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Kyung-Hyun Cho
High-Density
Lipoproteins as
Biomarkers and
Therapeutic Tools
Volume 1. Impacts of Lifestyle,
Diseases, and Environmental Stressors
on HDL
High-Density Lipoproteins as Biomarkers
and Therapeutic Tools
Kyung-Hyun Cho
High-Density Lipoproteins
as Biomarkers
and Therapeutic Tools
Volume 1. Impacts of Lifestyle, Diseases,
and Environmental Stressors on HDL
Kyung-Hyun Cho
LipoLab, Yeungnam University
Gyeongsan-si, Gyeongsangbuk-do
South Korea
ISBN 978-981-13-7386-2 ISBN 978-981-13-7387-9 (eBook)

https://doi.org/10.1007/978-981-13-7387-9
© Springer Nature Singapore Pte Ltd. 2019

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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
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The publisher, the authors, and the editors are safe to assume that the advice and information in this book
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Singapore
Preface
This book is designed to demonstrate many aspects of high-density lipoprotein

(HDL) in human growth, human disease, and aging process under different environ-
mental changes. Because HDL is dynamic and reversible, it can be changed upon
various health statuses, such as exercise, dietary patterns, exposure of infections,
and environmental pollutions. HDL can be a good biomarker to diagnose many
diseases and its progression via the monitoring of changes in its antioxidant and
anti-inflammation abilities.
HDL can be used for therapeutic tools and vehicle for drug delivery. HDL is a
potent antioxidant, anti-inflammatory macromolecule in body fluids to maintain
human health. Advantageous activities of HDL are well known as anti-atherosclerotic
and antidiabetic activity and recently expand to antiaging activities. The advanta-
geous virtues of HDL are highly dependent on its lipids, proteins, apolipoproteins,
and enzymes, specifically their compositions and ratios. In normal state, the HDL
particle is constituted with cholesterol, triacylglyceride (TG), and several HDL-
associated enzymes and apolipoproteins, including paraoxonase, lecithin/choles-
terol acyltransferase, and cholesteryl ester transfer protein (CETP).
HDL cholesterol (HDL-C) level should be more than 40 and 50 mg/dL for men
and women, respectively, to maintain healthy state. Lower HDL-C levels (<40 mg/
dL) have been recognized as an independent risk factor for coronary artery disease,
as well as a known component of metabolic syndrome. In addition to HDL-C, func-
tional and structural changes of HDL have also been recognized as factors pivotal to
the evaluation of HDL quality. HDL are susceptible to structural modifications
induced via several mechanisms, including oxidation, glycation, nitration, or pro-
tein degradation upon external stress such as infection of virus and bacteria, inflam-
mation, and pollutant exposure. The modification resulted in severe loss of
advantageous functions of HDL regarding anti-senescence and antidiabetic and
anti-atherosclerosis activity due to functional and structural modification with
increased protein degradation. In order to replace the dysfunctional HDL, blood
infusion of reconstituted HDL (rHDL) caused reduction of plasma glucose levels by
increasing plasma insulin in pancreatic beta cells, which raised the feasibility of a
wider clinical application of rHDL from cardiovascular disease to diabetes.
v
vi Preface
In this book, I have elected to focus on functional and structural correlations of

HDL and apoA-I in various health statuses and the roles of HDL-associated apoli-
poproteins and enzymes as therapeutic tools. Interestingly, HDL and apoA-I can be
found in many important body fluids in all age, including breast milk, cord blood,
vessel blood, lymph, and cerebrospinal fluid. Several clinical applications of HDL
have also been reviewed herein, particularly the therapeutic targeting of HDL
metabolism and reconstituted HDL, as these techniques represent promising emerg-
ing strategies for the treatment of diabetes and cardiovascular disease and for drug-
delivery. Herein are many aspects of HDL in diseases and environmental stresses to
change quantity and quality of HDL as shown in the illustration below. A reconsti-
tuted HDL can be synthesized with many other ingredients to test functionality or
drug delivery as shown in the left side. Many HDL from various subjects and
patients were characterized to compare native HDL and dysfunctional HDL as
shown in the right side.
Actually, HDL is a dynamic macrocomplex, which is not fixed in certain struc-

ture and functions. It has energetic structural and functional features of HDL
depends on health status and environmental circumstances, as well as change of
HDL by lifestyle and various diseases, we will see impairment of HDL by environ-
Preface vii
mental pollutant and food ingredient to produce dysfunctional HDL, which can
exacerbate pre-existed diseases. However, HDL functionality can be enhanced by
consumption of functional food, such as vitamin C and policosanol. The enhanced
HDL functionality is accompanied with reducing aortic stiffness and blood
pressure.
Finally, we would take a look about HDL quality and quantity to maintain our
healthy life and longevity. I do believe this book provides new aspects of HDL in
healthy aging and unique insight of HDL field.
Gyeongsan-si, Gyeongsangbuk-do Kyung-Hyun Cho

South Korea
Contents
1 Understanding HDL: Overview�� 1

1.1 HDL and Disease�� 1
1.1.1 Dysfunctional HDL and Diseases�� 2
1.2 HDL Functions and Clinical Applications�� 4
1.2.1 Functional and Structural Correlations of HDL�� 6
1.2.2 Anti-atherosclerotic Function of HDL�� 7
1.2.3 Antioxidant Properties of HDL�� 7
1.2.4 Anti-inflammatory Function of HDL�� 8
1.3 HDL Composition: Apolipoproteins and Enzymes�� 8
1.3.1 Apolipoprotein A-I�� 9
1.3.2 Apolipoprotein A-II�� 9
1.3.3 Apolipoprotein C-I, C-II and C-III �� 10
1.3.4 Cholesteryl Ester Transfer Protein (CETP)�� 11
1.3.5 Lecithin:Cholesterol Acyltransferase (LCAT)�� 11
1.3.6 Paraoxonase�� 12
1.3.7 Platelet Activating Factor-Acetyl Hydrolase
(PAF-AH)�� 12
1.4 Maturation of HDL �� 13
1.5 HDL and Blood Pressure�� 14
References�� 17
2 Change of HDL by Life Style�� 23
2.1 Exercise and HDL�� 23
2.1.1 Serum Parameters �� 24
2.1.2 Particle Distribution of VLDL, LDL, and HDL�� 24
2.1.3 Ferric Reducing Ability (FRA) as Antioxidant Ability�� 26
2.1.4 LCAT Ability and Protein Expression in HDL3�� 27
2.1.5 Paraoxonase Ability and Protein Expression�� 28
2.1.6 CETP Activity and Protein Expression�� 28
2.1.7 Expressional Level of apoA-I and A-II in HDL
Species�� 29
ix
x Contents
2.1.8 Runners and Wrestlers Had the Biggest HDL2 Size �� 30
2.2 Smoking and HDL�� 32
2.2.1 Subjects �� 33
2.2.2 Blood Analysis�� 34
2.2.3 Serum Profiles�� 34
2.2.4 Lipoprotein Properties�� 35
2.2.5 Lipoproteins from Smokers Are More Oxidized�� 36
2.2.6 Glycated Species and Modification of Electrophoretic
Properties�� 36
2.2.7 CETP Activity�� 39
2.2.8 Cellular Uptake of LDL into Macrophages�� 40
2.3 Elderly’s HDL�� 43
2.3.1 Recruitment of Elderly Subjects �� 44
2.3.2 Serum Profiles�� 45
2.3.3 Reduced Antioxidant Ability in the Elderly Group�� 45
2.3.4 PON Activity Was Reduced in the Elderly Group�� 46
2.3.5 CE-Transfer Ability Was Increased in the Elderly
Subjects �� 47
2.3.6 Expression of apoA-I in HDL and LPDS �� 48
2.3.7 The Elderly Group Showed Truncation
of the C-Terminal of A-I in HDL3 �� 50
2.3.8 The Elderly Group Showed Increased Glycated
Levels of apoA-I in HDL3 �� 50
2.3.9 HDL2 Particle Size Was Decreased in the Elderly�� 52
2.3.10 The Level of Expression of SAA and apoC-III�� 52
2.4 HDL Depends on Body Weight�� 55
2.4.1 Subjects �� 56
2.4.2 BMI and Serum HDL-C�� 57
2.4.3 Serum Lipid Level and Body Weight�� 57
2.4.4 CETP Mass and Ability�� 58
2.4.5 Correlation of HDL-C and Body Shape�� 58
2.4.6 Correlation of HDL-C and Blood Pressure�� 60
2.4.7 Antioxidant Ability �� 60
2.4.8 Compositions of Lipoproteins�� 61
2.4.9 Modification of Lipoproteins�� 62
2.4.10 Expression Level of apoA-I in HDL�� 63
2.4.11 HDL2 Particle Size and Cholesterol Efflux�� 64
2.5 HDL from Obese but Healthy Subject�� 67
2.5.1 Blood Sampling�� 68
2.5.2 Ultracentrifugation�� 69
2.5.3 Serum Profiles of the Hypolipidemic Obese Patient�� 69
2.5.4 Different Apolipoprotein Expression Levels
in HDL2 and HDL3�� 70
2.5.5 Particle Size Distribution of Lipoproteins�� 71
2.5.6 Composition of apoA-I and A-II in HDL Subtypes�� 71
Contents xi
2.5.7 LCAT Ability and Protein Levels in HDL-Subspecies �� 73

2.5.8 The Obese Patient Lacked CETP Activity�� 74
2.5.9 The Obese Subject Had Larger HDL2 and HDL3
Particles�� 74
2.6 HDL and apoA-I in Smokers’ Breast Milk�� 76
2.6.1 Recruiting of Breast Milk Donor�� 78
2.6.2 Microinjection of Zebrafish Embryos�� 78
2.6.3 Higher Body Fat in Smokers�� 79
2.6.4 Compositional Analysis�� 80
2.6.5 Embryo Survivability�� 81
2.6.6 Developmental Speed and ROS Production �� 81
2.6.7 Electrophoretic Analysis of Protein Composition�� 82
2.6.8 Expressional Level of apoA-I �� 82
2.6.9 Influential Factors for Embryo Survivability�� 84
2.7 Breast Milk from Frequent Trans-fatty Acid Consumers �� 88
2.7.1 Recruiting of Breast Milk Donor�� 89
2.7.2 Composition Analysis �� 89
2.7.3 Embryo Survivability and Developmental Speed �� 90
2.7.4 Electrophoretic Analysis of Protein Composition�� 91
2.7.5 Expression Level of apoA-I�� 92
2.7.6 Influential Factors for Embryo Survivability�� 92
2.8 HDL in Cord Blood from Small Neonates �� 95
2.8.1 Collection of Umbilical Cord Blood�� 96
2.8.2 Lipid Parameters in Cord Serum�� 97
2.8.3 Lipoprotein Profile in Cord Blood�� 99
2.8.4 SGA Shows Lower Antioxidant Ability�� 100
2.8.5 Expression Level of Growth Hormones and IL-6
in Cord Serum �� 100
2.8.6 Expression of apoA-I, Apo-B, and apoC-III
in Lipoproteins�� 101
2.8.7 Glycation and Oxidation Extent of HDL�� 103
2.8.8 Antioxidant Ability of Lipoproteins �� 103
2.8.9 Higher Atherogenic Properties�� 104
2.8.10 Diminished apoA-I Expressional in Amniotic
Fluid of SGA�� 107
References�� 108
3 Change of HDL in Various Diseases�� 119
3.1 HDL from Patients with Myocardial Infarction�� 119
3.1.1 Patients and Controls�� 120
3.1.2 Plasma and Lipoprotein�� 120
3.1.3 Serum Lipid Profile and Inflammatory Markers�� 121
3.1.4 TG and apoC-III Were Elevated in Lipoproteins
from MI�� 123
3.1.5 Increase of CETP Protein and Ability�� 123
xii Contents
3.1.6 Enzyme Activities of Lipoproteins �� 125

3.1.7 Ferric Ion Reducing Ability of Plasma (FRAP)�� 126
3.1.8 More Oxidized LDL Was Detected in MI Patients�� 127
3.1.9 Cupric Ion mediated Oxidation of HDL �� 128
3.2 HDL from Patients with Female Angina Pectoris�� 130
3.2.1 Patients and Controls�� 131
3.2.2 Lipid and Protein Composition in Lipoprotein�� 131
3.2.3 CETP and LCAT Activity �� 131
3.2.4 Antioxidant Ability of HDL2 and HDL3 Was
Decreased in the AP Group�� 133
3.2.5 HDL-Associated Paraoxonase and PAF-AH�� 134
3.2.6 LDL from AP Patient Was More Sensitive
to Oxidation�� 135
3.3 HDL and Metabolic Syndrome�� 137
3.3.1 Serum Profile�� 138
3.3.2 Decreased Antioxidant Ability�� 140
3.3.3 Susceptibility of Copper-Mediated LDL-Oxidation�� 140
3.3.4 Paraoxonase Activity Was Nearly Abrogated
in the MetS Group�� 141
3.3.5 Lipid Profile in Lipoprotein Species �� 141
3.3.6 ApoC-III Was Elevated in LDL and HDL
of the MetS Group�� 143
3.3.7 ApoA-I Was Elevated in Lipoprotein-Deficient
Serum (LPDS) of the MetS Group�� 143
3.3.8 CE-Transfer Ability Was Higher in the MetS Group�� 144
3.3.9 SAA Level Was Elevated in the MetS Group �� 145
3.4 HDL from Male Patients with Atrial Fibrillation �� 148
3.4.1 Patients�� 149
3.4.2 Echocardiography �� 149
3.4.3 Serum Parameters of AF �� 150
3.4.4 Antioxidant Ability of Serum �� 151
3.4.5 Lipoprotein Parameters�� 152
3.4.6 Oxidized Extent of Lipoprotein�� 152
3.4.7 AF-LDL Was More Sensitive to Oxidation�� 153
3.4.8 Glycated Extent of Lipoprotein�� 154
3.4.9 Antioxidant Ability of HDL and Protein Composition�� 154
3.4.10 Particle Size of Lipoproteins�� 156
3.4.11 Uptake of Lipoprotein Phagocytosis�� 157
3.5 HDL from Female Patients with Atrial Fibrillation�� 158
3.5.1 Patients�� 159
3.5.2 Baseline Characteristics�� 160
3.5.3 Lipoprotein Properties�� 161
3.5.4 AF-LDL Was More Sensitive to Oxidation�� 162
3.5.5 Antioxidant Potential Was Decreased in AF Group�� 163
Contents xiii
3.5.6 More Glycated Species in Lipoproteins From

the AF Group�� 163
3.5.7 Lower Level of apoA-I in AF-HDL2 �� 164
3.5.8 Particle Size of Lipoproteins�� 164
3.6 HDL From Patients with Hemorrhagic Fever with Renal
Syndrome�� 168
3.6.1 Blood Sampling�� 169
3.6.2 Change of Serum Parameters and Lipid Profile
in Oliguric State�� 170
3.6.3 Change of Lipid Composition in Lipoprotein Species �� 171
3.6.4 Antioxidant Ability Was Reduced in the Oliguric Phase�� 171
3.6.5 The 14 kDa Peptide Was Identified as apoC-III�� 171
3.6.6 ApoA-I in HDL Was Decreased in the Oliguric Phase�� 173
3.6.7 Serum Amyloid A Was Substantially Elevated
in Oliguric Phase�� 173
3.6.8 HDL-Associated Enzyme Activities Were Deprived
in Oliguric Phase�� 174
3.6.9 Particle Size of HDL2 Was Decreased in the Oliguric
Phase �� 176
3.7 HDL from Patients with Rheumatoid Arthritis�� 179
3.7.1 Patients Recruiting�� 180
3.7.2 Blood Profiles of RA Patients �� 180
3.7.3 Lipoprotein Profiles in RA Patients�� 181
3.7.4 Glycation and Oxidation of LDL in RA Patients�� 183
3.7.5 Glycation of HDL and Multimerization of apoA-I�� 183
3.7.6 Elevated CETP and Reduced PON Activity in HDL
from RA�� 184
3.7.7 Particle Size and Number of HDL�� 186
3.8 HDL and Prehypertension�� 190
3.8.1 Recruitment of Participants�� 190
3.8.2 Anthropometric Analysis�� 190
3.8.3 Measurement of Central Blood Pressure by
SphygmoCor XCEL�� 191
3.8.4 Diagnosis of Pre-hypertension�� 191
3.8.5 Characteristics of the Study Population�� 192
3.8.6 Baseline Characteristic of Body Composition,
Anthropometric and Biochemical Parameters
of Hypertensive and Non-hypertensive Participants�� 193
3.8.7 Correlation Analysis Among Various Variables (Body
Composition, Anthropometric, Biochemical Parameters,
Central Blood Pressure) in the Total Population�� 193
3.8.8 The Correlation Between Central Blood Pressure
and Other Diagnostic Techniques for Blood Pressure
Measurement and Lipid Profiles in Hypertensive
Participants�� 196
xiv Contents
3.8.9 The Correlation Between Central Blood Pressure

and Other Diagnostic Techniques for Blood Pressure
Measurement and Lipid Profiles in Non-hypertensive
Participants�� 196
4 Impairment of HDL by Pollutants �� 213
4.1 Particulate Matter and HDL�� 213
4.1.1 Collection and Extraction of PM2.5 �� 214
4.1.2 Modification of HDL by PM2.5�� 215
4.1.3 PM2.5 Accelerates Oxidation of LDL�� 216
4.1.4 PM2.5 Accelerates Degradation of LDL�� 216
4.1.5 PM2.5 Causes Atherogenesis and Cellular Senescence�� 216
4.1.6 Acceleration of Atherogenesis by Fructose and PM2.5�� 218
4.1.7 Waterborne Exposure of PM2.5 Causes Embryonic
Toxicity �� 219
4.1.8 Loss of Antioxidant Functions in the Embryo�� 220
4.1.9 Microinjection of PM2.5 with LDL and Fructose�� 220
4.2 Phthalate and HDL�� 224
4.2.1 Modification of LDL and HDL by DEP �� 225
4.2.2 Synthesis of rHDL with DEP�� 226
4.2.3 Oxidation of LDL by rHDL Containing DEP�� 227
4.2.4 Degradation of apoA-I and Apo-B�� 228
4.2.5 Facilitation of acLDL Uptake by DEP�� 229
4.2.6 Cellular Senescence Is Exasperated by DEP�� 229
4.2.7 Microinjection of Zebrafish Embryos�� 230
4.2.8 Waterborne Exposure of Zebrafish Embryos to DEP �� 230
4.2.9 Waterborne Exposure to DEP Induces Hypolipidemia�� 232
4.2.10 Fatty Liver Changes Induced by DEP�� 233
4.3 Cadmium and HDL�� 235
4.3.1 Modification and Glycation of HDL3 by CdCl2�� 236
4.3.2 Induction of LDL Oxidation by Cd-HDL3�� 236
4.3.3 Cd-HDL3 Inhibits Anti-Atherosclerotic Ability�� 238
4.3.4 Cd-HDL3 Increases Cellular Senescence�� 239
4.3.5 Embryonic Toxicity Induced by Cd-HDL3 �� 239
4.3.6 Embryonic Deformity Induced by CdCl2�� 241
4.3.7 Plasma Profile of Zebrafish�� 242
4.3.8 Hepatic Tissue Analysis�� 242
4.3.9 Hepatic Tissue TG Content and Peroxidation�� 244
4.4 Humidifier Sterilizer and HDL �� 246
4.4.1 Sterilizers�� 248
4.4.2 Treatment of Lipoprotein with the Sterilizers�� 248
4.4.3 Lipoprotein Modification by the Disinfectants �� 248
4.4.4 LDL Oxidation Was Enhanced by the Sterilizer�� 249
4.4.5 Enhanced oxLDL Uptake by the Sterilizer�� 250
Contents xv
4.4.6 Pro-Senescent Effects of the Sterilizer�� 251

4.4.7 Embryonic Toxicity�� 252
4.4.8 Survival in Disinfectant-Treated Water�� 254
4.4.9 Serum Analysis �� 255
4.4.10 Elevated Inflammation and Fatty Liver Induction
by the Sterilizer �� 255
4.4.11 Collagen Accumulation in the Bulbous Artery �� 256
4.5 Detection of Dysfunctional HDL by Microfluidics�� 259
4.5.1 Fabrication Process of PDMS Microchip �� 260
4.5.2 Purification of apoA-I �� 260
4.5.3 Isolation of HDL from Elderly and Young Groups�� 260
4.5.4 Glycation of apoA-I�� 261
4.5.5 Ampholyte-Based IEF Model �� 261
4.5.6 Assumptions for Simulation �� 262
4.5.7 Boundary Conditions�� 262
4.5.8 Numerical Scheme�� 262
4.5.9 Fluorescence of AGEs�� 263
4.5.10 Electromobility of HDL�� 263
4.5.11 Isoelectric Focusing on Polyacrylamide Gel�� 264
4.5.12 IEF in Microchannels and Simulation�� 265
4.5.13 Electromobility in the Microfluidic Channel�� 266
4.6 Evaluation of Dysfunctional HDL Using Zebrafish Embryo�� 269
4.6.1 gA-I-rHDL Accelerates the Death of Zebrafish
Embryos in the Presence of LPS�� 271
4.6.2 nA-I-rHDL Protects Zebrafish Embryos from Death
in the Presence of oxLDL �� 272
4.6.3 HDL from Elderly Caused More Rapid Death
of Zebrafish Embryos�� 276
5 Change of HDL by Food Ingredient�� 287
5.1 Fructose and apoA-I�� 287
5.1.1 Secondary Structure of Glycated apoA-I�� 288
5.1.2 BS3-Crosslinking�� 289
5.1.3 Synthesis of rHDL�� 289
5.1.4 Circular Dichroism Spectroscopy �� 289
5.1.5 FPLC Elution Profile of gA-I�� 290
5.1.6 Oxidation of LDL and Uptake of oxLDL �� 291
5.1.7 Cellular Senescence Was Induced by gA-I-rHDL
Treatment�� 292
5.2 Fructose and Impairment of HDL Functionality�� 294
5.2.1 Characterization of Fructated apoA-I (fA-I)�� 295
5.2.2 Increased Electromobility by Fructation�� 296
5.2.3 Reduction of Insulin Secretion by fA-I Treatment �� 297
5.2.4 fA-I-rHDL Induces Senescence in Endothelial Cell�� 299
xvi Contents
5.2.5 fA-I Aggravates Embryo Death of Zebrafish�� 300

5.3 Artificial Sweeteners and apoA-I�� 302
5.3.1 Change of apoA-I Structure by AS Treatment�� 303
5.3.2 Loss of Antioxidant Ability�� 305
5.3.3 Phospholipid Binding Ability �� 306
5.3.4 Secondary Structure�� 307
5.3.5 Native Electromobility in the Lipid-Free State�� 308
5.3.7 AcLDL Uptake by Macrophages�� 310
5.3.8 Saccharin-Treated Cells Showed the Most Severe
Cellular Senescence�� 311
5.4 Artificial Sweeteners (Aspartame, Saccharin) and HDL�� 315
5.4.1 Proteolytic Degradation by AS �� 316
5.4.2 Antioxidant Activities of HDL3 Are Impaired by AS �� 317
5.4.3 LDL Oxidation�� 318
5.4.4 CETP Ability Is Enhanced by AS Treatment�� 319
5.4.5 Uptake of oxLDL into Macrophages�� 320
5.4.6 Injection of AS Caused Embryonic Cell Death with
Oxidative Stress�� 321
5.5 Ketohexoses and HDL�� 325
5.5.1 Glycation by Ketohexose Treatment�� 326
5.5.2 Phospholipid Binding Ability �� 328
5.5.3 Inhibition of Cupric Ion Mediated LDL Oxidation�� 328
5.5.4 Uptake of oxLDL into Macrophage�� 329
5.5.5 Western Blotting with Cell Lysate�� 329
5.5.6 Microinjection of Ketohexose into Zebrafish �� 331
5.5.7 Consumption of Tagatose Lowered Blood TG
in Zebrafish �� 333
5.5.8 Histologic Analysis �� 334
5.6 Iron and HDL�� 336
5.6.1 Lipoprotein Modification by the FeSO4�� 337
5.6.2 Acceleration of HDL Glycation by FeSO4 �� 338
5.6.3 Synergetic Effect of apoA-I glycation by FeSO4
and Fructose�� 339
5.6.4 LDL Oxidation Was More Facilitated by FeSO4�� 339
5.6.5 Cellular Senescence Was More Accelerated by Fe2+�� 341
5.6.6 Survivability of Zebrafish Embryos�� 341
5.6.7 High Iron Diet Causes Hyperlipidemia in Zebrafish�� 342
5.6.8 Fatty Liver Induction Upon Iron Supplementation�� 344
5.6.9 FeSO4 Consumption Reduces Embryo Production�� 345
5.6.10 Ovarian Tissue Was Damaged by Iron Consumption �� 346
5.7 Trans Fat and HDL�� 349
5.7.2 LDL Oxidation and More Uptake of oxLDL
by EA-rHDL �� 353
Contents xvii
5.7.3 EA-rHDL Suppressed Cellular Uptake of apoA-I

in the rHDL �� 355
5.7.4 EA-rHDL Caused More ROS Generation and Cellular
Senescence�� 355
5.7.5 Survivability of Zebrafish Embryo �� 356
5.7.6 Serum Profiles of Zebrafish�� 357
5.7.7 Fatty Liver Change�� 359
5.8 Salt and HDL�� 361
5.8.1 Oxidation of LDL and HDL by Cupric Ion and NaCl�� 362
5.8.2 Acceleration of Lipoprotein Glycation by NaCl�� 364
5.8.3 NaCl Exasperates Phagocytosis of oxLDL by
Macrophages and Cytotoxicity �� 364
5.8.4 High Salt Intake Causes Hyperlipidemia
in Zebrafish Despite Weight Loss �� 365
5.8.5 NaCl Consumption Diminished Embryo Production
and Survivability �� 366
5.8.6 Salt Intake Impaired Male Fertility�� 367
5.8.7 Salt Intake Caused Hepatic Inflammation�� 368
Abbreviations
ABC ATP-binding cassette transporter

ABCA1 ATP-binding cassette transporter A1
ABCG1 ATP-binding cassette transporter G1
ACAT acyl-CoA/cholesterol acyltransferase
acLDL acetylated LDL
ACS acute coronary syndrome
Ad adenoviruses
AF atrial fibrillation
AFs amniotic fluids
AGA average for gestational age
AGEs advanced glycation end products
AHLs N-acyl homoserine lactones
AI augmentation index
ALT alanine aminotransferase
AMP adenosine 5’-monophosphate
AMPK AMP-activated protein kinase
AP augmentation pressure
Apo apolipoprotein
apoA-I apolipoprotein A-I
apoB apolipoprotein B
APs angina pectoris
ASF abdominal subcutaneous fat
ASs artificial sweeteners
AST aspartate aminotransferase
AU arbitrary units
BBB blood-brain barrier
BI band intensity
BLp apoB-containing lipoprotein particles
BMI body mass index
BP blood pressure
BPI bactericidal/permeability-increasing protein
xix
xx Abbreviations
BPM beats per minute

BSA bovine serum albumin
BUN blood urea nitrogen
C cholesterol
CAD coronary artery disease
cAMP cyclic AMP
CAO cortical alveolar oocytes
CE cholesteryl ester
CETP cholesteryl ester transfer protein
CHD coronary heart disease
CIMT carotid intima-media thickness
CKD chronic kidney disease
CK-MB creatine kinase MB
CM chylomicron
COPD chronic obstructive pulmonary disease
CPE ceramide phosphatidylethanolamine
Cpm count per minute
Cr creatine
CRE cAMP response elements
CRP C-reactive protein
CVD cardiovascular disease
DAMPs damage-associated molecular patterns
DAPI 4′,6-diamidino-2-phenylindole
DBP diastolic blood pressure
DEFINE Determining the Efficacy and Tolerability of CETP Inhibition with
Anacetrapib
DEP diethyl phthalate
DHE dihydroethidium
DM diabetes mellitus
DMPC dimyristoyl phosphatidylcholine
dpf day postfertilization
EA elaidic acid
ECG electrocardiogram
EDEA 2,2′-(ethylenedioxy)bis(ethylamine)
EDTA ethylenediaminetetraacetic acid
EL endothelial lipase
ELISA enzyme-linked immunosorbent assay
eNOS endothelial nitric oxide synthase
ER endoplasmic reticulum
ERASE Effect of rHDL on Atherosclerosis-Safety and Efficacy
ESRD end-stage renal disease
FC free cholesterol
FED fish-eye disease
FFA free fatty acid
FLD familial LCAT deficiency
Abbreviations xxi
FM fat mass
FMD flow-mediated dilation
FRA ferric ion reduction ability
FRAP ferric ion reduction ability of plasma
FRAS ferric ion reduction ability of serum
GAD gestational age at delivery
GGE gradient gel electrophoresis
GH growth hormone
GHD growth hormone deficiency
GOT glutamic oxaloacetic transaminase
GPT gamma-glutamic pyruvic transaminase
GST glutathione transferase
GWAS genome-wide association study
H&E hematoxylin and eosin
Hb hemoglobin
HC high cholesterol
HCD high cholesterol diet
HCHF high cholesterol and high fructose
HCHT high cholesterol and high tagatose
HDFs human dermal fibroblasts
HDL high-density lipoprotein
HDL-C high-density of lipoprotein cholesterol
HDMECs human dermal microvascular endothelial cells
HFCS high-fructose corn syrups
HFHC high-fat, high-cholesterol
HFRS hemorrhagic fever with renal syndrome
Hgb hemoglobin
HL hepatic lipase
HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
HMW high molecular weight
HNE 4-hydroxy-2-nonenal
HPLC high-performance liquid chromatography
Hpr haptoglobin-related protein
HR heart rate
hsCRP high-sensitivity C-reactive protein
HTGL hepatic triglyceride lipase
HUVECs human umbilical vein endothelial cells
ICAM intercellular adhesion molecule
IDI integrated discrimination improvement
IDL intermediate-density lipoprotein
IEF isoelectric focusing
IgG immunoglobulin G
IGF insulin-like growth factor
IHD ischemic heart disease
IL interleukin
xxii Abbreviations
INS insulinoma cell line

KO knockout
LA linoleic acid
LBP lipopolysaccharide-binding protein
LC liquid chromatography
LCAT lecithin/cholesterol acyltransferase
LDH lactate dehydrogenase
LDL low-density lipoprotein
LDL-C low-density lipoprotein cholesterol
LDLR LDL receptor
LGA large for gestational age
LP lipoprotein
LpA-I lipoprotein containing apoA-I
LPDS lipoprotein-deficient serum
LPL lipoprotein lipase
LPO lipoxygenase
LpPLA2 lipoprotein-associated phospholipase A2
LPS lipopolysaccharide
LpX lipoprotein X
LV left ventricle
LVEF left ventricular ejection fraction
LXR liver X receptor
LXRE LXR-responsive elements
Lyso-PC lysophosphatidylcholine
MALDI-MS matrix-assisted laser desorption ionization mass spectrometry
MAP mean arterial pressure
MCA monocyte chemotactic assay
MCP monocyte chemoattractant protein
MDA malondialdehyde
MEMS microelectromechanical system
MetO methionine sulfoxide
MetS Metabolic syndrome
MFG milk fat globules
MI myocardial infarction
miRNA microRNA
MMP matrix metalloproteinase
MPO myeloperoxidase
MS mass spectrometry
MW molecular weight
NADPH nicotinamide adenine dinucleotide phosphate
nA-I Native apoA-I
ND normal diet
NEFA nonesterified fatty acids
NEMS nanoelectromechanical system
NF-κB nuclear factor-kappa B
Abbreviations xxiii
NI no injection
NOX nitrogen oxide
NRI net reclassification improvement
OA oleic acid
oxHDL oxidized HDL
oxLDL oxidized LDL
PAD peripheral arterial disease
PAF platelet-activating factor
PAF-AH platelet-activating factor-acetyl hydrolase
PAGE polyacrylamide gel electrophoresis
PAGGE polyacrylamide gradient gel electrophoresis
PC phosphatidylcholine
PCB polychlorinated biphenyl
PCO policosanol
PCOS polycystic ovary syndrome
PDMS poly-dimethyl siloxane
PGH oligo-[2-(2-ethoxy)-ethoxyethyl]-guanidinium-chloride
PHMG polyhexamethylene guanidine
PL phospholipid
PLA2 phospholipase A2
PLD phospholipase D
PLTP phospholipid transfer protein
PM particulate matter
PON paraoxonase
PON1 paraoxonase1
POPC palmitoyloleoyl phosphatidylcholine
PPAR peroxisome proliferator-activated receptor
PS phosphatidylserine
PSVT paroxysmal supraventricular tachycardia
PVDF polyvinylidene difluoride
PWV pulse wave velocity
QS quorum sensing
RA rheumatoid arthritis
RAAS renin-angiotensin-aldosterone system
RAGE receptor for AGE
RAR retinoic acid receptor
RBC red blood cell
RCT reverse cholesterol transport
rHDL reconstituted HDL
rLCAT recombinant human LCAT
ROS reactive oxygen species
SA stearic acid
SAA serum amyloid A
SBP systolic blood pressure
SC spermatocytes
xxiv Abbreviations
SCWA sugar cane wax alcohol

SD standard deviation
sdLDL small dense LDL
SG spermatogonia
SGA small for gestational age
SHR spontaneously hypertensive rats
SLE systemic lupus erythematosus
SM sphingomyelin
SMS sphingomyelin synthase
SMSr sphingomyelin synthase-related protein
SNP single-nucleotide polymorphisms
SOX sulfur oxide
SPT serine palmitoyltransferase
SR-BI scavenger receptor class B type I
SREBP sterol regulatory element-binding protein
ST spermatids
STZ streptozotocin
SZ spermatozoa
TBARS thiobarbituric acid reactive substance
TBS Tris-buffered saline
TC total cholesterol
TDMA tridiagonal matrix algorithm
TEM transmission electron microscopy
TFA trans-fatty acid
TG triglyceride
TGRL triglyceride-rich lipoprotein
TLF trypanosome lytic factor
TNF tumor necrosis factor
TOR target of rapamycin
TP total protein
TRL triglyceride-rich lipoprotein
TSH thyroid-stimulating hormone
TSP total suspended particulate
VA-HIT Veterans Administration HDL Intervention Trial
VCAM vascular cell adhesion molecule
VFM visceral fat mass
Vit C vitamin C
VLDL very low-density lipoproteins
WBC white blood cell
WKY Wistar Kyoto
WMF wavelength maximum fluorescence
WT wild type
Chapter 1
Understanding HDL: Overview
1.1 HDL and Disease
As shown in below diagram, the first leading causes of death in the world are car-
diovascular disease (48%) and the second and the third one are respiratory disease
(12%) and diabetes (3%). Total 63% of leading cause of death is directly related
with HDL-cholesterol and its functionality. Interestingly, incidence of cancer is also
associated with change of HDL-cholesterol level. Yang et al. (2015) reported that
1 mg/dL reduction of HDL-C was associated with 14% increased risk of having
cancer. Furthermore, inverse correlations between HDL-C level and risk of develop-
ing cancer from several randomized controlled trials of lipid-altering therapy (Jafri
et al. 2010). Although the role of low HDL-C as a causative factor of cancer remains
uncertain, plasma HDL-C level was often decrease in patients with cancer (Dilman
et al. 1981). Typically, cancer induced dyslipidemia showed low HDL-C in various
solid tumors such as breast cancers (Touvier et al. 2015), liver cancers (Nderitu
et al. 2017), and lung cancers (Chi et al. 2014).
Several respiratory diseases, such as COPD, pulmonary arterial hypertension,
and influenza A pneumonia, are associated with dysfunctional HDL to cause more
emphysema, airflow obstruction, and monocyte chemotaxis (Gordon et al. 2016),
Native HDL and apoA-I maintain normal lung health and reduce asthma and lung
cancer via suppression of airflow obstruction and systemic inflammation. Overall, it
is no exaggeration to say that major diseases in world leading cause of death are
well accompanied with HDL quality and quantity (Fig. 1.1).
© Springer Nature Singapore Pte Ltd. 2019 1

K.-H. Cho, High-Density Lipoproteins as Biomarkers and Therapeutic Tools,
https://doi.org/10.1007/978-981-13-7387-9_1
2 1 Understanding HDL: Overview
Fig. 1.1 World leading cause of death
1.1.1 Dysfunctional HDL and Diseases
In blood, HDL and LDL are exposed to many aging stress to get oxidation, glyca-
tion, and infection by smoking, sweetener, and pollutant during entire life. The
accumulated stress make modifications in HDL and LDL to exasperate more inflam-
mation and damage of gene, protein, and cell. In blood vessel, these damage cause
build up atherosclerotic plaque and increase of aortic stiffness to elevate blood pres-
sure. These change of lipoproteins are accompanied with incidence of many dis-
eases, metabolic disease and autoimmune disease, with ageing as shown in Fig. 1.2.
As shown in Fig. 1.3, native HDL has healthy activities including anti-
inflammation, anti-infection, and anti-glycationa as well as anti-oxidant and anti-
thrombosis activities. IfHDL lost its healthy activities, which suppress many dis-
eases, dysfunctional HDL could be more produced. The dysfunctional HDL cannot
prevent progression of acute coronary syndrome, hypertension, and diabetes, etc.
Furthermore, risk of chronic inflammatory systemic diseases, psoriasis (skin dis-
ease) and rheumatoid arthritis (joint disease), also associated with dysfunctional
HDL (Paiva-Lopez and Delgado-Alves 2017; Kim et al. 2016). Because oxidative
stress and inflammation contribute to the etiology of dementia and cognitive disor-
ders, lowered apoA-I and dysfunctional HDL are accompanied with brain and neu-
rodegenerative disorders (Hottman et al. 2014). ApoA-I can bind to beta-amyloid
for removal and inhibits aggregation of beta-amyloid in brain. ApoA-I is also a tar-
get of myeloperoxidase (MPO) and lipoxigenase (LPO) to be truncated its peptide
bond and modified by oxidation, glycation, and nitration. Once the modification is
occurred in apoA-I in HDL, the HDL changed easily to be dysfunctional
Fig. 1.2 Change of lipoproteins by aging stress and incidence of disease
Fig. 1.3 Various diseases and dysfunctional HDL

HDL. Dysfunctional HDL can exasperate already existed disease and cause newly
onset disease such as coronar syndrome, hypertension, and diabetes as shown in
below diagram. As well as the cardiovascular diseases, skin disorders, brain disor-
ders, rheumatism, cancer, etc., are also associated with dysfunctional
HDL. Furthermore, several previous studies suggested that reproductive organ dis-
orders, polycystic ovary syndrome (PCOS), female infertility (Verit et al. 2017), and
male sexual dysfunctions (Turek et al. 2013; Dursun et al. 2016) are also associated
with low HDL-C.
1.2 HDL Functions and Clinical Applications
It has been established that plasma high-density lipoprotein-cholesterol (HDL-C)

levels are inversely associated with the risk of cardiovascular disease, as demon-
strated in the Framingham study (Gordon et al. 1977). HDL plays a critical role in
reverse cholesterol transport (RCT), which is involved in the removal of surplus
cholesterol from peripheral cells, and its delivery to the liver for excretion and
catabolism (Fielding and Fielding 1995). The RCT pathway works against patho-
logical accumulations of lipid deposit, especially in oxidized LDL (low-density
lipoprotein), in the peripheral cells—a process which eventually results in athero-
sclerosis and coronary artery disease (Ross 1993). The RCT concept was first intro-
duced by Glomset (Glomset 1968), and is basically as follows: HDL facilitates the
uptake of peripheral cholesterol and its return to the liver for excretion in the bile
acid and feces. As shown in Fig. 1.4, excess cholesterol in the peripheral cells can
be taken up by nascent HDL (discoidal type), and the nascent particles are caused to
mature into more spherical HDL (HDL3 and HDL2), by lecithin:cholesterol acyl-
transferase (LCAT) during their transport to the liver for excretion. Until now, this
RCT pathway has been thought to be a unique natural cholesterol excretion pathway
(Lewis and Rader 2005). Numerous reports have corroborated the assertion that
RCT functions as a protective mechanism against atherosclerosis. It has been sug-
gested that HDL may protect against atherosclerosis via the promotion of RCT
(Miller and Miller 1975).
Apolipoprotein (apo)A-I is the principal protein component of HDL. ApoA-I is
synthesized in the liver (~70%) and intestine (~30%), and is secreted into the blood
in a lipid-free state (Zannis et al. 1985). The lipid-poor or pre-beta forms (discoidal
shape) of apoA-I that evidence conformations different from the bulk of plasma
apoA-I may prove to be particularly efficient at the promotion of free cholesterol
(FC) efflux during the first step of RCT (Fig. 1.4). Although little remains known
regarding the details of this process, lipid-poor beta HDL (nascent HDL) is capable
of taking up cholesterol from macrophages in the artery wall via the ATP-binding
cassette A-1 receptor (ABCA-1) (Brewer 2004; Oram 2003). Disc-shaped HDL-
particles can be formed by association with phospholipid (PL), FC and apoA-I with
7 to 12 nm diameter.
1.2 HDL Functions and Clinical Applications 5
Fig. 1.4 Schematic illustration of reverse cholesterol transport. (LPL lipoprotein lipase, HDL
high-density lipoprotein, SR-BI scavenger receptor B-I, CETP cholesteryl ester transfer protein,
LCAT lecithin:cholesterol acyltransferase, PLTP phospholipid transfer protein)
In the blood circulation, these nascent particles are matured and rearranged by
lecithin:cholesterol acyltransferase (LCAT), which can esterify FC into cholesteryl
ester (CE), and apoA-I functions as an crucial modulator of this reaction (Jonas
1998). The accumulated CE is packaged into the core of the particle, resulting in the
formation of the HDL2 and HDL3 particles with spherical shape, which constitute
the main plasma HDL. On the delivery end of the pathway, apoA-I has important
role in that it provides HDL-cholesterol for steroid hormone and bile acid synthesis
in the adrenals and liver, via interactions with the scavenger receptor type B class I
(SR-BI) (Yancey et al. 2003). Alternatively, HDL-cholesterol can be transferred to
apo-B-containing proteins (LDL, IDL, VLDL), via the action of cholesteryl ester
transfer protein (CETP) in the stream. This results in a recycling of cholesterol and
an increasing attenuation in blood circulation especially in LDL-cholesterol, and
potentially back into the artery wall to build up atherosclerotic plaque (Barter et al.
2003).
Several healthy and advantageous functions of HDL and biomedical applications
were illustrated in Fig. 1.5. HDL has anti-aging effects including anti-oxidant, anti-
inflammatory, anti-atherosclerosis and anti-diabetic activity. In addition HDL can
undergo dynamic changes depends on health state such as acute infection, inflam-
mation, oxidative stress, and glycation stress. Therefore, native HDL can change
into dysfunctional HDL with different lipid and protein composition. This change
can be a biomarker to detect acute phase of HDL, which is more inflammatory and
atherogenic properties. HDL can used as protein drug for regression to take up cho-
lesterol from atherosclerotic lesion via ABCA-1 pump in macrophages. As well as
regression, HDL have capability to wield antioxidant ability in broad range since
apoA-I is potent antioxidant agent.
1.2.1 Functional and Structural Correlations of HDL
As illustrated in Figs. 1.5 and 1.6, HDL wields many advantageous effects for the
maintenance of a healthy physiological system, including antioxidant, anti-
inflammatory, and anti-thrombotic effects (Lewis and Rader 2005; Barter et al.
2004). These activities are enabled by in accordance with the composition of essen-
tial apolipoproteins and associated enzymes. However, the favorable characteristics
and functions of HDL can be hampered via interaction with reactive oxygen species
(ROS), glycation stress, and oxidized LDL (oxLDL)-induced inflammation
(Fig. 1.6).
Fig. 1.5 Many healthy activities of HDL and its application as a biomarker, protein drug, and
delivery vehicles
1.2 HDL Functions and Clinical Applications 7
Fig. 1.6 Various advantageous functions of HDL. In normal circulation, healthy HDL perform
anti-oxidative and anti-atherosclerotic functions. However, the advantageous functions of HDL
can deteriorate and become atherogenic and prooxidative as the result of modification by ROS,
MPO, and LPO, as well as inflammation stress. (ROS reactive oxygen species, MPO myeloperoxi-
dase, LPO lipoxygenase)
1.2.2 Anti-atherosclerotic Function of HDL
Multiple lines of epidemiological data and cohort studies have indicated that HDL-C
is an inverse predictor of progressive atherosclerosis and prospective coronary
artery disease (Gordon et al. 1977; Miller et al. 1977; Goldbourt and Medalie 1979).
Although HDL’s physiological effects were discovered long time ago, the first in
vivo experiment designed to characterize the anti-atherosclerotic functions of HDL
was conducted in 1990, using New Zealand White rabbits in which atherosclerosis
was induced. Weekly blood infusions of HDL (50 mg of protein) for 30 days under
a high-cholesterol diet induced a reduction in the development of aortic fatty streaks
in the experimental rabbits (Badimon et al. 1992).
1.2.3 Antioxidant Properties of HDL
ApoA-I has capability to remove LDL lipid hydroperoxide in vitro and also in vivo
when infused into mice and humans (Navab et al. 2000). A potent antioxidant abil-
ity against LDL oxidation has been recognized as one of the primary advantageous
effects of HDL in the prevention or attenuation of the progression of atherosclerotic
lesion formation. The antioxidant activities of apoA-I and its variants, apoA-IMilano
and apoA-IParis, in the lipid-bound state have been well-characterized thus far
(Bielicki and Oda 2002), but similar activities of the both apoA-I variants in the
lipid-free state have yet to be investigated. However, the review of Pownall and
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difficulty that the prudence of Turenne was able to keep under the
widespread dissatisfaction.
The policy of Mazarin’s “education” of the young king was already
bearing the fruit of the future misery of the country which his
Eminence’s alien authority so disastrously ruled.
The intimacy of Ninon and Marie Mancini grew into friendship, and
Marie’s confidences made it clear to Ninon that it was her uncle’s
intention, if not her own avowed one, that she should be the wife of
Louis XIV. But the constancy of the great young monarch was ever a
fragile thing.
CHAPTER XII
The Whirligig of Time, and an Old Friend—Going to the Fair—A Terrible

Experience—The Young Abbé—“The Brigands of La Trappe”—The New
Ordering—An Enduring Memory—The King over the Water—Unfulfilled
Aspirations—“Not Good-looking.”
Tempora mutantur. Ninon, in the course of the years which were now
bringing her to middle life, had seen many changes; but when her
friend St Evrémond came back about this time from the wars, after
seven or eight years’ absence, he told her that she had not changed
with them. Beautiful and youthful-looking as ever he assured her she
was, and to prove his words, he took a little mirror in one hand, and
in the other the portrait Rubens had painted of her years before, and
bade her make the comparison herself.
There is little doubt, at all events, that Time’s finger had scarcely
dulled the delicacy of her complexion, or the brightness of her eyes.
Were thanks due to the Man in Black for this? It was a question
she put to St Evrémond very seriously, but the cheery Epicurean had
only a smile and a witticism for answer. The devil, he assured her,
did not exist, and he proposed to escort her to the fair of St Germain
that fine February afternoon. This was scarcely the best way to make
good his assertion; for if his Satanic Majesty was to be found in
Paris, it was certainly in that quarter; for was not the rue d’Enfer,
whence the Capucins had ejected him from his house, hard by?
This, however, had by no means hindered the brethren of St
Germain des Prés countenancing the proceedings, which had come
to be near to an orgy, of the annual market, or fair of St Germain des
Prés—by the letting their ground for it to be held upon. From the
king, to the most villainous of the populace, everybody went to the
fair. The booths were within hail of the ground known as the Pré aux
Clercs, the haunt of the basochiens, the lawyers’ clerks of the Palais
de Justice, away upon the Ile de la Cité, between St Sulpice and St
Germain—the church of the three steeples. The roof of the modern
flower-market now covers this ground. Everything conceivable could
be purchased at the stalls, from the richest silks and velvets to a
pancake or a glass eye, or a wooden leg or a wax arm, or essences
and waters for turning old people young again; every game of
chance, thimblerig, lottery, cards, held out its temptation; every kind
of entertainment, dancing, tumbling, jugglery, music of fiddle and fife,
and drum and tabor—a deafening tintamarre; all kinds of beverages
—wine, cider, tea, coffee—“to drive away melancholy;” syrups were
concocted for the dust-dried throats of the surging crowd of fine
ladies, students, lackeys, soldiers, dainty-shod, short-cloaked, blond-
bewigged abbés, pages, beggars, gipsies. Respectable bourgeois
families rubbed shoulders with flaunting women, and the wretched
crew of mendicant impostors from the old cours de miracles. Often it
was the scene of fracas and fisticuffs and damaged countenances.
On one occasion, a page of the Duc de Bouillon cut off the ears of a
clerk of the basoche and put them in his pocket. The students of the
quarter fell to murderous assault upon the fellow, while the pages
retaliated, and many a dead body of page and student was found
afterwards in the ditches of the Abbaye. At once an earthly paradise
and a pandemonium was the time-honoured annual market of St
Germain des Prés, and in the midst of the madding riot and
confusion a great deal of serious business was transacted among
the merchants and foreign traders who came from afar to exhibit
their wares, as for centuries had been the custom, ever since
mediæval day, when church porches and convent gates were nearly
the only rendezvous for buying and selling.
Not absolutely accepting St Evrémond’s theory, Ninon and her
cavalier left the fair to walk homewards, little thinking that they were
to be confronted by the blood-chilling tale the pale lips of Madame de
Chevreuse poured hurriedly out to them from the window of her
carriage, which she called to a halt as they passed across the Pont
Neuf—a tale upon whose precise details the chronicles of the time
slightly differ, even to casting doubt upon it as a fact, though the
circumstances are no more than consonant with probability. The
beautiful but profligate Madame de Montbazon, it will be
remembered, had been sent by the queen, on account of her glaring
attempts at mischief-making, to reflect upon her misdeeds at Tours.
It was held that she would not find the punishment so tedious and
unpleasant as it might have been if M. l’Abbé de Rancé had not
been in the neighbourhood. He was her lover, and a most ardent
one, constantly by her side, but not to persuade her to penitence; on
the contrary, de Rancé was wild and profligate of life as the woman
he adored. He was brilliantly clever. At school he out-rivalled his
class-fellow Bossuet, and when but thirteen, he published an essay
on the dignity of the soul; and beneath his dissolute ways the gold of
a conscience, of which so many of the Courtly circle in which he
moved seemed absolutely devoid, often shone through. Armand
Jean de Rancé was one of an old and distinguished family, and he
was only ten years old when the Abbey of la Trappe in Normandy
was bestowed on him.
The monastery of la Grand Trappe du Perche, said to have been
so named from its hidden position among the dense forests of the
stormy Norman headland, is of very ancient foundation. It was
established in the twelfth century by Robion, Comte du Perche. The
brethren followed the Cistercian rule, and for several centuries it was
in high repute for the sanctity of its community, and for its wealth,
which was put to its legitimate charitable uses. In course of time, like
so many other abbeys, it was given in commendam, and its pious
repute fell away to such an extent that the seven monks—all that
remained in the monastery—were called by the surrounding
peasantry “the brigands of la Trappe.” They were notorious for their
evil-living, spending the time in drinking and hunting; and shunned
alike by men, women and children, the Trappist monks were the
terror of the district.
It was at this time that the child, Armand de Rancé, was made
Abbé, and affairs at la Trappe continued to fall from bad to worse. As
de Rancé grew up, among many benefices conferred on him, he was
appointed Almoner to the Duke of Orléans, and spent most of his
time in a whirl of dissipation in the Courtly circles in Paris. His
splendid entertainments, his magnificent house, the trappings of his
horses, especially those of the chase, were the talk of Paris, and his
daring intrigues startled even the licence indulged in by the society
he moved in. In this circle de Rancé specially singled out the
stepmother of the Duchesse de Chevreuse, Madame de Montbazon,
a woman as notorious for her profligacy and unscrupulous character
as she was physically beautiful.
After a time spent in banishment at Touraine, she had been
permitted to return to her Paris home, and de Rancé, who had been
absent for a short time, returning to Paris, hastened to call upon her.
Arrived at the house, he found it deserted, and passing in by an
open door, he hurried along the silent passages, calling for the
servants and upon her name, but there was no response. At last he
reached the door of her apartments, and rushing across the
anteroom, he flung aside the portières of her bedchamber. An open,
trestle-supported coffin, across which a sheet lay carelessly flung,
met his eyes, and turning from it to the table close by, the
decapitated head of Madame de Montbazon confronted him.
Momentarily he failed to recognise the features of the ghastly object;
for the face was blurred with the ravages of smallpox. The fell
disease had attacked Madame de Montbazon, and she had died of
it. The body and head were being prepared for embalming, and for
this end—or as some versions of the tale tell, because the coffin had
not been made long enough—the head had been cut off, and placed
upon the table.
The silent horror of this ghastly experience carried an eloquence
beyond all power of words to the heart of de Rancé. Swayed by a
revulsion of feeling, naturally sensitive and imaginative, he looked
back upon his past life with loathing. The hollowness of worldly
pleasures, and uncertainties of a worldly existence were yet still
more deeply impressed upon his mind, by a serious accident he
suffered in the hunting-field, and by the death of his patron, the Duc
d’Orléans. All seemed vanity.
De Rancé was at this time thirty-four years old. With the exception
of the ancient monastery of la Trappe, lost amid the wild forests
verging on the perilous rock-bound shores of extreme North-Western
Normandy, he divested himself of his property and possessions, and
went to take up his residence in la Trappe, endeavouring to establish
the old discipline in it. But the seven spirits he found there were
unruly, and had no mind for being disturbed. So entirely were they
opposed to the abbé’s reforms, that his life was in danger from them,
for they threatened to throw him into the fish-ponds; and Brigadier
Loureur, stationed at Mortagne, the nearest town of importance,
begged de Rancé to accept a guard of his soldiery; but de Rancé
decided that since the brigands of la Trappe had clearly less than no
vocation for the vows of poverty, chastity, and obedience, they were
best entirely got rid of—and he pensioned them off and sent them
away, not in wrath, but in peace. Their place was filled by Cistercian
brethren of the strict observance.
The position of an abbé, or for that matter, an abbess in the ranks
of the Church, had long become an anomalous one. The relaxation
of the old rigid conventual ruling had wrought great changes. It was
not unusual to find some lady of a noble family appointed to the
nominal charge of a monastery, and some equally nobly-born
gentleman set over a community of nuns; and in either case, as
likely as not, they had no knowledge, or next to none, of the
everyday mode of life or working of such community. At the fair of St
Germain the abbés always swarmed thick as flies, in their short
black habits and delicate little linen bands, as where did they not
congregate in the society of the time? The salons of the Hôtel de
Rambouillet and other brilliant assemblies were dotted all over with
them. They were the makers of petits vers and bouts rimés, and, if
nothing more, pretty well indispensable to the following of a fine lady
as cavaliere serventis. They were wont to make themselves
generally amusing and agreeable, everything, in short, but useful to
the spiritual needs of the Church in whose ranks they were
supposed to serve. They wore their vows too lightly for the Abbé de
Rancé to dream of exercising real authority in virtue of the title alone;
and he qualified himself for the dignity he intended to assume of
Superior of the monastery of la Trappe in Normandy—by entering as
a novice in the Cistercian Abbey of Persigny. This ended, he took the
vows, in company with a servant who was deeply attached to him,
and was confirmed abbot.
The order of strict Cistercian observance is rigid in the extreme—
almost utter silence, hard labour, total abstinence from wine, eggs,
fish, and any seasoning of the simple fare of bread and vegetables.
The earnestness and eloquence of de Rancé stirred the men
desirous of joining the brotherhood to such a deep enthusiasm, that
many of them wanted to take the full vows at once; but the Abbé of
la Trappe refused them this, lest they should not have truly counted
the cost of their sacrifice. And not only in this case, but in others the
famous reformer of the ancient monastery showed a singular
judgment and reasonableness in the ordering of his community. And
“his works do follow him”; for still as of old, hidden amid those dark
forests, though not far from the haunts of men, stands the Priory of
Notre Dame de Grâce de la Trappe, its brethren, spending their time
not given to devotion, in alms-giving and healing and acts of charity
of every kind.
In England, meanwhile, great if not unanticipated changes had
befallen. Oliver Cromwell was dead. He had passed away in
comparative peace in his bed. Had his days numbered even a few
more, they might have terminated in assassination, for deep-laid
schemes for this were hatching. The dreary Commonwealth was
growing daily more displeasing, and the English people were longing
for the king to have his own again. It was a day of joy indeed to
Queen Henrietta Maria which saw the progress of King Charles II. to
London. She had some desire that he should wed la Grande
Mademoiselle, Gaston d’Orléans’ daughter; but Mademoiselle
nursed a hope of becoming the wife of her cousin, Louis XIV., a hope
that was not to be realised. Possibly, as Mazarin had said, the
Bastille cannonading had killed that husband; but after her long
wanderings she was again at Court, and in fair favour.
Louis XIV., without being strictly handsome, had agreeable
features and a fine presence, which his pride and self-consciousness
knew very well how to make the most of. He had grown from the
mere youth into a dignified, courtly young manhood, and the want of
knowledge and defective bringing up were fairly well concealed by
“the divinity which doth hedge a king.” It certainly always enfolded
Louis XIV. “Ah, my dear cousin,” cried Queen Christina of Sweden,
when she first saw him, “some one told me you were not good-
looking! Sacré-bleu!” she added, bestowing a sounding kiss on both
of Louis’s cheeks, “if I had the man who told that lie here, I would cut
off his ears before you!” and she still stood gazing admiringly at the
king. So there could be no further doubt about his attractive
appearance; for Queen Christina was accounted an unerring judge
in such matters.
CHAPTER XIII
Christina’s Modes and Robes—Encumbering Favour—A Comedy at the Petit-

Bourbon—The Liberty of the Queen and the Liberty of the Subject—Tears and
Absolutions—The Tragedy in the Galérie des Cerfs—Disillusions.
Christina, ex-Queen of Sweden, was not more nice in style of dress

than she was in the choice of a word to add strength to her
affirmations, and “sacré-bleu” was a mild sponsor for the swear-word
she really selected on the occasion. The startling force of it,
combined with the extraordinary costume she wore, excited an
irrepressible burst of laughter from the queen and from Mazarin, and
all present followed suit—all but the king, who looked disconcerted
and rebukeful.
Christina wore a wig, standing up high over her forehead, with
tufts of curls sticking out, all rough and tousled, on each side of her
face, which was, however, far from really ill-looking. She had on a
coat, which was a cross between a man’s pourpoint and a woman’s
cape, put on so carelessly that it left one shoulder half-exposed. Her
skirt was not cut à la mode into a long train; it was merely a round
petticoat, so short as to afford ample display of leg. A man’s shirt and
a man’s boots completed this costume, in which the great King of
Sweden’s daughter presented herself to the Majesties of France.
She met the risible gaze of the Court with displeasure, and
inquired what they were all staring at. “Am I humpbacked?” she
demanded, “or aren’t my legs well-shaped?” The king, with courtly
good-nature, threw oil on the troubled waters, and Christina was
pacified, observing that Louis spoke like the king and gentleman he
was. “And as for you others,” she added to the rest, “mind
yourselves.”
Ninon, who was indisposed, was not present at this scene; but
recovering some days later, she went to the Louvre, where, thanks to
her friend Madame de Choisy, she came and went constantly; and
as she passed along a gallery leading to that lady’s apartments she
met Madame de Choisy and Christina, who was attired in very much
the same manner as already described, but slightly less outré.
The queen was fascinated at first sight with Ninon. She placed her
two hands on her shoulders and gazed long and fixedly into her face.
“Now I understand, my dear,” she said at last, “all the follies the men
commit, and will commit for you. Embrace me,” and she bestowed
two such sounding kisses on Ninon’s cheeks, as she had bestowed
on the king’s. Then taking her by the arm, she led her to her own
assigned apartments, at the door of which stood two bearded men,
one of them Count Monaldeschi, her Grand Master of the Horse, the
other the successor of the redoubtable Desmousseaux, the
Chevalier Sentinelli, captain of her guard.
Some time before her visit to Paris, Christina had abdicated,
declaring that the formalities and restrictions of the existence of a
crowned queen were unendurable, the cares of a kingdom rendered
life a slavery, and she desired perfect liberty. The liberty she sought
for herself, however, she in no wise extended to others; for while she
renounced her claims to her inherited kingdom, she reserved to
herself absolute and supreme authority, with the right of life and
death over all who should enter her service or be of her suite. Then,
a Protestant born, she joined the Catholic communion. It was
probably a mere caprice; for she did not spare her coarse witticisms
on the newly-adopted faith, and very soon she contrived so seriously
to offend the College of Cardinals that she was forced to leave
Rome, which she had entered on horseback, dressed almost like a
man. After a while she had come to France, and probably somewhat
impressed with the elegancies of the Court, she made some
modification of the hideous attire she had first appeared in. When
Ninon first met her in the Louvre gallery, Her Majesty wore a grey
petticoat skirt of decent length, trimmed with gold and silver lace, a
scarlet camlet coat, her wig was of the unvarying pale yellow hue,
and she carried a handkerchief of costly lace, and a broad-brimmed
hat, plumed with black ostrich feathers. With her white skin, her
aquiline nose and fine teeth, she would have made a very
presentable boy.
She was very voluble, and her immeasurable admiration of Ninon
to her face, was almost disconcerting, even to one so very well
accustomed to compliments. At last, the subject being exhausted,
the ex-queen fell to asking all sorts of questions about the king, the
queen, the cardinal, the new palace at Versailles, the Italian Opera.
Then she had much to say about her own country and her
abdication; about Descartes, who had died at her Court a victim to
the climate; about Count Monaldeschi, with whom, she confided to
Ninon, she was on terms of very close intimacy, and about a
hundred other things.
During Christina’s stay in Paris, Ninon had the delight of seeing
again that most dear friend and protégé of hers, Molière, after his
long absence in the provinces. Christina was with Ninon when he
arrived, and as he and his company were to play that same night the
Cocu Imaginaire, at the Petit-Bourbon, it was arranged that the two
ladies should be present.
Christina had the appetite of an ogress, and before they started for
the theatre, she did ample justice to the handsome repast Perrote
served up. Then Her ex-Majesty summoned her captain of the
Guards, and Grand Master of the Horse—who had been regaled in
another room on turkey and other dainties, and they repaired to the
Petit-Bourbon.
The evening proved anything but enjoyable to Ninon. A market-
woman would have comported herself more decently than this
eccentric, semi-barbarous royal person. She greeted the sallies of
the actors with loud shouts of laughter, and used language that was
rankly blasphemous; while she wriggled and lolled in her chair, and
stretched her feet out among the footstools and cushions, in
appalling fashion. It was in vain Ninon respectfully intimated that the
eyes of everybody were upon them; Christina’s only reply was to beg
her to let her laugh as much as ever she wanted.
The queen’s liking for Ninon grew embarrassing. Six months of her
constant society were almost more than the most good-natured
tolerance could endure, and for that length of time the favour of the
queen’s presence was bestowed on Paris. Then Cardinal Mazarin,
also more than tired of her, entertaining moreover, suspicions that
she was brewing political mischief, contrived to tempt her to seek
change of air and scene at Fontainebleau.
Christina caught the wily cardinal’s bait. Very well—yes, it was a
good idea. She had a great desire to see the renowned palace that
Francis I. had loved so well, and to Fontainebleau, to the relief of
Ninon and of divers other people, the ex-queen went: not to remain
long, however. One morning, at a very early hour, the Chevalier
Sentinelli arrived at the rue des Tournelles and informed Ninon that
she was wanted at the Palais Royal, by his royal mistress, who had
returned to Paris.
It was useless to devise some excuse for not obeying the
summons—invitation, or what it might be—for that was only to bring
the queen herself to the rue des Tournelles; and so to the Palais
Royal Ninon went, to find Christina stretched upon a miserable
pallet-bed, with an evil-smelling, just-extinguished candle on the
table beside her. A serviette did duty for a night-cap, tied round her
head, which was denuded of every hair; for she had had it shaved
close on the previous night. Christina presented a strangely
grotesque and wretchedly miserable picture. Seizing Ninon by both
hands, she told her that she was suffering the deepest agony of
mind—a grief that was horrible—and begged her to stay by her. At
this moment, Sentinelli entered, and a whispered conversation
ensued. “Oh, they will prevent me?” she cried then. “They will
prevent me, will they? Let them dare. Am I not a queen? Have I not a
right to high justice? Very well, then,” she went on, when again
Sentinelli had bent to whisper again. “We must dissimulate. I will go
back to Fontainebleau. There at least, I can do as I please,” and she
prevailed on Ninon to accompany her. And there in the Galérie des
Cerfs at Fontainebleau the hideous tragedy was enacted. The farce
of this woman’s daily life fades out in the thought of her ferocity and
revengeful instincts. Monaldeschi had offended her: he had done
worse, he had been treacherous towards her. Pitiless, with eyes
glittering with rage and hatred, she stood in the Galérie, where the
fading daylight was illumined by the flare of the torches held by her
pages, and taxed the wretched culprit—pleading for mercy at her
feet—with his crimes; but it was not accorded; “Ah, let me live!” he
entreated—“let me live!”
And Ninon, who had dreaded something, but was utterly
unprepared for such a frightful scene, joined her entreaties to his and
to those of his confessor, the monk Lebel. “Ah, no! A woman,” she
sobbed, “cannot give an order for this man to die.”
“I am not a woman,” replied Christina; “I am a queen, and I have
the right to punish a traitor.” She gave the signal. There was a fearful
struggle, the flash of Sentinelli’s sword, an agonised cry, a crimson
stream upon the floor—and then the silence of death.
It had been with extreme reluctance that Ninon had accompanied
the queen to Fontainebleau; but for all Christina’s enigmatical and
elaborate preparations before starting, any conception of her
murderous intentions did not occur to Ninon. She had grown
accustomed to the royal lady’s freaks and eccentricities. On this
occasion, Christina had sent for a confessor, and having attired
herself from head to foot in black, she knelt before him when he
arrived, and first desiring Ninon not to leave the apartment, but to
seat herself in a distant corner of it, she muttered out to the
perplexed-looking Bishop of Amiens—whom she had sent for, he
staying at that time at the Tuileries, spending a kind of brief retreat—
what she had to say.
It occupied some five minutes, and as she proceeded, an
expression of deep discomfiture and perplexity overspread the
bishop’s face. He gave her a hurried absolution, and departed, while
Christina went to the chapel of the Feuillants and communicated. All
these pious preparations had disarmed Ninon of any extreme of
uncomfortable suspicion she might have entertained. Christina could
not possibly be nursing any evil intentions—while Ninon was a
woman, and curiosity had impelled her to Fontainebleau, to see what
was the end of the affair, and find out the cause of such floods of
tears.
In the coach with them were Monaldeschi and Sentinelli. To the
first she did not address a single word throughout the journey. It was
nearing five o’clock, and night was shadowing in, when they arrived;
and when they had had supper, Christina commanded Monaldeschi
to go to the Galérie des Cerfs, where she would presently come to
him. Then she bade Sentinelli follow the count, and motioning Ninon
to accompany her, she proceeded between two rows of Swiss
Guards, armed with halberds tied about with black crape, to the
Galérie. Now thoroughly fearful, Ninon had followed with trembling
limbs. “In Heaven’s name,” she faltered, “what does this mean,
Madame?—something terrible is about to happen.” With an evil
smile Christina threw open the double doors, disclosing
Monaldeschi, with his hands fast bound, kneeling at the feet of
Lebel, whose features were ghastly with consternation at the task
imposed on him, of hearing the doomed man’s confession.
At sight of Christina, Monaldeschi turned, and his agonised cry for
pardon rang through the Galérie; but there was no mercy in that
hideously hate-distorted face; and so, in cold blood, the murder was
perpetrated, and out into the darkness Ninon rushed, calling for a
carriage to bear her from the terrible place, heedless of the queen’s
gibes and endeavours to persuade her at least to remain till morning.
It was nothing—what she had done, she said; “only a traitor had
received his deserts, and the world was well rid of him.”
But the coach drew up, and Ninon fled into its shelter, never
stopping till she reached home. There she took to her bed in a high
state of fever, having ever before her the terrible scene of blood at
Fontainebleau, and for three weeks she remained prostrated by the
memory of it. She never saw Christina again, neither did Paris.
Though the Court took no proceedings against her—insult to
hospitality as her act was, all other considerations apart—she was
avoided, and regarded with loathing, and she planned for herself a
visit to England. But Cromwell had already supped full of murder.
The image of it was sufficiently haunting, and the endeavours of his
conscience to make peace with Heaven before he died were not to
be disturbed by the presence of such a woman. He turned his face
from her instead, and Christina betook herself to Rome, where she
fell deep in debt, and quarrelled fiercely with the pope.
Overweening ambition was the bane of this undoubtedly clever
woman. In the murder at Fontainebleau, it is thought that vanity and
the love of power tempted her to display what she was pleased to
regard as a full length of it. Exactly the nature of Monaldeschi’s
offence remains unexplained. Christina said he had grossly betrayed
her, and some assert that it was politically he had done so; but it
seems more probable that he was a traitor in love. She defended
herself by saying that she had reserved every right of life and death
over all who were in her service. The atrocious deed caused a
sensation in Paris; especially among those of whom the ex-queen
had been a guest, and Anne of Austria sent for Ninon to relate all the
details of her fearful experience at Fontainebleau.
The chief topic of conversation and speculation now was the
marriage of the young king. It was well known that Mazarin hoped to
crown his successful ambitions, by marrying his niece, Marie
Mancini, to Louis, and that Anne of Austria was as strongly opposed
to any such alliance was equally well-known. It was her wish and her
will that Louis should wed the Infanta Maria Théresa. Any thwarting
of this project, the queen vowed, should bring about the setting aside
of Louis, and placing her second son on the throne of France in his
stead—“La reine le veut.” Mazarin had to bite the dust. The
preliminaries for the Spanish marriage were set on foot. The French
and Spanish emissaries met on the Isle of Pheasants. Poor Marie
Mancini, who had a sincere affection for her young royal admirer,
was sent out of the way for a month into the convent of the
Daughters of Calvary, which was hard by Ninon’s house. Louis
whispered in her ear at parting, that if the king was separated from
her, the man would never cease to think of her. Then he whistled to
his dogs, and with his courtly train went hunting in the woods of
Chambord. So ended the love-story of Mazarin’s niece, Marie
Mancini. So much “for the snows of yester year”; but there had been
warm affection between Ninon and the young girl, and they parted
with many tears.
CHAPTER XIV
Les Précieuses Ridicules—Sappho and Le Grand Cyrus—The Poets of the Latin

Quarter—The Satire which Kills—A Lost Child—Periwigs and New Modes—
The Royal Marriage and a Grand Entry.
Molière’s comedy, Le Cocu Imaginaire—which had created such

unrestrainable delight in the ex-queen of Sweden—had been
preceded a year earlier by the famous Précieuses Ridicules. To call
this play the dramatist’s masterpiece, is to do rank injustice to his
work of greater length and importance, notably, if one dare to
choose, to Le Tartufe. The Précieuses, however, took Paris by storm,
and was accounted a gem. Still a delightful little bit of humour, and
not lacking now in its way of a home-thrust, it carried a double-edged
power in the days of the Hôtel de Rambouillet, when the affectations
of speech and conversation had run to such absurd extravagance,
that Molière’s satire was little or no exaggeration. Mademoiselle de
Scudéri’s “Inutile! retranchez le superflu de cet ardente,” is distinctly
precious.
Of the queens of these intellectual réunions, Mademoiselle de
Scudéri was the reigning novelist. Her long life, exceeding Ninon’s in
years, was devoted to the production of romances and the lighter
sort of literature, which ran to a lengthy record. Le Grand Cyrus
stands best remembered, but is scarcely more than a memory. A
long day’s journey would be needed to find the most ardent of fiction-
readers who would now care to follow through the windings of that
romance which in its day created such enthusiasm, and made a
lioness of the amiable if some way from beautiful Madeleine de
Scudéri. Artamène; ou, le Grand Cyrus, after all, was, to be sure,
scarcely fiction. It was composed of little more than thinly-veiled
facts, presenting under classic names the living men and women of
society; heroes and heroines of antiquity stood sponsors to the fine,
broad-skirted, perruqued gentlemen and fashionable dames of
Versailles and the Louvre and the Palais Royal. Artaban, Agathyse,
Zenocrates—these were, in their modish habit as they lived,
severally the Duc de St Bignon, M. de Rainez, M. Ysern, and others
—while Mademoiselle de Scudéri herself was Sappho. It was in her
salon that was drawn up the famous Carte du Tendre—gazetteer of
articles necessary to the pursuit of love. Mademoiselle de Scudéri
wrote with grace and much sense; but her romances were
insufferably prolix. Ninon found them wearisome to a degree, even
though the Grand Cyrus is a record of the great Prince de Condé.
George de Scudéri, Madeleine’s brother, was also a very fertile
novelist of his day, scarcely to be rivalled in speed of production by
Dumas himself. Nor does there appear that the ghosts who worked
for this great, more modern enchanter of the realm of historical
romance, rendered any services to the seventeenth-century novelist.
The salons of Madame de Rambouillet and of Madame de Sablé
were the rendezvous of the most aristocratic of these versifiers and
epigram-makers, who really occasionally uttered something witty or
poetical; though for the most part the wit and poetry did not rise
above such greatness as that of Sir Benjamin Backbite, in Lady
Sneerwell’s drawing-room, on the macaroni ponies whose
“Legs were so slim,
And their tails were so long.”
The refinements and elegance of speech to be heard at those

réunions, fostered, and indeed were a powerful influence in, the
reformation effected by the Académie for the French language. But
the passion for these improvements was often torn to tatters, and the
puerilities and affectations excited a reaction among men of the
more Bohemian class of writers and versifiers, such as Scarron, St
Amand and others, and the curious mixture of real poetic expression
and thought, profanity and coarseness, in their productions, carry
back to the days of Rabelais and of Villon, with echoes of Ronsard
and of Charles of Orléans. But the simplicity and beauty of their
numbers only now and again shone through the grossness of their
compositions, and sheer opposition to the “Clélies” and “Uranies”
and “Sapphos” probably inspired the numerous parodies and the
odes to cheese and good feeding produced by these authors, who
hailed with delight the now famous actor-manager Molière’s
Précieuses Ridicules.
The piece was first produced at the Petit-Bourbon early in the
winter of 1659. The plot, deep-laid if simple, consists of the
successful playing off by two lovers respectively of the two charming
young women they love honestly and deeply, but who meet refusal
on the score of their language being too natural, and their attire not
sufficiently fashionable. The two young men thereupon dress up their
valets, Mascarille and Jodelet, in fine costumes, bestow on them the
titles of marquis and vicomte, and contrive to introduce them to the
précieuses. The exquisite humour of the dialogue between Gorgibus,
the father of one of the two girls, and uncle of the other, sets the ball
rolling; his contempt for the new names, Aminte and Policène, which
they have selected in place of those given them, as he says, by their
godfathers and godmothers; his dim grasp of what he calls their
jargon, when they try to instil into him some idea of its elegancies, is
the essence of genuine comicality, as are the compliments of the two
aristocratic visitors who inform the ladies that it is the reports of their
exquisite attractions and beauty, reaching far and wide, which has
brought them to their feet. Then follows the flutter of delight, veiled
under the attempt at calm graciousness, of the précieuses. “But
Monsieur,” says Cathos to Mascarille, the marquis, inviting him to sit
down, “I entreat you not to be inexorable to this armchair, which has
been stretching out its arms to you for this quarter of an hour past;
allow it the satisfaction of embracing you.” The fun grows apace, as
the slips of tongue and bearing of the two pretended gentlemen
begin to disconcert the two infatuated girls. At last a dance is
proposed, the fiddlers are sent for, and behind them enter the two
masters of the valets, who tear their fine coats off their backs, and
turn them out. “And you,” says Gorgibus, chasing the précieuses
from the room, to repent at leisure of their affectations and thirst for
la galantérie, “out of my sight, and to the devil with all these verses,
romances, sonnets, and the rest of it—pernicious amusements of
do-nothings and idlers!” So the curtain descended on the Précieuses
Ridicules, and the story goes that before very long the play
extinguished the glory of the salon of the Hôtel de Rambouillet.
The Comte de Fiesque, who had gone with Condé to Spain, was
killed in Catalonia by the bursting of a bomb. Ninon, not able
personally to ask the widow where the child was which de Fiesque
regarded as his, commissioned two persons to ascertain for her from
Madame de Fiesque some intelligence concerning its whereabouts,
but the countess asserted that she had no knowledge of this. The
remorse and regret of Ninon were of no avail: she was unable to
trace the lost one.
At last, after long negotiations, Maria Théresa of Austria was
united to Louis XIV. This brought Condé back to allegiance to
France, by the Peace of the Pyrenees, effected by Cardinal Mazarin,
one of the few of his achievements which really benefited France.
Ninon was one in the gorgeous cortège which proceeded to
Grosbois, beyond Charenton, to receive the young princess. It was a
brilliant show. The fashions of the early days of the young king had
greatly changed since his father’s time, which was so greatly
distinguished, at least as far as male attire went, for its elegant
simplicity. Bright hues had superseded the black, the beautiful but
sombre colouring of the material of the silk or satin or velvet doublets
with large, loose slashed sleeves; the falling bands of rich point lace;
the long, straight, fringed or pointed breeches meeting down to the
lace-ruffled or lawn wide-topped boots, and the eminently graceful
Flemish plumed beaver hat. In place of the long hair waving to the
neck, full-bottomed periwigs had come into vogue; the doublets were
short and waistcoatless, displaying a bulging shirt-front, tied with
ribbons to the nether garments, which, like the large loose sleeves,
were covered with points and bows; deep lace ruffles drooped from
the knees, and only the falling collar, with a hat higher crowned than
of yore, but still plumed, remained of the old style.

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High-Density Lipoproteins as

Biomarkers and Therapeutic Tools:

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This book is designed to demonstrate many aspects of high-density lipoprotein

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1.1 HDL and Disease

© Springer Nature Singapore Pte Ltd. 2019 1

Fig. 1.1 World leading cause of death

1.1.1 Dysfunctional HDL and Diseases

Fig. 1.3 Various diseases and dysfunctional HDL

1.2 HDL Functions and Clinical Applications

It has been established that plasma high-density lipoprotein-cholesterol (HDL-C)

1.2.1 Functional and Structural Correlations of HDL

1.2.2 Anti-atherosclerotic Function of HDL

1.2.3 Antioxidant Properties of HDL

The Whirligig of Time, and an Old Friend—Going to the Fair—A Terrible

Christina’s Modes and Robes—Encumbering Favour—A Comedy at the Petit-

Christina, ex-Queen of Sweden, was not more nice in style of dress

Les Précieuses Ridicules—Sappho and Le Grand Cyrus—The Poets of the Latin

Molière’s comedy, Le Cocu Imaginaire—which had created such

The refinements and elegance of speech to be heard at those

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1.1 HDL and Disease

1.1.1 Dysfunctional HDL and Diseases

1.2 HDL Functions and Clinical Applications

1.2.1 Functional and Structural Correlations of HDL

1.2.2 Anti-atherosclerotic Function of HDL

1.2.3 Antioxidant Properties of HDL