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Cancer
Oxidative Stress and Dietary Antioxidants
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Cancer
Oxidative Stress and Dietary Antioxidants
Second Edition
Edited by
Victor R. Preedy
Department of Nutrition and Dietetics, King’s College London, London, United Kingdom
Department of Clinical Biochemistry, King’s College Hospital, London, United Kingdom
Vinood B. Patel
University of Westminster, London, United Kingdom
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Preface
The book Cancer: Oxidative Stress and Dietary Antioxidants, Second Edition bridges the transdisciplinary divide and
covers the science of oxidative stress in cancer and the therapeutic use of antioxidants in food matrix in a single volume.
The second edition covers new investigations used to determine the comprehensive properties of antioxidants, food
items, and extracts, as well as any adverse properties they may have. It has been updated to include new clinical human
trials and studies dedicated to models of cancer. Furthermore, studies showing the beneficial effects of plant or natural
extracts provide the foundation for further rigorous studies in clinical trials. Throughout the book the processes within
the science of oxidative stress are described in concert with other processes, such as apoptosis, cell signaling, and
receptor-mediated responses. This approach recognizes that diseases are often multifactorial, and oxidative stress is a single
component of this.
The book Cancer: Oxidative Stress and Dietary Antioxidants, Second Edition contains two sections. Section A
covers oxidative stress and cancer in breast, prostate, lung, stomach, bladder, ovarian, cervical, and colorectal. In
Section B the focus is on antioxidants covering vitamins such as folic acid, vitamin C, vegetarian diets, fruit juices; caffeine
analogues, omega-3 fatty acids, Manuka honey; natural antioxidants such as lycopene, cinnamon, selenium, zinc, as well as
plant-derived products including anthocyanins, polyphenols, ginger root, Lycium barbarum, and fern extracts, where
models of cancer are also discussed.
Each chapter has Summary Points and a section on Applications to Other Areas of Cancer. Finally we conclude with a
chapter on resources and further reading, coverage includes:
Key books and further reading
Key societies
Key research organizations
Analytical platforms
Governmental bodies
Journals covering cancer and oxidative stress
Thus, this text is relevant to biologists, biochemists, nutritionists, dieticians, and nutrition researchers as cancer is a
multifaceted process covering disease processes, clinical research, and treatment.
Vinood B. Patel, Editor

University of Westminster, London, United Kingdom
Victor R. Preedy, Editor

King’s College London, London, United Kingdom
v
Contents
Contributors xix Oxidative stress in carcinogenesis and

cancer progression 19
Oxidative stress in castration resistance 20
Oxidative stress in resistance to other
Section A therapeutics 20
Oxidative stress and cancer Prostate cancer risk factors and their links to
oxidative stress 21
Aging 21
1. Paraoxonases, oxidative stress,
Genetic background (race and family
and breast cancer history) 21
Fatma Ceyla Eraldemir and Tuğcan Korak Androgens 22
Inflammation 22
Introduction 4
Diet 23
Functions and physiological roles of
Lifestyle 23
PON1 4
Conclusions 23
PON1 and cancer: Focusing on breast
Applications to other cancers or
cancer 5
conditions 23
PON1 signaling pathways 5
Summary points 24
PON1 polymorphisms 5
References 24
Function and physiological roles of PON2
and PON3 6
PON2/3 and cancer: Focusing on breast
3. Oxidative stress in lung cancer
cancer 7 Amir Mousapasandi,
PON2 signaling pathways 9 Wei Sheng Joshua Loke, Cristan A. Herbert,
PON3 signaling pathways 10 and Paul S. Thomas
PON2/3 polymorphisms 10 Introduction 28
The paradox: PON activities and BC Lung cancer 28
development 10 Etiology of lung cancer 28
Concluding remarks 11 Tobacco smoking 28
Application to other cancers 11 Air pollution 29
Summary points 12 Infection and inflammation 29
References 12 Radon 29
Genetics 29
2. Oxidative stress and prostate Tobacco smoking and oxidants 29
cancer Silica and oxidants 30
Asbestos and oxidants 31
Masaki Shiota
MicroRNAs and oxidative stress 32
Introduction 15 Radon and oxidative stress 32
Causes of oxidative stress in prostate Inflammation and oxidative stress 32
cancer 16 Oxidative stress leads to DNA mutations
Increased ROS production 16 and lung cancer 33
Impaired antioxidant defenses 17 Lipid and protein peroxidation 34
Role of oxidative stress in the pathogenesis Antioxidants and lung cancer
of prostate cancer 19 prevention 35
vii
viii Contents
Conclusion 35 Anatomy of the oral cavity 57

Summary points 35 Pathology 58
References 35 Premalignant lesions 58
Oral squamous cell carcinoma and
4. Endogenous antioxidants in the treatment 58
prognosis and treatment of lung Oxidative stress 58
cancer The causes of oxidative stress in the oral
cavity 60
Laurie Freire Boullosa, Jinthe Van Loenhout, Endogenous causes 60
and Christophe Deben
Exogenous causes 61
Double-edged sword of antioxidants in Oxidative stress in oral precancer and
cancer 40 cancer 62
Nrf2: Transcriptional regulator of the redox Applications to other cancers or
balance 41 conditions 63
Role of Nrf2 41 Summary points 63
Nrf2 in NSCLC 41 References 63
Nrf2-mediated chemoresistance and
therapeutic strategies 42 7. Oxidative stress, epigenetics, and
Glutathione and thioredoxin bladder cancer
antioxidant systems 42
GSH system 42 Chanchai Boonla
Trx system 44 Introduction 67
Dual targeting of the Trx and GSH Urothelial carcinoma 68
systems 46 Oxidative stress in bladder cancer 69
Application to other cancers 46 Epigenetics in cancer 69
Summary points 46 Epigenetic alterations in urothelial
References 47 carcinoma 70
ROS alters DNA methylation in urothelial
5. Oxidative stress in stomach cancer carcinoma 71
ROS causes alteration of histone
Hitoshi Tsugawa and Hidekazu Suzuki
modification in bladder cancer 72
Introduction 49 Oxidative stress and epigenetic change in
Oxidative stress and host cell 49 other diseased conditions 72
Oxidative stress and H. pylori 50 Summary points 73
Host damage by oxidative stress and References 73
gastric carcinogenesis 51
Oxidative stress and CD44v9-positive 8. Linking oxidative stress and
gastric cancer stem cells 51 ovarian cancers
Applications to other areas of
toxicology 52 Tsukuru Amano and Tokuhiro Chano
Summary points 52 Introduction 77
Acknowledgment 53 Oxidative stress promotes carcinogenesis
References 53 from endometriosis to OCCCs 78
Attempts to prevent development of
6. Oxidative stress and oral cavity OCCCs from endometriosis 78
cancer Antioxidative pathway in OCCC 80
Therapeutic targets for OCCC 80
Ayca Ant
Conclusion 82
Introduction 56 Applications to other cancers or
Oral cancer 56 conditions 82
Etiology 56 Summary points 83
Epidemiology 57 References 83
Contents ix
9. Redox-dependent mechanisms of Diet-induced oxidative stress in relation to

carcinogenesis in human noncommunicable diseases 114
papillomavirus infection Dietary fat in relation to cancer
and CVD risk 114
Cesira Foppoli and Marzia Perluigi Total fat 115
Introduction 87 Saturated fat 115
Cervical cancer 88 Unsaturated fat 115
HPV structure 88 TFAs and cancer risk 118
E6 oncoprotein 88 Cancer and heart disease 118
E7 oncoprotein 90 Summary points 118
E5 oncoprotein 91 References 119
HPV oncoproteins and transcription
factors 91 12. Cancer during pregnancy.
Oxidative stress and cervical cancer 92 Maternal, placenta, and fetal
Oxidative/nitrosative stress markers 92 damage. Nutrition, antioxidant
Antioxidant systems 93 defenses, and adult offspring
Protein oxidation 94 tumor-bearing
Redox control and adaptive mechanisms in
HPV-infected cells 96 Carla de Moraes Salgado,
Natalia Angelo da Silva Miyaguti,
Modulation of stress response markers 96 Sarah Christine Pereira de Oliveira,
Modulation of antioxidant response: Bianca Cristine Favero-Santos,
Peroxiredoxins 96 Laı́s Rosa Viana,
Suppression of oxidative stress-induced Melina de Moraes Santos Oliveira, and
apoptosis 97 Maria Cristina Cintra Gomes-Marcondes
Conclusion 98 Introduction: Cancer and pregnancy 121
Summary points 98 Cancer during pregnancy incidence 121
Acknowledgments 98 Cancer-induced metabolic changes in
References 98 pregnancy evolution 121
Carbohydrate metabolic changes 121
10. Polymorphisms, antioxidant genes, Lipid metabolic changes 122
and cancer Protein metabolic changes 122
Oxidative stress in pregnancy associated
Mazhar Al Zoubi and Alaa Aljabali
with cancer 123
Introduction 101 Placental and fetal changes and viability
Breast cancer 102 associated with cancer 123
MnSOD 103 Nutritional supplementation and positive
CAT 103 effects in pregnancy and oxidant and
MPO 104 antioxidant responses 124
GPXs 104 Maternal diet influence in cancer evolution
Prostate cancer 104 and host responses 125
Gastric, colorectal, and colon cancer 105 Maternal antioxidant diet could affect the
Lung cancer 106 defenses of the adult offspring
Other cancers 106 tumor-bearing hosts 125
Summary points 107 Conclusion 126
References 107 Summary points 127
Acknowledgments 127
11. The interconnection of high-fat References 127
diets, oxidative stress, the heart,
and carcinogenesis 13. Inflammation and oxidatively
induced DNA damage: A synergy
Bianka Bojková, Natalia Kurhaluk, and
Pawel J. Winklewski leading to cancer development
Oxidative stress: General introduction 111 Ioanna Tremi, Somaira Nowsheen,
Khaled Aziz, Shankar Siva, Jessica Ventura,
Obesity, oxidative stress, and Vasiliki I. Hatzi, Olga A. Martin, and
inflammation 113 Alexandros G. Georgakilas
x Contents
Introduction 132 15. Nrf2, YAP, antioxidant potential,

Oxidative DNA damage 132 and cancer
Mechanisms of induction 132
Pathways of repair 133 Giuseppina Barrera, Marie Angele Cucci,
Margherita Grattarola, and
Role of inflammation in the induction of Stefania Pizzimenti
oxidative stress and DNA damage leading
to cancer 133 Introduction 160
Extrinsic pathway of carcinogenesis 134 Nrf2 transcription factor 160
Intrinsic pathway 137 Nrf2 activity in cancer prevention 160
The link between extrinsic and intrinsic Nrf2 in cancer progression and
pathways 137 chemoresistance 162
Soluble mediators and cellular Hippo pathway and YAP regulation 163
components 138 YAP in cancer progression and
Tissue injury 138 chemoresistance 165
Nontargeted effects, inflammation, YAP and antioxidant regulation 165
oxidative stress, and DNA damage 139 YAP-Nrf2 cooperation and cross talk 167
Bystander and abscopal effects 139 Applications to other cancers or
Bystander signaling in vitro 139 conditions 168
Role of cytokines for bystander Summary points 168
signaling 140 References 169
Radiation-induced inflammation 142
Local tumor environment and radiation 142 16. Cancer, NFkappaB, and oxidative
Radiation exposure and the immunogenic stress-dependent phenotypes
effect 142
Daniela Sorriento, Jessica Gambardella, and
Conclusion 143 Guido Iaccarino
Summary points 143
References 143 Introduction 171
NFkB and cancer 171
14. Ferroptosis, free radicals, and The crosstalk between NFkB and oxidative
cancer stress in cancer 172
NFkΒ and oxidative stress-dependent
Rui Kang and Daolin Tang phenotypes in cancer 172
Introduction 149 Cell proliferation 172
The discovery of ferroptotic cancer cell Inflammation 173
death 150 Tumor angiogenesis 173
The central biochemical event of ferroptotic Apoptosis escape: Molecular bases of
cancer cell death 150 chemoresistance 173
The core molecular machinery of ferroptotic Tumor metabolism 174
cancer cell death 151 Application to other cancers or
System xc 151 conditions 174
GPX4 152 Summary points 174
TP53 153 References 176
NFE2L2 153
ACSL4 154 17. 8-Hydroxydeoxyguanosine:
Lipoxygenase 155 A valuable predictor of oxidative
The relationship between ferroptosis and DNA damage in cancer and
autophagy 155 diabetes mellitus
Conclusions and perspectives 155
Anmar Al-Taie, Mesut Sancar, and
Applications to other cancers or Fikret Vehbi Izzettin
conditions 156
Summary points 157 Introduction 179
Acknowledgments 157 Free radicals and oxidative DNA
References 157 damage 180
Contents xi
Biomarkers of oxidative repair products 181 Components of TIME and their

Measurement of 8-OHdG 181 functions 197
Practical impact of 8-OHdG in Oxidative stress and the impact of dietary
carcinogenesis and cancer therapy 181 products on the TIME 198
Impact of oxidative stress in diabetes Cross talk between DDR and the tumor
mellitus 182 immune microenvironment 199
Practical impact of 8-OHdG in diabetes Future perspectives 199
mellitus and diabetic complications 183 Summary points 200
Applications to other cancers or References 200
conditions 183
Summary points 183 19. Prostate cancer and food-based
References 184 antioxidants in India as plausible
therapeutics
Section B Ranjana Bhandari, Garima Khanna, and
Anurag Kuhad
Antioxidants and cancer
Introduction 203
18. Molecular approaches toward Cancer and its pathogenesis 203
Genetic factors 204
targeted cancer therapy with some
Environmental factors 205
food plant products: On the role of Prostate cancer 205
antioxidants and immune Introduction 205
microenvironment Types 205
Anisur Rahman Khuda-Bukhsh, Pathogenesis 205
Santu Kumar Saha, Sreemanti Das, and Current therapy and its limitations 206
Sweta Sharma Saha Functional food as therapeutics for prostate
Introduction 191 cancer 208
Oxidative stress, genomic instability, and Lycopene 208
cancer: Role of dietary antioxidants 192 Curcumin 208
Carotenoids (beta carotene Quercetin 209
and lycopene) 192 Genistein 210
Grapes 195 Resveratrol 210
Ginger 195 Epigallocatechin 211
Spinach 195 Beta-carotene 212
ROS-related signaling pathways for targeted Omega-3-fatty acids 212
cancer therapy 195 Future perspectives 214
Regulation of MAPK signaling pathways by Conclusion 214
ROS 195 Summary points 214
Regulation of PI3K signaling pathways by Author’s disclosure 214
ROS 195 References 215
Nrf2 and Ref-1-mediated redox cellular
signaling 196 20. Linking nonenzymatic antioxidants
Regulation of p66shc, mitochondrial
in the diet and colorectal cancer
oxidative stress 196
Regulation of IRE-IRP system and iron Esther Molina-Montes,
homeostasis by ROS 196 Belen Garcı́a-Villanova,
ROS and DNA damage response 196 Eduardo Jesús Guerra-Hernández, and
Pilar Amiano
Oxidative stress-mediated DDR pathway
inhibitors for cancer therapy 196 Introduction 219
Base excision repair (BER) 197 Epidemiology of colorectal cancer 219
Nonhomologous end-joining (NHEJ) 197 CRC risk and prevention factors with a focus
Nucleotide excision repair (NER) 197 on dietary factors 219
Tumor immune microenvironment (TIME) Molecular colorectal carcinogenesis 220
and the role of antioxidants as immune Dietary antioxidants: Their health benefits
modulators 197 and dietary sources 221
xii Contents
Role of nonenzymatic antioxidants in the Role of omega-3 PUFAs in chemoresistant

prevention of colorectal cancer 221 cancers 250
Molecular basis of dietary antioxidants in Application to other cancers and
CRC etiology 221 conditions 250
Levels of evidence of anti-CRC effects of Conclusions 250
antioxidants from human studies 223 Summary points 251
Insights into oxidative stress modulators and Acknowledgments 251
colorectal cancer 229 References 251
OS implications in CRC 229
Gut microbiome and the antioxidant- 23. Statins, cancer, and oxidative stress
oxidant balance 230
Tahoora Shomali and Mahboobeh Ashrafi
Conclusions and applications to other
cancers or conditions 230 Applications to other cancers or
Summary points 231 conditions 260
References 231 Summary points 260
References 260
21. Fruit and vegetable juices
and breast cancer 24. Role of anthocyanins in oxidative
Cı́ntia Ferreira-P^
ego, Bojana B. Vidovi
c,
stress and the prevention of cancer
Nuno G. Oliveira, Ana S. Fernandes, and in the digestive system
João G. Costa
Elvira Gonzalez de Mejia,
Introduction 235 Miguel Rebollo-Hernanz, Yolanda Aguilera,
In vitro and in vivo studies 236 and Maria A. Martı́n-Cabrejas
Berries juice 236 Introduction 265
Grape juice 237 Applications to other cancers 266
Pomegranate juice 237 Oxidative stress and gastrointestinal
Citrus juice 237 cancer 267
Apple juice 237 Oxidative stress 267
Noni juice 238 Oxidative stress in gastric cancer 267
Cruciferous juice 238 Oxidative stress in liver cancer 267
Beetroot juice 239 Oxidative stress in colorectal cancer 268
Other fruit and vegetable extracts and Oxidative stress in pancreatic cancer 269
juices 239 Anthocyanins: Properties and dietary
Epidemiological data 239 sources 269
FVJ in BC 239 Chemistry of anthocyanins 269
FVJ in combination with chemotherapy 241 Food sources 269
Conclusion 241 Bioavailability and metabolism 269
Fruit and vegetables juices in other Role of anthocyanins in the prevention of
cancers 241 oxidative stress 271
Summary points 242 Direct chemical mechanisms 271
References 242 Indirect molecular mechanisms 272
Role of anthocyanins in the prevention of
22. Oxidative stress and cancer: Role gastrointestinal cancer 272
of n-3 PUFAs Conclusions 277
Summary points 277
Concetta Finocchiaro, Maurizio Fadda,
Valentina D’Onofrio, Mirko Ippolito, References 278
Costanza Pira, and Andrea Devecchi
25. Caffeic Acid targets metabolism of
Introduction 245
Oxidative stress 245
cervical squamous cell carcinoma
Cancer and n-3 PUFAs 246 Malgorzata Tyszka-Czochara
Guidelines: Supplementation with omega-3
Introduction 281
in cancer 247
Metabolic reprogramming confers an
Omega-3 and cancer cachexia 248
adaptive advantage to cancer cells 282
Contents xiii
CA hampers glucose uptake and glucose Apple and oxidative balance 295
catabolism to lactate in cervical Apple and cancer 295
cancer cells 282 Grape and wine 295
CA induces oxidative stress in mitochondria Grape/wine and cancer 296
and elucidates metabolic-dependent Summary points 297
apoptotic death in epithelial cervical References 297
cancer cells 283
CA impairs energy generation in cervical 27. Oxidative stress and cancer:
cancer cells 284 Antioxidative role of Ayurvedic
Energetic stress caused by CA in cervical plants
cancer cells activates adenosine
50 -monophosphate AMP-activated Sahdeo Prasad and Sanjay K. Srivastava
protein kinase 284 Introduction 301
CA affects the cervical cancer cells Oxidative stress and cancer 302
phenotype and migration properties Ayurvedic plants with antioxidative
under implementation of the Epithelial- nature 302
to-Mesenchymal Transition process 285 Emblica officinalis 302
CA has the potency to regulate cell cycle Glycyrrhiza glabra 303
progress in cervical cancer cells with an Aloe vera 304
epithelial phenotype 286 Ocimum sanctum 304
Applications to other conditions 287 Tinospora cordifolia 305
Cervical cancer treatment in humans using Other Ayurvedic plants 305
Cisplatin 287 Conclusion 307
Co-treatment of cervical cancer cells with Summary points 307
CA and the antidiabetic drug, Metformin, Acknowledgments 307
augments the toxic action of Cisplatin via Conflict of interest 307
regulation of the cell cycle—In vitro References 308
study 287
CA and Met hamper proliferation and 28. Polyphenol chlorogenic acid,
enhance cell death in cervical cancer
antioxidant profile, and breast
cells but not in normal cells 287
CA alleviates lactic acidosis caused by
cancer
Metformin—In vitro study 288 Onur Bender and Arzu Atalay
Bioavailability of CA and perspectives of
Introduction 312
use in humans 288
Chlorogenic acid 312
Summary points 288
Antioxidant profile of chlorogenic acid 313
References 288
Antioxidant capacity of chlorogenic
acid isomers with conventional in
26. Effects of caffeic acid on oxidative vitro tests 313
balance and cancer Antioxidant properties of chlorogenic acid
Beatriz da Silva Rosa Bonadiman, in cellular level 313
Grazielle Castagna Cezimbra Weis, Antioxidant effects of chlorogenic acid
J
essica Righi da Rosa, Charles Elias Assmann, in vivo 314
Audrei de Oliveira Alves, P^
amela Longhi, and Computational evaluations for antioxidant
Margarete Dulce Bagatini
potential of chlorogenic acid 316
Coffee 291 Chlorogenic acid and breast cancer 316
Coffee and oxidative balance 291 Cytotoxic/antiproliferative effects of
Coffee and cancer 291 chlorogenic acid on breast cancer cells 316
Berries 292 Effects of chlorogenic acid on cell cycle
Raspberry 292 distribution in breast cancer 318
Blueberry 293 Apoptotic effects of chlorogenic acid on
Propolis 294 breast cancer 318
Propolis and oxidative balance 294 Effects of chlorogenic acid on
Propolis and cancer 294 mitochondrial membrane potential in
Apple 295 breast cancer 319
xiv Contents
Molecular simulations and validations Cocoa prevented AOM-induced oxidative

of chlorogenic acid effects on protein stress in colon tissues 344
kinase C 319 Cocoa prevented cell proliferation in AOM
Effects of chlorogenic acid on breast cancer treated animals 344
in vivo 319 Cocoa prevented AOM-induced
Applications to other cancers or inflammation in colon tissues 345
conditions 320 Cocoa-induced apoptosis in
Summary points 320 AOM-treated animals 345
References 320 Human studies 345
Epidemiologic studies 345
Intervention studies 346
29. Cinnamomum cassia, apoptosis, Summary points 346
STAT3 inactivation and reactive Acknowledgments 346
oxygen species in cancer studies Conflict of interest 347
Yae Jin Yoon and Byoung-Mog Kwon References 347
Introduction 323 31. Medicinal plants, antioxidant

Oxidative stress-mediated apoptosis
potential, and cancer
induced by cinnamaldehyde and
its derivatives 326 Emmanuel Mfotie Njoya
Regulation of intrinsic and extrinsic
Introduction 349
apoptotic pathways 326
Regulation of antioxidant defense
conditions 350
system 328
Oxidative stress resulting from the
Apoptotic cell death via STAT3
overproduction of free radicals 350
inactivation 329
Free radicals and their implication in
Direct binding targets of cinnamaldehyde
oxidative stress-related diseases 351
and its derivatives 330
Antioxidant mechanisms of free radical
Proteasome subunits 330
scavengers 352
Signal transducer and activator of
Methods used for the evaluation of
transcription 3 (STAT3) and pyruvate
antiradical activity 352
kinase M2 (PKM2) 330
Ferric reducing ability of plasma (FRAP)
Proviral insertion in murine lymphomas-1
assay 352
(Pim-1) 333
ABTS (2,20 -azino-bis
Low-density lipoprotein receptor-related
(3-ethylbenzothiazoline-6-sulfonic acid))
protein 1 (LRP1) 333
assay 353
Thioredoxin reductase (TrxR) 333
DPPH (2,2-diphenyl-1-picrylhydrazyl)
assay 353
conditions 334
ORAC (oxygen radical absorbance
Summary points 334
capacity) assay 353
References 334
Superoxide anion scavenging assay 353
Hydroxyl radical scavenging assay 353
30. Antioxidative stress actions of Free radical scavenger potency versus
cocoa in colonic cancer: Revisited polyphenolic contents of plants 354
Summary points 355
Sonia Ramos, Luis Goya, and References 355
Maria Angeles Martı́n
Introduction 337 32. Curcumin, oxidative stress, and
Chemopreventive mechanism of cocoa breast cancer
polyphenols in cultured colon
Gloria M. Calaf
cancer cells 339
Antioxidant effects 340 Introduction 359
Effects on apoptosis and proliferation 341 Estrogens (17b-estradiol) and oxidative
Antiinflammatory effects 343 stress 360
Chemopreventive mechanism of cocoa in Oxidative stress 360
animal models of colon cancer 343 Curcumin as an antioxidant 361
Contents xv
Curcumin and a multifunctional nuclear Infrared radiation (IR) and visible light (VIS)
transcription factor and the enzyme and oxidative stress 388
manganese superoxide dismutase protein Fernblock, oxidative stress, and
expression 362 photoprotection 389
Curcumin and lipid peroxidation 364 Photoprotective agents 389
Curcumin and epithelial-mesenchymal Polypodium leucotomos. Origen and
transition 364 composition 389
Curcumin and genomic instability 365 Composition 389
Curcumin and specific biomarkers for Molecular, cellular, and clinical evidence of
cancer 366 the photoprotective properties of
Summary points 368 Fernblock 389
Acknowledgments 368 Fernblock in DNA photodamage and
References 369 repair 389
Fernblock effect on free radicals during
33. Curcumin analogs, oxidative stress, inflammation 390
and prostate cancer Fernblock prevents UV radiation-mediated
immunosuppression 391
Marco Bisoffi and Justin M. O’Neill Fernblock, an anti-UV-induced tumor
Introduction 372 progression agent 391
Prostate cancer and oxidative stress 372 Fernblock and malignant melanoma 393
Prostate cancer: A brief introduction 372 Fernblock prevention of matrix remodeling
Prostate cancer and oxidative stress: and other cellular effects 393
Possible factors 373 Fernblock preventions of photodamage
Reactive oxygen species: A paradox in induced by visible light and infrared
(prostate) cancer 373 radiation 394
Curcumin, curcuminoids, and curcumin Potential use of Fernblock in the
analogs 374 treatment of other pathological skin
Chemistry and biochemistry of curcumin, conditions 395
curcuminoids, and curcumin analogs 374 Idiopathic photodermatosis 395
Antioxidant versus prooxidant activities of Pigmentary disorders 395
curcumin, curcuminoids, and curcumin Applications to Fernblock to skin cancers
analogs 376 or other conditions 396
The potential of curcumin, curcuminoids, Summary points 396
and curcumin analogs as oxidant agents in Acknowledgments 396
prostate cancer 380 References 396
Molecular targets of curcumin,
curcuminoids, and curcumin analogs in
prostate cancer 380 35. Lycium barbarum (goji berry),
Curcumin, curcuminoids, and curcumin human breast cancer, and
analogs as antioxidants in prostate antioxidant profile
cancer 380
Anna Wawruszak, Marta Halasa,
Curcumin, curcuminoids, and curcumin and Karolina Okla
analogs as prooxidants in prostate
cancer 381 Introduction 399
Summary points 384 Natural compounds in cancer therapy
References 384 and chemoprevention 400
Characteristics of Lycium barbarum
34. Fern extract, oxidative stress, and (goji berry) 400
skin cancer Anticancer properties of L. barbarum in
breast cancer 401
Concepción Parrado, Yolanda Gilaberte, Antioxidative properties of L. barbarum
Neena Philips, Angeles Juarranz, and in breast cancer 402
Salvador Gonzalez
Introduction 388 conditions 403
Ultraviolet radiation and Summary points 404
oxidative stress 388 References 404
xvi Contents
36. Manuka honey, oxidative stress, Antioxidant defense in cancer

5-fluorouracil treatment, and development 432
colon cancer cells P. ostreatus, oyster
mushroom 433
Sadia Afrin, Tamara Y. Forbes-Hernández, Extraction and purification of
Francesca Giampieri, and Maurizio Battino polysaccharides 433
Overview of etiology and risk factors of Treatment of cancer 434
colorectal cancer (CRC) 408 Summary points 435
Oxidative stress and CRC 409 References 435
Management and treatment of 5-FU
in CRC 410 39. “Skin cancer, polyphenols, and
Manuka honey (MH) 410 oxidative stress” or Counteraction
Nutritional composition of MH 410 of oxidative stress, inflammation,
MH as a source of natural antioxidant 410 signal transduction pathways, and
Chemopreventive effect of MH in colon extracellular matrix remodeling
cancer cells 411 that mediate skin carcinogenesis
Antiproliferative effect 411
by polyphenols
Apoptosis induction 412
Alteration of oxidative stress 412 Neena Philips, Richard Richardson,
Antimetastatic effects 413 Halyna Siomyk, David Bynum, and
Effect of MH on other cancer cells 413 Salvador Gonzalez
Conclusions 413 Introduction 439
Summary points 414 Oxidative stress, inflammation, and
References 414 associated signal transduction pathways:
Fundamental biology, the alteration, and
37. Piplartine (piperlongumine), counteraction by polyphenols 440
oxidative stress, and use in cancer ECM remodeling and associated growth
factors: Fundamental biology, the
Daniel Pereira Bezerra
alteration, and counteraction by
Introduction 417 polyphenols 443
Oxidative stress induction 417 Conclusion 447
Cancer cell death induction 418 Summary points 448
Antitumor, antiangiogenic, and Acknowledgment 448
antimetastatic effects 420 References 448
Conclusion 422
References 422 40. Pterostilbene and cancer
chemoprevention
38. Antioxidant of Pleurotus ostreatus
Rong-Jane Chen and Ying-Jan Wang
(Jacq.) P. Kumn and lymphoid
cancer cells Introduction 452
Md. Moyen Uddin Pk, Jane O’Sullivan, conditions 453
Rumana Pervin, and Matiar Rahman
Main text 453
Introduction 427 Pharmacokinetics of pterostilbene 454
Applications to other cancers or Oxidative stress and inflammation
conditions 428 in cancer development 454
Cancer 428 Antioxidant and anti-inflammatory effects
Oxidative stress (OxS) 429 of pterostilbene 455
Biomarkers of OxS 430 Chemopreventive mechanisms of
OxS and cell proliferation 431 pterostilbene in preclinical studies 455
OxS and apoptosis 431 Inhibiting inflammatory responses 456
ROS and mtDNA damage 432 Inducing apoptosis in cancer cells 456
Contents xvii
Pterostilbene induces autophagy Applications to other cancers or

in cancer cells 457 conditions 480
Pterostilbene induces cell cycle arrest Summary points 480
in cancer cells 459 References 480
Pterostilbene induces senescence
in cancer cells 459 43. Silybum marianum, antioxidant
Pterostilbene inhibits invasion and activity, and cancer patients
metastasis in cancer cells 460
Chemopreventive effects of pterostilbene Sepideh Elyasi
by regulation of microRNAs 460 Introduction 483
Summary points 461 Skin cancer 484
References 461 Larynx and lung cancer 485
Breast cancer 485
41. Resveratrol, reactive oxygen Hepatic and pancreatic cancers 486
species, and mesothelioma Ovarian cancer 486
Prostate cancer 486
Saime Batırel
Colorectal cancer 487
Introduction 465 Kidney and bladder cancer 488
Applications to other cancers or Cervical cancer 488
conditions 466 Leukemia 488
Resveratrol 466 Antimetastatic effect 489
Antioxidant effects of resveratrol 467 Radiotherapy- and chemotherapy-induced
Malignant pleural mesothelioma 468 adverse reaction management 489
Asbestos and malignant pleural Hepatoprotectant 489
mesothelioma 468 Kidney protectant 490
Antiapoptotic effects of resveratrol Cardioprotectant 490
on MPM cells 469 Mucocutaneous protection 490
Chemoprotective effects of resveratrol on Silymarin administration and dosing 490
MPM cells 469 Silymarin adverse reactions and drug
Effects of resveratrol on cell cycle interactions 491
of MPM cells 470 Summary points 491
Signaling pathways in anticancer effects of References 491
resveratrol 471
Chemopreventive properties of
resveratrol 471
44. Plants of the genus Terminalia:
Dual effects of resveratrol on cancer Phytochemical and antioxidant
cells 472 profiles, proliferation, and cancer
Conclusion 472 Ian Edwin Cock and Matthew Cheesman
Summary points 472
References 472 Introduction 495
Applications to cancers or other
42. Exercise, selenium, and cancer conditions 495
Antioxidant content 496
cells
The relationship between oxidative stress
Mahdieh Molanouri Shamsi and and cancer 496
Zuhair Mohammad Hassan Phytochemistry of the genus Terminalia 497
Introduction 475 Tannins 497
Selenium and human health 476 Stilbenes 498
Selenium and cancer 476 Other compounds with anticancer
Physical exercise and cancer 477 activities 498
Exercise and selenium: Possible metabolic Summary points 501
reprogramming in cancer cells 478 References 501
xviii Contents
45. Uncaria tomentosa: A promising Interaction between genetic polymorphism

source of therapeutic agents for and antioxidant vitamin on breast
prevention and treatment of cancer risk 529
oxidative stress and cancer One carbon metabolism-related gene
polymorphisms and dietary factors on
Francesca Ciani, Natascia Cocchia, breast cancer risk 530
Viola Calabrò, Alessandra Pollice, Oxidative stress-related gene
Lucianna Maruccio, Domenico Carotenuto,
Luigi Esposito, Luigi Avallone, and polymorphisms and dietary factors on
Simona Tafuri breast cancer risk 530
Research priorities for gene-diet interaction
Introduction 505 approach 536
Applications to other cancers or Conclusion 536
conditions 506 Summary points 537
Uncaria tomentosa 506 References 537
Botanical classification of Uncaria genus 508
Chemical composition of U. tomentosa 508 48. Antioxidant vitamins in acute
Oxidative stress 508
lymphoblastic leukemia
Oxidative stress and U. tomentosa 510
Cancer and U. tomentosa 511 Behnaz Abiri and Mohammadreza Vafa
Conclusions 512
Introduction 539
Summary points 513
Antioxidant compounds 540
References 513
Oxidative stress, antioxidant vitamins,
and ALL 540
46. Pharmacological ascorbate and The antioxidant mechanisms 542
use in pancreatic cancer Vitamin C 542
Rory S. Carroll, Garry R. Buettner, and Vitamin A 542
Joseph J. Cullen Vitamin E 542
Conclusion 542
Introduction 515
Summary points 543
Ascorbate biochemistry 515
References 543
Selective toxicity to cancer cells 516
P-AscH as chemosensitizer 517
P-AscH as radiosensitizer 518
P-AscH as a protector of normal tissue Section C
during chemoradiation 518 Online resources
Conclusions 519
Applications in other cancers 519 49. Recommended resources on
Summary points 520 cancer: Oxidative stress and
Acknowledgment 520 dietary antioxidants
References 520
Rajkumar Rajendram, Vinood B. Patel, and
Victor R. Preedy
47. Antioxidant vitamins and genetic
polymorphisms in breast cancer Introduction 547
Resources 547
Daehee Kang, Sang-Ah Lee, and Summary points 547
Woo-Kyoung Shin
Acknowledgments 551
Introduction 523 References 551
Effect of antioxidant vitamin on breast
cancer incidence 524
Antioxidant vitamins and genomic integrity: Index 553
Developmental and degenerative
correlates 527
Contributors
Numbers in parenthesis indicate the pages on which the authors’ Arzu Atalay (311), Biotechnology Institute, Ankara Uni-
contributions begin. versity, Ankara, Turkey
Behnaz Abiri (539), Department of Nutrition, Faculty of Luigi Avallone (505), Department of Veterinary Medicine
Paramedicine, Ahvaz Jundishapur University of and Animal Production, University of Naples Federico
Medical Sciences, Ahvaz, Iran II, Naples, Italy
Sadia Afrin (407), Department of Gynecology and Khaled Aziz (131), Medical Scientist Training Program,
Obstetrics, Johns Hopkins University, School of Med- Mayo Graduate School, Mayo Clinic, College of Med-
icine, Baltimore, MD, United States icine, Rochester, MN, United States
Yolanda Aguilera (265), Institute of Food Science Margarete Dulce Bagatini (291), Academic Coordination,
Research, CIAL (UAM-CSIC), Department of Agricul- Campus Chapecó, Federal University of Fronteira Sul,
tural Chemistry and Food Science, Universidad Chapecó, SC, Brazil
Autónoma de Madrid, Madrid, Spain Giuseppina Barrera (159), Department of Clinical and
Mazhar Al Zoubi (101), Department of Basic Medical Sci- Biological Sciences, University of Turin, Torino, Italy
ences, Faculty of Medicine, Yarmouk University, Irbid, Saime Batırel (465), Faculty of Medicine, Department of
Jordan Medical Biochemistry, Marmara University, Istanbul,
Alaa Aljabali (101), Department of Pharmaceutical Sci- Turkey
ences, Faculty of Pharmacy, Yarmouk University, Irbid, Maurizio Battino (407), Department of Analytical and
Jordan Food Chemistry, Nutrition and Food Science Group,
Anmar Al-Taie (179), Head of Clinical Pharmacy CITACA, CACTI, University of Vigo, Vigo Campus,
Department, Faculty of Pharmacy, Girne American Uni- Vigo, Spain; Department of Clinical Sciences, Uni-
versity, Kyrenia, Turkey versità Politecnica delle Marche, Ancona, Italy; Interna-
Tsukuru Amano (77), Department of Obstetrics & Gyne- tional Research Center for Food Nutrition and Safety,
cology, Shiga University of Medical Science, Ostu, Japan Jiangsu University, Zhenjiang, China
Pilar Amiano (219), Ministry of Health of the Basque Gov- Onur Bender (311), Biotechnology Institute, Ankara Uni-
ernment, Public Health Division of Gipuzkoa, Biodo- versity, Ankara, Turkey
nostia Health Research Institute, Donostia-San Daniel Pereira Bezerra (417), Gonçalo Moniz Institute,
Sebastian; CIBERESP (Consortium for Biomedical Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Sal-
Research in Epidemiology and Public Health), Madrid, vador, Bahia, Brazil
Spain Ranjana Bhandari (203), Pharmacology Research Labo-
Ayca Ant (55), Department of Otorhinolaryngology, Head ratory, University Institute of Pharmaceutical Sciences,
and Neck Surgery, University of Health Sciences UGC-Centre of Advanced Study, Panjab University,
Ankara A.Y. Oncology Education and Research Hos- Chandigarh, India
pital, Yenimahalle/Ankara, Turkey Marco Bisoffi (371), Chemistry and Biochemistry, Schmid
Mahboobeh Ashrafi (255), Division of Biochemistry, College of Science and Technology, Chapman Uni-
Department of Basic Sciences, School of Veterinary versity, Orange, CA, United States
Medicine, Shiraz University, Shiraz, Iran Bianka Bojková (111), Department of Animal Physiology,
Charles Elias Assmann (291), Department of Biochem- Institute of Biology and Ecology, Faculty of Science,
istry and Molecular Biology, PPGBTox, CCNE, Federal Pavol Jozef Šafárik University in Košice, Košice,
University of Santa Maria, Santa Maria, RS, Brazil Slovak Republic
xix
xx Contributors
Chanchai Boonla (67), Department of Biochemistry, Marie Angele Cucci (159), Department of Clinical and
Faculty of Medicine, Chulalongkorn University, Biological Sciences, University of Turin, Torino, Italy
Bangkok, Thailand Joseph J. Cullen (515), Free Radical and Radiation
Garry R. Buettner (515), Free Radical and Radiation Biology Program, Departments of Surgery and Radi-
Biology Program, Departments of Surgery and Radi- ation Oncology, Holden Comprehensive Cancer Center,
ation Oncology, Holden Comprehensive Cancer Center, The University of Iowa Hospitals and Clinics, The Uni-
The University of Iowa Hospitals and Clinics, The Uni- versity of Iowa College of Medicine, and the Iowa City
versity of Iowa College of Medicine, and the Iowa City Veterans Affairs, Iowa City, IA, United States
Veterans Affairs, Iowa City, IA, United States Jessica Righi da Rosa (291), Department of Technology
David Bynum (439), School of Natural Sciences, Uni- and Food Science, Rural Science Center, Federal Uni-
versity College, Fairleigh Dickinson University, versity of Santa Maria, Santa Maria, RS, Brazil
Teaneck, NJ, United States Beatriz da Silva Rosa Bonadiman (291), Department of
Viola Calabrò (505), Department of Biology, Complesso Biological Science: Biochemistry, Federal University
Universitario Monte S. Angelo, University of Naples of Santa Catarina, Florianópolis, SC, Brazil
Federico II, Naples, Italy Sreemanti Das (191), Cytogenetics and Molecular Biology
Gloria M. Calaf (359), Instituto de Alta Investigación, Laboratory, Department of Zoology, University of
Universidad de Tarapaca, Arica, Chile; Columbia Uni- Kalyani, Kalyani, India
versity Medical Center, New York, NY, United States Christophe Deben (39), Center for Oncological Research,
Domenico Carotenuto (505), UNMSM, Universidad University of Antwerp, Wilrijk, Belgium
Nacional Mayor San Marcos, Lima, Peru Andrea Devecchi (245), Department of Clinical Nutrition,
Rory S. Carroll (515), Free Radical and Radiation AOU Città della Salute e della Scienza, Turin, Italy
Biology Program, Departments of Surgery and Radi- Valentina D’Onofrio (245), Department of Clinical
ation Oncology, Holden Comprehensive Cancer Nutrition, AOU Città della Salute e della Scienza, Turin,
Center, The University of Iowa Hospitals and Clinics, Italy
The University of Iowa College of Medicine, and the
Iowa City Veterans Affairs, Iowa City, IA, United Sepideh Elyasi (483), Department of Clinical Pharmacy,
States Faculty of Pharmacy, Mashhad University of Medical
Sciences, Mashhad, Iran
Tokuhiro Chano (77), Department of Clinical Laboratory
Medicine and Medical Genetics, Shiga University of Fatma Ceyla Eraldemir (3), Department of Biochemistry,
Medical Science, Ostu, Japan Faculty of Medicine, Kocaeli University, Kocaeli,
Turkey
Matthew Cheesman (495), School of Pharmacy and Phar-
macology, Griffith University; Menzies Health Institute Luigi Esposito (505), Department of Veterinary Medicine
Queensland, Quality Use of Medicines Network, and Animal Production, University of Naples Federico
Southport, QLD, Australia II, Naples, Italy
Rong-Jane Chen (451), Department of Food Safety/ Maurizio Fadda (245), Department of Clinical Nutrition,
Hygiene and Risk Management, College of Medicine, AOU Città della Salute e della Scienza, Turin, Italy
National Cheng Kung University, Tainan, Taiwan Bianca Cristine Favero-Santos (121), Obesity and
Francesca Ciani (505), Department of Veterinary Med- Comorbidities Research Centre, Department of Struc-
icine and Animal Production, University of Naples Fed- tural and Functional Biology, Institute of Biology, Uni-
erico II, Naples, Italy versity of Campinas, Campinas, SP, Brazil
Natascia Cocchia (505), Department of Veterinary Med- Ana S. Fernandes (235), CBIOS, Research Center for Bio-
icine and Animal Production, University of Naples Fed- sciences & Health Technologies – School of Health Sci-
erico II, Naples, Italy ences and Technologies, Lusófona University, Lisbon,
Portugal
Ian Edwin Cock (495), School of Environment and
Science; Environmental Futures Research Institute, Cı́ntia Ferreira-P^ego (235), CBIOS, Research Center for
Griffith University, Nathan, QLD, Australia Biosciences & Health Technologies – School of Health
Sciences and Technologies, Lusófona University,
João G. Costa (235), CBIOS, Research Center for Biosci- Lisbon, Portugal
ences & Health Technologies – School of Health Sci-
ences and Technologies, Lusófona University, Lisbon, Concetta Finocchiaro (245), Department of Clinical
Portugal Nutrition, AOU Città della Salute e della Scienza, Turin,
Italy
Contributors xxi
Cesira Foppoli (87), CNR Institute of Molecular Biology Zuhair Mohammad Hassan (475), Department of Immu-
and Pathology, Sapienza University of Rome, Rome, nology, School of Medical Sciences, Tarbiat Modares
Italy University, Tehran, Iran
Tamara Y. Forbes-Hernández (407), Department of Ana- Vasiliki I. Hatzi (131), Laboratory of Health Physics &
lytical and Food Chemistry, Nutrition and Food Science Environmental Health, Institute of Nuclear Technology
Group, CITACA, CACTI, University of Vigo, Vigo & Radiation Protection, National Center for Scientific
Campus, Vigo, Spain Research “Demokritos”, Athens, Greece
Laurie Freire Boullosa (39), Center for Oncological Cristan A. Herbert (27), Mechanisms of Disease and
Research, University of Antwerp, Wilrijk, Belgium Translational Research, School of Medical Sciences,
Jessica Gambardella (171), Department of Advanced Bio- Faculty of Medicine, UNSW Sydney, Sydney, NSW,
medical Sciences, Federico II University, Napoli, Italy Australia
Belen Garcı́a-Villanova (219), Department of Nutrition Guido Iaccarino (171), Department of Advanced Bio-
and Bromatology, Faculty of Pharmacy, University of medical Sciences, Federico II University, Napoli, Italy
Granada, Granada, Spain Mirko Ippolito (245), Department of Clinical Nutrition,
Alexandros G. Georgakilas (131), DNA Damage Labo- AOU Città della Salute e della Scienza, Turin, Italy
ratory, Physics Department, School of Applied Mathe- Fikret Vehbi Izzettin (179), Head of Clinical Pharmacy
matics and Physical Sciences, National Technical Department, Faculty of Pharmacy, Bezmialem Vakif
University of Athens (NTUA), Athens, Greece University, Istanbul, Turkey
Francesca Giampieri (407), Department of Analytical and Angeles Juarranz (387), Biology Department, Sciences
Food Chemistry, Nutrition and Food Science Group, School, Universidad Autónoma de Madrid, Madrid,
CITACA, CACTI, University of Vigo, Vigo Campus, Spain
Vigo, Spain; Department of Clinical Sciences, Uni- Daehee Kang (523), Department of Preventive Medicine,
versità Politecnica delle Marche, Ancona, Italy; College Seoul National University College of Medicine, Seoul,
of Food Science and Technology, Northwest University, Republic of Korea
Xi’an, Shaanxi, China
Rui Kang (149), Department of Surgery, UT Southwestern
Yolanda Gilaberte (387), Dermatology Service, Miguel Medical Center, Dallas, TX, United States
Servet Hospital, Zaragoza, Spain
Garima Khanna (203), Pharmacology Research Labo-
Maria Cristina Cintra Gomes-Marcondes (121), Labo- ratory, University Institute of Pharmaceutical Sciences,
ratory of Nutrition and Cancer, Department of Structural UGC-Centre of Advanced Study, Panjab University,
and Functional Biology, Institute of Biology, University Chandigarh, India
of Campinas, Campinas, SP, Brazil
Anisur Rahman Khuda-Bukhsh (191), Emeritus of Uni-
Salvador Gonzalez (387, 439), Dermatology Service, versity Grants Commission at University of Kalyani,
Memorial Sloan-Kettering Cancer Center, New York, Kalyani, India
NY, United States; Medicine and Medical Specialties
Department, Alcala University, Madrid, Spain Tuğcan Korak (3), Department of Medical Biology,
Faculty of Medicine, Kocaeli University, Kocaeli,
Elvira Gonzalez de Mejia (265), Department of Food Turkey
Science and Human Nutrition, Division of Nutritional
Sciences, University of Illinois at Urbana-Champaign, Anurag Kuhad (203), Pharmacology Research Labo-
Champaign, IL, United States ratory, University Institute of Pharmaceutical Sciences,
UGC-Centre of Advanced Study, Panjab University,
Luis Goya (337), Department of Metabolism and Nutrition, Chandigarh, India
Institute of Food Science, Technology and Nutrition
(ICTAN-CSIC), Ciudad Universitaria, Madrid, Spain Natalia Kurhaluk (111), Department of Zoology and
Animal Physiology, Institute of Biology and Earth Sci-
Margherita Grattarola (159), Department of Clinical and ences, Pomeranian University, Slupsk, Poland
Biological Sciences, University of Turin, Torino, Italy
Byoung-Mog Kwon (323), Laboratory of Chemical
Eduardo Jesús Guerra-Hernández (219), Department of Biology and Genomics, Korea Research Institute of
Nutrition and Bromatology, Faculty of Pharmacy, Uni- Bioscience and Biotechnology, Daejeon, Republic of
versity of Granada, Granada, Spain Korea
Marta Halasa (399), Department of Biochemistry and Sang-Ah Lee (523), Department of Preventive Medicine,
Molecular Biology, Medical University of Lublin, Kangwon National University School of Medicine,
Lublin, Poland Chuncheon-si, Gangwon-do, Republic of Korea
xxii Contributors
Jinthe Van Loenhout (39), Center for Oncological Justin M. O’Neill (371), Chemistry and Biochemistry,
Research, University of Antwerp, Wilrijk, Belgium Schmid College of Science and Technology, Chapman
Wei Sheng Joshua Loke (27), Department of Respiratory University, Orange, CA, United States
Medicine, Prince of Wales Hospital, Randwick; Jane O’Sullivan (427), Department of Anaesthesiology
Prince of Wales’ Clinical School and Mechanisms of and Critical Care, Tallaght University Hospital, Dublin,
Disease and Translational Research, Faculty of Med- Ireland
icine, University of New South Wales, Sydney, NSW, Karolina Okla (399), The First Department of Gyneco-
Australia logical Oncology and Gynecology, Medical University
P^
amela Longhi (291), Department Life Science and of Lublin, Lublin, Poland
Health, University of the West of Santa Catarina, Melina de Moraes Santos Oliveira (121), Laboratory of
Xanxer^e, SC, Brazil Nutrition and Cancer, Department of Structural and
Olga A. Martin (131), Sir Peter MacCallum Department of Functional Biology, Institute of Biology, University of
Oncology, The University of Melbourne, Melbourne, Campinas, Campinas, SP, Brazil
VIC, Australia Nuno G. Oliveira (235), Research Institute for Medicines
Maria Angeles Martı́n (337), Department of Metabolism (iMed.ULisboa), Faculty of Pharmacy, Universidade de
and Nutrition, Institute of Food Science, Technology Lisboa, Lisbon, Portugal
and Nutrition (ICTAN-CSIC), Ciudad Universitaria, Sarah Christine Pereira de Oliveira (121), Laboratory of
Madrid, Spain Nutrition and Cancer, Department of Structural and
Maria A. Martı́n-Cabrejas (265), Institute of Food Functional Biology, Institute of Biology, University of
Science Research, CIAL (UAM-CSIC), Department of Campinas, Campinas, SP, Brazil
Agricultural Chemistry and Food Science, Universidad Audrei de Oliveira Alves (291), Department of Physiology
Autónoma de Madrid, Madrid, Spain and Pharmacology, Federal University of Santa Maria,
Lucianna Maruccio (505), Department of Veterinary Santa Maria, RS, Brazil
Medicine and Animal Production, University of Naples Concepción Parrado (387), Department of Histology and
Federico II, Naples, Italy Pathology, Faculty of Medicine, University of Málaga,
Emmanuel Mfotie Njoya (349), Institute of Pharmacy, Málaga, Spain
Martin-Luther University of Halle-Wittenberg, Halle Vinood B. Patel (547), University of Westminster, School
(Saale), Germany; Department of Biochemistry, Faculty of Life Sciences, London, United Kingdom
of Science, University of Yaounde I, Yaounde, Cameroon
Marzia Perluigi (87), Department of Biochemical Sci-
Natalia Angelo da Silva Miyaguti (121), Laboratory of ences, Sapienza University of Rome, Rome, Italy
Nutrition and Cancer, Department of Structural and
Functional Biology, Institute of Biology, University of Rumana Pervin (427), Biochemistry & Molecular
Campinas, Campinas, SP, Brazil Biology, University of Rajshahi, Rajshahi, Bangladesh
Mahdieh Molanouri Shamsi (475), Physical Education & Neena Philips (387, 439), School of Natural Sciences, Uni-
Sport Sciences Department, Faculty of Humanities, versity College, Fairleigh Dickinson University,
Tarbiat Modares University, Tehran, Iran Teaneck, NJ, United States
Esther Molina-Montes (219), Genetic and Molecular Epi- Costanza Pira (245), Department of Clinical Nutrition,
demiology Group, Spanish National Cancer Research AOU Città della Salute e della Scienza, Turin, Italy
Center (CNIO), Madrid; Department of Nutrition and Stefania Pizzimenti (159), Department of Clinical and
Bromatology, Faculty of Pharmacy, University of Biological Sciences, University of Turin, Torino, Italy
Granada, Granada, Spain Md. Moyen Uddin Pk (427), Institute of Biological
Amir Mousapasandi (27), Prince of Wales’ Clinical Science, University of Rajshahi, Rajshahi; Biochem-
School and Mechanisms of Disease and Translational istry, Primeasia University; Independent University of
Research, School of Medical Sciences, Faculty of Med- Bangladesh; Clinical Biochemistry (Diagnostic), Anwer
icine, UNSW Sydney; Department of Respiratory Med- Khan Modern Medical College & Hospital, Dhaka; Bio-
icine, Prince of Wales Hospital, Randwick, Sydney, chemistry & Molecular Biology, University of Rajshahi,
NSW, Australia Rajshahi, Bangladesh
Somaira Nowsheen (131), Medical Scientist Training Alessandra Pollice (505), Department of Biology, Com-
Program, Mayo Graduate School, Mayo Clinic, College plesso Universitario Monte S. Angelo, University of
of Medicine, Rochester, MN, United States Naples Federico II, Naples, Italy
Contributors xxiii
Sahdeo Prasad (301), Department of Immunotherapeutics Tahoora Shomali (255), Division of Pharmacology and
and Biotechnology and Center for Tumor Immunology Toxicology, Department of Basic Sciences, School of
and Targeted Cancer Therapy, Texas Tech University Veterinary Medicine, Shiraz University, Shiraz, Iran
Health Sciences Center, Abilene, TX, United States Halyna Siomyk (439), School of Natural Sciences, Uni-
Victor R. Preedy (547), Diabetes and Nutritional Sciences versity College, Fairleigh Dickinson University,
Research Division, Faculty of Life Science and Med- Teaneck, NJ, United States
icine, King’s College London, London, United Shankar Siva (131), Department of Radiation Oncology,
Kingdom Peter MacCallum Cancer Centre; Sir Peter MacCallum
Matiar Rahman (427), Biochemistry & Molecular Department of Oncology, The University of Melbourne,
Biology, University of Rajshahi, Rajshahi, Bangladesh Melbourne, VIC, Australia
Rajkumar Rajendram (547), College of Medicine, King Daniela Sorriento (171), Department of Advanced Bio-
Saud bin Abdulaziz University for Health Sciences; medical Sciences, Federico II University, Napoli, Italy
Department of Medicine, King Abdulaziz Medical Sanjay K. Srivastava (301), Department of Immunothera-
City, Ministry of National Guard Health Affairs, peutics and Biotechnology and Center for Tumor Immu-
Riyadh, Saudi Arabia; Diabetes and Nutritional Sci- nology and Targeted Cancer Therapy, Texas Tech
ences Research Division, Faculty of Life Science and University Health Sciences Center, Abilene, TX, United
Medicine, King’s College London, London, United States
Kingdom
Hidekazu Suzuki (49), Division of Gastroenterology and
Sonia Ramos (337), Department of Metabolism and Hepatology, Department of Internal Medicine, Tokai
Nutrition, Institute of Food Science, Technology and University School of Medicine, Isehara, Kanagawa,
Nutrition (ICTAN-CSIC), Ciudad Universitaria, Japan
Madrid, Spain
Simona Tafuri (505), Department of Veterinary Medicine
Miguel Rebollo-Hernanz (265), Institute of Food Science and Animal Production, University of Naples Federico
Research, CIAL (UAM-CSIC), Department of Agricul- II, Naples, Italy
tural Chemistry and Food Science, Universidad
Autónoma de Madrid, Madrid, Spain Daolin Tang (149), Department of Surgery, UT South-
western Medical Center, Dallas, TX, United States
Richard Richardson (439), School of Natural Sciences,
University College, Fairleigh Dickinson University, Paul S. Thomas (27), Department of Respiratory Medicine,
Teaneck, NJ, United States Prince of Wales Hospital, Randwick; Prince of Wales’
Clinical School and Mechanisms of Disease and Trans-
Santu Kumar Saha (191), Newcastle University Centre for lational Research, Faculty of Medicine, University of
Cancer, Translational and Clinical Research Unit, New- New South Wales, Sydney, NSW, Australia
castle University, Newcastle upon Tyne, United Kingdom
Ioanna Tremi (131), DNA Damage Laboratory, Physics
Sweta Sharma Saha (191), Newcastle University Centre Department, School of Applied Mathematics and
for Cancer, Translational and Clinical Research Unit, Physical Sciences, National Technical University of
Newcastle University, Newcastle upon Tyne, United Athens (NTUA), Athens, Greece
Kingdom
Hitoshi Tsugawa (49), Department of Biochemistry, Keio
Carla de Moraes Salgado (121), Laboratory of Nutrition University School of Medicine, Tokyo, Japan
and Cancer, Department of Structural and Functional
Biology, Institute of Biology, University of Campinas, Malgorzata Tyszka-Czochara (281), Jagiellonian Uni-
Campinas, SP, Brazil versity Medical College, Faculty of Pharmacy, Department
of Food Chemistry and Nutrition, Krakow, Poland
Mesut Sancar (179), Head of the Clinical Pharmacy
Department, Faculty of Pharmacy, Marmara University, Mohammadreza Vafa (539), Department of Nutrition,
Istanbul, Turkey School of Public Health; Pediatric Growth and Devel-
opment Research Center, Institute of Endocrinology
Woo-Kyoung Shin (523), Department of Preventive Med- and Metabolism, Iran University of Medical Sciences,
icine, Seoul National University College of Medicine, Tehran, Iran
Seoul, Republic of Korea
Jessica Ventura (131), Department of Obstetrics & Gynae-
Masaki Shiota (15), Department of Urology, Graduate cology, The University of Melbourne and Royal
School of Medical Sciences, Kyushu University, Women’s Hospital, Melbourne, VIC, Australia
Fukuoka, Japan
xxiv Contributors
Laı́s Rosa Viana (121), Laboratory of Nutrition and Cancer, Grazielle Castagna Cezimbra Weis (291), Department of
Department of Structural and Functional Biology, Technology and Food Science, Rural Science Center,
Institute of Biology, University of Campinas, Campinas, Federal University of Santa Maria, Santa Maria, RS,
SP, Brazil Brazil
Bojana B. Vidovic (235), Faculty of Pharmacy, University Pawel J. Winklewski (111), Department of Human
of Belgrade, Belgrade, Serbia Physiology, Medical University of Gdansk, Gdansk,
Ying-Jan Wang (451), Department of Environmental and Poland
Occupational Health, College of Medicine, National Yae Jin Yoon (323), Laboratory of Chemical Biology
Cheng Kung University, Tainan, Taiwan and Genomics, Korea Research Institute of Bioscience
Anna Wawruszak (399), Department of Biochemistry and and Biotechnology, Daejeon, Republic of Korea
Molecular Biology, Medical University of Lublin,
Lublin, Poland
Section A
Oxidative stress and cancer

Chapter 1
Paraoxonases, oxidative stress,

and breast cancer
Fatma Ceyla Eraldemira and Tuğcan Korakb
a
Department of Biochemistry, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey, b Department of Medical Biology, Faculty of Medicine,
Kocaeli University, Kocaeli, Turkey
List of abbreviations
OH hydroxyl radical
AhR aryl hydrocarbon receptor
AP-1 activator protein 1
ARNT Aryl hydrocarbon receptor nuclear translocator
BC Breast cancer
BRCA breast cancer susceptibility gene
CHOP CCAAT/enhancer-binding protein homologous protein
CoQ10 coenzyme Q10
CREB cAMP response element binding
cytC cytochrome C
E2 Estradiol
ER endoplasmic reticulum
ERK extracellular-regulated kinase
FXR Farnesol X receptor
GR glucocorticoid receptor
GRE glucocorticoid response element
H2O2 hydrogen peroxide
HDL high-density lipoprotein
IGF-1 insulin like growth factor-1
IL interleukin
IMM inner mitochondrial membrane
IRS-1 insulin Receptor Substrate-1
JAK janus kinase
JNK c-Jun N-terminal kinase
LDL low-density lipoprotein
MAPK mitogen-activated protein kinase
MICAL1 molecule interacting with CasL 1
NF-kB nuclear factor-kB
Nrf2 nuclear factor erythroid 2-related factor 2
O2 oxygen
O2 superoxide
OMM outer mitochondrial membrane
PDGFR-b platelet-derived growth factor receptors b
PI3K/Akt phosphatidylinositol-3-kinase
PKC protein kinase C
PKD protein kinase D
PON paraoxonase
PPAR peroxisome proliferator-activated receptor
PPRE PPAR response element
PTEN phosphatase and tensin homolog
Cancer. https://doi.org/10.1016/B978-0-12-819547-5.00001-8
© 2021 Elsevier Inc. All rights reserved. 3
4 SECTION A Oxidative stress and cancer
PTP1B protein tyrosine phosphatase 1B

PXR pregnane X receptor
PXRE pregnane X receptor response element
ROS reactive oxygen species
RXR retinoic acid X receptor
SP-1 specificity protein 1
SREBP sterol regulatory element-binding protein
STAT signal transducer of activation
TNF-a tumor necrosis factor a
uPA urokinase plasminogen activator
Introduction
Breast cancer (BC) is a frequently encountered and is a leading cause of death in women worldwide. Oxidative stress is one
of the precipitating factors in the development of BC and can be due to a variety of causes including genetic factors, envi-
ronmental factors, advanced age, and long-term exposure to estrogen.1–3 Reactive oxygen species (ROS) may occur at
pathological levels and/or insufficient antioxidants could disturb the normal balance between oxidants, which are essential
elements in many cellular functions, and antioxidants leading to oxidative stress. The end result of oxidative stress is the
overproduction of ROS, which are extremely reactive molecules that can damage and thus modify the function of mac-
romolecules, such as nucleic acids, proteins, lipids, and carbohydrates. Antioxidant systems are critical for the neutrali-
zation of ROS. Oxidative stress may lead to various pathological conditions and diseases including cancers.4 Oxidative
stress has been implicated in BC, and oxidative stress crucially affects cell proliferation and malignancy as the BC
develops.3 In this regard, paraoxonases (PONs) are essential with respect to their capacity to inhibit oxidative stress based
on their antioxidant properties.5 The paraoxonase (PON) gene family is composed of three genes PON1, PON2, and PON3,
which are localized on chromosome 7.2 All three PON enzymes are calcium-dependent hydrolases6 and are involved in
hydrolyzing a variety of substrates, such as organophosphorus, lactones, aryl esters, and estrogen esters. Although some
of the substrates are hydrolyzed by all PONs, specificity of each enzyme to substrates could be different.6, 7
Based on their antioxidative effects, all three enzymes warrant further investigation in terms of their effect on the devel-
opment and progress of BC. Some polymorphisms of PON1 were reported to contribute BC risk, through polymorphic
variation in PON1 activity.2 On the other hand, PON2 and PON3 decrease the formation of superoxide by reducing the
formation of intracellular ROS.8 Thus, higher concentrations of PON2 and PON3 in healthy breast cells are beneficial
for cellular homeostasis. However, the antiapoptotic effect of these two PONs, by decreasing ROS concentrations in
the cancerous cell, makes the treatment of BC more difficult. Therefore, an evaluation of the available data, in terms
of the relationship with ROS and possible PONs-dependent molecular mechanisms of cancers, especially in BC, is merited.
Functions and physiological roles of PON1

PON1 enzyme is synthesized predominantly in the liver, transported in the circulation, and then delivered to target tissues
through binding with HDL.9, 10 It acts as an antioxidant and plays a role in the hydrolysis of a wide range of substrates,
including estrogen esters.6 Although the exact mechanism has not yet been elucidated, there is evidence that PON1 provides
effective protection against oxidative damage through two pathways: hydrolysis of lipid hydroperoxides and prevention of
oxidative alteration of low-density lipoproteins (LDL).11 Despite the fact that increasing age and long-term exposure to
estrogen increases the risk of BC, estrogen has been shown, at certain concentrations, to have an inductive effect on
PON1 activity. One of the studies, conducted on human hepatoma cell line Huh7 and rat hepatocytes showed that
in vitro estradiol treatment of both cell types resulted in a two to threefold rise in catalytic activity of cell-associated
PON1.12 Along similar lines, estradiol treatment of postmenopausal women has been shown to increase serum PON1
activity.13
While PON1 is capable of hydrolyzing estrogen esters, it has been suggested that there is an interaction between them,
as at some concentrations of estradiol, PON1 activity has been shown to increase.12 HDL binds to estrogen esters with
PON1 in circulation. If the estrogen is esterified at the third position, PON1 can hydrolyze fatty acids thereby contributing
to an antioxidant effect of the estrogens.6 This mechanism is thought to be contributory to the enhanced antioxidative roles
of HDL in inhibiting LDL oxidation when associated with PON1. Studies have shown that PON1-inhibited LDL oxidation
was facilitated in the presence of hydrolysable estrogen esters. Therefore, PON1 may hydrolyze estrogen esters bound to
HDL through hydrophobic interaction and may contribute to uncover their antioxidant activities.6, 14 Furthermore, it has
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the Highlanders were scattered over the earth, to do what they
certainly have done well—a goodly share of the world’s work.
Now for Culloden! We—that is, four men of us—hired a horse,
driver, and carriage, and rode out to the desolate moor, which is
usually called “Culloden” by strangers and “Drummossie Moor” by
the natives. It is a tableland lying six miles northeast of Inverness
and not far from the Moray Firth. As we approached it, we could
discern the sunken lines of the trenches, in which about eighteen
hundred of the clansmen, killed in battle, were buried. In 1881, these
trenches of the different clans were marked by rough memorial
stones giving the clan names. At one part of the field was a stream
of water, to which the poor wounded wretches crawled to slake that
horrible thirst which comes so quickly to a soldier who has lost blood
and whose veins are drying up.
On one side was a cairn of stones about twenty feet high, reared
to mark the battle, in the front of which is set a tablet giving the
historical facts and date. But what touched us most deeply, as
Americans, was a colossal wreath of flowers and greenery hung
near the top. This token, though faded and its purple ribbons stained
by three months of summer rain and storm, told of “hands beyond
sea” and hearts that were saddened at the name of Culloden. I
asked who had hung that wreath upon the cairn and was told that it
had been sent by Scotsmen in America, whose ancestors had fallen
in that awful battle of April 16, 1746, in which the hopes of “Bonnie
Prince Charlie” were shattered and those of the House of Stuart to
reattain power came to an end. I understood that such a floral tribute
was offered annually.
THE CAIRN AT CULLODEN
Some distance away was the place where the English cavalry
were held in reserve, to charge upon the fugitives and slaughter
them after they had broken and fled. Near the field also was a large
flat rock, which the Pretender had mounted to see the action and
scan its results. From this point of vantage, he fled, to suffer untold
hardships, while wandering for weeks, disguised as a woman, under
the care of the heroic Flora Macdonald. He was finally able to reach
the French ships, then lying off the coast for him, by which he was
able to get back to the Continent, there to end his days as a
drunkard.
Cumberland, the British general, knew that a failure to win on
this field, or a drawn battle, would mean a long-continued guerilla
warfare in the Highlands. So he gave orders to put to the sword all
the clansmen known to have been on the field. As we rode back to
Inverness, over which the English cavalry had thundered after the
battle, the intelligent driver pointed out more than one place, such as
blacksmith’s shops, rocks, and hollows, where fugitives had hidden
and whence they had been dragged out to be killed.
Culloden enables us to see what war was to the Highlanders,
what they meant by a campaign, and how far these men of the
claymore, broadsword, and target had advanced in military science.
The idea of these stalwart warriors, trained in clan feuds and
inheriting the prejudices and traditions handed down to them from
ancestors, was to go out in summer time, without special equipment,
commissary train, or dépôt of supplies. They would make a foray,
fight a battle or two, burn the enemy’s houses, drive off some cattle,
and then come home to divide the spoil—a system hardly higher in
dignity than that of the North American Indian highlanders, the
Iroquois.
The men of the glens cared little for firearms, whether musket or
cannon. Their favorite weapons from of old were the dirk and the
claymore. The latter was a long-handled, double-edged sword
weighing from five to seven pounds, with a handle often a foot long
and with one cross-bar for a hilt. This claymore, in which they
gloried, was a weapon quite different from the later single-edged and
basket-hilted sword, which did not come into use until well into the
eighteenth century. Their one idea of fighting was to make an onset
and come to close quarters. On their left arm they carried the target,
or round shield, made of light, tough wood, covered with bull’s hide,
stretched in one or more thicknesses and with boss or studs, and
sometimes furnished with a rim of metal, or armed with a sharp point
in the middle. With this defence, protecting more or less their faces
and body, they rushed upon the foe, in order to be free at once to
use, in older times, their claymores, or double-handed blades, or, in
later days, the broadsword in close combat. When fighting with
infantry armed with smooth-bore muskets and bayonets, they could,
after the first volley, fired at more or less close range, dash into the
files. Before the soldiers could reload, the Highlanders would be
upon them, dashing aside the bayonet thrust. Then, with stabbing or
cutting blow, the clansmen slaughtered their foes and thus made
firearms of little account.
It is true that when large levies were made, as in the earlier
centuries, the Scottish spearmen were massed together and made a
formidable front, though as a rule, the English archers, with their
long-range missiles, were able to work havoc among the Scots, and
thus prevent them from getting into close hand-to-hand action. Thus,
the Southrons more than once ruined the chances and hopes of their
northern foes. In archery, the Scots never were able to compete with
the English.
Even when, later, some of the Highlanders possessed cannon,
they were apt to look with contempt upon anything which did not
permit them to charge in a rush and come to close quarters. In fact, it
was this unintelligent tenacity in holding on to a war equipment
which, even to the claymore, to say nothing of the target and
ordinary spear, had been discarded in other countries, that brought
the clans to final destruction at Culloden. On the Continent
improvements were made, first in favor of the pike and then of the
musket, with the dropping of anything like a shield, or defence, which
required the use of one hand and which could not resist a bullet. It
was a thorough knowledge of the Highlander’s conceit and
conservatism, which had become his weakness and was ultimately
to be his ruin, as well as the perception of the change in battle tactics
and the relative merits of bayonet and broadsword fighting, that
enabled the Duke of Cumberland, then only twenty-four years of
age, to win a decisive victory, such as older men of experience had
repeatedly tried to gain, but to no purpose.
Chambers wrote, in 1830, “The field of Culloden yet bears
witness to the carnage of which it was the scene. In the midst of its
black and blasted heath, various little eminences are to be seen
displaying a lively verdure, but too unequivocally expressive of the
dreadful chaos. They are so distinct and well defined that the eye
may almost, by their means, trace the position of the armies, or at
least discover where the fight was most warmly contested.”
The way toward Inverness, otherwise an unimproved, secondary
road, is fringed with many doleful memorials. There the daisy and
bluebell of Scotland have selected their abode, he tells us, as if
resolved to sentinel forever the last resting-place of their country’s
heroes. Not infrequently modern curiosity hunters have violated the
graves in order to secure some relic of the ill-fated warriors, to show
as a wonder in the halls of the Sassenach. The Gaels, with nobler
sentiments, have come more frequently to translate the bones of
their friends to consecrated ground afar, in their own dear glens of
the west. “But enough and more than enough yet remains to show
where Scotland fought her last battle and the latest examples of her
ancient chivalry fell to feed the eagles and to redeem the desert.”
Inverness in 1745, as Chambers describes it, was a royal burgh
in the vicinity of a half-civilized territory not yet emancipated from
feudal dominion. Though a seaport, it had only a slight local
commerce. The town bore every external mark of wretchedness. Its
people, even its shopkeepers, wore the Highland dress, in all its
squalor and scantiness; for the Highland plaids which we see to-day,
in silk and wool, and sold in shops of luxurious appointment, are
vastly different from the home-made fabrics of a century or more
ago. The Inverness people generally spoke Gaelic. A wheeled
vehicle had never yet been seen within the town, nor was there a
turnpike road within forty miles of its walls. Some contact by sea with
France and the dwelling in winter time of the Highland gentry in the
town shed some gleams of intelligence over the minds of the kilted
burghers. Yet when the Young Chevalier took up his residence at the
house of Lady Drummuir, hers was the only dwelling that had even
one room without a bed in it.
It was from Inverness that “Bonnie Prince Charlie,” in 1745,
marched out with his Highlanders to the gage of battle at Culloden,
of which we tell in another chapter. At neither of our two visits to the
Capital of the Highlands had we hosts or hostesses to invite us to
drink with them the inevitable cup of afternoon tea, without which a
Britisher does not feel that the island is safe, or that Britannia rules
the waves. So we must needs be satisfied with hotel service for our
Bohea and cups, though we are bound to say that the decoction was
excellent and the white-capped and snowy-aproned maid’s voice
was low and sweet.
As we chatted over our excursion to Drummossie Moor, we
recalled that the victor of Culloden, on arriving at Inverness, found
not only a considerable quantity of provisions, which had been
prepared for the poor Highlanders, but many of the Jacobite ladies,
who had attended their husbands during the campaign. They had
just enjoyed their afternoon tea-drinking and were preparing for an
evening ball, at which the Prince and his officers were to be
entertained, after his expected victory. It was the entrance of the
fugitives, who informed them of the fatal reverse their friends had
met with, which caused an abrupt change of plans.
Yet the lovers of the lost cause cease not their celebrations.
“Come o’er the stream, Charlie!” To this day, in the Highland glens,
one can hear old women singing to the tune of “Bonnie Prince
Charlie,” inviting him to “come over the border,” and feast himself on
“the red deer and the black steer,” promising, also, that his loyal
followers will “range on the heather, with bonnet and feather.” The
remnant of English Jacobites still drink to the health of the Stuarts
and hold an annual celebration in memoriam, in London and in
Philadelphia.
CHAPTER XV
“BONNIE PRINCE CHARLIE”
Mary Queen of Scots, and Bonnie Prince Charlie! How they live
with us yet, casting their spell over the centuries!
If there is one figure in the past that still acts powerfully upon the
tradition, literature, and imagination of Scotland,—in a word, upon
that which remains and is imperishable, after stone and brass are
but mouldering relics,—it is the figure and fortunes of Charles, the
Young Pretender to the throne of Great Britain. With him ended
Celtic Scotland, Scottish feudalism, and the age of Highland
romance.
About the “Young Chevalier”—the image on the Scottish mind is
that of the fair youth in the full splendor of manhood; not the
wretched dregs of the human form that many years afterwards was
cast out of memory like an abominable branch. It is of the bonnie
young fellow that such songs as “Wae’s me for Prince Charlie,”
“Charlie is my darling,” “Come o’er the stream, Charlie,” and “The
White Cockade,” were written and are still sung. His full name was
Charles Edward Louis Philippe Casimir Stuart.
This young man, of extraordinary beauty and fascinating
manners, against the advice of his friends and most loyal supporters,
landed in Scotland, and summoning the Highland chiefs, who, by
affinities of blood, politics, and religion, were most attached to the
Stuart dynasty, asked for their support. One and all, they declared
against the uprising, but they, nevertheless, agreed to follow their
liege lord.
Born at Rome, on December 31, 1720, grandson of King James
II of England, and eldest son of James, the Old Pretender, who
called himself James III, Charles was nominated by his family the
Prince of Wales. Educated under brilliant tutors, he travelled through
Italy. He was able to speak English, French, and Italian, but could
never write well in English. Despite the previous failure, in 1715, of
his father, and the loss at sea by storm of a French fleet, with seven
thousand men who were to assist his Highlanders, Charles landed in
Scotland when most of the British army was in the Belgic
Netherlands. On August 19, 1745, in Glen Finnan, he unfurled his
standard as “James VIII of Scotland and III of England” against
George II and the Hanoverian dynasty of Great Britain. He wore the
Highland costume and won the hearts of the women by his charming
manners and manly beauty.
After a meteoric career, including a brilliant series of marches,
victories, occupation of Holyrood Palace in Edinburgh, invasion of
England almost to London, and sudden retreat, he had to face with
his loyal clansmen the King’s son William, Duke of Cumberland, with
an army specially trained to the use of the bayonet. The two forces
met on Drummossie Moor, near Culloden, April 16, 1746.
Cumberland’s men were in high spirits and fine condition, while the
ill-fed followers of Charles, hungry and weary after a night march,
numbered five thousand. His attempt to surprise the Duke and settle
the issue with cold steel had failed!
Against the advice of his officers, Charles ordered the battle.
After various manœuvres the armies faced each other for the bloody
decision, on which depended the fate of the House of Stuart, the
fortunes of the Highlanders, and the continuance of Scottish
feudalism.
One dreadful surprise awaited the clansmen. Cumberland,
trusting in the bayonet, had carefully drilled each of his men to have
the nerve to neglect the man striking at him with his broadsword, but
to stab at the fellow who, in expectation of dashing aside the bayonet
of the soldier in front of him, would expose his body to the oblique
thrust of his comrade on the right, duly fore-warned.
The day was one of chilly weather, with fitful winds and flurries of
snow. Early in the afternoon, the battle was opened by discharges of
cannon from the side of the rebels. But with this kind of work, the
men from the glens never were satisfied. Indeed, all firearms and
long-range weapons were unpopular with these brave fellows, who,
like Indians and semi-barbarians, enjoyed most that action which
was, as far as possible, independent and personal.
In several of their victories over the royal troops, as at
Prestonpans, for example, they had felt little or no annoyance from
the royal cannon, and had almost lost their fear of artillery.
Cumberland had nine thousand men and eighteen well-served
guns. Here, for the first time, the Highlanders were under heavy fire
of grape and round shot, to which they could not proportionately
reply. It is thought that if Charles at Culloden had let his swordsmen
rush at once upon the enemy the issue might have been different.
For half an hour the Duke’s cannon played effectively upon the
clansmen, who saw scores of their kinsmen stretched upon the
heath. After a few moments’ cannonade from their own side, and still
under the withering fire of the enemy’s heavy guns, the Highlanders
ranged themselves in masses, and according to their clans, made
ready for the terrific onset, which they supposed would decide the
battle. This it did, but not in the way they had hoped. It was the
Mackintoshes, who, unable any longer to brook the unavenged
slaughter of their comrades, broke from the centre of the line and
rushed forward through the smoke and snow to mingle with the
enemy. Yet the order to advance, though never delivered, had
already been given by Charles, the bearer being killed by a cannon
shot.
Cumberland’s troops, seeing the dark masses moving up the
slope, as in a great wave, stood in steady line. As the Highlanders
came to shock, the oblique thrust of the bayonets was a dreadful
surprise, for it prevented hundreds of clansmen from wielding their
favorite weapon, as most of them were thrust through before they
could swing their broadswords, or make the terrible double-handed
sweep with their claymores, on which they had counted. Soon the
moor of Drummossie had proved itself to be the valley of decision for
the hopes of the House of Stuart.
Within two minutes the charge was general along the whole line.
Yet it was as if advancing into semi-darkness of whirling snow and
powder smoke. One survivor of the battle, a Highlander, said that
after rushing forward the first glimpse he received of the Duke’s
troops was, when the cloud of smoke and snow lifted, he saw the
white gaiters of the soldiers. The Duke’s cannon, now loaded with
grapeshot, and the musketry of his solid columns swept the field as
with a hailstorm. The three ranks in the front line of English Hessians
delivered simultaneous volleys, while the regiments of Wolfe—of
whom we Americans have heard in his later career at Quebec—
poured in a flank fire. Nevertheless, the right wing and centre of the
Highlanders fought with even more than usual gallantry and
resolution.
Notwithstanding the fact that they were outflanked, enfiladed,
and met by a heavy musketry fire in front of them, the right wing of
the Highlanders broke Barrel’s regimental front and passed the guns;
but their attack was checked by the bayonets of the second line.
Of the Highlanders who first rushed forward the majority were
hardly able to see their enemy for the smoke, until involved
inextricably among their weapons. Tn their onset, nearly all in the
front ranks fell before either bullets or the piercing weapons used
obliquely, as directed by the Duke, almost every bayonet being bent
or bloody with the strife. Nevertheless, the Highlanders, despite their
impending annihilation, kept on, line after line pushing forward, even
though only a few of those charging last reached the front files of the
royal troops. In parts of the plain, the dead lay three and four deep.
During all this time the Macdonalds, who, because their
ancestors at Bannockburn had fought on the right wing, had ever
afterwards, except on this occasion, occupied this position, would
not fight. They made no onset, and even received the fire of the
English regiments without flinching. They were dissatisfied because
they had been put on the left wing. At last, when the moment of
decision and defeat had come, there being no hope, they also fled
with the other clans.
Charles had yet in reserve his foreign troops, and these, after
the mountaineers had been ruined, he hoped, as he looked on from
the mound at some distance off, would redeem the day. But though
there were instances of bravery among these men, yet, demoralized
by the wreck of the clans coming as fugitives among them, and
seeing the Duke’s army getting ready to charge with the cold steel,
they fled in a body. Thus the rout was complete. Charles, who had
made his last cast for a crown, seemed now unable to realize what
had happened. Confounded, bewildered, and in tears, he seemed
unable to act. His attendants were obliged to turn his horse’s head
and compel him to retreat, Sullivan his friend seizing the horse’s
bridle and dragging him away.
During the uprising of 1745–46, the local clans wore a red or
yellow cross or ribbon, in order to distinguish themselves from the
Stuart Highlanders, who were all dressed in about the same way,
except as to their bonnets. The Jacobites all wore the white cockade,
like that of the Bourbons of France, friends of the Stuarts. One of the
liveliest tunes played by the Highland pipers was “The White
Cockade.” It was the same air, with different words, which the fifers
and drummers of the Continental army played when the flag of the
Revolution was raised in the War of Independence. In fact, in looking
over the American musicians’ repertoire, from 1775 to 1783, one
might almost imagine that the chief music sounded under “the
Congress flag” of thirteen stripes and, after 1777, under “Old Glory”
of later Revolutionary days, was Scottish. Even the strains of
mournful music, over the graves of the slain American patriots, was
“Roslyn Castle.”
One fifth of the Highland army was lost at Culloden. Of the five
regiments which charged the English, almost all the leaders and
front rank men were slain. These numbered nearly a thousand in all.
The actual battle lasted about forty minutes, much of it in distant
firing; but the charge and the crossing of the cold steel were all over
in a quarter of an hour. The number of killed, wounded, and missing
of the royal army was three hundred and ten. The victory was mainly
attributable to the effect of the artillery and musketry of the royalists;
but in Munro’s and Barrel’s regiments, many of the soldiers put to
death one, two, or more Highlanders each, with their bayonets, and
several of the dragoons, sent in pursuit, were known to have cut
down ten or twelve fugitives each in the pursuit.
CHAPTER XVI
THE OLD HIGHLANDS AND THEIR
INHABITANTS
The Highlands, geologically speaking, is an island of crystalline

rock set in a great sea of younger formations. The great glen which
forms the trough of the Caledonian Canal is a mighty earth rift. When
once across this line of rock and water, we were in the Highlands. In
one summer visit, we spent a part of our vacation at Crieff, which lies
at the base of the Grampian Hills and at the entrance to the
Highlands. Here the beauty, fashion, and intelligence of the United
Kingdom in August gather together. What was once a “hydro,” but is
now a fine hotel, was crowded to its utmost capacity. In the
evenings, entertainments of music, with dancing and recitations by
the young people, were enjoyed. In the mornings, we took horses
and carriages and drove through many leagues of the lovely
scenery. At another time, in a later year, the automobile served us
while glancing at a hundred linear and many more square miles of
Scotland’s glory.
Yet every time we were in the Highlands and in whatever shire,
the old song, learned in childhood, came to mind—“O where, tell me
where, has my Highland laddie gone?” Ross and Cromarty, now
united in one and the largest of all the counties in Scotland, is the
most thinly populated of all. In fact this great area has been
“improved” by its landed proprietors promoting the emigration of its
former inhabitants. There is only a fraction left of the Highlanders.
The Celtic element is but a survival, a remnant, and the Gaelic
tongue is like a flickering flame, almost ready to die out.
What is the reason? Is it, in part at least, because nature is so
niggardly? Again, is it not true that “those who take up the sword
shall perish by the sword”? Did the traditional Highlands and
Highlanders exist, or gain their place in romance and history, chiefly
through the human imagination?
Scottish history and poetry show that originally, even as a
swordsman and fighter, the Highlander possessed no special
superiority over the Lowlander, but in the seventeenth century, as in
the modern days, which we of ’61, as well as of 1915, remember,
and have seen demonstrated, the best prepared people, to whom
arms are habitual, and to whom military training is a personal
accomplishment, will, at the first beginning of war, at least, be pretty
sure to get the advantage. In a prolonged struggle, it is resources
that tell. Wars are not ended by battle, but by manifest reserves, with
power to follow up victory.
It was western Scotland, of azoic rock, a far-off corner of Europe,
that had the singular fortune of sheltering the last vestiges of the
Celts—that early race of people who, once placed upon the centre of
the ancient continent, were gradually driven to its western
extremities.
A notion, held tenaciously by the Highlanders, was that the
Lowlands had originally been their birthright. Many of them practised
a regular system of reprisal upon the frontier of that civilized region,
with as good a conscience as a Levant pirate crossed himself and
vowed to burn candles of gratitude before the Virgin’s picture, if
successful in robbery. To maintain this philosophy and practice, the
use of arms was habitual and necessary among the Highlanders.
While among the Lowlanders cattle-lifting and other methods of
rapine were considered as the business of thieves and scoundrels, it
was usually reckoned by the Highlanders to be an eminently
honorable occupation, partaking of the prestige of a profession. How
finely does Sir Walter Scott bring out this sentiment, when Roderick
Dhu answers Fitz-James, who charges the Highland chieftain with
leading a robber life.
Moreover, what still tended to induce military habits among the
Gaelic mountain folk, and what still maintains most wars, in the same
spirit, though on a larger scale,—national instead of private,—was
the hereditary enmity against each other, systematically maintained,
purposely cultivated and instilled in their children. In what respect
were the clan feuds and fights of the Celtic Scots any nobler than
those which so long distracted China, Japan, and Iroquois and
Algonquin America? With such philosophy dominant as still in our
day creates armies and navies, while being no more ethically worthy,
it was required that every man capable of bearing arms should be in
perpetual readiness to foment war, or to seize or repel opportunities
of vengeance. In fact, the hideous brutality of Confucian, Japanese,
Iroquois, Scottish, and Albanian codes of vengeance alike befitted
the common savagery that runs counter to the teachings of the
Universal Man of Nazareth.
The Celtic Highlanders were nominally subjugated by the iron
hand of Cromwell. Of this mighty man, Dr. Johnson says, “No faction
in Scotland loved the name of Cromwell or continued his fame.
Cromwell introduced, by useful violence, the arts of peace. People
learned to make shoes and plant kail.” Shoes were not common in
this part of Scotland until as late as 1773.
At the Restoration of the Stuarts, in the person of Charles II, the
Highlanders, with no illustrious and stimulating example before them,
rebounded into all their former privileges and vigor. They were kept
in arms during the reign of the last two monarchs, who fomented
those unhappy struggles, on account of religion, which have made
the Stuart name so detested. The patriarchal system of laws, upon
which Highland society was constituted, disposed these
mountaineers to look upon these unhappy princes, Charles I and
James II, and upon the Pretenders, who came after them, as the
general fathers or chiefs of the nation, whose natural and
unquestionable power had been wickedly disputed by their rebellious
children. Hence at Killiecrankie, Prestonpans, Falkirk, and Culloden,
they fought with the same ardor that would induce a man of
humanity to ward off the blow which an unnatural son had aimed at a
parent. In a word, as to political education, they had only the ideas of
feudalism in which they were steeped.
Having myself lived under feudal institutions, and seen the daily
workings of a society, graded from lowest to highest, although with
many variations, and fixed in customs which seemed to me to be
tedious, absurd, and ridiculous, as well as interesting and
fascinating, and living meanwhile under the shadow of castle walls
and towers, crossing daily the drawbridge and often visiting the
towers of the citadel, I could understand the mediæval processes of
thought, so long surviving in western Scotland. I was able to
appreciate also these Scottish castles, whether still maintained as of
old, intact and modernized, or in ruins, and easily re-create in
imagination the mental atmosphere and customs of the old feudal
days, when swords were an article of daily dress and frequent use,
and the steel blade the chief bond and instrument of social order.
The border ruffianism of “bleeding Kansas” in the West and much of
the old social situation down South, in cotton land,—the pride and
contempt on the one side and the hatred, with occasional cattle-
lifting propensities, on the other, especially in the Southern
Highlands,—of which in my boyhood I heard so much, helped me to
enjoy not only Scottish history, but Sir Walter Scott’s inimitable word
pictures in prose and verse. One can describe most of the
spectacular phenomena of Japanese as well as Scottish feudalism in
Scott’s verse and prose. His writings make illuminating commentary.
It was hard for the Lowlanders, after their discipline under the
feudal system had passed with the institution, to understand or get
along peaceably with the Highlanders, who hated industrialism,
shop-keeping, and money-making. Highland poverty and rawness
are in the main the immediate inheritances, even as the old semi-
civilized life was the direct result, of feudalism. The reason why the
dwellings of the plain people in the rocky regions were, even in our
day, so wretchedly poor and bare, is revealed in the book of Mair,
entitled “De Gestis,” published in Latin in 1518, concerning land
tenure. He says: “In Scotland the houses of the peasants are mere
small thatched huts, and the cause is, that they do not hold their land
in perpetuity, but only rent on a lease of four or five years at the will
of the lord; therefore, though there are plenty of stones, they will not
build neat houses, nor will they plant trees, or hedges to the woods,
nor will they enrich the soil; and this is to the no small loss and
disgrace of the whole realm. If the lords would give them their land in
perpetuity, they would get double or triple the money they now have,
because the peasants would cultivate the land incomparably better.”
This system of land tenure, which in theory and practice made
the laird the landowner and the tenant, or worker of the soil, a virtual
serf or semi-slave, sufficiently indicates the grounds and nature of
the Highland chief’s power and the degradation of the average or
common man. In almost every clan, there were subordinate chiefs,
cadets of the principal family, that had acquired a territory and
founded separate septs. In this community, the majority of
commoners were distinct from the “gentlemen,” who were persons
who could clearly trace their derivation from the chiefs of former
times and assert their kinsmanship to the present one. Below this
clan aristocracy were the mass of plain fellows (“kerns”) who could
not tell how or why they came to belong to the clan and who were
always distinctly inferiors.
There were several distinctions, based on ability, of status and
condition. The commoners were little better than serfs, having no
certain idea of a noble ancestry to nerve their exertions or to purify
their conduct. It was not to these, but to the gentry, that the chief
looked for active service and upon whom he depended in time of
war. These upper grades of men did most of the fighting, while the
larger body of common retainers (“kerns”) were left behind, during a
raid, to perform the humbler duties of driving the cows or tilling the
fields. Or, if they accompanied the foray, they were put in the rear
ranks and given poor arms, sometimes being provided only with
dirks. To illustrate these facts there were and are many stories told
and traditions handed down. Note the incident in “The Lady of the
Lake”:
“Because a wretched kern ye slew,

Homage to name to Roderick Dhu?”
In a word, in Scotland and in Japan, of which we can bear

witness from personal experience, social evolution among clansmen
and arms-bearing men had begun and continued, though separation
had early taken place between the fighters and the field laborers. In
both countries the process and result were much the same.
Moreover, after the Reformation, the proud Highlanders, clinging to
the old faith and traditions, looked down, with even greater contempt
than before, upon the commercial Presbyterians of the Low
Countries. They regarded with absolute horror the newer social and
political order, which in their eyes was but a dark system of
Parliamentary corruption. They were only too ready to believe the
stories of luxury, extravagance, and predatory dishonesty, which
were supposed to be rife and chronic in London. Here, too, human
nature, Japanese and Scotch, was as much alike as in a pair of
twins, born of the same mother, and throughout history running in
parallel lines of action.
Moreover, in both Scotland and Japan, it was the bayonet
against the sword. The men of mediæval mind in both countries
wore and wielded blades and looked upon the use of firearms as
something mean and cowardly. Believing, to the last, in the rush
against uniformed men in ranks and in slashing with two-handed
sword strokes (the Japanese swordsmen using a mat shield, where
the Highlander employed a target), both Scot and Nipponese met
failure against the triangular stabbing tools that ended feudalism. In
Tokio, the bayonet monument on Kudan Hill tells a story. Here,
history is told in steel.
What did more than anything else to open the Highlands and
break up the very idea of a “hermit nation” was a system of roads
which was carried out mainly during the sixteen years between 1726
and 1742, by the British field marshal, George Wade. Though born in
Ireland (whence also came the great soldier and diplomatist, Wade,
of China), he knew well the Gaels of both the island and the
mainland. He spent two years studying the problems of the
Highlands, economic and social. He had had long service with the
army in the Belgic Netherlands, Portugal, Spain, and the
Mediterranean Islands. During the Jacobite outbreak of 1715, he
acted effectively as military governor. Having later again made a
thorough study of the Highlands and their inhabitants, he was made
commander-in-chief, in order to give effect to his own
recommendations. He cut roads through the most important strategic
places and lines of country. In the course of this engineering work he
superintended the construction of no fewer than forty stone bridges.
It is this road-making which constitutes his chief title to fame, as the
old distich intimates:—
“Had you seen these roads before they were made,

You would lift up your hands and bless General Wade.”
In a word, he made possible the pacification of the Highlands, by

a system of hard-faced or “metalled” roads. Dr. Johnson, who saw
the results of Wade’s peaceful campaign, when the work was fresh
and the results novel, is unstinted in praise of Wade. In fact, it is
quite probable that, except for these new highways, the great man’s
“Journey to the Western Islands of Scotland,” in 1773, would not,
perhaps could not, have been taken.
The houses the Highlanders of a century ago lived in are
described by Dr. Johnson. The construction of a hut, he tells us, is of
loose stones, arranged for the most part with some tendency to
circularity and placed where the wind cannot act upon it with
violence, and where the water would run easily away, because it has
no floor but the naked ground. The wall, which is commonly about
six feet high, declines from the perpendicular a little inward. Some
rafters are raised for a roof, which makes a strong and warm thatch,
kept from flying off by ropes of twisted heather, of which the ends,
reaching from the centre of the thatch to the top of the wall, are held
firm by the weight of a large stone. No light is admitted, but at the
entrance and through a hole in the thatch, which gives vent to the
smoke. The hole is not directly over the fire, lest the rain should
extinguish it, and the smoke therefore fills the place before it
escapes.
THE SCOTCH BRIGADE MEMORIAL
Entering one of this better class of huts, Dr. Johnson found an
old woman whose husband was eighty years old. She knew little
English, but he had interpreters at hand. She had five children still at
home and others who had gone away. One youth had gone to
Inverness to buy meal—by which oatmeal is always meant. She was
mistress of sixty goats and many kids were in the enclosure. She
had also some poultry, a potato garden, and four shucks containing
each twelve sheaves of barley. Huts in building and equipment are
not more uniform than are palaces, and hers was divided into
several apartments. She was boiling goat’s flesh in the kettle for the
next meal. With true pastoral hospitality, she invited her guest to sit
down and drink whiskey. Sweetening was obtained from honey.
Probably the reason why marmalade is so much used by the modern
Scots is because of old their ancestors used a great deal of honey,
of which marmalade, usually made from oranges imported from
Spain, takes the place.

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Cancer: Oxidative Stress and Dietary

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Vinood B. Patel, Editor

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The Highlands, geologically speaking, is an island of crystalline

“Because a wretched kern ye slew,

In a word, in Scotland and in Japan, of which we can bear

“Had you seen these roads before they were made,

In a word, he made possible the pacification of the Highlands, by

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