60-35-5DLFVBJFMPXGRIB-UHFFFAOYSA-NDLFVBJFMPXGRIB-UHFFFAOYSA-N
AcetamideAcetamid
acetamida
Acetic acid amide
Acetimidic acid
Ethanamide
Ethanimidic acid
Methanecarboxamide
NSC 25945
DTXSID7020005103-90-2RZVAJINKPMORJF-UHFFFAOYSA-NRZVAJINKPMORJF-UHFFFAOYSA-N
Acetaminophen4-Acetamidophenol
APAP
Paracetamol
4-hydroxyacetanilide
Acetamide, N-(4-hydroxyphenyl)-
4-(Acetylamino)phenol
4-(N-Acetylamino)phenol
4-Acetaminophenol
4'-Hydroxyacetanilide
Abensanil
Acetagesic
Acetalgin
ACETAMIDE, N-(4-HYDROXYPHENYL)
Acetaminofen
Acetanilide, 4'-hydroxy-
ACETANILIDE, 4-HYDROXY-
Algotropyl
Alvedon
Anaflon
Apamide
Banesin
Ben-u-ron
Bickie-mol
Biocetamol
Cetadol
Citramon P
Claratal
Clixodyne
Dafalgan
Daphalgan
Dial-a-gesic
Disprol
Doliprane
Dolprone
Dymadon
Efferalgan
Endophy
Febrilex
Febrilix
Febro-Gesic
Febrolin
Fepanil
Finimal
Gattaphen T
Gelocatil
Gutte Enteric
Homoolan
Jin Gang
Lestemp
Liquagesic
Lonarid
Lyteca Syrup
Minoset
Momentum
N-(4-Hydroxyphenyl)acetamide
N-Acetyl-4-aminophenol
N-Acetyl-4-hydroxyaniline
N-Acetyl-p-aminophenol
Napafen
Naprinol
Nobedon
NSC 109028
NSC 3991
Ortensan
p-(Acetylamino)phenol
p-Aceaminophenol
Pacemol
p-Acetamidophenol
p-Acetoaminophen
P-ACETYLAMINOPHENOL
Paldesic
panadeine
Panadol
Panadol Actifast
Panadol Extend
Panaleve
Panasorb
Panodil
Paracetamol DC
Paracetamole
Parageniol
Paramol
Paraspen
Parelan
Pasolind N
Perfalgan
Phenaphen
Phendon
p-Hydroxyacetanilide
Prodafalgan
Puerxitong
Pyrinazine
Resfenol
Resprin
Rhodapop NCR
Salzone
Tabalgin
Tachipirina
Tempanal
Tralgon
Tylenol
TylolHot
Valadol
Valgesic
Vermidon
Vick Pyrena
DTXSID2020006968-81-0VGZSUPCWNCWDAN-UHFFFAOYSA-NVGZSUPCWNCWDAN-UHFFFAOYSA-N
AcetohexamideBenzenesulfonamide, 4-acetyl-N-[(cyclohexylamino)carbonyl]-
1-(p-Acetylbenzenesulfonyl)-3-cyclohexylurea
1-[(p-Acetylphenyl)sulfonyl]-3-cyclohexylurea
Acetohexamid
acetohexamida
Dimelin
Dimelor
Dymelor
Gamadiabet
Hypoglicil
Metaglucina
Minoral
N-(p-Acetylphenylsulfonyl)-N'-cyclohexylurea
Ordimel
Tsiklamid
Urea, 1-[(p-acetylphenyl)sulfonyl]-3-cyclohexyl-
DTXSID702000767-66-3HEDRZPFGACZZDS-UHFFFAOYSA-NHEDRZPFGACZZDS-UHFFFAOYSA-N
ChloroformTrichloromethane
Methane, trichloro-
CARBON TRICHLORIDE
Chloroforme
cloroformo
Formyl trichloride
Methane trichloride
Methane,trichloro-
NSC 77361
Trichloroform
UN 1888
DTXSID1020306110-00-9YLQBMQCUIZJEEH-UHFFFAOYSA-NYLQBMQCUIZJEEH-UHFFFAOYSA-N
FuranDivinylene oxide
furanne
Furfuran
Oxacyclopentadiene
Tetrole
UN 2389
DTXSID60206467429-90-5XAGFODPZIPBFFR-UHFFFAOYSA-NAZDRQVAHHNSJOQ-UHFFFAOYSA-N
AluminumAisin Metal Fiber
Al 050P-H24
ALC Fine
Alcan XI 1391
Almi-Paste SSP 303AR
Aloxal 3010
Alpaste 00-0506
Alpaste 0100M
Alpaste 0100MA
Alpaste 0100M-C
Alpaste 0200M
Alpaste 0200T
Alpaste 0230M
Alpaste 0230T
Alpaste 0241M
Alpaste 0300M
Alpaste 0500M
Alpaste 0539X
Alpaste 0620MS
Alpaste 0625TS
Alpaste 0638-70C
Alpaste 0700M
Alpaste 0780M
Alpaste 0900M
Alpaste 100M
Alpaste 100MS
Alpaste 100MSR
Alpaste 1100M
Alpaste 1100MA
Alpaste 1100N
Alpaste 1100NA
Alpaste 1109MA
Alpaste 1109MC
Alpaste 1200M
Alpaste 1200T
Alpaste 1260MS
Alpaste 1500MA
Alpaste 1700NL
Alpaste 1810YL
Alpaste 1830YL
Alpaste 1900M
Alpaste 1900XS
Alpaste 1950M
Alpaste 1950N
Alpaste 210N
Alpaste 2172EA
Alpaste 2173
Alpaste 240T
Alpaste 241M
Alpaste 417
Alpaste 46-046
Alpaste 4-621
Alpaste 4919
Alpaste 50-63
Alpaste 50-635
Alpaste 51-148B
Alpaste 51-231
Alpaste 5205N
Alpaste 5207N
Alpaste 52-509
Alpaste 52-568
Alpaste 5301N
Alpaste 5302N
Alpaste 53-119
Alpaste 5422NS
Alpaste 54-452
Alpaste 54-497
Alpaste 54-542
Alpaste 55-516
Alpaste 55-519
Alpaste 55-574
Alpaste 5620NS
Alpaste 5630NS
Alpaste 5640NS
Alpaste 56-501
Alpaste 5650NS
Alpaste 5653NS
Alpaste 5654NS
Alpaste 5680N
Alpaste 5680NS
Alpaste 60-600
Alpaste 60-760
Alpaste 60-768
Alpaste 62-356
Alpaste 6340NS
Alpaste 6370NS
Alpaste 6390NS
Alpaste 640NS
Alpaste 65-388
Alpaste 66NLB
Alpaste 710N
Alpaste 7130N
Alpaste 7160N
Alpaste 7160NS
Alpaste 725N
Alpaste 740NS
Alpaste 7430NS
Alpaste 7580NS
Alpaste 7620NS
Alpaste 7640NS
Alpaste 7670M
Alpaste 7670NS
Alpaste 7675NS
Alpaste 7679NS
Alpaste 7680N
Alpaste 7680NS
Alpaste 76840NS
Alpaste 7730N
Alpaste 7770N
Alpaste 7830N
Alpaste 8004
Alpaste 8080N
Alpaste 8260NAR
Alpaste 891K
Alpaste 91-0562
Alpaste 92-0592
Alpaste 93-0595
Alpaste 93-0647
Alpaste 94-2315
Alpaste 95-0570
Alpaste 96-0635
Alpaste 96-2104
Alpaste 97-0510
Alpaste 97-0534
Alpaste AW 520B
Alpaste AW 612
Alpaste AW 9800
Alpaste F 795
Alpaste FM 7680K
Alpaste FX 440
Alpaste FX 910
Alpaste FZ 0534
Alpaste FZU 40C
Alpaste G
Alpaste HR 8801
Alpaste HS 2
Alpaste J
Alpaste K 9800
Alpaste MC 666
Alpaste MC 707
Alpaste MF 20
Alpaste MG 01
Alpaste MG 1000
Alpaste MG 1300
Alpaste MG 500
Alpaste MG 600
Alpaste MH 6601
Alpaste MH 8801
Alpaste MH 9901
Alpaste MR 7000
Alpaste MR 9000
Alpaste MS 630
Alpaste N 1700NL
Alpaste NS 7670
Alpaste O 100N
Alpaste O 2130
Alpaste O 300M
Alpaste P 0100
Alpaste P 1950
Alpaste S
Alpaste SAP 110
Alpaste SAP 414P
Alpaste SAP 550N
Alpaste SCR 5070
Alpaste TCR 2020
Alpaste TCR 2060
Alpaste TCR 2070
Alpaste TCR 3010
Alpaste TCR 3030
Alpaste TCR 3040
Alpaste TCR 3130
Alpaste TD 200T
Alpaste UF 500
Alpaste WB 0230
Alpaste WD 500
Alpaste WJP-U 75C
Alpaste WX 0630
Alpaste WX 7830
Alpaste WXA 7640
Alpaste WXM 0630
Alpaste WXM 0650
Alpaste WXM 0660
Alpaste WXM 1415
Alpaste WXM 1440
Alpaste WXM 5422
Alpaste WXM 760b
Alpaste WXM 7640
Alpaste WXM 7675
Alpaste WXM-T 60B
Alpaste WXM-U 75
Alpaste WXM-U 75C
Altop X
Aluchrome Ultrafin Super
Alumat 1600
Alumet H 30
aluminio
Aluminium
Aluminium Flake
Aluminum 27
Aluminum atom
Aluminum element
Aluminum Flake PCF 7620
Aluminum granules
ALUMINUM METAL/GRANULE
ALUMINUM PASTE
ALUMINUM PIGMENT
ALUMINUM TURNINGS
Alumi-paste 640NS
Alumipaste 91-0562
Alumipaste 98-1822T
Alumipaste AW 620
Alumipaste CR 300
Alumipaste GX 180A
Alumipaste GX 201A
Alumipaste HR 7000
Alumipaste HR 850
Alumipaste MG 11
Alumipaste MH 8801
Aquamet NPW 2900
Aquapaste 205-5
Aquasilver LPW
Astroflake 40
Astroflake Black N 020
Astroflake Black N 070
Astroflake LG 40
Astroflake LG 70
Astroflake Silver N 040
Astroshine NJ 1600
Astroshine T 8990
Atomizalumi VA 200
C.I. PIGMENT METAL 1
Chromal IV
Chromal X
Decomet 1001/10
Decomet 2018/10
Decomet High Gloss Al 1002/10
Ecka AS 081
Eckart 9155
Eterna Brite 301-1
Eterna Brite 601-1
Eterna Brite 651-1
Eterna Brite EBP 251PA
Eterna Brite Primier 251PA
Ferro FX 53-038
Friend Color F 500GR-W
Friend Color F 500WT
Friend Color F 700RE-W
Friend Color F 701RE-W
Hi Print 60T
High Print 60T
Hisparkle HS 2
Hydro Paste 8726
Hydrolac WHH 2153
Hydrolan 3560
Hydrolux Reflexal 100
Hydroshine WS 1001
JISA 51010P
Kryal Z
Lansford 243
LE Sheet 800
Leafing Alpaste
LG-H Silver 25
Lunar Al-V 95
Metallux 161
Metallux 2154
Metallux 2192
Metalure
Metalure 55350
Metalure L 55350
Metalure L 59510
Metalure W 2001
Metapor
Metasheen 1800
Metasheen HR 0800
Metasheen KM 100
Metasheen KM 1000
Metasheen Slurry 1807
Metasheen Slurry 1811
Metasheen Slurry KM 100
Metax G
Metax S
Mirror Glow 1000
Mirror Glow 600
Mirrorsheen
Noral Aluminium
Noral Ink Grade Aluminium
Obron 10890
Offset FM 4500
Puratronic
Reflexal 145
Reynolds 400
Reynolds 4-301
Reynolds 4-591
Reynolds 667
SAP 260PW-HS
SAP-FM 4010
SBC 516-20Z
Scotchcal 7755SE
Serumekku
Setanium 50MIS-H8
Siberline ET 2025
Siberline ST 21030E1
Silvar A
Silver VT 522
Silverline SSP 353
Silvex 793-20C
Sparkle Silver 3141ST
Sparkle Silver 3500
Sparkle Silver 3641
Sparkle Silver 5000AR
Sparkle Silver 516AR
Sparkle Silver 5242AR
Sparkle Silver 5245AR
Sparkle Silver 5271AR
Sparkle Silver 5500
Sparkle Silver 5745
Sparkle Silver 7000AR
Sparkle Silver 7005AR
Sparkle Silver 7500
Sparkle Silver 960-25E1
Sparkle Silver E 1745AR
Sparkle Silver L 1526AR
Sparkle Silver Premier 751
Sparkle Silver SS 3130
Sparkle Silver SS 5242AR
Sparkle Silver SS 5588
Sparkle Silver SSP 132AR
Special PCR 507
Splendal 6001BG
Spota Mobil 801
SSP 760-20C
Stapa Aloxal PM 2010
Stapa Aloxal PM 3010
Stapa Aloxal PM 4010
Stapa Hydrolac BG 8n.1
Stapa Hydrolac BGH Chromal X
Stapa Hydrolac PM Chromal VIII
Stapa Hydrolac W 60NL
Stapa Hydrolac WH 16
Stapa Hydrolac WH 66NL
Stapa Hydrolux 2192
Stapa Hydrolux 8154
Stapa IL Hydrolan 2192-55900G
Stapa Metallic R 607
Stapa Metallux 1050
Stapa Metallux 211
Stapa Metallux 212
Stapa Metallux 2196
Stapa Metallux 274
Stapa Mobilux 181
Stapa Offset 3000
Stapa PV 10
Stapa VP 46432G
Starbrite 2100
Super Fine 18000
Super Fine 22000
Supramex 2022
Toyo Aluminum 02-0005
Toyo Aluminum 93-3040
Transmet K 102HE
Tufflake 3645
Tufflake 5843
UN 1396
US Aluminum 809
Valimet H 2
Valimet H 3
White Silver 7080N
White Silver 7130N
DTXSID30402737440-43-9BDOSMKKIYDKNTQ-UHFFFAOYSA-NBDOSMKKIYDKNTQ-UHFFFAOYSA-N
CadmiumCadimium
CADMIUM BLUE
CADMIUM, IN PLATTEN, STANGEN, BROCKEN,KOERNER
DTXSID10239407439-97-6QSHDDOUJBYECFT-UHFFFAOYSA-NQSHDDOUJBYECFT-UHFFFAOYSA-N
MercuryLiquid silver
Mercure
MERCURIC METAL TRIPLE DISTILLED
mercurio
Mercury element
Quecksilber
Quicksilver
UN 2024
UN 2809
DTXSID10241727440-61-1JFALSRSLKYAFGM-UHFFFAOYSA-NJFALSRSLKYAFGM-UHFFFAOYSA-N
UraniumUranium, isotope of mass 238
238U Element
UN 2979 (DOT)
Uranium I
DTXSID10425227440-38-2RQNWIZPPADIBDY-UHFFFAOYSA-NRQNWIZPPADIBDY-UHFFFAOYSA-N
ArsenicAs
Arsenic black
ARSENIC METAL
arsenico
Grey arsenic
UN 1558
DTXSID40238867440-22-4BQCADISMDOOEFD-UHFFFAOYSA-NBQCADISMDOOEFD-UHFFFAOYSA-N
SilverAg Nanopaste NPS-J 90
Ag Sphere 2
Ag-C-GS
Algaedyn
Arctic Silver 3
Argentum
Astroflake 5
Carey Lea silver
Colloidal silver
Dotite XA 208
Du Pont 4943
ECM 100AF4810
Enlight 600
Enlight silver plate 600
Epinall
Finesphere SVND 102
Fordel DC
FP 5369-502
Jelcon SH 1
Jungindai Takasago 300
KS (metal)
LCP 1-19SFS
Metz 3000-1
Nanomelt AGC-A
Nanomelt Ag-XA 301
Nanomelt Ag-XF 301
Nanomelt Ag-XF 301H
Nanopaste NPS-J 90
Perfect Silver
Puff Silver X 1200
RT 1710S-C1
SD (metal)
Shell Silver
Silbest E 20
Silbest F 20
Silbest J 18
Silbest TC 12
Silbest TC 20E
Silbest TC 25A
Silbest TCG 1
Silbest TCG 7
Silcoat AgC 103
Silcoat AgC 2011
Silcoat AgC 209
Silcoat AgC 2190
Silcoat AgC 222
Silcoat AgC 2411
Silcoat AgC 74T
Silcoat AgC-A
Silcoat AgC-AO
Silcoat AgC-B
Silcoat AgC-BO
Silcoat AgC-D
Silcoat AgC-G
Silcoat AgC-GS
Silcoat AgC-L
Silcoat AgC-O
Silcoat GS
Silcoat RF 200
Silflake 135
Silsphere 514
Silver atom
Silver element
Silver Flake 1
Silver Flake 25
Silver Flake 52
Silver Flake 7A
SILVER FLAKES
Silver metal
Silvest TCG 11N
Technic 299
Technic 450
Techno Alpha 175
DTXSID40243057439-96-5PWHULOQIROXLJO-UHFFFAOYSA-NPWHULOQIROXLJO-UHFFFAOYSA-N
ManganeseColloidal manganese
Cutaval
Manganese element
Manganese fulleride
Manganese metal alloy
Manganese-55
manganeso
DTXSID20241697440-02-0PXHVJJICTQNCMI-UHFFFAOYSA-NPXHVJJICTQNCMI-UHFFFAOYSA-N
NickelCarbonyl 255
Carbonyl Ni 123
Carbonyl Ni 283
Carbonyl Nickel 123
Carbonyl Nickel 283
Carbonyl Nickel 287
Cerac N 2003
CNS 10 Micron
Exmet 4 Ni X-4/0
Fibrex P
Incofoam
Nickel element
NICKEL ROUND ANODES
Nicrobraz LM:BNi 2
Ni-Flake 95
Novamet 123
Novamet 4SP
Novamet 4SP10
Novamet 525
Novamet CNS 400
Novamet HCA 1
Novamet NI 255
Raney nickel
Raney nickel 2800
UN 1325
UN 2881
DTXSID20209257440-66-6HCHKCACWOHOZIP-UHFFFAOYSA-NHCHKCACWOHOZIP-UHFFFAOYSA-N
ZincZn
Asarco L 15
C.I. Pigment Black 16
Merrillite
NC-Zinc
Rheinzink
Stapa TE Zinc AT
UF (metal)
UN 1436
Zinc dust
Zinc Dust 3
Zinc Dust 500 mesh
Zinc Dust LS 2
Zinc Dust MCS
Zinc Flakes GTT
ZINC METAL
ZINC MOSSY
ZINC STRIP
ZINC, MOSSY
Zincsalt GTT
DTXSID703501211056-06-7BleomycinBleo
Bleocin
Blenamax
Bleo-Kyowa
Bleomycins
NSC 125066
DTXSID1030862GO:0005739mitochondrionMP:0003674oxidative stressGO:0042116macrophage activationGO:0001775cell activation1increased2decreased7functional changeSilica nanoparticles2017-02-15T04:01:162017-02-15T04:01:16Acetaminophen2016-11-29T18:42:262016-11-29T18:42:26Chloroform2016-11-29T18:42:272016-11-29T18:42:27furan2020-05-01T14:35:222020-05-01T14:35:22Platinum2022-02-04T14:36:542022-02-04T14:36:54Aluminum2022-02-04T14:42:112022-02-04T14:42:11Cadmium2017-10-25T08:33:122017-10-25T08:33:12Mercury2016-11-29T18:42:192016-11-29T18:42:19Uranium2021-08-05T14:28:502021-08-05T14:28:50Arsenic2021-04-27T00:15:212021-04-27T00:15:21Silver 2022-02-03T11:20:112022-02-03T11:20:11Manganese2022-02-04T14:47:232022-02-04T14:47:23Nickel2022-02-04T14:47:592022-02-04T14:47:59Zinc2022-02-04T15:05:002022-02-04T15:05:00nanoparticles2016-12-21T09:40:062016-12-21T09:40:06Bleomycin<p><strong>Bleomycin</strong> is a potent anti-tumour drug, routinely used for treating various types of human cancers (Umezawa et al., 1967; Adamson, 1976). Lung injury and lung fibrosis are the major adverse effects of this drug in humans (Hay J et al., 1991). Bleomycin is shown to induce lung fibrosis in experimental animals - in dogs (Fleischman et al., 1971), mice (Adamson IY and Bowden DH, 1974), hamsters (Snider GL et al., 1978) and is widely used as a model chemical to study the mechanisms of fibrosis in humans (reviewed in <strong>Moeller</strong> et al., <strong>2008;</strong> Gilhodes et al., 2017).</p>
<ol>
<li>Adamson, I. (1976). Pulmonary Toxicity of Bleomycin. Environmental Health Perspectives, 16, p.119.</li>
<li>Adamson, IYR. and Bowden, DH. (1974). The Pathogenesis of Bleomycin-Induced Pulmonary Fibrosis in Mice. <em>The American Journal of Pathology</em>. 77(2), pp185-198.</li>
<li>Fleischman, R., Baker, J., Thompson, G., Schaeppi, U., Illievski, V., Cooney, D. and Davis, R. (1971). Bleomycin-induced interstitial pneumonia in dogs. Thorax, 26(6), pp.675-682.</li>
<li>Gilhodes, J., Julé, Y., Kreuz, S., Stierstorfer, B., Stiller, D. and Wollin, L. (2017). Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis. PLOS ONE, 12(1), p.e0170561.</li>
<li>Hay, J., Shahzeidi, S. and Laurent, G. (1991). Mechanisms of bleomycin-induced lung damage. Archives of Toxicology, 65(2), pp.81-94.</li>
<li>Moeller, A., Ask, K., Warburton, D., Gauldie, J. and Kolb, M. (2008). The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?. The International Journal of Biochemistry & Cell Biology, 40(3), pp.362-382.</li>
<li>Snider GL., Celli, BR., Goldstein, RH., O'Brien, JJ. and Lucey, EC. (1978). Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Lung volumes, volume-pressure relations, carbon monoxide uptake, and arterial blood gas studied. <em>Am Rev Respir Dis.</em> Feb; 117(2). pp289-97.</li>
<li>Umezawa, H., Ishizuka, M., Maeda, K. and Takeuchi, T. (1967). Studies on bleomycin. Cancer, 20(5), pp.891-895.</li>
</ol>
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2018-01-01T16:45:532019-10-29T13:08:19Carbon nanotubes, Multi-walled carbon nanotubes, single-walled carbon nanotubes, carbon nanofibres<p> </p>
<p>Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera,</p>
<p>Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison</p>
<p>Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera,</p>
<p>Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison</p>
2018-01-01T17:51:042018-01-01T17:52:30Nanoparticles and Micrometer Particles2022-02-04T13:43:432022-02-04T13:43:43WikiUser_26rodents9606Homo sapiensWCS_9606humans10090mouse10116ratWCS_9606humanIncrease, Reactive oxygen speciesIncrease, ROSMolecular2017-04-15T16:05:452019-03-19T09:41:07Oxidative Stress Oxidative Stress Molecular<p style="text-align:justify">Oxidative stress is defined as an imbalance in the production of reactive oxygen species (ROS) and antioxidant defenses. High levels of oxidizing free radicals can be very damaging to cells and molecules within the cell (Pizzino et al., 2017; Sharifi-Rad et al., 2020; Jena et al., 2023). As a result, the cell has important defense mechanisms to protect itself from ROS. For example, Nrf2 is a transcription factor and master regulator of the oxidative stress response. During periods of oxidative stress, Nrf2-dependent changes in gene expression are important in regaining cellular homeostasis (Nguyen, et al. 2009) and can be used as indicators of the presence of oxidative stress in the cell.</p>
<p style="text-align:justify">In addition to the directly damaging actions of ROS, cellular oxidative stress also changes cellular activities on a molecular level. Redox sensitive proteins have altered physiology in the presence and absence of ROS, which is caused by the oxidation of sulfhydryls to disulfides (2SH àSS) on neighboring amino acids (Antelmann and Helmann 2011). Importantly Keap1, the negative regulator of Nrf2, is regulated in this manner (Itoh, et al. 2010).</p>
<p><span style="font-size:16px"><span style="background-color:white"><span style="color:#2f5597">ROS also undermine the mitochondrial defense system from oxidative damage. The antioxidant systems consist of superoxide dismutase, <span style="background-color:white">catalase, glutathione peroxidase and glutathione reductase, as well as antioxidants such as α-tocopherol and ubiquinol</span></span></span><span style="color:#2f5597">, or antioxidant vitamins and minerals including vitamin E, C, carotene, lutein, zeaxanthin, selenium, and zinc (Fletcher, 2010). The enzymes, vitamins and minerals catalyze the conversion of ROS to non-toxic molecules such as water and O<sub>2</sub></span><span style="background-color:white"><span style="color:#2f5597"><span style="background-color:white">. However, these antioxidant systems are not perfect and endogenous metabolic processes and/or exogenous oxidative influences can trigger cumulative oxidative injuries to the mitochondria, causing a decline in their functionality and efficiency, which further promotes cellular oxidative stress (</span></span></span></span><span style="color:#2f5597">Balasubramanian, 2000; Ganea & Harding, 2006; Guo et al., 2013; Karimi et al., 2017)<span style="font-size:16px"><span style="background-color:white"><span style="background-color:white">.</span></span></span></span></p>
<p><span style="color:#27ae60"><span style="font-size:18px"><span style="background-color:white"><span style="font-family:"Times New Roman",serif"><span style="font-family:"Calibri",sans-serif"><span style="background-color:white">However, an emerging viewpoint suggests that ROS-induced modifications may not be as detrimental as previously thought, but rather contribute to signaling processes (Foyer et al., 2017). </span></span></span></span></span></span></p>
<p style="text-align:justify">Protection against oxidative stress is relevant for all tissues and organs, although some tissues may be more susceptible. For example, the brain possesses several key physiological features, such as high O2 utilization, high polyunsaturated fatty acids content, presence of autooxidable neurotransmitters, and low antioxidant defenses as compared to other organs, that make it highly susceptible to oxidative stress (Halliwell, 2006; Emerit and al., 2004; Frauenberger et al., 2016).</p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">Sources of ROS Production</span></span></strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">Direct Sources:</span></span></strong><span style="font-size:12.0pt"><span style="color:#2f5597"> Direct sources involve the deposition of energy onto water molecules, breaking them into active radical species. When ionizing radiation hits water, it breaks it into hydrogen (H*) and hydroxyl (OH*) radicals by destroying its bonds. The hydrogen will create hydroxyperoxyl free radicals (HO<sub>2</sub>*) if oxygen is available, which can then react with another of itself to form hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and more O<sub>2</sub> (Elgazzar and Kazem, 2015). Antioxidant mechanisms are also affected by radiation, with catalase (CAT) and peroxidase (POD) levels rising as a result of exposure (Seen et al. 2018; Ahmad et al. 2021). </span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">Indirect Sources:</span></span></strong><span style="font-size:12.0pt"><span style="color:#2f5597"> An indirect source of ROS is the mitochondria, which is one of the primary producers in eukaryotic cells (Powers et al., 2008). As much as 2% of the electrons that should be going through the electron transport chain in the mitochondria escape, allowing them an opportunity to interact with surrounding structures. Electron-oxygen reactions result in free radical production, including the formation of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) (Zhao et al., 2019). The electron transport chain, which also creates ROS, is activated by free adenosine diphosphate (ADP), O<sub>2</sub>, and inorganic phosphate (P<sub>i</sub>) (Hargreaves et al. 2020; Raimondi et al. 2020; Vargas-Mendoza et al. 2021). The first and third complexes of the transport chain are the most relevant to mammalian ROS production (Raimondi et al., 2020). The mitochondria have its own set of DNA and it is a prime target of oxidative damage (Guo et al., 2013). ROS are also produced through nicotinamide adenine dinucleotide phosphate oxidase (NOX) stimulation, an event commenced by angiotensin II, a product/effector of the renin-angiotensin system (Nguyen Dinh Cat et al. 2013; Forrester et al. 2018). Other ROS producers include xanthine oxidase, immune cells (macrophage, neutrophils, monocytes, and eosinophils), phospholipase A<sub>2</sub> (PLA<sub>2</sub>), monoamine oxidase (MAO), and carbon-based nanomaterials (Powers et al. 2008; Jacobsen et al. 2008; Vargas-Mendoza et al. 2021).</span></span></span></span></p>
<p><strong>Oxidative Stress. Direct measurement of ROS is difficult because ROS are unstable. The presence of ROS can be assayed indirectly by measurement of cellular antioxidants, or by ROS-dependent cellular damage.</strong><span style="color:#27ae60"> Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed</span></p>
<ul>
<li>Detection of ROS by chemiluminescence <span style="font-size:12px">(<span style="font-family:arial,helvetica,sans-serif">https://www.sciencedirect.com/science/article/abs/pii/S0165993606001683)</span></span></li>
<li>Detection of ROS by chemiluminescence is also described in OECD TG 495 to assess phototoxic potential.</li>
<li>Glutathione (GSH) depletion. GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html). </li>
<li>TBARS. Oxidative damage to lipids can be measured by assaying for lipid peroxidation using TBARS (thiobarbituric acid reactive substances) using a commercially available kit. </li>
<li>8-oxo-dG. Oxidative damage to nucleic acids can be assayed by measuring 8-oxo-dG adducts (for which there are a number of ELISA based commercially available kits),or HPLC, described in Chepelev et al. (Chepelev, et al. 2015).</li>
</ul>
<p><strong>Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assay for Nrf2 activity include:</strong></p>
<ul>
<li>Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus</li>
<li>Western blot for increased Nrf2 protein levels</li>
<li>Western blot of cytoplasmic and nuclear fractions to observe translocation of Nrf2 protein from the cytoplasm to the nucleus</li>
<li>qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences)</li>
<li>Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway (e.g., Jackson et al. 2014)</li>
<li>OECD TG422D describes an ARE-Nrf2 Luciferase test method</li>
<li>In general, there are a variety of commercially available colorimetric or fluorescent kits for detecting Nrf2 activation</li>
</ul>
<p> </p>
<table border="1" cellpadding="1" cellspacing="1">
<tbody>
<tr>
<td><strong>Assay Type & Measured Content</strong></td>
<td><strong>Description</strong></td>
<td><strong>Dose Range Studied</strong></td>
<td>
<p><strong>Assay Characteristics </strong><strong>(Length / Ease of use/Accuracy)</strong></p>
</td>
</tr>
<tr>
<td>
<p><strong>ROS Formation in the Mitochondria assay</strong> (Shaki et al., 2012)</p>
</td>
<td>“The mitochondrial ROS measurement was performed flow cytometry using DCFH-DA. Briefly, isolated kidney mitochondria were incubated with UA (0, 50, 100 and 200 μM) in respiration buffer containing (0.32 mM sucrose, 10 mM Tris, 20 mM Mops, 50 μM EGTA, 0.5 mM MgCl2, 0.1 mM KH2PO4 and 5 mM sodium succinate) [32]. In the interval times of 5, 30 and 60 min following the UA addition, a sample was taken and DCFH-DA was added (final concentration, 10 μM) to mitochondria and was then incubated for 10 min. Uranyl acetate-induced ROS generation in isolated kidney mitochondria were determined through the flow cytometry (Partec, Deutschland) equipped with a 488-nm argon ion laser and supplied with the Flomax software and the signals were obtained using a 530-nm bandpass filter (FL-1 channel). Each determination is based on the mean fluorescence intensity of 15,000 counts.”</td>
<td>0, 50, 100 and 200 μM of Uranyl Acetate</td>
<td>
<p>Long/ Easy</p>
<p>High accuracy</p>
</td>
</tr>
<tr>
<td>
<p><strong>Mitochondrial Antioxidant Content Assay</strong> Measuring GSH content</p>
(Shaki et al., 2012)</td>
<td>“GSH content was determined using DTNB as the indicator and spectrophotometer method for the isolated mitochondria. The mitochondrial fractions (0.5 mg protein/ml) were incubated with various concentrations of uranyl acetate for 1 h at 30 °C and then 0.1 ml of mitochondrial fractions was added into 0.1 mol/l of phosphate buffers and 0.04% DTNB in a total volume of 3.0 ml (pH 7.4). The developed yellow color was read at 412 nm on a spectrophotometer (UV-1601 PC, Shimadzu, Japan). GSH content was expressed as μg/mg protein.”</td>
<td>
<p>0, 50, 100, or 200 <em>μ</em>M Uranyl Acetate</p>
</td>
<td> </td>
</tr>
<tr>
<td>
<p><strong>H<sub>2</sub>O<sub>2</sub> Production Assay</strong> Measuring H<sub>2</sub>O<sub>2</sub> Production in isolated mitochondria</p>
(Heyno et al., 2008)</td>
<td>“Effect of CdCl<sub>2</sub> and antimycin A (AA) on H<sub>2</sub>O<sub>2</sub> production in isolated mitochondria from potato. H<sub>2</sub>O<sub>2</sub> production was measured as scopoletin oxidation. Mitochondria were incubated for 30 min in the measuring buffer (see the Materials and Methods) containing 0.5 mM succinate as an electron donor and 0.2 µM mesoxalonitrile 3âchlorophenylhydrazone (CCCP) as an uncoupler, 10 U horseradish peroxidase and 5 µM scopoletin.” (</td>
<td>
<p>0, 10, 30  <em>μ</em>M Cd<sup>2+</sup></p>
2  <em>μ</em>M<br />
antimycin A</td>
<td> </td>
</tr>
<tr>
<td>
<p><strong>Flow Cytometry ROS & Cell Viability</strong></p>
(Kruiderig et al., 1997)</td>
<td>“For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At <em>t </em>5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)”</td>
<td> </td>
<td>
<p>Strong/easy</p>
medium</td>
</tr>
<tr>
<td>
<p><strong>DCFH-DA Assay</strong> Detection of hydrogen peroxide production (Yuan et al., 2016)</p>
</td>
<td>
<p>Intracellular ROS production was measured using DCFH-DA as a probe. Hydrogen peroxide oxidizes DCFH to DCF. The probe is hydrolyzed intracellularly to DCFH carboxylate anion. No direct reaction with H<sub>2</sub>O<sub>2 </sub>to form fluorescent production. </p>
</td>
<td>0-400 µM</td>
<td>
<p>Long/ Easy</p>
<p>High accuracy</p>
</td>
</tr>
<tr>
<td>
<p><strong>H2-DCF-DA Assay</strong> Detection of superoxide production (Thiebault et al., 2007)</p>
</td>
<td>This dye is a stable nonpolar compound which diffuses readily into the cells and yields H2-DCF. Intracellular OH or ONOO- react with H2-DCF when cells contain peroxides, to form the highly fluorescent compound DCF, which effluxes the cell. Fluorescence intensity of DCF is measured using a fluorescence spectrophotometer.</td>
<td>0–600 µM</td>
<td>
<p>Long/ Easy</p>
<p>High accuracy</p>
</td>
</tr>
<tr>
<td><strong>CM-H2DCFDA Assay</strong></td>
<td>**Come back and explain the flow cytometry determination of oxidative stress from Pan et al. (2009)**</td>
<td> </td>
<td> </td>
</tr>
</tbody>
</table>
<p>Direct Methods of Measurement</p>
<table cellspacing="0" class="Table" style="border-collapse:collapse; width:623px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:141px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">Method of Measurement</span></span></strong> </span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:151px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">References</span></span></strong> </span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">Description</span></span></strong> </span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">OECD-Approved Assay</span></span></strong></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Chemiluminescence </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Lu, C. et al., 2006; </span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Griendling, K. K., et al., 2016)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">ROS can induce electron transitions in molecules, leading to electronically excited products. When the electrons transition back to ground state, chemiluminescence is emitted and can be measured. Reagents such as uminol and lucigenin are commonly used to amplify the signal. </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
<p> </p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Spectrophotometry </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">NO has a short half-life. However, if it has been reduced to nitrite (NO2-), stable azocompounds can be formed via the Griess Reaction, and further measured by spectrophotometry. </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Direct or Spin Trapping-Based Electron Paramagnetic Resonance (EPR) Spectroscopy </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">The unpaired electrons (free radicals) found in ROS can be detected with EPR, and is known as electron paramagnetic resonance. A variety of spin traps can be used. </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Nitroblue Tetrazolium Assay </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">The Nitroblue Tetrazolium assay is used to measure O</span></span><sub><span style="font-size:12.0pt"><span style="color:#2f5597">2</span></span></sub><span style="background-color:white"><span style="color:#2f5597">•</span></span><sup><span style="font-size:12.0pt"><span style="color:#2f5597">–</span></span></sup><span style="font-size:12.0pt"><span style="color:#2f5597"> levels. O</span></span><sub><span style="font-size:12.0pt"><span style="color:#2f5597">2</span></span></sub><span style="background-color:white"><span style="color:#2f5597">•</span></span><sup><span style="font-size:12.0pt"><span style="color:#2f5597">–</span></span></sup><span style="font-size:12.0pt"><span style="color:#2f5597"> reduces nitroblue tetrazolium (a yellow dye) to formazan (a blue dye), and can be measured at 620 nm. </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Fluorescence analysis of dihydroethidium (DHE) or Hydrocyans </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Fluorescence analysis of DHE is used to measure O</span></span><sub><span style="font-size:12.0pt"><span style="color:#2f5597">2</span></span></sub><span style="background-color:white"><span style="color:#2f5597">•</span></span><sup><span style="font-size:12.0pt"><span style="color:#2f5597">–</span></span></sup><span style="font-size:12.0pt"><span style="color:#2f5597"> levels. O</span></span><sub><span style="font-size:12.0pt"><span style="color:#2f5597">2</span></span></sub><span style="background-color:white"><span style="color:#2f5597">•</span></span><sup><span style="font-size:12.0pt"><span style="color:#2f5597">–</span></span></sup><span style="font-size:12.0pt"><span style="color:#2f5597"> is reduced to O2 as DHE is oxidized to 2-hydroxyethidium, and this reaction can be measured by fluorescence. Similarly, hydrocyans can be oxidized by any ROS, and measured via fluorescence. </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Amplex Red Assay </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Fluorescence analysis to measure extramitochondrial or extracellular H<sub>2</sub>O<sub>2</sub> levels. In the presence of horseradish peroxidase and H<sub>2</sub>O<sub>2</sub>, Amplex Red is oxidized to resorufin, a fluorescent molecule measurable by plate reader. </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Dichlorodihydrofluorescein Diacetate (DCFH-DA) </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">An indirect fluorescence analysis to measure intracellular H<sub>2</sub>O<sub>2</sub> levels. H<sub>2</sub>O<sub>2</sub> interacts with peroxidase or heme proteins, which further react with DCFH, oxidizing it to dichlorofluorescein (DCF), a fluorescent product. </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">HyPer Probe </span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Fluorescent measurement of intracellular H<sub>2</sub>O<sub>2</sub> levels. HyPer is a genetically encoded fluorescent sensor that can be used for <em>in vivo</em> and<em> in situ </em>imaging. </span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Cytochrome c Reduction Assay </span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">The cytochrome c reduction assay is used to measure O</span></span><sub><span style="font-size:12.0pt"><span style="color:#2f5597">2</span></span></sub><span style="background-color:white"><span style="color:#2f5597">•</span></span><sup><span style="font-size:12.0pt"><span style="color:#2f5597">–</span></span></sup><span style="font-size:12.0pt"><span style="color:#2f5597"> levels. O</span></span><sub><span style="font-size:12.0pt"><span style="color:#2f5597">2</span></span></sub><span style="background-color:white"><span style="color:#2f5597">•</span></span><sup><span style="font-size:12.0pt"><span style="color:#2f5597">–</span></span></sup><span style="font-size:12.0pt"><span style="color:#2f5597"> is reduced to O2 as ferricytochrome c is oxidized to ferrocytochrome c, and this reaction can be measured by an absorbance increase at 550 nm. </span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Proton-electron double-resonance imagine (PEDRI)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">The redox state of tissue is detected through nuclear magnetic resonance/magnetic resonance imaging, with the use of a nitroxide spin probe or biradical molecule. </span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Glutathione (GSH) depletion </span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Biesemann, N. et al., 2018) </span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">A downstream target of the Nrf2 pathway is involved in GSH synthesis. As an indication of oxidation status, GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., </span></span><span style="color:#2f5597"><a href="http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html"><span style="font-size:12.0pt"><span style="color:#2f5597">http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html</span></span></a></span><span style="font-size:12.0pt"><span style="color:#2f5597">). </span></span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Thiobarbituric acid reactive substances (TBARS) </span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Griendling, K. K., et al., 2016)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Oxidative damage to lipids can be measured by assaying for lipid peroxidation with TBARS using a commercially available kit. </span></span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Protein oxidation (carbonylation)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Azimzadeh et al., 2017; Azimzadeh etal., 2015; Ping et al., 2020)</span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Can be determined with enzyme-linked immunosorbent assay (ELISA) or a commercial assay kit. Protein oxidation can indicate the level of oxidative stress.</span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:141px"><span style="color:#27ae60">Seahorse XFp Analyzer </span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"><span style="color:#27ae60">Leung et al. 2018 </span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:255px"><span style="color:#27ae60">The Seahorse XFp Analyzer provides information on mitochondrial function, oxidative stress, and metabolic dysfunction of viable cells by measuring respiration (oxygen consumption rate; OCR) and extracellular pH (extracellular acidification rate; ECAR). </span></td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:76px"><span style="color:#27ae60">No </span></td>
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<p><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">Molecular Biology:</span></span></strong><span style="font-size:12.0pt"><span style="color:#2f5597"> Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assays for Nrf2 activity include: </span></span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">Method of Measurement</span></span></strong> </span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">References</span></span></strong> </span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">Description</span></span></strong> </span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="color:#2f5597">OECD-Approved Assay</span></span></strong></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Immunohistochemistry </span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Amsen, D., de Visser, K. E., and Town, T., 2009)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus </span></span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:75px">
<p style="text-align:center"><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:154px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Quantitative polymerase chain reaction (qPCR) </span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:139px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Forlenza et al., 2012)</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences) </span></span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:75px">
<p style="text-align:center"><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Whole transcriptome profiling via microarray or via RNA-seq followed by a pathway analysis</span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">(Jackson, A. F. et al., 2014)</span></span></span></span></span></p>
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<p><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway</span></span></span></span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:46px; vertical-align:top; width:75px">
<p style="text-align:center"><span style="font-size:11pt"><span style="background-color:white"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="color:#2f5597">No</span></span></span></span></span></p>
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<p><span style="color:#27ae60"><strong>Taxonomic applicability: </strong>Occurrence of oxidative stress is not species specific. </span></p>
<p><span style="color:#27ae60"><strong>Life stage applicability:</strong> Occurrence of oxidative stress is not life stage specific. </span></p>
<p><span style="color:#27ae60"><strong>Sex applicability: </strong>Occurrence of oxidative stress is not sex specific. </span></p>
<p><span style="color:#27ae60"><strong>Evidence for perturbation by prototypic stressor:</strong> There is evidence of the increase of oxidative stress following perturbation from a variety of stressors including exposure to ionizing radiation and altered gravity (Bai et al., 2020; Ungvari et al., 2013; Zhang et al., 2009). </span></p>
HighMixedHighAll life stagesHighHigh<p style="margin-left:48px; text-align:left"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Ahmad, S. et al. (2021), “60Co-γ Radiation Alters Developmental Stages of Zeugodacus cucurbitae (Diptera: Tephritidae) Through Apoptosis Pathways Gene Expression”, <em>Journal Insect Science,</em> Vol. 21/5, Oxford University Press, Oxford, </span><a href="https://doi.org/10.1093/jisesa/ieab080" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1093/jisesa/ieab080</a></span></span></p>
<p style="margin-left:48px; text-align:left"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Antelmann, H. and J. D. Helmann (2011), “Thiol-based redox switches and gene regulation.”, <em>Antioxidants & Redox Signaling</em>, Vol. 14/6, Mary Ann Leibert Inc., Larchmont, <a href="https://doi.org/10.1089/ars.2010.3400" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1089/ars.2010.3400</a></span></span></p>
<p style="margin-left:48px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Amsen, D., de Visser, K. E., and Town, T. (2009), “Approaches to determine expression of inflammatory cytokines”, in <em>Inflammation and Cancer</em>, Humana Press, Totowa, </span></span><a href="https://doi.org/10.1007/978-1-59745-447-6_5" style="color:#0563c1; text-decoration:underline"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:#1155cc">https://doi.org/10.1007/978-1-59745-447-6_5</span></span></span></a> </span></span></p>
<p style="margin-left:48px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Azimzadeh, O. et al. (2015), “Integrative Proteomics and Targeted Transcriptomics Analyses in Cardiac Endothelial Cells Unravel Mechanisms of Long-Term Radiation-Induced Vascular Dysfunction”, <em>Journal of Proteome Research</em>, Vol. 14/2, American Chemical Society, Washington, </span></span></span><a href="https://doi.org/10.1021/pr501141b" style="color:#0563c1; text-decoration:underline"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">https://doi.org/10.1021/pr501141b</span></span></a></span></span></p>
<p style="margin-left:48px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Azimzadeh, O. et al. (2017), “Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways”, <em>International Journal of Radiation Biology</em>, Vol. 93/9, Informa, London, </span></span></span><a href="https://doi.org/10.1080/09553002.2017.1339332" style="color:#0563c1; text-decoration:underline"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">https://doi.org/10.1080/09553002.2017.1339332</span></span></a></span></span></p>
<p style="margin-left:48px"><span style="color:#27ae60">Azzam, E. I. et al. (2012), “Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury”, Cancer Letters, Vol. 327/1-2, Elsevier, Ireland, https://doi.org/10.1016/j.canlet.2011.12.012 </span></p>
<p style="margin-left:48px"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Bai, J. et al. (2020), “Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling”, <em>American Journal of Physiology - Cell Physiology</em>, Vol. 318/5, American Physiological Society, Rockville, </span></span></span><a href="https://doi.org/10.1152/ajpcell.00520.2019." style="color:#0563c1; text-decoration:underline"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">https://doi.org/10.1152/ajpcell.00520.2019.</span></span></a></span></span></p>
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2017-05-30T13:58:172024-03-08T12:28:08Airway epithelial injuryAirway epithelial injuryCellular<p>Inhalation of to low concentrations of α-diketones generally does not result in airway injury. However, above a certain threshold the airway epithelium becomes persistently damaged.</p>
<p>Histopathological abnormalities in exposed rats, airway epithelial necrosis, flattening of the airway epithelial cells, loss of cilia (Foster et al. 2017), gaps in the epithelial layer (Hubbs et al. 2002, 2008). Also a reduced expression of club cell secretory protein in airway epithelium has been observed after a-diketone exposure (Palmer et al. 2011). Within <em>in vitro</em> models of airway epithelium, the loss of epithelial barrier function following exposure can be measured as a reduction in transepithelial electrical resistance (TEER, Fedan et al. 2006, Zaccone et al 2015)</p>
<p>Foster, M. W., Gwinn, W. M., Kelly, F. L., Brass, D. M., Valente, A. M., Moseley, M. A., … Palmer, S. M. (2017). Proteomic Analysis of Primary Human Airway Epithelial Cells Exposed to the Respiratory Toxicant Diacetyl. <em>Journal of Proteome Research</em>, <em>16</em>(2), 538–549. <a href="https://doi.org/10.1021/acs.jproteome.6b00672"><u>https://doi.org/10.1021/acs.jproteome.6b00672</u></a></p>
<p>Hubbs, A. F., Goldsmith, W. T., Kashon, M. L., Frazer, D., Mercer, R. R., Battelli, L. A., … Castranova, V. (2008). Respiratory Toxicologic Pathology of Inhaled Diacetyl in Sprague-Dawley Rats. <em>Toxicologic Pathology</em>, <em>36</em>(2), 330–344. https://doi.org/10.1177/0192623307312694</p>
<p>Palmer, S. M., Flake, G. P., Kelly, F. L., Zhang, H. L., Nugent, J. L., Kirby, P. J., … Morgan, D. L. (2011). Severe airway epithelial injury, aberrant repair and Bronchiolitis obliterans develops after diacetyl instillation in rats. <em>PLoS ONE</em>, <em>6</em>(3). https://doi.org/10.1371/journal.pone.0017644</p>
<p>Zaccone, E. J., Goldsmith, W. T., Shimko, M. J., Wells, J. R., Schwegler-Berry, D., Willard, P. A., … Fedan, J. S. (2015). Diacetyl and 2,3-pentanedione exposure of human cultured airway epithelial cells: Ion transport effects and metabolism of butter flavoring agents. <em>Toxicology and Applied Pharmacology</em>, <em>289</em>, 542–549. https://doi.org/10.1016/j.taap.2015.10.004</p>
2019-01-30T09:32:522019-01-30T10:25:29Activation, MacrophagesActivation, MacrophagesCellularCL:0000235macrophage2016-11-29T18:41:302017-09-16T10:17:41Pulmonary epithelial injuryPulmonary epithelial injuryCellular2023-01-09T11:27:092023-07-11T05:59:30Activation, FibroblastsActivation, FibroblastsCellularCL:0000057fibroblast2016-11-29T18:41:302017-09-16T10:17:41Airway inflammationAirway inflammationOrgan2023-01-09T11:29:502023-01-17T05:07:56Pulmonary inflammationPulmonary inflammationOrgan2022-05-31T02:59:312022-05-31T03:03:08Pulmonary fibrosisPulmonary fibrosisOrgan<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Pulmonary fibrosis is broadly defined as the thickening or scarring of lung tissue, due to excessive deposition of extracellular matrix. In the normal human lung, the nasopharynx and the conducting airways are mainly covered by epithelium composed of ciliated, mucous secreting cells in direct contact with the basement membrane with submucosal glands containing goblet, duct, and serous cells also contributing to the fluid balance and mucous production (Koval and Sidhaye, 2017). Within this epithelium, basal cells are found which are stimulated to proliferate and differentiate in response to injury (Koval and Sidhaye, 2017). Further down the lung, in the terminal bronchiole region, the epithelium does not contain submucosal glands, but instead contains club cells which produce pulmonary surfactant and can differentiate into bronchiolar or alveolar epithelial cells (AECs). Finally, in the terminal airspaces, the epithelium is made up entirely of type I and type II AECs. In between the two adjacent alveoli are two layers of alveolar epithelium resting on basement membrane, which consists of interstitial space, pulmonary capillaries, elastin and collagen fibres. Thus, the alveolar capillary membrane (ACM), where gas exchange takes place, is made up of the alveolar epithelium and alveolar endothelium (Gracey et al, 1968). In pulmonary fibrosis, damage to the pulmonary epithelium results in excessive deposition of collagen by constitutively activated myofibroblasts during the wound healing response. This causes a pronounced decrease in the number of capillaries within the alveolar septa with asymmetric deposition of collagen and cells between part of the surface of a capillary and the nearby alveolar lining. In areas where capillaries are not present, the ACM is occupied with collagen and cells. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em>In vivo</em>, histopathological analysis is used for assessing fibrotic lung disease. Morphometric analysis of the diseased area versus total lung area is used to quantitatively stage the fibrotic disease. Although, some inconsistencies can be introduced during the analysis due to the experience of the individual scoring the disease, the histological stain, etc., a numerical scale with grades from 0 to 8, originally developed by Ashcroft et al., 1988 is assigned to indicate the amount of fibrotic tissue in histological samples. This scale is applied to diagnose lung fibrosis in both human and animal samples. Modifications to this scoring system were proposed (Hubner et al., 2008), which enables morphological distinctions thus enabling a better grading of the disease. Using the modified scoring system, bleomycin induced lung fibrosis in rats was scored as follows: Grade 0 – normal lung, Grade 1 – isolated alveolar septa with gentle fibrotic changes, Grade 2 – knot like formation in fibrotic areas in alveolar septa, Grade 3 – contiguous fibrotic walls of alveolar septa, Grade 4 – single fibrotic masses, Grade 5 – confluent fibrotic masses, Grade 6 – large contiguous fibrotic masses, Grade 7 – air bubbles and Grade 8 – fibrotic obliteration. Further morphometric analysis can be conducted to quantify the total disease area (Nikota et al., 2017).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Lungs are formalin fixed and paraffin embedded such that an entire cross section of lung can be presented on a slide. The entire cross section is captured in a series of images using wide field light microscope. Areas of alveolar epithelium thickening and consolidated air space are identified. ImageJ software (freely available) is used to trace the total area (green line) and the diseased area (red line) imaged and quantified. The diseased area is equal to disease area/total area (Nikota et al., 2017).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em>In vitro</em>, there is no single assay that can measure the alveolar thickness. However, a combination of assays spanning various KEs described above provide a measure of the extent of fibrogenesis potential of tested substances. Real-time reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays<strong><em> </em></strong>(ELISA) measuring increased collagen, Transforming growth factor beta 1 (TGF-β1) and various pro-inflammatory mediators are used as sensitive markers of potential of substances to induce the adverse outcome of lung fibrosis.</span></span></p>
UBERON:0002048lungHighUnspecificHighAdultsHighHighHigh<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">1. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988 Apr;41(4):467-70. doi: 10.1136/jcp.41.4.467.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">2. Gracey DR, Divertie MB, Brown AL Jr. Alveolar-capillary membrane in idiopathic interstitial pulmonary fibrosis. Electron microscopic study of 14 cases. Am Rev Respir Dis. 1968 Jul;98(1):16-21. doi: 10.1164/arrd.1968.98.1.16.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">3. Hübner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, Freitag-Wolf S, Bewig B. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques. 2008 Apr;44(4):507-11, 514-7. doi: 10.2144/000112729. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">4. Koval M, Sidhaye VK. Introduction: The Lung Epithelium. In: Sidhaye VK, Koval M, editors. Lung Epithelial Biology in the Pathogenesis of Pulmonary Disease. Boston: Academic Press; 2017. p. xiii-xviii. Elsevier.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">5. Nikota J, Banville A, Goodwin LR, Wu D, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0. </span></span></p>
2017-07-26T19:13:542023-05-12T17:09:50Increased incidence of respiratory diseaseIncreased incidence of respiratory diseaseIndividual2023-01-09T11:35:092023-01-09T11:35:09Dysfunction of respiratory systemRespiratory dysfunctionIndividual2023-01-09T11:39:092023-01-09T11:39:09N/A, Mitochondrial dysfunction 1N/A, Mitochondrial dysfunction 1Cellular<p>Mitochondrial dysfunction is a consequence of inhibition of the respiratory chain leading to oxidative stress.</p>
<p>Mitochondria can be found in all cells and are considered the most important cellular consumers of oxygen. Furthermore, mitochondria possess numerous redox enzymes capable of transferring single electrons to oxygen, generating the superoxide (O2-). Some mitochondrial enzymes that are involved in reactive oxygen species (ROS) generation include the electron-transport chain (ETC) complexes I, II and III; pyruvate dehydrogenase (PDH) and glycerol-3-phosphate dehydrogenase (GPDH). The transfer of electrons to oxygen, generating superoxide, happens mainly when these redox carriers are charged enough with electrons and the potential energy for transfer is elevated, like in the case of high mitochondrial membrane potential. In contrast, ROS generation is decreased if there are not enough electrons and the potential energy for the transfer is not sufficient (reviewed in Lin and Beal, 2006).</p>
<p>Cells are also able to detoxify the generated ROS due to an extensive antioxidant defence system that includes superoxide dismutases, glutathione peroxidases, catalase, thioredoxins, and peroxiredoxins in various cell organelles (reviewed in Lin and Beal, 2006). It is worth mentioning that, as in the case of ROS generation, antioxidant defences are also closely related to the redox and energetic status of mitochondria. If mitochondria are structurally and functionally healthy, an antioxidant defence mechanism balances ROS generation, and there is not much available ROS production. However, in case of mitochondrial damage, the antioxidant defence capacity drops and ROS generation takes over. Once this happens, a vicious cycle starts and ROS can further damage mitochondria, leading to more free-radical generation and further loss of antioxidant capacity. During mitochondrial dysfunction the availability of ATP also decreases, which is considered necessary for repair mechanisms after ROS generation.</p>
<p>A number of proteins bound to the mitochondria or endoplasmic reticulum (ER), especially in the mitochondria-associated ER membrane (MAM), are playing an important role of communicators between these two organelles (reviewed Mei et al., 2013). ER stress induces mitochondrial dysfunction through regulation of Ca2+ signaling and ROS production (reviewed Mei et al., 2013). Prolonged ER stress leads to release of Ca2+ at the MAM and increased Ca2+ uptake into the mitochondrial matrix, which induces Ca2+-dependent mitochondrial outer membrane permeabilization and apoptosis. At the same, ROS are produced by proteins in the ER oxidoreductin 1 (ERO1) family. ER stress activates ERO1 and leads to excessive production of ROS, which, in turn, inactivates SERCA and activates inositol-1,4,5- trisphosphate receptors (IP3R) via oxidation, resulting in elevated levels of cytosolic Ca2+, increased mitochondrial uptake of Ca2+, and ultimately mitochondrial dysfunction. Just as ER stress can lead to mitochondrial dysfunction, mitochondrial dysfunction also induces ER Stress (reviewed Mei et al., 2013). For example, nitric oxide disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca2+ flux which induce ER stress. Increased Ca2+ flux triggers loss of mitochondrial membrane potential (MMP), opening of mitochondrial permeability transition pore (mPTP), release of cytochrome c and apoptosis inducing factor (AIF), decreasing ATP synthesis and rendering the cells more vulnerable to both apoptosis and necrosis (Wang and Qin, 2010).</p>
<p><u>Metal-induced Mitochondrial Dysfunction</u><br />
Mitochondria are an important site of Ca2+ regulation and storage, taking up Ca2+ ions electrophoretically from the cytosol through a Ca2+ uniporter, which can then accumulate in the mitochondria (Roos et al., 2012; Orrenius et al., 2015). Similarities between calcium and metals, such as cadmium and lead, makes the entrance and accumulation of these metals into the mitochondria via calcium metals possible by mode of molecular mimicry (Mathews et al., 2013; Adiele et al., 2012). The outer mitochondrial membrane also contains the divalent metal transporter (DMT1), which allows for mitochondrial uptake of divalent metals such as Fe and Mn. When cells are under heavy metal-induced stress, DMT has been shown to be overexpressed in the mitochondrial membrane, making the mitochondria targets of metal toxicity and accumulation.</p>
<p>Heavy metal exposure in aerobic organisms increases ROS formation through redox cycling, where metals with different valence states (Fe, Cu, Cr, etc.) directly produce ROS as they are reduced by cellular antioxidants and then react with oxygen (Shaki et al., 2012; Shaki et al., 2013; Pourahmad et al., 2006; Santos et al., 2007). The production of highly reactive hydroxyl radicals under mitochondrial oxidative stress and in the presence of transition metals occurs via the Fenton reaction or Haber-Weiss reaction (Hancock et al., 2001; Valko et al., 2005; Adam-Vizi et al., 2010). Metals and ROS are capable of damaging mitochondrial DNA as well as mechanisms of DNA repair and proliferation arrest (Valko et al., 2005). Metals and ROS have the potential to directly damage mitochondrial membranes and structure by binding to and oxidizing membrane lipids and proteins. This structural damage can collapse the MMP and lead to the opening of the MPTP (Orrenius et al., 2015; Roos et al., 2012; Pourahmad et al., 2006). Uranium and mercury, for example, have both been shown to directly inhibit the mitochondrial electron transport chain and interfere with ATP production (Shaki et al., 2012; Roos et al., 2012). Furthermore, as previously mentioned, metals have been shown to inhibit ROS-detoxifying enzymes. By binding to these enzymes, metals can inhibit their antioxidant functions, and cause an accumulation of ROS and increased synthesis of more antioxidant enzymes in order to combat the oxidative stress (Blajszczak and Bonini, 2017).</p>
<p><strong>Summing up:</strong> Mitochondria play a pivotal role in cell survival and cell death because they are regulators of both energy metabolism and apoptotic/necrotic pathways (Fiskum, 2000; Wieloch, 2001; Friberg and Wieloch, 2002). The production of ATP via oxidative phosphorylation is a vital mitochondrial function (Kann and Kovács, 2007; Nunnari and Suomalainen, 2012). The ATP is continuously required for signalling processes (e.g. Ca2+ signalling), maintenance of ionic gradients across membranes, and biosynthetic processes (e.g. protein synthesis, heme synthesis or lipid and phospholipid metabolism) (Kang and Pervaiz, 2012), and (Green, 1998; McBride et al., 2006). Inhibition of mitochondrial respiration contributes to various cellular stress responses, such as deregulation of cellular Ca2+ homeostasis (Graier et al., 2007) and ROS production (Nunnari and Suomalainen, 2012; reviewed Mei et al., 2013).). It is well established in the existing literature that mitochondrial dysfunction may result in: (a) an increased ROS production and a decreased ATP level, (b) the loss of mitochondrial protein import and protein biosynthesis, (c) the reduced activities of enzymes of the mitochondrial respiratory chain and the Krebs cycle, (d) the loss of the mitochondrial membrane potential, (e) the loss of mitochondrial motility, causing a failure to re-localize to the sites with increased energy demands (f) the destruction of the mitochondrial network, and (g) increased mitochondrial Ca2+ uptake, causing Ca2+ overload (reviewed in Lin and Beal, 2006; Graier et al., 2007), (h) the rupture of the mitochondrial inner and outer membranes, leading to (i) the release of mitochondrial pro-death factors, including cytochrome c (Cyt. c), apoptosis-inducing factor, or endonuclease G (Braun, 2012; Martin, 2011; Correia et al., 2012; Cozzolino et al., 2013), which eventually leads to apoptotic, necrotic or autophagic cell death (Wang and Qin, 2010). Due to their structural and functional complexity, mitochondria present multiple targets for various compounds.</p>
<p>Mitochondrial dysfunction can be detected using isolated mitochondria, intact cells or cells in culture as well as in vivo studies. Such assessment can be performed with a large range of methods (revised by Brand and Nicholls, 2011) for which some important examples are given. All approaches to assess mitochondrial dysfunction fall into two main categories: the first assesses the consequences of a loss-of-function, i.e. impaired functioning of the respiratory chain and processes linked to it. Some assay to assess this have been described for KE1, with the limitation that they are not specific for complex I. In the context of overall mitochondrial dysfunction, the same assays provide useful information, when performed under slightly different assay conditions (e.g. without addition of complex III and IV inhibitors). The second approach assesses a ‘non-desirable gain-of-function’, i.e. processes that are usually only present to a very small degree in healthy cells, and that are triggered in a cell, in which mitochondria fail.</p>
<p>I. Mitochondrial dysfunction assays assessing a loss-of function.</p>
<p>1. Cellular oxygen consumption.</p>
<p>See KE1 for details of oxygen consumption assays. The oxygen consumption parameter can be combined with other endpoints to derive more specific information on the efficacy of mitochondrial function. One approach measures the ADP-to-O ratio (the number of ADP molecules phosphorylated per oxygen atom reduced (Hinkle, 1995 and Hafner et al., 1990). The related P/O ratio is calculated from the amount of ADP added, divided by the amount of O<sub>2</sub> consumed while phosphorylating the added ADP (Ciapaite et al., 2005; Diepart et al., 2010; Hynes et al., 2006; James et al., 1995; von Heimburg et al., 2005).</p>
<p>2. Mitochondrial membrane potential (Δψm ).</p>
<p>The mitochondrial membrane potential (Δψm) is the electric potential difference across the inner mitochondrial membrane. It requires a functioning respiratory chain in the absence of mechanisms that dissipate the proton gradient without coupling it to ATP production. The classical, and still most quantitative method uses a tetraphenylphosphonium ion (TPP+)-sensitive electrode on suspensions of isolated mitochondria. The Δψm can also be measured in live cells by fluorimetric methods. These are based on dyes which accumulate in mitochochondria because of Δψm. Frequently used are tetramethylrhodamineethylester (TMRE), tetramethylrhodaminemethyl ester (TMRM) (Petronilli et al., 1999) or 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazole carbocyanide iodide (JC-1). Mitochondria with intact membrane potential concentrate JC-1, so that it forms red fluorescent aggregates, whereas de-energized mitochondria cannot concentrate JC-1 and the dilute dye fluoresces green (Barrientos et al., 1999). Assays using TMRE or TMRM measure only at one wavelength (red fluorescence), and depending on the assay setup, de-energized mitochondria become either less fluorescent (loss of the dye) or more fluorescent (attenuated dye quenching).</p>
<p>3. Enzymatic activity of the electron transport system (ETS).</p>
<p>Determination of ETS activity can be dene following Owens and King's assay (1975). The technique is based on a cell-free homogenate that is incubated with NADH to saturate the mitochondrial ETS and an artificial electron acceptor [l - (4 -iodophenyl) -3 - (4 -nitrophenyl) -5-phenylte trazolium chloride (INT)] to register the electron transmission rate. The oxygen consumption rate is calculated from the molar production rate of INT-formazan which is determined spectrophotometrically (Cammen et al., 1990).</p>
<p>4. ATP content.</p>
<p>For the evaluation of ATP levels, various commercially-available ATP assay kits are offered based on luciferin and luciferase activity. For isolated mitochondria various methods are available to continuously measure ATP with electrodes (Laudet 2005), with luminometric methods, or for obtaining more information on different nucleotide phosphate pools (e.g. Ciapaite et al., (2005).</p>
<p><br />
II. Mitochondrial dysfunction assays assessing a gain-of function.</p>
<p><br />
1. Mitochondrial permeability transition pore opening (PTP).</p>
<p>The opening of the PTP is associated with a permeabilization of mitochondrial membranes, so that different compounds and cellular constituents can change intracellular localization. This can be measured by assessment of the translocation of cytochrome c, adenylate kinase or AIF from mitochondria to the cytosol or nucleus. The translocation can be assessed biochemically in cell fractions, by imaging approaches in fixed cells or tissues or by life-cell imaging of GFP fusion proteins (Single 1998; Modjtahedi 2006). An alternative approach is to measure the accessibility of cobalt to the mitochondrial matrix in a calcein fluorescence quenching assay in live permeabilized cells (Petronilli et al., 1999).</p>
<p>2. mtDNA damage as a biomarker of mitochondrial dysfunction.</p>
<p>Various quantitative polymerase chain reaction (QPCR)-based assays have been developed to detect changes of DNA structure and sequence in the mitochondrial genome. mtDNA damage can be detected in blood after low-level rotenone exposure, and the damage persists even after CI activity has returned to normal. With a more sustained rotenone exposure, mtDNA damage is also detected in skeletal muscle. These data support the idea that mtDNA damage in peripheral tissues in the rotenone model may provide a biomarker of past or ongoing mitochondrial toxin exposure (Sanders et al., 2014a and 2014b).</p>
<p>3. Generation of ROS and resultant oxidative stress.</p>
<p>a. General approach. Electrons from the mitochondrial ETS may be transferred ‘erroneously’ to molecular oxygen to form superoxide anions. This type of side reaction can be strongly enhanced upon mitochondrial damage. As superoxide may form hydrogen peroxide, hydroxyl radicals or other reactive oxygen species, a large number of direct ROS assays and assays assessing the effects of ROS (indirect ROS assays) are available (Adam-Vizi, 2005; Fan and Li 2014). Direct assays are based on the chemical modification of fluorescent or luminescent reporters by ROS species. Indirect assays assess cellular metabolites, the concentration of which is changed in the presence of ROS (e.g. glutathione, malonaldehyde, isoprostanes,etc.) At the animal level the effects of oxidative stress are measured from biomarkers in the blood or urine.</p>
<p>b. Measurement of the cellular glutathione (GSH) status. GSH is regenerated from its oxidized form (GSSH) by the action of an NADPH dependent reductase (GSSH + NADPH + H+ à 2 GSH + NADP+). The ratio of GSH/GSSG is therefore a good indicator for the cellular NADH+/NADPH ratio (i.e. the redox potential). GSH and GSSH levels can be determined by HPLC, capillary electrophoresis, or biochemically with DTNB (Ellman’s reagent). As excess GSSG is rapidly exported from most cells to maintain a constant GSH/GSSG ratio, a reduction of total glutathione (GSH/GSSG) is often a good surrogate measure for oxidative stress.</p>
<p>c. Quantification of lipid peroxidation. Measurement of lipid peroxidation has historically relied on the detection of thiobarbituric acid (TBA)-reactive compounds such as malondialdehyde generated from the decomposition of cellular membrane lipid under oxidative stress (Pryor et al., 1976). This method is quite sensitive, but not highly specific. A number of commercial assay kits are available for this assay using absorbance or fluorescence detection technologies. The formation of F2-like prostanoid derivatives of arachidonic acid, termed F2-isoprostanes (IsoP) has been shown to be more specific for lipid peroxidation. A number of commercial ELISA kits have been developed for IsoPs, but interfering agents in samples requires partial purification before analysis. Alternatively, GC/MS may be used, as robust (specific) and sensitive method.</p>
<p><br />
d. Detection of superoxide production. Generation of superoxide by inhibition of complex I and the methods for its detection are described by Grivennikova and Vinogradov (2014). A range of different methods is also described by BioTek (<a class="external free" href="http://www.biotek.com/resources/articles/reactive-oxygen-species.html" rel="nofollow" target="_blank">http://www.biotek.com/resources/articles/reactive-oxygen-species.html</a>). The reduction of ferricytochrome c to ferrocytochrome c may be used to assess the rate of superoxide formation (McCord, 1968). Like in other superoxide assays, specificity can only be obtained by measurements in the absence and presence of superoxide dismutase. Chemiluminescent reactions have been used for their increased sensitivity. The most widely used chemiluminescent substrate is lucigenin. Coelenterazine has also been used as a chemiluminescent substrate. Hydrocyanine dyes are fluorogenic sensors for superoxide and hydroxyl radical, and they become membrane impermeable after oxidation (trapping at site of formation). The best characterized of these probes are Hydro-Cy3 and Hydro-Cy5. generation of superoxide in mitochondria can be visualized using fluorescence microscopy with MitoSOX™ Red reagent (Life Technologies). MitoSOX™ Red reagent is a cationic derivative of dihydroethidium that permeates live cells and accumulates in mitochondria.</p>
<p>e. Detection of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) production. There are a number of fluorogenic substrates, which serve as hydrogen donors that have been used in conjunction with horseradish peroxidase (HRP) enzyme to produce intensely fluorescent products in the presence of hydrogen peroxide (Zhou et al., 1997: Ruch et al., 1983). The more commonly used substrates include diacetyldichloro-fluorescein, homovanillic acid, and Amplex® Red. In these examples, increasing amounts of H<sub>2</sub>O<sub>2</sub> form increasing amounts of fluorescent product (Tarpley et al., 2004).</p>
<p>Summing up, mitochondrial dysfunction can be measured by: • ROS production: superoxide (O2-), and hydroxyl radicals (OH−) • Nitrosative radical formation such as ONOO− or directly by: • Loss of mitochondrial membrane potential (MMP) • Opening of mitochondrial permeability transition pores (mPTP) • ATP synthesis • Increase in mitochondrial Ca2+ • Cytochrome c release • AIF (apoptosis inducing factor) release from mitochondria • Mitochondrial Complexes enzyme activity • Measurements of mitochondrial oxygen consumption • Ultrastructure of mitochondria using electron microscope and mitochondrial fragmentation measured by labelling with DsRed-Mito expression (Knott et al, 2008) Mitochondrial dysfunction-induced oxidative stress can be measured by: • Reactive carbonyls formations (proteins oxidation) • Increased 8-oxo-dG immunoreactivity (DNA oxidation) • Lipid peroxidation (formation of malondialdehyde (MDA) and 4- hydroxynonenal (HNE) • 3-nitrotyrosine (3-NT) formation, marker of protein nitration • Translocation of Bid and Bax to mitochondria • Measurement of intracellular free calcium concentration ([Ca2+]i): Cells are loaded with 4 μM fura-2/AM). • Ratio between reduced and oxidized form of glutathione (GSH depletion) (Promega assay, TB369; Radkowsky et al., 1986) • Neuronal nitric oxide synthase (nNOS) activation that is Ca2+-dependent. All above measurements can be performed as the assays for each readout are well established in the existing literature (e.g. Bal-Price and Brown, 2000; Bal-Price et al., 2002; Fujikawa, 2015; Walker et al., 1995). See also KE <a href="/wiki/index.php/Event:209" title="Event:209"> Oxidative Stress, Increase</a></p>
<table border="1" cellpadding="1" cellspacing="1">
<tbody>
<tr>
<td>
<p><strong>Assay Type & Measured Content</strong></p>
</td>
<td><strong>Description</strong></td>
<td><strong>Dose Range Studied</strong></td>
<td>
<p><strong>Assay Characteristics</strong></p>
<p><strong>(Length/Ease of use/Accuracy)</strong></p>
</td>
</tr>
<tr>
<td>
<p><strong>Rhodamine 123 Assay</strong></p>
<p>Measuring Mitochondrial membrane potential (MMP) and its collapse </p>
<p>(Shaki et al., 2012)</p>
</td>
<td>
<p>Mitochondrial uptake of cationic fluorescent dye, rhodamine 123, is used for estimation of mitochondrial membrane potential. The fluorescence was monitored using Schimadzou RF-5000U fluorescence spectrophotometer at the excitation and emission wavelength of 490 nm and 535 nm, respectively.</p>
</td>
<td>50, 100 and 500 μM of uranyl acetate</td>
<td>
<p>Short / easy</p>
<p>Medium accurancy</p>
</td>
</tr>
<tr>
<td>
<p><strong>TMRE fluorescence Assay</strong></p>
<p>Measuring Mitochondrial permeability transition pore (mPTP) opening</p>
<p>(Huser et al., 1998)</p>
</td>
<td>Laser scanning confocal microscopy in combination with the potentiometric fluorescence dye tetramethylrhodamine ethyl ester to monitor relative changes in membrane potential in single isolated cardiac mitochondria. The cationic dye distributes across the membrane in a voltage-dependent manner. Therefore, the large potential gradient across the inner mitochondrial membrane results in the accumulation of the fluorescent dye within the matrix compartment. Rapid depolarizations are caused by the opening of the transition pore.</td>
<td>1 µM cyclosporin A</td>
<td>
<p>Short / easy</p>
<p>Low accurancy</p>
</td>
</tr>
<tr>
<td>
<p><strong>GSH / GSSG Determination Assay</strong></p>
<p>Measuring cellular glutathione (GSH) status; ratio of GSH/GSSG</p>
<p>(Owen & Butterfield, 2010; Shaki et al., 2013)</p>
</td>
<td>GSH and GSSG levels are determinted biochemically with DTNB (Ellman’s reagent). The developed yellow color was read at 412 nm on a spectrophotometer.</td>
<td>100 µM uranyl acetate</td>
<td>
<p>Short / easy</p>
<p>Low accurancy</p>
</td>
</tr>
<tr>
<td>
<p><strong>TBARS Assay</strong></p>
<p>Quantification of lipid peroxidation</p>
<p>(Yuan et al., 2016)</p>
</td>
<td>MDA content, a product of lipid peroxidation, was measured using a thiobarbituric acid reactive substances (TBARS) assay. Briefly, the kidney cells were collected in 1 ml PBS buffer solution (pH 7.4) and sonicated. MDA reacts with thiobarbituric acid forming a colored product which can be measured at an absorbance of 532 nm.</td>
<td>200, 400, 800 µM uranyl acetate</td>
<td>
<p>Medium / medium</p>
<p>High accurancy</p>
</td>
</tr>
<tr>
<td>
<p><strong>Aequorin-based bioluminescence assay</strong></p>
<p>Increase in mitochondrial Ca<sup>2+</sup> influx</p>
<p>(Pozzan & Rudolf, 2009)</p>
</td>
<td>Together with GFP, the aequorin moiety acts as Ca<sup>2+</sup> sensor <em>in vivo</em>, which delivers emission energy to the GFP acceptor molecule in a BRET (Bioluminescence Resonance Energy Transfer) process; the Ca2+ can then be visualized with fluorescence microscopy.</td>
<td> </td>
<td>
<p>Short / easy</p>
<p>Low accurancy</p>
</td>
</tr>
<tr>
<td>
<p><strong>Western blot & immunostaining analyses</strong></p>
<p>Measuring cytochrome c release</p>
(Chen et al., 2000)</td>
<td>Examining the redistribution of Cyto c in cytosolic and mitochondrial cellular fractions. Cells are homogenized and centrifuged, then prepared for immunoblots. Cellular fractions were washed in PBS and lysed in 1% NP-40 buffer. Cellular proteins were separated by SDS–PAGE, transferred onto nitrocellulose membranes, probed using immunoblot analyses with antibodies specific to cyto c (6581A for Western and 65971A for immunostaining; Pharmingen)</td>
<td> </td>
<td>
<p>Short / easy</p>
<p>Medium accurancy</p>
</td>
</tr>
<tr>
<td>
<p><strong>Quantikine Rat/Mouse Cytochrome c Immunoassay</strong></p>
<p>Measuring cytochrome c release</p>
<p>(Shaki et al., 2012)</p>
</td>
<td>Cytochrome C release was measured a monoclonal antibody specific for rat/mouse cytochrome c was precoated onto the microplate. Seventy-five microliter of conjugate (containing mono- clonal antibody specific for cytochrome c conjugated to horseradish peroxidase). After 2 h of incubation, the substrate solution (100 μl) was added to each well and incubated for 30 min. After 100 μl of the stop solution was added to each well; the optical density of each well was determined by the aforementioned microplate spectrophotometer set to 450 nm.</td>
<td> </td>
<td>
<p>Short / easy</p>
<p>Low accurancy</p>
</td>
</tr>
<tr>
<td>
<p><strong>Membrane potential and cell viability – Flow Cytometry</strong></p>
<p>Measuring cytochrome c release</p>
<p>(Kruidering et al., 1997)</p>
</td>
<td>“Dc and viability were determined by analyzing the R123 and propidium iodide fluorescence intensity with a FACScan flow cytometer (Becton Dickinson, San Jose, CA) equipped with an argon laser, with the Lysis software program (Becton Dickinson). R123 is a cationic dye that accumulates in the negatively charged inner side of the mitochondria. When the potential drops, less R123 accumulates in the mitochondria, which results in a lower fluorescence signal. The potential was measured as follows: at the indicated times, a 500-ml sample of the cell suspension was taken and transferred to an Eppendorf minivial. To this sample, 100 ml of 6 mM R123 in buffer D was added. After incubation for 10 min at 37°C, the cell suspension was centrifuged for 5 min at 80 3 <em>g</em>. The cell pellet was resuspended in 200 ml of buffer D, containing 0.2 mM R123 and 10 mM propidium iodide, to prevent loss of R123 and to stain nonviable cells, respectively. The samples were transferred to FACScan tubes and analyzed immediately. Analysis was performed at a flow rate of<br />
60 ml/min. R123 fluorescence was detected by the FL1 detector with an emission detection limit below 560 nm. Propidium iodide fluorescence was detected by the FL3 detector, with emission detection above 620 nm. Per sample 3,000 to 5,000 cells were counted (Van de Water <em>et al.</em>, 1993)”</td>
<td> </td>
<td>
<p>Short / easy</p>
<p>Medium accurancy</p>
</td>
</tr>
</tbody>
</table>
<p>Mitochondrial dysfunction is a universal event occurring in cells of any species (Farooqui and Farooqui, 2012). Many invertebrate species (drosophila, C, elegans) are considered as potential models to study mitochondrial function. New data on marine invertebrates, such as molluscs and crustaceans and non-Drosophila species, are emerging (Martinez-Cruz et al., 2012). Mitochondrial dysfunction can be measured in animal models used for toxicity testing (Winklhofer and Haass, 2010; Waerzeggers et al., 2010) as well as in humans (Winklhofer and Haass, 2010).</p>
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2016-11-29T18:41:232024-03-14T11:12:186c2687a8-da7f-46de-9750-3a8a9e81014d8f1e2dda-61fc-47c6-8168-1007b659d41a2023-01-09T11:48:212023-01-09T11:48:218f1e2dda-61fc-47c6-8168-1007b659d41ae7673f06-8b12-4ed8-bbaf-946990326e7e2024-02-17T13:18:352024-02-17T13:18:35AOPs of amorphous silica nanoparticles: ROS-mediated oxidative stress increased respiratory dysfunction and diseases.AOPs of SiNPs: ROS-mediated oxidative stress increased respiratory toxicity.<ul>
<li>Hailin Xu</li>
</ul>
Under development: Not open for comment. Do not citeadjacentHighHighadjacentHighHighNot SpecifiedAdultsNot Specified2023-01-09T11:14:582024-02-17T13:19:36