Inhibition, IKK complex

547757-23-3

MIDKPVLYXNLFGZ-UHFFFAOYSA-N

BMS 345541

DTXSID70203243

20554-84-1

KTEXNACQROZXEV-QLIGOWBFSA-N

Parthenolide

NFkB inhibitor PTL

DTXSID2040579

15502-74-6

OWTFKEBRIAXSMO-UHFFFAOYSA-N

Arsenite

DTXSID0074007

38194-50-2

MLKXDPUZXIRXEP-MFOYZWKCNA-N

MLKXDPUZXIRXEP-MFOYZWKCSA-N

Sulindac

1H-Indene-3-acetic acid, 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-, (1Z)- (Z)-5-Fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]indene-3-acetic acid 1H-Indene-3-acetic acid, 5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-, (Z)- 5-Fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid Aflodac Algocetil Arthrocine Artribid cis-5-Fluoro-2-methyl-1-[(p-methylsulfinyl)benzylidenyl]indene-3-acetic acid cis-Sulindac Citireuma Clinoril Clisundac Imbaral Mobilin Reumofil Sulindac sulfoxide sulindaco Sulinol Sulreuma

DTXSID4023624

15687-27-1

HEFNNWSXXWATRW-UHFFFAOYNA-N

HEFNNWSXXWATRW-UHFFFAOYSA-N

Ibuprofen

Benzeneacetic acid, α-methyl-4-(2-methylpropyl)- (.+-.)-2-(p-Isobutylphenyl)propionic acid (.+-.)-Ibuprofen (.+-.)-Ibuprophen (.+-.)-α-Methyl-4-(2-methylpropyl)benzeneacetic acid (4-Isobutylphenyl)-α-methylacetic acid (RS)-Ibuprofen 2-(4-Isobutylphenyl)propanoic acid 2-(4'-Isobutylphenyl)propionic acid 2-(4-Isobutylphenyl)propionic acid 2-(p-Isobutylphenyl)propionic acid 4-Isobutylhydratropic acid 4-Isobutyl-α-methylphenylacetic acid Actiprofen Algi-Flanderil Algiflex Algofen Amibufen Anflagen Antarene Antiflam Apo-Ibuprofen Apsifen Artofen Balkaprofen Betaprofen Brufanic Brufen Retard Bruflam Brufort Buburone Buluofen Butacortelone Butylenin Codral Period Pain Combiflam Dansida Dentigoa Dibufen dl-Ibuprofen Dolgirid Dolmaral Dolocyl Dolo-Dolgit Dolofen Dolofen F Dolomax Donjust B Doretrim Dorival Easifon Epobron Femadon Fenspan Gynofug Haltran Hydratropic acid, p-isobutyl- Ibosure Ibu-Attritin Ibuflamar Ibugesic Ibuleve Ibulgan Ibumetin Ibupirac Ibupril Ibuprocin Ibuprofene ibuprofeno Ibuprohm Ibu-slow Ibu-Tab Inabrin Iprogel Lamidon Librofem Lidifen Mensoton Motrin IB Mynosedin Nagifen-D Napacetin Nobafon Nobfelon Noritis Novogent Novoprofen NSC 256857 Nurofen Optifen Opturem Ostarin Ostofen p-(2-Methylpropyl)-α-methylphenylacetic acid Paduden Panafen Pantrop Paxofen Pediaprofen Perofen PHENYLACETIC ACID, 2-METHYL-4-(2-METHYLPROPYL)- p-Isobutyl-2-phenylpropionic acid p-Isobutylhydratropic acid Proartinal Proflex Prontalgin Quadrax Ranofen Recidol Relcofen Roidenin Seclodin Suspren Syntofene Tabalon Tabalon 400 Tatanal Trendar Unipron Uprofen α-(4-Isobutylphenyl)propionic acid α-Methyl-4-(2-methylpropyl)benzeneacetic acid

DTXSID5020732

50-78-2

BSYNRYMUTXBXSQ-UHFFFAOYSA-N

Aspirin

Acetylsalicylic acid Benzoic acid, 2-(acetyloxy)- 2-(ACETYLOXYBENZOIC) ACID 2-(Acetyloxy)benzoic acid 2-Acetoxybenzoic acid 2-Carboxyphenyl acetate A.S.A. Empirin Acenterine Acetard Aceticyl Acetilum acidulatum Acetisal Acetonyl Acetophen Acetosal Acetosalic acid Acetosalin Acetylin Acetylsal ACETYLSALICYLSAEURE Acetyonyl Acetysal Acide O-acetylsalicylique acido O-acetilsalicilico Acidum acetylsalicylicum Acimetten Acylpyrin Albyl E Asaflow Asagran Asatard Ascolong Ascriptin Aspalon Aspergum Aspirdrops Aspirina 03 Aspirin-Direkt Aspro Clear Aspropharm Asteric Benaspir Bialpirina Bialpirinia Cardioaspirina Claradin Colfarit Contrheuma Retard Coricidin Coricidin D Dolean pH 8 Dominal Duramax Easprin Ecotrin Empirin Endosprin Endydol Entericin Enterophen Enterosarine Entrophen Gelprin Globentyl Globoid Helicon Idragin Istopirin Kapsazal Magnecyl Measurin Medisyl Melhoral Micristin Miniasal Neuronika NSC 27223 NSC 406186 Nu-seals o-(Acetyloxy)benzoic acid o-Acetoxybenzoic acid O-acetylsalicylic acid O-Acetylsalicylsaure o-Carboxyphenyl acetate Persistin Polopiryna Rheumintabletten Rhodine Rhodine 2312 Rhodine NC RP Salacetin Salcetogen Saletin Salicylic acid acetate SALICYLIC ACID, ACETYL- Salospir Salycylacetylsalicylic acid Solpyron Temperal Triple-sal Trombyl Zorprin

DTXSID5020108

2257-09-2

IZJDOKYDEWTZSO-UHFFFAOYSA-N

Phenethyl isothiocyanate

DTXSID5021120

4478-93-7

SUVMJBTUFCVSAD-UHFFFAOYNA-N

SUVMJBTUFCVSAD-UHFFFAOYSA-N

Sulforaphane

DTXSID8036732

PR:000001753

PR transcription factor NF-kappa-B subunit

GO:0007249

GO I-kappaB kinase/NF-kappaB signaling

GO:0008219

GO cell death

WIKI decreased

WIKI increased

SC-839

2019-03-07T06:13:06

Beta-carboline

2019-03-07T06:13:29

BMS 345541

2019-03-07T06:13:41

Parthenolide

2019-03-07T06:13:51

Arsenite

2019-03-07T06:14:00

Sulindac

2019-03-07T06:15:12

Ibuprofen

2016-11-29T18:42:26

Aspirin

2019-03-07T06:15:33

Phenethyl isothiocyanate

2019-03-07T06:16:25

Sulforaphane

2019-03-07T06:16:36

IL-1 receptor antagonist（IL-1Ra）(Anakinra)

2019-06-01T00:37:57

anti-IL-1b antibody (Canakinumab)

2019-06-01T00:38:21

soluble IL-1R (Rilonacept)

2019-06-01T00:38:52

9606

NCBI Homo sapiens

10090

NCBI Mus musculus

10116

NCBI Rattus norvegicus

WCS_9606

common toxicological species human

WikiUser_25

Wikiuser: Cyauk human and other cells in culture

10090

NCBI mouse

Inhibition, IKK complex

Molecular

The IKK complex consists of 3 subunits: IKKa, IKKb and NEMO. Normally, this complex can activate NFkB signaling. However, in this MIE, this complex will be disturbed in such a way it can not perform that function anymore. Currently, 3 types of IKK disturbances have been described: (Gupta et al. 2010) <ol> <li>Adenosine triphosphate (ATP) analogues (e.g. beta-carboline, SC-839): specific IKK interaction, preference for IKK subunits(Kishore et al. 2003)</li> <li>Allosteric effect on IKK complex (Burke et al. 2003)</li> <li>Interaction with Cys-179 in activation loop of IKKb</li> </ol> <ul> <li>List of Cys-179 interacting compounds: (Heyninck et al. 2014)</li> </ul> However, not many studies performed tests on compounds of interest to identify the specific mechanisms of IKK complex inhibition (Gupta et al. 2010).

Interaction compound-IKK complex: Western blot with IKK antibodies in purified IKK complexes (Heyninck et al. 2014). IKK activity: In vitro IKK kinase assay (CycLex IKKb inhibitor screening kit) (Heyninck et al. 2014). Specific Cys-179 interaction: Mutant IKKb treatment followed by Western blotting with antiFLAG (Heyninck et al. 2014).

Burke, J.R. et al., 2003. BMS-345541 is a highly selective inhibitor of I??B kinase that binds at an allosteric site of the enzyme and blocks NF-??B-dependent transcription in mice. Journal of Biological Chemistry, 278(3), pp.1450–1456. Gupta, S.C. et al., 2010. Inhibiting NF-??B activation by small molecules as a therapeutic strategy. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1799(10–12), pp.775–787. Available at: http://dx.doi.org/10.1016/j.bbagrm.2010.05.004. Heyninck, K. et al., 2014. Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKβ. Biochemical Pharmacology, 91(4), pp.501–509. Available at: http://dx.doi.org/10.1016/j.bcp.2014.08.004. Kishore, N. et al., 2003. A selective IKK-2 inhibitor blocks NF-κB-dependent gene expression in interleukin-1β-stimulated synovial fibroblasts. Journal of Biological Chemistry, 278(35), pp.32861–32871. Zhou, P. et al., 2010. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF- B and MAPK signaling pathways. The FASEB Journal, 24(12), pp.4722–4732. Available at: http://www.fasebj.org/cgi/doi/10.1096/fj.10-163311. AOPWiki 2019-01-07T08:39:09

2019-01-07T10:54:25

Inhibition, Nuclear factor kappa B (NF-kB)

Molecular

The NF-κB pathway consists of a series of events including IRAK (IL-1 receptor-associated kinase) signaling, where the transcription factors of the NF-κB family play the key role. The canonical NF-κB 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 NF-κB inhibitor will be K48-linked ubiquitinated and degradated, allowing NF-κB 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 NF-κB pathway is inhibited, its translocation will be delayed (or absent), resulting in less or no regulation of NF-κB 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 NF-κB.   In addition to the NF-kB 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).

NF-κB transcriptional activity: Beta lactamase reporter gene assay (Miller et al. 2010) NF-κB transcription: Lentiviral NF-κBGFP reporter with flow cytometry (Moujalled et al. 2012) IκBα phosphorylation: Western blotting (Miller et al. 2010) NF-κB p65 (Total/Phospho) ELISA： ELISA for IL-6, IL-8, and Cox

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). Evidence for perturbation of this molecular initiating event by stressor Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-κB/Rel and AP-1 activation (Jeon et al., 2000). Various inhibitors for NF‐κB, such as dimethyl fumarate, curcumin, iguratimod, epigalocathechin gallate (EGCG), and DHMEQ inhibits lLPS-induced NF-κB activation and LPS-induced secretion of IL-1β (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). TAK-242 (Matsunaga et al., 2011) inhibit TLR4 itself. There are several IRAK4 inhibitors (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). 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 (Wang et al., 2005). Caspase-1 inhibition reduced the release of IL-1β in organotypic slices exposed to LPS+ATP. Administration of pralnacasan (intracerebroventricular, 50 μg) or belnacasan (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 (Ravizza et al., 2006). Belnacasan, 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 (Stack et al., 2005). 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) (Huang and Wang, 2017). 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 mM, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion (Ho et al., 2018). 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 (Xu et al., 2017). IL-1Ra binds IL-1R but does not initiate IL-1 signal transduction (Dripps et al., 1991). 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 (Kapur and Bonk, 2009). The binding of IL-1β to IL-1R1 can be inhibited by anti-IL-1β antibody (canakinumab and gevokizumab) (Church and McDermott, 2009) (Roell et al., 2010). 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 (Quartier, 2011). Dex inhibits IL-1β gene expression in LPS-stimulated RAW 264.7 cells by blocking NF‐κB/Rel and AP-1 activation (Jeon et al., 2000). 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.

UBERON:0002405

UBERON immune system

CL:0000084

CL T cell

High Unspecific

High

All life stages

High High High

Chaudhary, D., Robinson, S., Romero, D.L. (2015), Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. J Med Chem 58: 96-110, 10.1021/jm5016044 Church, L.D., McDermott, M.F. (2009), Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders. Curr Opin Mol Ther 11: 81-89, Dripps, D.J., Brandhuber, B.J., Thompson, R.C., et al. (1991), Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266: 10331-10336, Gupta, S.C., Sundaram, C., Reuter, S., et al. (2010), Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta 1799: 775-787, 10.1016/j.bbagrm.2010.05.004 Ho, S.C., Chang, Y.H., Chang, K.S. (2018), Structural Moieties Required for Cinnamaldehyde-Related Compounds to Inhibit Canonical IL-1beta Secretion. Molecules 23, 10.3390/molecules23123241 Huang, H., Wang, Y. (2017), The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice. Cell Mol Biol (Noisy-le-grand) 63: 58-63, 10.14715/cmb/2017.63.8.13 Jain, A., Kaczanowska, S., Davila, E. (2014), IL-1 receptor-associated kinase signaling and its role in inflammation, cancer, progression, and therapy resistance. Frontiers in Immunology 5:553. Jeon, Y.J., Han, S.H., Lee, Y.W., et al. (2000), Dexamethasone inhibits IL-1 beta gene expression in LPS-stimulated RAW 264.7 cells by blocking NF-kappa B/Rel and AP-1 activation. Immunopharmacology 48: 173-183, Kapur, S., Bonk, M.E. (2009), Rilonacept (arcalyst), an interleukin-1 trap for the treatment of cryopyrin-associated periodic syndromes. P t 34: 138-141, Klein, S.L., Flanagan, K.L. (2016), Sex differences in immune responses. Nat Rev Immunol 16: 626-638, 10.1038/nri.2016.90 Lee, K.L., Ambler, C.M., Anderson, D.R., et al. (2017), Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoli ne-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. J Med Chem 60: 5521-5542, 10.1021/acs.jmedchem.7b00231 Liu, T., Zhang, L., Joo, D., et al. (2017), NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2, 10.1038/sigtrans.2017.23 Matsunaga, N., Tsuchimori, N., Matsumoto, T., et al. (2011), TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol 79: 34-41, 10.1124/mol.110.068064 McGuire, V.A., Ruiz-Zorrilla Diez, T., Emmerich, C.H., et al. (2016), Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Sci Rep 6: 31159, 10.1038/srep31159 McKay, L.I., Cidlowski, J.A. (1999), Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. Endocr Rev 20: 435-459, 10.1210/edrv.20.4.0375 Mucke, H.A. (2012), Iguratimod: a new disease-modifying antirheumatic drug. Drugs Today (Barc) 48: 577-586, 10.1358/dot.2012.48.9.1855758 Peng, H., Guerau-de-Arellano, M., Mehta, V.B., et al. (2012), Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor kappaB (NF-kappaB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem 287: 28017-28026, 10.1074/jbc.M112.383380 Pernis, A.B. (2007), Estrogen and CD4+ T cells. Curr Opin Rheumatol 19: 414-420, 10.1097/BOR.0b013e328277ef2a Quartier, P. (2011), Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome. Open Access Rheumatol 3: 9-18, 10.2147/oarrr.S6696 Ravizza, T., Lucas, S.M., Balosso, S., et al. (2006), Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47: 1160-1168, 10.1111/j.1528-1167.2006.00590.x 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. J Biol Chem 285: 20607-20614, 10.1074/jbc.M110.115790 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. J Immunol 175: 2630-2634, Straub, R.H. (2007), The complex role of estrogens in inflammation. Endocr Rev 28: 521-574, 10.1210/er.2007-0001 Suzuki, E., Umezawa, K. (2006), Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin. Biomed Pharmacother 60: 578-586, 10.1016/j.biopha.2006.07.089 Wang, A.L., Yu, A.C., Lau, L.T., et al. (2005), Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 47: 152-158, 10.1016/j.neuint.2005.04.018 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. Oral Dis 26: 815-821, 10.1111/odi.13290 Wang, Y., Tang, Q., Duan, P., et al. (2018), Curcumin as a therapeutic agent for blocking NF-kappaB activation in ulcerative colitis. Immunopharmacol Immunotoxicol 40: 476-482, 10.1080/08923973.2018.1469145 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. J Nutr 134: 1039-1044, 10.1093/jn/134.5.1039 Xu, F., Wang, F., Wen, T., et al. (2017), Inhibition of NLRP3 inflammasome: a new protective mechanism of cinnamaldehyde in endotoxin poisoning of mice. Immunopharmacol Immunotoxicol 39: 296-304, 10.1080/08923973.2017.1355377   AOPWiki 2016-11-29T18:41:23

2023-03-02T01:58:01

Activation, Caspase 8 pathway

Molecular

In the caspase 8 pathway, the TRADD adaptor protein recruits FADD after TNFa stimulus and forms a complex together with pro-caspase 8. Caspase 8 will be activated and can directly activate caspase-3 which leads to apoptosis (Melino & Vaux 2010). Furthermore, Caspase 8 can also splice Bid to tBid which promotes disruption of the membrane of mitochondria. Cytochrome C will be released and activate Caspase 9 and Apaf1, which in turn stimulate caspase 8, causing apoptosis (Frederiksson 2012).(Cullen & Martin 2009)

WesternBlot (pro) caspase 8 (Fotin-Mleczek et al. 2002)(Schattenberg et al. 2011) Caspase 8 specific fluorogenic substrates(Schattenberg et al. 2011)

Melino, G. & Vaux, D., 2010. Cell Death G. Melino & D. Vaux, eds., Frederiksson, L., 2012. TNFalpha-signaling in drug induced liver injury. University of Leiden. Cullen, S.P. & Martin, S.J., 2009. Caspase activation pathways: Some recent progress. Cell Death and Differentiation, 16(7), pp.935–938. Available at: http://dx.doi.org/10.1038/cdd.2009.59. Fotin-Mleczek, M. et al., 2002. Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8. Journal of cell science, 115(Pt 13), pp.2757–2770. Schattenberg, J.M. et al., 2011. Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo. Journal of Hepatology, 55(6), pp.1272–1280. Available at: http://dx.doi.org/10.1016/j.jhep.2011.03.008. AOPWiki 2019-01-07T08:47:40

2019-03-07T04:16:06

Cell injury/death

Cellular

Two types of cell death can be distinguished by morphological features, although it is likely that these are two ends of a spectrum with possible intermediate forms. Apoptosis involves shrinkage, nuclear disassembly, and fragmentation of the cell into discrete bodies with intact plasma membranes. These are rapidly phagocytosed by neighbouring cells. An important feature of apoptosis is the requirement for adenosine triphosphate (ATP) to initiate the execution phase. In contrast, necrotic cell death is characterized by cell swelling and lysis. This is usually a consequence of profound loss of mitochondrial function and resultant ATP depletion, leading to loss of ion homeostasis, including volume regulation, and increased intracellular Ca2+. The latter activates a number of nonspecific hydrolases (i.e., proteases, nucleases, and phospholipases) as well as calcium dependent kinases. Activation of calpain I, the Ca2+-dependent cysteine protease cleaves the death-promoting Bcl-2 family members Bid and Bax which translocate to mitochondrial membranes, resulting in release of truncated apoptosis-inducing factor (tAIF), cytochrome c and endonuclease in the case of Bid and cytocrome c in the case of Bax. tAIF translocates to cell nuclei, and together with cyclophilin A and phosphorylated histone H2AX (γH2AX) is responsible for DNA cleavage, a feature of programmed necrosis. Activated calpain I has also been shown to cleave the plasma membrane Na+–Ca2+ exchanger, which leads to build-up of intracellular Ca2+, which is the source of additional increased intracellular Ca2+. Cytochrome c in cellular apoptosis is a component of the apoptosome. DNA damage activates nuclear poly(ADP-ribose) polymerase-1(PARP-1), a DNA repair enzyme. PARP-1 forms poly(ADP-ribose) polymers, to repair DNA, but when DNA damage is extensive, PAR accumulates, exits cell nuclei and travels to mitochondrial membranes, where it, like calpain I, is involved in AIF release from mitochondria. A fundamental distinction between necrosis and apoptosis is the loss of plasma membrane integrity; this is integral to the former but not the latter. As a consequence, lytic release of cellular constituents promotes a local inflammatory reaction, whereas the rapid removal of apoptotic bodies minimizes such a reaction. The distinction between the two modes of death is easily accomplished in vitro but not in vivo. Thus, although claims that certain drugs induce apoptosis have been made, these are relatively unconvincing. DNA fragmentation can occur in necrosis, leading to positive TUNEL staining (see explanation below). Conversely, when apoptosis is massive, it can exceed the capacity for rapid phagocytosis, resulting in the eventual appearance of secondary necrosis. Two alternative pathways - either extrinsic (receptor-mediated) or intrinsic (mitochondria-mediated) - lead to apoptotic cell death. The initiation of cell death begins either at the plasma membrane with the binding of TNF or FasL to their cognate receptors or within the cell. The latter is due to the occurrence of intracellular stress in the form of biochemical events such as oxidative stress, redox changes, covalent binding, lipid peroxidation, and consequent functional effects on mitochondria, endoplasmic reticulum, microtubules, cytoskeleton, or DNA. The intrinsic mitochondrial pathway involves the initiator, caspase-9, which, when activated, forms an “apoptosome” in the cytosol, together with cytochrome c, which translocates from mitochondria, Apaf-1 and dATP. The apoptosome activates caspase-3, the central effector caspase, which in turn activates downstream factors that are responsible for the apoptotic death of a cell (Fujikawa, 2015). Intracellular stress either directly affects mitochondria or can lead to effects on other organelles, which then send signals to the mitochondria to recruit participation in the death process (Fujikawa, 2015; Malhi et al., 2010). Constitutively expressed nitric oxide synthase (nNOS) is a Ca2+-dependent cytosolic enzyme that forms nitric oxide (NO) from L-arginine, and NO reacts with the free radical such as superoxide (O2−) to form the very toxic free radical peroxynitrite (ONOO−). Free radicals such as ONOO−, O2 − and hydroxyl radical (OH−) damage cellular membranes and intracellular proteins, enzymes and DNA (Fujikawa, 2015; Malhi et al., 2010; Kaplowitz, 2002; Kroemer et al., 2009).

Necrosis: Lactate dehydrogenase (LDH) is a soluble cytoplasmic enzyme that is present in almost all cells and is released into extracellular space when the plasma membrane is damaged. To detect the leakage of LDH into cell culture medium, a tetrazolium salt is used in this assay. In the first step, LDH produces reduced nicotinamide adenine dinucleotide (NADH) when it catalyzes the oxidation of lactate to pyruvate. In the second step, a tetrazolium salt is converted to a colored formazan product using newly synthesized NADH in the presence of an electron acceptor. The amount of formazan product can be colorimetrically quantified by standard spectroscopy. Because of the linearity of the assay, it can be used to enumerate the percentage of necrotic cells in a sample (Chan et al., 2013).  The MTT assay is a colorimetric assay for assessing cell viability. NAD(P)H-dependent cellular oxidoreductase enzymes may reflect the number of viable cells present. These enzymes are capable of reducing the tetrazolium dye MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to its insoluble formazan, which has a purple color. Other closely related tetrazolium dyes include XTT, MTS and the WSTs. Tetrazolium dye assays can also be used to measure cytotoxicity (loss of viable cells) or cytostatic activity (shift from proliferation to quiescence) of potential medicinal agents and toxic materials. MTT assays are usually done in the dark since the MTT reagent is sensitive to light (Berridgeet al.,2005). Propidium iodide (PI) is an intercalating agent and a fluorescent molecule used to stain necrotic cells. It is cell membrane impermeant so it stains only those cells where the cell membrane is destroyed. When PI is bound to nucleic acids, the fluorescence excitation maximum is 535 nm and the emission maximum is 617 nm (Moore et al.,1998) Alamar Blue (resazurin) is a fluorescent dye. The oxidized blue non fluorescent Alamar blue is reduced to a pink fluorescent dye in the medium by cell activity (O'Brien et al., 2000) (12). Neutral red uptake, which is based on the ability of viable cells to incorporate and bind the supravital dye neutral red in lysosomes (Repetto et al., 2008)(13). Moreover, quantification of ATP, signaling the presence of metabolically active cells, can be performed (CellTiter-Glo; Promega). ATP assay: Quantification of ATP, signaling the presence of metabolically active cells (CellTiter-Glo; Promega). Apoptosis: TUNEL is a common method for detecting DNA fragmentation that results from apoptotic signalling cascades. The assay relies on the presence of nicks in the DNA which can be identified by terminal deoxynucleotidyl transferase or TdT, an enzyme that will catalyze the addition of dUTPs that are secondarily labeled with a marker. It may also label cells that have suffered severe DNA damage. Caspase activity assays measured by fluorescence. During apoptosis, mainly caspase-3 and -7 cleave PARP to yield an 85 kDa and a 25 kDa fragment. PARP cleavage is considered to be one of the classical characteristics of apoptosis. Antibodies to the 85 kDa fragment of cleaved PARP or to caspase-3 both serve as markers for apoptotic cells that can be monitored using immunofluorescence (Li, Peng et al., 2004). Hoechst 33342 staining: Hoechst dyes are cell-permeable and bind to DNA in live or fixed cells. Therefore, these stains are often called supravital, which means that cells survive a treatment with these compounds. The stained, condensed or fragmented DNA is a marker of apoptosis (Loo, 2002; Kubbies and Rabinovitch, 1983).  Acridine Orange/Ethidium Bromide staining is used to visualize nuclear changes and apoptotic body formation that are characteristic of apoptosis. Cells are viewed under a fluorescence microscope and counted to quantify apoptosis.

Cell death is an universal event occurring in cells of any species (Fink and Cookson,2005).

CL:0000255

CL eukaryotic cell

Not Specified Unspecific

Not Specified

All life stages

High High High High

<ul> <li>Fujikawa, D.G. (2015), The role of excitotoxic programmed necrosis in acute brain injury, Comput Struct Biotechnol J, vol. 13, pp. 212-221.</li> <li>Malhi, H. et al. (2010), Hepatocyte death: a clear and present danger, Physiol Rev, vol. 90, no. 3, pp. 1165-1194.</li> <li>Kaplowitz, N. (2002), Biochemical and Cellular Mechanisms of Toxic Liver Injury, Semin Liver Dis, vol. 22, no. 2, <a class="external free" href="http://www.medscape.com/viewarticle/433631" rel="nofollow" target="_blank">http://www.medscape.com/viewarticle/433631</a> (accessed on 20 January 2016).</li> <li>Kroemer, G. et al., (2009), Classification of cell death: recommendations of the Nomenclature Committee on Cell Death, Cell Death Differ, vol. 16, no. 1, pp. 3-11.</li> <li>Chan, F.K., K. Moriwaki and M.J. De Rosa (2013), Detection of necrosis by release of lactate dehydrogenase (LDH) activity, Methods Mol Biol, vol. 979, pp. 65–70.</li> <li>Berridge, M.V., P.M. Herst and A.S. Tan (2005), Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnology Annual Review, vol. 11, pp 127-152.</li> <li>Moore, A, et al.(1998), Simultaneous measurement of cell cycle and apoptotic cell death,Methods Cell Biol, vol. 57, pp. 265–278.</li> <li>Li, Peng et al. (2004), Mitochondrial activation of apoptosis, Cell, vol. 116, no. 2 Suppl,pp. S57-59, 2 p following S59.</li> <li>Loo, D.T. (2002), TUNEL Assay an overview of techniques, Methods in Molecular Biology, vol. 203: In Situ Detection of DNA Damage, chapter 2, Didenko VV (ed.), Humana Press Inc.</li> <li>Kubbies, M. and P.S. Rabinovitch (1983), Flow cytometric analysis of factors which influence the BrdUrd-Hoechst quenching effect in cultivated human fibroblasts and lymphocytes, Cytometry, vol. 3, no. 4, pp. 276–281.</li> <li>Fink, S.L. and B.T. Cookson (2005), Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells, Infect Immun, vol. 73, no. 4, pp.1907-1916.</li> <li>O'Brien J, Wilson I, Orton T, Pognan F. 2000. Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. European journal of biochemistry / FEBS 267(17): 5421-5426.</li> <li>Repetto G, del Peso A, Zurita JL. 2008. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nature protocols 3(7): 1125-1131.</li> </ul> AOPWiki 2016-11-29T18:41:22

2022-07-15T09:46:25

Activation, Tissue resident cells (Kuppfer cells)

Cellular

AOPWiki 2019-01-07T09:04:22

2019-01-07T09:04:22

Necrotic Tissue

Tissue

Taxa = necrotic tissue in the liver During the process of towards necrotic tissue, too many cells die. In practice it is difficult to distinguish separate forms of cell death (apoptosis, necrosis and necroptosis), especially in vivo.

Histopathology: performed on tissue sections · Hematoxylin (nuclei) and eosin staining: determine morphology · TUNEL staining: cell death https://medical-dictionary.thefreedictionary.com/Necrotic+tissue https://livertox.nih.gov/Phenotypes_ahn.html (Weng et al. 2015) (Guicciardi et al. 2013)

Guicciardi, M.E. et al., 2013. Apoptosis and Necrosis in the Liver. Comprehensive Physiology, 3(2), pp.977–1010. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3867948&tool=pmcentrez&rendertype=abstract. Weng, H. et al., 2015. Two sides of one coin: Massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure. Frontiers in Physiology, 6(MAY), pp.1–12. AOPWiki 2018-12-19T09:40:01

2019-03-07T04:19:14

Liver Injury

Organ

Hepatic Injury after apoptosis.(Landesmann, 2016) Liver injury is the altered state of the liver wherein the normal homeostasis of all process in the liver are perturbed.   4 types of liver injury are distinguished in patients:   Hepatocellular (= acute hepatitis) Characteristics = elevation of serum transaminases (ALT+AST)   Choleostatic (= obstruction of the bile duct (bile cannot flow from liver to duodenum)) Characteristics = a) elevation in serum alkaline phosphatase (ALP) with normal or mild elevations in serum transaminases (ALT+AST) b) elevated bilirubin levels   Infiltrative (= sarcoidosis, tuberculosis, liver abscess, metastatic malignancy) Characteristics = a) elevation in serum alkaline phosphatase with normal or mild elevations (less than five times normal) in serum transaminases b) no effects at bilirubin levels   Autoimmune (= autoimmune disease against liver components) Characteristics = can present itself as hepatocellular when hepatocytes are target (= autoimmune hepatitis) or cholestatic when biliary ducts is the target (primary biliary cirrhosis) Drug induced liver injury mostly manifest itself as hepatocellular injury, cholestasis or a mixture of both. In a mixture hepatitis the amount of hepatocellular and cholestatic features vary per case. Biopsy results with mixed hepatitis is a combination of: Hepatocellular = liver cell necrosis, inflammation Choleostatic = bile stasis, portal inflammation, injury of bile ducts Patient with any kind of mixed hepatitis demonstrates the following symptoms: First symptoms = Fatigue, anorexia and nausea Later symptoms = jaundice (=skin and eye white become yellows/greenish) dark urine and pruritus (= sensitization of itch)

Indicators of liver injury include: Levels of: ALT, AST, ALP, bilirubin, GGT, NTP, Ceruloplasmin, AFP (Guicciardi et al. 2013)   Test in patients or in vivo(Gowda et al. 2009) (Musana et al. 2004): · Biochemistry assays · Levels of: ALT, AST, ALP, bilirubin, GGT, NTP, Ceruloplasmin, AFP, · Imaging scans · Ultrasound · CT · MRI · Biopsy

Landesmann, B. (2016). Adverse Outcome Pathway on Protein Alkylation Leading to Liver Fibrosis, (2). Guicciardi ME, Malhi H, Mott JL, Gores GJ (2013) Apoptosis and Necrosis in the Liver Maria. Compr Physiol 3:977–1010 . doi: 10.1002/cphy.c120020.Apoptosis Musana, K.A., Yale, S.H. & Abdulkarim, A.S., 2004. Tests of liver injury. Clin Med Res, 2(2), pp.129–131. Gowda, S. et al., 2009. A review on laboratory liver function tests. The Pan African medical journal, 3(November), p.17. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21532726%5Cnhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC2984286. AOPWiki 2018-12-19T09:40:21

2019-03-07T04:23:21

Increase, proinflammatory mediators (TNFalpha)

Molecular

AOPWiki 2019-01-07T10:44:46

2019-01-07T10:44:46

<upstream-id>cbb7523d-d34e-4349-b6f6-8ea3dc1afebb</upstream-id> <downstream-id>154fa975-42a5-4486-8046-b7a147a40eaf</downstream-id> Phosphorylated IKK complex will activate the IkBa complex by phosphorylation. For an overview of the phosphorylation sites of NFkB see (Christian, Smith, & Carmody, 2016).The IkBa complex will be K48-ubiquitinated and degraded, allowing NFkB to translocate to the nucleus. If the IKK complex is inhibited the IkBa complex will not be phosphorylated anymore whereupon the IkBa complex is not degraded and the NFkB complex stays inside the cytoplasm. Therefore no downstream target genes will be transcribed.

The road to discovery of NFkB is described by David Baltimore (Baltimore 2009). Later it became clear that the main event of NFkB activation was IkB phosphorylation. In order the phosphorylate IkB, a kinase was necessary. This turned out to be the IkB kinase, or IKK complex (DiDonato et al. 1997; Karin 1999). Now, it has been well established that IKK complex can activate the NFkB pathway and inhibition leads to NFkB inhibition. This is described in the following reviews: (Liu et al. 2017) (Gamble et al. 2012) (Karin et al. 2004) (Perkins 2007) (Li & Verma 2002) (Ghosh & Hayden 2008) (Hayden & Ghosh 2012) (Gupta et al. 2010)

Knockout studies: Hepatocyte NEMO KO mice stimulated with TNF show no IkBa degradations, inhibition of NFkB and inhibition of target gene transcription (BCL2). (Beraza et al. 2007) Hepatocyte NEMO KO mice stimulated with TNF related cytokines (TRAIL) are hypersensitive for liver injury (upregulation pJNK and Caspase 3). Protected against Fas-mediated apoptosis (Beraza et al. 2009). Parenchymal (hepatocyte and endothelial cells) NEMO KO mice show steatohepatitis and hepatocellular carcinoma. TUNEL staining showed increased apoptosis in KO mice (compared to WT and IKK2 KO). NfkB activation induced by LPS is blocked and increased LPS toxicity is observed (Luedde et al. 2007). Massive liver apoptosis in full NEMO KO mouse embryo’s, lack of NFkB activation after TNF in KO MEFs and sensitized to TNF cytotoxicity (Rudolph et al. 2000).   Specific compound studies: Flavokawain B (FKB), the hepatotoxic constituent from kava root, induces cell death in HepG2. This is observed with oxidative stress, GSH depletion, IKK activity inhibition and downstream NFkB target inhibition (IkBa). MAPKs were also activated (phosphorylated variants of JNK, p38 and ERK). Addition of GSH rescues cell from death (Zhou et al. 2010).

Few compounds found which inhibit IKK complex and could cause liver injury. Many more compounds which inhibit NFkB pathway and cause liver injury. Hepatocytes exposed to di-(2-ethylhexyl)phthalate (DEHP) show activation of IKK and NFkB and this lead to hepatic cell death. Cell death is decreased by preexposure to PS-1145, a specific IKK inhibitor (and no Caspase3 activation observed). (Ghosh et al. 2010)

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4310c00958> AOPWiki 2019-01-07T09:10:08

2019-03-07T05:52:23

<upstream-id>9a270278-e3fb-4d6f-9ce8-8546632f3cdc</upstream-id> <downstream-id>010e9ce3-711a-4950-8ab6-1f039f521877</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4310a854c0> AOPWiki 2019-01-07T09:14:00

2019-01-07T09:14:00

<upstream-id>154fa975-42a5-4486-8046-b7a147a40eaf</upstream-id> <downstream-id>e25a739c-1402-4c88-92fa-0591722269b0</downstream-id> The downstream targets of NFkB are genes involved in cell survival and proliferation. When NFkB is inhibited, less of these cell survival genes will be transcribed, making the cell more susceptible for cell death pathways, like the caspase 8 pathway. (Frederiksson, 2012).In other words, lack of NFkB inhibition will lead to no inhibition of the capase pathway.

It has been well established that NFkB inhibits apoptosis. This is shown in the following reviews: (Oeckinghaus et al. 2011) RIP1 dependent signaling pathways (Kruidering & Evan 2000) Mechanisms of caspase 8 (Brenner et al. 2015) TNF induced necroptosis via procaspase8 and RIPK1 (Hayden & Ghosh 2012) Extensive review NFkB

Experiments supporting the plausibility In vitro TNF induced NFkB activation is not impaired in caspases 8 deficient (or FLIP deficient) MEFs, but caspase 8 is required for TNF to cause cell death. (Moujalled et al. 2012) Griseofulvin: Inhibit NFkB signaling in combination with TNF measured by ICAM1 reduction in HepG2. Also shows synergistic cell death with TNF. Knockdown of Caspase8 rescued the cell from apoptosis (Huppelschoten 2017). Diclofenac: Inhibit NFkB signaling in combination with TNF measured by ICAM1 reduction in HepG2. Also shows synergistic cell death with TNF. Knockdown of Caspase8 rescued the cell from apoptosis (Huppelschoten 2017). Valproic acid: Synergistic cell death with TNF, rescues upon caspase8 knockdown in HepG2. VPA inhibit Nfkb-pathway in HepG2? [Testing planned].

Caspase 8 activation leads to cell death but this is blocked in healthy cells by NFkB (Murphy 2012). The balance between NfkB activation and cell death is complicated and includes crosstalk between several pathways. For example, not only target genes of NFkB signaling can induce survival, but also RIPK1 signaling with pro caspase8 block necrosis. (Brenner et al. 2015) (Dondelinger et al. 2015) IKK subunits alpha and beta phosphorylate RIPK1, thereby inducing apoptosis via FADD/caspase-8: IKK inactivation induces cell death via RIPK1. NFkB is indeed inhibited and induces cell death, however, in parallel, RIPK1 dependent cell death is quicker. This pathway is also activated by IKK complex inactivation.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4308998268> AOPWiki 2019-01-07T09:11:22

2019-03-07T05:56:50

<upstream-id>e25a739c-1402-4c88-92fa-0591722269b0</upstream-id> <downstream-id>9a270278-e3fb-4d6f-9ce8-8546632f3cdc</downstream-id> After recruitment, dimerization and activation of Caspase8, the active caspase will clear executioner caspases (3,6,7) or activate the intrinsic apoptotic pathway via BID. (McIlwain et al. 2015)

It has been well established that caspase activation leads to cell death. In the caspase 8 pathway, the TRADD adaptor protein recruits FADD and forms a complex together with pro-caspase 8. Then caspase 8 can directly activate caspase-3, -6, or -7, which leads to apoptosis. Furthermore, Caspase8 can also splice Bid to tBid which promotes disruption of the membrane of mitochondria. Cytochrome C will be released and forms an apoptosome with followed by activation of Caspase 9 and Apaf1. These can stimulate procaspases 3,6,7 which can induce apoptosis. (Murphy 2012; Melino & Vaux 2010)

Evidence caspase 8 leads to cell death: Reviewed by (McIlwain et al. 2015) Cells from caspase 8 deficient mice are resistant to death receptor induced apoptosis. Cells from FADD or TRADD deficient mice are resistant for TNFa mediated apoptosis. Inactivating Caspase 8 mutations are associated with cancers. A selective caspases inhibitor in patients with hepatitis virus C infection showed reduced ALT levels and CK-18 fragments through reduction of apoptosis in the liver, according to authors (Manns et al. 2010) Hepatocyte specific Caspase 8 KO protects from LPS or Fas mediated apoptosis. However, increased necrotic damage is observed. Double KO Caspase8 and NEMO were protected against steatosis and hepatocarcinogenesis but have massive liver necrosis, cholestasis and biliary lesions, caused RIP complex accumulation(Liedtke et al. 2011)

Hepatocellular deletion of Caspase 8 in mice show less apoptosis after DCC treatment (model hepatocholestasis)(Chaudhary et al. 2013)

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b4308a28ef8> AOPWiki 2019-01-07T09:11:53

2019-03-07T06:03:40

<upstream-id>9a270278-e3fb-4d6f-9ce8-8546632f3cdc</upstream-id> <downstream-id>c483d86b-a66c-424c-97a8-c7a386fc98d4</downstream-id> Cell death can help the maintenance of the organ, for example by avoiding cancer. However, in the KER, cell death will lead to necrotic tissue. If too many cells die, the tissue will fall apart. There are several types of necrotic tissue caused by cell death: Apoptosis (individual cell necrosis), spotty and focal necrosis, zonal necrosis confluent necrosis. Every type can have a different underlying disease. All types can occur by drug induced liver injury.(Krishna 2017).

It has been well established that cell death can lead to necrotic tissue. Reviews: (Guicciardi et al. 2013): Apoptosis and necrosis in the liver. (Luedde et al. 2014): Cell death in liver disease.

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc7129c8> AOPWiki 2019-01-07T09:12:27

2019-03-07T06:05:19

<upstream-id>c483d86b-a66c-424c-97a8-c7a386fc98d4</upstream-id> <downstream-id>c5b27aa1-02ce-41a7-9036-9589ba5483eb</downstream-id> Logically when liver tissue is degraded, the liver will fail to execute its function. Again, this can be tissue type dependent(Krishna 2017)

Necrotic tissue is frequently observed in liver disease, e.g. a failing liver. Reviews: (Guicciardi et al. 2013): Apoptosis and necrosis in the liver. (Luedde et al. 2014): Cell death in liver disease. (Krishna 2017): Patterns of Necrosis in Liver disease. (Malhi et al. 2006): Apoptosis and necrosis in the liver (including TNF signaling (NFkB and Caspase8) part)

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc477178> AOPWiki 2018-12-19T09:45:26

2019-03-07T06:07:46

<upstream-id>010e9ce3-711a-4950-8ab6-1f039f521877</upstream-id> <downstream-id>902281ae-1e7c-434d-be42-8b041a5c5e2d</downstream-id>

#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc67d648> AOPWiki 2019-01-07T10:48:02

2019-01-07T10:48:02

IKK complex inhibition leading to liver injury

Brendan Ferreri-Hanberry

Vrijenhoek, N.G. 1 1Leiden Academic Center for Drug Research, Leiden Univeristy, Leiden, The Netherlands

BY-SA

2.0

Inflammation has a critical role in liver and other types of injury. Activation of inflammatory events leads to the release of several cytokines, including TNFalpha. When this proinflammatory cytokine is released it can stimulate the TNF-receptor (TNFR), leading to a cascade of pathway activations. However, chemicals can alter these pathways in several ways and influence the TNFR related cascades. This AOP describes the key events of chemically induced IKK complex inhibition which leads to liver injury during TNF signaling. This AOP starts with the molecular initiating event  “inhibition of the IKK complex”. When the IKK complex is inhibited, the NFkB pathway activation is disturbed, leading to less transcription of anti-apoptotic genes. Then, without apoptosis protection, the activation of Caspase 8, is not inhibited anymore. Caspase 8 activates caspase 3, leading to apoptosis, or cell death. Finally, too much cell death will lead to necrotic tissue and eventually liver failure. This AOP will collect information about NFkB signaling and will contribute to the mechanistic insights of the inflammatory pathways during hepatotoxicity. Furthermore, since inflammation is a reoccurring KE in several AOPs, this AOP will expand the knowledge of current AOPs of the influence of TNF signaling and compound induced toxicity.

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AOPWiki 2019-01-07T08:00:15

2023-09-25T16:26:59