Index
Note: Page numbers with “f” denote figures; “t” tables; “b” boxes.
A Aldose reductase (AR), 123–124
AA. See Arachidonic acid
Acacetin, 208
ACSO. See S-alk(en)yl-l-cysteine sulfoxide
Acute ischemic stroke, 168
Adenosine 5′-diphosphate (ADP), 193
Adenosine monophosphate-activated protein
kinase (AMPK), 101
in cultured skeletal muscle cells, 45–46
in endothelial cells, 101
and SirT1 activation, 101
Adenosine triphosphatase (ATPase), 6
Adenosine triphosphate (ATP), 70–71
in β-cells, 102
ATP-dependent ion channels, 17
GLN, 121
using INS-1 (beta) cell-line, 102
in mitochondria, 111–112
mitochondrial ETC, 37
oxidative phosphorylation, 225
Adiponectin, 76
NADPH oxidase, 185
NF-κB activation, 105–106
SirT1activation, 101
Adiposity, 114
ADP. See Adenosine 5′-diphosphate
Advanced glycation end product (AGE), 6
in diabetes pathogenesis, 89–90
DM, 146, 237
during hyperglycemia, 16
intracellular, 79, 146
metabolic pathways, 201–202
mitochondrial ROS, 44
non-enzymatic glycation, 57
protein kinase C, 114
ROS production, 37
Advanced oxidation protein products
(AOPPs), 117
AGE. See Advanced glycation end product
Age-Related Eye Disease Study (AREDS), 225
micronutrients, 215
supplementation, 231
Age-related macular degeneration (AMD),
223
using donor eyes, 225
MPOD, 225
preventive therapy for, 225
Akt, 104–105
in DM, 100
eNOS gene expression, 105
iNOS, 104
NF-κB activation, 126
ALA. See 5-amino levulinate; α-linolenic
acid
Alanine transaminase (ALT), 203
activity, 146
CF effect on AR inhibition
low affinity for glucose, 206
methanolic extracts, 206
polyol pathway, 206
NADPH, 206
polyol pathway flux, 204–205
relative mRNA expressions, 124f
Alkaline phosphatase (ALP), 203
Alkoxyl (RO·), 56
Allele 1, 157
ALP. See Alkaline phosphatase
α-glucosidase inhibitor, 205–206
α-linolenic acid (ALA), 130–131
DHA and EPA, 215
structures, 131f
α-lipoic acid, 215
α-tocopherol (AT), 67–68
antioxidant potential, 68–69
ATBC, 71
CAM expression, 71
correlation with lipid profile, 70
insulin sensitivity
antioxidant capabilities, 74
biochemical pathways, 71
pro-oxidant effect, 71
relationship of vitamin E, 74
vitamin E, 71
lipid profile
development of DM2, 70
diabetic dyslipidemia, 70
DM2 complications, 74
doses of AT, 74
effects of vitamin E, 71–74
and oxidative stress, 70, 72t–73t
respiratory mitochondrial chain, 70–71
TBARS levels, 74
plasma levels of, 69t
RRR-α-tocopherol, 68
α-Tocopherol, Beta-Carotene Cancer
­Prevention (ATBC), 71
α-tocopherol transfer protein (α-TTP), 68
ALT. See Alanine transaminase
Alveolar-capillary network, 238
Alzheimer’s disease, 227
AMD. See Age-related macular degeneration
2-amino ethane sulfonic acid, 174
5-amino levulinate (ALA), 54
synthase, 53
AMPK. See Adenosine monophosphate-
activated protein kinase
Angiotensin II (AT-II), 176
Angiotensin II type 1 receptor (AT1R), 227
Animal studies, 215
257
carotenoids, 215
CD and LP, 215
curcumin, 215
long-term administration, 215
MnSOD mimetics, 215
redox balance, 215
Vitamins C and E, 215
in vivo studies in, 216t–217t
Anthocyanins, 240–241
hypoglycemic effects, 242
polyphenols found in PJ, 240t
pomegranate, 241
Anti-inflammatory activity, 207
Anti-obesity effect, 241
Antibacterial activity, 207
Antidiabetic properties, Pomegranate
hypoglycemic activity, 241–242
PJ consumption, 241
polyphenols, 242
Antimutagenic activity, 207
Antioxidant-related micronutrients
carotenoids, 232–233
exposure definition studies on, 234, 234t
outcome, 234–235, 235t
study design, 233t
study population sources, 233–234, 233t
study sample, 234t
Vitamin C, 231
using food frequency questionnaire, 232
hospital-based studies, 232
NHANES, 232
population-based studies, 232
Vitamin E, 232
Antioxidants, 16, 161, 214
defense mechanisms, 58
enzymes levels, 39
protein delivery
cell-penetrating peptide technologies, 10
Tat-MT and Tat-SOD, 10–11
status
in PE, 249–250
pre-clinical studies, 251t
in pregnancies complication, 248
supplementation and PE, 250–251
supplementation
clinical trials, 252, 253t
experimental studies, 250–251
mechanistic effects, 250–251
non-proliferative DR, 219
pre-clinical studies, 251t
treatment
glucose neurotoxicity, 8
NATHAN 1, 9–10
prophylactic using glycemic control, 8–9
theoretic framework for pathogenesis, 9f
258
AOPPs. See Advanced oxidation protein
products
APE. See Apurinic/apyrimidinic
­endonuclease
Apigenin, 208
apolipoprotein A (apoA), 160
apolipoprotein E (apoE), 159, 169
Apoptosis, 19, 227
Apurinic/apyrimidinic endonuclease (APE),
20
AR. See Aldose reductase
Arachidonic acid (AA), 131
brain, 132–133
membrane phospholipids, 131
AREDS. See Age-Related Eye Disease Study
Ascorbic acid. See Vitamin C
Aspartate transaminase (AST), 203
CF effect on serum marker enzymes, 203f
hepatoprotective activity, 207
AST. See Aspartate transaminase
AT. See α-tocopherol
AT-II. See Angiotensin II
AT1R. See Angiotensin II type 1 receptor
ATBC. See α-Tocopherol, Beta-Carotene
­Cancer Prevention
Atherosclerosis Risk in Communities Study,
25–26
micronutrients, 233–234
prospective association, 232
vitamin E, 232
Atherothrombosis, 170
Atorvastatin, 185
ATP. See Adenosine triphosphate
ATPase. See Adenosine triphosphatase
B Cardioprotective activity, 207
BAECs. See Bovine aortic endothelial cells
Bay leaves. See Laurel
BDNF. See Brain-derived neurotrophic
factor
β-carotenes, 232, 249–250
BH4. See Tetrahydrobiopterin
Biomarkers, 234
antioxidant function, 117
non-preeclampsia pregnancies, 248t
oxidative stress and antioxidant ­capacity,
39
in serum or plasma samples, 233–234
supplementation, 75
Black mustard (Brassica nigra), 94
Black pepper (Piper nigrum), 94–95
Blood pressure (BP), 213
long-term diabetes, 15
in obese patients, 101
retinal vascular abnormalities, 231
taurine, 173
Blood urea nitrogen (BUN), 83
diabetic rats, 137–138
tocotrienol, 138, 138t
BODIPY C-11 probe, 226–227
Body weight, 203
CAM expression, 71
CF effect on, 203t
GLN supplementation, 122–123
Borneol, 208
Bovine aortic endothelial cells (BAECs), 167
INDEX
Bovine retinal microvascular endothelial cells dimeric phosphoserine binding ­proteins,
(BRECs), 215 31
BP. See Blood pressure hyperglycemia, 30
Brain-derived neurotrophic factor (BDNF), Cell-penetrating peptide technologies, 10
227 Cell’s antioxidant defense system, 16
lutein’s effects model, 227f Cellular antioxidant defense system, 80f
reduction in, 227 Central nervous system (CNS), 131, 223
BRECs. See Bovine retinal microvascular Cerebral arterioles
endothelial cells to nitroglycerin, 194
BUN. See Blood urea nitrogen NOS-dependent reactivity, 195
reactivity, 194f
C Cerebral ischemia
c-Jun-N-terminal kinase (JNK), 101 cardiac arrest, 17
Ca Dob. See Calcium dobesilate cell damage, 17, 17f
Caffeic acid, 148 cell death pathways, 20f
antioxidant and active compounds, 93t DNA oxidation, 19
daidzein, 148 free radicals effect, 20
lipophilic diterpenoids, 81 lipid peroxidation, 20
polyphenols, 148 oxidative stress, 19
Caffeic acid phenethyl ester, 45–46 protein oxidation, 19–20
Caffeoylquinic acids (CQAs), 208 diabetes mellitus, 15
Calbindin. See Calcium-binding free radicals
protein antioxidants, 16
Calcitriol, 112 cell’s antioxidant defense system, 16
antioxidant effect, 116 pathophysiological roles, 15–16
direct up-regulating effect, 117–118 oxidative stress
human studies, 118t dehydroepiandrosterone treatment, 21
non-calcemic functions, 115 in diabetic patients, 20–21
vitamin D, 112–113 focal cerebral ischemia, 21
Calcium dobesilate (Ca Dob), 219 reperfusion, 19
Calcium-binding protein (calbindin), 112 role of iron, 18
Caloric restriction, 101 Cerebral microvessel, 16–17
CAM. See Cell adhesion molecule Cerebrovascular diseases
Camphor, 208 acute ischemic stroke, 168–169
Cannabidiol (CBD), 215 cognitive dysfunction, 167–168
EGb761, 168
Cardiovascular disease (CVD), 160 CF. See Chrysanthemi Flos
epidemiology, 25–26 CGD. See Chronic granulomatous disease
primary prevention, 165 CGMS. See Continuous glucose monitoring
ROS formation, 43 system
vitamin D, 112 Chemical constituents
Carotenes, 223–224 acacetin, 208
Carotenoids, 215 apigenin, 208
epidemiologic evidence, 232–233 camphor and borneol, 208
lutein, 223–224 chlorogenic acid, 208
in PE development, 249–250 CQAs, 208
in visual function, 232 DPPH, 208
vitamins C and E, 247 kikkanol A, B, and C, 208
Caspase-3, 140–141, 214 pharmacological research, 208
Catalase (CAT), 42–43 Chemokine receptor 6 (CCR6), 101–102
enzymatic activities, 204 Chemokine receptor-4 (CXCR-4), 152–153
reactive species, 242 Chinese medicine, 202–203
tocotrienol effect on, 139t Chlorogenic acid, 148, 208
Catechin, 148 Cholecalciferol, 112
flavonoids, 239 Chronic granulomatous disease (CGD), 111
Gingko leaves, 166t Chronic hyperglycemia, 6f
polyphenols, 239t–240t Chrysanthemi Flos (CF), 202
CBD. See Cannabidiol aldose reductase inhibition
CCR6. See Chemokine receptor 6 low affinity for glucose, 206
CD. See Conjugated dienes methanolic extracts, 206
CDDP. See Compound danshen dripping polyol pathway, 206
pills biological activities
CDI. See Compound danshen injection anti-inflammatory activity, 207
CDT. See Compound danshen tablet antibacterial activity, 207
Cell adhesion molecule (CAM), 71 antimutagenic activity, 207
Cell signaling pathways modulation cardioprotective activity, 207

effect on urinary infection, 207
free radical scavenging activity, 207
hepatoprotective activity, 207
inflammatory bone diseases, 207
neuroprotective activity, 207
osteoporosis, 207
body weight changes, 203, 203t
Chinese medicine, 202–203
DNA fragmentation
in diabetic liver, 206f
effect on, 205
enzymic antioxidants, 204
effect on, 204t
SOD, CAT and GPx, 204
glucosidase inhibition
α-glucosidase inhibitor, 205–206
IC50 values for, 206
LPO, 203
effect on, 204f
TBARS, 203–204
protective effects, 209f
retina, effect on, 205
serum marker enzymes, 203, 203f
toxic effects, 209
vasorelaxation, 207
Chrysanthemum indicum (C. indicum), 202
antioxidant effect, 207
CF, 209
DPPH, 208
methanolic extracts, 206
modern pharmacological research, 208
Chrysanthemum morifolium
(C. morifolium), 202
antioxidant effect, 207
DPPH, 208
methanolic extracts, 206
Cilostazol, 169
CL. See Lipid cardiolipin
Clinical studies in, DR, 215, 217t–218t
α-lipoic acid administration, 219
antioxidant supplementation, 219
Ca Dob, 219
CALDIRET study, 220
combination, 219
Ginkgo biloba, 219
MDA-TBARS serum concentrations, 218
OHT and POAG, 220
oral administration, 219–220
Pycnogenol®, 215–218
vitamin E, 219
Clinically significant macular edema
(CSME), 219
CNS. See Central nervous system
Compound danshen, 81
Compound danshen dripping pills (CDDP),
81–82
Compound danshen injection (CDI), 81
application of, 81
T2DM, 81
therapeutic effect, 81
Compound danshen tablet (CDT), 81
ECG results, 81
polyol pathway in hyperglycemic
­condition, 82f
therapeutic mechanism, 81–82
Conjugated dienes (CD), 215
INDEX 259
Continuous glucose monitoring system complications, 157
(CGMS), 106–107 AGEs pathways, 201–202
Coriander (Coriandrum sativum), 94 AR inhibitors, 206
Cotton wool spots, 35 peroxy radicals, 203
COX. See Cytochrome c oxidase controls, 233–234
COX-2. See Cyclooxygenase 2 coronary artery disease
CQAs. See Caffeoylquinic acids CDDP, 82, 83t
CSME. See Clinically significant macular control and treatment groups, 83t
edema IMA, 82
Culinary herbs, 89–90 diabetes-induced oxidative stress, 174
garlic, 92–93 DM2, 67
lamiaceae, 90 dyslipidemia, 70
anti-diabetic effects, 92 encephalopathy, 129
anti-glycant activity, 91t GLN, 122–123
antioxidant and active compounds, 91t hallmarks of, 26, 26f
beneficial effects of sage, 90–91 hyperglycemia, 202f
hypoglycemic effects, 92t impairments in, 130f
mints, 92 lung as target organ
oregano, 91–92 alveolar-capillary network, 238
laurel, 93 antioxidant capacity and structural
Cumin (Cuminum cyminum), 94 changes, 238
Curcumin, 94, 215 complication, 238
CV. See Cardiovascular hyperglycemia, 238
CVD. See Cardiovascular disease proteins and carbohydrates, 238
CXCR-4. See Chemokine receptor-4 pulmonary function, 238
Cyanidinis, 148 pulmonary infections, 238
Cyclooxygenase 2 (COX-2), 132 lung tissue, 238
Cytochrome c oxidase (COX), 43 on myocardial dysfunction, 173
in organs, 237
D oxidative stress, 237
DAG. See Diacylglycerol pathways, 249f
Daidzein, 148 polyphenols, 100
DAPIT. See Diabetes and Preeclampsia resveratrol in prevention, 100f
­Intervention Trial beneficial effects, 100
DBP. See Vitamin D binding protein eNOS, 100
DCCT. See Diabetes Control and polyphenols in red wine, 100–101
­Complications Trial relationships, 101
DCFDA. See 2′,7′-dichlorofluorescein type 1 diabetes mellitus, 101–102
­diacetate resveratrol in treatment, 100f
Dehydroepiandrosterone treatment, 21 direct and indirect antioxidant ­effects,
Dendranthema, 202 103f
Deoxyribonucleic acid (DNA), 19 effect on insulin resistance by, 104–106
excessive ROS, 226 effect on insulin secretion, 102
fragmentation resveratrol affects serum glucose ­levels,
CF effect, 205 106–107
in diabetic liver, 206f resveratrol and oxidative stress, 103–104
mitochondrial dysfunction, 214 urinary excretion rates, 104f
oxidation, 19 ROS and RNS, 201–202
oxidative stress, 223 type 1 and type 2, 146
DHA. See Docosahexaenoic acid World Health Organization, 173
DHBA. See 2,5- and 2,3-dihydroxybenzoic Diabetes mellitus type 2 (DM2), 67
acid Diabetic cardiomyopathy
DHE. See Dihydroethidium cell signaling pathways modulation
DHR. See Dihydrorhodamine dimeric phosphoserine binding ­proteins,
Diabetes. See Diabetes mellitus (DM) 31
Diabetes and Preeclampsia Intervention Trial hyperglycemia, 30
(DAPIT), 252 epidemiology, 25–26
Diabetes Control and Complications Trial hallmarks of DM, 26
(DCCT), 3–4 hydroxyl radicals, 30
Diabetes mellitus (DM), 25, 238 hyperglycemia
Akt and GLUT4 translocation, 100 apoptosis, 28f
antioxidants, 100 chronic hyperglycemia, 27f
causes, 223 diabetic patients, 28
chronic disease, 15 mitochondrial function, 27
by chronic hyperglycemia, 89 role of, 27–28
combined effect, 237 lipotoxicity
260 INDEX

Diabetic cardiomyopathy (Continued ) prognostic role of polyneuropathy, 5 histopathology

GLUT, 28 symmetrical neuropathies, 5 blood cells, 33
oxidative stress, 28 oxidative stress, 83 cells, 33
pathogenesis, 29f diabetic conditions, 7 cotton wool spots, 35, 35f
nitric oxide and peroxynitrite, 29–30 DN therapeutic interventions, 8f dual circulation, 33
oxidative stress pivotal role, 7 dysfunctional autoregulation, 34
free radicals, 26–27 sources of ROS, 8 endothelial cell membranes, 33
hyperglycemia, 26 prevalence, 4 local tissue ischemia, 35
ROS/RNS, 28 rosuvastatin therapy, 187 macular edema, 34–35
superoxide, 28–29 Diabetic peripheral neuropathy (DPN), 3 microaneurysms, 34
Diabetic lung injury, pomegranate effect on risk factors, 4 microvascular lesions, 35
antioxidant enzyme activity, 242 peripheral nerves, 3 neuronal retina degeneration, 35
antioxidative properties, 243 sets of nerve fibers, 3–4 non-vascular retinal cells, 35
cellular antioxidant defense system, 242 Diabetic rats, 203 pericytes, 34
diabetic lung tissue, 243f DR in, 215 proliferative DR, 35, 35f
eNOS immunohistochemistry, 244f glucose-lowering effect, 102 retinal capillary wall structure, 34f
GSH and SOD, 242–243 hypoglycemic effects, 92t vascular microscopic changes, 34f
oxidative injury, 243 nicanartine, 215 medical care, 233–234
PCC derivatives, 242 retinal VEGF levels, 37 metabolic memory, 213–214
reactive species, 242 treatment with tocotrienol, 137–138 outcome definition, 235, 235t
sialic acid, 242 type 1 diabetes, 21 outcome measurement, 234–235, 235t
Diabetic macrovascular disease Vitamins C and E, 215 oxidative stress
clinical trials of statins, 187t Diabetic retina antioxidant defenses, 37
diabetic nephropathy, 187 lutein’s neuroprotective effects antioxidant enzymes levels, 39
diabetic neuropathy, 187 AT1R, 227 blue light, 37
DR, 187 BDNF, 227 cellular functions, 36
heart protection study, 187 diabetic model mice, 228 cellular sources, 36
Scandinavian Simvastatin survival study, in diabetic retina, 227f in DR context, 37
187 ER stress and productions, 228 FRs, 35–36
impact of statin therapy, 186 synaptic network system, 227 glycaemic control, 38
Diabetic nephropathy. See Diabetic synaptophysin, 227, 227f hyperglycemic conditions, 37
­neuropathy (DN) ROS accumulation metabolic memory, 38
Diabetic neuropathy (DN), 3, 135 biological systems, 226 mitochondrial lipid membrane, 37
in animals, 187 using DHE, 226 MMP, 38
to diabetic neuropathy in man, 10 hyperglycemia, 225 nitrotyrosine concentration, 38
extensive accumulation of AGEs, 10 lutein’s effect on, 226f oxidation and reduction process, 36f
sensory neuropathy in man, 10 transcription factor, 226 pathogenesis of DR, 38
STZ-induced rat, 10 Diabetic retinopathy (DR), 34, 213 reactive hydroxyl radical, 36
antioxidant protein delivery animal studies, 215 retina, 37, 231
cell-penetrating peptide technologies, 10 carotenoids, 215 retinal non-capillary cells, 38–39
Tat-MT and Tat-SOD, 10–11 CD and LP, 215 ROS, 36–37, 38f
antioxidant treatment curcumin, 215 serum biomarkers, 39
glucose neurotoxicity, 8 long-term administration, 215 superoxide formation, 37
NATHAN 1, 9–10 MnSOD mimetics, 215 VEGF levels, 37
prophylactic use of glycemic redox balance, 215 in vitro studies, 38
control, 8–9 vitamins C and E, 215 pathogenesis, 225
theoretic framework for pathogenesis, 9f in vivo studies in, 216t–217t study design, 233t
biological markers antioxidant agents, 220 study population sources, 233–234, 233t
metabolic factors, 135–136 carotenoids, 232–233 study sample, 234t
renoprotective strategies, 136 CDDP, 83–84 therapies, 220
chronic complication of diabetes, 3 clinical resources, 231 type 1 diabetes, 231
ESRD, 135 clinical studies in, 215, 217t–218t vitamin C, 231
hyperglycemia α-lipoic acid administration, 219 using food frequency questionnaire, 232
chronic hyperglycemia, 6f antioxidant supplementation, 219 hospital-based studies, 232
diabetic chronic complications, 5 Ca Dob, 219 NHANES, 232
DPN development, 6 CALDIRET study, 220 population-based studies, 232
excess glucose in neurons, 7 combination, 219 vitamin E, 232
incidence and severity of Ginkgo biloba, 219 in vitro studies in, 214, 214t
­neuropathy, 7–8 MDA-TBARS serum concentrations, 218 Caspase-3, 214
oxidative stress, 6–7 OHT and POAG, 220 mitochondrial dysfunction, 214
role, 5–7 oral administration, 219–220 Müller cells in hyperglycemic ­medium,
microalbumin in urine, 83 Pycnogenol®, 215–218 214–215
microalbuminuria, 135 vitamin E, 219 omega-3 fatty acids, 215
natural history diabetes mellitus, 84 PEDF, 214
NCV, 4–5 epidemiologic studies, 233 ROS production, 214
peripheral nervous system, 4f exposure definition studies on, 234, 234t TBARS, 214
 INDEX 261
Diacylglycerol (DAG), 6, 176 Electron transport chain (ETC), 36 Flow mediated dilation (FMD), 186
2,7-dichlorofluorescein, 160 Electroretinogram (ERG), 205, 225 FLVCR1. See Feline leukemia virus subgroup
2′,7′-dichlorofluorescein diacetate (­DCFDA), lutein, 215 C receptor 1
21, 226 plasma antioxidants, 219 FM. See Fat mass
Diet, 89 End stage renal disease (ESRD), 135 FMD. See Flow mediated dilation
Dietary antioxidants Endogenous antioxidant mechanisms, 176, Food factor, 224
beneficial effects, 46 177f Fork-head Box O (FOXO), 101
excessive energy intake, 45 Endoplasmic reticulum (ER), 8 FRDA. See Friedreich’s ataxia
HOMA, 46 endothelium, 146–147 Free radicals (FRs), 26–27, 35–36
meta-analyses, 46 neurodegenerative influences, 228 antioxidants, 16
polyphenols, 45–46 Endothelial cell membranes, 33 cell’s antioxidant defense system, 16
tissue damage, 45f endothelial nitric oxide synthase (eNOS), damage, 18t
Dietary iron, 53, 59 18, 57 hyperglycemia, 16
Dietary polyphenols in endothelially-dependent ­vasodilation, hypoglycemia, 16
production of NO, 151 100 mitochondrial production, 18–19
sites of action, 151f hexosamine pathway flux, 146 NADPH, 16
sources, 149t–150t NF-κB, 238 pathophysiological roles, 15–16
Dietary Supplement Health and Education NOS uncoupling, 186 production, 17
Act (DSHEA), 165–166 statins, 185 ATP-dependent ion channels, 17
Dihydroascorbic acid, 205 uncoupling, 44 intracellular calcium, 17–18
Dihydroethidium (DHE), 226 Endothelial progenitor cells (EPC), 152 rate of ROS production, 16–17
Dihydrorhodamine (DHR), 159–160 early, 152–153 scavenging activity, 207
2,5- and 2,3-dihydroxybenzoic acid (DHBA), loss of, 153–154 French Paradox study, 100
19 Endothelium, 207 Friedreich’s ataxia (FRDA), 46–47, 59
1,25-dihydroxycholecalciferol Endothelium derived hyperpolarizing factor FRs. See Free radicals
(1,25(OH)2D3), 112, 113f (EDHF), 193 Fufang danshen. See Compound danshen
5,7-dihydroxy-4′-methoxyflavone. See eNOS. See endothelial nitric oxide synthase
Acacetin Enzymatic antioxidants, 36, 204t G
Direct repeat-3 (DR3), 116 Enzymatic sources. See also Nonenymatic G-CSF. See Granulocyte colony-stimulating
Distal symmetric polyneuropathy (DSP), 3 sources factor
Divalent metal transporter 1 (DMT1), 53 NOS isoforms, 57 G6PD. See Glucose-6-phosphate
DLP1. See Dynamin-like protein Nox, 57 ­dehydrogenase
DM. See Diabetes mellitus Enzymic antioxidants, 16. See also γ-glutamyl transpeptidase (GGT), 117–118
DM2. See Diabetes mellitus type 2 ­Non-­enzymic antioxidants γ-glutamyl-cysteinyl-glycine. See Glutathione
DMT1. See Divalent metal transporter 1 CF effect on, 204t (GSH)
DN. See Diabetic neuropathy Cu, Zn-SOD, 204 Garlic (Allium sativum), 92–93
Docosahexaenoic acid (DHA), 130–131, 215 in diabetes, 204 Gastrointestinal tract, 90
CNS, 131 EPA. See Eicosapentanoic acid GFAT. See Glutamine fructose-6-phosphate
l-arginine, 252 EPC. See Endothelial progenitor cells transaminase 1
oxidative stress ER. See Endoplasmic reticulum GGT. See γ-glutamyl transpeptidase
in brain, 132–133 ERG. See Electroretinogram Ginger (Zingiber officinalis), 93–94
docosanoids, 131 ERK. See Extracellular signal regulated Ginkgo biloba L. (Ginkgoaceae), 165–166, 219
fatty acids, 131–132 kinase atherothrombosis, 170
neuroprostanes, 131 Erythropoiesis, 53 bleeding disorders, 170
photoreceptors, 131 ESRD. See End stage renal disease cerebrovascular diseases
photosynthetic and heterotrophic ETC. See Electron transport chain acute ischemic stroke, 168–169
­microalgae, 130–131 Exogenous antioxidants, 214 cognitive dysfunction, 167–168
structure, 131f Extracellular signal regulated kinase (ERK), EGb761, 168
Docosanoids, 131 104, 227 characteristics of, 166
Double bonds, 223–224 components of EGb761, 166t, 168f
DPN. See Diabetic peripheral neuropathy F extract, 219
DR. See Diabetic retinopathy FA. See Fatty acid on glucose metabolism
DR3. See Direct repeat-3 Fat mass (FM), 116 kaempferol, 166–167
DSHEA. See Dietary Supplement Health and Fatty acid (FA), 175 oxidative stress, 167
Education Act Feline leukemia virus subgroup C receptor 1 treatment with EGb761, 166
DSP. See Distal symmetric polyneuropathy (FLVCR1), 54 heart and coronary artery diseases
Dynamin-like protein (DLP1), 174 Fenton/Haber Weiss reactions, 56f direct anti-atherosclerotic effect, 167
Ferrireductase, 54 endothelial function, 167
E Ferritin, 54 Ginkgolide B, 167
ECG. See Electrocardiography Ferritin-bound iron’s dissociation, 18 in vivo inhibition, 169f
EDHF. See Endothelium derived Ferulic acid, 148 lipid peroxidation, 167
­hyperpolarizing factor Flat-slope phenomenon, 233–234 vasodilatory effect, 167
Eicosapentanoic acid (EPA), 130–131 Flavonoids, 148 major compounds, 166f
ROS overproduction, 215 component, 208 peripheral vascular diseases
structures, 131f polyphenol antioxidants, 239 beneficial effects, 169
Electrocardiography (ECG), 81 ROS, 166 cilostazol, 169
262
Ginkgolide B, 167
GLN. See Glutamine
Glucagon-like peptide 1 (GLP-1), 102, 122–123
Glucosamine-6 phosphate, Fructose-
6-phosphate amidotransferase. See
Glutamine fructose-6-phosphate
transaminase 1 (GFAT)
Glucose, 27, 46
Glucose control, 165
Glucose neurotoxicity, 8
Glucose transporter (GLUT), 28
Glucose transporter 4 (GLUT4), 99–100
Glucose-6-phosphate dehydrogenase
(G6PD), 116, 175
Glucose-lowering effect, 102
Glucosidase inhibition, CF effect
α-glucosidase inhibitor, 205–206
IC50 values for, 206
GLUT. See Glucose transporter
GLUT4. See Glucose transporter 4
Glutamine (GLN), 121
cellular apoptosis, 126
diabetes, 122–123, 123t
functions in body, 122f
hyperglycemia-induced complications
hypotheses, 123
metabolic pathways, 123–124, 124t
mRNA expressions, 124f
immunomodulatory effects, 122
mechanisms, 124
antioxidant enzyme activities, 125
GSH, 124–125
GSH synthesis, 125–126
HSP expression, 126
HSPs, 125
NO oxidation, 125, 125f
oxidative stress, 124
metabolic functions, 121
NF-κB-DNA binding activity, 126
outcomes in diabetes, 126t
PPAR, 126
Glutamine fructose-6-phosphate
­transaminase 1 (GFAT), 123–124
hexosamine pathway flux, 175
mRNA expressions, 124f
protein kinase C activation, 146
Glutathione (GSH), 75, 124
direct scavenger, 242
H2O2, 204
non-enzymic antioxidants, 204
oxidative stress in brain injury, 129
streptozotocin-induced diabetic rats,
242–243
Glutathione disulfide (GSSG), 124
Glutathione peroxidase (GSH-Px), 55
antioxidant enzymes levels, 248
diabetic retinopathy, 83–84
in dose-dependent manner, 214–215
GSSG, 124
H2O2, 204
reactive species, 242
ROS, 42–43
up-regulation, 116
Glutathione reductase (GR), 215, 242
Glycated transferrin, 57
Glycosylation, 238
INDEX
GM-CSF. See Granulocyte macrophage
colony-stimulating factor
GPx. See Glutathione peroxidase (GSH-Px)
GR. See Glutathione reductase
Granulocyte colony-stimulating factor
(­G-CSF), 152–153
Granulocyte macrophage colony-stimulating
factor (GM-CSF), 152–153
Greek sage (Salvia fruticosa), 90–91
GSH. See Glutathione
GSH-Px. See Glutathione peroxidase
GSSG. See Glutathione disulfide
GTP cyclohydrolase I (GTPCH-I), 186
Guanosine 5′-triphosphate cyclohydrolase I
(GTPCH), 147–148
H highly sensitive C-reactive protein (hsCRP),
H2O2. See Hydrogen peroxide
Haptoglobin (Hp), 157
antioxidant function
atherosclerotic plaques, 159f
diabetic individuals, 159
monomer binds, 158–159
radioactivity loss in blood, 159
gene, 157
geographical distribution, 158
Hb redox activities
2,7-dichloroflurescein, 160
heme iron, 159–160
HDL, 160
antioxidant enzymes, 160
CVD incidence, 161
LCAT, 160
vascular complications in Hp, 160t
heme iron, 159
polymer structure, 158f
protein, 157–158
structure, 158f
Hb. See Hemoglobin
hCG. See human chorionic gonadotropin
HCV. See Hepatitis C infection
HDL. See High density lipoprotein
HDL-c. See High density lipoprotein
­cholesterol
Healthy dietary habits, 201–202
Heart and coronary artery diseases, 167
direct anti-atherosclerotic effect, 167
endothelial function, 167
Ginkgolide B, 167
in vivo inhibition, 169f
reperfusion-induced lipid ­peroxidation,
167
vasodilatory effect, 167
Heart failure (HF), 25
Heart Outcomes Prevention Evaluation
(HOPE), 75, 161–162
Heart protection study, 187
Heat Shock Proteins (HSPs), 125
Heme iron, 51
Heme oxygenase-1 (HO-1), 53
Hemodynamic factors, 135–136
Hemoglobin (Hb), 157
Hemoproteins, 51
Hemosiderin, 54–55
Hepatitis C infection (HCV), 59
Hepatoprotective activity, 207
Hepcidin, 53
Hereditary hemochromatosis (HH), 53
Hesperetin, 148
Hexosamine biosynthetic pathway, 30
Hexosamine pathway flux, 175
HF. See Heart failure
HH. See Hereditary hemochromatosis
HIFα. See Hypoxia inducible factor alpha
High density lipoprotein (HDL), 160
antioxidant enzymes, 160
incidence of CVD, 161
LCAT, 160
vascular complications in Hp, 160t
High density lipoprotein cholesterol
(HDL-c), 70
Higher serum ferritin levels, 60–61
118
HMG. See Hydroxymethyl-glutaryl
HMG CoA. See 3-hydroxy-3-methylglutaryl
coenzyme A
HNE. See 4-hydroxynonenal
HO-1. See Heme oxygenase-1
Homeostasis Model Assessment (HOMA),
46, 101
HOPE. See Heart Outcomes Prevention
Evaluation
Hp. See Haptoglobin
hsCRP. See highly sensitive C-reactive protein
HSPs. See Heat Shock Proteins
human chorionic gonadotropin (hCG), 250–251
Human fundus macula, 224, 224f
Human umbilical vein endothelial cells
(HUVEC), 84
Hydrogen peroxide (H2O2), 15–16
in DNA damage, 205
pomegranate flower extract, 241
SOD, 204
superoxide radicals, 18–19
Hydroxybenzoic acid, 239
8-hydroxy-2′-deoxyguanosine (8-OHdG), 116
Hydroxyl radical (OH·), 15–16
in DNA damage, 205
formation of, 30
pomegranate flower extract, 241
24R-hydroxylase, 112
Hydroxymethyl-glutaryl (HMG), 183
3-hydroxy-3-methylglutaryl coenzyme A
(HMG CoA), 184
4-hydroxynonenal (HNE), 20, 26–27
Hypercholesterolemia, 28
Hyperglycemia, 16
apoptosis, 28f
body weight, 203
chronic hyperglycemia, 6f
diabetes mellitus, 201–202
diabetic chronic complications, 5
diabetic patients, 28
DM, 157
DNA fragmentation, 205
DPN development, 6
excess glucose in neurons, 7
incidence and severity of neuropathy, 7–8
induced metabolic pathways, 202f
microangiopathy role, 5–6
mitochondrial function, 27
 INDEX 263
oxidative stress, 6–7, 26, 184f Insulin-mediated signaling cascades, 99–100 Iron overload states, 53
pomegranate flower extract, 238 Intercellular adhesion molecule-1 ­(ICAM-1), dietary overload, 59
role, 7, 27–28 135–136, 146–147 idiopathic hemochromatosis
ROS Intercellular cell adhesion molecule (ICAM), HH, 58–59
formation, 80f 219 type 2 diabetes, 58
production, 225 Interleukin (IL-1β), 132 mitochondrial overload
Hypoglycemia, 16 Interleukin 6 (IL-6), 43, 116, 146–147 β-cells, 59–60
Hypoxia inducible factor alpha (HIFα), 43 Internal blood-retinal barrier (iBRB), 215 FRDA, 59
International Diabetes Federation Diabetes iron stores, 59
I Atlas, 99 oxidative stress parameters, 59f
iBRB. See inner blood retina barrier; Internal Intracellular oxidative stress, 207 transfusions, 59
blood-retinal barrier IRE. See Iron response elements Iron regulatory proteins-1 (IRP1), 55
ICAM. See Intercellular cell adhesion molecule Iron, 51 Iron response elements (IRE), 55
ICAM-1. See Intercellular adhesion chelation, 58 Iron-sulfur clusters (ISC), 51
­molecule-1 deficiency, 53, 60t IRP1. See Iron regulatory proteins-1
ICARE study. See Israel Cardiovascular blood donation, 60 IRS. See Insulin receptor substrates
­Vitamin E study glycemic control, 60 ISC. See Iron-sulfur clusters
Idebenone, 47 iron role in diabetes, 61f Ischemia-modified albumin (IMA), 82
Idiopathic hemochromatosis oxidative stress in, 61f Israel Cardiovascular Vitamin E study
HH, 58–59 tissue hypoxia, 60 (ICARE study), 161–162
type 2 diabetes, 58 and diabetes
IFG. See Impaired fasting glucose formation of bilirubin, 58 J
IL-1β. See Interleukin insulin, 58 JNK. See c-Jun-N-terminal kinase
IL-6. See Interleukin 6 iron chelation, 58
IMA. See Ischemia-modified albumin serum ferritin levels, 58 K
Impaired fasting glucose (IFG), 117 distribution in body, 52, 52f Kaempferol, 166–167
In vitro studies, DR in, 214, 214t deficiency, 53 Ginkgo biloba leaves, 166f
caspase-3, 214 erythropoiesis, 53 onion and garlic, 92–93
mitochondrial dysfunction, 214 hemoproteins, 51 ROS production, 167
Müller cells in hyperglycemic ­medium, homeostasis Kikkanol A, 208
214–215 ALA, 54
omega-3 fatty acids, 215 dietary iron, 53 L
PEDF, 214 ferritin, 54 l-arginine, 252
ROS production, 214 hepcidin, 53 enzymatic sources, 57
TBARS, 214 HO-1 reaction, 53f NOS, 51
inducible nitric oxide synthase (iNOS), 18 ISC, 54 Labile iron pool (LIP), 51–52
enzymatic sources, 57 levels of regulation, 53 Lamiaceae, 90
expression, 43 liver, 54–55 anti-diabetic effects, 92
hyperglycemia, 146–147 mitoferritin, 54 anti-glycant activity, 91t
non-PE pregnancies, 248 splenic reticuloendothelial ­macrophages, antioxidant and active compounds, 91t
oxidative-stress-induced deleterious 53 beneficial effects of sage, 90–91
­effects, 104 Tf, 53–54 hypoglycemic effects, 92t
Inflammatory bone diseases, 207 TfR1, 54–55 mints, 92
Inflammatory cytokines, 101–102 iron levels, 62 oregano, 91–92
inner blood retina barrier (iBRB), 33 LIP, 51–52 Laurel, 91t, 93
iNOS. See inducible nitric oxide synthase overload states, 58–60 LCAT. See Lecithin acetyl transferase
Insulin receptor substrates (IRS), 99–100 oxidative stress LDL. See Low density lipoprotein
Insulin resistance, resveratrol effect on, antioxidant capacity, 55 LDL-c. See Low-density, lipoprotein
104–105 antioxidant defense systems, 55 ­cholesterol
changes, 106f biochemical processes, 55 Lecithin acetyl transferase (LCAT), 160
eNOS activation, 105 biochemical reactions, 55 LHP. See Lipid hydroperoxides
HOMA indices, 106 cellular reactions, 56 Lignans, 239
insulin-mediated signaling responses, 106 in diabetes, 56–58, 57f LIP. See Labile iron pool
MAPK pathway, 105 diabetic and non-diabetic Lipid cardiolipin (CL), 42
phosphorylation activation changes, 105f parents, 62t Lipid hydroperoxides (LHP), 215, 248
by reducing oxidative stress, 104–105 Fenton/Haber Weiss reactions, 56f Lipid peroxidation (LPO), 203
resveratrol treatment, 105–106 iron nutrition and, 62t anthocyanins, 241
Insulin secretion, resveratrol effects on redox active iron, 56 antioxidative properties, 243
β-cell depletion, 102 ROS, 55, 56f CF effect on, 204f
antioxidant enzymes, 102 superoxide anion, 55 diabetic state, 237
ATP synthesis, 102 toxicity of iron, 55 end-product of, 242
glucose-lowering effect, 102 role of, 18 non-PE pregnancies, 248
HOMAβ, 102 serum ferritin levels, 60–61 prevalence of PE, 249–250
Insulin sensitivity serum iron levels, 52 radical extracts, 20
biochemical pathways, 71 stores, 59 TBARS, 203–204
vitamin E, 71 vascular endothelium, 61–62 tocotrienol effect on, 139t
264
Lipid profile
development of DM2, 70
diabetic dyslipidemia, 70
oxidative stress, 70
respiratory mitochondrial chain, 70–71
Lipoperoxidation, 242
Lipoprotein lipase (LPL), 28, 161
Lipotoxicity
GLUT, 28
oxidative stress, 28
pathogenesis, 29f
Lipoxygenase (LOX), 131
15-lipoxygenase-1 (15-LOX-1), 132
Liver, 54–55
CF effect, 204t
export of iron, 53
GLN on glycemia, 122–123
iron influences glucose metabolism, 58
lutein, 224
macrophages, 52
Loupe effect, 37
Lovastatin
molecular structure, 184f
statin agents and doses, 184t
Low density lipoprotein (LDL), 84, 117
Low-density, lipoprotein cholesterol
(LDL-c), 70
LOX. See Lipoxygenase
15-LOX-1. See 15-lipoxygenase-1
LP. See Lipid hydroperoxides (LHP)
LPL. See Lipoprotein lipase
LPO. See Lipid peroxidation
Lutein, 215, 223–224, 232
biosynthetic pathway, 224f
chemical structure, 224f
clinical data for, 225
food factor, 224
human fundus macula, 224, 224f
lutein-binding protein, 224–225
neuronal network layer, 224
neuroprotective effects
AT1R, 227
BDNF, 227
diabetic model mice, 228
in diabetic retina, 227f
ER stress and productions, 228
synaptic network system, 227
synaptophysin, 227, 227f
phytochemicals, 224
ROS effect in diabetic retina, 226f
suppressive effects on ROS
cytotoxic influence, 226
retinal disease models, 226–227
STZ-induced diabetes model, 226
Luteolin, 208
Lycopene, 232
M mitochondrial function, 46
Macroglial cells, 35
Macular edema, 34–35
Macular pigment optical density (MPOD),
225
Maidenhair Tree. See Ginkgo biloba L.
­(Ginkgoaceae)
Malondialdehyde (MDA), 20–21
CDI, 81
INDEX
fat mass, 116 damaging effects, 41
LPO, 203–204 deleterious effects, 41–42
MDA-TBARS serum concentrations, 218 diabetes, 43
non-PE pregnancies, 248 H2O2, 42–43
Manganese superoxide dismutase (­MnSOD), levels of, 42
225 oxidants, 43
MAPK. See Mitogen-activated protein sources and antioxidant defenses, 42t
kinases species, 41
Marjoram (Oregano majorana), 91–92 Mitochondrial sources
Matrix metalloproteinase-9 (MMP-9), 167 mitoNEET, 58
Matrix metalloproteinases (MMPs), 38 ROS, 57–58
activation, 29–30 Mitochondrial superoxide dismutase
capillary basement membrane, 38 ­(MnSOD), 16
retinal mitochondria in diabetes, 38 hyperglycemia, 225
MCI. See Mild cognitive impairment mimetics, 215
MCP-1. See Monocyte chemoattractant mitochondrial dysfunction, 214
protein-1 Mitochondrial superoxide production, 146
MCSO. See S-methyl-l-cysteine sulfoxide Mitochondrial swelling, 18–19
MDA. See Malondialdehyde Mitochondrial-specific superoxide
Metabolic memory, 213–214 ­dismutase. See Mitochondrial
Metabolic syndrome, 101 ­superoxide dismutase (MnSOD)
Microaneurysms, 34 Mitochondrion, 28, 41
Microangiopathy Mitoferritin, 54
EPCs, 153–154 Mitogen-activated protein kinases
role of, 5–6 (MAPK), 8
T1DM and T2DM, 5 in human umbilical cells, 105
turmeric, 94 intracellular calcium channels, 112
Mild cognitive impairment (MCI), 132–133 MitoQ, 47, 47f
Minimum luminal diameter (MLD), 162 MLD. See Minimum luminal diameter
Mints, 92 MMP-9. See Matrix metalloproteinase-9
mitochondrial DNA (mtDNA), 36, 214 MMPs. See Matrix metalloproteinases
Mitochondrial dysfunction, 214 MnSOD. See Manganese superoxide
Mitochondrial electron transport chain, 19 ­dismutase; Mitochondrial superoxide
Mitochondrial function, 46 dismutase
Mitochondrial overload Monocyte chemoattractant protein-1
β-cells, 59–60 (MCP-1), 146–147
FRDA, 59 MPO. See Myeloperoxidase
iron stores, 59 MPOD. See Macular pigment optical density
oxidative stress parameters, 59f mtDNA. See mitochondrial DNA
Mitochondrial oxidases, 186 Myeloperoxidase (MPO), 44
Mitochondrial oxidative stress diabetic host responses, 117
antioxidant systems, 45 vitamin D status, 116
diabetes, 43–44
chronic pro-inflammatory, 44 N
complications, 44 N-methyl-D-aspartic acid (NMDA), 193
hyperglycemia, 44f N2O. See Nitrous oxide
dietary antioxidants Na+–Ca2+ exchangers (NCX), 175
beneficial effects, 46 Na+–H+ exchangers (NHE), 175
excessive energy intake, 45 NADPH oxidase 4 (Nox4), 28–29
HOMA, 46 NADPH oxidases, 105–106
meta-analyses, 46 atherosclerosis-risk conditions, 185
polyphenols, 45–46 Atorvastatin, 185
tissue damage, 45f blood-retinal barrier breakdown, 185
endothelial ROS production, 44f Naringenin, 151
Friedreich’s ataxia, 46–47 National Health and Nutrition Examination
glucose, 46 Survey (NHANES), 67, 232
idebenone, 47 NCV. See Nerve conduction velocity
NCX. See Na+–Ca2+ exchangers
mitochondrial impairment and damage, 41 Necrosis, 19
MitoQ, 47, 47f Neovascularization, 152
oxidative stress and ROS production, 46–47 Nerve conduction velocity (NCV), 4–5
RNS Neurological Assessment of Thioctic Acid in
iNOS expression, 43 Diabetic Neuropathy (NATHAN), 8
nitrogen dioxide, 43 Neuronal network layer, 224
ROS neuronal NOS (nNOS), 18, 57
cellular sources, 42f Neuronal retina degeneration, 35

Neurons, 227
Neuropathies, 4
DN, 4–5
etiology of, 7–8
Neuroprostanes, 131
Neuroprotectin D1 (NPD1), 131, 132f
Neuroprotective activity, 207
Neurovascular unit, 35
NF-κB. See Nuclear factor kappa B
NHANES. See National Health and Nutrition
Examination Survey
NHE. See Na+–H+ exchangers
Nicanartine, 215
Nitric oxide (NO), 18
anti-inflammatory activity, 207
diabetic retinopathy, 83–84
DM, 237
in DNA damage, 205
eNOS expression, 238
free radicals, 15–16
insulin-mediated signaling cascades, 99–100
iron, 51
NO-eNOS pathway, 100–101
pathophysiological implications, 43
PKC activity, 146
pomegranate flower extract, 241
superoxide radicals, 36
tocotrienol effect on, 139t
Nitric oxide synthase (NOS), 17–18
in endothelial cells, 219
iron, 51
l-arginine into l-citrulline, 18
peripheral blood vessels, 191–192
peroxynitrite, 29–30
uncoupling
plasma nitrotyrosine, 186
vascular oxidative stress, 186
Nitrogen dioxide (NO2), 43
Nitrotyrosine, 116, 125
Nitrous oxide (N2O), 43
NMDA. See N-methyl-D-aspartic acid
nNOS. See neuronal NOS
Non-enzymatic antioxidants, 36
Non-enzymatic glycation, 238
Non-enzymic antioxidants, 16. See also
­Enzymic antioxidants
CF effect, 205t
AR activity, 204–205
GSH, 204
Vitamin C and E, 205
Non-heme iron, 51. See also Heme iron
Non-proliferative diabetic retinopathy
(NPDR), 225
Non-protein thiols
decreased in kidneys of diabetic rats, 139
tocotrienol effect on, 139t
Non-ROS oxidative stress, 186
Non-transferrin-bound iron (NTBI), 52
Nonenymatic sources
Glycated transferrin, 57
protein glycation, 57
NOS. See Nitric oxide synthase
Nox4. See NADPH oxidase 4
NPD1. See Neuroprotectin D1
NPDR. See Non-proliferative diabetic
­retinopathy
INDEX
Nrf2. See Nuclear factor erythroid 2-related
factor 2
NTBI. See Non-transferrin-bound iron
Nuclear factor erythroid 2-related factor 2
(Nrf2), 104
in ROS production, 175
T1D, 192
Nuclear factor κB (NF-κB), 20, 43
diabetic state, 237
mitochondrial sources, 57–58
mRNA levels, 140
reactive oxygen species generation,
135–136
SirT1, 101
O effect, 36
oBRB. See outer blood retina barrier
OCT. See Optical coherence tomography
Ocular hypertension (OHT), 220
OH·. See Hydroxyl radical
8-OHdG. See 8-hydroxy-2′-deoxyguanosine
OHT. See Ocular hypertension
Onion (Allium cepa), 92–93
ONL. See Outer nuclear layer
OPL. See Outer plexiform layer
OPs. See Oscillatory potentials
Optical coherence tomography (OCT), 225
Oregano (Origanum vulgare), 91–92
OS. See Oxidative stress; Outer segment
Oscillatory potentials (OPs), 225
Osteoporosis, 207
outer blood retina barrier (oBRB), 33
Outer nuclear layer (ONL), 224
Outer plexiform layer (OPL), 224
Outer segment (OS), 224
oxidative low density lipoprotein ­(oxLDL),
82, 117
Oxidative phosphorylation, 225
Oxidative stress (OS), 36, 249f
antioxidant defenses, 37
antioxidant enzymes levels, 39
ATP in mitochondria, 111–112
blue light, 37
cellular functions, 36
cellular sources, 36
in diabetes
diabetic encephalopathy, 129
GSH concentration, 130f
neuronal cells, 129
TUNEL-positive cells, 130f
use of antioxidants, 130
diabetic conditions, 7
diabetic retinopathy, 223
DN therapeutic interventions, 8f
in DR context, 37
endothelial dysfunction, 146–147
free radicals, 26–27
FRs, 35–36
glycaemic control, 38
hyperglycemia, 26
hyperglycemic conditions, 37
intracellular, 207
in vitro studies, 38
lipids, 70
LPO, 203
metabolic memory, 38
265
mitochondrial lipid membrane, 37
MMP, 38
nitrotyrosine concentration, 38
NO pathway, 147f
non-preeclampsia pregnancies, 248t
in overt diabetes mellitus, 99
oxidation and reduction process, 36f
in pathogenesis, 145
pathogenesis of DR, 38
PE, 247
pivotal role, 7
in pregnancies complication, 248
reactive hydroxyl radical, 36
retina, 37–39, 231
ROS, 36, 223
overproduction in mitochondria, 37
production, 36, 38f
sources, 8
serum biomarkers, 39
superoxide formation, 37
in T1DM pathogenesis, 101–102
TBARS, 203–204
type 1 DM, 99
UPS, 147–148
VEGF levels, 37
oxLDL. See oxidative low density lipoprotein
Oxygen-centered free radicals, 208
P
p22 phagocyte oxidase (p22phox), 28–29
p22phox. See p22 phagocyte oxidase
p38 MAPK. See p38 mitogen-activated
­protein kinase
p38 mitogen-activated protein kinase (p38
MAPK), 151
PAD. See Peripheral vascular disease
PAF. See Platelet-Activating Factor
PAI. See Plasminogen activator inhibitor
Parathyroid hormone (PTH), 112
Parkinson’s disease (PD), 208
PARP. See Poly(ADP-ribose) polymerase
PBMC. See Peripheral blood mononuclear
cells
PC. See Phosphatidylcholine
PCBP1. See Poly (rC) binding protein 1
PCC. See Protein carbonyl content
PCO. See Protein carbonyl
PD. See Parkinson’s disease; Plain doogh
(PD)
PDGF. See Platelet-derived growth factor
PDH. See Pyruvate dehydrogenase
PDR. See Proliferative diabetic retinopathy
PE. See Phosphatidylethanolamine;
­Preeclampsia
1-PeCSO. See S-1-propenyl-l-cysteine
­sulfoxide
PEDF. See Pigment-epithelium-derived factor
Pericytes, 34
endothelial cells, 34
loss of, 34
Peripheral blood mononuclear cells (PBMC),
153–154
Peripheral vascular disease (PAD), 146–147
beneficial effects, 169
cilostazol, 169
266 INDEX

Peroxisome proliferator-activated receptor phytochemical-bearing foods, 239 Protein kinase C (PKC), 6, 237
gamma (PPARγ), 45–46 preventive effects, 100 activation, 6, 146
GLN, 126 in red wine, 100–101 pathway, 202f
pomegranate compounds, 241–242 red wine, 151 Protein oxidation, 19–20. See also DNA
vitamin E, 71 Pomegranate (Punica granatum L.), 239 ­oxidation
Peroxisome proliferator-activated antidiabetic properties PSUR. See Pharma safety update reports
­receptor-gamma coactivator-1α hypoglycemic activity, 241–242 PTH. See Parathyroid hormone
(PGC-1α), 101 PJ consumption, 241 Pycnogenol®, 215–218
Peroxyl radical (ROO·), 56, 203 polyphenols, 242 Pyruvate dehydrogenase (PDH), 19–20
Peroxynitrite, 29–30, 146–147 clinical evidence, 241
PGC-1α. See Peroxisome proliferator-activated anthocyanins, 241 Q
receptor-gamma coactivator-1α anti-obesity effect, 241 Quantitative insulin sensitivity check index
PGI2. See Prostaglandin I2 epidemiological studies, 241 (QUICKI), 117–118
Pharma safety update reports (PSUR), 219 ROS, 241 Quantitative sensory testing (QST), 3–4
Phenolic acids, 239 effect on diabetic lung injury Quercetin, 148
Phenolic compounds, 208 antioxidant enzyme activity, 242
PhNR. See Photopic negative response antioxidative properties, 243 R
Phosphatidylcholine (PC), 179 cellular antioxidant defense system, 242 RAGE. See Receptor of advanced glycated
Phosphatidylethanolamine (PE), 179 diabetic lung tissue, 243f end products
Phosphatidylinositol 3-kinase (PI3-K), 99–100 eNOS immunohistochemistry, 244f RAS. See Renin-angiotensin system
Phospholipase A2 (PLA2), 131 GSH and SOD, 242–243 RCT. See Reverse cholesterol transport
Phospholipid transfer protein (PLTP), 161 oxidative injury, 243 Reactive hydroxyl radical, 36
Photopic negative response (PhNR), 225 PCC derivatives, 242 Reactive nitrogen species (RNS), 15–16
Phytochemicals, 224 reactive species, 242 effect, 201–202
PI3-K. See Phosphatidylinositol 3-kinase sialic acid, 242 formation by hyperglycemia, 202f
Pigment-epithelium-derived factor (PEDF), 214 flower extract, 241 free radicals, 26–27
PJ. See Pomegranate juice fruit, 239, 239t overproduction of, 145
PKC. See Protein kinase C anthocyanins, 240 role in pathogenesis development, 173
PLA2. See Phospholipase A2 arils of, 239–240 Reactive oxygen species (ROS), 6
Plain doogh (PD), 117 content by subclass for, 240t effect of, 36
Plasma ceruloplasmin, 53 nutritional value, 240t accumulation in diabetic retina
Plasminogen activator inhibitor (PAI), 146, seeds, 239 biological systems, 226
153–154 leaf extract, 240 using DHE, 226
Platelet-Activating Factor (PAF), 153–154 Pomegranate fruit hyperglycemia, 225
Platelet-derived growth factor (PDGF), 167 anthocyanins, 240 lutein’s effect on, 226f
PLTP. See Phospholipid transfer protein arils of, 239–240 transcription factor, 226
PMS. See Postmarketing surveillance content by subclass for, 240t AGEs, 174
POAG. See Primary open-angle glaucoma flower extract, 241 antioxidant defenses, 42t
Poly (rC) binding protein 1 (PCBP1), 54 leaf extract, 240 AT-II role, 176
Poly ADP-ribosylation, 205 nutritional value, 240t CaMKII role, 175
Poly(ADP-ribose) polymerase (PARP), 19 in pure juice, 240t cardiac oxidative stress, 174f
cellular pathways/networks, 192 seeds, 239 and cellular damage, 145
hyperglycemic spikes, 146–147 Pomegranate juice (PJ), 241 cellular sources, 36, 42f
STZ induced diabetes, 102 Post-ischemia reperfusion, 19 chain reactions, 7
Polyneuropathy Postmarketing surveillance (PMS), 219 damaging effects, 41
DSP, 3 Postprandial interstitial glucose levels, 106f deleterious effects, 41–42
prognostic role of, 5 PPARγ. See Peroxisome proliferator-activated diabetes, 43
Polyol pathway, 8, 206 receptor gamma eNOS expression, 238
activation of, 30 Preeclampsia (PE), 247, 249f FA role, 175
AGE, 237 antioxidant supplementation formation, 111, 202f
glucose effects, 7–8 clinical trials, 252, 253t as free radicals, 15–16
hyperglycemia via, 81–82 experimental studies, 250–251 glucose levels, 129
hyperglycemic conditions, 175 pre-clinical studies, 251t H2O2, 42–43
NADPH, 16 micronutrients and nutraceutical hexosamine pathway flux, 175
Polyphenols, 45–46 ­supplementation effects, 254t homeostatic control and, 41
antioxidants, 152f, 239 oxidative stress and antioxidant ­status, levels of, 42
chain breakers, 148 249–250 lutein’s suppressive effects
classification and food sources, 150f Primary open-angle glaucoma (POAG), 220 cytotoxic influence, 226
compounds, 242 Pro-oxidants, 111–112 retinal disease models, 226–227
concentrations, 90 Programd cell death. See Apoptosis STZ-induced diabetes model, 226
dietary polyphenols sources, 149t–150t Proliferative diabetic retinopathy (PDR), 225 mitochondria role, 174
disorders, 239 Prostaglandin I2 (PGI2), 153–154 mitochondrial production of, 6
flavonoids, 148 Protein carbonyl (PCO), 117 NADPH oxidase, 174–175
glucose metabolism, 148 Protein carbonyl content (PCC), 242 neurodegenerative processes, 129
health benefits, 151 Protein glycosylation, 237 neuroprotective effects
organic chemicals, 238–239 Protein kinase B. See Akt AT1R, 227

BDNF, 227
diabetic model mice, 228
in diabetic retina, 227f
ER stress and productions, 228
synaptic network system, 227
synaptophysin, 227, 227f
Nrf2 role, 175
NTBI, 52
overproduction of, 79–80, 123–124, 157, 183
oxidants, 43
oxidative stress and, 223
in pathogenesis, 226
PKC activation, 176
polyol pathway role, 175
pomegranate flower extract, 241
production of, 70, 214
role in pathogenesis development, 173
sources, 8, 42t
xanthine oxidase role, 175
Reactive species, 242
Receptor of advanced glycated end products
(RAGE), 122–123, 237
Redox active iron, 56
Renal apoptosis, 140–141
Renal oxidative stress prevention, 139
Renin-angiotensin system (RAS), 57, 176, 227
Reoxygenation phase. See Reperfusion
Reperfusion, 19
Respiratory burst, 111
Respiratory mitochondrial chain, 70–71
Resveratrol, 154, 192
affecting serum glucose levels
beneficial effects, 107
possible targets, 107f
postprandial interstitial glucose ­levels,
106f
by reducing oxidative stress, 106–107
time until maximum interstitial glucose
level, 107f
antioxidant effects, 103f
effects, 101
on insulin resistance
changes, 106f
eNOS activation, 105
HOMA indices, 106
insulin-mediated signaling responses,
106
MAPK pathway, 105
phosphorylation activation changes,
105f
by reducing oxidative stress, 104–105
resveratrol treatment, 105–106
on insulin secretion, 102
β-cell depletion, 102
antioxidant enzymes, 102
ATP synthesis, 102
glucose-lowering effect, 102
HOMAβ, 102
reactive oxygen species, 104, 104f
on vascular function
ADP, 193–194
anti-inflammatory properties, 195
blood glucose concentration, 194–195,
195f
cerebral arterioles reactivity, 194f
enzyme systems, 196
INDEX
increase in oxidative stress, 195–196
NMDA, 194
nNOS protein levels, 197f
oxidant/antioxidant pathways, 197f
peripheral blood vessels, 193
protein levels, 196–197, 196f
resistance arterioles, 193
T1D, 196
Retina, CF effect on, 205
Retinal blood vessels, 33
Retinal disease models, 226–227
Retinal neurodegeneration in diabetes
diabetic retinopathy pathogenesis, 225
using OCT, 225
OP changes and apoptotic changes, 225
oscillatory potentials, 225
Retinal non-capillary cells, 38–39
Retinal pigment epithelium (RPE), 33, 215,
224
Reverse cholesterol transport (RCT), 160
RNS. See Reactive nitrogen species
RO·. See Alkoxyl
ROO·. See Peroxyl radical
ROS. See Reactive oxygen species
Rosuvastatin therapy, 187
RPE. See Retinal pigment epithelium
RS·. See Thiyl
RSOO·. See Thiyl-peroxyl
S source of, 93
S-1-propenyl-l-cysteine sulfoxide
(1-PeCSO), 92–93
S-alk(en)yl-l-cysteine sulfoxide (ACSO),
92–93
S-methyl-l-cysteine sulfoxide (MCSO), 92–93
S-propyl-l-cysteine sulfoxide, 92–93
SA. See Sialic acid
Sage (Salvia officinalis L), 90–91
SalA. See Salvianolic acid A
Salicylate, 19
Salvia miltiorrhiza (S. miltiorrhiza), 81
components
apolipoprotein E gene knock-out, 86
cellular dysfunction, 86
Tanshinone IIA, 85–86
compound danshen, 81–84
diabetic coronary artery disease
CDDP, 82, 83t
control and treatment groups, 83t
IMA, 82
diabetic nephropathy
microalbumin in urine, 83
oxidative stress, 83
diabetic retinopathy
CDDP, 83–84
diabetes mellitus, 84
hydrophilic extract
antioxidative effect, 84
lipid peroxidation, 84
therapeutic effect, 84
VCAM-1 and vWF, 85f
Salvianolate
hydrophilic extract, 84
T2DM, 84–85
vascular disease and atherosclerosis, 85
Salvianolic acid A (SalA), 81
267
Salvianolic acid B (SalB), 81
San Luis Valley Diabetes Study, 232
dietary intake of vitamin E, 232
Scandinavian Simvastatin survival study, 187
Scavenged superoxide (O2·−), 241
SDF-1. See Stromal cell-derived factor-1
SDH. See Sorbitol dehydrogenase
Self-reported dietary methods, 233–234
Sensory fibers, 4–5
Serum marker enzymes, CF effect on,
203, 203f
Sialic acid (SA), 242–243
Silent information regulator 1 (SIRT1), 151
Silent myocardial ischemia (SMI), 46
SIRT1. See Silent information regulator 1
SirTs. See Sirtuins
Sirtuin1 (SirT1), 101, 192
Sirtuins (SirTs), 101
Six-transmembrane epithelial antigen of
prostate-3 (STEAP 3), 54
SMI. See Silent myocardial ischemia
SOD. See Superoxide dismutase
Soluble vascular cell adhesion molecule-1
(sVCAM-1), 84
Sorbitol dehydrogenase (SDH), 206
Spices
anti-glycant activity, 93t
antioxidant
and active compounds, 93t
coriander, 94
cumin, 94
ginger, 93–94
hypoglycemic effects, 93t
mustards, 94
pepper, 94–95
turmeric, 94
Splenic reticuloendothelial macrophages, 53
StARD3. See Steroidogenic acute regulatory
domain 3
STAT3 transcription factor, 226
Statins
agents and doses, 184t
on oxidative stress, 185t
clinical benefits, 184–185
mitochondrial oxidases, 186
NADPH oxidases, 185
non-ROS oxidative stress, 186
NOS uncoupling, 186
effect of oxidized LDL, 185
Xanthine oxidases, 185
plasma cholesterol synthesis, 184
STEAP 3. See Six-transmembrane epithelial
antigen of prostate-3
Steroidogenic acute regulatory domain 3
(StARD3), 224–225
Stilbenes, 239
Streptococcus pneumonia (S. pneumonia), 238
Streptozotocin (STZ), 7
Stroke, 17
Stromal cell-derived factor-1 (SDF-1), 152–153
STZ. See Streptozotocin
STZ induced diabetes, 79–80
DHE staining intensity reduction, 226
STZ induced rats, 137–138
resveratrol pre-treatment effect in, 102
268
Sun's emission angle, 114
Superoxide, 28–29, 146
radicals, 18–19
Superoxide dismutase (SOD), 7, 204
generating both O2·− and H2O2, 42–43
O2·− dismutation, 55
overexpression effect, 146
oxidative stress and, 167
protective effects of, 248
ROS accumulation, 226
in streptozotocin-induced diabetic rats,
242–243
tocotrienol effect on, 139t
up-regulation, 116
sVCAM-1. See Soluble vascular cell adhesion
molecule-1
Synaptic network system, 227
Synaptophysin, 227
in diabetic retina, 227, 227f
T Total antioxidant capacity (TAC), 20–21,
T1D. See Type 1 diabetes
T1DM. See Type 1 diabetes mellitus
T2D. See Type 2 diabetes
T2DM. See Type 2 diabetes mellitus
TAC. See Total antioxidant capacity
Tanshinone llA (TIIA), 81
S. miltiorrhiza, 85
signaling pathways, 86
STZ-induced diabetic rats, 85–86
treatment with, 86
TAS. See Total antioxidant status
Taurine, 173
anti-diabetic role, 177
anti-oxidant role of, 176f, 177
antioxidant enzymes and xanthine
­oxidase, 179t
diabetic pancreatic tissue, 178f
intracellular ROS, 179t
NADPH oxidase, 179f
activation, 179f
inactivation, 180f
rodents, 176–177
structure, 174f
thiol based antioxidants, 179t
TBARS. See Thiobarbituric acid reactive
substance
TCA. See Total antioxidant capacity (TAC)
Teratogenic effects, 250–251
Terpene lactones, 166
Tetrahydrobiopterin (BH4), 186, 192–193
3′,4′,5,7-tetrahydroxyflavone. See Luteolin
Tf. See Transferrin
TfR1. See Transferrin receptor 1
TGF-β. See Transforming growth factor-β
Thermal perception threshold (TPT), 3–4
Thiobarbituric acid reactive substance
(TBARS), 56–57, 214
in kidneys of diabetic rats, 139
LPO end product detection, 203–204
oxidative stress evaluation, 74
in pregnant women with T1DM, 248
Thioredoxin-interacting protein (Txnip),
123–124
Thiosulfinates, 92–93
Thiyl (RS·), 56
INDEX
Thiyl-peroxyl (RSOO·), 56
TIIA. See Tanshinone llA
tissue plasminogen activator (tPA), 21,
153–154
TNF-α. See Tumor necrosis factor-α
Tocochromanols, 136
Tocopherols
in DN
diabetic control, 136
drug treatment, 136–137
experimental protocol, 137f
glomerular changes, 137
study design, 136f
effects, 138t–139t, 140f
isomers
chemical structures, 68f
structural formula, 68f
natural vitamin E, 136
renal damage, 138
STZ-injected rats, 137–138
117–118
Total antioxidant status (TAS), 39, 219
Toxic effects
of CF, 209
of diabetes in pregnant rats, 250–251
tPA. See tissue plasminogen activator
TPT. See Thermal perception threshold
Trace elements, 250–251
Transferase-mediated dUTP nick end
­labeling (TUNEL), 167
Transferrin (Tf), 53–54
Transferrin receptor 1 (TfR1), 54
Transforming growth factor-β (TGF-β), 57
Transforming growth factor-β1 ­(TGF-β1),
139–140
4′,5,7-trihydroxyflavone. See Apigenin
3,4′,5-trihydroxystilbene. See Resveratrol
Tubulointerstitial fibrosis, 139–140
Tumor necrosis factor-α (TNF-α), 43, 101, 226,
250–251
TUNEL. See Transferase-mediated dUTP nick
end labeling
Turmeric (Curcuma longa), 93–94
Txnip. See Thioredoxin-interacting protein
Type 1 diabetes (T1D), 191
cerebrovascular dysfunction, 192
endothelial cell function, 191–192
eNOS-dependent reactivity, 192–193
increase in oxidative stress, 193
NADPH oxidase, 193
PARP, 193
superoxide, 192
Type 1 diabetes mellitus (T1DM), 247
antioxidant status
in PE, 249–251
pre-clinical studies, 251t
in pregnancies complication, 248
oxidative stress, 247
non-preeclampsia pregnancies, 248t
in pregnancies complication, 248
preeclampsia, 249f
pregnancies in women, 250t
resveratrol and prevention
oxidative stress, 101–102
STZ induced diabetes, 102
Type 2 diabetes (T2D), 58, 89, 114
comparison with T1D, 191
patients died from CVD, 165
Type 2 diabetes mellitus (T2DM), 79–80
U
Ubiquitin proteasome system (UPS), 147–148
Uncoupling protein 2 (UCP2), 102
Uncoupling protein-1 (UCP1), 225
United Kingdom (UK), 252
Untranslated regions (UTR), 55
Urinary infection effect, 207
Urine albumin excretion rate (UAER), 83
V
Vascular cell adhesion molecule-1
(VCAM-1), 46
with increased cardiovascular risk,
146–147
Vascular endothelial growth factor (VEGF),
153–154, 186, 213, 225
protein concentration, 215
Vascular endothelium, 61–62
Vascular regeneration
diabetes mellitus, 151–152
early EPCs, 152–153
endothelial function, 154
neovascularization in adults, 152
polyphenols in, 153f
resveratrol, 154
Vascular smooth muscle cell (VSMC),
85–86, 167
Vasorelaxation, CF effect on, 207
VCAM-1. See Vascular cell adhesion
­molecule-1
VDR. See Vitamin D receptor
VEGF. See Vascular endothelial growth factor
Very low-density lipoproteins (VLDL), 68
Vibration perception threshold (VPT), 3–4
Vitamin C, 231
using food frequency questionnaire, 232
hospital-based studies, 232
NHANES, 232
PE and, 249–250
population-based studies, 232
role in oxidative damage reduction, 205
Vitamin D, 112
adiposity, 114
antioxidant, 116t
calcitriol, 116
deficiency-induced vascular OS, 116
FM, 116
non-calcemic functions, 115
in vitro and animal studies, 116, 116t
biosocial factors, 114
biosynthesis and functions, 113f
direct vs. indirect effect, 117, 117f
diabetic host responses, 117
human studies, 118t
OS biomarkers, 117–118
role of genetic factors, 118
endocrine system, 112–113
forms, 112
non-genomic actions, 112
optimizing effect, 115
oxidative stress and complications, 115f
 INDEX
relation of, 112 TBARS values, 75
T2D, 114–115 in vivo, 75–76
VDR, 112 and diabetic retinopathy, 232
Vitamin D binding protein (DBP), 112 enterocytes, 68
Vitamin D receptor (VDR), 112 epidemiological studies
Vitamin E, 67–68 heme iron reactivity, 162f
AT, 68 HOPE study, 161–162
administering type 1 diabetics, 219 Kaplan-Meier plot of effect, 161f
CVD, 161 WAVE, 162
cytotoxicity, 68–69 lipid phase compartment, 161
diabetic complications lipid radicals, 161
adiponectin, 76 reactive species generation, 70f
antioxidant vitamins, 75 role in oxidative damage reduction, 205
effects of antioxidants, 75 supplementation, 252
failure of vitamin E therapy, 75 tocopherol isomers, 68f
HOPE study, 75 tocotrienol structure, 69f
LDL-c, 75 VLDL. See Very low-density lipoproteins
metabolism of tocopherols, 75 von Willebrand factor (vWF), 84, 152–153
269
VPT. See Vibration perception threshold
VSMC. See Vascular smooth muscle cell
vWF. See von Willebrand factor
W
White mustard (Brassica or Sinapis alba), 94
Women's Angiographic Vitamin and
­Estrogen (WAVE), 162
World Health Organization (WHO), 67
X
Xanthine oxidase (XO), 43, 175, 185
Xanthophylls, 223–224
Z
zeaxanthin, 232
Zrt-IRt-like protein 14 (ZIP 14), 54