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what is narcosis?
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the bigger picture, downstream cellular effects that toxins can have
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what is necrosis?
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what do dying cells do during necrosis?
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what affect will this have on neighbouring cells?
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non-programmed cell death
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membrane integrity is lost and the cell body swells and bursts open
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it can trigger an inflammatory response or long term inflammation
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what is apoptosis?
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what will dying cells do during apoptosis?
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what affect will this have on neighbouring cells?
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programmed cell death
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fragment into membrane-bound apoptotic bodies
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none, the membrane makes it so cellular contents are not released, so cannot effect neighbouring cells
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what are the 3 primary causes of necrosis?
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what kind of 'essential function disruption' are these causes?
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ATP depletion
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disruption to energy generation & protein synthesis
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excitotoxicity
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oxidative stress
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what do we need ATP for?
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what are the 4 key mechanisms by which ATP can be depleted?
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what is the role of ion gradients in necrosis?
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what does this ion gradient cause that leads to necrosis?
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active transport, especially ion transport, biosynthetic reactions, cell division, cell morphology, cytoskeletal polymerisation, essential part of DNA, muscle contraction, regulation of signal transduction
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inhibition of electron transport (eg. cyanide inhibits cytochrome oxidase)
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it sets off a positive feedback loop of Na+ and Ca2+ entering the cell, opening voltage-gated channels, which lets more ions enter etc.
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loss of volume control: water influx & cell swelling until the cell lyses (dies)
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inhibition of oxygen delivery to the ETC (eg. cocaine, carbon monoxide)
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inhibition of ADP phosphorylation (eg. DDT)
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physical damage to mitochondria (eg. chronic ethanol abuse)
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what is Ca2+ involved in?
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why are the levels of calcium ions tightly regulated within a cell?
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when does calcium become toxic in the cytoplasm?
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what is the consequence of increased intracellular Ca2+?
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activation of enzymes (e.g. TCA cycle), cytoskeletal polymerisation, muscle contraction, neurotransmission, regulation of signal transduction and exocytosis, transporters
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because it is so important and so reactive
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at high levels
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excitotoxicity
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what are the 4 mechanisms of calcium removal from the cell?
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what are four consequences of excitotoxicity? |
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extracellular Ca2+ ATPase
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depletion of ATP (Mitochondrial ATP production is decreased; activation of Ca2+ ATPase uses ATP)
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endoplasmic reticulum Ca2+ ATPase
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activation of Ca2+-dependent hydrolytic enzymes (leads to disintegration of membranes, proteins etc.)
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extracellular Na+/Ca2+ exchanger
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production of reaction oxygen and nitrogen species (leads to disintegration of membranes, proteins etc.)
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mitochondrial Ca2+ uniporter
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microfilament dysfunction (disrupted morphology and function, impaired motility)
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what are oxidants?
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what are antioxidants?
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which is more reactive?
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molecules that can accept an electron
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molecules that can donate an electron
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oxidants
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what is oxidative stress?
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what causes oxidative stress?
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how are these species generated directly?
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how are these species generated indirectly?
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when the balance of oxidants and antioxidants is disrupted, meaning that more oxidants are present
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reactive oxygen (ROS) and reactive nitrogen (RNS) species
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activation of foreign compounds (e.g. benzene), redox cycling (e.g. paraquat), transition metals, inhibition of mitochondrial electron transport (blocking the electron transport chain)
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activation of cytochrome P450, increased intracellular Ca2+
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how do these species cause oxidative stress?
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what do these species do to ATP?
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what other issues can these species cause?
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activation of dehydrogenases in the TCA cycle (increases electron output via the electron transport chain, causing increased production of superoxide)
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drain the ATP reserves
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affecting the function of oxidise proteins, mutate DNA causing cellular dysfunction and reducing ATP synthesis, lipid peroxidation, cell swelling, cell lysis
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activation of Ca2+-dependent proteases (convert xanthine dehydrogenase to xanthine oxidase, which also produces superoxide and hydrogen peroxide)
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activation of constitutively-expressed nitric oxide synthases in neuronal and endothelial cells (increases NO production, which reacts with superoxide to form highly reactive peroxynitrite)
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what is lipid peroxidation?
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how is this further broken down?
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what eventuates?
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peroxidative degradation of lipids by removal of hydrogen from fatty acids, producing a lipid radical.
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this can be further broken down by reaction w oxygen, forming a lipid peroxyl radical
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eventually the lipid fragments release reactive aldehydes and more free radicals
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how can oxidative stress be avoided within a cell?
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which is most important?
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how does it stop oxidative stress?
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it can be quenched by enzymes
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superoxide dismutase (SOD)
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it converts the superoxide radical (O2-) into H2O2 using metals such as Cu, Fe, Mn, or Ni. H2O2 is then degraded to H2O by catalase
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