APRIL 10, 2017 DR GARY SAMUELSON

COMMENTSWe are now traveling directly through the middle of the beauti

ful flowing seascape of redox signaling country.This country extends in all directions for miles, far beyond what it is possible for the eye to see.We are just starting to see how far it goes.We get the sense that redox signaling is a fundamental part of the communication networks that hold all of the cells inside our body into unified and thriving communities; communities of trillions of cells that comprise all the tissues that form all of the organs and systems of our body.As we have traveled a while down the rivers of life (blood vessels) that supply these vast communities of cells, we have watched with fascination everywhere around us as cells are constantly becoming damaged, being repaired or taken down, dividing, and being rebuilt from the supplies found in the blood.Messenger molecules are running around coordinating all of these construction efforts.As we watch all the activity, we venture to enter into one of the cells along the way to explore a bit deeper what is going on inside.We follow a sugar molecule (glucose) into one of the glucose doors (GLUT receptors) of one of the cells.It really doesn't matter which cell we pick, any cell will do.

It is cozy inside the living cell, there are hundreds of fire places (mitochondria) where the sugar molecules are being burned (oxidized) to produce fuel.About 90% of the oxygen we breathe goes into these mitochondria fireplaces.We notice, as we have seen before, that redox signaling molecules (ROS such as hydrogen peroxide, superoxides, hypochlorites, etc.) are also billowing out of these fireplaces just like smoke comes out of fire.As you can imagine, with hundreds of fireplaces in the cell there are quite a lot of these redox signaling ROS (smoke) being produced in the cell.Recall that we explored this part before also.We can see that the excess ROS molecules building up inside the cell are activating messengers (smoke detectors) that rush off to push genetic buttons that produce the cell's master antioxidants [Glutathione Peroxidase (GPx), Superoxide Dismutase (SOD), and Catalase].This super team of antioxidants is perfectly built by the cell to eliminate the ROS (smoke) in the cell.They are stationed around the areas in the cell that can be damaged by ROS, such as the DNA databases and the mitochondria.This super team of antioxidants are super effective in eliminating the ROS smoke in the cell.Superoxide Dismutase (SOD) eliminates Superoxides, Catalase eliminates Hydrogen Peroxide and Glutathione Peroxidase (GPx) pretty much eliminates everything at the rate of about 70 million oxidant molecules per second.

So far, inside the living cell, we have seen the mitochondrial fire places burning sugar to produce energy along with billowing clouds of redox signaling molecules (the ROS smoke) that contain oxidants.We have also seen antioxidants stationed around the cell that effectively eliminate the ROS smoke, especially around sensitive parts of the cell.This is the scene that scientists discovered 30 years ago.Their assessment of the scene was that the oxidant smoke produced by the mitochondria is bad and the antioxidants that clean it up are good.It seemed pretty obvious, "oxidants are bad, the antioxidants cleaning them up are good".The only problem with this viewpoint is that it is not entirely true. In recent years it has been well established that these ROS oxidants are not only good, they are absolutely essential.The reason for this becomes obvious when you consider what happens when the cell is damaged.

Our tour of the inside of the cell is interrupted by a bacterium that attaches itself to the outside of the cell. We can see that the bacterium starts to attack the cell by injecting digestive juices into the cell that begin wreaking havoc with the machinery inside the cell, including some of the fireplaces.These damaged fire places don't work very well, the fires go out and allow a large excess of ROS smoke to pour into the cell.The "smoke detector" messengers now relay this condition to the DNA database.The cell takes this signal very seriously and starts to flood the cell with repair molecules in order to fix the damage and to send distress messengers to the immune system.In this scene, the ROS smoke plays a very important role.It starts the signaling process necessary to repair the damaged cell and to call the immune system.Without the ROS smoke, cells cannot activate the processes needed to repair themselves.If there is too much damage done to the cell, this redox signaling process will eventually result in the cell dying, taking itself apart and recycling its parts.These parts will be used as supplies to build a new cell when a healthy neighboring cell divides to take the place of the previously damaged cell.

It now becomes clear to us that these redox signaling molecules (the ROS smoke) have been the signaling molecules all along that have been instrumental in ordering the repairs, instigating demolition of damaged cells, and causing the replacement of damaged cells – a process that we have seen all around us throughout our journey.These redox signaling molecules stimulated the cells to detect internal damage, to order repairs, or cause the damaged cells to die and be replaced.They are responsible for maintaining all of the healthy beautiful rows of well-maintained healthy cells we have seen everywhere around us on our journey. We can now see why these redox signaling molecules, ROS oxidants (smoke), are so important in our cell communities.

Imagine what would happen in our body without these redox signaling molecules.If the redox signaling molecules did not exist, if our mitochondria stopped producing them, then cell damage could not be detected, repairs would not be ordered, and damaged cells would not die or be replaced.If a bacteria landed on a cell and started injecting digestive fluids, the cell could not order repair molecules, it could not send out a distress call to the immune system.It would just sit there and "take it" and become more and more damaged over time.If the damaged cell could not die and be replaced, then it would just sit there and become more and more beat-up over time until it stops functioning as it should.Can you imagine what our cell communities would look like if that were to happen.

Cancer cells and pre-cancerous cells, in fact, are our own damaged cells that cannot be detected.They cannot repair themselves or be replaced and they certainly do not function as they should.It is not surprising, then, that we found that in cancer cells the mitochondrial fire places have been shut down and thus their production of redox signaling molecules has been shut down.Without redox signaling processes, cancer cells cannot be detected, they cannot order repairs, and they cannot die.If they lose their ability to interpret the signal to stop dividing and continue to multiply then they become malignant tumors that can grow without restraints.Scientists have given rats mega-doses of Intravenous vitamin C (an antioxidant) to see what would happen if they removed much of the oxidants (ROS smoke) from the cells of the animals.With high doses of antioxidants, these animals developed cancers, infections, diabetes, and died early in morbid conditions. This was a clue that started the scientists on the journey to discover the importance of this ROS smoke (later known as redox signaling molecules).We now know that ROS is universally and fundamentally important for all types of cells in all forms of life on earth.

We emerge from the cell much better informed and look around.We see beautiful rows of well-maintained cells stretching outward in all directions.We see constant construction projects, cells being taken down, repaired, cells being duplicated and rebuilt all around us. In the back of our mind we think, thank heavens for redox signaling.