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a'M' of MEH COPY (SC) > Lecture 1- Oxidative stress > Flashcards

Lecture 1- Oxidative stress Flashcards

1
Q

Oxidative stress and disease

A

Cellular damage caused by ROS and RNS (reactive nitrogen species) is a significant component in a wide range of disease states.

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2
Q

which diseases are associated with oxidative stress

A
  • CVD
  • MS
  • Alzheimers
  • RA
  • Crohns
  • COPD
  • Ischaemia/reperfusion injury
  • cancer
  • pancreatitis
  • parkinsons
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3
Q

reactive oxygen species

A

Umbrella term which describes all types of free radicals (counts as reactive nitrogen species too )

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4
Q

free radicals

A

A free radical is an atom or molecule, that contains one or more unpaired electrons and is capable of independent (free) existence

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5
Q

why are free radicals bad for you

A
  • Free radicals are very reactive and tend to acquire electrons from other atoms, molecules or ions
  • Reaction of a radical with another molecule typically generates a second radical thereby propagating damage
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6
Q

A superscript dot used to denote

A

free radical (e.g. OH)

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7
Q

name 4 reactive oxygen species

A

oxygen

superoxide

hydrogen peroxide

hydroxyl radical

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8
Q

Oxygen

A

itself is a free radical (2 unpaired electrons in two diff energy levels-relatively stable)

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9
Q

When oxygen gains an electron it becomes

A

superoxide

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10
Q

Superoxide

A
  • produced by adding electron to moelcular oxygen
  • important sourc eof ROS
  • Can incorporate with hydrogen to form hydrogen peroxide - damaging
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11
Q

hydrogen peroxide is

A

not a free radical but can react with Fe2+ to produce free radicals –> readily diffusible

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12
Q

hydroxyl radical

A

most reactive and damaging free radical –> reacts with anything

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13
Q

reactive nitrogen species

A

Superoxide can also combine with nitric oxide to produce peroxynitrite (powerful oxidant that damages cells- not a ROS)

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14
Q

peroxynitrite

A

is not itself a free radical–> powerful oxidatn that can damage cells

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15
Q
A
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16
Q

two types of DNA damage caused by ROS

A
  • ROS reacts with base
  • ROS reacts with sugar (ribose or deoxyribose)
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17
Q
  • ROS reacts with base
A
  • Modified base can lead to mispairing and mutation
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18
Q

ROS reacts with sugar (ribose or deoxyribose)

A

can cause strand break and mutation on repair

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19
Q

what can be used as a measurment of oxidativve damage in cells

A

8-oxo-dG

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20
Q

how can ROS cause cancer

A
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21
Q

ROS damage to lipids

A
  • Free radical extracts hydrogen atom from polyunsaturated fatty acid in membrane lipid
  • Lipid radical formed which can react with oxygen to form lipid peroxyl radical
  • Chain reaction formed as lipid peroxyl radical extracts hydrogen from nearby fatty acid
  • Hydrophobic environment of bilayer disrupted and membrane integrity fails
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22
Q

ROS damage to protein

A

Can damage the backbone or sidechain

  • Leading to either:
    • Loss of function
    • Protein degradation
    • Gain of function
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23
Q

disulphide bonds are formed between

A

thiol groups of cysteine residues

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24
Q

ROS and disulphide bone formation

A

Inappropriate bond formation can occur if… ROS takes electrons from cysteines causing misfolding, crosslinking and disruption of function e.g. enzymes

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25
Q

purpose disulphide bonds

A

Role in folding and stability of some proteins (secreted proteins or in extracellular domains of membrane proteins)

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26
Q

soruces of biological oxidants can be

A

endogenous or exogenous

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27
Q

endogenous biological oxidants

A
  • ETC
  • Nitric oxide synthases
  • NADPH oxidases
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28
Q

exogenous biological oxidants

A
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29
Q

nitric oxide synthase (NOS) as an endogenous sourc of ROS

A

Nitric oxide synthases are a family of enzymes catalyzing the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development.

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30
Q

3 types of NOS

A

iNOS

eNOS

nNOS

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31
Q

iNOS

A

Inducible nitric oxide synthase. Produces high NO concentrations in phagocytes for direct toxic effect.

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32
Q

eNOS

A

Endothelial nitric oxide synthase (Signalling)

33
Q

nNOS

A

Neuronal nitric oxide synthase (Signalling)

34
Q

NOS converts ………. to……………

A

NOS converts arginine to citrulline and NO

NO- signalling role

35
Q

the electron transport chain as an endogenous sourc of ROS

A
  • Electrons from NADH and FADH2 (which usually reduce oxygen to form H20 at complex IV) escape the chain and react with dissolved O2 to form superoxide
36
Q

describe respiratory burst

A
  • Rapid release of superoxide and H2O2 from phagocytic cells e.g. neutrophils and monocytes
37
Q

role of respiratory bursh

A
  • ROS and peroxynitrite destroy invading bacteria
38
Q

Chronic granulomatous disease

A

Genetic defect in NADPH oxidase complex causes enhanced susceptibility to bacterial infections (less respiratory burst)

  • Atypical infections
  • Pneumonia
  • Abscesses
  • Impetigo
  • Cellulitis
39
Q

cellular defences to ROS (4)

A
  1. Superoxide dismutase
  2. Catalse
  3. Glutathione (GSH)
  4. Free radical scavengers
40
Q

Superoxide dismutases

A
  • Converts superoxide to H2O2 and oxygen
41
Q

superoxide dismutase i the priamryd efence because

A

superodide is strong inititaotr of chanin reactions

42
Q

3 isoenzymes of superodide dismutase

A

o Cu+-Zn2+ Cytosolic

o Cu+-Zn2+ Extracellular

o Mn2+ Mitochondria

43
Q

catalase

A
  • Converts H2O2 to water and oxygen
  • Widespread enzyme
  • Protects against oxidative burst
44
Q

catalse and grey hair

A

Declining levels of catalase in hair follicles with age may explain grey hair

45
Q

glutathione (GSH) is a

A

tripeptide synthesied by the body to protext again oxidative damage

46
Q

How does glutathione act to protect against? oxidative damage

A
  1. Thiol group of Cys from reduced form of GSH donates e- to ROS (e..g H2O2–> H2O)
  2. Glutathione peroxidase catalayses GSH to react with another GSH to form disulphide (GSSG)
  3. GSSG reduced back to GSH by glutathione reductase which catalyses the transfer of electrons from NADPH to disulphide bone
  4. NADPH from pentose phosphate pathways is therefore essential for protection against free radical damage
47
Q

Glutathione peroxidase requires

A

selenium

48
Q

GSSG

A
49
Q

why is the pentose phosphate pathway important for glutathione (GSH) productuon and therefore protection against oxidative damage?

A
  • GSSG reduced back to GSH by glutathione reductase which catalyses the transfer of electrons from NADPH to disulphide bone
  • NADPH from pentose phosphate pathways is therefore essential for protection against free radical damage
50
Q

pentose phosphate pathway starts from

A

glucose-6-phosphate

51
Q

role of the PPP

A

Important source of NADPH required for

  • Reducing power for biosynthesis
  • Maintenance of glutathione (GSH) levels
  • Detoxification reactions
52
Q

PPP produces

A
  • C5- sugar ribose required for synthesis of :
    • Nucleotides
    • DNA and RNA
53
Q

In the PPP what is produced

A

CO2

*no ATP produced*

54
Q

rate limiting enzyme of PPP

A

glucose-6-phosphate dehydrogenase (G6PDH)

55
Q

G6PDH deficiency

A
  1. decreased G6PDH activity limits amount of NADPH produced
  2. NADPH is requrired for the reduction of oxidised glutathione) GSSG) back to reduced glutathione (GSH)
  3. lower GSH means less protection against dmaage from oxidative stress
56
Q

oxidative stress such as

A

infection

drugs (antimalarial)

broad beans

–> produce the ROS H2O2

57
Q

H2O2 effect on lipid and proteins

A

lipid peroxidtion

protein damage

–> leading to haemolysis

58
Q

lipid peroxidation

A

cell membrane damage –> lack of deformity leads to mechanical stress

59
Q

protein damage

A

aggregates of cross-linked haemoglobin (heinz bodies)

60
Q

Heinz bodies are a

A

clinical sign of G6PDH deficiency

61
Q

why do heinz bodies appear the way they do

A
  • Dark staining within red blood cells resulting from precipitated haemoglobin
62
Q

why does G6PDH cause haemolyis

A
  • precipitated haemoglobin
    • Binds to cell membrane altering rigidity
    • Increase mechanical stress when cells squeeze through small capillaries
    • Spleen removed bound heinz bodies resulting in blister cells
63
Q

Free radical scavengers

A

Free radical scavengers reduce free radical damage by donating hydrogen atom (and its electrons) to free radicals in a Nonenzymatic reaction

64
Q

name 2 free radical scavengers

A

1. Vitamin E

  • Lipid soluble antioxidant
  • Important for protection against lipid peroxidation

2. Vitamin C

  • Water soluble antioxidant
  • Important role in regenerating
65
Q

name 5 oxidants

A
66
Q

name 6 cellular defences

A
67
Q

Galactosaemia results due to a deficiency in

A
  • Galactokinase
  • Uridylyl transferase
  • UDP- galactose epimerase
68
Q

explain galactosaemia

A
  1. Deficiency in :Galactokinas, Uridylyl transferase or UDP- galactose epimerase
  2. build up of galactose
  3. galactose converted to galacititol by aldose reductase
    • consumes excess NADPH
    • compromises dfences against ROS (less GSH formed)
  4. galactitiotl causes osmotic pressure in the eye denautres crystallin protein in lens of eye–> cataract
69
Q

symptoms of galactosaemia

A
  • heptamegaly and cirrhosis
  • renal failure
  • vomiting
  • seizure and brain damage
  • cataract
  • hypoglycaemia
70
Q

metabolism of paracetamol: at prescribed dosage

A

at prescibed doasge paracetamol can be safely metabolised by conjunction with glucoronide or sulphate

71
Q

metabolism of paracetamol: with high level of paracetamol (overdose)

A
  1. with high level of paracetamol the toxi metabolite NAPQI accumulates
  2. Glutathione plays an importnant role in protecting against NAPQI, therefore GSH depletion
  3. GSH depletion results in oxidative dmaage to liver cells
    • lipid peroxidation
    • dmaage to proteins
    • damage to DNA
72
Q

treatment for paracetamol overdose

A

antedote acetylcysteine–> replenished glutathione levels

73
Q
A
74
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79
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a'M' of MEH COPY (SC) (11 decks)

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