Week 4 - Cell Tissue And Injury 2

Front 1

What is oxidative stress caused by? What diseases is it associated with?

Back 1

It is caused by increased exposure to an ROS (reactive oxygen species), and or a decrease in defense mechanism against it. It is believed to be involved in atherosclerosis, alzheimers disease, smoking complications, cancer, diabetes, chronic inflammatory disease

Front 2

What are free radicals? What are some examples?

Back 2

A free radical is an atom or molecule with one or more unpaired electrons. An example is the superoxide radical O2-, or the hydroxyl radical, OH

Front 3

What are reactive oxygen species (ROS)?

Back 3

These are oxygen derived free radicals or derived species that are reactive. They include hydrogen peroxide H2O2, singlet oxygen, and peroxyl radical

Front 4

What are endogenous and exogenous ways to develop free radicals?

Back 4

Endogenous
- Oxygen exposure, inflammation, hormones, free radicals from energy generation

Exogenous
- xenobiotics (phase I reactions), radiation (UV, ionizing), drugs / toxins

Front 5

Where are most ROS generated?

Back 5

These are generated from the electron transport chain. 2% of all O2 processed lead to formation of superoxide radical or hydrogen peroxide

Front 6

Where do ROS molecules come from?

Back 6

The mitochondria! When O2 is incompletely reduced, it forms O2- the superoxide anion. This is turned into hydrogen peroxide by SOD in the mitochondria. Hydrogen peroxide can diffuse throughout the cell. It can be turned into the hydroxyl radical anywhere in the cell (via the Fenton reaction). The hydroxyl reaction is the most damaging species, whereas O2- and H2O2 are weakly reactive

Front 7

What is ROS's effect on proteins?

Back 7

1. Modification of SH groups
2. Adduct formation with lysine, cysteine, tyrosine,
3. Protein unfolding
4. Protein scission (splitting apart) - ESPECIALLY CYSTEINE

Front 8

What is ROS's effect on lipids?

Back 8

1. Lipid ROS propagates ROS formation
2. Fatty acid oxidation
3. Lipid cross linking
4. Scission of lipids and malondialdehyde formation
5. Changes in membrane fluidity

Front 9

What are ROS's effects on DNA?

Back 9

1. Base mutation
2. Chromosome breaks
3. Base changes inducing apoptosis

Front 10

What are some components of the antioxidant defense mechanism?

Back 10

Superoxide dismutase converts O2- into H2O2, which is further reduced by catalase or glutathione. Glutathione reductase regenerates glutathione.
Heme oxygenase sequesters iron away from H2O2 (as iron is needed to convert H2O2 into the hydroxyl radical)
Abscobic acid reduces vitamin E and quenches free radicals

Front 11

What is glutathione's role in anti-oxidation?

Back 11

It is the major antioxidant. The levels of GSSG (oxidized glutathione) relative to GSH (reduced glutathione) indicate the relative level of oxidative stress in the cell. Selenium, which can be taken as a supplement, is required to make glutathione active.
Eventually most all radicals get reduced by glutatione. In turn, glutathione is reduced by NADPH.

Front 12

What is Vitamin E's role in anti oxidation? Vitamin C?

Back 12

Vitamin E's role is to scavenge phospholipids and to find free radicals to reduce. Vitamin C replenishes Vitamin E

Front 13

How are damaged proteins repaired? How are they destroyed?

Back 13

Repair - Chaperone proteins bind to misfolded proteins that underwent oxidative damage, and try to restore it
Destroy - If that doesn't work, then ubiquitin is added to the protein. This tags it go to the proteosome, where it is degraded.

Front 14

What is the UPR response?

Back 14

The UPR response involves proteins in the ER that recognize misfolded proteins. This leads to increased translation of some proteins (glutathione synthase, NADPH oxidoreductase, ubiquitin ligase, folding proteins, etc), and inhibits translation of certain proteins (cell cycle, most other proteins).
In other words, it gears cell energy toward "survival," or apoptosis if the damage is severe

Front 15

How does the cell deal with DNA damage?

Back 15

It has sensor proteins that detect DNA damage, which can recruit other proteins to generate a signalling cascade. This cascade has many effects, including DNA repair, cell cycle arrest, or apoptosis if the damage is severe

Front 16

How does the Nrf2 pathway work?

Back 16

Nrf2 is a protein that is sensitive to oxidant stress. It is normally bound to Keap protein, which sequesters it. While sequestered, it is ubiquinated and destroyed, constantly. However, if Keap is oxidized (a sign that the cell is under oxidant stress), Nrf2 is released from Keap, and it can do its job as a transcription factor. It binds to an antioxidant response element, and upregulates antioxidant enzymes, GSH synthesis enzymes, proteosome pathway genes, etc.

Front 17

How does the HIF pathway work?

Back 17

HIF works like Nrf2, but is sensitive to hypoxia instead of oxidant stress. It is also constantly ubiquinated and degraded. This happens because PHD adds a hydroxyl group to HIF, making it ubiquinated more. In low O2 conditions, PHD is inactivated, so HIF levels increase. It acts as a transcription factor, upregulating proteins that promote blood vessel formation, promote non oxidative phosphorylation, and systemic affects like increased RBC formation in the liver

Front 18

How does sublethal stress help a cell?

Back 18

Exposure to small, repeated injuries prime the defense mechanism, so the cell is better protected