7. Kane lecture 11/9 – Flashcards
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| target cells of ionizing radiation |
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| thymic lymphocytes, intestinal epithelium (undergo apoptosis) |
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| target cells of hormonal withdrawal |
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| prostatic atrophy, breast epithelial cells (undergo apoptosis) |
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| target cells of toxicants like dioxin |
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| thymic lymphocytes (undergo apoptosis) |
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| target cells of ischemia and reperfusion |
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| cardiac myocytes, neurons (stroke) (undergo apoptosis) |
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| Parkinson's disease |
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| apoptosis of midbrain dopaminergic neurons; unknown cause |
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| ced genes |
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| regulate apoptosis in humans and C. Elegans (Death) |
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| caspases |
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| Cysteine ASPartate-specific proteASES = homologues of ced genes |
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| procaspases / structure |
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| substrates for active caspases; active caspase then cleaves another procaspase in a catalytic cascade. NH2-----ala-leu-asp-----glut---- |
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| substrates for active caspases (4) |
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| 1. procaspases, 2. cytoplasmic DNase (CAD) 3. cytoskeletal proteins 4. nuclear lamins (scaffold of nuclear envelope) |
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| Apaf-1 |
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| Apoptotic Protease Activating Factor. binds procaspase 9; this complex is cleaved by cytochrome C; cleavage requires ATP |
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| 2 pathways leading to apoptosis and their mechanisms |
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| intrinsic (mitochondrial) - injury or hormone or growth factor withdrawal > active caspase 9. extrinsic (death receptor) - FAS, TNF receptor > active caspase 8 |
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| active caspases 8 and 9 |
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| activate executioner caspases 3, 6, and 7, which are responsible for the morphlogical aspects of apoptosis |
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| executioner caspases 3>6>7 do what (3) |
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| proteolysis of cytoskeleton and nuclear laminin, transglutaminase cross-linking of proteins, endonuclease activation |
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| Bcl-2 functions |
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| an antiapoptotic factor balanced with Bax, a proapoptotic factor. an increase in Bax relative to Bcl-2 allows release of cytochrome C from the mitochondrion to the cytoplasm where it activates Apaf-1; this activation requires ATP (vs. necrosis which happens because there is no ATP), and it triggers the caspase cascade leading to apoptosis |
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| increased cytosolic calcium, ROS, lipid peroxidation> |
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| mitochondrial injury or dysfunction. membrane is perforated with necrosis but intact with apoptosis (its just that cytochrome c gets released to destroy cell) |
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| apoptosis serves to eliminate severely damaged cells without |
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| eliciting a host response |
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| anticancer treatments act through |
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| apoptosis |
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| irreversible mitochondrial damage= (3) |
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| inability to generate ATP, release of mitochondrial calcium stores, mitochondrial membrane damage |
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| irreversible plasma membrane damage = (3) |
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| structural breakdown, enzymatic breakdown, loss of permeability barrier to calcium |
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| how do you necrose a cell |
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| need both irreversible mitochondrial and plasma membrane damage |
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| t/f final pathways of cell damage are often the same, regardless of the initial cellular targets |
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| true |
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| consequences of injury depend on cell type |
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| heart - necrosis fast. T cells in thymus - apoptosis. |
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| response depends on nature of injury, duration and severity |
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| hormonal withdrawal vs. apoxia |
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| calcium overload |
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| is hypothesized to mediate the structural and functional alterations characteristic of necrotic cell injury. |
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| acute liver damage |
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| jaundice (bilirubin build-up), high serum transaminases (holes in plasma membrane let enzymes out into the blood) |
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| chronic liver damage |
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| jaundice (decreased bilirubin metabolism), decreased serum albumin, clotting factors (decreased protein synthesis) |
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| prototypes and pathogenesis of cell injury (3) |
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| free radical induced injury (stealing electrons from stuff), chemical toxicity (CCl4 - mediated by free radicals, and ethanol), ischemia |
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| biochemical pathways which may generate reactive oxygen species (4) |
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| respiratory chain enzymes of mitochondria - reduction to H20 to make ATP. peroxisomes are membrane-bound organelles in liver that metabolize long-chain FAs to H2O2. NADPH oxidase - activates phagocytes to generate H2)2 or hypochlorous acid. P450 mixed function oxidase - metabolizes drugs/hormones/chemicals in sER in liver |
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| NO that is synthesized from _ by _ can generate _ |
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| arginine, nitric oxide synthase, other oxidizing species - important in killing infectious organisms at the expense of damage to adjacent host tissue |
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| sources of free radicals (3) |
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| hyperoxia, ionizing radiation, reperfusion following ischemia (oxidants released from phagocytic cells in the restored circulation) |
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| catalase |
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| defense mechanism in peroxisomes |
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| Mn-superoxide dismutase |
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| defense mechanism in the mitochondria |
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| Cu-Zn SOD |
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| defense mechanism in cytosol |
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| which vitamins have antioxidant properties / what are the properties |
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| A, C, E, beta-carotene / effective against damage to lipids by OH* = third layer of defense against free radicals (antioxidants) |
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| 3 tiers of antioxidant defense mechanisms |
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| 1. SOD converts superoxide anion to H2O2. 2. catalase converts H2O2 to water and oxygen. 3. metal chelators |
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| superoxide-driven Fenton reaction |
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| = iron-catalyzed Haber-Weiss reaction. O2-* + H2O2 > OH* = really bad because OH* is very reactive. reaction is catalyzed by free iron or copper |
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| superoxide anion |
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| O2-* |
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| normally iron/copper is tightly bound to (3)/(1) |
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| ferritin, transferrin, or hemoglobin / ceruloplasmin |
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| GSH |
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| =glutathione. glutathione peroxidase reduces GSH into GSSG while turning hydrogen peroxide into 2water |
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| glutathione reductase |
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| converts GSSG back to GSH |
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| depletion of cellular GSH can result from 4 mechanisms: |
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| decreased synthesis because of fasting or AA deficiency (cysteine, serine, glycine, and homocysteine - requires ATP); generation of high levels of oxidants/toxic metabolites leads to accumulation of GSSG and its transport out of the cell; redox cycling of chemicals such as the herbicide paraquat = oxidative stress; metabolism of exogenous chemicals by p450 may produce intermediates that covalently bind to SH groups in proteins - these thiols then react with GSSG (or the intermediates react directly with GSH and deplete its stores) |
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| what causes protein breakdown and DNA damage (specifically) |
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| increased intracellular calcium and ROS |
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| what happens when oxidants attack proteins? (3) |
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| cross-linking at suflhydryl groups, decreased enzyme activity (especially ATP-dependent ion umps), abnormal protein folding or aggregation |
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| what happens to misfolded proteins |
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| they're degraded by the proteasome complex |
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| hsp |
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| heat shock proteins are induced in cells under stress (infections, oxidant stress, high temp) = chaperones for proper folding |
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| ubiquitin |
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| a hsp that binds to damaged proteins and targets them to the proteasome complex for degradation |
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| accumulation of excess misfolded proteins does what? where do they accumulate? |
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| can trigger apoptosis / in ER |
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| ER stress |
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| unfolded protein response |
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| alzheimer disease |
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| disease induced by chronic accumulation of misfolded proteins in the ER of cells (ubiquitin isn't doing its job) |
