7440-61-1JFALSRSLKYAFGM-UHFFFAOYSA-NJFALSRSLKYAFGM-UHFFFAOYSA-N
UraniumUranium, isotope of mass 238
238U Element
UN 2979 (DOT)
Uranium I
DTXSID1042522NOCAS_24374Uranium, soluble saltsDTXSID702437483-79-4JUVIOZPCNVVQFO-HBGVWJBISA-NJUVIOZPCNVVQFO-HBGVWJBISA-N
Rotenone(1)Benzopyrano(3,4-b)furo(2,3-h)(1)benzopyran-6(6a H)-one, 1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-m ethylethenyl)-, (2R-(2.alpha.,6a.alpha.,12a.alpha. ))-
[1]Benzopyrano[3,4-b]furo[2,3-h][1]benzopyran-6(6aH)-one, 1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-, (2R,6aS,12aS)-
(-)-cis-Rotenone
(-)-Rotenone
(2R,6aS,12aS)-1,2,6,6a,12,12a-hexahidro-2-isopropenil-8,9-dimetoxicromeno[3,4-b]furo[2,3-h]cromen-6-ona
(2R,6aS,12aS)-1,2,6,6a,12,12a-Hexahydro-2-isopropenyl-8,9-dimethoxychromeno[3,4-b]furo[2,3-h]chromen-6-on
(2R,6AS,12aS)-1,2,6,6a,12,12a-hexahydro-2-isopropenyl-8,9-dimethoxychromeno[3,4-b]furo[2,3-h]chromen-6-one
(2R,6aS,12aS)-1,2,6,6a,12,12a-hexahydro-2-isopropenyl-8,9-dimethoxychromeno[3,4-b]furo[2,3-h]chromene-6-one
(2R,6AS,12aS)-1,2,6,6a,12,12a-Hexahydro-2-isopropenyl-8,9-dimethoxychromenol[3,4b]furo[2,3-h]chromen-6-one
[1]Benzopyrano[3,4-b]furo[2,3-h][1]benzopyran-6(6aH)-one, 1,2,12,12a-tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-, [2R-(2α,6aα,12aα)]-
[1]Benzopyrano[3,4-b]furo[2,3-h][1]benzopyran-6(6aαH)-one, 1,2,12,12aα-tetrahydro-2α-isopropenyl-8,9-dimethoxy-
5'β-Rotenone
Cube-Pulver
Dactinol
Dri-kil
Liquid Derris
Nicouline
Noxfish
NSC 26258
NSC 8505
Paraderil
ROTENON
Rotenox
Rotocide
Tubatoxin
DTXSID60212487440-43-9BDOSMKKIYDKNTQ-UHFFFAOYSA-NBDOSMKKIYDKNTQ-UHFFFAOYSA-N
CadmiumCadimium
CADMIUM BLUE
CADMIUM, IN PLATTEN, STANGEN, BROCKEN,KOERNER
DTXSID10239407440-22-4BQCADISMDOOEFD-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
DTXSID40243057439-92-1WABPQHHGFIMREM-UHFFFAOYSA-NWABPQHHGFIMREM-UHFFFAOYSA-N
LeadPb
Blei in massiver form(nicht pulver)
Blei(pulver)
C.I. Pigment Metal 4
Lead element
Lead Flake
LEAD INGOT
Lead metal
Plomb(poudre)
Plumbum
Rough lead bullion
DTXSID20241617440-38-2RQNWIZPPADIBDY-UHFFFAOYSA-NRQNWIZPPADIBDY-UHFFFAOYSA-N
ArsenicAs
Arsenic black
ARSENIC METAL
arsenico
Grey arsenic
UN 1558
DTXSID40238867440-47-3VYZAMTAEIAYCRO-UHFFFAOYSA-NVYZAMTAEIAYCRO-UHFFFAOYSA-N
ChromiumAlpaste RRA 030
Alpaste RRA 050
Chromium element
Chromium metal
DTXSID303102215663-27-1DQLATGHUWYMOKM-UHFFFAOYSA-LDQLATGHUWYMOKM-UHFFFAOYSA-L
CisplatinCis
Platinum, diamminedichloro-, (SP-4-2)-
Abiplatin
Biocisplatinum
Briplatin
cis-DDP
cis-Diaminedichloroplatinum
cis-Diaminedichloroplatinum(II)
cis-Diaminodichloroplatinum(II)
cis-Diamminedichloroplatinum
cis-Diamminedichloroplatinum(II)
cis-Dichlorodiamineplatinum(II)
cis-Dichlorodiammineplatinum
cis-Dichlorodiammineplatinum(II)
Cismaplat
cis-Platin
cisplatine
cis-Platine
cisplatino
cis-Platinous diaminodichloride
Cisplatinum
cis-Platinum
cis-Platinum diaminodichloride
cis-Platinum II
cis-Platinum(II) diaminodichloride
cis-Platinum(II) diamminedichloride
cis-Platinumdiamine dichloride
cis-Platinumdiammine dichloride
Cisplatyl
Citoplatino
Lederplatin
lipoplatin
Neoplatin
NSC 119875
Platamine
Platiblastin
Platidiam
Platinex
Platinol
Platinol AQ
Platinoxan
Platinum, diamminedichloro-, cis-
Platistin
Platosin
SPI 077B103
cis-Dichlorodiamine platinum
cis-Dichloro diaminoplatinum II
DTXSID40249837439-96-5PWHULOQIROXLJO-UHFFFAOYSA-NPWHULOQIROXLJO-UHFFFAOYSA-N
ManganeseColloidal manganese
Cutaval
Manganese element
Manganese fulleride
Manganese metal alloy
Manganese-55
manganeso
DTXSID20241697440-57-5PCHJSUWPFVWCPO-UHFFFAOYSA-NPCHJSUWPFVWCPO-UHFFFAOYSA-N
GoldAGC Micro
Britecote
Burnish Gold
C.I. Pigment Metal 3
Colloidal gold
Finesphere Gold W 011
Furuuchi 8560
Gold black
Gold element
Gold Flake
Gold Leaf
Keradec
Palegold 5550
Perfect Gold
Shell Gold
Technic 504
DTXSID30646977439-97-6QSHDDOUJBYECFT-UHFFFAOYSA-NQSHDDOUJBYECFT-UHFFFAOYSA-N
MercuryLiquid silver
Mercure
MERCURIC METAL TRIPLE DISTILLED
mercurio
Mercury element
Quecksilber
Quicksilver
UN 2024
UN 2809
DTXSID10241727440-66-6HCHKCACWOHOZIP-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
DTXSID70350127429-90-5XAGFODPZIPBFFR-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
DTXSID3040273PR:000001753transcription factor NF-kappa-B subunitUBERON:0002113kidneyGO:0007249I-kappaB kinase/NF-kappaB signalingMP:0003674oxidative stressMP:0004154renal tubular necrosisQ000633toxicityMP:0003606kidney failure2decreased1increased3occurrenceUranium2021-08-05T14:28:502021-08-05T14:28:50Uranium, soluble salts2022-04-08T08:55:282022-04-08T08:55:28Rotenone2016-11-29T18:42:232016-11-29T18:42:23Cadmium2017-10-25T08:33:122017-10-25T08:33:12Silver 2022-02-03T11:20:112022-02-03T11:20:11Gold nanoparticles2022-02-03T11:20:312022-02-03T11:20:31Lead2016-11-29T18:42:262016-11-29T18:42:26Arsenic2021-04-27T00:15:212021-04-27T00:15:21Chromium2022-02-03T11:22:012022-02-03T11:22:01Other heavy metals2022-02-03T11:30:272022-02-03T11:30:27Cisplatin2022-02-03T11:34:572022-02-03T11:34:57Nanoparticles and Micrometer Particles2022-02-04T13:43:432022-02-04T13:43:43IL-1 receptor antagonist(IL-1Ra)(Anakinra)2019-06-01T00:37:572019-06-01T00:37:57anti-IL-1b antibody (Canakinumab)2019-06-01T00:38:212019-06-01T00:38:21soluble IL-1R (Rilonacept)2019-06-01T00:38:522019-06-01T00:38:52Manganese2022-02-04T14:47:232022-02-04T14:47:23Gold2022-02-07T15:25:562022-02-07T15:25:56Mercury2016-11-29T18:42:192016-11-29T18:42:19Zinc2022-02-04T15:05:002022-02-04T15:05:00Aluminum2022-02-04T14:42:112022-02-04T14:42:119606Homo sapiens10090Mus musculus10116Rattus norvegicusWikiUser_15Sprague-DawleyWCS_9606humanInhibition, Mitochondrial Electron Transport Chain ComplexesInhibition, ETC complexes of the respiratory chainMolecular<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">The electron transport chain, otherwise known as the respiratory chain, is composed of large protein complexes (CI, CII, CIII, CIV, CV) and two freely mobile electron transfer carriers, ubiquinone and cytochrome c, which are embedded in the inner membrane cristae of the mitochondria (Zhao et al., 2019). Three of these complexes (CI, CIII, CIV; NADH dehydrogenase, cytochrome c reductase, and cytochrome c oxidase, respectively) act as proton pumps and contribute to the formation of an electrochemical proton gradient across the inner mitochondrial membrane, which then drives ATP synthesis by complex V (ATP synthase) (Alberts et al., 2014). In eukaryotes, the electron transport chain is the major site of ATP production via oxidative phosphorylation. Superoxides (O<sub>2</sub><sup>‑</sup>) are generated in low quantities as by-products of oxidative phosphorylation during electron transfer. The O<sub>2</sub><sup>‑</sup> released into the inter-membrane space (IMS) by CIII can be converted into H<sub>2</sub>O<sub>2</sub> in a reaction catalyzed by superoxide dismutase 1 and H<sub>2</sub>O<sub>2</sub> then may diffuse into the cytoplasm (Zhao et al., 2019). Superoxides behave as signalling molecules important in cell proliferation, hypoxia adaption, and cell fate determination but when present in excess or unregulated, induce cell damage and death.</span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">While it is well known that heavy metals target the mitochondria, the exact mechanism of this targeting and inhibition is poorly understood (Belyaeva et al., 2012; Gobe & Crane, 2010). Respiratory complexes CI and CIII are shown to be particularly susceptible to perturbation by heavy metals such as chromium and cadmium (Adiele et al., 2012; Santos et al., 2007). In addition, Uranyl Acetate (UA) induced nephrotoxicity has been linked to the impairment of CII and CIII leading to inhibition of<strong> </strong>the mitochondrial electron transport chain (Shaki et al., 2012; Shaki & Pourahmad, 2013). </span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Several studies have been conducted in order to understand the exact mechanisms of inhibition by heavy metals. They show that these divalent cations bind to electron transport chain enzyme complexes and modify them, disturbing electron transfer and redox reactions (Blajszczak & Bonini, 2017). For example, rotenone blocks Complex I (Li et al., 2003) and cadmium has the capability to noncompetitively inhibit CIII (Wang et al., 2004). This blocking and inhibition interrupts the transport of electrons through the respiratory chain, specifically resulting in the increase of semiubiquinone formation and subsequently the generation of mitochondrial superoxides (Li et al., 2003). Shaki et al. (2012) have shown, as well, that uranyl acetate (UA) interferes with CII and CIII activity. Function of the electron transport chain can also be suppressed by indirect effects of heavy metals: cisplatin causes oxidative damage of mitochondrial membrane lipids such as cardiolipin, impacting mitochondrial membrane potential (MMP). This lipid is responsible for maintaining the inner mitochondrial membrane structure and linking CIII and CIV in a super complex through which protons and electrons move, producing ATP (Santos et al., 2007). Cardiolipin function is therefore vital and its disruption results in inhibition of mitochondrial integrity and function. </span></span></p>
<div><span style="font-family:"Times New Roman",serif; font-size:12pt">The inhibition of the electron transport chain initiates a sequence of events in the mitochondria, including: overproduction of reactive oxygen species (ROS); a reduced ability for oxidative phosphorylation and therefore decreased ATP synthesis; a lowered ATP/ADP ratio; the release of cytochrome c from the mitochondrial cristae; and the collapse of mitochondrial membrane potential (MMP) (Shaki et al., 2012; Adiele et al., 2012). All of these occurrences contribute to overall mitochondrial dysfunction and more adverse outcomes.</span></div>
<table border="1" cellpadding="1" cellspacing="1" style="width:500px">
<tbody>
<tr>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Assay Type & Measured Content</span></span></strong></td>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Description</span></span></strong></td>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Dose Range Studied</span></span></strong></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Assay Characteristics</strong></span></span></p>
<strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Length / Ease of use/Accuracy)</span></span></strong></td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>MTT assay</strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring enzymatic activity of the electron transport system</span></span></p>
<p><span style="font-family:"Times New Roman",serif; font-size:12pt">(Thiebault et al., 2007; Shaki et al., 2012)</span></p>
</td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">CII and CIII, transmembrane electrical potential change was measured.</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">The metabolic activity of mitochondrial complex II was assayed by measuring the reduction of MTT to a blue formazan compound. Mitochondrial suspensions were incubated with different concentrations of uranyl acetate prior to addition of MTT. The product of formazan crystals were dissolved in DMSO and the absorbance at 570nm was measured with an ELISA reader.</span></span></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">50, 100 and 500 μM of uranyl acetate;</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">0-1000µM U</span></span></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Long </span></span></p>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Easy/Difficult</span></span></p>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">High accuracy (mathematical measurement)</span></span></p>
<p> </p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Medium Precision</span></span></td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Cell Respiration Assay</strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring cellular oxygen consumption and uptake</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Belyaeva et al., 2012)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Cell respiration is determined polarographically with the help of a Clark oxygen electrode in a thermostatic water-jacketed vessel with magnetic stirring at 37°C. PC12 cells (10<sup>7</sup> cells) were incubated in 10 mL of the complete DMEM medium (with serum) in Petri dishes for different lengths of time with various concentrations of the corresponding heavy metal, then collected by centrifugation and transferred to the DMEM medium without serum.</span></span></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">10, 50, 100, or 500 <em>μ</em>M</span></span></p>
</td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Long</span></span></p>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Difficult</span></span></p>
<p> </p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Medium accuracy (estimated spectrophotometrically)</span></span></td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Luciferin-luciferase assay (ATP determination)</strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring ATP content of the cell</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Li et al., 2003)</span></span></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">For ATP measurement, a commercially available</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">luciferin-luciferase assay kit was used. Briefly, HL-60 cells were treated with various concentrations of rotenone for 24 h and then collected. After a single wash with ice-cold PBS, cells were lysed with the somatic cell ATP-releasing reagent provided by the kit. Luciferin substrate and luciferase enzyme were</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">added and bioluminescence was assessed on a spectroflurometer. Whole-cell ATP content was determined by running an internal standard. </span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">0-1000nM of rotenone</span></span></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Short</span></span></p>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Easy</span></span></p>
<p> </p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">High accuracy and precision</span></span></td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Cytochrome c binding domain determination</strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring identification of the inhibitory site of Cd in CIII</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Wang et al., 2004)</span></span></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Cytochrome c binding domain determination was</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">performed in 2 ml of an assay mixture containing 30</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">mM phosphate, 100 mM KCl, 2 mM KCN, and</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">0.1% DM, pH 7.0. The final concentration of the</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">electron donor DBH2 ranged from 20 to 400 µM.</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">The final concentration of the mitochondrial protein was 13.7 mg/ml. The reaction was started with addition of cytochrome c. DBH2 binding determination was done in the same reaction system as described above. The final concentration of DBH2 was 20 µM. The reaction was started with</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">addition of DBH2.</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">5-40µM Cytochrome c</span></span></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Short</span></span></p>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Easy</span></span></p>
<p> </p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">High accuracy and precision</span></span></td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Enzyme Activity Determination</strong></span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Kruiderig et al., 1997)</span></span></td>
<td><span style="font-size:11.0pt"><span style="font-family:"Times New Roman",serif">“</span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">Enzymatic activities of the complexes I to IV were determined by</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">dual wavelength spectrophotometry with an Aminco Dual Wavelength 2 ATM UV-VIS spectrophotometer (Silver Spring, MD). All</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">concentrations below are final concentrations.</span></span></span><br />
<span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">Complex I (NADH:ubiquinone oxidoreductase) activity was determined at 340 nm with 380 nm as reference wavelength, with a slit</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">width of 3.0 nm according to Estornell </span></span></span><span style="font-family:NewCenturySchlbk-Italic,serif"><span style="color:black"><em><span style="font-size:11.0pt">et al. </span></em></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">(1993). The assay was</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">performed with 10 to 30 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">g protein in a final volume of 1 ml of buffer,</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">pH 7.4, containing 10 mM Tris-HCl, 50 mM KCl, 1 mM EDTA and 2</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">mM KCN. After addition of 75 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">l of 1 mM NADH and stabilization of</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">the signal, the reaction was started by addition of 100 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">l of 1 mM</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">ubiquinone-10. The activity was calculated from the rate of decrease</span></span></span><br />
<span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">of NADH (e </span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">5 </span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">5.5 mM</span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">2</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">1 cm</span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">2</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">1) per </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">g protein.</span></span></span><br />
<span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">Complex II (succinate dehydrogenase) activity was determined by</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">the difference in absorbency between 270 and 330 nm according to</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">Estornell </span></span></span><span style="font-family:NewCenturySchlbk-Italic,serif"><span style="color:black"><em><span style="font-size:11.0pt">et al. </span></em></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">(1993). The assay was performed with 10 to 30 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">g</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">protein in a final volume of 1 ml of 50 mM potassium phosphate</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">buffer, pH 7.4, containing 100 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">M EDTA, 1 mM KCN and 0.1% (w/v)</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">BSA. After addition of 80 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">l of 1 mM ubiquinone-0 and stabilization</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">of the signal, the reaction was started by addition of 100 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">l of 0.1 M</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">sodium succinate. The activity was calculated from the rate of decrease in ubiquinone (e </span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">5 </span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">9.6 mM</span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">2</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">1 cm</span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">2</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">1).</span></span></span><br />
<span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">Complex III (Ubiquinol-cytochrome c reductase) activity was determined by the difference in absorbency between 550 and 580 nm</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">according to Birch-Machin </span></span></span><span style="font-family:NewCenturySchlbk-Italic,serif"><span style="color:black"><em><span style="font-size:11.0pt">et al. </span></em></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">(1993b). The assay was performed</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">with 10 to 30 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">g protein in a final volume of 1 ml of 25 mM potassium</span></span></span><br />
<span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">phosphate buffer, pH 7.2, containing 5 mM MgCl2, 2 mM KCN, 2.5</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">mg/ml BSA, 2 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">g/ml rotenone and 0.5 mM N-D-maltoside. After</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">addition of 10 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">l of 3.5 mM ubiquinol and stabilization of the signal,</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">the reaction was started by the addition of 10 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">l of 1.5 mM cytochrome cIII. The activity was calculated from the rate of reduction of</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">cytochrome cIII (e </span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">5 </span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">19 mM</span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">2</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">1 cm</span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">2</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">1).</span></span></span><br />
<span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">Complex IV (cytochrome c oxidase) activity was determined by the</span></span></span> <span style="font-family:HelveticaNeue-Bold,serif"><span style="color:black"><strong><span style="font-size:11.0pt">640 Kruidering et al. </span></strong></span></span><span style="font-family:HelveticaNeue-Italic,serif"><span style="color:black"><em><span style="font-size:11.0pt">Vol. 280</span></em></span></span><br />
<span style="font-family:Times-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">Downloaded from jpet.aspetjournals.org at ASPET Journals on June 28, 2019</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">difference in absorbency between 550 and 580 nm according to BirchMachin </span></span></span><span style="font-family:NewCenturySchlbk-Italic,serif"><span style="color:black"><em><span style="font-size:11.0pt">et al. </span></em></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">(1993a). The assay was performed with 10 to 30 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">g</span></span></span><br />
<span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">protein in a final volume of 1 ml of 25 mM potassium phosphate</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">buffer, pH 7.0, containing 0.5 mM N-D-maltoside. After addition of 10</span></span></span> <span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">l of 1.5 mM cytochrome cII and stabilization of the signal, the</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">reaction was started by the addition of 10 to 30 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-size:11.0pt">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">g cells. The activity</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">was calculated from the rate of increase in absorbency caused by</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">oxidation of cytochrome cII to cytochrome cIII (e </span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">5 </span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">19 mM</span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">2</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">1 cm</span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-size:11.0pt">2</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">1).</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">All activities were expressed per microgram of protein, which was</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">determined according to Lowry </span></span></span><span style="font-family:NewCenturySchlbk-Italic,serif"><span style="color:black"><em><span style="font-size:11.0pt">et al. </span></em></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-size:11.0pt">(1951)”</span></span></span></td>
<td> </td>
<td> </td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">The inhibition of mitochondrial electron transport chain can occur in any eukaryotic cell.</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Adiele, R. C., Stevens, D., & Kamunde, C. (2012). Differential inhibition of electron transport chain enzyme complexes by cadmium and calcium in isolated rainbow trout (oncorhynchus mykiss) hepatic mitochondria.<em> Toxicological Sciences, 127</em>(1), 110-119. doi:10.1093/toxsci/kfs091</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2014). <em>Molecular biology of the cell</em>. New York: Garland Science. Retrieved from </span><a href="https://www.ncbi.nlm.nih.gov/books/NBK21054/" style="color:blue; text-decoration:underline" target="_blank">https://www.ncbi.nlm.nih.gov/books/NBK21054/</a></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Belyaeva, E. A., Sokolova, T. V., Emelyanova, L. V., & Zakharova, I. O. (2012). Mitochondrial electron transport chain in heavy metal-induced neurotoxicity : Effects of cadmium , mercury , and copper.<em> Thescientificworld, 2012</em>, 1-14. doi:10.1100/2012/136063</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Blajszczak, C., & Bonini, M. G. (2017). Mitochondria targeting by environmental stressors : Implications for redox cellular signaling.<em> Toxicology, 391</em>, 84-89. doi:10.1016/j.tox.2017.07.013</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Gobe, G., & Crane, D. (2010). Mitochondria, reactive oxygen species and cadmium toxicity in the kidney.<em> Toxicology Letters, 198</em>(1), 49-55. doi:</span><a href="https://doi.org/10.1016/j.toxlet.2010.04.013" style="color:blue; text-decoration:underline" target="_blank">https://doi.org/10.1016/j.toxlet.2010.04.013</a></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Li, N., Ragheb, K., Lawler, G., Sturgis, J., Rajwa, B., Melendez, J. A., & Robinson, J. P. (2003). Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production.<em> The Journal of Biological Chemistry, 278</em>(10), 8516-8525. doi:M210432200 [pii]</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Ma, L., Liu, J., Dong, J., Xiao, Q., Zhao, J., & Jiang, F. (2017). Toxicity of Pb2+ on rat liver mitochondria induced by oxidative stress and mitochondrial permeability transition.<em> Toxicol.Res., 6</em>, 822. doi:10.1039/c7tx00204a</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Prakash, C., Soni, M., & Kumar, V. (2015). Biochemical and molecular alterations following arsenic-induced oxidative stress and mitochondrial dysfunction in rat brain.<em> </em></span><em><span style="color:black">Biol.Trace Elem.Res., 167</span></em><span style="color:black">, 121-129. doi:10.1007/s12011-015-0284-9</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Santos, N. A. G., Catão, C. S., Martins, N. M., Curti, C., Bianchi, M. L. P., & Santos, A. C. (2007). </span><span style="color:black">Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria.<em> Archives of Toxicology, 81</em>(7), 495-504. doi:10.1007/s00204-006-0173-2</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Shaki, F., Hosseini, M. J., Ghazi-Khansari, M., & Pourahmad, J. (2012). Toxicity of depleted uranium on isolated rat kidney mitochondria.<em> Biochimica Et Biophysica Acta - General Subjects, 1820</em>(12), 1940-1950. doi:10.1016/j.bbagen.2012.08.015</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Shaki, F., Hosseini, M., Ghazi-Khansari, M., & Pourahmad, J. (2013). Depleted uranium induces disruption of energy homeostasis and oxidative stress in isolated rat brain mitochondria.<em> Metallomics, 5</em>(6), 736-744. doi:10.1039/c3mt00019b</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Thiébault, C., Carrière, M., Milgram, S., Simon, A., Avoscan, L., & Gouget, B. (2007). Uranium induces apoptosis and is genotoxic to normal rat kidney (NRK-52E) proximal cells.<em> Toxicological Sciences : An Official Journal of the Society of Toxicology, 98</em>(2), 479-487. doi:kfm130 [pii]</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Wang, Y., Fang, J., Leonard, S. S., & Krishna Rao, K. M. (2004). Cadmium inhibits the electron transfer chain and induces reactive oxygen species.<em> Free Radical Biology and Medicine, 36</em>(11), 1434-1443. doi:10.1016/j.freeradbiomed.2004.03.010</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Yu, L., Li, W., Chu, J., Chen, C., Li, X., Tang, W., . . . </span><span style="color:black">Xiong, Z. (2021). Uranium inhibits mammalian mitochondrial cytochrome c oxidase and ATP synthase.<em> </em></span><em><span style="color:black">Environmental Pollution, 271</span></em><span style="color:black">, 116377. doi:</span>10.1016/j.envpol.2020.116377</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Zhao, R., Jiang, S., Zhang, L., & Yu, Z. (2019). </span><span style="color:black">Mitochondrial electron transport chain, ROS generation and uncoupling (review).<em> International Journal of Molecular Medicine, 44</em>(1), 3-15. doi:10.3892/ijmm.2019.4188</span></span></span></p>
2016-11-29T18:41:222023-03-22T11:04:58Increase, Mitochondrial DysfunctionIncrease, Mt DysfunctionCellular<p style="text-align:justify"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Mitochondria are organelles found in all eukaryotic cells, crucial to the cellular consumption of oxygen, production of energy through the generation of ATP during oxidative phosphorylation, and regulation of cell death pathways (Alberts et al., 2014). The mitochondria are responsible for reduction of oxygen into water via the action of cytochrome c oxidase and other redox enzymes which transfer single electrons to oxygen and partially reduce it. The electron transfer is coupled with H<sup>+</sup> ion transport across a membrane, producing the ion gradient that powers ATP synthesis (Alberts et al., 2014; Adiele et al., 2012).</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Under normal metabolic function, </span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">approximately 1-2% of the oxygen reduced by mitochondria converts into reactive oxygen species (ROS; such as superoxide, hydrogen peroxide, or hydroxyl radicals) at intermediate steps of the respiratory chain, as a result of electron transport (Kowaltowski and Vercesi, 1998; Volka et al., 2005; Li et al., 2003). This consistent and regular production of ROS and their signalling functionality at regulated levels contrasted with their harmful effects at high concentrations, justify the presence of antioxidant systems to regulate these processes.</span></span></p>
<p style="text-align:justify"><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">Mitochondrial dysfunction, the loss of function or efficiency of oxidative phosphorylation, can be caused by a variety of factors and be apparent in a number of measurable ways. Some pathways of mitochondrial damage include: direct inhibition of mitochondrial proteins, indirect inhibition in upstream processes that affect mitochondrial metabolism, and indirect metabolic inhibition by ROS and physical damage to mitochondria.</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Dysfunction can be characterized through indicators of proton gradient loss, complex inhibition, or respiratory impairment such as mitochondrial permeability transition increase, mitochondrial membrane potential decrease, and ATP production (Shaki et al., 2013; Kruiderig et al., 1997)</span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">.</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Any mitochondrial dysfunction impairs electron transfer and ATP production, which leads to deviation of electrons from their normal pathway in the electron transport chain (ETC), and increased ROS production. This, in turn, results in oxidative stress, mitochondrial permeability transition, and deregulation of cellular</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Ca<sup>2+ </sup>homeostasis (Nicholson, 2014; Shaki et al., 2013).</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Calcium, an imperative divalent cation to mitochondrial function, can be present at unsustainable levels </span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">due to increasing Ca<sup>2+</sup> uptake, related to ROS generation and oxidative stress (reviewed Mei et al., 2013; Wang and Qin, 2010). Ca<sup>2+</sup> accumulation and oxidative stress due additional ROS can trigger the opening of mitochondrial permeability transition pore (MPTP) by perturbing the osmolarity of mitochondria, disturbing Calcium homeostasis (Orrenius et al., 2015; Roos et al., 2012). The opening of the MPTP is a Ca<sup>2+</sup>-dependent process, that along with free proton movement collapses the mitochondrial membrane potential (MPP), halting ATP synthesis (Orrenius et al., 2015). ROS produced by the mitochondria can oxidize proteins and induce lipid peroxidation, compromising the barrier properties of the mitochondrial membrane (Orrenius et al., 2015) and therefore the proton gradient and ATP production. Respiration can also be impaired through mitochondrial DNA damage and increased permeability transition of the membrane as the mitochondrial inner membrane loses its impermeability to ions and other small molecules (up to a molecular weight of approximately 2kDa), this is loss of MPP and therefore proton gradient loss (Nicotera et al., 1998). Cytochrome c release is a major indicator of mitochondrial dysfunction as a combined result of a compromised mitochondrial membrane due to lipid peroxidation and the opening of the MPTP, and is commonly seen as an endpoint to mitochondrial toxicity (Chen et al., 2000). Mitochondrial damage can also be defined by loss of protein import and biosynthesis, as well as loss of mitochondrial motility as a result of failure to re-localize to sites with increased energy demands.</span></span></span></span></p>
<h3><span style="font-family:Times New Roman,Times,serif"><span style="font-size:11pt"><span style="font-size:12.0pt">Metal-induced Mitochondrial Dysfunction</span></span></span></h3>
<p style="text-align:justify"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Mitochondria are an important site of Ca<sup>2+</sup> regulation and storage, taking up Ca<sup>2+</sup> ions electrophoretically from the cytosol through a Ca<sup>2+</sup> 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. </span></span></p>
<p style="text-align:justify"><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">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 </span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">the Fenton reaction or Haber-Weiss reaction (Hancock et al., 2001; Valko et al., 2005; Adam-Vizi et al., 2010). </span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">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</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(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).</span></span> <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">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 </span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Blajszczak and Bonini, 2017).</span></span></p>
<table border="1" cellpadding="1" cellspacing="1" style="width:500px">
<tbody>
<tr>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Assay - What is being Measured</span></span></strong></td>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Description</span></span></strong></td>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Dose Range Studied</span></span></strong></td>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Assay Length / Ease of use, accuracy</span></span></strong></td>
</tr>
<tr>
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<div>
<div><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Rhodamine 123 Assay</span></span></strong></div>
<p><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">Measuring Mitochondrial membrane potential (MMP) and its collapse </span></span></span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Shaki et al., 2012)</span></span></p>
</div>
</td>
<td>
<div><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">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. </span></span></div>
</td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">50, 100 and 500 μM of uranyl acetate</span></span></td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Short / easy</span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Medium accurancy</span></span></p>
</td>
</tr>
<tr>
<td>
<div>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">TMRE fluorescence Assay</span></span></strong></span></span></p>
<p><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">Measuring Mitochondrial permeability transition pore (MPTP) opening</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="font-family:"Times New Roman",serif">(Huser et al., 1998)</span></span></span></span></p>
</div>
</td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">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.</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">1 µM cyclosporin A</span></span></td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Short / easy</span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Low accurancy</span></span></p>
</td>
</tr>
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<td>
<div><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">GSH / GSSG Determination Assay</span></span></strong></span></span></div>
<p><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">Measuring cellular glutathione (GSH) status; ratio of GSH/GSSG</span></span></span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Owen & Butterfield, 2010; Shaki et al., 2013)</span></span></p>
</td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">GSH and GSSG levels are determinted biochemically with DTNB (Ellman’s reagent). The developed yellow color was read at 412 nm on a spectrophotometer.</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">100 µM uranyl acetate</span></span></td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Short / easy</span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Low accurancy</span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">TBARS Assay</span></span></strong></span></span></p>
<p><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">Quantification of lipid peroxidation</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="font-family:"Times New Roman",serif">(Yuan et al., 2016)</span></span></span></span></p>
</td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">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.</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">200, 400, 800 µM uranyl acetate</span></span></td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Medium / medium</span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">High accurancy</span></span></p>
</td>
</tr>
<tr>
<td>
<div><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Aequorin-based bioluminescence assay</span></span></strong></div>
<p><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">Increase in mitochondrial Ca<sup>2+</sup> influx</span></span></span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Pozzan & Rudolf, 2009)</span></span></p>
</td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">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.</span></span></td>
<td> </td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Short / easy</span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Low accurancy</span></span></p>
</td>
</tr>
<tr>
<td>
<div><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Western blot & immunostaining analyses</span></span></strong></span></span></div>
<p><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">Measuring cytochrome c release</span></span></span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Chen et al., 2000)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">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)</span></span></td>
<td> </td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Short / easy</span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Medium accurancy</span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Quantikine Rat/Mouse Cytochrome c Immunoassay</span></span></strong></span></span></p>
<p><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">Measuring cytochrome c release</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="font-family:"Times New Roman",serif">(</span></span></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Shaki et al., 2012)</span></span></p>
</td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">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.</span></span></td>
<td> </td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Short / easy</span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Low accurancy</span></span></p>
</td>
</tr>
<tr>
<td>
<div><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Membrane potential and cell viability – Flow Cytometry</span></span></strong></span></span></div>
<div><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">Measuring cytochrome c release</span></span></span></span></div>
<p><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></span></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Kruiderig et al., 1997)</span></span></p>
</td>
<td><span style="font-size:16px"><span style="font-family:"Times New Roman",serif">“</span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">D</span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">c </span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">and viability were determined by analyzing</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">the R123 and propidium iodide fluorescence intensity with a FACScan flow cytometer (Becton Dickinson, San Jose, CA) equipped with</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">an argon laser, with the Lysis software program (Becton Dickinson).</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">R123 is a cationic dye that accumulates in the negatively charged</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">inner side of the mitochondria. When the potential drops, less R123</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">accumulates in the mitochondria, which results in a lower fluorescence signal. The potential was measured as follows: at the indicated</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">times, a 500-</span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">l sample of the cell suspension was taken and transferred to an Eppendorf minivial. To this sample, 100 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">l of 6 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">M R123</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">in buffer D was added. After incubation for 10 min at 37°C, the cell</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">suspension was centrifuged for 5 min at 80 </span></span></span><span style="font-family:Universal-GreekwithMathPi,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">3 </span></span></span><span style="font-family:NewCenturySchlbk-Italic,serif"><span style="color:black"><em><span style="font-family:"Times New Roman",serif">g</span></em></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">. The cell pellet was</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">resuspended in 200 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">l of buffer D, containing 0.2 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">M R123 and 10</span></span></span> <span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">M propidium iodide, to prevent loss of R123 and to stain nonviable</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">cells, respectively. The samples were transferred to FACScan tubes</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">and analyzed immediately. Analysis was performed at a flow rate of</span></span></span><br />
<span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">60 </span></span></span><span style="font-family:MathematicalPi-One,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">m</span></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">l/min. R123 fluorescence was detected by the FL1 detector with</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">an emission detection limit below 560 nm. Propidium iodide fluorescence was detected by the FL3 detector, with emission detection</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">above 620 nm. Per sample 3,000 to 5,000 cells were counted (Van de</span></span></span> <span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">Water </span></span></span><span style="font-family:NewCenturySchlbk-Italic,serif"><span style="color:black"><em><span style="font-family:"Times New Roman",serif">et al.</span></em></span></span><span style="font-family:NewCenturySchlbk-Roman,serif"><span style="color:black"><span style="font-family:"Times New Roman",serif">, 1993)”</span></span></span></span></td>
<td> </td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Short / easy</span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Medium accurancy</span></span></p>
</td>
</tr>
</tbody>
</table>
<p> </p>
<p><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">Mitochondrial dysfunction can occur in any eukaryotic cell.</span></span></span></span></p>
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<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Zhao, R., Jiang, S., Zhang, L., & Yu, Z. (2019). Mitochondrial electron transport chain, ROS generation and uncoupling (review).<em> International Journal of Molecular Medicine, 44</em>(1), 3-15. doi:10.3892/ijmm.2019.4188</span></span></span></p>
2022-02-03T14:09:002022-02-09T11:48:18Decrease, Mitochondrial membrane potentialDecrease, MMPCellular2020-04-30T12:41:402020-04-30T12:41:40Altered gene expression, NRF2 dependent antioxidant pathwayAltered expression of NRF2 pathway-dependent genesMolecular2021-08-17T02:18:452021-08-19T07:35:29Inhibition, Nuclear factor kappa B (NF-kB)Inhibition, Nuclear factor kappa B (NF-kB)Molecular<p><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black">The NF-</span></span>κ<span style="font-size:12pt"><span style="color:black">B pathway consists of a series of events </span></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">including IRAK (IL-1 receptor-associated kinase) signaling, </span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black">where the transcription factors of the </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> family play the key role. The canonical</span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black"> NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> pathway can be activated by a range of stimuli, including TNF receptor activation by TNF-a. Upon pathway activation, the IKK complex will be phosphorylated, which in turn phosphorylates IkBa. This </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> inhibitor will be K48-linked ubiquitinated and degradated, allowing </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> to translocate to the nucleus. There, this transcription factor can express pro-inflammatory and anti-apoptotic genes. Furthermore, negative feedback genes are also transcribed and include IkBa and A20. When the </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> pathway is inhibited, its translocation will be delayed (or absent), resulting in less or no regulation of </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black"> target genes. This can be achieved by IKK inhibitors, proteasome inhibitors, nuclear translocation inhibitors or DNA-binding inhibitors (Gupta et al., 2010; Liu et al., 2017). Therefore, inhibition of IL-1R activation suppresses </span></span></span><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span></span></span><span style="font-family:Times New Roman,Times,serif"><span style="font-size:12pt"><span style="color:black">.</span></span></span></p>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック""><span style="font-family:"Times New Roman",serif"><span style="color:black">In addition to the NF-</span></span><span style="font-family:Symbol"><span style="color:black">k</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B pathway, IRAK activates a variety of transcription factors, including Interferon regulatory factor 5 (IRF5), Adaptor protein-1 (AP-1) and cAMP response element binding protein (CREB), resulting in the expression of broad array of inflammatory molecules and apoptosis-related proteins (Jain, 2014).</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010)</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κB transcription: Lentiviral NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">BGFP reporter with flow cytometry (Moujalled et al. 2012)</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">I</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">α</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black"> phosphorylation: Western blotting (Miller et al. 2010)</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:Times"><span style="color:black">NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:Times"><span style="color:black">B p65 (Total/Phospho) ELISA</span></span><span style="color:black">:</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">ELISA for IL-6, IL-8, and Cox</span></span></span></span></p>
<p><span style="font-family:Times New Roman,Times,serif">The binding of sex steroids to their respective steroid receptors directly influences NF-κB signaling, resulting in differential production of cytokines and chemokines (McKay and Cidlowski, 1999; Pernis, 2007). 17b-estradiol regulates pro-inflammatory responses that are transcriptionally mediated by NF‑κB through a negative feedback and/or transrepressive interaction with NF-κB (Straub, 2007). Progesterone suppresses innate immune responses and NF-κB signal transduction reviewed by Klein et al. (Klein and Flanagan, 2016). Androgen-receptor signaling antagonises transcriptional factors NF-κB(McKay and Cidlowski, 1999).</span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><strong><span style="font-family:"Times New Roman",serif"><span style="color:black">Evidence for perturbation of this molecular initiating event by stressor</span></span></strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B/Rel and AP-1 activation</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(Jeon et al., 2000)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Various inhibitors for NF‐κB, such as dimethyl fumarate, </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">curcumin, iguratimod, epigalocathechin gallate (</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">EGCG), and DHMEQ inhibits lLPS-induced NF-</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">κ</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">B activation and LPS-induced secretion of IL-1</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">β</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(McGuire et al., 2016; Mucke, 2012; Peng et al., 2012; Suzuki and Umezawa, 2006; Wang et al., 2020; Wang et al., 2018; Wheeler et al., 2004)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">TAK-242 </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Matsunaga et al., 2011)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black"> inhibit TLR4 itself. There are several IRAK4 inhibitors </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Lee et al., 2017). These molecules block the upstream signal to NF‐κB activation. IRAK4 has recently attracted attention as a therapeutic target for inflammation and tumor diseases (Chaudhary et al., 2015)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">LPS treatment induced a significant upregulation of the mRNA and release of IL-1β from retinal microglia. Minocycline inhibited its releases. Thus, minocycline might exert its antiinflammatory effect on microglia by inhibiting the expression and release of IL-1β </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Wang et al., 2005)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Caspase-1 inhibition reduced the release of IL-1β in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 μg) or </span></span><span style="font-family:Times"><span style="color:black">belnacasan</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black"> (intraperitoneal, 25–200 mg/kg) to rats blocked seizure-induced production of IL-1β in the hippocampus, and resulted in a twofold delay in seizure onset and 50% reduction in seizure duration </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Ravizza et al., 2006)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">B</span></span><span style="font-family:Times"><span style="color:black">elnacasan</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">, an orally active IL-1β converting enzyme/caspase-1 inhibitor, blocked IL-1β secretion with equal potency in LPS-stimulated cells from familial cold urticarial associated symdrome and control subjects </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Stack et al., 2005)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">In LPS-induced acute lung injury (ALI) mice model, LPS induced inflammatory cytokines such as TNF-α, IL-6, IL-13 and IL-1β were significantly decreased by cinnamaldehyde (CA) </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Huang and Wang, 2017)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">The suppressing capacities of six cinnamaldehyde-related compounds were evaluated and compared by using the LPS-primed and ATP-activated macrophages. At concentrations of 25~100 </span></span><span style="font-family:Symbol"><span style="color:black">m</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">M, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Ho et al., 2018)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">In vitro, CA decreased the levels of pro-IL-1β and IL-1β in cell culture supernatants, as well as the expression of NLRP3 and IL-1β mRNA in cells. In vivo, CA decreased IL-1β production in serum. Furthermore, CA suppressed LPS-induced NLRP3, p20, Pro-IL-1β, P2X7 receptor (P2X7R) and cathepsin B protein expression in lung, as well as the expression of NLRP3 and IL-1β mRNA </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Xu et al., 2017)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Dripps et al., 1991)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">. Recombinant IL-1Ra (anakinra) is fully active in blocking the IL-1R1, and therefore, the biological activities of IL-1α and IL-1β. The binding of IL-1α and IL-1β to IL-1R1 can be suppressed by soluble IL-1R like rilonacept </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Kapur and Bonk, 2009)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">. The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (canakinumab and gevokizumab)</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(Church and McDermott, 2009)</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(Roell et al., 2010)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">IL-1 is known to mediates autoinflammatory syndrome, such as cryopyrin-associated periodic syndrome, neonatal-onset multisystem inflammatory disease and familial Mediterranean fever. Blocking of binding of IL-1 to IL-1R1 by anakinra, canakinumab, and rilonacept have been already used to treat these autoinflammatory syndrome associated with overactivation of IL-1 signaling </span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">(Quartier, 2011)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">. </span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Dex inhibits IL-1</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">β</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black"> gene expression in LPS-stimulated RAW 264.7 cells by blocking NF‐κB/Rel and AP-1 activation</span></span> <span style="font-family:"Times New Roman",serif"><span style="color:black">(Jeon et al., 2000)</span></span><span style="font-family:"Times New Roman",serif"><span style="color:black">.</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"MS Pゴシック",sans-serif"><span style="font-family:"Times New Roman",serif"><span style="color:black">Inhibition of IL-1 binding to IL-1R or the decreased production of IL-1b leads to the suppression of IL-1R signaling leading to NF‐κB activation.</span></span></span></span></p>
<p><!--![endif]----><!--![endif]----></p>
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<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Quartier, P. (2011), Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome.<em> Open Access Rheumatol</em> 3: 9-18, 10.2147/oarrr.S6696</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Ravizza, T., Lucas, S.M., Balosso, S., et al. (2006), Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy.<em> Epilepsia</em> 47: 1160-1168, 10.1111/j.1528-1167.2006.00590.x</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Roell, M.K., Issafras, H., Bauer, R.J., et al. (2010), Kinetic approach to pathway attenuation using XOMA 052, a regulatory therapeutic antibody that modulates interleukin-1beta activity.<em> J Biol Chem</em> 285: 20607-20614, 10.1074/jbc.M110.115790</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Stack, J.H., Beaumont, K., Larsen, P.D., et al. (2005), IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients.<em> J Immunol</em> 175: 2630-2634, </span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Straub, R.H. (2007), The complex role of estrogens in inflammation.<em> Endocr Rev</em> 28: 521-574, 10.1210/er.2007-0001</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Suzuki, E., Umezawa, K. (2006), Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin.<em> Biomed Pharmacother</em> 60: 578-586, 10.1016/j.biopha.2006.07.089</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Wang, A.L., Yu, A.C., Lau, L.T., et al. (2005), Minocycline inhibits LPS-induced retinal microglia activation.<em> Neurochem Int</em> 47: 152-158, 10.1016/j.neuint.2005.04.018</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Wang, F., Han, Y., Xi, S., et al. (2020), Catechins reduce inflammation in lipopolysaccharide-stimulated dental pulp cells by inhibiting activation of the NF-kappaB pathway.<em> Oral Dis</em> 26: 815-821, 10.1111/odi.13290</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Wang, Y., Tang, Q., Duan, P., et al. (2018), Curcumin as a therapeutic agent for blocking NF-kappaB activation in ulcerative colitis.<em> Immunopharmacol Immunotoxicol</em> 40: 476-482, 10.1080/08923973.2018.1469145</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Wheeler, D.S., Catravas, J.D., Odoms, K., et al. (2004), Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 beta-dependent proinflammatory signal transduction in cultured respiratory epithelial cells.<em> J Nutr</em> 134: 1039-1044, 10.1093/jn/134.5.1039</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Abadi MT Condensed Extra Bold",sans-serif"><span style="font-family:"Times New Roman",serif">Xu, F., Wang, F., Wen, T., et al. (2017), Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice.<em> Immunopharmacol Immunotoxicol</em> 39: 296-304, 10.1080/08923973.2017.1355377</span></span></span></p>
<p style="margin-left:-10px"> </p>
2016-11-29T18:41:232023-03-02T01:58:01Activation of ER stressER stressCellular2020-11-02T07:09:482020-11-02T07:09:48Increased, Oxidative StressIncreased, Oxidative StressMolecularCL:0000255eukaryotic cell2016-11-29T18:41:292022-02-03T14:20:13Increase, ApoptosisIncrease, ApoptosisCellular2017-04-15T16:17:342017-04-15T16:17:34Increase in inflammationIncrease in inflammationTissue2019-05-03T14:27:002019-05-03T14:27:00Occurrence, renal proximal tubular necrosisOccurrence, renal proximal tubular necrosisTissueUBERON:0004134proximal tubule2016-11-29T18:41:292017-09-16T10:16:38Occurrence, Kidney toxicityOccurrence, Kidney toxicityOrgan<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">The kidneys are a crucial site of regulation of divalent cation levels in the plasma through filtration, reabsorption, and concentration (cite). On top of their excretion capabilities, the kidneys are also responsible for the production of hormones crucial for hematologic, cardiovascular, and skeletal muscle homeostasis (Bonventre et al., 2010). Nephrons are the functional units of the kidney and each kidney is made up of approximately 1 million nephrons (Bonventre et al., 2010). The nephrons are vital in reabsorption of these cations where 70% of transport has been shown to occur in the proximal tubule (Barbier et al., 2005). The kidneys are thought to be very susceptible to toxicity due to the increased concentration through their filtering structures with the tubular uptake mechanisms, specifically those of the proximal tubule, magnifying intracellular concentrations (Bonventre et al., 2010; Weber et al., 2017). Commonly, biomarkers like serum creatinine (sCr) and blood urea nitrogen (BUN) are utilized to identify kidney toxicity; however, these markers have been identified as nonspecific to the area of the kidney and slow in identification. Bonventre et al. (2010) has explored other biomarkers that may be used to identify segment specific injury. Proximal tubule injury can be identified using: albumin, RPB, NAG, clusterin, osteopontin, a1-microglobulin, and many others. Glomerulus damage can be identified through urinary Cystatin C, b2-microglobulin, a1-microglobulin, albumin, and more (Bonventre et al., 2010). These biomarkers do show some overlap between regions and can indicate damage to various areas of the nephron, though it is important to note the development of these specific techniques and therefore, the ability to develop more tailored and earlier identifying testing procedures. </span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Since there are many essential metals for cellular function, there are also many transporters responsible for facilitating ionic entry into the cell and the designated cellular compartment (cite). Some of these transporters are very specific to a given metal and some are more diverse in the metals they handle, therefore, these transporters can facilitate the transport of toxic metals into the cell, often through mimickery exhibited by those metals (Ballatori, 2002). DMT1 (divalent metal transporter 1) is a strong example of such transporters. The introduction of toxic divalent cations (Cd<sup>2+</sup>, Pb<sup>2+</sup>, Pt<sup>2+</sup>, etc.) is highly problematic in the kidneys due to increased toxicity and occupancy of DMT1 limiting the transport of essential trace elements. DMT1 is an essential transport molecule that is highly expressed in the kidneys, and is responsible for transport of essential trace divalent cations, as well as highly toxic ones; this competition increases strain on the kidneys exposed to toxic heavy metals (Barbier et al., 2005; Ballatori, 2002). DMT1 has been shown to transport Fe, Zn, Mn, Co, Cd, Cu, Ni, and Pb via a proton-coupled, membrane potential dependant mechanism (Ballatori, 2002). Some toxic metals can also enter a cell by forming complexes that mimic endogenous molecules in their structure. Arsenate and vanadate, for example, act as phosphate mimics both for transport and metabolism, assaulting cellular function by the same mechanism as their initial entry; cromate, selenite and molybdate mimic sulfate in a similar way (Ballatori, 2002). Many of the identified transporters fooled by this mimicry have been localized to the brush border membrane of the renal proximal tubule and epithelial cells. Some divalent metals such as Cd, Ba, and Sr have been shown to enter cells through voltage gated calcium channels. Another important example focused on by Ballatori (2002) is the action of inorganic mercury and methyl mercury (MeHg) that were shown to have high affinity for reduced sulfhydryl groups. These groups are seen on the amino acid cysteine, and importantly on glutathione (GSH), a vital enzymatic antioxidant. MeHg mimics methionine to enter the cell, after which it binds to GSH, and interferes with ATP production (Ballatori, 2002). Uranium has been shown to enter the blood rapidly and then either form stable complexes with plasma proteins, due to its high affinity for phosphate, carboxyl and hydroxyl groups, or binds to bicarbonate in the blood (Keith et al., 2013). In the kidneys, uranium can be released from bicarbonate to combine with other small proteins in the kidney tubular walls, disrupting cellular function (Keith et al., 2013). Uranium has been seen to enter the glomerulus, where it is filtered, via endocytosis as UO<sup>+2</sup> binding to anionic sites of proximal tubular epithelial brush borders (Shaki et al., 2012). </span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">To further understand the mode of action of heavy metals within the kidneys, many studies have been conducted to determine the specific region primarily damaged. It is also important to note that variation of results may be found in some studies as experimental conditions as well as other factors may influence the mode of action of some metals. Zamora et al. (1998) found that kidney function decrease and cytotoxicity increase were correlated with uranium ingestion. However, no glomerular injury was detected, indicating that chronic uranium ingestion in rats (0.004 <span style="font-size:11.0pt">µ</span>g/kg to 9 <span style="font-size:11.0pt">µ</span>g/kg body weight) damages the proximal tubule and not the glomerulus (Zamora et al., 1998). Homma-Takeda et al. (2013) identifies the kidneys as the major site of depleted uranium toxicity. Studying the kidneys of rats of varying ages, exposed to 0.1-2mg/kg uranyl acetate, they found that the younger kidneys did not flush the uranium out as well. Accumulation of uranium and its damages was seen in the S3 segment of the proximal tubules (Homma-Takeda et al., 2013). Shaki et al. (2012), assessed the mechanism of depleted uranium-induced nephrotoxicity that revealed damage to the mitochondria isolated from uranyl acetate treated rat kidney cells. The damage included oxidative stress, mitochondrial swelling, mitochondrial membrane potential collapse, cytochrome C release, impaired ATP production, and damage to the electron transport chain complexes. Utilizing rat renal brush border vesicles, Goldman et al. (2006) found that exposure to uranyl acetate induced decreased rates of glucose transport, in part due to a decreased number of sodium-coupled glucose transporters; this decreased the ability of the kidneys to reabsorb glucose properly. Berradi et al. (2008) assessed the red blood cell (RBC) count of rats drinking water containing 40mg DU/L and found that chronic exposure to DU causes RBC reduction, pointing to nephrotoxicity as the kidneys play a major role in RBC synthesis. Heavy metals consistently aggregate in the kidneys, and more specifically in the S3 segment of the proximal tubules. Evidence also suggests <span style="color:black">that uranium and other heavy metals induce nephrotoxicity after endocytosis into cells by disrupting the electron transport chain, inducing oxidative stress. The oxidative stress leads to mitochondrial dysfunction followed by, apoptosis at low doses of uranium and necrosis at high doses of uranium. Finally, this induces renal injury and tissue damage to the proximal tubules, or nephrotoxicity.</span></span></span></p>
<table border="1" cellpadding="1" cellspacing="1" style="width:500px">
<tbody>
<tr>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Assay Type & Measured Content</span></span></strong></td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman""><strong>Description</strong></span></span></p>
</td>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Dose Range Studied</span></span></strong></td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman""><strong>Assay Characteristics</strong></span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman""><strong>(Length/Ease of use/Accuracy)</strong></span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Kidney Function Assay</strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring total urinary protein, albumin, transferrin, b2-microglobulin, retinolbinding protein, brush border tubular antigens, N-acetyl-b-Dglucosaminidase activity, serum and urinary creatine</span></span></p>
<p><span style="font-family:"Times New Roman",serif; font-size:12pt">(de Burbure et al., 2003)</span></p>
</td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">“All analyses of a given parameter were performed under similar experimental conditions in the same laboratories within 6mo of collection. Total urinary protein (Prot-T-U) was determined by the Coomassie blue G250 binding method. Albumin (Alb-U), transferrin (Transf-U), β2-microglobulin (β2m-U), and retinolbinding protein (RBP-U) in urine were quantified by latex immunoassay (Bernard & Lauwerys, 1983). Acceptable limits for precision and accuracy of measurements and external quality controls were the same as those described in the Cadmibel study (Lauwerys et al., 1990). The brush border tubular antigens (BBA-U) were analyzed by a sandwich enzyme-linked immunoassay using monoclonal antibodies (Mutti et al., 1985). The total activity of N-acetyl-β-Dglucosaminidase (NAG-T-U) in urine was determined colorimetrically using a kit (PPR Diagnostics Ltd.) as described elsewhere (Price et al., 1996). Only total NAG (NAG-T) was used for the purpose of this study. Serum and urinary creatinine (Creat-U) were measured by the methods of Heinegard and Tiderström (1973), and Jaffé, respectively (Henry, 1965).” (de Burbure et al., 2003)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">“The soil contamination in the area varied from 100 to 1700ppm lead (with values higher than 1000ppm in the immediate vicinity of the factories), 0.7 to 233ppm cadmium, and 101 to 22,257ppm zinc, with the highest concentrations being recorded within 500 m of the 2 factories”</span></span></td>
<td> </td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>NAG Assay</strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring N-acetyl-b-D-Glucosaminidase urinary content</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Lim et al., 2016)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">“Urinary NAG activity was measured by using NAG Quantitative Kit (Shionogi, Osaka, Japan). After storing a synthetic substrate solution (1 mL) at 37°C for five minutes, the solution was mixed with the supernatant of the urine samples (50 mL) received after centrifugation. After storing it at 37°C for 15 min, stopping solution (2 mL) was added to and mixed with it. By using a spectrophotometer, its fluorescence intensities were measured with a wavelength of 580 nm (</span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057" style="color:#0563c1; text-decoration:underline">13</a></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057" style="color:#0563c1; text-decoration:underline">14</a>). Urinary β2-MG was measured by using Enzygnost β2-MG Micro Kit (Behring Institute, Mannheim, Germany). Its method used the principle of solid phase enzyme-linked immunosorbent assay (ELISA). Monoclonal anti-β2-MG antibody and anti-2-MG-horseradish peroxidase conjugate solution were used. After that, color intensities were measured with a wavelength of 450 nm by using a spectrophotometer (</span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057" style="color:#0563c1; text-decoration:underline">13</a></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057" style="color:#0563c1; text-decoration:underline">14</a>).” (Lim et al., 2016)</span></span></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Pb: 0.0221ppm</strong><br />
(converted from blood Pb <span style="font-size:11.0pt">µg/dL)</span></span></span></p>
<strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Cd: 1.08ppm</span></span></strong><br />
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(converted from Urinary Cd μg/g creatinine)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Fast, easy, accurate</span></span></td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Kidney Dysfunction Assay </strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring BUN and creatinine serum blood levels</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Shaki et al., 2012)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">“For studies in vivo rats were fasted overnight, then animals were divided into two groups, with six rats in each group. The control group (vehicle) received a single intraperitoneal (i.p.) injection of saline solution (1 ml per 100 g body weight). Uranyl acetate was<br />
dissolved in normal saline. Rats were treated with single intraperitoneal (i.p.) injections of UA in doses 0.5, 1 and 2 mg/kg body weight. These dosages was selected based on previous studies [28], which is sufficient to induce oxidative stress in kidney without causing death and none died within the duration of experiments. Blood urea nitrogen (BUN) and creatinine, marker of kidney dysfunction, were determined by commercial reagents (obtained from Parsazmoon Co., Iran). The rats were killed by decapitation 24 h after injection. The kidney were immediately removed and placed in ice-cold mitochondria isolation medium (0.225 M D-mannitol, 75 mM sucrose, and 0.2 mM EDTA, pH=7.4)” (Shaki et al., 2012)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Control, 0.5, 1, 2 mg/kg Uranyl Acetate (UA) </span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Fast, easy, medium accuracy </span></span></td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Higher order animals (mammals) with functional and complete kidneys </span></span></p>
UBERON:0002113kidneyNot SpecifiedNot Specified<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Al Dera, H. S. (2016). Protective effect of resveratrol against aluminum chloride induced nephrotoxicity in rats.<em> Saudi Med J, 37</em>(4), 369-378. doi:10.15537/smj.2016.4.13611</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Andjelkovic, M., Djordjevic, A. B., Antonijevic, E., Antonijevic, B., Stanic, M., Kotur-Stevuljevic, J., . . . Bulat, Z. (2019). Toxic effect of acute cadmium and lead exposure in rat blood, liver, and kidney.<em> International Journal of Environmental Research and Public Health, 16</em>, 247. doi:10.3390/ijerph16020274</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Arzuaga , X., Rieth, S. H., Bathija, A. & Cooper, G. S. (2010) Renal Effects of Exposure to Natural and Depleted Uranium: A Review of the Epidemiologic and Experimental Data, Journal of Toxicology and Environmental Health, Part B, 13:7-8, 527-545, DOI:10.1080/10937404.2010.509015</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Ballatori, N. (2002). Transport of toxic metals by molecular mimicry.<em> Environmental Health Perspectives, 110</em>, 689-694. doi:10.1289/ehp.02110s5689</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Barnes, P., Yeboah, J. K., Gbedema, W., Saahene, R. O., & Amoani, B. (2020). Ameliorative effect of <em>vernonia amygdalina</em> plant extract on heavy metal-induced LIver and kidney dysfunction in rats.<em> Advances in Pharmacological and Pharmaceutical Sciences, 2020</em>, 1-7. doi:10.1155/2020/2976905</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Barbier, O., Jcquillet, G., Tauc, M., Cougnon, M., & Poujeol, P. (2005). Effect of heavy metals on, and handling by, the kidney. Nephron Physiology, 99, 105-110. doi:10.1159/000083981</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="background-color:white"><span style="color:#303030">Bonventre, J. V., Vaidya, V. S., Schmouder, R., Feig, P., & Dieterle, F. (2010). Next-generation biomarkers for detecting kidney toxicity. </span></span><em><span style="background-color:white"><span style="color:#303030">Nature biotechnology</span></span></em><span style="background-color:white"><span style="color:#303030">, <em>28</em>(5), 436–440. </span></span><a href="https://doi.org/10.1038/nbt0510-436" style="color:#0563c1; text-decoration:underline"><span style="background-color:white">https://doi.org/10.1038/nbt0510-436</span></a></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Brzoska, M. M., Kaminski, M., Supernak-Bobko, D., Zwierz, K., & Moniuszko-Jakoniuk, J. (2003). </span><span style="color:black">Changes in the strucutre and function of the kidney of rats chronically exposed to cadmium. I. biochemical and histopathological studies.<em> Arch.Toxicol., 77</em>, 344-352. doi:10.1007/s00204-003-0451-1</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Buelna-Chontal, M., Franco, M., Hernandez-Esquivel, L., Pavon, N., Rodriguez-Zalvala, J. S., Correa, F., . . . Chavez, E. (2017). CDP-choline circumvents mercury-induced mitochondrial damage and renal dysfunction.<em> Cell Biology International, 41</em>, 1356-1366. doi:10.1002/cbin.10871</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Chtourou, Y., Garoui, E. m., Boudawara, T., & Zeghal, N. (2014). </span><span style="color:black">Protective role of silymarin against manganese-induced nephrotoxicity and oxidative stress in rat.<em> </em></span><em><span style="color:black">Environ Toxicol, 29</span></em><span style="color:black">, 1147-1154. doi:10.1002/tox.21845</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Durante, P., Romero, F., Perez, M., Chavez, M., & Parra, G. (2010). </span><span style="color:black">Effect of uric acid on nephrotoxicity induced by mercuric chloride in rats.<em> Toxicology and Industrial Health, 26</em>(3), 163-174. doi:10.1177/0748233710362377</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">García-Niño, W. R., Tapia, E., Zazueta, C., Zatarain-Barrón, Z. L., Hernández-Pando, R., Vega-García, C. C., & Pedraza-Chaverrí, J. (2013). Curcumin pretreatment prevents potassium dichromate-induced hepatotoxicity, oxidative stress, decreased respiratory complex I activity, and membrane permeability transition pore opening.<em> Evidence-Based Complementary and Alternative Medicine, </em>(424692), 1-19. doi:10.1155/2013/424692</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Goldman, M., Yaari, A., Doshnitzki, Z., Cohen-Luria, R., & Moran, A. (2006). Nephrotoxicity of uranyl acetate: Effect on rat kidney brush border membrane vesicles.<em> Archives of Toxicology, 80</em>(7), 387-393. doi:10.1007/s00204-006-0064-6</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="background-color:white"><span style="color:#212121">Homma-Takeda S, Kokubo T, Terada Y, Suzuki K, Ueno S, Hayao T, Inoue T, Kitahara K, Blyth BJ, Nishimura M, Shimada Y. Uranium dynamics and developmental sensitivity in rat kidney. J Appl Toxicol. 2013 Jul;33(7):685-94. doi: 10.1002/jat.2870. Epub 2013 Apr 26. PMID: 23619997.</span></span></span></span></p>
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2016-11-29T18:41:272022-03-04T10:58:19Increased, Kidney FailureIncreased, Kidney FailurePopulation2016-11-29T18:41:262019-01-16T08:57:09d801851a-4c82-46aa-b9a2-6d4302f46a52a1297e59-5006-4358-94ed-59801372ccf12022-04-08T08:27:422022-04-08T08:27:42a1297e59-5006-4358-94ed-59801372ccf121610a5c-e5c0-403c-8a48-fa9ee44ba8732022-04-08T08:28:372022-04-08T08:28:3721610a5c-e5c0-403c-8a48-fa9ee44ba87367f8f354-85ee-451b-98ff-5013cdab5dfe2022-04-08T08:29:402022-04-08T08:29:4021610a5c-e5c0-403c-8a48-fa9ee44ba8735b58c760-f51b-4d78-ae09-bc1e16a9b7c52022-04-08T08:30:192022-04-08T08:30:1921610a5c-e5c0-403c-8a48-fa9ee44ba8737d3f3c79-6538-429b-9ddf-9652e53a95632022-04-08T08:31:122022-04-08T08:31:1267f8f354-85ee-451b-98ff-5013cdab5dfe5f15129d-9ecc-4b6c-b433-24806d94e0f72022-04-08T08:31:372022-04-08T08:31:3767f8f354-85ee-451b-98ff-5013cdab5dfee1139a67-9d55-471a-90c4-b5d6650469162022-04-08T08:32:132022-04-08T08:32:135f15129d-9ecc-4b6c-b433-24806d94e0f77d3f3c79-6538-429b-9ddf-9652e53a95632022-04-08T08:32:432022-04-08T08:32:435b58c760-f51b-4d78-ae09-bc1e16a9b7c55d6c9a5a-8d84-4645-a6ad-0af67a3041812022-04-08T08:32:572022-04-08T08:32:57e1139a67-9d55-471a-90c4-b5d6650469160559ca5a-c4c0-4b4c-8994-ffab30eb14552016-11-29T18:41:362016-12-03T16:38:047d3f3c79-6538-429b-9ddf-9652e53a95630559ca5a-c4c0-4b4c-8994-ffab30eb14552022-04-08T08:34:212022-04-08T08:34:215d6c9a5a-8d84-4645-a6ad-0af67a3041810559ca5a-c4c0-4b4c-8994-ffab30eb14552022-04-08T08:34:532022-04-08T08:34:530559ca5a-c4c0-4b4c-8994-ffab30eb1455d98177a9-a6d5-467b-b020-87dab3a878452022-04-08T08:35:082022-04-08T08:35:08d98177a9-a6d5-467b-b020-87dab3a878454d8b2853-785b-4e56-8cf5-a3268128ac3d2022-04-08T08:35:222022-04-08T08:35:22Kidney failure induced by inhibition of mitochondrial electron transfer chain through apoptosis, inflammation and oxidative stress pathwaysKidney failure induced by inhibition of mitochondrial ETC<p><span style="font-size:8.0pt"><span style="font-family:"Palatino Linotype",serif"><span style="color:black">Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-SANTE, SESANE, Fontenay-aux-Roses, France</span></span></span></p>
Under development: Not open for comment. Do not cite<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:9.0pt">U metal-ions are filtered through the glomerular membrane of the kidneys, then concentrate in cortical and juxtaglomerular areas and bind to the brush border membrane of the proximal convoluted tubules. U uptake by epithelial cells occurs through endocytosis and the sodium-dependent phosphate co-transporter (NaPi-IIa). Molecular key events start with U induce mitochondrial ETC inhibition (KE1), decrease MMP (KE2) and mitochondrial disruption (KE3). The collapse of mitochondrial membrane potential triggers the Nrf2 (KE3), NF-κB (KE4) or endoplasmic reticulum-stress (KE5) pathways. The resulting cellular key events include oxidative stress (KE6), apoptosis (KE7), and pro-inflammatory effects (KE8). Finally, the main adverse outcome is tubular cell necrosis (KE9), leading to kidney toxicity (KE10) and then kidney failure (AO).</span></span></span></p>
adjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedNot SpecifiedNot Specified2022-04-08T07:56:322023-04-29T13:02:20