- •Preface
- •Contents
- •1 Extracellular and Intracellular Signaling – a New Approach to Diseases and Treatments
- •1.1 Introduction
- •1.1.1 Linear Model of Drug Receptor Interactions
- •1.1.2 Matrix Model of Drug Receptor Interactions
- •1.2 Experimental Approaches to Disease Treatment
- •1.3 Adipokines and Disease Causation
- •1.4 Questions in Disease Treatment
- •1.5 Toxic Lifestyles and Disease Treatment
- •References
- •2.1 Introduction
- •2.2 Heterogeneity of Adipose Tissue Composition in Relation to Adipokine and Cytokine Secretion
- •2.3 Feedback between FA and the Adipocyte
- •2.6 Metabolic Programming of Autocrine Signaling in Adipose Tissue
- •2.8 Cell Heterogeneity in the Pancreatic Islet
- •2.16 Concluding Remarks
- •Acknowledgements
- •References
- •3 One Receptor for Multiple Pathways: Focus on Leptin Signaling
- •3.1 Leptin
- •3.2 Leptin Receptors
- •3.3 Leptin Receptor Signaling
- •3.3.4 AMPK
- •3.3.5 SOCS3
- •3.4 Leptin Receptor Interactions
- •3.4.1 Apolipoprotein D
- •3.4.2 Sorting Nexin Molecules
- •3.4.3 Diacylglycerol Kinase Zeta
- •3.4.4 Apolipoprotein J
- •References
- •4.1 Introduction
- •4.2 Leptin: A Brief Introduction
- •4.3 Expression of Leptin Receptors in Cardiovascular Tissues
- •4.6 Post Receptor Leptin Signaling
- •4.6.2 Mitogen Activated Protein Kinase Stimulation
- •4.7 Adiponectin
- •4.7.1 Adiponectin and Cardiovascular Disease
- •4.7.2 Adiponectin and Experimental Cardiac Hypertrophy
- •4.8 Resistin
- •4.8.1 Cardiac Actions of Resistin
- •4.8.1.1 Experimental Studies on the Cardiac Actions of Resistin
- •4.9 Apelin
- •4.9.1 Apelin and Heart Disease
- •4.10 Visfatin
- •4.11 Other Novel Adipokines
- •4.12 Summary, Conclusions and Future Directions
- •Acknowledgements
- •References
- •5 Regulation of Muscle Proteostasis via Extramuscular Signals
- •5.1 Basic Protein Synthesis
- •5.2.1 Hormones
- •5.2.1.1 Mechanisms of Action: Glucocorticoids
- •5.2.1.2 Mechanisms of Action: TH (T3)
- •5.2.1.3 Mechanisms of Action: Testosterone
- •5.2.1.4 Mechanisms of Action: Epinephrine
- •5.2.2 Local Factors (Autocrine/Paracrine)
- •5.2.2.1 Mechanisms of Action: Insulin/IGF Spliceoforms
- •5.2.2.2 Mechanisms of Action: Fibroblast Growth Factor (FGF)
- •5.2.2.3 Mechanisms of Action: Myostatin
- •5.2.2.4 Mechanisms of Action: Cytokines
- •5.2.2.5 Mechanisms of Action: Neurotrophins
- •5.2.2.7 Mechanisms of Action: Extracellular Matrix
- •5.2.2.8 Mechanisms of Action: Amino Acids (AA)
- •5.3 Regulation of Muscle Proteostasis in Humans
- •5.3.1 Nutrients as Regulators of Muscle Proteostasis in Man
- •5.3.2 Muscular Activity (i.e. Exercise) as a Regulator of Muscle Proteostasis
- •5.4 Conditions Associated with Alterations in Muscle Proteostasis in Humans
- •5.4.2 Disuse Atrophy
- •5.4.3 Sepsis
- •5.4.4 Burns
- •5.4.5 Cancer Cachexia
- •References
- •6 Contact Normalization: Mechanisms and Pathways to Biomarkers and Chemotherapeutic Targets
- •6.1 Introduction
- •6.2 Contact Normalization
- •6.3 Cadherins
- •6.4 Gap Junctions
- •6.5 Contact Normalization and Tumor Suppressors
- •6.6 Contact Normalization and Tumor Promoters
- •6.7 Conclusions
- •References
- •7.1 Introduction
- •7.2 Background on Migraine Headache
- •7.3 Migraine and Neuropathic Pain
- •7.4 Role of Astrocytes in Pain
- •7.5 Adipokines and Related Extracellular Signalling
- •7.6 The Future of Signaling Research to Migraine
- •Acknowledgements
- •References
- •8.1 Alzheimer’s Disease
- •8.1.2 Target for AD Therapy
- •8.2 AD and Metabolic Dysfunction
- •8.2.1 Impaired Glucose Metabolism
- •8.2.2 Lipid Disorders
- •8.2.3 Obesity
- •8.3 Adipokines
- •8.3.1 Leptin
- •8.3.2 Adiponectin
- •8.3.3 Resistin
- •8.3.4 Visfatin
- •8.3.5 Plasminogen Activator Inhibitor
- •8.3.6 Interleukin-6
- •8.4 Conclusions
- •References
- •9.1 Introduction
- •9.1.1 Structure and Function of Astrocytes
- •9.1.1.1 Morphology
- •9.1.1.2 Astrocyte Functions
- •9.1.2 Responses of Astrocytes to Injury
- •9.1.2.1 Reactive Astrocytosis
- •9.1.2.2 Cell Swelling
- •9.1.2.3 Alzheimer Type II Astrocytosis
- •9.2 Intracellular Signaling System in Reactive Astrocytes
- •9.2.1 Oxidative/Nitrosative Stress (ONS)
- •9.2.2 Protein Kinase C (PKC)
- •9.2.5 Signal Transducer and Activator of Transcription 3 (STAT3)
- •9.3 Signaling Systems in Astrocyte Swelling
- •9.3.1 Oxidative/Nitrosative Stress (ONS)
- •9.3.2 Cytokines
- •9.3.3 Protein Kinase C (PKC)
- •9.3.5 Protein Kinase G (PKG)
- •9.3.7 Signal Transducer and Activator of Transcription 3 (STAT3)
- •9.3.10 Ion Channels/Transporters/Exchangers
- •9.4 Conclusions and Perspectives
- •Acknowledgements
- •References
- •10.1 Adipokines, Toxic Lipids and the Aging Brain
- •10.1.1 Toxic Lifestyles, Adipokines and Toxic Lipids
- •10.1.2 Ceramide Toxicity in the Brain
- •10.3 Oxygen Radicals, Hydrogen Peroxide and Cell Death
- •10.4 Gene Transcription and DNA Damage
- •10.5 Conclusions
- •References
- •11.1 Introduction
- •11.2 Cellular Signaling
- •11.2.1 Types of Signaling
- •11.2.2 Membrane Proteins in Signaling
- •11.3 G Protein-Coupled Receptors
- •11.3.1 Structure of GPCRs
- •11.3.1.1 Structure Determination
- •11.3.1.2 Structural Diversity of Current GPCR Structures
- •11.3.1.3 Prediction of GPCR Structure and Ligand Binding
- •11.3.2 GPCR Activation: Conformation Driven Functional Selectivity
- •11.3.2.2 Ligand or Mutation Stabilized Ensemble of GPCR Conformations
- •11.3.2.4 GPCR Dimers and Interaction with Other Proteins
- •11.3.3 Functional Control of GPCRs by Ligands
- •11.3.3.1 Biased Agonism
- •11.3.3.2 Allosteric Ligands and Signal Modulation
- •11.3.4 Challenges in GPCR Targeted Drug Design
- •11.4 Summary and Looking Ahead
- •Acknowledgements
- •References
- •12.1 Introduction
- •12.5.1 Anthocyanins
- •12.5.2 Gallates
- •12.5.3 Quercetin
- •12.5.5 Piperine
- •12.5.6 Gingerol
- •12.5.7 Curcumin
- •12.5.8 Guggulsterone
- •12.6.1 Phytanic Acid
- •12.6.2 Dehydroabietic Acid
- •12.6.3 Geraniol
- •12.7 Agonists of LXR that Reciprocally Inhibit NF-jB
- •12.7.1 Stigmasterol
- •12.7.3 Ergosterol
- •12.8 Conclusion
- •References
- •13.1 Introduction
- •13.2 Selective Dopaminergic Neuronal Death
- •13.3 Signaling Pathways Involved in Selective Dopaminergic Neuronal Death
- •13.3.1 Initiators and Signaling Molecules
- •13.3.1.1 Response to Oxidative and Nitrosative Stress
- •13.3.1.2 Response to Altered Proteostasis
- •13.3.1.3 Response to Glutamate
- •13.3.1.4 Other Initiators
- •13.3.2 Signal Transducers, Intracellular Messengers and Upstream Elements
- •13.3.2.2 Small GTPases
- •13.3.3 Intracellular Signaling Cascades
- •13.3.3.1 Mitogen Activated Protein Kinases (MAPK) Pathway
- •13.3.3.2 PI3K/Akt Pathway
- •13.3.3.4 Unfolded Protein Response (UPR)
- •13.3.4 Potentially Involved Intracellular Signaling Components
- •13.3.4.3 PINK1
- •13.3.5.2 Dopamine Metabolism
- •13.3.5.3 Cell Cycle
- •13.3.5.4 Autophagy
- •13.3.5.5 Apoptosis
- •13.4 Conclusions
- •References
- •Subject Index
Subject Index
Note: page numbers in italic refer to tables, page numbers in bold refer to figures
5HT see serotonin
5HT receptors (5HTR) 117, 121, 124 6-OHDA see 6-hydroxydopamine
(6-OHDA)
acetylcholine (ACh) 83, 86–7 acetylcholine receptor (AChR) 83 aconitase 256
actin 63, 94, 101, 106
acyl CoA cholesterol transferase (ACAT) 136
adenomatosis polyposis coli (APC) 30
adenosine 50 monophosphateactivated protein kinase see AMPactivated protein kinase (AMPK)
adenovirus 18
adenylyl cyclase (AC) 211 adherens 106
adhesion molecules 179 adhesion proteins 5 adipo-insular axis 11, 30–1 adipocytes see also leptin; lipids
3T3-L1 17 adiponectin 17, 63–4
AMP-activated protein kinase (AMPK) 14, 15
autocrine e ects 15–17 circadian clock 20–1 ectopic fat 27
fatty acids feedback 14–15, 19
glucose uptake 12, 18, 140 interleukin-6 (IL-6) 141 leptin receptors (Ob-R) 15–16 MCP-1 14, 15
MLP e ect 20, 26, 30 plasminogen activator inhibitors
(PAI) 140 PPARa 17–19 STATs 46
toll-like receptors (TLR) 14, 19 transforming growth factor-b1
(TGF-b1) 141
triglycerides (TAG) 12, 14, 18, 19 visfatin secretion 178, 179
Wnt proteins 31 adipogenesis 21 adipoinsular axis 30–1
adipokines 69 see also adiponectin; apelin; ghrelin; leptin; resistin; visfatin
Alzheimer’s disease (AD) 130–42 cardiac actions 57–70, 69 circadian clock e ects 21 lifestyle e ects 176
migraine headache 116–25 neurodegeneration 178 secretion by adipose tissue 4,
11, 175 adiponectin
AdipoR 17, 28, 64 aging 175
284
adiponectin (continued) Alzheimer’s disease (AD) 139 antihypertrophic e ects 65–6 arthritis levels 5–6
autocrine e ects 15 blood plasma levels 16
cardioprotective e ects 65–6 cardiovascular disease 64–5 circadian clock e ects 21 diabetes e ect 139
fatty acids e ect 15, 139 insulin resistance 13–14, 16,
16–17, 139 lifestyle e ects 176 migraine e ect 118 obesity levels 14, 139
pancreatic b cell 27–9 production 63–4 receptors 16–17, 28, 139 relation to nitric oxide
production 5 structure 63–4, 139 TNFa expression 16–17
adiponectin receptor 1 (AdipoR1) 69 adiponectin 17, 28, 64 AMP-activated protein kinase
(AMPK) 16 insulin 118
adiponectin receptor 2 (AdipoR2) 69 adiponectin 17, 28, 64
metformin 17
peroxisome proliferator-activated receptor a (PPARa) 16,
29, 139 adipose tissue
adipoinsular axis 30–1 adipokine release 13, 32 autocrine signaling 17–21 composition 12
peroxisome proliferator-activated receptor a (PPARa) 18
ADP-ribose 179 ADP-ribosylate 181 aging
apelin 68
brain 175, 177, 178–9, 248, 254
Subject Index
central nervous system (CNS) 142 DNA repair 256
muscle proteostasis 95, 96–7 NADH oxidase 178–9 substantia nigra (SN) 248, 254 testosterone levels 81
agoutiregulated peptide (AgRP) 13 AgRP see agoutiregulated peptide
(AgRP)
AKT see protein kinases (AKT) allostasis 123
allosteric agonism 220 allosteric antagonism 220 allosteric modulators 219–21
allosteric partial antagonism 220–1 alternative medicine theories 3 Alzheimer’s disease (AD)
adipokines 130–42 astrocytosis 154–5 brain lesions 184 ceramide e ect 176
decreased glucose metabolism link 177
decreased muscle mass link 176 e ect of diet 176
FAD 130, 132
glucose metabolism 134–5 inflammation 231–2
link to diabetes 134–6 lipid metabolism 176 monocytes 177 neovascularization 183–4 pathogenesis 130, 176 plaques 5, 133 protection of blood-brain
barrier 178
reactive astrocytosis 151, 157 therapy 133–4, 175–6
amino acids (AA) burns 101 diet-derived 83, 92 disuse atrophy 98
muscle proteostasis 87–8, 89–91, 92
muscle wasting release 95–6 sarcopenia 97
Subject Index |
285 |
AMP-activated protein kinase |
leptin role 48, 49 |
(AMPK) |
lipid peroxidation 256 |
adiponectin 13, 65 |
MAPK role 263 |
fatty acids 14 |
muscle proteostasis 87 |
leptin 13, 15, 139 |
NF-kB role 266 |
muscle contraction 95 |
p38 role 257, 264, 265 |
Parkinson’s disease 257, 266–7 |
p53 role 162, 267–8 |
resistin 139 |
pancreatic b cells 24, 28 |
signaling pathway 49–50 |
Parkinson’s disease 259, 270 |
AMP:ATP ratio 14, 95, 257, 266 |
PINK1 role 267 |
AMPK see AMP-activated protein |
protein kinase C (PKC) role 87 |
kinase (AMPK) |
TNFa role 29 |
amylin 125 |
UPR role 266 |
amyloid precursor protein |
APP see amyloid precursor protein |
(APP) 131–2, 177 |
(APP) |
amyloidb (Ab) |
AQP-4 see aquaporin-4 (AQP-4) |
Alzheimer’s disease (AD) 131–4, |
aquaporin-4 (AQP-4) 163 |
135, 138, 232 |
arachidonic acid 121–2, 160 |
ceramide 177 |
2-arachidonoyl glycerol 177–8, 211 |
e ect on 2-arachidonyl |
arrestins |
glycerol 178 |
binding 209, 213, 218 |
e ect on anandamide 178 |
signaling pathway 210, 214–16 |
insulin signaling 133 |
arteries 177 |
NADH oxidase activity 178–9 |
arterioles 177, 184 |
phagocytosis 235 |
astrocytes 152 |
plaques 131–3, 177, 178 |
calcium levels 123–4 |
anandamide 177–8 |
central nervous system |
angiotensinogen 5 |
(CNS) 149–51, 163–4 |
anorexia nervosa 118, 120 |
ceramide increase 176 |
anthocyanins 235–6 |
damage to 177 |
anxiety disorders 4 |
function 149–51, 153 |
APC see adenomatosis polyposis coli |
neurobiology 121–2 |
(APC) |
neurological disorders 149–64 |
apelin 67–8 |
reactive 151–3, 155–8 |
apolipoprotein D (Apo D) 51 |
reactive astrocytosis 156 |
apolipoprotein E (ApoE) 132, 135, |
response to injury 151–5 |
138, 176 |
serotonin 121, 122 |
apolipoprotein J (Apo J) 52 |
sleep regulation 121 |
apoptosis 181–3 |
structure 149–50 |
ATP role 182 |
swelling 154, 158–63 |
calpain role 262 |
types 150 |
CHOP role 260 |
atherosclerosis 176, 231, 234 |
endoplasmic reticulum (ER) 257, |
ATP |
258, 264 |
apoptosis 182 |
ERK role 264 |
Cx43 role 108 |
JNK role 257, 264, 267–8 |
fatty acids (FA) as substrate 12 |
286
ATP (continued) G proteins 211
mitochondrial complex I activity 248, 256–7
muscle proteostasis 93, 95 Parkinson’s disease 248, 257 PARP e ect 181, 182 proteostasis 260
PTEN phosphatase 49
reactive astrocytosis 152–3, 160 UPS role 259
visfatin e ect 178, 179 ATP-binding cassette (ABC) transporter A1 136, 242
ATP-sensitive Kþ 49 ATPase 95, 102
autocrine signaling 17–21, 191 adipokines 15, 32
insulin 22–6 leptin 58
muscle proteostasis 82–8 autophagy
muscle proteostasis 78, 84, 88, 91
Parkinson’s disease 258, 260, 269–70
axin 30
Ayurvedic medicine 240
beta adrenergic receptor (BAR) 123 bHLH-PAS domain proteins 21 biased agonists 218–19, 220
bitopic modulators 220–1 blood-brain barrier 184
adiponectin 139 astrocytes 150, 164 insulin transport 134
leptin transport 13, 15, 137 nicotinamide (Nam) 181 permeability 177, 178, 180 T-cells 231
TGF-b1 142 visfatin 140
blood-clot-dissolving factor 175 Bmal1 gene 21
box3 46
Subject Index
brain
aging 175, 177, 178–9, 248, 254 lifestyle factors 176 metabolism 121, 135–6
brain-derived growth factor (BDNF) 261
brain edema 154, 158, 159–60, 161–2, 163, 164
brain infarction 182 brain lesions 184 brain plaques
Alzheimer’s disease (AD) 232, 234 amyloidb e ect 131–3, 136, 177,
178 instability 5
interleukin-6 (IL-6) 141 therapy targets 133–4
breast cancer 105–6, 108 2-bromopalmitate 27 bulimia nervosa 118, 120 burns 80, 96, 100–1
C/EBP homologous protein-10 (CHOP) 260, 266
c-jun NH2-terminal protein kinase (JNK) 29, 62, 161, 236, 257, 263–4, 270
C-peptide 176
C-reactive protein (CRP) 13 Ca21
G protein-coupled receptors (GPCRs) 211, 213
glutamate e ect 260, 261–2 mitochondria 256–7, 262
muscle proteostasis 81, 86–7, 94–5 neurons 251
Parkinson’s disease 251–3, 256–7, 261–3
protein kinase C (PKC) 156 sepsis 100
signaling 69 cachetin see TNFa cachexia 85, 96, 101–2 cadherins 106–7 calbindin 262 calcineurin 86
Subject Index
calcium
channels 118, 120, 211 homeostasis 219 intramuscular 86 mobilizing agents 179 neural e ect 123–4 signaling 121
calcium-mobilizing agents 179 calpains 78–9, 87, 100, 262 cAMP see cyclic adenosine
monophosphate (cAMP) cancer cachexia 96, 101–2 cannabidiol (CBD) 3, 121 cannabinoid receptors 178, 222
cannabis 3, 222 see also cannabidiol (CBD); tetrahydrocannabinol (THC)
cardiac actions of adipokines 57–70 cardiomyocytes
function 59–61
leptin receptors (Ob-R) 58 resistin 67
cardiovascular disease adipokines 5 adiponectin 64 apelin 68
leptin 61
lifestyle factors 176 resistin 66–7 visfatin 68–9
cardiovascular tissues 58–9 Cas adaptor protein 108–9
caspases 78–9, 100, 183, 257, 266, 270 b-catenin 30–1, 106
caveolae 63
CBD see cannabidiol (CBD) CCR5 chemokine receptor
206–9, 221 CD38 178 CDCrel-1 259
cell cycle in Parkinson’s disease 269 cell death 179–82
cell swelling 154, 159–60, 161–2, 164 e ectors 162–3
central nervous system (CNS) adiponectin 139 astrocytes 149–51, 163–4
287
cholesterol 136 dopaminergic neurons 248 injury 151–5
insulin 133, 134 TGF-b1 141–2
ceramide 4, 5, 176, 177–8, 179 endothelial cells 177, 180 glycolysis 177
chaperones 255, 258, 259, 266, 267, 269
chemical signals 191 chemotaxis 179 chemotransduction 94 chi 3
Chinese medicine 3 cholesterol
brain metabolism 135–6
central nervous system (CNS) 136 peroxisome proliferator-activated
receptor g (PPARg) 234 transport pathway 234
cholinesterase inhibitors 176 CHOP see C/EBP homologous
protein-10 (CHOP) chromatid pairs 183 cilliary neurotrophic factor
(CNF) 83, 86 circadian clock 20–1, 32 circulatory system 179
clatherin-coated pits (CCPs) 214 Clock gene 21
CNF see cilliary neurotrophic factor (CNF)
cofilin 63 cohesin 183 collagenase 181
colony stimulating factor-1 (CSF-1) 6 connexins 107–8
contact normalization 106–10 cortical-spreading depression
(CSD) 119
corticotrophin releasing factor (CRF; CRH) 118
COX-2 see cyclooxygenase-2 (COX-2) cranial nerve system 119, 121, 122 Criegee rearrangement 180
288
CRP see C-reactive protein (CRP) Cryptochrome (Cry) gene 21
CSF-1 see colony stimulating factor-1 (CSF-1)
curcumin 239–40 cuttlefish 190 Cx43 107–8
cyclic adenosine monophosphate (cAMP)
5HTR 121, 124
adenylyl cyclase (AC) role 82, 211 arrestins e ect 214
dopamine metabolism 268 ERK pathway 264 GTPases 263
nuclear factor kappa B (NF-kB) activation 82
cyclic ADP-ribose 179 cyclins 269
cyclooxygenase-2 (COX-2) 14, 66, 162, 230, 268
cyproheptadine 125
cytokine signaling 3 (SOCS3) 13, 50 cytokines see also interleukin-6 (IL-6);
tumor necrosis factor alpha (TNFa)
adiponectin 139
adipose tissue secretion 11 anthocyanins 236
cell swelling 159–60 gallates 236
immune cell secretion 7 inflammation 30, 231, 234 levels in obesity 14
mitogen-activated protein kinases (MAPKs) 29
muscle proteostasis 83, 85–6 oxidative/nitrosative stress
(ONS) 156, 159, 163 reactive astrocytosis 151 resistin 140
sepsis 100
transforming growth factor-b1 (TGF-b1) 142
visfatin 140, 179 cytoskeleton 94–5, 106, 131
Subject Index
DAG see diacylglycerol (DAG) dehydroabietic acid 241 dementia
body mass index 136 hypertension 176 leptin 138 pellagra-induced 179 tau 131
therapy targets 133–4 deoxyribose radical cleavage 180 depression 120
DGK see diacylglycerol kinase zeta (DGKs)
diabetes mellitus (DM) 10–11
early life programming 11, 19, 21, 26, 30
etiology 5
link to Alzheimer’s disease 134–6 serotonin levels 122
Type 1 (T1DM) etiology 11
Type 2 (T2DM) etiology 11, 31, 32 Wnt proteins 31
diacylglycerol (DAG) 211, 214, 250, 252, 262–3
diacylglycerol kinase zeta (DGKs) 51–2
diet 8
Alzheimer’s disease (AD) 176 early life programming 11, 19, 21,
26, 30
e ect on migraine 120 muscle proteostasis 89–91
disease mechanisms 192, 230 disease treatment 6–8 Dishevelled (Dvl) protein 30 disuse atrophy 96, 97–9
DJ1 251, 255–6, 257, 258, 260, 265, 268, 270
DNA
damage 180–4, 182, 256
e ect of hydrogen peroxide 180 fragmentation mechanisms 180 neuronal 181
repair 179, 256 tertiary-butylhydroperoxide
(tBuOOH) model 183
Subject Index
dopamine
brain reward system 118, 119 ghrelin 119
metabolism 268–9
Parkinson’s disease 248–51, 250, 252, 268–9
dopamine D2 receptor 217, 221 dopamine D3 receptor 221 dopaminergic neuronal death 138,
247, 248–54
signaling pathways 254–70
drug receptor interaction models 1–3 drugs
design 7, 221–3 half-lives 2
receptor desensitization 6 side e ects 110, 189, 222 targets 110, 192, 223 toxicity 2, 7
Dvl see Dishevelled (Dvl) protein dyslipidemia 10, 136
early life programming 11, 19, 21, 25–6, 30
eating disorders 118, 120 ectopic fat 27, 175 electrical signaling 191
endocannabinoids 4, 5, 15, 177–8, 211 endocrine signaling 190
endocytosis mechanisms 215 endogenous ligands 3–4 endoplasmic reticulum (ER) 257,
258, 264 endorphin synthesis 8
endosomal vesicles 214 endothelial cells
adipokines 137 adiponectin 5, 137
c-jun NH2-terminal protein kinase (JNK) 62
ceramide 177, 180 gallates 236 genistein 238 MCP-1 178
NADH oxidase 178–9 piperine 238
289
endothelial nitric oxide synthase (eNOS) 5, 65–6, 177
endothelial tight junctions 178 endothelin-1 ETA receptor 60 energy metabolism 45, 177–8, 179 eNOS see endothelial nitric oxide
synthase (eNOS) enterokines 6
enzyme-linked receptors (ELRs) 191 epinephrine 80, 81–2, 100–1 epithelial-mesenchymal transition
(EMT) 107
ER see endoplasmic reticulum (ER) ER stress 29
ergosterol 243 ergot drugs 117–18
ERK see extracellular signalregulated kinase (ERK)
essential amino acids (EAA) 88, 89–90, 97
estrogen 233 exercise 6, 8
Alzheimer’s disease (AD) 176 burn recovery 101
muscle proteostasis 92–5 extracellular dehydrogenases 178 extracellular enzymes 178 extracellular matrix in muscle
proteostasis 87 extracellular plaques 177
extracellular signal-regulated kinase (ERK) 263–4
activation 29, 62, 156–7 anthocyanins 236 apoptosis 48
dopamine metabolism 268 pathway 48
reactive astrocytosis 156–7, 161
extramuscular signals 77–102
FA see fatty acids (FA)
familial hemiplegic migraine 118 fasting 17
fatty acid transport protein (FATP)-1 16
290
fatty acids (FA)
Alzheimer’s disease (AD) role 136 catabolism rate 176
diabetes role 11, 14–15 e ect on GSIS 27 feedback e ect on
adipocytes 14–15 leptin role 59 lipolysis 14 pancreatic b cell 26–7
substrates for ATP production 12 feedback 14
fenofibrate 17 Fenton reaction 248 feverfew 117
FGF see fibroblast growth factor (FGF)
fibroblast growth factor (FGF) 82–3, 84–5, 261
fibromyalgia 120–1 flunarizine 125
focal adhesion kinase (FAK) 87 forkhead transcription factors 49, 84,
183
FOXO1 see forkhead transcription factors
Foxp3 see forkhead transcription factors
frizzled (Fzd) family receptors 30, 193 Fzd see frizzled (Fzd) family receptors
G protein-coupled receptors (GPCRs) 188–224 activation 203–17
allosteric modulators 219–21 biased agonists 218–19, 220 classification 193–5, 194 conformation selectivity 203–17 crystal structures 195–6 desensitization 214
dimers 216–17
drug design 3, 221–3 endocytosis mechanisms 215
energy levels of conformations 205 epinephrine 82
GPR40 27
Subject Index
helical axis 198 identity 196–9
ligand binding 199–202, 204–6 ligand control 217–21 migraine drug target 125 mutation stabilized 204–6 orientation parameters 196–8 orthosteric binding 205, 219
sequence comparison 196–9, 197 serotonin 117
signaling 216
structure 193–217, 194, 212 testosterone e ect 81
G protein-regulated inward-rectifier K1 channels (GIRKs) 211–13
Gproteins coupling 209–14 cytosolic 218
GPCR activation 212 signal diversification 209–14
gallates 236–7
gap junctions 106, 107–8, 122 gate theory 4
GCL see glutamate cysteine ligase (GCL)
gender di erences adiponectin 16 insulin resistance 26
leptin receptors (Ob-R) 58–9 gene transcription 23, 84, 108, 181,
183, 255 genistein 237–8
GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) method 201
geraniol 242 ghrelin 21, 119 gingerol 239 ginkgo 176
GIRKs see G protein-regulated inward-rectifier K1 channels (GIRKs)
glial cell line-derived neurotrophic factor (GDNF) 261
global proteostasis 79–88 glucagon 21–2
Subject Index
glucocorticoids 80, 100, 101, 233 glucolipotoxicity 11, 29
glucose metabolism
link to Alzheimer’s disease 134–5, 177 serotonin 121
glucose-oxygen-serum-deprivation (GOSD) injury 48
glucose production 12–13 glucose-stimulated insulin secretion
(GSIS)
early life programming 26 e ect of fatty acids 26–7 insulin signaling 23, 25 leptin e ect 27–8
TNFa e ect 29
Type 2 (T2DM) diabetes 11 Wnt proteins 31
glutamate 153, 253, 254, 260–1, 264, 268
glutamate cysteine ligase (GCL) 252, 255
glutamate family of GPCRs 193 glutamate-glutamine cycle
150–1
glutamine 88, 96, 150–1 glutathione (GSH) 181, 255, 256 glycerol 12–13
glycerol 3-phosphate 12 glycerol kinase deficiency 13 glycogen metabolism 121, 122 glycogen synthase kinase 3b
(GSK3b) 30–1, 90, 135, 138 glycohydrolase 179
glycolysis 177, 181 glycoproteins 30
GPCRs see G protein-coupled receptors (GPCRs)
growth hormone (GH) 80, 93 GSH see glutathione (GSH)
GSIS see glucose-stimulated insulin secretion (GSIS)
GSK3b see glycogen synthase kinase 3b (GSK3b)
GTPase dynamin 214 GTPases 260–1, 263, 267 guggulsterone 240
291
heart disease see cardiovascular disease
helical axis 198
heparin-binding epidermal growth factor (EGF) signaling 66
herbal drugs 117–18, 230–1 HierDock procedure 200 high blood pressure
see hypertension histamine 119, 125 histone activation 183 HIV 85, 96, 156, 206, 221
HNE see 4-hydroxynonenal (HNE) holistic care 8
homology modeling 200 hormones 190
burn recovery 101 gut 6
muscle proteostasis 79–82, 93 Huntington’s disease 151, 152 hydrogen peroxide 179–82
extracellular 177 generation 177
Parkinson’s disease 251, 254, 255, 257, 264
tertiary-butylhydroperoxide (tBuOOH) model 183 6-hydroxydopamine (6-OHDA)
251, 255, 256, 257, 260, 264–5, 266, 270
4-hydroxynonenal (HNE) 256
5-hydroxytryptamine see serotonin hyperglycemia 10 hyperleptinaemia 18, 20 hyperplasia
leptin e ect 63 myostatin 85
pancreatic b cells 11, 22, 24 hypertension 5, 59 hypertrophy
adiponectin 64–6 leptin 59–61, 63
hypoglycemia 13, 17, 122, 177 hypoketonemia 17
hypothalamic physiology migraine headache 118–19
292
IAP see inhibitor of apoptosis proteins (IAP)
IDE see insulin degrading enzyme (IDE)
IGF-1 see insulin-like growth factor (IGF-1)
IkB inhibitors 158 IkB kinase
curcumin 239 genistein 237 gingerol 239 guggulsterone 240
nuclear factor kappa B (NF-kB) signaling 265–6
piperine 238 quercetin 237
IL-1 receptor (IL-1R) 27 IL-6 see interleukin-6 (IL-6)
inducible nitric oxide synthase (iNOS) adiponectin 65–6
ceramide 177 dysfunction 5 geraniol 242
nicotinamide (Nam) 181 nuclear factor kappa B
(NF-kB) 158, 162, 230, 234 Parkinson’s disease 268
inflammation adipokines 137 astrocytes 131, 150 brain 178
cascade 231–2 cytokines 30
early life programming 30 endocannabinoids 178 interleukin-6 (IL-6) 159 leptin 6, 15, 28 neutrophils 181 nicotinamide (Nam) 181 nuclear factor kappa B
(NF-kB) 158 obesity 4, 14 pancreatic b cell 29–30
Parkinson’s disease 268 phytochemicals 230–44 resistin 139–40
Subject Index
rheumatoid arthritis 5–6 sepsis 99
visfatin 140
inhibitor of apoptosis proteins (IAP) 183
iNOS see inducible nitric oxide synthase (iNOS)
inositol 1,4,5-triphosphate (IP3) 211 insulin see also glucose-stimulated
insulin secretion (GSIS) adiponectin 13, 16, 28, 139 Alzheimer’s disease (AD) 134–6 amyloidb (Ab) 133, 177 autocrine e ects 22–6
burns 101
central nervous system (CNS) 133 diabetes mellitus (DM) 11
fatty acids (FA) 12, 26–7
gene transcription regulation 23 leptin 27–8
migraine headache 123
muscle proteostasis 79–80, 83–4, 90, 91
peroxisome proliferator-activated receptor g (PPARg) 234
resistin 66 sarcopenia 97 serotonin 122 signaling 23–5 SOCS3 50 TNFa 14
insulin degrading enzyme (IDE) 133, 134, 136
insulin-like growth factor (IGF-1) 80, 81, 82, 83–4, 93, 101
insulin receptor (IR) 22–3, 69 ceramide 5, 177
isoforms 23 MLP 26
protein synthesis 84 signalling pathway 23, 25 sorting nexins (SNXs) 51 TNFa 29
visfatin 68, 178 insulin receptor substrates
(IRS) 22–4, 29, 66–7, 80, 84
Subject Index
insulin resistance 11–12 adiponectin 13–14, 16, 139 AdipoR 17
Alzheimer’s disease (AD) factor 134
ceramide 5 disuse atrophy 98
early life programming 19, 25–6, 30 interleukin-6 (IL-6) 141
IRS 19, 24 MCP-1 15, 19 obesity 136
plasminogen activator inhibitors (PAI) 141
PPARa 18 resistin 139 saturated fats 27 SOCS3 50
thiazolidinediones 234 TNFa 29
tumor necrosis factor alpha (TNFa) 14
Wnt proteins 31 integrin complexes 87
intercellular adhesion molecule 1 181 Interferon gamma (IFNg) 83 interleukin-6 (IL-6)
adiponectin 16, 139 Alzheimer’s disease (AD) 141 anthocyanins 236
cancer cachexia 101 inflammation 159, 268 link to diabetes 5 muscle proteostasis 85–6 obesity 13, 137, 141 osteoarthritis 5
reactive astrocytosis 151 relation to nitric oxide
production 5 resistin 139
rheumatoid arthritis 5–6, 231 STAT3 activation 157 stigmasterol 242 transforming growth factor-b1
(TGF-b1) 142 visfatin 140, 179
293
intracrine signaling 191 ion-channel receptors (ICRs) 191 ion channels 162–3
ion exchangers 162–3
ion transporters 161, 162–3
IP3 see inositol 1,4,5-triphosphate (IP3) IRS see insulin receptor substrates
(IRS) ischemia
apelin 68
aquaporin-4 (AQP-4) 163 astrocytes 150–1, 155, 156, 158,
159, 160, 161 cytokines 159
ion transporting systems 163 mitogen-activated protein kinases
(MAPKs) 161 nuclear factor kappa B
(NF-kB) 158, 161 oxidative/nitrosative stress
(ONS) 159 PI3K 156, 160
protein kinase C (PKC) 160 resistin 67, 139
visfatin 140
islet amyloid polypeptide (IAPP) see amylin
islets of Langerhans 11, 21–2 isoflavones 237–8
JAK-STATs pathway 28, 45–8 activation 61–2, 86
leptin receptors (Ob-R) 58, 59, 137 Janus kinase family JAK 45–6, 48,
49, 50
leptin e ects 61–2, 137–8
JNK see c-jun NH2-terminal protein kinase (JNK)
joint mobility 181 juxtacrine signaling 190–1
kinase insert domain receptor (Kdr) 109, 110
LBs see Lewy bodies (LBs)
LDL-C 5
294
LDL receptor (LDLR) 52, 135 LDLR see LDL receptor (LDLR) leptin see also adipocytes
adipose mass relationship 13, 45, 58
Alzheimer’s disease (AD) 137–9 appetite peptides 13, 137–8 artery wall defects 5
arthritis levels 6
autocrine e ects 15, 18–19, 58 cardiomyocyte function 59–61 cardiovascular actions 58–61 circadian clock e ects 21 function 45
hypertrophic e ects 59–61, 63 lifestyle e ects 176
LMB loop 123 migraine e ect 118–19 MLP e ect 20 neuropathic pain 120 obesity levels 14, 15, 58
oxygen radical formation 5 pancreatic b cell 27–9 paracrine e ects 58 Parkinson’s disease 138
peroxisome proliferator-activated receptor a (PPARa) 17–19, 20, 32
production 44, 58
resistin relationship 139–40 sciatic nerve injury 120 structure 44, 58 sympathetic nervous system
e ects 59
leptin receptors (Ob-R) 15 Alzheimer’s disease (AD) 137 cardiovascular tissues 58–9 interactions 50–2
isoforms 45, 58 levels in obesity 16
signaling 15, 45–50, 47, 61–3 leucine 88, 89, 91
leucine-rich repeat kinase 2 (LRRK2) 260, 267
Lewy bodies (LBs) 251, 256, 258, 260, 269
Subject Index
lifestyle e ects 6, 7–8, 175–6, 184 ligands see also adipokines; cytokines
endogenous 2
GPCR binding 199–202, 204–6, 217–21
receptor binding 1–3 linear model 1–2
lipid phosphatase PTEN 49 lipid rafts 136, 138
lipids see also adipocytes; ceramide; endocannabinoids
adiponectin 13
brain accumulation 176, 178 disorders 135–6
GPCRs 199, 200 homeostasis 11, 234 insulin 11, 18 liberation 2
metabolism 51, 123, 135, 137, 176 obesity 4
peroxidation 256 phospholipase mechanisms 2 PI3K/AKT signaling 265 toxic 4, 6, 176
lipocalins 51 lipolysis
circadian clock e ects 20 insulin regulation 123
lipoprotein lipase (LPL) 12 lipotoxicity 5 liver-X-receptor (LXR)
agonists 242–3
NF-kB regulation 234–5 phytochemicals 234
LMB loop 123
LPL see lipoprotein lipase (LPL) LRRK2 see leucine-rich repeat kinase
2 (LRRK2)
LXR see liver-X-receptor (LXR) lymphocytes 178
lysosomes 78–9, 84, 88, 132 autophagy 260, 269
macrophages adipokines 4, 119
cytokines 13, 30, 83, 164, 231, 234
Subject Index
diabetes mellitus (DM) 19, 119 fatty acids (FA) 15
foam cells 5, 234 glutamine 96 interleukin-6 (IL-6) 13, 86 leptin 6
LXRs 231
MCP-1 13–14, 15, 19 muscle communication 83 NADH oxidase 178 NADPH oxidase (NOX) 178 obesity 4, 13, 119
PPARa 18–19 PPARg 231 resistin 6
sciatic nerve injury 120 TNFa 13–14
visfatin 179
MAO see monoamine oxidase (MAO) MAPKs see mitogen-activated
protein kinases (MAPKs) Maraviroc 206
Maternal Low Protein (MLP) 19–20, 26, 30
maternal nutrition 11, 19, 21, 26, 30 matrix model 2–3
MCP-1 see monocyte chemoattractant protein 1 (MCP-1)
MechanoGrowth Factor (MGF) 82 mechanotransduction 94 membrane proteins
APP 177 classes 191–2
signaling 189, 191–2 MembStruk method 200 metabolic syndrome 175
Apo D 51
endocannabinoids increase 178 fatty acids increase 12 lipolysis increase 12
plasminogen activator inhibitors (PAI) 141
metabolism
Alzheimer’s disease (AD) 134–6 autocrine signaling 19–20 dysfunction 134–6
295
fasting 17
migraine 120, 121, 124 Parkinson’s disease 248
metalloproteases 5, 132, 133, 136 metformin 17 1-methyl-4-phenylpyridinium
(MPP1) 248, 251, 254–6, 260, 263, 264, 266
methyl-beta-cyclodextrin 63 methysergide 117
MGF see MechanoGrowth Factor (MGF)
microadenomas 105–6 migraine headache 117–25
pathophysiology 118–19 mitochondria 249, 256–7
burns 100
c-jun NH2-terminal protein kinase (JNK) 264
disuse atrophy 99 DJ1 255
DNA damage 181, 182 migraine headache 118 monoamine oxidase (MAO) 251 muscle proteostasis 88, 98 nicotinamide (Nam) 179
p53 162
PINK1 255, 262, 267 reactive astrocytosis 151 sepsis 100
visfatin 69
mitochondrial complex I activity 248, 256
mitochondrial membrane potential (MMP) 162, 242, 249, 256–7 mitogen-activated protein kinases
(MAPKs)
Alzheimer’s disease (AD) 138 cardiomyocytes 59
connexin phosphorylation 108 cytokines 29
GTPases e ect 263 muscle proteostasis 84
p38 59–60, 62–3, 156, 161, 213, 218, 263–5
p44/42 60
296 |
|
Subject Index |
mitogen-activated protein kinases |
muscle proteostasis 77–102 |
|
(MAPKs) (continued) |
aging 96–7 |
|
Parkinson’s disease |
263–5 |
exercise 92–5 |
reactive astrocytosis |
156–7, 161 |
global 79–88 |
signaling 69 |
|
humans 88–102 |
stimulation 62–3 |
|
nutrition 89–91 |
mitogenic pathways 106, 214–16 |
protein degradation 78–9 |
|
MLP see Maternal Low Protein |
protein synthesis 77–8 |
|
(MLP) |
|
regulation 88–95 |
MMP see mitochondrial membrane |
wasting conditions 95–6 |
|
potential (MMP) |
|
muscular activity 6 |
molecular dynamics (MD) |
myelin 231 |
|
simulations 200 |
|
myokines see interleukin-6 (IL-6); |
monoamine oxidase (MAO) 251 |
TNFa |
|
monocyte chemoattractant protein 1 |
myostatin 83, 85, 91 |
|
(MCP-1) 13–14, 15, 19, 178 |
|
|
monocytes |
|
n-methyl D-aspartate (NMDA) |
NADH oxidase 178 |
|
glutamate receptors 250, 252, 253 |
penetration of blood-brain |
naADP see nicotinic acid ADP |
|
barrier 177, 178 |
|
(NaADP) |
MPP1 see 1-methyl-4- |
|
NAD see nicotinamide |
phenylpyridinium (MPP1) |
phosphoribosyl transferase (NAD) |
|
mRNA 77–8 |
|
NADH 178–9, 248 |
AdipoR 28 |
|
NADH oxidase 140, 178–9 |
adipose tissue 16, 17, 18 |
NADH pyrophosphatase 178 |
|
amino acids (AA) 88, 90, 91 |
NADPH 181 |
|
anabolic signals 90, 91 |
NADPH oxidase (NOX) 177, |
|
contact normalization 109 |
178–9 |
|
diacylglycerol kinase zeta |
Nam see nicotinamide (Nam) |
|
(DGKs) 52 |
|
Nampt see visfatin |
focal adhesion kinase (FAK) 87 |
NAMs see negative allosteric |
|
glucocorticoids 80 |
|
modulators (NAMs) |
HIV 156 |
|
necrosis 181–3 |
IGF-1 84 |
|
negative allosteric modulators |
myostatin 85, 91 |
|
(NAMs) 220 |
nuclear factor kappa B (NF-kB) 158 |
neovascularization 183 |
|
pancreatic b cells 23, 25 |
neprylisin 133 |
|
testosterone 81 |
|
nerve growth factor (NGF) 82, 83, |
TGF-b1 141 |
|
86, 153, 177, 261 |
thyroid hormone (TH) 80 |
neuregulin 83, 86 |
|
mTORc1 see rapamycin complex 1 |
neurodegenerative conditions 175–6, |
|
(mTORc1) |
|
178, 231 |
multiple conformational states 203–4 |
neurokines 7 |
|
multiple sclerosis 231 |
|
neurological disorders 149–64 |
muscarinic acetylcholine receptors |
neuromelanin 251 |
|
(mAChRs) 221 |
|
neuronal death 177, 248–70 |
Subject Index
neurons 152 acetylcholine 86 aging 175
Apo D 51
ApoE 135
astrocyte function 121, 122, 123, 150 Ca21 251
DNA damage 181 glutamate 150 glutamine 150 glutathione (GSH) 255 hypothalamic 13 interleukin-6 (IL-6) 141 leptin 13, 48, 49, 51, 52 NADH 179 neurotrophins 83 oligomers 131
plasminogen activator inhibitors (PAI) 141
TGF-b1 142 visfatin 140
neuropathic pain 119–21 neuropeptide Y (NPY) 13 neurotransmitter synthesis 181 neurotrophins 83, 86, 261 neutrophils
inflammation 5, 181 penetration of blood-brain
barrier 177
NF-kB see nuclear factor kappa B (NF-kB)
NGF see nerve growth factor (NGF) niacin 179
nicotinamide mononucleotide (NMN) 140, 178, 179
nicotinamide (Nam) 140, 178, 179, 181, 183
nicotinamide phosphoribosyl transferase (NAD) 140, 178–9, 181
nicotinic acid ADP (NaADP) 179 nitric oxide synthase 177, 254, 262 NMN see nicotinamide
mononucleotide (NMN) nocioception 4, 121 non-chemical signals 191 normal aging 177
297
NOX see NADPH oxidase (NOX) NPY see neuropeptide Y (NPY) NSAIDs 119
nuclear factor kappa B (NF-kB) 265–6
activation 14–15, 161–2 bacteria activation 232 cancer cachexia 102 function 232 inflammation 230, 232–3 inhibitors 233–43
LXRs 242
muscle proteostasis 85, 94 pancreatic b cells 29 Parkinson’s disease 265–6 peroxisome proliferator-activated
receptor g (PPARg) 241–2 reactive astrocytosis 158, 161–2 signal transduction pathway 233,
265–6 structure 232
nuclear swelling 182 nutrition
Alzheimer’s disease (AD) 176 early life programming 11, 19, 21,
26, 30
e ect on migraine 120 muscle proteostasis 89–91
Ob-R see leptin receptors (Ob-R) obesity
Alzheimer’s disease link 136, 176 circadian clock e ects 20–1, 32 decrease in adiponectin 5 diabetes link 11–12
early life programming 11, 19, 21, 25–6, 30
e ect of MLP 19–20
e ect on signal transduction networks 4–5
hypertrophy 60 increase in adipokines 4 leptin resistance 13 pancreatic b cell
inflammation 29–30 shift work link 20
298
oleate 26, 28 oncomirs 109
ONS see oxidative/nitrosative stress (ONS)
opioids 6
OPM (Orientation of Proteins in Membrane) database 196
orexins 119
orientation parameters 196–8 orthosteric binding 205, 219, 220–1 osteoarthritis 5
osteoclasts 6 osteokines 6
oxidative/nitrosative stress (ONS) 155–6, 159, 160, 254–7
oxLDL 233, 234
oxygen radicals 177, 179–82 oxysterols 234
p38 pathway 59–60, 62–3, 69, 257, 263–5, 268, 270
p53 162, 181, 183, 266
p75 neurotrophin receptor (p75NTR) 177, 261
p75NTR see p75 neurotrophin receptor (p75NTR)
p85 regulatory subunit 25, 26
p110 protein 25, 26 Pael-R 251, 259, 260 palmitate 26, 28–9
PAMs see positive allosteric modulators (PAMs)
pancreas islets of Langerhans 11, 21–2 pancreatic a cells 21–2
pancreatic b cells 11, 21–32, 90 paracrine signaling 190
leptin 58
muscle proteostasis 82–8 Paraquat 248, 254–5, 260
parkin 255–6, 257, 258, 259, 260, 265, 266
Parkinson’s disease 247–71 Alzheimer’s disease link 176 brain lesions 184
dopamine D2 receptor agonists 221
Subject Index
etiology 247–8, 256 ghrelin 119 inflammation 268 leptin 138
Lewy bodies (LBs) 251 mitochondrial complex I
activity 248 neovascularization 183–4 pathological events 249–50, 252 reactive astrocytosis 151
PARP see poly(ADP-ribose) polymerase (PARP)
PBEF see visfatin
PDCD2 see programmed cell death-2 (PDCD2) protein
PDE see phosphodisterases (PDEs) Pdpn 109–10
pellagra-induced dementia 179 pentose phosphate 181 peptides 13
Period (Per) gene 21 PERK 29, 266 peroxide migration 180
peroxisome proliferator-activated receptor a (PPARa) 13 adipocyte glucose uptake 18 adiponectin 16, 66, 139 AdipoR2 16, 29, 139 deficiency 17–19
fatty acids catabolism 234 leptin 17–19, 20, 32
peroxisome proliferator-activated receptor g (PPARg) 12 adipocyte di erentiation 233–4 adiponectin 17, 64, 66, 139 agonists 241–2
cholesterol 234 function 233–4 insulin sensitizing 234 leptin 18, 46, 139
NF-kB regulation 233–4 phytochemicals 231 STAT1 signaling 46
peroxynitrite radicals 177, 179–80
phenylalanine 82, 88, 89
Subject Index
phosphatidylinositide 3-kinase (PI3K) see PI3K
phosphatidylinositol 3-kinases (PI3K) see PI3K
phosphatidylinositol 3,4,5- triphosphate (PI3P) 49
phosphodisterases (PDEs) 124 phosphoinositide 3-kinase (PI3K)
see PI3K 3-phosphoinositide-dependent
protein kinase1 (PDK1) 49 phosphoinositide-specific
phospholipase C (PI-PLC) 211 phospholipase C (PLC) 81, 86, 211,
250, 252, 263 phospholipase D (PLD1) 95
phospholipase mechanisms 2, 95 phospholipids 135, 262 phosphorylation 179–80 phosphotyrosine residues 46, 47, 48,
49, 50 phytanic acid 241
phytochemical inhibitors 235–40 phytochemicals 230–44
PI-PLC see phosphoinositide-specific phospholipase C (PI-PLC)
PI3K
amino acids e ect 90 astrocytes 156, 160 classes 24–5 glucocorticoid e ect 80 GTPases e ect 263
insulin e ect 25, 26, 84, 135 leptin signaling 15, 49 MAPK e ect 264 neurotrophins 86
Parkinson’s disease 250, 252, 265 signaling pathway 49, 69, 265 visfatin e ect 69
PI3K/AKT signaling 49, 265 apoptosis 270
insulin 135 MAPK e ect 264 neurotrophins 86 resistin e ect 67 sepsis 100
299
PINK1 255–6, 257, 260, 262, 265, 267 piperine 238, 239
PKA see protein kinase A (PKA) PKC see protein kinase C (PKC) PKG see protein kinase G (PKG) placebo e ect 4
plaques
Alzheimer’s disease (AD) 234 amyloidb e ect 131–3, 136, 177, 178 atherosclerosis 234
instability 5 interleukin-6 (IL-6) 141 therapy targets 133–4
plasma membranes acetylcholine 86 ATP 257
C-terminal cleavage 131 epinephrine 82 essential amino acids 88
fibroblast growth factor (FGF) 84 G protein-coupled receptors
(GPCRs) 81, 82, 192, 203, 213, 214
GTPases 214 insulin receptor 84
integrin complexes 87 ion-channel receptors (ICRs) 191 NADH oxidase 178 neurotrophins 86
PI3K 265
protein kinase C (PKC) 156, 263 proteins 189, 190, 191
secretases 131–2
stretch-activated channels (SAC) 94 testosterone 81
plasminogen activator 178 plasminogen activator inhibitors
(PAI) 140–1, 178
PLC see phospholipase C (PLC) PLD1 see phospholipase D (PLD1) pleiotropic receptors 204, 209 poly(ADP-ribose) 181 poly(ADP-ribose) polymerase
(PARP) 179, 180–1, 182, 183, 256 poly(ADP-ribosylate) 181 pomegranate 236
300
positive allosteric modulators (PAMs) 220
positive cofactor 1 181
PP2A see protein phosphatase type 2A
PPARa see peroxisome proliferatoractivated receptor a (PPARa)
PPARg see peroxisome proliferatoractivated receptor g (PPARg)
pre-B cell colony enhancing factor see visfatin
preadipocytes 20
programmed cell death-2 (PDCD2) protein 259
prostaglandin (PG) synthesis 66 proteasome 78
protein kinase A (PKA) beta adrenergic receptor
(BAR) 123
dopamine metabolism 268 fatty acid feedback 14 muscles 82
Parkinson’s disease 250, 252 protein kinase B (Akt)
muscle proteostasis 80, 84, 85, 90–1 Parkinson’s disease 250, 252, 257,
265
protein kinase C (PKC) 156, 159, 160, 163
apelin 68
Ca21 86–7, 211, 262–3 neurotrophins 86 Parkinson’s disease 250, 252 signaling 69
protein kinase G (PKG) 160 protein kinases (AKT) see also
mitogen-activated protein kinases (MAPKs)
apelin e ect 68 cancer 108 desensitization 214 matrix model 2 muscle proteostasis 87 Rho 63
signaling 47, 49, 69, 135 stimulation 62–3
Subject Index
protein phosphatase type 2A 179–80 protein tyrosine phosphatase 1B
(PTP1B) 62
proteostasis 258–60 see also muscle proteostasis
Prozac 222
PTEN phosphatase 49 purines 157
quercetin 237
rapamycin complex 1 (mTORc1) 84, 88, 90–1, 93–4, 97
reactive astrocytosis 151–3, 155–8, 159, 164
reactive oxygen species (ROS) muscle proteostasis 94–5, 99 Parkinson’s disease 248, 249–50,
252, 255, 256, 257, 262 sepsis 100
receptor activator of NF-kB (RANK) 232
receptor of G protein signaling (RGS) 6
receptors 1–3 see also specific receptors
reperfusion 184 Rescriptor 222 resistin
Alzheimer’s disease (AD) 139–40 cardiac actions 67 cardiovascular actions 66–7 glucose transport 67
leptin relationship 139–40 production 66–7, 139 relation to nitric oxide
production 5 structure 66–7, 139 vasodilation 5
Rev-Erba transcription factor 21 RGS see receptor of G protein
signaling (RGS) rheumatoid arthritis 5–6, 231 RhoA/ROCK system 63
Rhodopsin family of GPCRs 193 rimonabant 222
Subject Index
RNA polymerase II 181 RNA polymerase III 181 rosiglitazone 28–9 Rotenone 248, 254–5, 256
sarcopenia 81, 96–7, 98 saturated fats 27 sca olding proteins 30 schizophrenia 118 sciatic nerve injury 120
secretases 131–2, 133, 136 Secretin/Adhesion family of
GPCRs 193
selective dopaminergic neuronal death 248–54
signaling pathways 254–70 sepsis 80, 87, 96, 99–100, 101 serine phosphorylation 29, 90, 156,
157, 160
serine/threonine kinases 157, 160, 191, 262, 264, 265, 269 see also glycogen synthase kinase 3b (GSK3b); protein kinase C (PKC)
serotonin 117–18 astrocyte role 121
metabolic e ects 121, 122 shift work link to obesity 20 signal diversification 189, 209–14 signal modulation 189, 230–44
Signal Transducers and Activators of Transcription proteins
(STATs) 46–8 see also transcription 3 (STAT3) leptin signaling 62 STAT5 28
signaling cascades 190–1, 263–6 signaling proteins 188 signaling types 190–1 b-sitosterol 243
sleep mechanisms 119, 120, 121 SN see substantia nigra (SN) SNX see sorting nexins (SNXs) SOCS3 see cytokine signaling 3
(SOCS3)
soluble proteins 190 sorting nexins (SNXs) 51
301
spatio-temporal separation of signaling 190–1
sphingomyelin catabolism 176 sphingomyelinase 177 spirituality 8
Src 107, 108–9
STAT3 see transcription 3 (STAT3) STATs see Signal Transducers and
Activators of Transcription proteins (STATs)
stearate 26 stigmasterol 242
stretch-activated channels (SAC) 94 stroke see also brain infarction
cell swelling 154 etiology 176 immediate care 175 inflammation 181
oxidative/nitrosative stress (ONS) 155–6
reactive astrocytosis 151 recovery 183
toxic lifestyle e ects 184 Structure-Activity- Relationship
(SAR) data 200
substantia nigra (SN) 247, 248, 251, 254, 256, 260, 267
superoxide 178–9
superoxide dismutases 248, 255 superoxide radicals 177, 254 swelling e ectors 162–3 sympathetic nervous system 15, 123 synapses 177
synovitis 231
a-Synuclein 258, 259, 260, 262, 268–9
T-cell-specific transcription factor/ lymphoid enhancer binding factor 1 (TCF/LEF1) family binding proteins 31
T-cells 231
T1DM see diabetes mellitus (DM) T2DM see diabetes mellitus (DM) TAG see triglycerides (TAG) tankyrase 181
taranabant 222
302
targeted drug design 221–3 Taste2 family of GPCRs 193 tau
Alzheimer’s disease (AD) 131–3, 232 lipid disorders 135
therapy target 134 tBuOOH see tertiary-
butylhydroperoxide (tBuOOH) TCF/LEF1 see T-cell-specific
transcription factor/lymphoid enhancer binding factor 1 (TCF/ LEF1) family binding proteins
terpinoids 241–2 tertiary-butylhydroperoxide
(tBuOOH) 183 testosterone 81, 93, 101
tetrahydrocannabinol (THC) 3 TGF-b1 see transforming growth
factor-b1 (TGF-b1)
THC see tetrahydrocannabinol (THC) thiazolidinediones 234–5 thioredoxins (Trx) 257
threonine phosphorylation 156, 157, 160
thrombosis 176
thyroid hormone (TH) 80–1, 100–1, 268
titin 94
TLR see toll-like receptors (TLR) Tmem163 109, 110
TNFa see tumor necrosis factor alpha (TNFa)
TNFR see tumor necrosis factor receptor (TNFR)
toll-like receptors (TLR) 14, 27, 232 tonabersat 122
toxic lifestyles 6, 7–8, 175–6, 184 transcription 3 (STAT3)
activation 46, 157–8, 161 e ect of SOCS3 50 resistin 139
transforming growth factor-b1 (TGF-b1) 141–2, 156
transient receptor potential cation channel vanilloid 1 (TRPV1) 178
transmembrane enzymes 177
Subject Index
transmembrane (TM) signal transduction 189
trigeminal nerve 119, 121, 122 triglycerides (TAG)
accumulation 12, 176 leptin 15–16, 18 lipolysis 14
peroxisome proliferator-activated receptor g (PPARg) 234
transport 176 uptake 176
TrkA see tropomyosin related kinase A (TrkA)
tropomyosin related kinase A (TrkA) 177
TRPV1 see transient receptor potential cation channel vanilloid 1 (TRPV1)
tumor necrosis factor alpha (TNFa) adhesion molecule secretion 179 adiponectin 16–17
anthocyanins 236 cancer cachexia 101 CSF-1 production 6 fatty acids 15 genistein 237–8
insulin resistance 14, 29 levels in obesity 13–14, 15 lifestyle e ects 176 lymphocyte suppression 15 muscle proteostasis 85–6 pancreatic b cell 29 piperine 238
quercetin 237
relation to nitric oxide production 5 sepsis 100
visfatin 179
tumor necrosis factor receptor (TNFR) 29, 83, 85, 183, 232, 268
tumor promoters 108, 109–10 tumor suppressors 106–7, 108–9, 181 tyrosine kinases see also enzyme-
linked receptors (ELRs); insulin receptor (IR)
arrestins 216 insulin 22, 24
Subject Index
neurotrophins 86, 261 sorting nexins (SNXs) 51
tyrosine phosphorylation 24, 29, 46, 62, 106
ubiquitin 82, 251, 255, 263, 265, 266 ubiquitin proteasome system
(UPS) 78, 257, 258–60 cachexia 85, 101–2 disuse atrophy 99 glucocorticoids e ect 80 insulin/IGF-1 e ect 84 myostatin 85
NF-kB e ect 85, 232 unfolded protein response
(UPR) 257, 266 unsaturated fats 27
UPR see unfolded protein response (UPR)
UPS see ubiquitin proteasome system (UPS)
vacuole formation 182 Vadilex 222
Vegfr2 109, 110
ventral tegmental area (VTA) 251
303
visceral fat 175 visfatin 68–9
Alzheimer’s disease (AD) 140 arthritis 6
blood-brain barrier 179 circadian clock e ects 21 function 178–9 inflammation 140
insulin mimetic activity 178 link to diabetes 5
oxygen radical formation 5, 179 structure 140
vasodilation 5
VTA see ventral tegmental area (VTA)
WHIMS trial 176
white adipose tissue 12, 18, 32 Wnt proteins 30–1, 193
xanthine oxidoreductase 178
yang 3 yin 3
zinc-metallopeptidase 133