Akt is the first responder. Essential role of Vanadium
I would like to share my discovery and related personal experience, as I believe it can be very important for this group.
Over the past few years, I have extensively researched oxidative stress, including the Nrf2 pathway (see my notes on the topic), AMPK, PGC1a, biogenesis, and all pathways related to energy production.
Akt - is where it all begins
Contrary to what many people think, the first responder to increased oxidative stress is the Akt protein (R1), not KEAP1 that marks Nrf2 protein for degradation under normal conditions.
When discussing high oxidative stress, Nrf2 is mostly mentioned, and the PI3K/Akt signaling line is often omitted.
The normal way of responding to stress begins with pulling the Akt protein to the membrane, phosphorylating it, and then inhibiting GSK3b, allowing Nrf2 to escape degradation and enter the nucleus.
A weak Akt signal results in weaker activation of Nrf2 due to overactive GSK3b.
The proper function of Akt requires phosphatidylinositol in the membranes of the cells, myristic acid to transport Akt to the membrane, and chromium and vanadium to amplify the signal, reduce inhibition of Akt, and maintain its activity longer.
Therefore, it is my proposal that deficiencies in vanadium and chromium result in chronically high oxidative stress, which can be directly treated with Nrf2 activators.
The Hypothesis
Recently, I have delved deeper into the PI3K/Akt pathway and GSK3b and discovered that the first responder to increased oxidative stress is not Nrf2, as many believe, but the Akt protein.
This discovery led to an “aha!” moment, and it could explain my family’s case, where the body does not seem to increase the antioxidant defense system in response to normal triggers like food but responds well to manual Nrf2 activation (MSM, sulforaphane, etc).
My hypothesis, which I plan to confirm through further research, is that Nrf2 activation via the dissociation of KEAP1 (when KEAP1 gets oxidized) only happens on much stronger signals that directly target KEAP1.
The normal antioxidant defense system should start from Akt activation, which leads to GSK3b inhibition, allowing Nrf2 to escape degradation and enter the nucleus to do its job.
Vanadium plays an important role in maintaining Akt signaling.
I propose that vanadium and chromium deficiencies impair the early response to stressors such as food (insulin technically), delaying the expression of the antioxidant defense system (downstream of Nrf2), and leading to damage of membranes, which, in turn, leads to further impairment due to the release of DHA (Akt inhibitor) and lowered PIP2.
Personal Experience
The response to Vanadyl Sulfate was instantaneous, with the same feelings as from NRF2 activators or OSR. Mood and attitude quickly improved, and a good neurological sensation was observed. I became less dependent on taking magnesium.
Another subject with strong OCD improved remarkably within days as well, whereas nothing else had been able to achieve that level of improvement previously.