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U7 MCP > CP 4: ROS - RM > Flashcards

CP 4: ROS - RM Flashcards

1
Q

What is the main source of NADPH in RBCs?

A

pentose phosphate shunt

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2
Q

Why is NADPH important for preventing oxidative stress?

A

regenerates reduced forms of glutathione and peroxiredoxin to scavenge ROS

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3
Q

What happens in RBCs of individuals with defect in pentose phosphate shunt?

A

unable to supply NADPH, don’t have adequate levels of reduced glutathione or peroxiredoxin, hemoglobin sulfhydryl groups become oxidized, Hb precipitates in RBCs forming Heinz bodies

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4
Q

What is the key enzyme for generating NADPH in pentose phosphate shunt?

A

Glucose-6-phosphate dehydrogenase

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5
Q

Why is G6PD deficiency so common?

A

selective advantage due to protective effects from malaria (due to defective home for merozoite)

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6
Q

What changes occur from G6PD mutation that can be tested clinically?

A

electrophoreitc mobility, enzyme kinetics, pH optimum, heat stability

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7
Q

Where is the G6PD gene located? What is the inheritance pattern?

A

X chromosome, X-linked

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8
Q

List the activity and electrophoretic speed of these variants:
G6PD B
G6PD A+
G6PD A-

A

G6PD b–normal
G6PD A+–electrophoretically faster, normal catalytic
G6PD A- comigrates with A+ (so faster than normal electrophoretically), subnormal catalytic

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9
Q

What agents can precipitate hemolysis, jaundice, and anemia?

A

antimalarial drugs, broad beans, other chemicals

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10
Q

What is the Beutler fluorescent spot test?

A

identifies fluorescence of NADPH produced by G6PD under UV light
-if doesn’t fluoresce, it is deficient

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11
Q

What does crystal violet stain for?

A

Heinz bodies

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12
Q

How is superoxide radical formed in RBCs?

A

O2 bound to Hb in Fe2+ state reacts with heme to form Fe3+ met-Hb that doesn’t bind oxygen and generates a superoxide radical

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13
Q

What enzymes regenerate reduced gluathione and peroxiredoxin after they scavenge hydrogen peroxide?

A

gluathione reductase, thioredoxin reductase

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14
Q

How do Heinz bodies cause damage to RBCs?

A

become attached to cytoskeleton making it less deformable
membrane-bound heinz bodies protruding from cells are shed, leaving bite out deformities
those with too many heinz bodies to shed are destroyed in spleen–> hemolytic anemia

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15
Q

What is the first stage in Heinz body production?

A

formation of disulfide bonds by the exposed –SH groups on beta chains

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16
Q

What is the possible mechanism of protection against malaria?

A

hemoglobin oxidation product (hemichrome) is enhanced in Hb-S and Hb-C RBCs and inhibits actin polymerization

  • affects generation of vesicle transport system essential for delivery of parasite-encoded adhesins to surface of infected cell
  • reduced cytoadhesive capacity prevents sequestration of infected RBCs in postcapillary microvessels of brain and other organs
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17
Q

Why do antimalarial drugs increase oxidative stress?

A

act as redox cyclers–the drug is oxidized by ROS and reduced by antioxidant system such as GSH
(reduces the amount of cell’s redox reserves leading to eventual oxidative stress)

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18
Q

What variant does not show favism?

A

A- variant

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19
Q

What is chronic granulomatous disease a result of?

A

defect in ROS-generating enzyme, NADPH oxidase, causing difficulty in forming ROS used to kill ingested pathogens

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20
Q

What is the respiratory burst?

A

increase in O2 consumption resulting in superoxide release into phagosome

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21
Q

What enzymes are in the primary and secondary granules in neutrophils and macrophages?

A

myeloperoxidase, acid hydrolases, proteases, lysozymes

22
Q

What is the catalytic core of the oxidase that transfers electrons from NADPH to oxygen? What are its 2 subunits?

A

cytochrome b558, gp91, p22

23
Q

How can you measure enzyme activity in neutrophils? what does this indirectly reflect?

A

nitroblue tetrazolium–reduction of oxygen sensitive dye that acts as terminal electron acceptor instead of oxygen and turns to black insoluble deposit
-indirectly reflects the ROS generating activity

24
Q

What is superoxide used by myeloperoxidase for?

A

to generate HOCl (hypochlorus acid), a highly reactive microbicide

25
Q

What 2 functions does NADPH play in phagocytes?

A

enables cell to produce ROS that are released into extracellular space
protect itself against ROS (by reducing GSSG to GSH and thioredoxin to peroxiredoxin)

26
Q

Is NADPH oxidase always on? How is it turned on if not?

A

no, at rest is it inactive with its components dispersed between cytosol and membrane
activated by phosphorylation of subunits in cytosol and transport to membrane due to IC signaling cascade from neutrophil activation by pathogen

27
Q

What subunit has a defect if chronic granulomatous disease is inherited by X-linked? What is its inheritance if it is any other subunit?

A

gp91 for X-linked

autosomal recessive for all other subunits

28
Q

What is the mechanism of reperfusion injury?

A

oxidative stress–physiological antioxidant defenses are overwhelmed after reperfusion
calcium overloading

29
Q

What are the sources of ROS in reperfused tissue?

A
  • in cardiomyocytes, highly reduced, damaged ETC get sudden burst of O2 resulting in overproduction of superoxide
  • in endothelial cells, XO and NOS produce O2- and NO which react to form ONOO-
  • phagocytes that accumulated in damaged tissue produce ROS by NADPH oxidase when oxygen reintroduced
30
Q

What are the changes occurring in the cell from ROS burst?

A

cell membrane injury–lipid peroxidation
cytochrome c release–apoptosis
opening of permeability transition pore–dissipates membrane potential, no ATP produced–necrosis

31
Q

What is ischemic preconditioning?

A

expose heart to several short ischemic episodes, followed by recovery
protects heart upon prolonged ischemia because has induced

32
Q

What is postconditioning?

A

early reperfusion is interrupted by intermittment brief periods of ischemia before extended reperfusion (slow waking up approach)

33
Q

What have experimental studies shown about ROS scavenging interventions during myocardial reperfusion?

A

reduction in MI size by 50% (haven’t seen effects with MIs in clinical trials with antioxidants Vit E or carotene)

34
Q

What do cyclosporin A and sanglifehrin do?

A

inhibit opening of PTP to preserve mitochondrial function, prevent necrosis and reduce MI infarct size

35
Q

Why are chelators able to help prevent reperfusion injury?

A

bind ETC members’ cores to prevent superoxide formation, prevent Fenton reaction

36
Q

Why is allopurinol able to help prevent reperfusion injury?

A

inhibits XO so it can’t form h202 from O2-

37
Q

What is the inheritance of Freidreich’s ataxia?

A

autosomal recessive

38
Q

What is Freidreich’s ataxia caused by?

A

mutations in the gene coding for protein frataxin

39
Q

What is the most common mutation in FDRA gene?

A

GAA triple repeat expansion in intron 1 leading to poor expression of protein

40
Q

Up to how many triplets is normal? How many for disease?

A

up to 38 normal

70-1000 triplets in disease (average 600-900)

41
Q

When is expansion or contraction seen equally? When is contraction seen most commonly?

A

maternal transmission equally like to expand or contract

paternal transmission most commonly contracts

42
Q

How does the GAA-expansion affect frataxin production?

A

partially silences the frataxin gene resulting in low levels of frataxin based on the length of GAA repeat, formation of abnormal DNA structure affecting gene transcription

43
Q

What 2 things does a longer GAA repeat correlate to?

A

more clinical severity and earlier onset of disease

44
Q

Where is frataxin localized to? What effect does it have?

A

localized to mitochondrial matrix, reduced rate of ATP synthesis

45
Q

What markers show oxidative stress in Freidreichs ataxia patients?

A

malondialdehyde (lipid peroxidation product)
urninary 8-hydroxy-2-deoxyguanosine (marker of oxidative DNA damage)
decreased GSH
increased glutathione S-transferase activity (that produces more GSH)

46
Q

What vit. deficiency phenotype mimics FA?

A

vit. E, shows that it is due to oxidative stress in FA

47
Q

What does frataxin do?

A

binds/stores Fe2+ and delivers it for synthesis of iron-sulfur clusters and heme
(Fe-S needed for ETC, aconitase, DNA repair, ferrochelatase for heme biosynthesis)

48
Q

Why is frataxin important for protection against oxidative damage?

A

binds free iron to reduce its availability so it can’t react in Fenton reaction

49
Q

What causes oxidative stress in FA?

A

iron not stored in mitochondria–> gets engaged in redox reactions and produces ROS, and Fe-S deficiency in ETC causes impaired electron transport and increased superoxide production

50
Q

What is ldebenone?

A

lipid-soluble antioxidant related to coenzyme Q being used for FA

51
Q

What is deferiprone?

A

iron chelator that reduces its bioavailability

U7 MCP (19 decks)

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