This article is not intended to be medical or healthcare advice. Before starting any healthcare related regimen seek the advice of your M.D. or Primary Care Physician first.
There are many ways we can solve problems, trial and error, analysis - by breaking down complex problems into simpler problems that are understandable and solveable; synthesis by looking across various systems that can be affected by an underlying factor; pattern analsyis in data. And then there is good old fashioned reverse engineering. I use whatever I can get my hands on.
iNOS / NOS2
This gene generates nitric oxide when it is functional, expressed in the GI tract and other places as well. It gets activated in the presence of viral and bacterial infections, and is like a little welding torch in your gut wiping out the invaders. Nice. Unless you have mutations on 3 key locations, that upregulate it. One location upregulates NOS2 by over 450%, and turns it into a flame thrower. Ouch. NOS2 consumes NAD. Um, yes we get tired. Yes, we, I, am homozygous on 2 locations (yes the 450% one) and heterozygous on the other. How common is the mutation that upregulates iNOS 450%+, ~10% for homozygous.
Folks like this generally have super low blood pressure, 85-90 / 50-55 not uncommon. And it needs BH4 to stay coupled to NOS3. NOS3 can be downregulated, its the 'heart attack' named by Ben Lynch, and is responsible for vaso dilation of blood vessels and capillaries; especially the heart and lungs. When NOS2 is upregulated and NOS3 is downregulated, caution is needed to avoid NOS Uncoupling which yields the depletion of BH4, and generation of massive amounts of super oxide (damaging free radical), instead of nitric oxide. Some 86% of cardiac events are preceeded by NOS Uncoupling (Pall). One may imagine that upregulations in NOS2 could yield high levels of oxidative stress in the GI tract. In families with these mutations i consistently see colon cancer, diverticulitis, and GI issues in general. Mine has all this. One can imagine the anti inflammatory marker in the gut, IL-10 would get up regulated and super busy with these folks. Just sayin.
Why Does IL-10 Matter so Much ?
Hmm. Super good question. It regulates TNF-A, and we could just stop there. Its blocked by the mycotoxin Citrinin, often found in grains. Hmm. And it helps regulate IL-6, yes, one of the most common inflammatory markers talked about in CFS / LH. Hmmm. Thats not the real interesting part though - IL-10 REGULATES ONE OF TWO RATE LIMITING GENES IN THE HEME PATHWAY. uh oh. Back to heme again. Without heme , well , we dont have much going on folks, see my earlier blog articles:
IL-10 regulates CPOX !!!. CPOX is also super sensitive to being blocked by Mercury, even very low level mercury if you have specific mutation on CPOX4. Details in the above blog article, 2nd one.
Who Says IL-10 Is Important In CFS ? 4,000 Clinically Diagnosed CFS Folks Say So
In my travels of research, i came across a Long Haul and CFS Researcher at a very famous ivy league university. They had a genetic database of 4,000 clinically diagnosed CFS folks. I asked them to run some simple regression analysis on genes and locations i kept seeing mutated in my CFs / LH folks. What was the single most statistically significant mutation that by itself could differentiate CFS folks from Non-CFS folks over 90% of the time. IL-10. Insert clearing of throat, foot stomp, should shruggle, double birds, and arms crossing. You may ask, why the 'f' didn't this researcher publish based on this? I will say this, they were looking for a single mutation that would pass the 95% confidence interval by itself, not a series of mutations linked together. No interest. Their level of understanding of phenotypes, and how the body works is pedestrian, and they were just looking for one marker to write a paper about. There were a whole set of additional genetics, that by themselves were not statistically significant, but grouped together, were in the 'very interesting' pile. Do i need to even ask if iNOS is 'interesting' ? Some wonder why i dont seek to collaborate with these folks, it should be obvious, there are agenda's, other than getting people better.
CPOX (Coproporphyrinogen-III oxidase) - The Connection To IL-10
ALAS1 and CPOX are the two rate limiting genes in the heme pathway under most circumstances. Genetic mutations, and other factors can make other steps rate limiting in some cases, but barring any insults or genetic issues, or nutrient deficiencies, these are the two rate limiting genes. ALAS1 is on the input step, and CPOX is 75% through the pathway. Ok, ok, you get it, IL-10 is important, and so is CPOX to make heme, and we know heme is foundational. Ok. Move on.
Not So Fast......Where AM I Going With All This ? Rosemary Freaks, thats where:)
I try and ask folks what has worked or helped and what has not when i get to know their situation. It gives me clues sometimes, sometimes not. There is a select group of folks who i have worked with and a famous practitioner, who all swear Rosemary is like liquid gold for them, and when i say this, the response isn't after a month on it, but a few days. I love it too. Yeah, rosemary is a super oxide scavenger, supports phase 2 glucuronidation, the rosamarinic acid helps cognition and lower oxidatve stress in the brain, and also calms down the Aryl Hydrocarbon Receptor. All noteworthy things. Perhaps more importantly, Rosemary is the single most powerful herb to lower IL-10 , and one of handful that are potent iNOS/NOS2 inhibitors too. What did all these 'Rosemary freaks' have in common......i looked their data up one at a time.......... Yep. Double mutated on the iNOS location that upregulates it 450%. Bam. Most had some IL-10 mutations, but didnt seem to matter. Its the flamethower that raises IL-10 in the gut, and shuts down CPOX. Some had CPOX mutations, some not. Rosemary gave them heme, oxygen, and thus a number of key functioning pathways. And with that, they can finally detox, contain mast cell activation, and process sulfur. Whoa. Yep. And thats just the start:).
1. Adherence modifies the regulation of gene expression induced by interleukin-10. Anne-France Petit-Bertron a, Thierry Pedron b, et al. Cytokine. Volume 29, Issue 1, 7 January 2005, Pages 1-12. https://doi.org/10.1016/j.cyto.2004.09.001
2. Anti-inflammatory activity of extracts from fruits, herbs and spices Monika Mueller, Stefanie Hobiger, Alois Jungbauer. Christian Doppler Laboratory for Receptor Biotechnology. Food Chemistry. Food Chemistry 122 (2010) 987–996.