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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Virtual Screening, The Good Parts and the Bad Ones | Main | Is Obesity An Infectious Disease? »

January 14, 2013

Another Reactive Oxygen Paper

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Posted by Derek

Picking up on that reactive oxygen species (ROS) business from the other day (James Watson's paper suggesting that it could be a key anticancer pathway), I wanted to mention this new paper, called to my attention this morning by a reader. It's from a group at Manchester studying regeneration of tissue in Xenopus tadpoles, and they note high levels of intracellular hydrogen peroxide in the regenerating tissue. Moreover, antioxidant treatment impaired the regeneration, as did genetic manipulation of ROS generation.

Now, inflammatory cells are known to produce plenty of ROS, and they're also involved in tissue injury. But that doesn't seem to be quite the connection here, because the tissue ROS levels peaked before the recruitment of such cells did. (This is consistent with previous work in zebrafish, which also showed hydrogen peroxide as an essential signal in wound healing). The Manchester group was able to genetically impair ROS generation by knocking down a protein in the NOX enzyme complex, a major source of ROS production. This also impaired regeneration, an effect that could be reversed by a rescue competition experiment.

Further experiments implicated Wnt/bet-catenin signaling in this process, which is certainly plausible, given the position of that cascade in cellular processes. That also ties in with a 2006 report of hydrogen peroxide signaling through this pathway (via a protein called nucleoredoxin.

You can see where this work is going, and so can the authors:

. . .our work suggests that increased production of ROS plays a critical role in facilitating Wnt signalling following injury, and therefore allows the regeneration program to commence. Given the ubiquitous role of Wnt signalling in regenerative events, this finding is intriguing as it might provide a general mechanism for injury-induced Wnt signalling activation across all regeneration systems, and furthermore, manipulating ROS may provide a means to induce the activation of a regenerative program in those cases where regeneration is normally limited.

Most of us reading this site belong to one of those regeneration-limited species, but perhaps it doesn't always have to be this way? Taken together, it does indeed look like (1) ROS (hydrogen peroxide among others) are important intracellular signaling molecules (which conclusion has been clear for some time now), and (2) the pathways involved are crucial growth and regulatory ones, relating to apoptosis, wound healing, cancer, the effects of exercise, all very nontrivial things indeed, and (3) these pathways would appear to be very high-value ones for pharmaceutical intervention (stay tuned).

As a side note, Paracelsus has once again been reaffirmed: the dose does indeed make the poison, as does its timing and location. Water can drown you, oxygen can help burn you, but both of them keep you alive.

Comments (5) + TrackBacks (0) | Category: Biological News


COMMENTS

1. ptm on January 14, 2013 4:42 PM writes...

I am afraid it will take much more advanced molecular tools then what we currently have available to disentangle this Gordian knot.

I'm hoping nanotechnology will eventually deliver such tools. One type of tool in particular would be incredibly useful - a 3d atomic microscope. One that would let you freeze a whole cell and then scan it in 3D, identifying atoms (or molecules) and their chemical neighborhood and then removing them and doing it with enough precision to reconstruct the whole cell with angstrom resolution. That would be a true revolution.

What's interesting is that such a tool doesn't even seem that far removed from current technologies even though there are certainly huge barriers to overcome. High throughput single molecule mass spectrometry in particular would probably be required. We could certainly use a Manhattan like project to focus research and funding on building such a tool. If successful the payoff would be immense.

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2. Scarodactyl on January 14, 2013 11:23 PM writes...

So, can we finally agree that his self-given name is accurate? Is he, indeed, equal to or greater than Celcus?

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3. Oldwellcie on January 15, 2013 7:43 AM writes...

Interesting follow up, Derek. Got me thinking how many peroxides I know that are drugs. Only the anti-malarial Artemisinin comes to mind. Don't know if tumour cells and malaria parasites have similarities or whether artemisinin has been looked at in cancer patients.

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4. eugene on January 15, 2013 8:55 AM writes...

Not too many comments, but both this and the previous post (in silico screening) gave me a lot of food for thought in different directions.

Well, if there is cosmic justice, some of these 'natural supplements' peddlers who didn't have to go through FDA hurdles, will now be sued by someone who has cancer (and who is foolish and has lots of money), based on these results.

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5. Lane Simonian on January 15, 2013 1:12 PM writes...

Hydrogen peroxide and peroxynitrites are antimicrobial and this is likely the main means by which they assist in wound healing. However, their use for this purpose is minimal due to the existence of many other antibiotics.

Reactive oxygen and nitrogen species may have some very limited role in the treatment of some diseases, but the role of antioxidants is potentially much greater. It is simply (or not so simply) a matter of delivering the right antixodants in the right amounts to the right places (to paraphrase Paracelsus).

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