Cancer
		Glioma
		Glioblastoma
			Pharmacoepigenetics of Glioblastoma
		Meningioma
		Neuroblastoma
		Intracranial Germ Cell Tumors
		Medulloepithelioma
		Medulloblastoma
		Ependymomas
		Astrocytomas
		Intracranial Effects of Systemic Cancer and Chemotherapy
	Cerebrovascular Disorders
	Conclusions
	References
23
Pharmacoepigenetics and Toxicoepigenetics in Neurodevelopmental Disorders
	Introduction
	Sensitive Periods for Environmental Toxicant Exposure and NDDs
	Epigenetics and Drug Exposure in Neurodevelopmental Disorders
		Antiepileptic Drugs
		Antidepressants
	Epigenetics and Environmental Toxicants in Neurodevelopmental Disorders
		Plastic-Derived Chemicals
		Persistent Organic Pollutants
	Conclusion and Perspectives
	References
24
Pharmacoepigenetics of Autism Spectrum Disorder
	Introduction
	Pharmacotherapy of Autism Spectrum Disorder in the Light of Epigenetics
		Epigenetic Effects of Currently Used Medication in Autism Spectrum Disorder
		Epigenetic Regulation of Autism Spectrum Disorder Drug Pharmacokinetics and Pharmacodynamics
	Epidrugs
		Histone Deacetylase Inhibitors
			Valproic Acid
			Sodium Butyrate
		Inhibitors of DNA Methyltransferases
	RNA-Based Therapies
	Dietary Epigenetic Therapeutics
	Conclusion and Perspectives
	References
25
Pharmacoepigenetics of Antipsychotic Drugs
	Introduction
	Mechanisms of Epigenomic Regulation by Drugs
	Epigenetic Effects of Antipsychotic Drugs
		Effect of Antipsychotic Drugs on DNA Methylation
		Effect of Antipsychotic Drugs on Histone Modification and Chromatin Remodeling
		Effect of Antipsychotics on miRNA
	Regulation of Immune Response by Antipsychotic Drugs
	Conclusion
	References
26
Pharmacoepigenetics of Bipolar Disorder
	Introduction
	Pharmacotherapy of Bipolar Disorder
	Genetic Biomarkers of Treatment Response in Bipolar Disorder
	Pharmacoepigenetics of Bipolar Disorder
	Clinical Implications and Future Directions
	References
27
Pharmacoepigenetics of Major Depression
	Introduction
	Clinical Pharmacogenetic Studies in Major Depression
		Nonspecified Antidepressant Type
		Selective Serotonin Reuptake Inhibitors
		Tricyclic Antidepressants
		Other Antidepressants and Epigenetic-Modifying Drugs
	Guidelines and Commercial Tools in Major Depression
		Clinical Guidelines for Antidepressants
		Commercial Pharmacogenetics Tools for Antidepressants
	Discussion
	References
28
Pharmacoepigenetics of Vertigo and Related Vestibular Syndromes
	Introduction
	Pathogenic Mechanisms of Vertigo and Vestibular Syndromes
	Genetics of Vertigo and Related Syndromes
		Ménière Disease
		Sensorineural Hearing Loss and Vestibulopathy
		Neurofibromatosis
		Migraine
		Arnold-Chiari Malformation Type I (CM1)
		Ataxia
		Other Genetic Syndromes
	Pharmacology of Vertigo
		Corticosteroids
		Anticonvulsants
		Anticholinergics
		Calcium Channel Blockers
		Beta-Blockers
		Other Blockers
		Antihistamines
		Diuretics
		Ergotamines
		Nootropics
		Benzodiazepines
		Antidepressants
		Vasodilators
		Other Drugs With Central Effect
	Pharmacogenetics of Vertigo
		Cytochrome P450 and Vertigo
		Drug Transporter Genes
		Histamine Receptor (HRH) Genes
		Brain-Derived Neurotrophic Factor (BDNF)
		Potassium Voltage-Gated Channel 1 (KNCE1)
		Vitamin D Receptor
	Epigenetics of Vertigo
		Epigenetics and Inner Ear
		Epigenetics in Vertigo-Associated Disorders
		Epigenetics and Nonpharmacological Treatments
	Pharmacoepigenetics of Vertigo
		HDAC Inhibitors
		Anticonvulsants
		Corticosteroids
		Antidepressants and Benzodiazepines
		Antioxidants
		Antipsychotics
		Beta-Blockers
		Diuretics
		Other Epigenetic Drugs
	Conclusion
	References
29
Pharmacological Nicotinamide: Mechanisms Centered Around SIRT1 Activity
	Biochemistry and Functions of NAD+ and NAM
		NAD+ as a Coenzyme in Redox Reactions: A Key Determinant of the Levels of ATP and ROS
		NAD+ as a Substrate for Enzymes in Nonredox Reactions
			PARPs
			Sirtuins
			SIRT1
			SIRT3
	Regulation of SIRT1 by NAM
		Dual Effects of NAM on SIRT1 Activity
		Pharmacokinetics of NAM: Interconversion of NAD+ and NAM in Cells
		Factors That May Affect the Cellular Levels of NAD+ and NAM and SIRT1 Activity
	Therapeutic Effects of NAM and Underlying Mechanisms
		Antiinflammatory Effect
		Antidiabetic Effect
		Neuroprotection Effect
		Factors That May Cause the Side Effects of NAM
		Perspectives
	Acknowledgments
	References
30
Pharmacoepigenetics and Pharmacoepigenomics of Valproate in Neurodegenerative Disease
	Introduction
	History of Valproate
	Neuroprotective Properties of Valproate in Neurodegenerative Disease
		Retinal Degeneration and Ischemia
		Multiple Sclerosis
		Alzheimer's Disease
		Parkinson's Disease
		Amyotrophic Lateral Sclerosis
		Huntington's Disease
		Spinocerebellar Ataxia
	Conclusion
	References
31
Pharmacoepigenetics of Statins
	Statins: An Overview
		Cholesterol-Lowering Mechanism of Statins
	Genetics and Statin Response
	Epigenetics and Therapeutic Variability of Statin Treatment
		Statins and Alterations in DNA Methylation
		Statins and Histone Modifications
		Statins and miRNA Deregulation
			miRNAs and Variable Response to Statins
	Pleiotropic and Adverse Effects of Statins Mediated by Epigenetic Mechanisms
	Acknowledgments
	References
32
Pharmacoepigenetics of Memantine in Dementia
	Overview of Epigenetic Modifications
		DNA Methylation
		Histone Modifications
		microRNAs
	Pharmacoepigenetics
	Epigenetically Mediated Effects on Memantine Response
	The lntersection of Epigenetics and Memantine
		Epigenetic Aspect of Memantine in Protection Against Glutamate-lnduced Neurotoxicity
		Epigenetic Aspect of Memantine in Aβ-lnduced Oxidative Stress and Neuroinflammation
		Epigenetic Aspect of Memantine in Restoration of Mitochondrial Dysfunction
		Epigenetic Aspect of Memantine in Prevention of Hyperhomocysteinemia-lnduced Neurodegeneration
	Conclusions and Future Perspective
	References
33
Epigenetics in Doxorubicin Cardiotoxicity
	Introduction
	Doxorubicin: From Chemotherapeutic to Cardiotoxic
	Doxorubicin Risk: Genetic and Epigenetic Profiling
	Interplay Between DOX, Energy Metabolism, and Epigenetics in DOX Cardiotoxicity
		DOX-Induced Mitochondrial Dysfunction
		Links Between DOX-Induced Mitochondrial Dysfunction and Epigenetics
	Conclusions
	Acknowledgments
	References
34
Pharmacoepigenetics of Brassica-Derived Compounds
	General Health-Promoting Effects of Compounds Derived From Brassicaceae
	Epigenetic Modulation by Brassicaceae
		DNA Methylation
		Histone Modifications
		MicroRNAs
	Pharmacoepigenetics of Brassica-Derived Compounds in the Context of Chronic Diseases
		Cancer
		Cardiovascular Disorders
		Immune-Related Disorders
		Neurodegenerative and Age-Related Disorders
	Pharmacoepigenetics of Brassicaceae: a Potential Element in Disease Prevention
	Acknowledgments
	References
35
Pharmacoepigenetics of Chinese Herbal Components in Cancer
	Introduction
	Epigenetic Modification Types
		DNA Methylation
		Histone Modification
		MicroRNAs
	Epigenetic Biomarkers in Various Cancers
	Chinese Herbal Medicines Used as Epigenetic Modulators
		Phenols and Polyphenols
		Flavonoids
		Terpenoids and Alkaloids
		Other Active Compounds
	Conclusion and Perspectives
	References
36
Epigenetics of Aging and Age-Related Disorders
	Introduction
		Models and Molecular Mechanisms
	Epigenetics of Aging
		DNA Methylation and Aging
		Posttranslational Histone Modifications and Nucleosome Occupancy and Aging
			Histone Acetylation
			Histone Methylation
			Histone Ubiquitination
		ncRNA Expression and Aging
			miRNAs
			Other ncRNAs
	Epigenetics of Age-Related Disorders
		Cancer
		Cardiovascular Diseases
		Immune Responses
		Neurodegenerative Disorders
	Conclusions
	Conflict of Interest Statement
	Acknowledgments
	References
37
Epigenetics of Aging and Cancer: A Comprehensive Look
	Introduction
	Epigenetic Signatures in Aging
		Changes in DNA Methylation
		Changes in Histone Posttranslational Modifications
		Changes in Noncoding RNAs (ncRNAs)
	Epigenetic Signatures in Cancer
		Changes in DNA Methylation
		Changes in Histone Posttranslational Modifications
		Changes in Noncoding RNAs (ncRNAs)
	Epigenetic Changes Linking Aging and Cancer
		DNA Methylation
		ncRNAs
		Chromatin Structure and Remodeling
	Therapeutic Targets and Current Pharmacoepigenetic-Based Strategies for Aging and Cancer
		Pharmacoepigenetic-Based Therapies in Cancer
		Pharmacoepigenetic-Based Aging Therapies
	Perspectives
	Acknowledgments
	References
38
Epigenetics and Pharmacoepigenetics of Age-Related Neurodegenerative Disorders
	Introduction
	Epigenetic Mechanisms of Aging
	Brain Aging
	Progeroid Syndromes
	Alzheimer's Disease
		Epigenetics
			DNA Methylation and Pathogenic Genes
			Histone Modifications
			miRNAs
			Other Epigenetic Determinants
		Pharmacogenetics and Pharmacoepigenetics
			Pathogenic genes
			APOE
			Other Genes
			Metabolic Genes
			Transporters
			Antidementia Drugs
			Pharmacoepigenetic Component of Novel AD Treatments
	Other Forms of Dementia
		Frontotemporal Dementia
		Lewy Body Dementia
		Prion Disease
	Parkinson's Disease
		Pathogenomics
		Epigenetics
		Antiparkinsonian Drugs
		Pharmacogenomics
	Multiple Sclerosis
	Amyotrophic Lateral Sclerosis
	Polyglutamine Disorders
		Huntington Disease
	Other Age-Related Degenerative Disorders
	Conclusions
	References
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