NOCAS_35060Food deprivationDTXSID70350601403-66-3GentamicinGentacycol
Gentalline
gentamicina
gentamicine
GENTAMYCIN
Gentavet
Lyramycin
Oksitselanim
Septigen
Centicin
Gentamycins
DTXSID5034642UBERON:0005386olfactory segment of nasal mucosaMP:0002006neoplasm1increasedFood deprivation2021-09-06T07:33:542021-09-06T07:33:54Gentamicin2017-10-25T08:30:152017-10-25T08:30:15WCS_7955zebrafishWCS_9606human10116rat10090mouseInhibition, cytochrome oxidaseInhibition, cytochrome oxidaseMolecular2021-02-19T13:59:552021-02-19T13:59:55Increase, Cell deathIncrease, Cell deathCellular<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Cell death is part of normal development and maturation cycle, and is the component of many response patterns of living tissues to xenobiotic agents (i.e.. micro organisms and chemicals) and to endogenous modulations, such as inflammation and disturbed blood supply (Kanduc et al., 2002). Many physiological processes require cell death for their function (e.g.., embryonal development and immune selection of B and T cells) (Bertheloot et al., 2021). Defects in cells that result in their inappropriate survival or untimely death can negatively impact development or contribute to a variety of human pathologies, including cancer, AIDS, autoimmune disorders, and chronic infection. Cell death may also occur following exposure to environmental toxins or cytotoxic chemicals. Although this is often harmful, it can be beneficial in some cases, such as in the treatment of cancer (Crowley et al., 2016). </span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Cell death can be </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">divided into: programmed cell death (cell death as a normal component of development) and non-programmed cell death (uncontrolled death of the cell). Although this simplistic view has blurred the intricate mechanisms separating these forms of cell death, studies have and will uncover new effectors, cell death pathways and reveal a more complex and intertwined landscape of processes involving cell death </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Bertheloot et al., 2021).</span></span></p>
<p><span style="font-size:18px"><em><span style="font-family:"Calibri",sans-serif">Programmed cell death:</span></em></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> is a form of cell death in which the dying cell plays an active part in its own demise </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Cotter & Al-Rubeai, 1995)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">.</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Apoptosis</u></strong> At a morphological level, it is characterized by cell shrinkage rather than the swelling seen in necrotic cell death. It is characterized by a number of characteristic morphological changes in the structure of the cell, together with a number of enzyme‐dependent biochemical processes. The result of it being the clearance of cells from the body, with minimal damage to surrounding tissues. An essential feature of apoptosis is the release of cytochrome c from mitochondria, regulated by a balance between proapoptotic and antiapoptotic proteins of the BCL-2 family, initiator caspases (caspase-8, -9 and -10) and effector caspases (caspase-3, -6 and -7). Apoptosis culminates in the breakdown of the nuclear membrane by caspase-6, the cleavage of many intracellular proteins (e.g., PARP and lamin), membrane blebbing, and the breakdown of genomic DNA into nucleosomal structures (Bertheloot et al., 2021). Mechanistically, two main pathways contribute to the caspase activation cascade downstream of mitochondrial cytochrome c release: </span></span></p>
<ul>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><u>Intrinsic pathway</u> is triggered by dysregulation of or imbalance in intracellular homeostasis by toxic agents or DNA damage. It is characterized by mitochondrial outer membrane permeabilization (MOMP), which results in the release of cytochrome c into the cytosol.</span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><u>Extrinsic pathway</u> is initiated by activation of cell surface death receptors. Proapoptotic death receptors include TNFR1/2, Fas and the TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5.</span></span></li>
</ul>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><u>Other pathways of programmed cell death are called »non-apoptotic programmed cell-death« or »caspase-independent programmed cell-death« </u>(Blank & Shiloh, 2007)<u>.</u></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Necroptosis:</u></strong> This type of regulated cell death, occurs following the activation of the tumor necrosis receptor (TNFR1) by TNFα. Activation of other cellular receptors triggers necroptosis. These receptors include death receptors (i.e., Fas/FasL), Toll-like receptors (TLR4 and TLR3) and cytosolic nucleic acid sensors such as RIG-I and STING, which induce type I interferon (IFN-I) and TNFα production and thus promote necroptosis in an autocrine feedback loop. Most of these pathways trigger NFκB- dependent proinflammatory and prosurvival signals. </span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Pyroptosis</u></strong> is a type of cell death culminating in the loss of plasma membrane integrity and induced by activation of so-called inflammasome sensors. These include the Nod-like receptor (NLR) family, the DNA receptor Absent in Melanoma 2 (AIM2) and the Pyrin receptor.</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Autophagy:</u></strong> is a process where cellular components such as macro proteins or even whole organelles are sequestered into lysosomes for degradation (Mizushima et al., 2008; Shintani & Klionsky, 2004). The lysosomes are then able to digest these substrates, the components of which can either be recycled to create new cellular structures and/or organelles or alternatively can be further processed and used as a source of energy (D’Arcy, 2019).</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Anoikis</u></strong> is apoptosis induced by loss of attachment to substrate or to other cells (anoikis). Anoikis overlaps with apoptosis in molecular terms, but is classified as a separate entity because of its specific form od induction (Blank & Shiloh, 2007). Induction of anoikis occurs when cells lose attachment to ECM, or adhere to an inappropriate type of ECM, the latter being the more relevant <em>in vivo </em>(Gilmore, 2005).</span></span></p>
<p><strong><u><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Cornification</span></span></u></strong><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">: is programmed cell death of keratinocytes. Cell death in the context of cornification involves distinct enzyme classes such as transglutaminases, proteases, DNases and others </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Eckhart et al., 2013)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">.</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><span style="font-size:18px"><em>Non-programmed cell death:</em></span> occurs accidentally in an unplanned manner.</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Necrosis</u></strong> is generally characterized to be the uncontrolled death of the cell, usually following a severe insult, resulting in spillage of the contents of the cell into surrounding tissues and subsequent damage thereof (D’Arcy, 2019).</span></span></p>
<p> </p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong>Assays for Quantitating Cell Death:</strong></span></span></p>
<ul>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Cell death can be measured by staining a sample of cells with trypan blue, assay is described in protocol: Measuring Cell Death by Trypan Blue Uptake and Light Microscopy (Crowley, Marfell, Christensen, et al., 2015d). Or with propidium Iodide, assay is described in protocol: Measuring Cell Death by Propidium Iodide (PI) Uptake and Flow Cytometry (Crowley & Waterhouse, 2015a) </span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">TUNEL technique: in situ terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling can be used to detect apoptotic cells (Bever & Fekete, 1999; Uribe et al., 2013).</span></span></li>
</ul>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong>Assays for Quantitating Cell Survival </strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Colony-forming assay can be used to define the number of cells in a population that are capable of proliferating and forming large groups of cells. Described in Protocol: Measuring Survival of Adherent Cells with the Colony-Forming Assay (Crowley, Christensen, & Waterhouse, 2015c); Measuring Survival of Hematopoietic Cancer Cells with the Colony-Forming Assay in Soft Agar (Crowley & Waterhouse, 2015b).</span></span></p>
<p><em><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong>ASSAYS TO DISTINGUISH APOPTOSIS FROM NECROSIS AND OTHER DEATH MODALITIES</strong></span></span></em></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Detecting Nuclear Condensation:</u></strong> The nucleus is generally round in healthy cells but fragmented in apoptotic cells. Dyes such as Giemsa or hematoxylin, which are purple in color and therefore easily viewed using light microscopy, are commonly used to stain the nucleus. Other features of apoptosis and necrosis, such as plasma membrane blebbing or rupture, can be identified by staining the cytoplasm with eosin. Eosin is pinkish in color and can also be viewed using light microscopy. Hematoxylin and eosin are, therefore, commonly used together to stain cells. Assay is described in Protocol: Morphological Analysis of Cell Death by Cytospinning Followed by Rapid Staining (Crowley, Marfell, & Waterhouse, 2015c); Analyzing Cell Death by Nuclear Staining with Hoechst 33342 (Crowley, Marfell, & Waterhouse, 2015a).</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Detection of DNA Fragmentation: </u></strong>Apoptotic cells with fragmented DNA can be identified and distinguished from live cells by staining with Propidium Iodide (PI) and measuring DNA content by flow cytometry. This assay is described in Protocol: Measuring the DNA Content of Cells in Apoptosis and at Different Cell-Cycle Stages by Propidium Iodide Staining and Flow Cytometry (Crowley, Chojnowski, & Waterhouse, 2015a).<strong><u> TUNEL technique </u></strong>can also be used<strong>:</strong> in situ terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling can be used to detect apoptotic cells (Bever & Fekete, 1999; Crowley, Marfell, & Waterhouse, 2015b; Uribe et al., 2013).</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Detecting Phosphatidylserine Exposure:</u></strong> Apoptosis is also characterized by exposure of phosphatidylserine (PS) on the outside of apoptotic cells, which acts as a signal that triggers removal of the dying cell by phagocytosis. Annexin V, can selectively bind to PS to label apoptotic cells in which PS is exposed. Purified annexin V can be conjugated to various fluorochromes, which can then be visualized by fluorescence microscopy or detected by flow cytometry. This assay is described in protocol: Quantitation of Apoptosis and Necrosis by Annexin V Binding, Propidium Iodide Uptake, and Flow Cytometry (Crowley, Marfell, Scott, et al., 2015e). </span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><strong><u>Detecting Caspase Activity:</u></strong> antibodies that specifically recognize the cleaved fragments of caspases and their substrates can be used to specifically detect caspase activity in apoptotic cells by immunocytochemistry. Flow cytometry (using primary antibodies conjugated to fluorescent molecules, or by counter staining with fluorescently labeled antibodies against the primary antibody) can then be used to quantitate the number of apoptotic cells. This assay is described in protocol: Detecting Cleaved Caspase-3 in Apoptotic Cells by Flow Cytometry (Crowley & Waterhouse, 2015a).</span></span></p>
<p><strong><u><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Detecting Mitochondrial Damage:</span></span></u></strong><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> flow cytometry can be used to quantitate the number of cells that have reduced mitochondrial transmembrane potential, which is commonly associated with cytochrome c release during apoptosis. For this assay see protocol: Measuring Mitochondrial Transmembrane Potential by TMRE Staining </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Crowley, Christensen, & Waterhouse, 2015b)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">.</span></span></p>
<p> </p>
<p> </p>
<p><span style="font-size:11px"><span style="color:#e74c3c">Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed. </span></span></p>
<p> </p>
<p><span style="display:none"> </span><span style="font-size:11px"><span style="color:#e74c3c">Measures of apoptotic cytomorphological alterations: </span></span></p>
<p><span style="display:none"> </span><span style="font-size:11px"><span style="color:#e74c3c">Apoptotic cells exhibit electron dense nuclei, nuclear fragmentation, intact cell membrane up to the disintegration phase, disorganized cytoplasmic organelles, large clear vacuoles, blebs at cell surface, and apoptotic bodies, which can be visualized with various methods. (Elmore, 2007; Watanabe et al., 2002) </span></span></p>
<table border="1">
<tbody>
<tr>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Method of Measurement </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Reference </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Description </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">OECD Approved Assay </span></strong></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Transmission electron microscopy (TEM) / Scanning electron microscopy (SEM)/ Fluorescence microscopy </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Martinez, Reif, and Pappas, 2010; Watanabe et al., 2002 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">TEM and SEM can image the cytomorphological alterations caused by apoptosis. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td colspan="3">
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Stains: </span></strong></span></p>
</td>
<td>
<p> </p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Hematoxylin with eosin </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Elmore, 2007 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Hematoxylin stains nuclei blue and eosin stains the cytoplasm/extracellular matrix pink, allowing for the visualization of the cytomorphological alterations of cells. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Toluidine blue or methylene blue </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Watanabe et al., 2002 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Toluidine blue stains cellular nuclei, and identifies malignant tissue, which has an increased DNA content and a higher nuclear-to-cytoplasmic ratio. </span></span></p>
<p><span style="font-size:11px"><span style="color:#e74c3c">Methylene blue stain applied to a healthy cell sample results in a colorless stain. This is due to the cell's enzymes, which reduce the methylene blue, thereby, reducing its color. Methylene blue stain applied to a dead cell sample turns blue. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">DAPI </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Crowley, Marfell, and Waterhouse, 2016 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Binds strongly to adenine–thymine-rich regions in the DNA. DAPI can stain live and fixed cells. It passes less efficiently through the membrane in live cells. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Yes </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Hoescht 33342 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Crowley, Marfell, and Waterhouse, 2016 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Binds to DNA in live and fixed cells, used to measure DNA condensation. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Yes </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Acridine Orange (AO) </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Watanabe et al., 2002 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Interacts with DNA/RNA through intercalation/electrostatic interaction, is able to penetrate cell membranes. Stains live cells green and dead cells red. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Nile blue sulfate </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Watanabe et al., 2002 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Stains cell nuclei and lysosomes, indicating apoptotic bodies. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Neutral red </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Watanabe et al., 2002 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Measures lysosomal membrane integrity </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">LysoTracker Red </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Watanabe et al., 2002 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Measures phagolysosomal activity that occurs due to the engulfment of apoptotic bodies. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="font-size:11px"><span style="color:#e74c3c">DNA damage/fragmentation assays: </span></span></p>
<table border="1">
<tbody>
<tr>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Assay </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Reference </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Description </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">OECD Approved Assay </span></strong></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Kressel and Groscurth, 1994 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Apoptosis is detected with the TUNEL method to assay the endonuclease cleavage products by enzymatically end-labeling the DNA strand breaks. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Yes </span></span></p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Nicoletti Assay (SubG1 cell fragment measurement) </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Nicoletti et al., 1991 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Measures DNA content in nuclei at the pre-G1 phase of the cell cycle (apoptotic nuclei have less DNA than nuclei in healthy cells). </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Cell Death Detection ELISA kit </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Parajuli, 2014 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Apoptotic nucleosomes are detected using the Cell Death Detection ELISA kit, which were calculated as absorbance subtraction at 405 nm and 490 nm. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="font-size:11px"><span style="color:#e74c3c">Measurement of apoptotic markers through immunochemistry: </span></span></p>
<table border="1">
<tbody>
<tr>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Method of Measurement </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Reference </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Description </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">OECD Approved Assay </span></strong></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Western blot / immunofluorescence microscopy / immunohistochemistry </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Elmore 2007; Martinez, Reif, and Pappas, 2010; Parajuli et al, 2014 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Apoptosis can be detected with the expression of various apoptotic markers by western blotting using antibodies. Markers can include: cytosolic cytochrome-c; caspases 2, 3, 6, 7, 8, 9, 10; Bax; Bcl-2 (apoptosis inhibitor); BIRC2; BIRC3; GAPDH; PARP; CDK2; CDK4; cyclin D1; p53; p63; p73; cytokeratin-18 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="font-size:11px"><span style="color:#e74c3c">Measures of altered caspase activity: </span></span></p>
<table border="1">
<tbody>
<tr>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Method of Measurement </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Reference </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Description </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">OECD Approved Assay </span></strong></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Caspase-3 and caspase-9 activity is measured with the enzyme-catalyzed release of p-nitroanilide (pNA) and quantified at 405 nm </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c"> Wu, 2016 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Visualizes caspase-3 and caspase-9 activity </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">PhiPhiLux Assay </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Watanabe et al., 2002 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">The PhiPhiLux molecule becomes fluorescent once it is cleaved by caspase-3, indicating caspase activity. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Ferrocene reporter </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Martinez, Reif, and Pappas, 2010 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">An electrochemical method to detect apoptosis. Ferrocene is attached to a peptide. The peptide sequence is a caspase 3 cleavage site and the ferrocene acts as the electrochemical reporter. The more caspase cleavage that occurs, the more ferrocene molecules are cleaved, the stronger the signal. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Self-assembled monolayers for matrix assisted laser desorption ionization time-of-flight mass spectrometry (SAMDI-MS) assay </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Martinez, Reif, and Pappas, 2010 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">This assay detects caspase activity. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="font-size:11px"><span style="color:#e74c3c">Measures of altered mitochondrial physiology: </span></span></p>
<table border="1">
<tbody>
<tr>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Method of Measurement </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Reference </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Description </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">OECD Approved Assay </span></strong></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Laser scanning confocal microscopy (LSCM) </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Watanabe et al., 2002 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">LCSM can monitor many mitochondrial events following staining of cells, such as: mitochondrial permeability transition, depolarization of the inner mitochondrial membrane, which may be indicative of apoptosis. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Fluorescent, cationic, lipophilic mitochondrial dyes, such as: JC-1 dye, Rhodamine, DiOC6, Mitotracker red </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Martinez, Reif, and Pappas, 2010; Sivandzade, Bhalerao, and Cucullo, 2019 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">These mitochondrial dyes can indicate disintegration of the mitochondrial outer membrane’s electrochemical gradient, as different fluorescence is observed between healthy and apoptotic cells. In healthy cells the dye accumulates in aggregates, but in apoptotic cells missing the electrochemical membrane, the dye will spread out into the cytoplasm providing different fluorescent signals. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="font-size:11px"><span style="color:#e74c3c">Other measures: </span></span></p>
<table border="1">
<tbody>
<tr>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Method of measurement </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Reference </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">Description </span></strong></span></p>
</td>
<td>
<p><span style="font-size:11px"><strong><span style="color:#e74c3c">OECD Approved Assay </span></strong></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Apoptosis PCR microarray </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Elmore, 2007 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">A method to profile the gene expression of many apoptotic-related genes, for example: ligands, receptors, intracellular modulators, and transcription factors. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Fluorescence correlation spectroscopy (FCS) or dual-colour fluorescence cross-correlation spectroscopy (dcFCCS) </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Martinez, Reif, and Pappas, 2010 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Used to measure protease activity. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">No </span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Apoptosis is measured with Annexin V-FITC probes </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Elmore, 2007; Wu et al., 2016 </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">A measure of apoptotic membrane alterations. Annexin-V detects externalized phosphatidylserine residues, a result of apoptosis. Can be conducted in conjunction with propidium iodide (PI) staining. The relative percentage of Annexin V-FITC-positive/PI-negative cells is analyzed by flow cytometry. </span></span></p>
</td>
<td>
<p><span style="font-size:11px"><span style="color:#e74c3c">Yes </span></span><span style="display:none"> </span><span style="display:none"> </span></p>
</td>
</tr>
</tbody>
</table>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">The process of cell death is highly conserved within multi‐cellular organisms. </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Lockshin & Zakeri, 2004)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">.</span></span></p>
<p> </p>
<p><span style="font-size:11px"><span style="color:#e74c3c"><strong>Taxonomic applicability</strong>: Increased cell death is applicable to all animals. This includes vertebrates such as humans, mice and rats (Alberts et al., 2002). </span></span></p>
<p><span style="font-size:11px"><span style="color:#e74c3c"><strong>Life stage applicability</strong>: There is insufficient data on life stage applicability of this KE. </span></span></p>
<p><span style="font-size:11px"><span style="color:#e74c3c"><strong>Sex applicability</strong>: This key event is not sex specific (Forger and de Vries, 2010; Ortona Matarrese, and Malorni, 2014). </span></span></p>
<p><span style="font-size:11px"><span style="color:#e74c3c"><strong>Evidence for perturbation by a stressor</strong>: Multiple studies show that cell death can be increased or disrupted by many types of stressors including ionizing radiation and altered gravity (Zhu et al., 2016). </span></span></p>
UBERON:0000062organCL:0000000cellHighUnspecificHighAll life stagesHighHighHighHigh<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Alberts, B. et al. (2002), “Programmed Cell Death (Apoptosis)”, in Molecular Biology of the Cell. 4th edition, Garland Science, New York, https://www.ncbi.nlm.nih.gov/books/NBK26873/ </span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Bertheloot, D., Latz, E., & Franklin, B. S. (2021). Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. <em>Cellular & Molecular Immunology</em>, <em>18</em>, 1106–1121. https://doi.org/10.1038/s41423-020-00630-3</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Bever, M. M., & Fekete, D. M. (1999). Ventromedial focus of cell death is absent during development of Xenopus and zebrafish inner ears. <em>Journal of Neurocytology</em>, <em>28</em>(10–11), 781–793. https://doi.org/10.1023/a:1007005702187</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Blank, M., & Shiloh, Y. (2007). Cell Cycle Programs for Cell Death: Apoptosis is Only One Way to Go. <em>Cell Cycle</em>, <em>6</em>(6), 686–695. https://doi.org/10.4161/cc.6.6.3990</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Cotter, T. G., & Al-Rubeai, M. (1995). Cell death (apoptosis) in cell culture systems. <em>Trends in Biotechnology</em>, <em>13</em>(4), 150–155. https://doi.org/10.1016/S0167-7799(00)88926-X</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., Chojnowski, G., & Waterhouse, N. J. (2015a). Measuring the DNA content of cells in apoptosis and at different cell-cycle stages by propidium iodide staining and flow cytometry. <em>Cold Spring Harbor Protocols</em>, <em>10</em>, 905–910. https://doi.org/10.1101/pdb.prot087247</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., Christensen, M. E., & Waterhouse, N. J. (2015b). Measuring mitochondrial transmembrane potential by TMRE staining. <em>Cold Spring Harbor Protocols</em>, <em>12</em>, 1092–1096. https://doi.org/10.1101/pdb.prot087361</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., Christensen, M. E., & Waterhouse, N. J. (2015c). Measuring survival of adherent cells with the Colony-forming assay. <em>Cold Spring Harbor Protocols</em>, <em>8</em>, 721–724. https://doi.org/10.1101/pdb.prot087171</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., Marfell, B. J., Christensen, M. E., & Waterhouse, N. J. (2015d). Measuring cell death by trypan blue uptake and light microscopy. <em>Cold Spring Harbor Protocols</em>, <em>7</em>, 643–646. https://doi.org/10.1101/pdb.prot087155</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., Marfell, B. J., Scott, A. P., Boughaba, J. A., Chojnowski, G., Christensen, M. E., & Waterhouse, N. J. (2016). Dead cert: Measuring cell death. <em>Cold Spring Harbor Protocols</em>, <em>2016</em>(12), 1064–1072. https://doi.org/10.1101/pdb.top070318</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., Marfell, B. J., Scott, A. P., & Waterhouse, N. J. (2015e). Quantitation of apoptosis and necrosis by annexin V binding, propidium iodide uptake, and flow cytometry. <em>Cold Spring Harbor Protocols</em>, <em>11</em>, 953–957. https://doi.org/10.1101/pdb.prot087288</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., Marfell, B. J., & Waterhouse, N. J. (2015a). Analyzing cell death by nuclear staining with Hoechst 33342. <em>Cold Spring Harbor Protocols</em>, <em>9</em>, 778–781. https://doi.org/10.1101/pdb.prot087205</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., Marfell, B. J., & Waterhouse, N. J. (2015b). Detection of DNA fragmentation in apoptotic cells by TUNEL. <em>Cold Spring Harbor Protocols</em>, <em>10</em>, 900–905. https://doi.org/10.1101/pdb.prot087221</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., Marfell, B. J., & Waterhouse, N. J. (2015c). Morphological analysis of cell death by cytospinning followed by rapid staining. <em>Cold Spring Harbor Protocols</em>, <em>9</em>, 773–777. https://doi.org/10.1101/pdb.prot087197</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., & Waterhouse, N. J. (2015a). Detecting cleaved caspase-3 in apoptotic cells by flow cytometry. <em>Cold Spring Harbor Protocols</em>, <em>11</em>, 958–962. https://doi.org/10.1101/pdb.prot087312</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Crowley, L. C., & Waterhouse, N. J. (2015b). Measuring survival of hematopoietic cancer cells with the Colony-forming assay in soft agar. <em>Cold Spring Harbor Protocols</em>, <em>8</em>, 725. https://doi.org/10.1101/pdb.prot087189</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">D’Arcy, M. S. (2019). Cell death: a review of the major forms of apoptosis, necrosis and autophagy. <em>Cell Biology International</em>, <em>43</em>(6), 582–592. https://doi.org/10.1002/cbin.11137</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Eckhart, L., Lippens, S., Tschachler, E., & Declercq, W. (2013). Cell death by cornification. <em>Biochimica et Biophysica Acta - Molecular Cell Research</em>, <em>1833</em>(12), 3471–3480. https://doi.org/10.1016/j.bbamcr.2013.06.010</span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Elmore, S. (2007), “Apoptosis: A Review of Programmed Cell Death”, Toxical Pathology, Vol. 35/4, SAGE, </span><a href="https://doi.org/10.1080%2F01926230701320337" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1080/01926230701320337</span></a><span style="color:#e74c3c">. </span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Forger, N. G. and G. J. de Vries (2010), “Cell death and sexual differentiation of behavior: worms, flies, and mammals”, Current opinion in neurobiology, Vol. 20/6, Elsevier, Amsterdam, </span><a href="https://doi.org/10.1016/j.conb.2010.09.006" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1016/j.conb.2010.09.006</span></a><span style="color:#e74c3c"> </span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Gilmore, A. P. (2005). Anoikis. <em>Cell Death and Differentiation</em>, <em>12</em>, 1473–1477. https://doi.org/10.1038/sj.cdd.4401723</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Kanduc, D., Mittelman, A., Serpico, R., Sinigaglia, E., Sinha, A. A., Natale, C., Santacroce, R., Di Corcia, M. G., Lucchese, A., Dini, L., Pani, P., Santacroce, S., Simone, S., Bucci, R., & Farber, E. (2002). Cell death: apoptosis versus necrosis (review). <em>International Journal of Oncology</em>, <em>21</em>(1), 165–170. https://doi.org/10.3892/ijo.21.1.165</span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Kressel, M. and P. Groscurth (1994), "Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA", Cell and tissue research, Vol. 278/3, Nature, </span><a href="https://doi.org/10.1007/BF00331373" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1007/BF00331373</span></a><span style="color:#e74c3c">. </span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Lockshin, R. A., & Zakeri, Z. (2004). Apoptosis, autophagy, and more. <em>International Journal of Biochemistry and Cell Biology</em>, <em>36</em>(12), 2405–2419. https://doi.org/10.1016/j.biocel.2004.04.011</span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Martinez, M. M., R. D. Reif, and D. Pappas (2010), “Detection of apoptosis: A review of conventional and novel techniques”, Analytical Methods, Vol. 2/8, Royal Society of Chemistry, </span><a href="https://doi.org/10.1039/C0AY00247J" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1039/C0AY00247J</span></a><span style="color:#e74c3c"> </span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Mizushima, N., Levine, B., Cuervo, A. M., & Klionsky, D. J. (2008). Autophagy fights disease through cellular self-digestion. <em>Nature</em>, <em>451</em>(7182), 1069–1075. https://doi.org/10.1038/nature06639</span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Nicoletti I. et al. (1991), “A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry”, Journal of Immunological Methods, Vol. 139/2, Elsevier, Amsterdam, https://doi.org/10.1016/0022-1759(91)90198-O</span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Ortona, E., P. Matarrese, and W. Malorni (2014), “Taking into account the gender issue in cell death studies”, Cell Death & Disease, Vol. 5, Nature, </span><a href="https://doi.org/10.1038/cddis.2014.73" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1038/cddis.2014.73</span></a><span style="color:#e74c3c">. </span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Parajuli, K. R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", American journal of clinical and experimental urology, Vol. 2/4, pp. 300-312. </span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Shintani, T., & Klionsky, D. J. (2004). Autophagy in health and disease: A double-edged sword. <em>Science</em>, <em>306</em>(5698), 990–995. https://doi.org/10.1126/science.1099993</span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Sivandzade, F., A. Bhalerao and L. Cucullo (2019), “Analysis of the Mitochondrial Membrane Potential Using Cationic JC-1 Dye as a Sensitive Fluorescent Probe”, Bio Protocol, Vol. 9/1, </span><a href="https://doi.org/10.21769/BioProtoc.3128" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.21769/BioProtoc.3128</span></a><span style="color:#e74c3c">. </span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Uribe, P. M., Sun, H., Wang, K., Asuncion, J. D., & Wang, Q. (2013). Aminoglycoside-Induced Hair Cell Death of Inner Ear Organs Causes Functional Deficits in Adult Zebrafish (Danio rerio). <em>PLoS ONE</em>, <em>8</em>(3), 58755. https://doi.org/10.1371/journal.pone.0058755</span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Wade, M. G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biology of Reproduction, Vol. 78/5, Oxford University Press, Oxford, </span><a href="https://doi.org/10.1095/biolreprod.107.065151" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1095/biolreprod.107.065151</span></a><span style="color:#e74c3c"> </span></span></p>
<p style="margin-left:32px"><span style="font-size:11px"><span style="color:#e74c3c">Watanabe, M., et al. (2002), “The pros and cons of apoptosis assays for use in the study of cells, tissues, and organs”, Microscopy and microanalysis, Vol. 8/5, Cambridge University Press, Cambridge, </span><a href="https://doi.org/10.1017/S1431927602010346" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1017/S1431927602010346</span></a><span style="color:#e74c3c">. </span></span></p>
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2020-12-04T15:13:072023-03-22T11:07:45Increase, Site of Contact Nasal TumorsIncrease, Site of Contact Nasal TumorsOrganUBERON:0002268olfactory organHighLowLow2016-11-29T18:41:272017-09-16T10:16:38Cytochrome oxidase inhibition leading to olfactory nasal lesionsCytochrome oxidase inhibition to nasal tissues outcomes<p>Katy Goyak. <span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><em>ExxonMobil Biomedical Sciences, Inc., Annandale, NJ, USA</em></span></span></p>
<p><span style="font-size:14pt"><span style="font-family:"Times New Roman",serif">R. Jeffrey Lewis. </span></span><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><em>ExxonMobil Biomedical Sciences, Inc., Annandale, NJ, USA</em></span></span></p>
Under development: Not open for comment. Do not cite<p>The AOP is initiated by inhibition of cytochrome oxidase, one of the complexes that carry out oxidative phosphorylation, the main process through which cellular energy is created in the form of ATP <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Kühlbrandt 2015; Cogliati et al. 2018)</span></span>. With sufficient inhibition, cell death can occur, particularly for cells with high energy demand like neurons <span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Kann and Kovács 2007; Rugarli and Langer 2012)</span></span>. <span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Under continued chemical insult, neuronal cell death in the olfactory epithelium may exceed the capacity of olfactory neurons to generate, resulting in adaptive tissue remodeling and basal cell hyperplasia (here defined as olfactory nasal lesions) (Monticello et al. 1990; Hardisty et al. 1999; Teeguarden 2017). </span></span></p>
<p>This AOP was developed for the purpose of bringing mechanistic information as one input into the selection of a point of departure in chemical-specific exposure limit. Based on that purpose, key events were defined and organized into hypothesized AOPs based on previously published systematic reviews on a single chemical (hydrogen sulfide); follow-up literature searches were conducted to inform the WOE assessment to include additional chemical stressors that activate the MIE (potassium cyanide, sodium azide, beta amyloid peptides). </p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Cogliati S, Lorenzi I, Rigoni G, Caicci F, Soriano ME. 2018. Regulation of Mitochondrial Electron Transport Chain Assembly. Journal of Molecular Biology. 430(24):4849-4873.</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Hardisty JF, Garman RH, Harkema JR, Lomax LG, Morgan KT. 1999. Histopathology of Nasal Olfactory Mucosa from Selected Inhalation Toxicity Studies Conducted with Volatile Chemicals. Toxicologic Pathology. 27(6):618-627.</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Kann O, Kovács R. 2007. Mitochondria and neuronal activity. American Journal of Physiology-Cell Physiology. 292(2):C641-C657.</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Kühlbrandt W. 2015. Structure and function of mitochondrial membrane protein complexes. BMC Biology. 13(1):89.</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Monticello TM, Morgan KT, Uraih L. 1990. Nonneoplastic nasal lesions in rats and mice. Environmental health perspectives. 85:249-274.</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Rugarli EI, Langer T. 2012. Mitochondrial quality control: a matter of life and death for neurons. The EMBO Journal. 31(6):1336-1349.</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Teeguarden JG. 2017. AOP136: Intracellular acidification induced olfactory epithelial injury leading to site of contact nasal tumors (status as of 5 July 2019: "Open for citation & Comment"). Last modified 20 March 2017. <span style="color:#0563c1"><u><a href="https://aopwiki.org/aops/136" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/aops/136</a></u></span>.</span></span></p>
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