Index

  • 2D gel electrophoresis  131–132

a

  • A549 cells
    • cell cycle/apoptosis tests  145–148
    • cisplatin/leptomycin B tests  143–148, 152, 158–159
    • curcumin tests  142–144, 149–150
    • doxorubicin tests  142–143, 155–156, 158
    • leptomycin B tests  143–148, 152, 155–156
    • reactive oxygen species induction  146, 148
  • AC see adenylyl cyclases
  • ACC see acetyl‐CoA carboxylase
  • acetyl‐CoA  12, 25, 67
  • acetyl‐CoA carboxylase (ACC)  63–64
  • acetyltransferases  25, 55–57
  • activation
    • caspases  13
    • G‐protein coupled receptors  34–37
    • guanylyl cyclase  37–38
    • stellate cells  77–78
  • activator protein 1 (AP‐1) 97
  • active transport  9–10
  • acute toxicity studies  135
  • acylation  24–25, 55–57
  • adaptation, definition  4
  • adenine nucleotide transferase (ANT)  248–249
  • adenosine diphosphate (ADP), active transport  9–10
  • adenosine monophosphate‐activated protein kinase (AMPK)  14, 281–282
  • adenosine triphosphate (ATP)
    • active transport  9–10
    • assays  193
    • glucose metabolism  65–66
    • mitochondrial production  12–13
    • phosphorylation  23
    • post‐exposure measurement  248–249, 252
  • adenylyl cyclases (AC)  32, 37
  • adiponectin  69
  • adipose tissue  67
  • ADP see adenosine diphosphate
  • adrenergic receptors  32
  • AGC family see PKA‐PKG‐PKC family
  • AKAPs see A kinase anchoring proteins
  • A kinase anchoring proteins (AKAPs)  41
  • Akt  51–53, 66, 67, 83, 149–151
  • Akt2  61–65, 68
  • alamar blue (resazurin) assay  196
  • alimentary canal  282–284
  • alkylation  25–26
  • α‐subunits, GPCRs  31–34
  • amino acids
    • acylation  24–25
    • phosphorylation  22–24
  • AMPK see adenosine monophosphate‐activated protein kinase
  • amplification  4, 93
  • analysis of variance (ANOVA)  114–116
  • animal models  76, 137–138
  • anoikis  160
  • ANOVA see analysis of variance
  • antimycin A  192
  • antiporters  10
  • AP‐1 see activator protein 1
  • aPKC see atypical protein kinase C
  • apoptosis  13, 126, 144–146, 156–160, 253–256
  • AREs see AU‐rich elements
  • aseptic technique  116–118
  • ATP see adenosine triphosphate
  • ATPase pumps  9–10
  • atypical protein kinase C (aPKC)  51–53, 59–64, 66–67
  • audition  6–7
  • AU‐rich elements (AREs)  56, 58–59
  • autocrine signaling  57–58, 93
  • autophagy  13–14
  • average distance  212–213, 228–229
  • AXL  89, 93

b

  • BAF see Brg1/Brm‐associated factor
  • BAK see Bcl‐2‐homologous antagonistic killer protein
  • BaP see benzo(a)pyrene
  • basic helix‐loop‐helix (bHLH) domains  63–64
  • BAX see Bcl‐2‐associated X protein
  • Bcl‐2‐associated X protein (BAX)  13
  • Bcl‐2‐homologous antagonistic killer (BAK) protein  13
  • BEAS‐2B cells  141–142, 148–149
  • benzo(a)pyrene (BaP)  144
  • β‐cells  65–66
  • bHLH see basic helix‐loop‐helix domains
  • biased signaling  31, 41
  • bioenergetics  1–2
    • experimental design  191–194
    • post‐exposure effects  248–249
  • 2,3‐bis‐(2‐methoxy‐4‐nitro‐5‐sulfophenyl)‐2H‐tetrazolium‐5‐carboxyanilide (XTT)  195
  • bisphenol A (BPA)  68–69
  • bisulfite pyrosequencing  133
  • Bliss independence  242, 253–255
  • blood, sample collection  119–120
  • BPA see bisphenol A
  • Bradford assay  131
  • BRAF + MEKi dual therapy  90–91
  • BRAFi see inhibitors of BRAF
  • BRAF see v‐Raf murine sarcoma viral oncogene homolog B (BRAF)
  • Brg1/Brm‐associated factor (BAF) family  64–65
  • bridging centrality  221
  • 5‐bromodeoxyuridine (BUdr)  127
  • “burn‐in”, cancer  96–97

c

  • calcium signaling  13, 14–15, 39, 65–66
  • calnexin  14
  • calreticulin  14–15
  • calsequestrin  15
  • cAMP see cyclic adenosine monophosphate
  • cancer
    • combination treatments  90–91, 93–96
    • drug‐resistant pathogenesis  85–99
      • drug‐induced rewiring  91–93
      • epigenetics  96–98
      • genomic resistance  85–88, 90–91
      • non‐genomic mechanisms  88
      • parallel pathways  93–96
      • tumor heterogeneity  89–90
  • cancer stem cells (CSCs)  97
  • CAPPs see ceramide‐activated protein phosphatases
  • carbon tetrachloride (CCl4)  76
  • carcinotoxicity studies  136
  • case–control studies  139
  • caspase‐3‐independent cell death see autophagy
  • caspases  13, 156–157
  • caveolin  11
  • CBP/p300 binding protein  55, 57
  • CCl4 see carbon tetrachloride
  • CDKs see cyclin‐dependent kinases
  • cell culture
    • preparation  120–121
    • toxicity testing  250–256
  • cell‐cycle analysis  126, 145–146, 151–162
  • cell death  13–14, 156–162, 253–256
  • cell lines  120, 251
  • cell membranes  9
  • cell‐proliferation assays  152–154
  • cellular signal transduction
    • definition  2
    • endocytosis  10–11
    • endoplasmic reticulum  14–15
    • exosomes  11–12
    • experimental designs  171–199
    • integration mechanisms  50–60
    • ion channels, transporters and pumps  9–10
    • key features  3–4
    • and life  3
    • mechanisms  21–48
    • mitochondria  12–14
    • nucleus  15–16
    • organelles  12–16
    • physiological responses  49–72
    • post‐exposure changes  245–248, 253–255, 262–266
    • posttranslational modifications  22–27
    • primary transport systems  8–9
    • reactive oxygen species  43
    • receptors  10, 27–43
    • regulation  54–60
    • secondary messengers  37–39
    • sensory perception  4–8
  • CentiScaPe (software)  231
  • centralities
    • definitions  211
    • relative  222
  • centrality analysis  224–226
  • centroid value  217–218
  • ceramide  38–39
  • ceramide‐activated protein phosphatases (CAPPs)  39
  • CFP see cyan fluorescent protein
  • cGMP see cyclic guanosine monophosphate
  • challenges
    • crosstalk elucidation  272–276
    • epigenetic targets  276–278
    • nutrition research  278–284
    • posttranslational modifications  274–276
    • secondary messengers  270–272
    • spatiotemporal understanding  267–270
  • chaperones  14
  • chemical mixture toxicity  241–242, 253–255, 262–266
  • chemoprevention trials  140
  • chemViz (software)  233
  • ChIP see chromatin immunoprecipitation
  • ChIP‐on‐Chip  133–134
  • chromatin immunoprecipitation (ChIP)  132
  • chromatin remodelling  55–56, 63–64
  • chromogranins  15
  • chromophores, vision  8–9
  • chronic toxicity studies  135
  • cisplatin treatment  143–146, 158
  • c‐Jun N‐terminal kinase (JNK)  82, 224–226
  • Clark electrodes  191
  • classifications for toxicity  240–244
  • clathrin‐dependent endocytosis  11
  • clinical trials  139–140
  • clonogenic assays  125–126
  • closeness  215
  • cluster/Maker2 (software)  232–233
  • cluster randomized trials  140
  • clusters  222–223
  • cohort studies  139
  • COL1a1 see collagen type I, alpha 1
  • collagen type I, alpha 1 (COL1a1) 77
  • colony formation assays  125–126
  • colorectal cancer (CRC)  92
  • combination treatments, cancer  90–91, 93–96
  • Comet assay  127
  • community intervention trials  140
  • competitive ELISA  179–180
  • computational methods  201–237
    • average distance  212–213, 228–229
    • bridging centrality  221
    • centrality analysis  224–226
    • centroid value  217–218
    • closeness  215
    • clusters  222–223
    • degree  213–214
    • diameter  211–212
    • eccentricity  214
    • edge betweenness  221–222, 228–229
    • eigenvectors  220–221
    • global parameters  211–213
    • local parameters  213–222
    • methodology  209–224
    • network assembly  203–209
      • mapping  204–208
      • probes  203–204
      • small vs. large  208–209
    • normalization  222
    • radiality  215–217
    • software available  229–236
    • S.‐P. betweenness  219–220
    • stress  219, 224–226
    • virtual knockout experiments  226–229
    • weighting  204–205, 228–229
  • cones  8–9
  • confocal microscopy  174–175
  • construction, networks  203–209
  • contaminants, type 2 diabetes 68–69
  • Coomassie Brilliant Blue G250 dye  131
  • copy number alterations (CNAs)  85–88
  • CREB binding proteins  55, 57
  • cross‐sectional studies  139
  • crosstalk  60–65, 272–276
  • crystal violet staining  124, 125
  • CSCs see cancer stem cells
  • curcumin  142–144
  • cyan fluorescent protein (CFP)  178–179
  • cyclic adenosine monophosphate (cAMP)  32, 37–39, 50
  • cyclic guanosine monophosphate (cGMP)  6, 37–39
  • cyclin‐dependent kinases (CDKs)  155–156
  • cytokines  76
  • Cytoscape (software)  229–233
  • cytotoxicity studies  123, 141–144

d

  • D3.js (software)  234
  • ΔG see diameter
  • DAB see 3,3prime*‐diaminobenzidine
  • DAG see diacylglycerol
  • damage‐associated molecular patterns (DAMPs)  14
  • DAMPs see damage‐associated molecular patterns
  • deactivation of G‐protein coupled receptors  36–37, 40
  • “dead assay”  196
  • degree  213–214
  • deguelin  205, 224–226, 253–256, 262–266
  • ΔG see diameter
  • dependent sample t tests  115
  • dephosphorylation  23–24, 59–60, 246
  • dermal exposure  136–137
  • development
    • drug‐resistant cancer  85–99
    • fibrosis  75–76
  • developmental toxicity studies  135–136
  • DHB see 2,5‐dihydroxybenzoic acid
  • diacylglycerol (DAG)  38
  • diameter (ΔG)  211–212
  • 3,3prime*‐diaminobenzidine (DAB)  177
  • digestion  282–284
  • 2,5‐dihydroxybenzoic acid (DHB)  190
  • dimethyl sulfoxide (DMSO)  122–123
  • 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium (MTS)  194–195
  • 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT)  194–195
  • direct cellular ELISA  180–181
  • diseases  73–112
    • drug‐resistant cancer  85–99
    • fibrosis  75–85
    • gut microbiota  282–283
    • type 2 diabetes 67–69
  • dispersion of energy  1–2
  • dithiothreitol (DTT)  189
  • DNA
    • damage assays  127–128, 144
    • epigenetic alterations  16
    • isolation  121
    • microarray assays  130–131
  • DNA‐dependent protein kinases (DNA‐PK)  64–65
  • DNA‐PK see DNA‐dependent protein kinases
  • dose addition  241–242
  • dose–response models  135, 240–244
  • doxorubicin (DOX)  142–143, 158–159
  • drug‐induced pathway alterations
    • cancer  91–93
    • experimental designs  146–148
  • drug resistance
    • cancer pathogenesis  85–99
      • drug‐induced rewiring  91–93
      • epigenetics  96–98
      • mutations  85–88, 90–91
      • parallel pathways  93–96
      • tumor heterogeneity  89–90
  • drug‐tolerant persisters (DTPs)  97
  • DTT see dithiothreitol

e

  • early cellular changes 239–266
    • bioenergetics  248–249
    • dose‐response relationships  240–244
    • intracellular signaling perturbations  245–248, 253–255, 262–266
    • phosphorylation  253–255, 262–266
    • timescales  249
  • early genes, InsR‐aPKC‐NF‐κB signaling axis  55, 58–59
  • EC50 see half maximal effective concentration
  • eccentricity  214
  • ECL assay see electrochemiluminescence assay
  • EDC see endocrine‐disrupting chemicals
  • edge betweenness  221–222
  • EDTA see ethylenediaminetetraacetic acid
  • EGCG see epigallocatechin gallate
  • EGFR see epidermal growth factor receptor
  • eigenvectors  220–221
  • electrochemiluminescence (ECL) assay  182–183
  • electron‐transport chains (ETC), post‐exposure  248–249, 253–256
  • ELISA see enzyme‐linked immunosorbent assay
  • EMT see epithelial‐to‐mesenchymal transition
  • endocrine‐disrupting chemicals (EDC)  68–69
  • endocrine gut signaling  283–284
  • endocytosis  10–11
  • endoplasmic reticulum (ER)  14–15, 65–66
  • energy flow  1–2
  • environmental toxicity, type 2 diabetes 68–69
  • enzyme‐linked immunosorbent assay (ELISA)  131, 179–183
  • epidemiological experimental design  138–140
  • epidermal growth factor receptor (EGFR)  11, 85–87, 90–91, 152–154
  • epigallocatechin gallate (EGCG) treatment  146, 148
  • epigenetic alterations
    • challenges  276–278
    • drug‐resistant cancer  96–98
    • principles  16
  • epithelial‐to‐mesenchymal transition (EMT)  78, 82–83
  • ER see endoplasmic reticulum
  • ergodic systems  173
  • ERK see extracellular signal‐related kinase
  • erlotinib  90, 93
  • erythrosin B/FDA staining  124
  • ETC see electron‐transport chains
  • ethidium homodimer‐1 (EthD‐1) assay  196
  • ethylenediaminetetraacetic acid (EDTA)  189
  • N‐ethylmaleimide‐sensitive factor (NSF)  11
  • EV see extracellular vesicles
  • exosomes  11–12
  • experimental design  113–169
    • adenosine triphosphate assays  193
    • advantages and disadvantages  138
    • anoikis  160
    • apoptosis assays  126, 144–146, 156–160
    • aseptic technique  116–118
    • bioenergetics  191–194
    • cell‐cycle analysis  126, 144–146, 151–162
    • cell proliferation–EGFR pathway  152–154
    • centrality analysis  224–226
    • crosstalk elucidation  272–276
    • cytotoxicity studies  123, 141–144
    • DNA‐related assays  126–128, 144
    • early cellular changes  250–256
    • enzyme‐linked immunosorbent assay  131, 179–183
    • epidemiological studies  138–140
    • epigenetics  133–134, 276–278
    • gel electrophoresis  131–132, 183
    • gene expression assays  129–131
    • high‐throughput vs. high‐content  172–173
    • in vitro studies  123–134, 250–256
    • in vivo studies  134–138
    • mass spectrometry  187–190
    • metabolic viability assays  123–125, 144, 194–196
    • microscopy  173–179
    • molecular epidemiology  140
    • necrosis  161–162
    • network analysis  201–237
      • centrality analysis  224–226
      • computational methods  201–237
      • construction methods  203–209
      • dataset capture  187–191
      • methodology  209–224
      • virtual knockouts  226–229
    • nicotinamide adenine dinucleotide assay  193
    • nutritional research  278–284
    • overview  113–116
    • oxygen consumption  191–192
    • posttranslational modifications  274–276
    • protein assays  131–133
    • protein nuclear magnetic resonance spectroscopy  186–187
    • proteomics  150, 152
    • reactive oxygen species  146, 162–163, 192–193
    • RNA assays  128–131
    • sample collection  119–121
    • sample processing  121–122
    • sample storage  122–123
    • secondary messenger integration  270–272
    • signaling pathways  146–155
    • signal transduction  171–199
    • spatiotemporal  267–270
    • survival assays  125–126
    • toxicology testing  250–256
    • unrecognized pathways  150–151
    • viability assays  123–125, 144, 194–196
    • virtual knockouts  226–229
    • Western blot  131–132, 183–186
  • exposure, routes of  136–137
  • expression patterns
    • assays  129–131
    • drug‐resistant cancer  96–98
    • gluconeogenesis  61–65
    • InsR‐aPKC‐NF‐κB signaling axis  55–59
    • network analysis  224–226, 228
  • extracellular matrix (ECM)  75–85
  • extracellular signal‐related kinase (ERK) pathway  25, 82–83, 224–226
  • extracellular vesicles (EV), exosomes  11–12
  • extraction

f

  • FAS see fatty acid synthase
  • fatty acid synthase (FAS)  63–64, 67
  • FCCP see 4‐trifluoromethoxyphenylhydrazone
  • FDA see fluorescein diacetate
  • FGF2 see fibroblast growth factor 2
  • fibroblast growth factor 2 (FGF2) 93
  • fibrosis  75–85
    • animal models  76
    • development  75–76
    • epithelial‐to‐mesenchymal transition  78, 82–83
    • hypoxia‐inducible factor‐1α  83–84
    • kinases  82–83
    • Kupffer cells  75–76, 79
    • microRNAs  84
    • natural killer cells  79–80
    • signaling pathways  80–85
    • sinusoidal endothelial cells  77, 79
    • toll‐like receptors  84–85
    • transforming growth factor‐β1  76, 80–82
  • flexible modularity, receptors  31–34
  • flow cytometry  126
  • fluorescein diacetate (FDA)  124
  • follicle‐stimulating hormone (FSH)  32
  • forkhead box O1 (Foxo1)  61–62
  • Förster resonance energy transfer (FRET) microscopy  178–179, 252
  • Foxo1 see forkhead box O1
  • FRET see Förster resonance energy transfer microscopy
  • FSH see follicle‐stimulating hormone
  • functional selectivity  31, 41

g

h

i

  • IκBα see inhibitor of NF‐κB
  • IC50 see half maximal inhibitory concentration
  • idelalisib  38
  • IKKβ see inhibitor of NF‐κB kinase
  • IL‐1B see interleukin 1B
  • IL6 see interleukin‐6
  • ILVs see intraluminal vescicles
  • IMAC see immobilized metal ion affinity chromatography
  • immobilized metal ion affinity chromatography (IMAC)  189
  • immunohistochemistry (IHC)  174–178
  • immunolocalization  132
  • immunoprecipitation assays  132, 133–134
  • induced pluripotent stem cells (iPSCs)  121, 251
  • inflammasomes  14
  • inhalation exposure  137
  • inhibitor of NF‐κB (IκBα)  52–53, 55–56
  • inhibitor of NF‐κB kinase (IKKβ)  52–53, 58
  • inhibitors of BRAF (BRAFi)  85, 88–93, 96
  • inhibitors of MAPK (MAPKi)  89
  • injections  137
  • INM see inner nuclear membrane
  • innate immunity  14
  • inner nuclear membrane (INM)  15
  • 1,4,5‐inositol trisphosphate (IP3)  38–39
  • INSIG2 see insulin‐induced gene 2
  • in silico experiments see network analysis
  • InsR see insulin receptor
  • InsR‐aPKC‐NF‐κB signaling axis  51–60
    • autocrine signaling  57–58
    • pathway  51–54
    • phosphatase‐mediated regulation  59–60
    • regulation  54–60
    • transcriptional regulation  54–59
  • insulin‐induced gene 2 (INSIG2) 63–64
  • insulin receptor (InsR)  51
  • insulin receptor substrates (IRS)  51–54, 59–65
  • insulin response element (IRE)  61
  • insulin responses
    • adipose tissue  67
    • crosstalk  60–65
    • dysregulation  67–69
    • InsR‐aPKC‐NF‐κB axis  51–60
    • pancreatic β‐cells  65–66
    • skeletal muscles  66–67
  • integration
    • definition  4
    • mechanisms  50–60
    • physiological responses  49–72
  • Interference (software)  231–232
  • interleukin 1B (IL‐1B)  54, 76
  • interleukin‐6 (IL‐6)  76
  • interleukins (ILs)  26, 76
  • intracellular receptors  28–30, 43
  • intraluminal vescicles (ILVs)  11–12
  • in vitro studies
    • designs  123–134
    • sample collection  120–121
    • toxicology testing  250–256
  • in vivo studies
    • designs  134–138
    • sample collection  119–120
  • ion channels  9–10
    • audition  6–7
    • glucose metabolism  65–66
    • somatosensation  8
    • vision  6–7
  • ion pumps  9–10, 88–89
  • IP3 see 1, 4,5‐inositol trisphosphate
  • iPSCs see induced pluripotent stem cells
  • IRE see insulin response element
  • IRS see insulin receptor substrates
  • isobaric labeling (iTRAQ)  190
  • isoforms, G‐protein coupled receptor subunits  31–34
  • isolation
    • DNA  121
    • mass spectrometry  188–189
    • proteins  122
    • RNA  121–122
  • iTRAQ see isobaric labeling

j

k

  • K48‐linked polyubiquitin chains  54
  • K63‐linked polyubiquitin chains  58
  • KCN see potassium cyanide
  • kinases
    • assays  155–156
    • fibrosis  82–83
    • methylation  25
    • phosphorylation  22–24
    • receptors  33–34, 42–43
    • regulation  50
  • knockout experiments, virtual  226–229
  • Kupffer cells (KCs)  75–76, 79

l

m

n

o

p

  • p53  148–151, 158–160
  • p65  55
  • PAABD see phosphoamino acid binding domains
  • PAMPs see pathogen‐associated molecular patterns
  • pancreatic β‐cells  65–66
  • paracrine signaling  93
  • parallel pathways, drug resistance  93–96
  • pathogen‐associated molecular patterns (PAMPs)  14
  • pathogenesis  73–112
    • cancer drug resistance  85–99
    • fibrosis  75–85
    • type 2 diabetes 67–69
  • pattern recognition receptors (PRRs)  14
  • PDE see phosphodiesterase
  • PDK1 see phosphoinositide‐dependent protein kinase 1
  • PEPCK see phosphoenolpyruvate carboxykinase
  • personal hygiene  117–118
  • PesCa (software)  231
  • phagocytosis  10
  • phases of clinical trials  140
  • PH domains see pleckstrin homology domains
  • phosphatase‐mediated regulation  59–60
  • phosphatases  22–24
  • phosphatase and tensin homolog (PTEN)  39, 59–60, 62
  • phosphatidylinositol 4,5‐bisphosphate (PIP2) 39, 51, 53
  • phosphatidylinositol trisphosphate (PIP3)  38–39, 51, 53, 60–65
  • phosphoamino acid binding domains (PAABD)  54
  • phosphodegrons  52
  • phosphodiesterase (PDE)  32, 37, 39
  • phosphoenolpyruvate carboxykinase (PEPCK)  61
  • phosphoinositide‐3‐kinase (PI3K)  51, 53
  • phosphoinositide‐dependent protein kinase 1 (PDK1) 51–53, 59–60
  • phosphoinositide synthesis  14
  • phospholipase C (PLC)  38
  • phosphoprotein enrichment  189–190
  • phosphorylation  22–24
    • expression regulation  57–59, 61–65
    • glucose metabolism  57–59, 61–67
    • post‐exposure  246–247, 253–255, 262–266
  • phosphotyrosine binding domains (PTB)  51, 53
  • photoreceptors  6
  • physiological responses  49–72
    • adipose tissue  67
    • hepatocytes  51–65, 67–69
    • pancreatic β‐cells  65–66
    • skeletal muscles  66–67
    • systemic  65–67
  • PI3K see phosphoinositide‐3‐kinase
  • PI see propidium iodide
  • pinocytosis  10–11
  • PIP2 see phosphatidylinositol 4,5‐bisphosphate
  • PIP3 see phosphatidylinositol trisphosphate
  • PKA see protein kinase A
  • PKAc see protein kinase A catalytic subunits
  • PKA‐PKG‐PKC (AGC) family  52–53
  • plasma membrane degradation assay  196
  • pleckstrin homology (PH) domain proteins  51–53
  • polar amino acids, phosphorylation  22–24
  • polymerase chain reaction (PCR)  130
  • polyubiquitin chains  53–54, 58
  • pore formation, apoptosis  13, 253–256, 262–266
  • positive feedback, InsR‐aPKC‐NF‐κB axis  56–57
  • post‐exposure changes
    • bioenergetics  248–249
    • dose addition  241–242
    • intracellular signaling perturbations  245–248
    • response addition  242, 253–255, 262–266
    • timescales  249
  • posttranslational modifications (PTMs)  22–27
    • acylation  24–25
    • alkylation  25–26
    • glucose metabolism  57–59, 61–67
    • glycosylation  26–27
    • p53 localization  148–149
    • phosphorylation  22–24
    • post‐exposure  245–248, 253–255, 262–266
    • RelA  55–57
    • target identification  274–276
    • unrecognized pathway identification  150, 152
  • potassium cyanide (KCN)  253–256, 262–266
  • prediction, response addition  242, 253–255, 262–266
  • primary cultures  120, 250–251
  • primary transport systems  8–9
  • probes, network construction  203–204
  • ProF  61–63, 68
  • programmed cell death see apoptosis; autophagy; necrosis
  • promoter deletion analysis  129
  • propidium iodide (PI)  126
  • protein folding, chaperones  14
  • protein kinase A catalytic subunits (PKAc)  55
  • protein kinase A (PKA)  37, 50, 52–53, 67
  • protein kinase B (PKB) see Akt
  • protein kinase C (PKC)  38–39, 52–53, 66
  • proteins
    • acylation  24–25
    • alkylation  25–26
    • assays  131–133
    • extraction  122
    • glycosylation  26
    • nuclear magnetic resonance spectroscopy  186–187
    • phosphorylation  22–24
    • see also receptors
  • protein tyrosine phosphatase, non‐receptor type 1 (PTPN1) 59, 62
  • proteomics  150, 152, 187–190
  • PRRs see pattern recognition receptors
  • PTB see phosphotyrosine binding domains
  • PTEN see phosphatase and tensin homolog
  • PTPN1 see protein tyrosine phosphatase, non‐receptor type 1
  • pumps  9–10, 88–89
  • pyrin domain containing 3 (NLRP3) inflammasomes 14
  • pyruvate  12

q

r

  • radiality  215–217
  • radioimmunoprecipitation assay buffer (RIPA buffer)  122
  • Ran see Ras‐like GTPase
  • randomized analysis  114–115
  • randomized block design  115–116
  • randomized factorial design  116
  • RAPTOR see regulatory‐associated protein of mTOR
  • Ras, methylation  25–26
  • Ras‐like domains  34–36
  • Ras‐like GTPase (Ran)  15
  • reactive oxygen species (ROS)
    • experimental designs  146, 162–163
    • fibrosis development  75–76
    • fluorescent probes  192–193
    • mitochondria  13
    • signaling  43
  • reagent preparations  118
  • real‐time in vitro toxicology assays  251–256
  • real‐time PCR see quantitative real‐time polymerase chain reaction
  • receptor‐β‐arrestin complexes  41
  • receptor‐associated GEFs  36
  • receptor‐interacting protein 1 (RIP1) 57
  • receptor‐interacting serine/threonine‐protein kinase 3 (RIPK3) 13
  • receptor‐mediated endocytosis  11
  • receptors  10, 27–43
  • receptor tyrosine kinases (RTKs)  33–34, 42–43
    • drug‐resistant cancer  85, 88–93, 96
    • InsR‐aPKC‐NF‐κB signaling axis  51–60
  • recognition, by receptors  28, 31
  • regulation
    • epigenetic alterations  16
    • InsR‐aPKC‐NF‐κB signaling axis  54–60
    • phosphatase‐mediated  59–60
    • signal integration  54–60
    • transcriptional  54–59
  • regulators of G‐protein signaling (RGS)  37, 40
  • regulatory‐associated protein of mTOR (RAPTOR)  14
  • RelA subunit  55–57
  • relative centralities  222
  • reproductive toxicity studies  135–136
  • resazurin (alamar blue) assay  196
  • response addition  242, 253–255, 262–266
  • retinoic acid‐inducible gene 1‐like receptor pathway (RLR)  14
  • reversed‐phase liquid chromatography (RPLC)  190
  • rhodopsins  39
  • RIP1 see receptor‐interacting protein 1
  • RIPA buffer see radioimmunoprecipitation assay buffer
  • RIPK3 see receptor‐interacting serine/threonine‐protein kinase 3
  • RLR see retinoic acid‐inducible gene 1‐like receptor pathway
  • RNA
    • assays  128–131
    • extraction  121–122
  • RNase protection assay  129
  • RNA‐Seq see RNA sequencing
  • RNA sequencing (RNA‐Seq)  190–191
  • rociletinib  90
  • rodent studies  137–138
  • rods  8–9
  • ROS see reactive oxygen species
  • rotenone  192
  • routes of exposure  136–137
  • RPLC see reversed‐phase liquid chromatography
  • R‐smads  81–82
  • RTKs see receptor tyrosine kinases

s

  • S1P and S2P see site‐1/site‐2 protease
  • Saccharomyces cerevisiae, G‐protein coupled receptors  31
  • samples
    • advantages and disadvantages  138
    • bioenergetics data  191–194
    • collection  119–121
    • epidemiological studies  138–140
    • network analysis data  187–191
    • processing  121–122
    • sterile handling  118
    • storage  122–123
  • sandwich ELISA  180
  • sarcoplasmic reticulum  14
  • sarcoplasmic reticulum calcium transport ATPase (SERCA)  14
  • scaffold proteins, ProF  61–63, 68
  • SCAP see SREBP cleavage‐associated protein
  • SCF proteins see skip1‐Cullin‐F‐box proteins
  • SDS‐PAGE see sodium dodecyl sulfate‐polyacrylamide gel electrophoresis
  • Seahorse bioanalyzer  192
  • secondary messengers
    • cyclic adenosine monophosphate  32, 37–39, 50
    • cyclic guanosine monophosphate  6, 37–39
    • experimental integration efforts  270–272
    • lipids  38–39, 51–53, 59–65
  • second mitochondria‐derived activator of caspases (SMAC)  13
  • SECs see sinusoidal endothelial cells
  • selectivity of receptors  31
  • sensory perception  4–8
  • separation, mass spectrometry  188–189
  • SERCA see sarcoplasmic reticulum calcium transport ATPase
  • serial metal oxide affinity chromatography (SMOAC)  190
  • serine (SER), phosphorylation  22–24
  • serine/threonine kinases (STKs)
    • AGC family  52–53
    • drug‐resistant cancer  85, 88
    • InsR‐aPKC‐NF‐κB signaling axis  52–53, 57
    • phosphorylation  23
    • RIP1  57
  • SGLTs see sodium‐dependent glucose‐coupled transporters
  • SH2 see Src homology domain 2
  • SH2 domain‐containing inositol‐5‐phosphatase 1 (SHIP1) 59–60, 62
  • shortest paths analysis  206–208
  • sight  6, 39–40
  • signal integration
    • adipose tissue  67
    • dysregulation  67–69
    • hepatocytes  51–65
    • mechanisms  50–60
    • nutritional research  278–284
    • pancreatic β‐cells  65–66
    • physiological responses  49–72
    • regulation  54–60
    • skeletal muscles  66–67
    • systemic  65–69
  • signal‐mediated cell death  13–14, 156–161
  • signal transduction
    • definition  2
    • in diseases  73–112
    • drug‐induced rewiring  91–93
    • endocytosis  10–11
    • endoplasmic reticulum  14–15
    • exosomes  11–12
    • integration mechanisms  50–60
    • ion channels, transporters and pumps  9–10
    • key features  3–4
    • and life  3
    • mechanisms  21–48
    • mitochondria  12–14
    • nucleus  15–16
    • nutritional research  278–284
    • organelles  12–16
    • physiological responses  49–72
    • post‐exposure changes  245–248
    • posttranslational modifications  22–27, 274–276
    • primary transport systems  8–9
    • reactive oxygen species  43
    • receptors  10, 27–43
    • regulation  54–60
    • secondary messengers  37–39
    • sensory perception  4–8
    • spatiotemporal experiments  267–270
  • sinusoidal endothelial cells (SECs)  77, 79
  • sister chromatid exchange assay  127
  • site‐1/site‐2 protease (S1P/S2P)  63–64
  • skeletal muscles  66–67, 224–226
  • skip1‐Cullin‐F‐box (SCF) proteins  52–53, 61
  • SMAC see second mitochondria‐derived activator of caspases
  • Smads  81–82
  • Smad ubiquitination regulatory factors (SMURFs)  82
  • small GTPases  34–37
  • smell  5–6
  • SMOAC see serial metal oxide affinity chromatography
  • SMURFs see Smad ubiquitination regulatory factors
  • Snail1  83
  • SNARE see soluble N‐ethylmaleimide‐sensitive attachment receptor complexes
  • sodium‐dependent glucose‐coupled transporters (SGLTs)  10
  • sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE)  189
  • soluble N‐ethylmaleimide‐sensitive attachment receptor (SNARE) complexes  66–67
  • somatosensation  8
  • Sox10  96–97
  • spatiotemporal experiments  267–270
  • S.‐P. betweenness  219–220
  • specificity, definition  4
  • Src homology domain 2 (SH2)‐containing effector proteins 51–53, 59–60
  • SREBP‐1c see sterol response element binding protein 1c
  • SREBP cleavage‐associated protein (SCAP)  64
  • stellate cells  76–78
  • stem cells
    • cancer  97
    • cell lines  120
    • induced pluripotent  121
    • toxicology testing  251
  • sterility see aseptic technique
  • steroid hormone receptors  16
  • steroid receptors  43
  • sterol response element binding protein 1c (SREBP‐1c)  63–65, 67
  • STKs see serine/threonine kinases
  • streptavidin‐biotin  177
  • stress, network analysis  219, 224–226
  • structureViz/RINalyzer (software)  231
  • subchronic toxicity studies  135
  • α‐subunits, G‐protein coupled receptors  31–34
  • sugars, glycosylation  26
  • sulfonylurea receptor 1 (SUR1) 65
  • SUR1 see sulfonylurea receptor 1
  • survival assays  125–126
  • SWI/SNF complex see SWItch/Sucrose Non Fermentable complex
  • SWItch/Sucrose Non Fermentable (SWI/SNF) complex  64
  • symporters  10
  • synthetic lethality  93
  • systemic signal integration  65–69

t

  • TAB2  58
  • TAK1 see TNF‐associated kinase 1
  • T‐ALL see T‐cell‐derived acute lymphocytic leukemia
  • tandem mass tagging (TMT)  190
  • target identification for posttranslational modifications  274–276
  • target‐soluble N‐ethylmaleimide‐sensitive factor attachment protein (t‐SNARE)  11
  • taste  4–5
  • T‐cell‐derived acute lymphocytic leukemia (T‐ALL)  97
  • TEAD1 see transcriptional enhancer factor domain family member 1
  • TF see transcription factors
  • TGF‐β1 see transforming growth factor‐β1
  • thioacetamide  76
  • threonine phosphorylation  22–24
  • timescales, post‐exposure changes  249
  • tissues, sample collection  119
  • TLRs see toll‐like receptors
  • T lymphocytes, fibrosis development  76
  • TMT see tandem mass tagging
  • TNFα see tumor necrosis factor alpha
  • TNF‐associated kinase 1 (TAK1) 58
  • TNFR‐associated factor 2 (TRAF2) 57
  • TNF receptor‐associated protein with a death domain (TRADD)  57
  • toll‐like receptors (TLRs)  84–85, 157
  • topological analysis see network analysis
  • touch  8
  • toxicity
    • acute studies  135
    • animal models  137–138
    • bioenergetics  248–249
    • carcinogenicity studies  136
    • chemical mixtures  241–242, 253–255, 262–266
    • chronic studies  135
    • classifications  240–244
    • developmental  135–136
    • dose–response models  135, 240–244
    • early changes  239–266
    • genotoxicity studies  136
    • intracellular signaling perturbations  245–248
    • in vitro studies  250–256
    • maximum tolerated dose studies  134–135
    • modes vs. mechanisms of action  242–244
    • reproductive  135–136
    • response addition  253–255, 262–266
    • routes of exposure  136–137
    • subchronic studies  135
    • timescales  249
    • type 2 diabetes  68–69
  • toxicodynamics  245
  • toxicokinetics  245
  • TRADD see TNF receptor‐associated protein with a death domain
  • TRAF2 see TNFR‐associated factor 2
  • transcription, role in signal transduction  15
  • transcriptional enhancer factor domain family member 1 (TEAD1) 97
  • transcriptional regulation
    • InsR‐aPKC‐NF‐κB axis  54–59
    • post‐exposure  246–247
  • transcription factors (TF)
    • drug‐resistant cancer  96–98
    • InsR‐aPKC‐NF‐κB signaling axis  54–57
    • nuclear receptors  15–16
  • transducin (Gαt1)  32, 39–40
  • transforming growth factor‐β1 (TGF‐β1)  76, 80–82
  • transient receptor potential (TRP) ion channels  8
  • translocation  13
  • transmembrane (TM) receptors  27–34
  • transporters  9–10
  • transport systems, primary  8–9
  • traumatic injuries  224–226
  • 4‐trifluoromethoxyphenylhydrazone (FCCP)  192
  • TRP see transient receptor potential
  • trypan blue exclusion assay  123–124
  • TSC2 see tuberous sclerosis complex 2
  • t‐SNARE see target‐soluble N‐ethylmaleimide‐sensitive factor attachment protein
  • t tests  114, 115
  • tuberous sclerosis complex 2 (TSC2) 14
  • tumor heterogeneity  89–90
  • tumor necrosis factor alpha (TNF‐α)  54, 76, 156–157
  • turn‐off, G‐protein coupled receptors  36–37, 40
  • type 2 diabetes (T2D) 67–69
  • tyrosinase  96–97
  • tyrosine kinase inhibitors (TKIs)  85, 88–93, 96
  • tyrosine kinases (TKs)  23, 33–34

u

  • ubiquitin E3 ligase complexes  52–53, 58
  • uncoordinated‐51‐like autophagy activating kinase (ULK1)  14
  • uniporters  10
  • unrecognized pathways, experimental designs  150, 152
  • upstream stimulatory factor 1 (USF1) 64–65
  • USF1 see upstream stimulatory factor 1

v

  • VAMP2 see vesicle‐associated membrane protein 2
  • v‐Raf murine sarcoma viral oncogene homolog B (BRAF)  85, 87–92, 95, 96, 107–111, 152
  • vesicle‐associated membrane protein 2 (VAMP2) 66
  • vesicles  11–12
  • vesicle‐soluble N‐ethylmaleimide‐sensitive factor (vesicle‐soluble NSF)  11
  • viability assays  123–125, 144, 194–196
  • virtual knockout experiments  226–229
  • VisANT (software)  234–236
  • vision  6, 39–40

w

  • Warburg effect  159
  • water‐soluble tetrazolium salts (WST)  195
  • weighting  204–205, 228–229
  • Western blot  131–132, 183–186
  • widefield epifluorescence microscopy  173–174
  • work environment considerations  117–118
  • WST see water‐soluble tetrazolium salts
  • WW phosphoamino acid binding domain  54

x

y

  • yellow fluorescent protein (YFP)  179
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