MCAS, COVID & Cancer: Advanced Genetics Part 2

Now fascinatingly, BH4 plays other roles as well. It isn’t only just here, it helps turn something called phenylalanine into tyrosine. Tyrosine into L-dopa. And this is where we’ll get tremors or if worse enough, one of the contributing factors to Parkinson’s. And that’s why many times people have tremors, because their tyrosine into L-Dopa is inadequate. The amino acid tryptophan turns into serotonin. And if we don’t convert our phenylalanine into tyrosine, we’re anxious. So how much anxiety and depression are we seeing now compared to before? Now I’m not gonna say that’s the case in everybody, but this has to be a contributing factor to people who might be depressed. And we have just clinically observed as we stop the loss of BH4, and boost BH4. By the way, royal jelly is a source of biopterin. Many people report, not just anecdotal, that’s all, but anecdotal reports of feeling much happier when we restore the BH4 levels. So that’s the cliff notes there on this one. And again, if somebody wants to really dig into this, they’re welcome to it. You know, down here we get into how it creates hydrogen peroxide, how the NF-kappa-B stimulates all this. So that’s all in there for those who really wanna geek out on this. Now, iNOS activation and platelet secretion. iNOS activation influences platelet secretion. iNOS knock-out mice have prolonged bleeding time, meaning that they don’t have enough platelets. So here’s something else that will stimulate those platelets. And here they’re saying the activity levels of eNOS enzyme were significantly lower in patient’s platelets with coronary thrombosis. So what they’re saying is that eNOS slows down the platelet activation. So iNOS makes your platelets more sticky, eNOS calms them down. So the more you have increased iNOS and decreased eNOS, the more we’re gonna have sticky platelets.

Beth O’Hara, FN

And I think of all of this, Bob, just to tie it back again, anything that’s increasing superoxide peroxynitrite beyond that Goldilocks sweet spot, is gonna increase inflammation. Anything that’s increasing inflammation is gonna trigger mast cell activation. So this is how it’s tying back into what people are experiencing, these chronic inflammatory issues.

Bob Miller, CTN

Absolutely. Now, look at what’s stimulating iNOS. Aluminum, mercury, uranium, I mean we’re gonna look back someday and see, “What were we thinking with antiperspirants? Smearing aluminum into our armpits?” More and more evidence is talking about plastics. I just literally, somebody sent me an article yesterday, that said, “It’s estimated we are consuming the equivalent of a credit card in plastics every week.” Not year, not month, every week. We love our cell phones, they’ve changed our lives, but we don’t know the long-term effect of EMF. Same way with high-fructose corn syrup. This has only been around since the 1970s. Glyphosate, this hasn’t been around forever. And then high homocysteine and high iron. So no wonder we’re having trouble. Plastic’s everywhere. I’m in Pennsylvania, and in Pennsylvania they did a study they could not find one waterway that was not filled with microplastics.

Beth O’Hara, FN

Hmm.

Bob Miller, CTN

And more and more foods have high-fructose corn syrup. So is it any wonder that we’re seeing, you know, autism going from one out of a thousand to one out of 45? These poor kids are just exposed to things that those of us who are older weren’t exposed to. You know, when I was born, 1954, very little plastic, most things was in glass. We didn’t give our animals growth hormones. There was no high-fructose corn syrup when I was born. Glyphosate wasn’t being put on anything. The animals weren’t being given growth hormones. So from a historical standpoint, it’s an incredibly short period of time that we have changed the environment that we’re living in.

Beth O’Hara, FN

And you know, while we have- So we have this nutrient depletion across generations. And then in addition to that, we have these chemicals and even mold toxins that cross the placenta and cross through the breast milk. And there’s studies showing the level of chemicals in the cord blood of infants is just skyrocketed as well. So children aren’t even starting in same starting point as generations before. And then they’re coming into this world already highly toxic. And this is where we’re seeing these young children… I just- Like they’re coming in younger and younger and younger to the clinic. And I’m sure you’re seeing that too.

Bob Miller, CTN

Oh, sure. You know, when I was young, we used to call it adult-onset diabetes. You know, you’re usually overweight and over 40. Now eight and 10 year-old kids are getting diabetes. And it’s just frightening the way- I mean the younger people, I think those people that are like 28 to 30, I saw a study that they’re sicker now than any other time in history for that age group. And it certainly makes sense with all they’re being exposed to.

Beth O’Hara, FN

Absolutely.

Bob Miller, CTN

So here’s mercury. Induces NF-kappa-B, and so it also- And then expresses COX-2 and iNOS, so that mercury just goes down through. Glyphosate. This is a great plain’s glyphosate test.

Beth O’Hara, FN

That’s a lot of glyphosate too.

Bob Miller, CTN

Yeah, this is one of our clients. Oh, boy. Glyphosate exposure inhibits superoxide dismutase, catalase, glutathione peroxidase. It promotes the expression of NF-kappa-B, iNOS, tumor necrosis factor alpha. Which of course, is going to then lead to the RANTES. This is just a little clip from our software. There’s actually a gene called PON1, that’s partially responsible for a clearing glyphosate. Whenever I see someone has a lot of PON1s, we usually recommend that we take a peak at their glyphosate levels. Uncannily correlated when there’s a lot of twos down through here, I mean this one isn’t too bad, but when there’s a lot of twos down through here, many times these people have high levels of glyphosate. Particularly, I’m in a farming area, so many people have wells next to farms, and their glyphosate is just incredibly high. Very, very sad. Here again, histamine stimulates iNOS expression. I think this is just another study, but we just wanna reinforce that histamine stimulates the iNOS. Interleukin 6. Again, if somebody really finds this fascinating and they wanna hear me drone on for one hour and 51 minutes, interview number 42 talking about Interleukin 6, ’cause we’re gonna get into that in a little bit. So NOS uncoupling. We spoke about that a little bit. I mean, you mentioned it and I showed you the chart, so I won’t spend a lot of time on this, but here’s your eNOS enzyme. 

And if we have BH4, we make nitric oxide. If this BH4 gets depleted and we have BH2, we make superoxide. And I’m gonna show you in a moment, there’s an enzyme called PLA-2 that is stimulated by superoxide, so hold onto that thought. One of my favorite sayings now is I believe superoxide is public enemy number one. Now, here’s what can increase the iNOS function. In addition to all those environmental factors, there is gain of function mutations in the iNOS enzymes that when you have these mutations, the iNOS is overactive. And here’s the RS number, 2779249. And when it’s the A, the A is the risk, there’s a 4.73 increased iNOS expression when someones studied this. So we don’t know why this happened, but I’ll just give you a speculation. There was probably a time in history where there was a lot of pathogens, you know, maybe some parasites or something. And the people who had this overactive, it was probably to your advantage at one point in history. And that’s just Bob Miller thinking out loud. But I can’t think of any other reason why this would persist.

Beth O’Hara, FN

And just for anybody who’s new to genetics, a reminder that you can go watch the mini presentation on the genetics 101 to get the background on that, and then come back into the steep dive here.

Bob Miller, CTN

Absolutely. Then here’s another one. There’s the RS number. Again, increased iNOS activity, increased nitric oxide production. It’s associated with early onset Crohn’s disease, ulcerative colitis, and irritable bowel disease. Now, this is the iNOS2 enzymes. And interestingly, many of you know Dr. Jill Carnahan, well-known functional medicine doctor. She speaks-

Beth O’Hara, FN

She’s one of our speakers.

Bob Miller, CTN

Oh, cool. She speaks openly about this. I mean, this isn’t any secret. When she was young, she had Crohn’s disease and breast cancer. And she’s allowed us to show this. She says, “Yeah, if I can be of help to people by,” she calls herself the lab rat. So she says, “Go right ahead.” So here’s that NOS2, mother and father gave her a mutation. Mother and father gave her a mutation.

Beth O’Hara, FN

So she had one bad copy from both parents on each of these SNPs.

Bob Miller, CTN

Yes. And that’s why we’ve named it after her, the Carnahan reaction. So, this is an honor of her willingness to show this and show people that despite that by using functional medicine, she was able to get well. But here again, aluminum, mercury, uranium, plastics, EMF, high-fructose corn syrup, chlorine and fluoride, glyphosate, excess iron, and these are all the mutations that could affect this. NOS2, gain of function. And there’s actually NOS3, lack of function if you don’t make enough antioxidant superoxide dismutase, again, the SIRT1, SIRT1 helps make superoxide dismutase, and helps eNOS, that’s why that’s so important. Typo here, this should be DHFR. That recycles your BH4. The MTHFR 1298, and there’s many others that are involved in BH4 production, I just didn’t wanna list them all here, but there’s a lot that can go wrong here. And then again, bottom line is, this will activate the platelets. Now, if somebody wants a deep dive into this and can listen to this for an hour and 15 minutes, go to Dr. Jill Carnahan’s YouTube channel and listen to our talk on iNOS. Now this is the next pathway, pathway number two. We’ve now covered pathway number one. Fascinated by this one. There’s an enzyme called PLA2, phospholipase A2. And when it’s stimulated, tell you what, let me just zoom in on that a little bit. There we go. There we go. So when phospholipases A2 is stimulated by superoxide, peroxynitrite, Calmodium for EMF, again, lipopolysaccharides, histamine, excess mTOR, smoking or ozone, allergens or injury, this guy kicks in and pulls arachidonic acid out of the cell membrane. 

Our adrenals make cortical steroids, Ginkgo Biloba, curcumin, something called CDP-choline that I’m really becoming a fan of, inhibits this PLA2. So when we have any of these things stimulating, arachidonic acid gets pulled out, which is an omega-6, which we need, but in excess, goes down a pathway here, and makes something called thromboxane A2, which then, hold onto your hat, stimulates platelets, which then creates RANTES that then stimulates mast cells and histamine. So yet another pathway. So one of the things that we’ve been doing, there’s simple finger prick tests that you can do that measures your arachidonic acid. I’ll show that towards the end of the presentation. And there’s urine tests that you can measure your thromboxane A2. And I’m now doing hundreds of these. And perhaps by the time the conference comes around, we might even actually put in some of our results. ‘Cause what I wanna do is I wanna look at mutations associated with the arachidonic acid being high, omega-3 is being low, and thromboxane A2 being high. See if there’s any correlations. I think that’d be absolutely fascinating to define. So I’m gonna get back to this later, but this is yet another pathway that this can be apparently. If you remember when I showed you that bigger picture, tumor necrosis factor A comes over here, and stimulates the COX two enzymes to pull that thromboxane A2 out. 

So yet another pathway to stimulate the platelets. And then we need our adrenal glands to make cortisol to knock down histamine, but also to make the cortical steroids. So I’m sure most everybody listening to this has heard of POTS, where their adrenal glands get a little tired, they get dizzy if they stand up quickly. CDP-choline inhibits this. Interestingly, aspirin and your NSAIDs, and COX inhibitors, this would be your Advil, Aleve, ibuprofen, actually block this pathway a little bit. And that’s why I know it’s controversial now, but that’s why in the past they’d recommend maybe a baby aspirin. I know that recommendations been taken away, but that was the thought behind it, that it slowed this pathway down to prevent the blood clotting. So here’s phospholipase A2. It liberates arachidonic acid by catalyzing the hydrolysis of the SN-2 position of membranes. And when rat platelets are incubated with phospholipase A2, that thromboxane A2-like activity and prostaglandins that are inflammatory are formed. So in that phospholipase A2 gets stimulated, they now show that the thromboxanes get activated, which constricts blood vessels and makes your platelets get sticky. Great planes used to measure this, then they were not able to get the regent that was needed. And I’m leaning on them. Come on guys, let’s try to get that back.

Beth O’Hara, FN

I would love to get that back too. I ran that on everybody because there’s a link directly between this PLA2, this arachidonic acid mast cell activation, that it was one of my core markers to look at.

Bob Miller, CTN

And what I’ve asked them to do is, if possible, if they could combine that with thromboxane A2. So we’ll see if that, let’s see if that happens. Now PLA2, again, it’s not our enemy. It breaks down the membranes of bacteria, fungus, and parasites leading to their death. So it’s not just this guy that hurts us. However, inflammation often becomes excessive. How many times now, Beth, have we used the word excessive? When it’s overshooting. So the same phospholipase that attacks infectious agents, may also attack the cell membranes of the human host, damaging or killing those cells. So our protection becomes our enemy under some conditions. And here they’re just saying that it’s the arachidonic acid, which we talked about. Superoxide stimulates phospholipase A2. This could be prevented by superoxide dismutase scavenging agents. So there are people who have mutations that their superoxide dismutase production is weakened. Okay? Or the SIRT1 weakness will do that. So they’re saying that this… The products of phosphates A2 may be responsible for mitochondrial damage during the oxidative stress DLA2 and tumor necrosis factor. A study of cultured intestinal cells has shown that TNF alpha potentiates the release and metabolism of arachidonic acid. I’ve spoken to people who have the cleanest diet, no omega-6s, and they look in their arachidonic acid, and it’s like, “What is going on here?” Okay- Well, it’s because the TNF alpha or other things is causing that arachidonic acid to be increased, you know, actually taken out of the cell membranes.

Beth O’Hara, FN

And that again, just to remind people, is getting stimulated by things like mycotoxins, Bartonella, having these gram negative bacteria issues in our gut that are passing into the bloodstream, and have the lipopolysaccharides, the LPs in the cell wall.

Bob Miller, CTN

Well… Now we’re gonna soon talk about sCD40L. We haven’t covered that yet. So the activated platelet stimulates the RANTES, but it also stimulates sCD40L. Side note, there’s some experimentation going on by some doctors that there are some AIDS drugs that block these cell receptors. And when they take those, a lot of the pain and discomfort from their antis goes away. But there’s side effects from that. So certainly not, you know, we’re not in any position to recommend a drug, I’m just passing that on, that that experiment is happening. That people are getting pain relief by taking CCR5 antagonists. Now interestingly, we all know the benefit of olive oil, and this might be so one of the benefits of the Mediterranean diet. One of the components is oleanolic acid. It actually induces an enzyme that shunts this away from going down this direction, making something called PGI2 prostacyclin, which is a vasodilator and calms down the platelets. So interestingly, and that’s where aspirin does its job as well, it shuns over here. So that’s why that olive oil can be so important, and that might be the benefit that it takes us over to process the cyclin rather than thromboxane A2. Yeah, how cool is that?

Beth O’Hara, FN

That’s very interesting. And you know, olive oil is one of those things that is naturally a little higher histamine, but some people find that it gives them a good amount of relief, and I have a couple clients, Bob, I never knew why, they had to do this, but they have found that they had to have about a fourth to a half a cup of olive oil a day to keep their inflammation levels down. And they’re using one of the lower histamine ones that we can link to on our resources page. So this is such a great pearl, Bob, this explains why that’s working for them.

Bob Miller, CTN

Absolutely. So I wouldn’t be surprised, it’d be fun to look at their genomics to see if maybe they have tumor necrosis factor or something else that’s really pushing this and therefore they have the need for it. So again, we have to be careful. We can’t just say, “Oh, olive oil fixes that problem,” it did for them.

Beth O’Hara, FN

Right.

Bob Miller, CTN

For somebody els- If this is not the pathway being upregulated, I mean the olive oil’s good for them, but it may not give the relief if this is not what being upregulated.

Beth O’Hara, FN

And that’s where this in-depth look, that the genetics can be a game changer for people.

Bob Miller, CTN

Mm-hm. Absolutely. So anyway, there’s the Mediterranean diet benefit as the olive oil may take us over to this “good guy”, prostacyclin, that vasodilates and also makes little platelets less sticky. Now, prostaglandin counterbalance is a thrombotic and vasoconstrictive properties of a TXA2. This balance can become dysregulated, and that increased activity of that thromboxane could be associated with myocardial infarction, stroke, atherosclerosis, and bronchial asthma. When activation of thromboxane A2 is uncontrolled, there could be pathological consequences. I’m not gonna read all of this, but it just talks about all of the things that happens when platelets get too activated. But the key that I wanna point out here, is they express sCD40L, and that’s what we’re gonna talk about. So I encourage people to get the slides and read this, ’cause I just don’t wanna be a slide reader here.

Beth O’Hara, FN

Can we just say the very last part of that slide, Bill, that there’s a role in the cardiovascular diseases, uncontrolled inflammation, which I always say, if there’s uncontrolled inflammation in two or more systems, you’ve got mast cell involvement somewhere.

Bob Miller, CTN

Yes.

Beth O’Hara, FN

But also tumor metastasis and then neurodegenerative diseases, including Alzheimer’s. I just wanted to pull that part in, Bob.

Bob Miller, CTN

Oh, sure. Glad you did. Yeah. So it binds to damage blood vessels, aggregates to form thrombi. And so it can cause all kinds of problems for us, our heart disease.

Beth O’Hara, FN

And well, when we think about platelets just being involved in the cardiovascular system, that’s where I thought that part was so important, that we’re looking at in terms of the neurology and the neurodegeneration we’re looking at in terms of cancer as well.

Bob Miller, CTN

Mm-hm. Now, serotonin. I was blown away when I learned that platelets carry serotonin, I had no clue. Serotonin is transported by platelets and released upon activation. Now I’ll be honest, this is an area I haven’t dug into a lot, and this is one of my next areas of research. I don’t know how that affects the serotonin in the brain. I don’t know if it creates the serotonin storm, but interestingly, I was sharing this with a psychiatrist and she said, “Well, that’s what the SSRIs do, they interfere with this in some way.” And I don’t know the mechanism of it yet, but need to know more, but the serotonin induces constriction of injured blood vessels, enhances platelet aggregation to minimize blood loss. So we all thought serotonin was the “feel good” hormone. So there’s almost so much more to learn and stay tuned for this. Maybe we’ll do a, you know, a Facebook live with Dr. Jill in the future where we really dig into this, but we don’t have this down yet. Platelets contain high amounts of serotonin and a dysfunction of that system is depression, anxiety disorders, and self aggressive disturbances. And we’re seeing such a high level of that occurring now. Platelets were able to take up dopamine and express various dopamine receptors. Which make them to an interesting tool to study the underlying mechanisms of schizophrenia. So I was kind of surprised by this, that platelets are playing a role in psychiatric disorders.

Beth O’Hara, FN

That’s very interesting. And this is also saying that there’s a role with dopamine as well.

Bob Miller, CTN

Yes.

Beth O’Hara, FN

Quite interesting.

Bob Miller, CTN

Yeah. So they’re saying that platelets in the brain, which makes them studying the psychiatric disorder such as Alzheimer’s, depression, schizophrenia, and anxiety. I never connected those together. That’s all brand new to me. It’s like, wow. And this was published all the way back in 2012. 9 and a half years ago. So this isn’t anything new, but a lot of times these studies get done, they’re published and it doesn’t get out to the public to understand it. So much more to to learn here. Platelets store large amounts of serotonin. They release during the thrombus formation and modulates the inflammatory response and also gets involved in the release of hydrogen peroxide. Who’d have thought? And as we know, that’s what we’ve been talking about for years, that if we don’t have enough glutathione, catalase, and thyroxine, we don’t clear then hydrogen peroxide that combined with iron to make hydroxyl radicals that are very inflammatory.

Beth O’Hara, FN

And gray hair.

Bob Miller, CTN

And gray hair too, yes. All right. Now, off to sCD40L. And that’s why, you know, sometimes when I see the people aren’t clearing hydrogen peroxide, I’ll say, “At what age did you start going gray?” And they’ll say, “Oh, my early twenties.” And that’s a telltale sign that you’re not clearing your hydrogen peroxide. All right, now we’re off to sCD40L, and we are just beginning to see some blood results. There are labs available that can measure the RANTES, the sCD40L, the VEGF, and the tumor necrosis factor in the Interleukin 6. So activated platelets are a major source of sCD40L, which has been implicated in platelet and leukocyte activation. So the sCD40L is related to inflammation and vascular disease. So high early sCD40L levels in trauma patients, reflect tissue injury, shock coagulability, and sympathoadrenal activation, and predict mortality. As sCD40L has pro-inflammatory activity, and inactivates the endothelium, sCD40L may be involved in trauma-induced endothelial damage and blood clotting. So you can see how when somebody’s having an event, having these sCD40L higher is a problem. Here’s a chart that shows when the platelets get activated, and ad sCD40L gets gets higher, we stimulate VEGF, which is related to the growth of new blood cells, can increase tumors. And the MDSC reduces the immune system. Not a good combination.

Beth O’Hara, FN

So this is really showing us this link between chronic inflammation, mast cell activation, and cancer. I mean, you’re really building this biochemical linking here for us and why managing mast cell activation, managing the inflammation, and getting to these root triggers, are so critical even in helping reduce the likelihood that we may- Some of these cells may turn into cancer cells.

Bob Miller, CTN

Mm-hm. Absolutely. So these myeloid-derived suppressor cells, are characterized by the ability to suppress the immune responses. And the role of this in solid tumors, has been extensively characterized as pro-tumor. Circulating or infiltrating MDSC at the tumor site, where associated with poor prognosis in patients with solid tumors.

Beth O’Hara, FN

We’ve gotta get these triggers handled and get this inflammation down.

Bob Miller, CTN

Mm-hm. In a study of breast cancer patients, the overall survival with MDSC levels greater than one, with stage-four disease was significantly shorter compared to other disease stages when compared with patients with MDSC levels less than 1%. So they’re saying the MDSC levels could work as a good prognostic indicator, especially in those with advanced breast cancer. And if anybody wants to look them up, here’s the peer-reviewed studies. Now, the VEGF increases angiogenesis, the formation of new blood vessels from preexisting vasculature. Obviously we need this, but if we’ve got a tumor, that’s the last thing we want to have, because it just increases. And a lot of the people in, you know, even traditional medicine are looking at ways, how do we slow down angiogenesis? And if you slow that down, the tumor won’t grow. The VEGF is a potent and specific angiogenic factor, and the inhibition of VEGF significantly inhibits tumor growth. So again, inhibition is one thing, but maybe not encouraging it by high sCD40L, which goes back to the platelet activation, which goes back to everything else we’ve spoken about today. Now the next pathway is the last pathway that makes it. I call this the home cycle. And don’t let this worry you too much. I mean I know it looks complex, but bottom line is here, there’s many things, we just blow this up here a little bit. Here we go. So these are histamine, dopamine, angiotensin two, enzymes, bradykinin, I’m not gonna read these all, will stimulate Interleukin 6. Then environmental things will stimulate Interleukin 6. And again, I’m not gonna read that whole list, but-

Beth O’Hara, FN

I just wanna point oxalates there to stimulate the IL-6, that’s important for people as well with mast cell activation.

Bob Miller, CTN

Absolutely. Yeah. And again, some of your omega-6s like canola oil, pesticides, any mTOR stimulator. Now, IL-6 is like, “Bob, you’ve said this before,” is our friend, unless it’s our enemy. Okay? So IL-6 is a cytokine. And when we’re faced with a pathogen it says, “Whoa, we got somebody here that shouldn’t be here. Let’s make some superoxide, stimulate some mast cells, make some histamine, let’s get rid of this guy.” Is that a good thing? You’ve heard me say this four or five times now. Yes, unless it’s excessive. And you can have genetic gain of functions in IL-6, or you can have all these factors that are stimulating it. Then on top of that, if you’d have a a KIT gene that makes this overactive, it’s difficult that you don’t degrade your histamine, all of that will just get this thing going in a cycle. Histamine stimulates Interleukin 6. We’ve got a pattern going on here that just feeds upon itself, the hamster wheel. Then what’s also fascinating is that mast cells, histamine, and superoxide, stimulate what’s called the renin angiotensin system, which stimulates angiotensin one and two that then stimulates Interleukin 6. And again, another pathway going on. But look at this, angiotensin two stimulates RANTES. And then the RANTES stimulates histamine, the histamine stimulates more Interleukin 6, and we’ve got another hamster wheel spitting along here.

Beth O’Hara, FN

And here’s another COVID connections. There’s a lot of research looking at that ACE2.

Bob Miller, CTN

Yes.

Beth O’Hara, FN

And IL- and COVID.

Bob Miller, CTN

Mm-hm. Yeah. The ACE1 takes what’s called angiotensin one and two that are pro-inflammatory, turns it into the angiotensin 1-7, which is anti-inflammatory. Then also, ACE2 degrades something called bradykinin, which lowers your blood pressure, that’s why sometimes people take ACE inhibitors, but bradykinin will stimulate Interleukin 6. So the angiotensin two stimulates Interleukin 6, the bradykinin stimulates Interleukin 6, and we’re on another little Mary-go-round here. And then more stimulation of RANTES. And here’s some potential IL-6 inhibitors. Again, I mentioned it before, Dr. Jill and I did a nearly two-hour talk on Interleukin 6. And we go through all the conditions that are related Interleukin 6, all the literature on all these things that will overstimulate them, and then all the things that will help calm them down. So as you can see now, this could be the case of the RANTES in the histamine, the arachidonic acid could be the case, the tumor necrosis factor could be, or some combination. So we don’t have a way to say, “Oh, yeah, here’s what causes mast cell activation.” There’s just so many of them that can cause this to happen. So that’s why we call it the “Holmes Cycle: Mast Cells, Histamine, and Superoxide Stimulating the Renin Angiotensin System.”

Beth O’Hara, FN

And it occurs to me too, Bob, that these are getting out of control when we have these chronic trigger exposures, or these chronic infections. But when we have a new active infection, we also don’t wanna start taking 30 things that are gonna shut these pathways down if it’s just starting to go, because then we’re gonna be shutting down that immune response. And this is where that timing of everything is so critical.

Bob Miller, CTN

Absolutely. Yeah. You don’t wanna shut this down when you’ve got something to fight. I’m not gonna read these, but these are all the SNPs that would impact this going too fast. And of course, we measure this all in the, your genomic resource genetic test. A major pathway that just gets people into a lot of trouble. And I just put this in again, I mean it’s probably the third time you’ve seen this, but the mast cells create the histamine stimulates the production of the RANTES. And we put that in because the histamine is again being stimulated by the IL-6. Now, mast cells are an additional renin source. So mast cells by themselves can actually stimulate that angiotensin system or the renin system. So they’re saying mast cells could be targeted along with renin angiotensin system inhibitors to manage angiotensin two related dysfunctions. And by the way, to know if you have a little problem with this, angiotensin two makes aldosterone, which causes you to hold on to sodium excrete potassium. One of the common things is a little bit of swelling of the ankles. Like if you wear socks with an elastic band, you take it off at night, and there’s this indentation, and that’s often when you’re holding sodium and it’s greeting potassium.

Beth O’Hara, FN

Along with high blood pressure. Right? Whereas then we might see that similar imitation in ADS but we’re more likely to have that low blood pressure. So then you can start to differentiate that.

Bob Miller, CTN

Absolutely. And these are just the studies that histamine shows- Has been shown to stimulate the release of renin, and superoxide activates renin as well. So both histamine and superoxide will stimulate the renin angiotensin system. And this is a study that was published I think all the way back in 2016. The angiotensin two-induced activation of the NADPH oxidases, creates this cascade that we just showed you. And it acts as an upstream regulator of the renin angiotensin system, creating a vicious cycle that amplifies the pathways. So I was so surprised to find this, that somebody actually, you know, did a paper on this. And I think this needs more attention so that we can realize these pathways. So here it is Interleukin 6, the good, the bad, and the ugly. If somebody wants to listen for an hour and 51 minutes, feel free YouTube and just search Dr. Jill Carnahan, Interleukin 6. And this is her most viewed video. I think around 3,500 people have watched this. And by the way, right behind that is your interview. So we’re neck and neck. We’re the… So we are the ones that are the most popular on Dr. Carnahan’s YouTube channel.

Beth O’Hara, FN

She does great interviews.

Bob Miller, CTN

She really does. And maybe you’ll pass me someday on- I believe that was one on mast cells, wasn’t it?

Beth O’Hara, FN

I talked to mast cells and molds and, yeah. But I always see us as collaborating, Bob.

Bob Miller, CTN

Absolutely.

Beth O’Hara, FN

Supporting each other. We’re great for one another.

Bob Miller, CTN

Absolutely, I’m just teasing you. All right. There’s another one on understanding the NOX pathway, explaining that Holmes Cycle and the creation of angiotensin two and histamine. All right, we’re gonna wrap things up now with the omega-3s resolvins and protectins.

Beth O’Hara, FN

This is exciting, ’cause this is what we’re gonna do about it. It’s what we’re gonna do about RANTES.

Bob Miller, CTN

Yep. A meta-analysis revealed an association between your polyunsaturated fatty acid supplementation and a reduction in platelet aggregation. So this is a lot here, but I do wanna cover all this. When you look at your fish oils, you see things like EPA and DHA. They get incorporated into platelet phospholipids at the expense of arachidonic acid. How about that? Which may help reduce platelet aggregation via reduction of the arachidonic acid-derived platelet aggregating procoagulant metabolites. It competes with arachidonic acid for that COX enzyme reducing action. EPA both directly and indirectly, reduces the formation of arachidonic acid and thromboxane A2. It also gets incorporated in neutrophils in red blood cells of the expense of linoleic acid and arachidonic acid. Oops. The incorporation seems to decrease whole blood viscosity and increase red blood cell flexibility, thus likely reducing the risk of thrombosis. Wow. So we tend to think, “Oh, all I have to do is take fish oils, right?” Well, maybe.

Beth O’Hara, FN

So if you’ve not tolerated fish oils because they’re high histamine, or for some people they cause other issues, keep listening, ’cause Bob’s gonna give you another option here.

Bob Miller, CTN

Sure. So what happens is, your omega-3s, they go through multiple processes and I’m gonna show you a chart, I probably should add that chart first here. It’ll be coming. But they go through multiple steps and they create something called protectins and resolvins. Now what do they do? Associated with beneficial effects. Immune modulation. Helps with autoimmune disease, rheumatoid arthritis, cardiovascular, Alzheimer’s, type two diabetes, and cancer. So here, when you have tissue injury, prostaglandins and leukotrienes are involved. Makes it a acute inflammation. And if you just keep going with prostaglandin and leukotrienes, chronic inflammation, scar formation. But if you’ve got lipoxins, resolvins, and protectins, complete resolution. That’s pretty exciting.

Beth O’Hara, FN

And that’s huge for resolving mast cell activation.

Bob Miller, CTN

Well I think we can now see why. I mean, there might be multiple processes in here, but if we slow down the RANTES, that might be one of the processes that calms it down. They’re potent lipid mediators, they’re the molecular basis for the health benefits to your omega-3 fatty acids. And we’re not gonna go over this chart in detail, but here is arachidonic acid.

Beth O’Hara, FN

So it’s inflammatory.

Bob Miller, CTN

It’s inflammatory. There are some ways that arachidonic acid can actually be anti-inflammatory. I’m hoping over the rest of the year here, we really dig into the genetics that helps us understand, you know, like are there mutations in the COX2 that cause this to be upregulated? I’m sure that we’re gonna find some nutrients that can calm down that COX2. But here’s your EPA and DHA, your omega-3s, and these are all your protectins and resolvins. Which is the resolution of inflammation and homeostasis. So again, we tend to think, “Oh, well let’s just take some omega-3s.”

Beth O’Hara, FN

Can we stop for just a second?

Bob Miller, CTN

Sure.

Beth O’Hara, FN

This is the first time I’ve seen this, but there’s been research coming out in the past few years about that it’s really about the balance of the omega-3s and the omega-6s, not cutting out all the omega-6s.

Bob Miller, CTN

Oh, absolutely. Yeah.

Beth O’Hara, FN

This just shows why, ’cause it depends on which pathway they’re going down. So for some people cutting out the omega-6s, if they’re upregulated to the pathway on the left, I mean, inflammation it’s gonna reduce that arachidonic acid. But if they… If they’re gonna flow down into that resolution of inflammation, for some people they need- They’re gonna need that balance of those omega-3s, omega-6s. And we’re missing out on something important here.

Bob Miller, CTN

Absolutely.

Beth O’Hara, FN

Knowing what’s happening in those pathways could be really key in sorting out who’s going to experience what with those.

Bob Miller, CTN

Excellent point. And look who’s over here, COX2, which is stimulated by tumor necrosis factor. So that all goes back to the Lyme, to the mold, the other things that may upregulate this to make this happen possibly more than coming over here to the resolution, yeah. Arachidonic acid is not all bad. We need it for various purposes inside the body, but it can be used for good or for bad.

Beth O’Hara, FN

So we need to know what flow, what causes it, what else causes it to flow down those pathways on the left. And then how can we support it in coming down the resolution of inflammation if we’ve got chronic inflammation. But to remind people again, that acute inflammatory phase is so critical when we first catch a virus or have a bacterial infection. We don’t wanna always shut it down, it’s just when it’s outta control, then we need to bring it back into balance.

Bob Miller, CTN

Very well said. So here’s resolvins E1. It’s generated during the resolution of inflammation. A study has shown that it has potent agonist-specific antiplatelet actions. These words together, agonist means “helps” antiplatelet actions. We think of antagonist as going against, agonist, helping. This could underscore some of the beneficial actions of EPA in humans. Now, this is the chart I probably should have shown first. Here’s your omega-6s. And I just saw a study that showed that when people have excess linoleic acid, if they have a burn, they do much poorly, much more poorly than those who don’t have the linoleic acid. Fascinating. But this is where you get your arachidonic acid. On the other hand there’s enzymes called FADS, fatty acid desaturases. And these FADS enzymes take your fish oils and move them down through FADS1, FADS2. Then there’s something called ELOVL2, we just started looking at this in the last few months, but this is where the EPA turns into the DHA. And then FADS2 finishes the job of getting your protectins and resolvins. So one of the things we have observed is that people that are struggling, oftentimes have genetic weakness in their FADS1, FADS2, and ELOVL2. Consistently. So this is what calms down that platelet aggregation and the RANTES. So over here we just talked about the arachidonic acid, but we could certainly put all three pathways in here. But I just put the one, but these omega-3s are so important, but if somebody’s got mutations in here, it doesn’t make it. So that’s why there are supplements now available called protectins and resolvins, that you can actually just get right down to here. And I believe you’re gonna have a link for that somewhere.

Beth O’Hara, FN

Yeah. So the SPMs. There’s a couple different types of products that are protectins and resolvins. They are fish oil-derived, but I don’t know why, Bob, but something in the processing makes them lower histamine. I don’t find that everybody tolerates them, but in my population anyway, it’s much, much better tolerated than fish oil, which can be higher histamine. And we’re bypassing the conversion here. So if you have issues in those FADSs, or the L- I’m not sure how to pronounce that thing.

Bob Miller, CTN

ELOVL2, yes.

Beth O’Hara, FN

ELOVL 2s. Then if we have issues in that pathway converting, we’ve just bypassed it, it’s like having an activated… an activated product. It’s further down the chain, And then you can skip over any blockages in here.

Bob Miller, CTN

Absolutely, big fan. Now, another thing I’d like to point out, if you get too many omega-6s, they’ll use up the available FADS2. So even if you don’t have mutations on FADS2, and you’re getting way too many omega-6s, you can further impair this. Now, it’s estimated that our diet used to consist of 1:1 ratio of omega-6s to threes. People have really poor diets, can have a 20:1 ratio. And no wonder we are not doing well, because of all of our processed foods. And unfortunately, the processed foods has a lot of these omega-6s, just throwing this way out of balance. So for anybody who’s concerned, I highly recommend there’s a couple of tests out there that can measure your arachidonic acid, your EPA, DHA, look at the ratios. And I’m gonna show a slide here in a minute, but first I wanna talk a little bit more about the FADS. And here they’re saying FADS and ELOVL2 genes may play a role in the differences in omega-3 requirements. And in the software, here’s our FADS1 and FADS2. And this is not unusual, I’m sure you see this a lot as well. FADS1 and FADS2, this person has a what’s called heterozygous. These two are considered pathological. So when- And I- Sometimes you’ll see some people that each of these is homozygous. And these are the people that are-

Beth O’Hara, FN

All the way down.

Bob Miller, CTN

All the way down, yeah. And these are the folks that they’re going from one clinic to another, “Help me with the inflammation.” And they can’t seem to get the help. And it’s simply because they’re not utilizing their fats to make those protectins and resolvins, and they’re very, very inflamed. And here’s the information, here’s the- There’s one ELOVL2, and this is the one regulates the polyunsaturated fatty acid’s metabolism by altering the expression. And when this one is homozygous, in other words from both parents, again, it’s not the only cause of inflammation, but many of these people have lots of inflammation inside the body. And here we’re saying marine omega-3s provide antiplatelet effects. In healthy borderline overweight men, three grams of omega-3 polyunsaturated fatty acids for four weeks lowered fibrinogen, which is related to clotting, thrombin and factor five levels. And that occurred mainly in those with high fibrinogen. Both EPA and DHA get incorporated into platelet phospholipids at the expense of the arachidonic acid, which may help prevent platelet aggregation by a reduction of the arachidonic acid-derived platelet aggregating protocol metabolites. And then additionally, the EPA competes with the arachidonic acid for that COX2 reducing action on the arachidonic acid. So they directly and indirectly reduce the formation of the arachidonic acid, thromboxane A2.

Beth O’Hara, FN

Now, Bob, this is specifically talking about marine omega-3s. Some people take the algae forms. Do you know if that has the same benefits here?

Bob Miller, CTN

I don’t. But what I’ve been experimenting with, I’ve been experimenting with an algae-based high DHA. And we’re gonna see how people do on them.

Beth O’Hara, FN

I’d love to hear.

Bob Miller, CTN

Yeah, yeah. It’s way too early. Now here’s a test that’s called OmegaQuant. And this is an individual who was really struggling. And you can see here the omega-3s, should be in the eight to 12% range. They were down here at three and a half. The ratio of omega-6 should be 3.1 to 5.1, and almost 12, 11.9, off the charts. In other words, the chart didn’t even go that high. And then the arachidonic acid to EPA should be 2.5 to 11.1. Again, off the chart at 35.1. And this was a person who was struggling and called us in a panic, said, “I don’t know what’s going on. All I did was I had some crab cakes with peanut butter and banana, and I had to go to the hospital due to palpitations.” And those were all histamine liberating. But this is probably one of the most severe imbalances. And this person’s really struggling, and we’re working now to try to bring that into balance. So people can even order this themselves. It’s called “Make a Quant”. And I mean, there’s other blood tests that your health professional can do. And I have no associat- Pardon me?

Beth O’Hara, FN

We’ll put a link for that, Bob.

Bob Miller, CTN

Okay, yeah. And I have no association with them. I mean, I have no personal interest in that company. But it’s called OmegaQuant, and you can just prick your finger, put on a piece of paper, send it to the lab, they email it back to you. And I think this is valuable information that everybody should have. Now, if you are outta balance, you know, work with a dietician or a health professional, or do something to figure this out. We are looking at, you know, I’m suspecting that this arachidonic acid might be related to, again, that tumor necrosis factor in PLA being up regulated. And what we’re gonna do, we are going to be- We’re getting hundreds of these. We wanna put this into a spreadsheet. Look at these along with the thromboxane A2 and the genetic mutations, and see if there’s any correlations. That’ll be a fascinating study. Maybe we’ll have that done by the time this summit is playing. Then here’s a test that measures thromboxane A2. It measures it in the urine, which is thromboxane B2, which comes from A2. 

And this is the same individual. That thromboxane A2 ideally should be less than 141. 643. So we’re in the process of measuring their RANTES, and sCD40L, we don’t have a chip. And this was someone who was just getting over COVID. All right, wrap it up here with what do we do? And there’s a lot, but I just hit some of the key components here. Make sure you’re at a mold. I’m sure you talk to people all the time, say, “Do you think you have any mold?” “Nope, no, no, there’s no mold in my house.” And then it turns out, “Well there is.” You can do some urine testing to see if there’s mold. Check for heavy metals, glyphosate. Check for Lyme disease, Clostridia, lipopolysaccharides. Probably a good idea for everybody to cut high-fructose corn syrup, but I realize everybody’s not gonna do that. But if you got that certain mutation, probably a good idea.

Beth O’Hara, FN

Probably this audience will. They’re pretty well educated and eating pretty clean.

Bob Miller, CTN

Absolutely. Low histamine diet if recommended. And I know you’ve got gazillion resources on this, I mean, I hear when I talk to people all the time, they sing your praises that you have got such great information that you give out. So thank you for that.

Beth O’Hara, FN

Thank you.

Bob Miller, CTN

Check omega-3,6 arachidonic acid. Work with a health professional to balance. Might be a good idea to check that thromboxane A2. You know, this is if you are really think it’s upregulated, but there are blood tests now that you can do that you can even order yourself. You don’t need a health professional. Check the RANTES, sCD40L, VEGF, TNF-A, and IL-6. And if you wanna know the genetics, consider the ergonomic resource test to find the mutations that can make exposure to all of these words. So that’s what we’re presenting for that. Just a quick commercial here, this is for the health profession-

Beth O’Hara, FN

Can I introduce this a little bit?

Bob Miller, CTN

Oh, sure. Go ahead.

Beth O’Hara, FN

I just wanna share with people that your NutriGenetic Research Institute, and I’ve been on your board with you, and that this institute was one of our sponsors and supporters to make the summit possible. So I wanna thank you greatly for that.

Bob Miller, CTN

Well, my honor.

Beth O’Hara, FN

And I have gone through your certification course. It’s amazing, it’s the best genetic course I’ve ever seen, and I’ve studied genetics for a long time.

Bob Miller, CTN

Well, thank you. So this is where we do the research. Then this is the saliva test that measures 260,000 SNPs. Totally confidential, never shared. I know there’s people that are concerned, “Is my DNA gonna get out there somewhere?” Nope. We have it locked up. If somebody’s really concerned, use a fake name. Nobody will ever know, is just a saliva test. Functional Genomic Analysis, the software that crunches all that data. And then we’ve created some supplements called Functional Genomic Nutrition, where Beth has formulated some of them as well. So the software, and again, this is only for health professionals, I’m sorry if you’re just general public, you can’t have access to this, you have to show that you’re a health professional. But for the health professionals watching this, consider looking at this to get that data. Now, there’s a lot to learn. So that’s why we have an online certification course. And this is not for the faint of heart. I mean, this is for people who are serious about what they wanna do. So the first few modules are free. And then you can see if you like it or not. Once you decide to move forward, the course is $595, but if you use this coupon code, Mastcell360, you’ll save a hundred dollars. So we try to make- I mean there are courses out there that charge thousands. So we are very reasonably pricing this. Nutrigeneticresearch.talentlms.com, but we can put a link in the resource.

Beth O’Hara, FN

I’ll have it in the summit page. Yeah, mastcell360.com/summit. And your coupon code will be there.

Bob Miller, CTN

Yeah, so check it out. And then also on the software, if somebody’s not sure if they wanna do it, just apply for a free account. We have a sample in there. If you have like an old 23 version, three and four, you’re welcome to load it up, take it for a test drive, see if you like it, doesn’t cost you a cent. We only want you to use it if you like it. And it’s only $25 a month for the licensing fee, and then the cost of the genetic test. So we’re trying to keep it very reasonable. So if anybody who’s a non-professional wants to contact our clinic, there’s our information, tolhealth.com. Health professionals, functionalgeonomicanalysis.com is where you can request a free account. Here is the contact people, Yvonne Lucchese and Chrissy Bannon, who can answer any questions. And the the nutrition we use is freedomtoformulate.com. And you can check it out there. And if you’re a health professional, you can order. Again, this is only for health professionals, this is not for the public. So there we go. I’m looking for my way to stop the share. There we go. Okay.

Beth O’Hara, FN

So I wanna share Bob, too, that your platform is what we use for our in-depth analysis genetic in our clinic. And it’s… I was in there when you first released it, and it has gone through- Well, it’s so powerful, just the amount of analysis that’s in there, the reports and then the way that you have the genes embedded into the biochemistry charts like you were showing. So people can drill in to the charts and just open up and see for each person they’re working with their genetics at each point in time. It’s huge, and it’s made analyzing the genetics so much easier for us. And then if people aren’t healthcare practitioners but they wanna order some of the supplements that you talked about, they wanna order some of the formulas that we discussed, and they can call your office. Is that right?

Bob Miller, CTN

True, mm-hm.

Beth O’Hara, FN

Okay, that’s great.

Bob Miller, CTN

Absolutely.

Beth O’Hara, FN

I just really wanna thank you for the extent of your expertise, all of your generous sharing. This was like a graduate/doctoral-level masterclass in mast cell and COVID genetics and a number of areas. And you have both… What you put out in the world has changed me as a practitioner. I wouldn’t be where I am today without the work that you do. And I know that there are so many other people out there that feel the same way. Thank you for all of this.

Bob Miller, CTN

Well, my pleasure. Our goal is to make a contribution to humanity. And we’re hoping to do that, ’cause there’s so many people that are struggling. And again, so proud of the work that you’re doing. You’re doing a phenomenal job, and I’m sure it takes a boatload of effort to put together this summit. So congratulations to you on doing all of this.

Beth O’Hara, FN

Thank you, Bob. And thank you again for your support to make this summit happen, I really appreciate it. Check out our mastcell360.com/summit page where you’re gonna find the links to the various things that we talked about. You’ll find coupon codes, both for the practitioner resources we talked about, but also if you’re not a practitioner you’ll find lots of resources there, and that’s where you’ll find access to all these various things you learned about from Bob. Thank you again, Bob.

Bob Miller, CTN

My pleasure.