NFE2/Nrf2 repression

7429-90-5

XAGFODPZIPBFFR-UHFFFAOYSA-N

AZDRQVAHHNSJOQ-UHFFFAOYSA-N

Aluminum

Aisin 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

DTXSID3040273

7440-43-9

BDOSMKKIYDKNTQ-UHFFFAOYSA-N

Cadmium

Cadimium CADMIUM BLUE CADMIUM, IN PLATTEN, STANGEN, BROCKEN,KOERNER

DTXSID1023940

7439-97-6

QSHDDOUJBYECFT-UHFFFAOYSA-N

Mercury

Liquid silver Mercure MERCURIC METAL TRIPLE DISTILLED mercurio Mercury element Quecksilber Quicksilver UN 2024 UN 2809

DTXSID1024172

7440-61-1

JFALSRSLKYAFGM-UHFFFAOYSA-N

Uranium

Uranium, isotope of mass 238 238U Element UN 2979 (DOT) Uranium I

DTXSID1042522

7440-38-2

RQNWIZPPADIBDY-UHFFFAOYSA-N

Arsenic

As Arsenic black ARSENIC METAL arsenico Grey arsenic UN 1558

DTXSID4023886

7440-22-4

BQCADISMDOOEFD-UHFFFAOYSA-N

Silver

Ag 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

DTXSID4024305

7439-96-5

PWHULOQIROXLJO-UHFFFAOYSA-N

Manganese

Colloidal manganese Cutaval Manganese element Manganese fulleride Manganese metal alloy Manganese-55 manganeso

DTXSID2024169

7440-02-0

PXHVJJICTQNCMI-UHFFFAOYSA-N

Nickel

Carbonyl 255 Carbonyl Ni 123 Carbonyl Ni 283 Carbonyl Nickel 123 Carbonyl Nickel 283 Carbonyl Nickel 287 Cerac N 2003 CNS 10 Micron Exmet 4 Ni X-4/0 Fibrex P Incofoam Nickel element NICKEL ROUND ANODES Nicrobraz LM:BNi 2 Ni-Flake 95 Novamet 123 Novamet 4SP Novamet 4SP10 Novamet 525 Novamet CNS 400 Novamet HCA 1 Novamet NI 255 Raney nickel Raney nickel 2800 UN 1325 UN 2881

DTXSID2020925

7440-66-6

HCHKCACWOHOZIP-UHFFFAOYSA-N

Zinc

Zn 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

DTXSID7035012

Platinum

2022-02-04T14:36:54

Aluminum

2022-02-04T14:42:11

Cadmium

2017-10-25T08:33:12

Mercury

2016-11-29T18:42:19

Uranium

2021-08-05T14:28:50

Arsenic

2021-04-27T00:15:21

Silver

2022-02-03T11:20:11

Manganese

2022-02-04T14:47:23

Nickel

2022-02-04T14:47:59

Zinc

2022-02-04T15:05:00

nanoparticles

2016-12-21T09:40:06

WCS_9606

common toxicological species human

10090

NCBI mouse

WCS_7955

common ecological species zebrafish

NFE2/Nrf2 repression

Molecular

AOPWiki 2017-06-02T16:27:39

2017-06-02T16:27:39

Increase, Oxidative Stress

Molecular

“Oxidative stress is traditionally defined as an imbalance between production of ROS and endogenous antioxidants” (Small et al., 2018). Reactive Oxygen Species (ROS), the core perpetrators of oxidative stress, are highly reactive free radical oxygen molecules (Turrens, 2003; Valko et al., 2005; Hancock et al., 2001). These free radicals are strong oxidants that in high amounts, could irreversibly damage the cell and its organelles. ROS, however, are not by default detrimental to cellular function but contribute to normal activities, under physiological conditions. Reactive oxygen species can behave as signaling molecules by oxidizing proteins, lipids, and polynucleotides (Zhao et al., 2019; Hancock et al., 2001; Gorlach et al., 2015). When present in tolerable amounts, superoxides (O2-) 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 (Zhao et al., 2019). Under normal oxidative phosphorylation, approximately 1-2% of the oxygen reduced by mitochondria converts into reactive oxygen species (ROS) at intermediate steps of the respiratory chain, during electron transfer (Kowaltowski and Vercesi, 1998; Volka et al., 2005; Li et al., 2003). On top of ROS generation occurring during natural cell metabolism, several other mitochondrial enzymes, such as cytochrome P450, are linked to ROS production and, interestingly many of these systems are modulated by calcium (Gorlach et al., 2015; Hancock et al., 2001). The main reasons that these antioxidant systems are in place are to regulate the constant, regular production of ROS and their signalling functionality. Oxidative stress is defined as a disruption of the pro-oxidant-antioxidant balance, favouring pro-oxidants, potentially damaging cellular components (Sies, 1991). It is important to note the fact that oxidative stress is generally caused by one of three reasons: either there is a significant increase in ROS; or there is a significant decrease in antioxidant function; or the two factors working in tandem. This distinction is crucial in determining methods of assessment of oxidative stress. Other than mitochondrial ROS production, one of the primary producers of superoxide (O2-) is NADPH, doing so by a single electron reduction of molecular oxygen (Panday et al., 2014). NADPH oxidase, is a cytosolic-membrane protein, implicated in host defence, cellular signalling, and gene expression regulation. It is thought to produce ROS partly for defence against microbial pathogens (Panday et al., 2014). Due to its volatile nature, once formed, O2‑ released into the inter-membrane space (IMS) by CIII inevitably generates hydrogen peroxide (H2O2), a reaction is catalyzed by superoxide dismutase (SOD) (Hancock et al., 2001). Once present, the fate of H2O2 is variable and its reduction to H2O can be catalyzed by glutathione peroxidase (GPx) or peroxisomal catalase. Otherwise, it can be further converted into highly reactive hydroxyl radicals, particularly in the presence of metal ions (Hancock et al., 2001; Valko et al., 2005; Adam-Vizi et al., 2010). Under normal mitochondrial conditions, antioxidant enzymes and molecules – such as, superoxide dismutase, glutathione peroxidase, catalase, and glutathione – balance ROS generation by scavenging or binding to ROS (Santos et al., 2007). ROS disposal involves superoxide dismutase (SOD) converting O2- to H2O2, then detoxified into H2O by glutathione and catalase (Xu & Møller, 2010). Also, in case of mitochondrial damage or dysfunction, the antioxidant defence system may be impaired and its capacity drops. The resultant imbalance of the production and removal of ROS is oxidative stress. Due to the nature of oxidative stress induction and the short half-life of ROS, measuring oxidative stress through antioxidant function is a more accurate and effective way to determine the state of the cell. Oxidative stress behaves as a positive feedback loop, leading to the over-production of free-radicals as ROS further damage the mitochondria and antioxidant capacity continues to decrease (Hancock et al., 2001; Turrens, 2003; Valko et al., 2005). Antioxidant defenses can also be inhibited, further contributing to mitochondrial dysfunction; this is commonly induced by exposure to heavy metals (Blajszczak and Bonini, 2017). Due to the formation of this positive feedback loop, we experience a gap in knowledge as to which event initiated the cycle; was the increased ROS production the cause of mitochondrial dysfunction or did the mitochondrial dysfunction lead to increased ROS production? <div>Heavy metal exposure in aerobic organisms increases ROS formation through redox cycling, where metals with different valence states (for example Fe, Cu, and Cr) 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 in the presence of transition metals occurs via the Fenton reaction or Haber-Weiss reaction (Hancock et al., 2001; Valko et al., 2005; Adam-Vizi et al., 2010). Metals 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 antioxidants in order to combat the oxidative stress (Blajszczak and Bonini, 2017).</div>

<table border="1" cellpadding="1" cellspacing="1" style="width:500px"> <tbody> <tr> <td>Assay Type & Measured Content</td> <td>Description</td> <td>Dose Range Studied</td> <td> Assay Characteristics (Length / Ease of use/Accuracy) </td> </tr> <tr> <td> ROS Formation in the Mitochondria assay Measuring (Shaki et al., 2012) </td> <td>“The mitochondrial ROS measurement was performed flow cytometry using DCFH-DA. Briefly, isolated kidney mitochondria were incubated with UA (0, 50, 100 and 200 μM) in respiration buffer containing (0.32 mM sucrose, 10 mM Tris, 20 mM Mops, 50 μM EGTA, 0.5 mM MgCl2, 0.1 mM KH2PO4 and 5 mM sodium succinate) [32]. In the interval times of 5, 30 and 60 min following the UA addition, a sample was taken and DCFH-DA was added (final concentration, 10 μM) to mitochondria and was then incubated for 10 min. Uranyl acetate-induced ROS generation in isolated kidney mitochondria were determined through the flow cytometry (Partec, Deutschland) equipped with a 488-nm argon ion laser and supplied with the Flomax software and the signals were obtained using a 530-nm bandpass filter (FL-1 channel). Each determination is based on the mean fluorescence intensity of 15,000 counts.” (Shaki et al., 2012)</td> <td>0, 50, 100 and 200 μM of Uranyl Acetate</td> <td> Long/ Easy High accuracy </td> </tr> <tr> <td> Mitochondrial Antioxidant Content Assay Measuring GSH content (Shaki et al., 2012)</td> <td>“GSH content was determined using DTNB as the indicator and spectrophotometer method for the isolated mitochondria. The mitochondrial fractions (0.5 mg protein/ml) were incubated with various concentrations of uranyl acetate for 1 h at 30 °C and then 0.1 ml of mitochondrial fractions was added into 0.1 mol/l of phosphate buffers and 0.04% DTNB in a total volume of 3.0 ml (pH 7.4). The developed yellow color was read at 412 nm on a spectrophotometer (UV-1601 PC, Shimadzu, Japan). GSH content was expressed as μg/mg protein.” (Shaki et al., 2012)</td> <td> 0, 50, 100, or 200 μM Uranyl Acetate </td> <td> </td> </tr> <tr> <td> H2O2 Production Assay Measuring H2O2 Production in isolated mitochondria (Heyno et al., 2008)</td> <td>“Effect of CdCl2 and antimycin A (AA) on H2O2 production in isolated mitochondria from potato. H2O2 production was measured as scopoletin oxidation. Mitochondria were incubated for 30 min in the measuring buffer (see the Materials and Methods) containing 0.5 mM succinate as an electron donor and 0.2 µM mesoxalonitrile 3‐chlorophenylhydrazone (CCCP) as an uncoupler, 10 U horseradish peroxidase and 5 µM scopoletin.” (Heyno et al., 2008) </td> <td> 0, 10, 30  μM Cd2+ 2  μM antimycin A</td> <td> </td> </tr> <tr> <td> Flow Cytometry ROS & Cell Viability (Kruiderig et al., 1997)</td> <td>“For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At t 5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)” </td> <td> </td> <td> Strong/easy medium</td> </tr> <tr> <td> DCFH-DA Assay Detection of hydrogen peroxide production (Yuan et al., 2016) </td> <td> Intracellular ROS production was measured using DCFH-DA as a probe. Hydrogen peroxide oxidizes DCFH to DCF. The probe is hydrolyzed intracellularly to DCFH carboxylate anion. No direct reaction with H2O2 to form fluorescent production.    </td> <td>0-400 µM</td> <td> Long/ Easy High accuracy </td> </tr> <tr> <td> H2-DCF-DA Assay Detection of superoxide production (Thiebault et al., 2007) </td> <td>This dye is a stable nonpolar compound which diffuses readily into the cells and yields H2-DCF. Intracellular OH or ONOO- react with H2-DCF when cells contain peroxides, to form the highly fluorescent compound DCF, which effluxes the cell. Fluorescence intensity of DCF is measured using a fluorescence spectrophotometer.</td> <td>0–600 µM</td> <td> Long/ Easy High accuracy </td> </tr> <tr> <td>CM-H2DCFDA Assay</td> <td>**Come back and explain the flow cytometry determination of oxidative stress from Pan et al. (2009)**</td> <td> </td> <td> </td> </tr> </tbody> </table>

Oxidative stress can happen in all forms of life.

Adam-Vizi, V., & Starkov, A. A. (2010). Calcium and mitochondrial reactive oxygen species generation: How to read the facts. Journal of Alzheimer's Disease : JAD, 20 Suppl 2, S413-S426. doi:10.3233/JAD-2010-100465 Al Dera, H. S. (2016). Protective effect of resveratrol against aluminum chloride induced nephrotoxicity in rats. Saudi Med J, 37(4), 369-378. doi:10.15537/smj.2016.4.13611 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. International Journal of Environmental Research and Public Health, 16, 247. doi:10.3390/ijerph16020274 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 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. Thescientificworld, 2012, 1-14. doi:10.1100/2012/136063 Bhadauria, S., & Flora, S. J. S. (2007). Response of arsenic-induced oxidative stress, DNA damage, and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats. Cell Biol Toxicol, 23, 91-104. doi:10.1007/s10565-006-0135-8 Blajszczak, C., & Bonini, M. G. (2017). Mitochondria targeting by environmental stressors : Implications for redox cellular signaling. Toxicology, 391, 84-89. doi:10.1016/j.tox.2017.07.013 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. Cell Biology International, 41, 1356-1366. doi:10.1002/cbin.10871 Chtourou, Y., Garoui, E. m., Boudawara, T., & Zeghal, N. (2014). Protective role of silymarin against manganese-induced nephrotoxicity and oxidative stress in rat. Environ Toxicol, 29, 1147-1154. doi:10.1002/tox.21845 Ferreira, G. K., Cardoso, E., Vuolo, F. S., Michels, M., Zanoni, E. T., Carvalho-Silva, M., . . . Paula, M. M. S. (2015). Gold nanoparticles alter parameters of oxidative stress and energy metabolism in organs of adult rats. Biochem. Cell Biol., 93, 548-557. doi:10.1139/bcb-2015-0030 Görlach, A., Bertram, K., Hudecova, S., & Krizanova, O. (2015). Calcium and ROS: A mutual interplay. Redox Biology, 6, 260-271. doi:doi:10.1016/j.redox.2015.08.010 Hancock, J. T., Desikan, R., & Neill, S. J. (2001). Role of reactive oxygen species in cell signalling pathways. Biochemical Society Transactions, 29(Pt 2), 345-350. doi:10.1042/0300-5127:0290345 [doi] Hao, Y., Huang, J., Liu, C., Li, H., Liu, J., Zeng, Y., . . . Li, R. (2016). Differential protein expression in metallothionein protection from depleted uranium-induced nephrotoxicity. Scientific Reports, doi:10.1038/srep38942 Heyno, E., Klose, C., & Krieger-Liszkay, A. (2008). Origin of cadmium-induced reactive oxygen species production: Mitochondrial electron transfer versus plasma membrane NADPH oxidase. New Phytologist, 179, 687-699. doi:10.1111/j.1469-8137.2008.02512.x Huerta-García, E., Perez-Arizti, J. A., Marquez-Ramirez, S. G., Delgado-Buenrostro, N. L., Chirino, Y. I., Iglesias, G. G., & Lopez-Marure, R. (2014). Titanium dioxide nanoparticles induce strong oxidative stress and mitochondrial damage in glial cells. Free Radical Biology and Medicine, 73, 84-94. doi:10.1016/j.freeradbiomed.2014.04.026 Jozefczak, M., Bohler, S., Schat, H., Horemans, N., Guisez, Y., Remans, T., . . . Cuypers, A. (2015). Both the concentration and redox state of glutathione and ascorbate influence the sensitivity of arabidopsis to cadmium. Annals of Botany, 116(4), 601-612. doi:10.1093/aob/mcv075 Kehrer, J. P. (2000). The Haber–Weiss reaction and mechanisms of toxicity. Toxicology, 149(1), 43-50. doi:<a href="https://doi.org/10.1016/S0300-483X(00)00231-6" style="color:#0563c1; text-decoration:underline" target="_blank">https://doi.org/10.1016/S0300-483X(00)00231-6</a> Kharroubi, W., Dhibi, M., Mekni, M., Haouas, Z., Chreif, I., Neffati, F., . . . Sakly, R. (2014). Sodium arsenate induce changes in fatty acids profiles and oxidative damage in kidney of rats. Environ Sci Pollut Res, 21, 12040-12049. doi:10.1007/s11356-014-3142-y Kowaltowski, A. J., & Vercesi, A. E. (1999). Mitochondrial damage induced by conditions of oxidative stress. Free Radical Biology and Medicine, 26(3), 463-471. doi:<a href="https://doi.org/10.1016/S0891-5849(98)00216-0" style="color:#0563c1; text-decoration:underline" target="_blank">https://doi.org/10.1016/S0891-5849(98)00216-0</a> Kruidering, M., Van De Water, B., De Heer, E., Mulder, G. J., & Nagelkerke, J. F. (1997). Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: Mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. The Journal of Pharmacology and Experimental Therapeutics, 280(2), 638-649. Li, N., Ragheb, K., Lawler, G., Sturgis, J., Melendez, J. A., & Robinson, J. P. (2003). Mitochondrial complex I inhibitor rotenone induced apoptosis through enhancing mitochondrial reactive oxygen species production. The Journal of Biological Chemistry, 278(10), 8516-8525. Liang, Shih-Shin & Shiue, Yow-Ling & Kuo, Chao Jen & Guo, Su-Er & Liao, Wei-Ting & Tsai, Eing. (2013). Online Monitoring Oxidative Products and Metabolites of Nicotine by Free Radicals Generation with Fenton Reaction in Tandem Mass Spectrometry. TheScientificWorldJournal. 2013. 189162. 10.1155/2013/189162. Liu, S., Xu, L., Zhang, T., Ren, G., & Yang, Z. (2010). Oxidative stress and apoptosis induced by nanosized titanium dioxide in PC12 cells. Toxicology, 267, 172-177. doi:10.1016/j.tox.2009.11.012 Lunyera, J., & Smith, S. R. (2017). Heavy metal nephropathy: Considerations for exposure analysis. Kidney International, 92, 548-550. doi:http://dx.doi.org/10.1016/j.kint.2017.04.043 Miyayama, T., Arai, Y., Suzuki, N., & Hirano, S. (2013). Mitochondrial electron transport is inhibited by disappearance of metallothionein in human bronchial epithelial cells follwoing exposure to silver nitrate. Toxicology, 305, 20-29. doi:10.1016/j.tox.2013.01.004 Pan, Y., Leifer, A., Ruau, D., Neuss, S., Bonrnemann, J., Schmid, G., . . . Jahnen-Dechent, W. (2009). Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small, 5(8), 2067-2076. doi:10.1002/smll.200900466 Panday, A., Sahoo, M., Osorio, D., Barta, S. (2014). NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol 12, 5–23 (2015). <a href="https://doi.org/10.1038/cmi.2014.89" style="color:#0563c1; text-decoration:underline">https://doi.org/10.1038/cmi.2014.89</a> Pourahmad, J., Ghashang, M., Ettehadi, H. A., & Ghalandari, R. (2006). A search for cellular and molecular mechanisms involved in depleted uranium (DU) toxicity. Environmental Toxicology, 21(4), 349-354. doi:10.1002/tox.20196 Sabath, E., & Robles-Osorio, M. L. (2012). Renal health and the environment: Heavy metal nephrotoxicity. Revista Nefrologia, doi:10.3265/Nefrologia.pre2012.Jan.10928 Santos, N. A. G., Catão, C. S., Martins, N. M., Curti, C., Bianchi, M. L. P., & Santos, A. C. (2007). Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Archives of Toxicology, 81(7), 495-504. doi:10.1007/s00204-006-0173-2 Shaki, F., Hosseini, M. J., Ghazi-Khansari, M., & Pourahmad, J. (2012). Toxicity of depleted uranium on isolated rat kidney mitochondria. Biochimica Et Biophysica Acta - General Subjects, 1820(12), 1940-1950. doi:10.1016/j.bbagen.2012.08.015 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. Metallomics, 5(6), 736-744. doi:10.1039/c3mt00019b Sies, H. (Ed.), Oxidative Stress, Oxidants and Antioxidants, Academic Press, San Diego, CA (1991), pp. XV-XXII Small, D. M., Sanchez, W. Y., Roy, S. F., Morais, C., Brooks, H. L., Coombes, J. S., . . . Gobe, G. (2018). N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenous antioxidant responses. American Physiological Society - Renal Physiology, 314, F956-F968. doi:10.1152/ajprenal.00057.2017 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. Toxicological Sciences : An Official Journal of the Society of Toxicology, 98(2), 479-487. doi:kfm130 [pii] Turk, E., Kandemir, F. M., Yildirim, S., Caglayan, C., Kucukler, S., & Kuzu, M. (2019). Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Biological Trace Element Research, 189, 95-108. doi:10.1007/s12011-018-1443-6 Turrens, J. F. (2003). Mitochondrial formation of reactive oxygen species. The Journal of Physiology, 552(Pt 2), 335-344. doi:jphysiol.2003.049478 [pii] Tyagi, R., Rana, P., Gupta, M., Khan, A. R., Bhatnagar, D., Bhalla, P. J. S., . . . Kushu, S. (2011). Differntial biochemical response of rat kidney towards low and high doses of NiCl2 as revealed by NMR spectroscopy. Journal of Applied Toxicology, 33, 134-141. doi:10.1002/jat.1730 Valko, M., Morris, H., & Cronin, M. T. (2005). Metals, toxicity and oxidative stress. Current Medicinal Chemistry, 12(10), 1161-1208. doi:10.2174/0929867053764635 [doi] Wang, L., Li, J., Li, J., & Liu, Z. (2009). Effects of lead and/or cadmium on the oxidative damage of rat kidney cortex mitochondria. Biol.Trace Elem.Res., 137, 69-78. doi:10.1007/s12011-009-8560-1 Xu, X. M., & Moller, G. S. (2010). ROS removal by DJ-1. Plant Signaling & Behaviour, 5(8), 1034-1036. doi:10.4161/psb.5.8.12298 Yeh, Y., Lee, Y., Hsieh, Y., & Hwang, D. (2011). Dietary taurine reduces zinc-induced toxicity in male wistar rats. Journal of Food Science, 76(4), 90-98. doi:10.1111/j.1750-3841.2011.02110.x Yuan, Y., Zheng, J., Zhao, T., Tang, X., & Hu, N. (2016). Uranium-induced rat kidney cell cytotoxicity is mediated by decreased endogenous hydrogen sulfide (H2S) generation involved in reduced Nrf2 levels. Toxicology Research, 5(2), 660-673. doi:10.1039/C5TX00432B Zhao, R., Jiang, S., Zhang, L., & Yu, Z. (2019). Mitochondrial electron transport chain, ROS generation and uncoupling (review). International Journal of Molecular Medicine, 44(1), 3-15. doi:10.3892/ijmm.2019.4188 AOPWiki 2022-02-04T13:55:38

2022-03-03T10:40:06

Activation of inflammation pathway

Activation, inflammation pathway

Cellular

AOPWiki 2022-05-31T02:47:29

2022-05-31T02:47:29

increased, Vascular endothelial dysfunction

increased，Vascular endothelial dysfunction

Tissue

AOPWiki 2021-08-19T11:45:28

2024-06-19T19:48:26

Increase, Vascular disrupting effects

Individual

AOPWiki 2023-08-19T20:12:04

2023-08-19T20:12:04

Angiogenesis dysfunction

Organ

AOPWiki 2023-08-28T05:00:15

2023-08-28T05:00:15

<upstream-id>b91cc6e0-3545-46dc-83d8-90eb27ff7eb9</upstream-id> <downstream-id>93b4a76a-3752-4fdf-ad55-a048ee78b796</downstream-id>

AOPWiki 2023-08-19T20:13:14

2023-08-19T20:13:14

<upstream-id>b91cc6e0-3545-46dc-83d8-90eb27ff7eb9</upstream-id> <downstream-id>cfb2319b-b0d3-46aa-bda6-3134a22a128d</downstream-id>

AOPWiki 2023-08-28T07:47:46

2023-08-28T07:47:46

<upstream-id>93b4a76a-3752-4fdf-ad55-a048ee78b796</upstream-id> <downstream-id>cfb2319b-b0d3-46aa-bda6-3134a22a128d</downstream-id>

AOPWiki 2023-08-19T20:13:39

2023-08-19T20:13:39

<upstream-id>cfb2319b-b0d3-46aa-bda6-3134a22a128d</upstream-id> <downstream-id>d5aa6d88-4865-4572-925b-98d09b256f64</downstream-id>

AOPWiki 2023-08-19T20:14:03

2023-08-19T20:14:03

<upstream-id>d5aa6d88-4865-4572-925b-98d09b256f64</upstream-id> <downstream-id>6aaf14fd-0ab8-4e03-a5c0-d7ffc6cd44d6</downstream-id>

AOPWiki 2023-08-28T05:01:05

2023-08-28T05:01:05

<upstream-id>6aaf14fd-0ab8-4e03-a5c0-d7ffc6cd44d6</upstream-id> <downstream-id>a2fa6097-aca4-4d4b-8655-777b4deb0adf</downstream-id>

AOPWiki 2023-08-28T05:03:20

2023-08-28T05:03:20

Nrf2 inhibition leading to vascular disrupting effects via inflammation pathway

Vascular disrupting effects

Brendan Ferreri-Hanberry

Yanhong Wei1, Xiali Zhong1, Jianshe Wang2 1 Sun Yat-sen University, Guangzhou, 510080, China. 2 Yantai University, Yantai, 264005, China.

BY-SA

2.6

Data-driven analysis and pathway-based approaches contribute to reasonable arrangements of limited resources and laboratory tests of potential vascular disrupting compounds (pVDCs), which provides opportunities to save time and effort for toxicity research. With the widespread usage of chemicals related to vascular disrupting effects on a global scale, the concentrations generally reached up to micromolar range in environmental media and even in organisms. However, potential adverse effects and toxicity pathways of vascular disrupting compounds have not been systematically assessed. Therefore, it is necessary to review the current situation, formulate future research priorities, and characterize toxicity mechanisms. Results showed that this AOP may be invoked by effects on the inhibition of Nrf2. Downstream key events (KEs) include oxidative stress, Inflammation, Vascular endothelial dysfunction. KE relationships (KERs) lead to Angiogenesis dysfunction. The severity of adverse outcomes (vascular disrupting effects) would ultimately vary by anatomical region, organ system, and physiological state when an MIE is invoked. This study brought insights into facilitating the complement of AOP efficiently, as well as establishing toxicity pathways framework to inform risk assessment of emerging pVDCs.<a name="_Hlk136427273"></a> This AOP focuses on the <a name="_Hlk136152466">vascular disrupting effect</a> via inhibiting the <a name="_Hlk139144228">Nrf2</a>-signaling pathway. The abnormal expression of Nrf2 plays an important role in the vasculogenesis and angiogenesis. The postulated molecular initiating event (MIE) for this AOP may be invoked by effects on the inhibition of Nrf2. Downstream key events (KEs) include oxidative stress, Inflammation, Vascular endothelial dysfunction. KE relationships (KERs) leading to Angiogenesis dysfunction. The severity of adverse outcomes (vascular disrupting effects) would ultimately vary by anatomical region, organ system, and physiological state when an MIE is invoked. Furthermore, in order to elucidate the AOP of vascular disrupting effect better, the established AOPs are included.

adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

High non-adjacent

High

High Mixed

High

All life stages

Low High High

The biological plausibility of KERs is strong due to the available mechanistic evidence present in studies from a wide variety of taxa. Nrf2 inhibition causes oxidative stress and a variety of cellular responses.  Jeong et al. used a weight-of-evidence approach in analyzing TOXCAST data, and proposed the putative AOP pathway from MIE Increased Reactive Oxygen Species to KE Oxidative Stress to KE Increase, Inflammation. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab rats, mice, cell lines, and zebrafish.  Some studies provided evidence including antagonism, knock-outs, or knock-ins to probe the necessity of MIE and KE. Furthermore, the AOP can be anticipated based on broader chemicals, which include PCBs, BPA, arsenic, cadmium, lead, and air pollution (PM2:5). The empirical support of KERs is largely found in toxicological studies derived from reference chemicals with dose-response and temporal concordance assessed. However, more studies are needed to explore the dose concordance, incidence concordance, and temporal concordance.  <ol> <li style="text-align:justify"><a name="_Hlk139480582">Life Stage</a> Applicability</li> </ol> The AOPs are not life stage specific <ol start="2"> <li style="text-align:justify">Taxonomic Applicability</li> </ol> <table align="center" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:75px"> Term </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; width:85px"> Scientific Term </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; width:76px"> Evidence </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; width:317px"> Links </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; width:75px"> Human </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:85px"> Homo sapiens </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:76px"> Low </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:317px"> https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; width:75px"> Mouse </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:85px"> Mus musculus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:76px"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:317px"> https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; width:75px"> Zebrafish </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:85px"> Danio rerio </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:76px"> High </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; width:317px"> https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=7955 </td> </tr> </tbody> </table> <ol start="3"> <li style="text-align:justify">Sex Applicability</li> </ol> Mixed

The essentiality of KERs is strong due to various evidence from different controlled experimental designs with controls.  Exposure to various chemical stressors has induced oxidative stress from Nrf2 inhibition. In this AOP we are focusing on the KERs between Nrf2 inhibition, oxidative stress, inflammation, vascular endothelial dysfunction, angiogenesis disfunction, vascular disrupting effects. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab rats, mice, cell lines, and zebrafish.

The QWOE approach is an analytical method that utilizes causality criteria to assess the evidence-supported postulated AOP[4]. Firstly, the hypothesis of action was presented and the quantitative evaluation of evidence ranging from no evidence (0) to strong for each category (3, strong and −3, strong counter) utilizing the evolved MIEs, KEs, and KERs. Subsequently, a ranked importance-based numerical weight was assigned to Bradford Hill causal considerations, and the composite score and confidence score for MIEs, KEs, and entire AOP were evaluated. <table cellspacing="0" style="border-collapse:collapse; width:725px"> <tbody> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap; width:293px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:72px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:72px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:72px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:72px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:72px"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap; width:72px"> </td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">Assigned weight</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap"> Qualitative rating</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">　</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">　</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">MIE</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">KE1</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">KE2</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">KE3</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">KE4</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Biological plausibility</td> <td colspan="6" style="border-bottom:none; border-left:none; border-right:none; border-top:1px solid black; text-align:center; vertical-align:middle; white-space:nowrap">Some in vivo and in vitro evidence suggest that the chemicals can cause the vascular toxicity</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Essentiality empirical support</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.4</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Dose and incidence concordance</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.2</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Empirical support temporal concordance</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.2</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Consistency across test systems</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Analogy mutiple studies support KE and KER</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.1</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">3</td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; height:20px; text-align:center; vertical-align:middle; white-space:nowrap">Score</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">1</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:bottom; white-space:nowrap">2.2</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:bottom; white-space:nowrap">2.2</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">2.2</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">2.2</td> <td style="border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">2.2</td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; height:41px; text-align:center; vertical-align:middle; white-space:nowrap">AOP Score</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap">0.733333</td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; text-align:center; vertical-align:middle; white-space:nowrap"> </td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

[1]        ELLIS-HUTCHINGS R G, SETTIVARI R S, MCCOY A T, et al. Embryonic vascular disruption adverse outcomes: Linking high throughput signaling signatures with functional consequences [J]. Reproductive toxicology (Elmsford, NY), 2017, 70: 82-96. [2]        KLEINSTREUER N C, JUDSON R S, REIF D M, et al. Environmental impact on vascular development predicted by high-throughput screening [J]. Environ Health Perspect, 2011, 119(11): 1596-603. [3]        LIND L, ARAUJO J A, BARCHOWSKY A, et al. Key Characteristics of Cardiovascular Toxicants [J]. Environ Health Perspect, 2021, 129(9): 95001. [4]        BECKER R A, DELLARCO V, SEED J, et al. Quantitative weight of evidence to assess confidence in potential modes of action [J]. Regulatory toxicology and pharmacology : RTP, 2017, 86: 205-20. [5]        HE F, RU X, WEN T. NRF2, a Transcription Factor for Stress Response and Beyond [J]. International journal of molecular sciences, 2020, 21(13). [6]        KIM Y W, BYZOVA T V. Oxidative stress in angiogenesis and vascular disease [J]. Blood, 2014, 123(5): 625-31. [7]        KIM Y W, WEST X Z, BYZOVA T V. Inflammation and oxidative stress in angiogenesis and vascular disease [J]. Journal of molecular medicine (Berlin, Germany), 2013, 91(3): 323-8. [8]        DEANFIELD J E, HALCOX J P, RABELINK T J. Endothelial function and dysfunction: testing and clinical relevance [J]. Circulation, 2007, 115(10): 1285-95. [9]        GODO S, SHIMOKAWA H. Endothelial Functions [J]. Arteriosclerosis, thrombosis, and vascular biology, 2017, 37(9): e108-e14. [10]       INCALZA M A, D'ORIA R, NATALICCHIO A, et al. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases [J]. Vascul Pharmacol, 2018, 100: 1-19. [11]       WEI Y, GONG J, XU Z, et al. Nrf2 promotes reparative angiogenesis through regulation of NADPH oxidase-2 in oxygen-induced retinopathy [J]. Free radical biology & medicine, 2016, 99: 234-43. [12]       ZHONG X, QIU J, KANG J, et al. Exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) induces vascular toxicity through Nrf2-VEGF pathway in zebrafish and human umbilical vein endothelial cells [J]. Environmental pollution (Barking, Essex : 1987), 2019, 247: 293-301. [13]       WEI Y, GONG J, XU Z, et al. Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A [J]. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(50): E6927-36. [14]       WEI Y, GONG J, THIMMULAPPA R K, et al. Nrf2 acts cell-autonomously in endothelium to regulate tip cell formation and vascular branching [J]. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(41): E3910-8. [15]       XU Z, WEI Y, GONG J, et al. NRF2 plays a protective role in diabetic retinopathy in mice [J]. Diabetologia, 2014, 57(1): 204-13. [16]       WEI Y, GONG J, YOSHIDA T, et al. Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury [J]. Free radical biology & medicine, 2011, 51(1): 216-24. [17]       CIMINO F, SPECIALE A, ANWAR S, et al. Anthocyanins protect human endothelial cells from mild hyperoxia damage through modulation of Nrf2 pathway [J]. Genes & nutrition, 2013, 8(4): 391-9. [18]       CHEN B, LU Y, CHEN Y, et al. The role of Nrf2 in oxidative stress-induced endothelial injuries [J]. The Journal of endocrinology, 2015, 225(3): R83-99. [19]       ISHIKADO A, SONO Y, MATSUMOTO M, et al. Willow bark extract increases antioxidant enzymes and reduces oxidative stress through activation of Nrf2 in vascular endothelial cells and Caenorhabditis elegans [J]. Free radical biology & medicine, 2013, 65: 1506-15. [20]       HAN S G, HAN S S, TOBOREK M, et al. EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes [J]. Toxicol Appl Pharmacol, 2012, 261(2): 181-8. [21]       SAHA S, BUTTARI B, PANIERI E, et al. An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation [J]. Molecules (Basel, Switzerland), 2020, 25(22). [22]       ZHONG X, YU Y, WANG C, et al. Hippocampal proteomic analysis reveals the disturbance of synaptogenesis and neurotransmission induced by developmental exposure to organophosphate flame retardant triphenyl phosphate [J]. J Hazard Mater, 2021, 404(Pt B): 124111. [23]       ZHONG X, WU J, KE W, et al. Neonatal exposure to organophosphorus flame retardant TDCPP elicits neurotoxicity in mouse hippocampus via microglia-mediated inflammation in vivo and in vitro [J]. Archives of toxicology, 2020, 94(2): 541-52. [24]       TARANTINI S, VALCARCEL-ARES M N, YABLUCHANSKIY A, et al. Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype [J]. The journals of gerontology Series A, Biological sciences and medical sciences, 2018, 73(7): 853-63. [25]       ZHENG S, WANG Y, GUO W, et al. FOXO6 transcription inhibition of CTRP3 promotes OGD/R-triggered cardiac microvascular endothelial barrier disruption via SIRT1/Nrf2 signaling [J]. Folia morphologica, 2023. [26]       WANG D P, KANG K, SUN J, et al. URB597 and Andrographolide Improve Brain Microvascular Endothelial Cell Permeability and Apoptosis by Reducing Oxidative Stress and Inflammation Associated with Activation of Nrf2 Signaling in Oxygen-Glucose Deprivation [J]. Oxidative medicine and cellular longevity, 2022, 2022: 4139330. [27]       ZHANG Q, LIU J, DUAN H, et al. Activation of Nrf2/HO-1 signaling: An important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress [J]. Journal of advanced research, 2021, 34: 43-63. [28]       ZHANG H, YUAN B, HUANG H, et al. Gastrodin induced HO-1 and Nrf2 up-regulation to alleviate H2O2-induced oxidative stress in mouse liver sinusoidal endothelial cells through p38 MAPK phosphorylation [J]. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 2018, 51(10): e7439. [29]       ZHANG C, KONG X, MA D. miR-141-3p inhibits vascular smooth muscle cell proliferation and migration via regulating Keap1/Nrf2/HO-1 pathway [J]. IUBMB life, 2020, 72(10): 2167-79. [30]       YANG K, SONG H, YIN D. PDSS2 Inhibits the Ferroptosis of Vascular Endothelial Cells in Atherosclerosis by Activating Nrf2 [J]. Journal of cardiovascular pharmacology, 2021, 77(6): 767-76. [31]       SHA W, ZHAO B, WEI H, et al. Astragalus polysaccharide ameliorates vascular endothelial dysfunction by stimulating macrophage M2 polarization via potentiating Nrf2/HO-1 signaling pathway [J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2023, 112: 154667. [32]       LIU L, WANG R, XU R, et al. Procyanidin B2 ameliorates endothelial dysfunction and impaired angiogenesis via the Nrf2/PPARγ/sFlt-1 axis in preeclampsia [J]. Pharmacological research, 2022, 177: 106127. [33]       LI H, ZHUANG W, XIONG T, et al. Nrf2 deficiency attenuates atherosclerosis by reducing LOX-1-mediated proliferation and migration of vascular smooth muscle cells [J]. Atherosclerosis, 2022, 347: 1-16. [34]       ASHINO T, YAMAMOTO M, YOSHIDA T, et al. Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia [J]. Arteriosclerosis, thrombosis, and vascular biology, 2013, 33(4): 760-8. [35]       WANG Q, LIU Y, GUO J, et al. Microcystin-LR induces angiodysplasia and vascular dysfunction through promoting cell apoptosis by the mitochondrial signaling pathway [J]. Chemosphere, 2019, 218: 438-48. [36]       UNGVARI Z, TARANTINI S, KISS T, et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature [J]. Nature reviews Cardiology, 2018, 15(9): 555-65.             [37]       ALEXANDER Y, OSTO E, SCHMIDT-TRUCKSäSS A, et al. Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on                 Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis [J]. Cardiovascular research, 2021, 117(1): 29-42. AOPWiki 2023-08-19T19:52:00

2024-05-26T20:39:59