 Bob Miller, we're live again for, this is like third now in our series. We're gonna have to start numbering them so people can keep track. But I will say, like I said, last time your lectures here have been some of the most popular, not surprising, because the information you have to share is so relevant to some of the top and complexities that we see. I've introduced you before, but I'm gonna just give another brief intro for those of you who haven't met Bob Miller. And just a little background. If you would like to review this, this will be live on Facebook now, but it will be recorded. It will also be on my YouTube channel, which you can find just at, search YouTube, Jill Carnahan, and all the videos are there. And the previous two, if you have not seen them, they are there as well. Just search for Bob Miller and they'll be there. And like I said, we're gonna do a little overview to start, but they are very interesting and very relevant to some of the complexities. So let me introduce Bob Miller. He's a traditional naturopath, specializing in genetic specific nutrition here in his traditional naturopathic degree from Trinity School of Natural Health and board certified through the A-N-M-A. In 93, he opened the Tree of Life Practice and served as traditional naturopath for 27 years. For the past several years, he's engaged exclusively with functional nutritional genetic variants and related research. And what I really love is he brings some clarity to, I always say, 20 years ago when I first started, I would have patients coming in with hypothyroid or menopausal symptoms or a sore throat. And within sometimes a few days, sometimes a few weeks and definitely a few months, these patients would come back and they felt great. That rarely happens anymore. And one of the things we see that we are going to address today is the environmental toxic load. And so we're gonna also talk about Bob's conference coming up at the end. So stay tuned, we'll give you those dates and you can sign up for that. It's all virtual. And he's gonna especially address this year, the load of mycotoxins and mold. So that's all relevant to today. Welcome Bob, glad to have you here as always. Well, what a pleasure to be back. You and I've had so much fun. The feedback has been incredible that people think the two of us bounce each other, off each other nicely. And they're quite enjoyable to watch and I'm just having a blast doing them as well. So thank you for the opportunity. Bob, I'm gonna tell our secret. So the very first time we're texting back and forth and I'm just checking on time and make sure he has the links and I'm voice texting into my Siri. And I looked at the text, I hit send and it said, hey babe, are we on in 30 minutes? So I don't laugh so then we joke about new name is babe, hey babe. There you go. So here in Pennsylvania, Dutch country, the old saying is call me anything but late for dinner, you know, so. Yeah, so that's our little personal joke with Siri. So let's jump right into overstimulation of NOx and ADPH. I know you have some slides to share. Absolutely. Hopefully share them. The child locks are off. They sure are. Okay, so here's what we're gonna do. We are going to share the screen and let's see, do you see the screen there now? Yes, perfect. Okay, so the subject is gonna be the NADPH steal and what I'm calling the home cycle. And I actually had this graphic drawn. I actually hired someone to draw this graphic. Because one of my favorite sayings is there's nothing simple about this. As you said, things are getting more complex. So I call it the 3D chess game played under water. And you'll see as we go through everything today, you're gonna understand why I kind of like that little bit of analogy. Now I would encourage everyone to go back and watch our June Facebook live where we spoke about perox nitrite. Now just we're gonna do like cliff notes on it. So in case you didn't see it and if you did, you may wanna go back and see it. And if you didn't see it, go watch it. It's a very oxidizing and damaging molecule that actually damages DNA in cells and suppresses the immune system. Now it's created when something called superoxide that we'll talk about today combines with nitric oxide. And then perox nitrite creates carbonate radicals that actually damages the DNA. Now there's a couple of ways that can do this. It's not just one. The Fenton reaction where iron combines with hydrogen peroxide, EMF that may stimulate superoxide in the cell and that makes perox nitrite. There's something called the NaS enzyme, nitric oxide synthase, where we're supposed to make nitric oxide, Nobel Prize winning back in the 1980s. But rather than making nitric oxide, we make superoxide and again then into perox nitrite. And then finally, if we don't take our oxidized glutathione, the master antioxidant back to reduced due to an NADPH deficiency that was our other subject, that oxidized glutathione combines with oxygen. Here we go again, makes superoxide combines with nitric oxide to make perox nitrite. And we spoke about this on our other Facebook lives that sometimes glutathione is wondrous for individuals, but other times people take it do well for a short period of time than it backfires. And that can be when the oxidized doesn't go back to the reduced. So all of those are ways that we can make perox nitrite and does a lot of damage. Perox nitrite weakens the immune system. It's behind inflammatory bowel disease. It's behind cancers. It's behind osteoporosis. I used to call it the elephant or the gorilla in the room because of all the damage that it can do. So again, go back and listen to the other one if you want a whole seminar on perox nitrite. Then last month we talked about NAD plus and NADPH. You're hearing a lot about that, a lot of lectures. NAD plus supports PARP DNA repair that we just spoke about. Some important enzymes called certuans and foxogenes that make very important antioxidants. We spoke a little bit before about the importance of m-torinotophagy. NAD balances those. It supports vitamin D receptors. In our kidneys we have something called the urea cycle that takes out ammonia. And it also provides energy to the mitochondria. I mean, that's a lot of stuff because NADH is at the top of the electron transport chain. And if that's not enough, it supports phase one detox. The transport of iron into ferritin. And if we don't do that properly, that iron can become one nasty free radical. The production of a very important antioxidant called bilirubin, the production of nitric oxide and the recycling of oxidized glutathione and thredoxin back to their reduced form. Dr. Jill, I can't think of another molecule that wears so many hats on the good side. But what's really unique about NADPH, it's also used by another enzyme to actually make inflammation. And that's our subject today. So I want to just jump in here really quick because after our last Facebook live, we had a couple of questions and one lady in particular, she said, well, if this is the case, why shouldn't everyone stop everything else and just take NADPH or NAD plus? And that's part of the answer to today's lecture as far as everything is in balance and everything depends on your genetics and your pathways. And there's a good and a bad side to every nutrient. So as Bob explained some of this, I'll hopefully bring some just clinical pearls of what I've seen because I have seen this at the exclusion of everything else, especially methylation factors, we'll kind of see how that works today can be detrimental, even though it's a wonderful molecule. Absolutely, we tend to get on bandwagons. We tend to think, oh, this is the latest greatest thing. So everybody should be taking it all the time and the more we take, the better. One of the analogies I always give without oxygen, we're dead within three to five minutes. Breathe pure oxygen a couple of days, you'll oxidize. No water, you've got a couple of days, drink three, four gallons and you'll wash out your electrolytes and your heart will stop. So one of my favorite jokes is everything we really need to learn is goalie locks and the three bears, not too hot, not too cold, balanced. Now, I am intrigued by NADPH oxidase. I learned about this a couple of years ago and just something instinctively said, this is a big deal. Now, this enzyme has one purpose and actually to create free radicals such as superoxide, hydrogen peroxide and stimulate mast cells to fight an invading agent such as bacteria, parasites. Now, we tend to categorize, you know, antioxidants is good, free radicals is bad. Obviously excess free radicals is bad and is behind a lot of problems but we do need free radicals when we have a fight to fight. So when we get a bacteria or a parasite, if we did not have the NOx enzyme, we would die of infection. In animal studies where they took the NOx out, the animal died. But as we just, you know, perfectly alluded to, it has to be in balance and over activation and overstimulation of the NOx enzyme by environmental factors may cause inflammation, over activation of mast cells and high histamine. And, you know, I'm sure, Dr. Jill, when you started out in your practice, you probably didn't hear too much about mast cell activation and now, you know, it's quite common. Are you seeing that increase in mast cells? Yes, absolutely. Again, it was almost unheard of and it's literally been the last decade and for sure extremely much more common in the last five years. And again, I feel like the mast cells are the canaries, the cells that are reactive to environment, whether it's mold or infection or other toxic exposures. And so then they tend to get activated and again, we'll hear more about that in your lecture, but it's, I think, evidence of the increasing toxic load. Absolutely. Now, the NOx enzyme uses oxygen from iron and listen to this, an electron from NADPH to create the superoxide. And I've sort of coined this phrase because I don't think anybody else did. I'm calling it the NADPH steel, where NADPH is used excessively to make superoxide, thus depriving the other ways it's used. Now, I sat back for a while and I tried to figure out, all right, why would God make us this way that this NADPH that's needed to do all these good things actually gets used to do bad things? And what I came to realize is that when we have a pathogen, we really want a full cord press of free radical damage for a short period of time. So then it makes sense that the body says, okay, we're gonna shut down recycling of antioxidants. We're gonna do a full cord press. We're gonna be in battle and we're gonna kill this invader. Perfect sense, unless it's happening all the time. Then we have a problem. So as we said, NADPH supports phase one detox. We mentioned all of those things. So here's what the latest discovery we've made and that, and I'll show a chart here in just a moment. When we have this NOx enzyme up-regulated and it might be just a good idea to do that right now. Let me pull this guy over. You seeing the chart there? Yeah, perfect. So here's the NOx enzyme, NADPH oxidase and it grabs oxygen from iron and electron from NADPH. And here we see that it stimulates hydrogen peroxide, superoxide, the superoxide combines with nitric oxide to make peroxynitrite and we make the mast cells. So consequently, it's not going to be available for doing all those other things. And again, we want this to happen when we have that going on. However, what we're gonna point out and probably the most important thing we're gonna speak about today is as we've combed the literature because through the NutriNIC Research Institute we have researchers who look these things up. As we learned, the superoxide makes peroxynitrite, we make the mast cells and then we make the histamine. And I have a slide later, I'll show, we tend to think of histamine as just allergies but it can affect a lot of body systems, not just allergic reactions. Well, and Bob, just like anything, you need some histamine and too much is a big problem. We see that all the time with mast cell patients and rashes and dermatograph fear where you can draw a line on your skin and it's raised and read for several hours and many, many other things such as breathing issues, chest tightness, congestion, all of these things are histamine related. But what's very interesting I find is there is some research on high histamine and intelligence and IQ levels. So there is a connection because histamine is much more kind of red alert molecule and there is some evidence that those that run slightly higher histamine actually have more attention, focus and higher IQs. Have you heard that research? Oh yes, I have. Yeah, they call it the histidolic personality. Yes. And many times people who are leaders in industry, I heard one time that for example, the Kennedy clan, many of those were considered histidolic and that's why they had such power for such a long time. Yeah, so it does make you intelligent, but it also can cause all kinds of inflammatory problems too. Yes, the blessing and the curse at the same time. Now I wanna pay attention to this. This is really the crux of what we're gonna be talking about today. And then I wanna set this stage, then we wanna go through how all of these other factors can create a problem. But here's our main factor that we wanna point out today that there's an enzyme called renin that takes something called angiotensinogen and turns it into angiotensin one, which then goes into angiotensin two that makes aldosterone and look what aldosterone does. It stimulates NOx. And then that begins the chain and then what happens, they all feedback on each other. The histamine, the peroxanitrite, the mast cells come back and they stimulate renin and keep this guy spinning around in what I'm calling the Holmes cycle. So here you see high glucose, peroxanitrite, mast cells, histamine, dopamine and testosterone all will stimulate the renin enzyme to take that angiotensinogen and push it down this pathway more robustly. Now to complete our 3D chess game, there's an enzyme called ACE2. And ACE2 takes these inflammatory and vasoconstrictive molecules and turns them into angiotensin one dash seven, which is anti-inflammatory and vasodilative. Now I'm sure some people have heard that COVID comes in using ACE2. So one of the concerns we have is that if this is already weak and COVID comes in here, question, not a statement, might that make more of this happen, which stimulates NOx? And then you'll also notice that angiotensin 2 stimulates inner lukin 6. Inner lukin 6 is one of the players behind the cytokine storm where the lung inflammation makes COVID a very serious and or deadly condition. Yes, and they're studying IL-6 inhibitors, some of these expensive drugs and many, many of these types of conditions, including there is a research study going on with the virus. So it's interesting to see that because the IL-6 is such a big point of inflammation and those patients, I'm assuming you test genetics around IL-6 in activity? Absolutely. And what we're finding because of COVID, we started looking at this, but on the other hand, for people who don't have COVID and they had inflammation that we could never seem to crack the code, we're finding that when people have genetic mutations in renin that's an up-regulation, genetic mutations in ACE2 that inhibits these inflammatory molecules to go into anti-inflammatory, weakness in H-mox, HEMoxygenase that inhibits angiotensin 2, and mutations in IL-6 that are up-regulations, these are the people that have a lot of inflammation and nobody's able to crack the code. So I'm real excited about this. Now, I have a slide. I mean, we literally saw this two days ago. So this is the first time we're presenting this information. I literally drew this this afternoon. We're gonna talk about glutamate. Just like histamine, glutamate makes you intelligent, highly motivated, go get her. And I would tend to think the people on this call probably have some high glutamate. And, but however, glutamate needs to turn into GABA. GABA is the don't worry, relax, be happy. I just about fell off my chair, Dr. Jill. I'll show you the literature. Glutamate inhibits ACE2. Wow, this is amazing. I agree, the profoundness of this. Yeah. So the more you make histamine, the more you make glutamate, the more you make glutamate, the more you inhibit ACE2. I have this slide, I'll show that a little bit later. Quick question for you, Bob. This may or may not have an answer, but I'm seeing the list of things that stimulate REN, high glucose, oxy nitrate, mast cells, histamine, dopamine, testosterone. Do you think there's any correlation with those as like synergistic factors making each other worse? They seem to me like independent risk factors, but I could also see a lot of people hang in that category with, you know, higher dopamine due to gut issues, mast cell issues, higher glucose. Do you think they're independent or do you think there's a synergy of those things acting together or coming as a more of a package? Well, it's an excellent question and I think you're absolutely correct that the more factors you get together, the more it compounds. And I've been saying that for a long time. We're looking for simple answers. What causes this? What do we do for that? The pill for the ill. And as your opening statement, that was so correct, things are getting much more complex. So I think it is multiple factors that go together. So I would agree if someone's diabetic and they've got higher testosterone and they've got clostridia or genetic issues, they don't convert dopamine and norepinephrine. It all compounds. Then if you've got mutations that are not regulation, mutations that are a down regulation, all these factors go together. You know, incredibly complex method. So when people say, what is the SNP that's important or what is the nutrient that's important? I don't think we're gonna have any of those in this complex world that we're living in today. Yeah, and I'm just gonna, this is gonna be way out on a limb, but just for fun, I'm gonna say it and say there's no evidence behind it. Just I love to go where my brain wants to speculate. And what I'm thinking is, you have these like executive driven, successful entrepreneurial types that we already talked about. You know, could the Kennedys have had high histamine and high dopamine, because those can go together as well, the drive, the ambition. And then a lot of times that high stress level will create high cortisol, which creates glucose intolerance and insulin resistance. I wonder if you would look at studies of that type of personality and the risk of this virus or some of these inflammatory infections, could there be a correlation? Again, I'm just clearly speculating, but I'm interested because a lot of those factors are, you know, seen in those types of patients. Sure, well, I mean, you're correct at speculation, hypothetical, but that's how we discover things. And my instinct would tell me that's probably correct. But obviously, you know, universities need to do studies. Absolutely. It's fun to speculate. We're not saying any of this is fact. We're just interestingly observing. Could that be? I always like to say what if. What if, yes. That's how we find things by saying the what ifs. So I was really excited about this glutamate because I believe that we are having a real problem with the glutamate. You know, if you talk to elementary school teachers who taught more than five years, college professors who teach more than five years and they asked them, how are the kids today versus five years ago? Every time they'll tell me more anxious, more difficulty focusing, more behavioral issues, sensitive, can't handle stress. And I think it's a combination of the glutamate, the mass cells and the histamine. And also when we just look at behavior, just turn on the news. Many of us are shaking our heads saying, what is going on with people? Why are they so irrational? Clearly multiple factors. And again, I wonder, I speculate if some of this isn't accountable for some of the behavioral issues we're seeing as people seem to be changing and becoming more angry. Yeah. So this is what I call the home's hypothesis. So what I want to go back to the slide and then I'd like to go through each of these and show you how they can do that. So here's what I've come up with the home's hypothesis. Again, just that theory. Toxic environmental factors that we were not exposed to historically with their negative effects amplified in those with genetic predispositions. So I often say that many people that are ill today, they had, if they had their genetics but lived 75 years ago, they'd probably be just fine. It was good enough. But if you have a little genetic weakness and in the toxic soup that we're in today, it's pushing us over the edge. And then this is causing stimulation of NOx. We get the superoxide, peroxynitrite, mast cells, histamine, glutamate, the NADPHTO that we just talked about, all the things that it does. And then as we just pointed out, these free radicals produced by NOx simulate renin, ansiutensin one and two, aldosterone. And let me just park on aldosterone for a second. Aldosterone is what causes you to hold on to sodium, excrete, potassium. And that's when you get the edema, the swollen ankles. And as I do my health coaching and consulting, I'm asking people, when you take your socks off at night, do you see an indentation? Didn't ask that before, but I'm surprised how many people are having just mild edema as a result of the higher levels of aldosterone. Are you seeing a little bit more of that as well? Oh, I love that you mentioned this because I find, first of all, my personal experience with mold five years ago, I had three plus pitting edema for probably over a year. And you'll see a period of time where I taught in pants and everywhere dresses because I had these huge elephant ankles. It was all related to that and it was related to the toxic mold stimulating probably the NOx enzyme in this whole pathway. I have another patient right now as well who's been really struggling with the edema. Same thing, mold exposure. And of course, there's other causes, but absolutely. In fact, we tested aldosterone. It's actually just normal now, but I suspect earlier. And most of these patients, like myself, do very well on extra potassium, which makes sense. Absolutely. So that's what's happening as aldosterone is going up. Then it stimulates the interleukin-6 NOx in a positive feedback loop that creates that perpetuating vicious cycle of inflammation. We've named the Holmes cycle. So I think when we start looking at this, we realize this might be happening more often than we ever anticipated. Okay, just a couple of facts on NOx. As we said, it's the only known enzyme with a sole function to produce reactive oxygen species. We spoke about it uses oxygen and electron to prevent to create the superoxide. Immune cells express the NOx enzyme. Mass cells may express NOx and NOx may stimulate the mass cells. Another positive loop. And as we're gonna just demonstrate soon, if there's a relationship between M-tor, a mammalian target of rapamycin. So I have a sneaking suspicion. This is a very short list of what all that it does. But NOx activity has been associated with cardiovascular disease. Neurodegeneration, organ failure, cancer and autism. But let's think about this. If this creates histamine and glutamate and peroxynitrite and aldosterone, what conditions could that create? How many ways could that make you ill? It almost becomes mind-boggling when you think of all the downstream effects of what this could be causing. Yeah, absolutely. I can see it dramatically affecting the gut. So almost any gut disorder, socially inflammatory bowel disease and IBS types of things. I could see it affecting skin and tegmentum. So sinuses, lungs, skin issues. I could see it potentially affecting the brain as we saw in neurodegeneration, but even just classical, the non-medical term brain fog that patients often tell me they have. And then any sort of inflammatory disorder or autoimmune disorder, which isn't listed there, but and many, many more. Absolutely, the list goes on. And here we were referencing a study that says targeting these sources with natural compounds may be an important tool. Now, hang on to your hat. Nox2 activation in COVID-19 published just July 25th. And it's saying oxidative stress by Nox2 activation is associated with a severe disease in thrombotic events in COVID-19 patients. Isn't that mind-boggling, Dr. Jill? Wow, it isn't it yet. It isn't, right? It's amazing that this is published, but it makes so much sense, doesn't it, Bob? Absolutely, yeah, it sure does. So, and we've been saying that for a while, that now I want to be very clear. We're not talking about, you know, taking care of Nox would cure or not have you get COVID, but the activation of Nox2 is what gives that cytokine storm that's a part of it. So I think a lot of research needs to go into this, but we were very shocked that one of our researchers found this. And again, just a little over a month ago was this published. So quite fascinating. And then I just wanted to show this slide because it makes the histamine, and you alluded to this a little earlier. We tend to think of histamine as allergies, but the skin, the cardiovascular system, vertigo, nausea and vomiting, circadian rhythm, bone marrow, the gastrointestinal tract, as you mentioned, the uterus, the respiratory tract. As this is upregulated and we make all this histamine, these are all the things that can be impacted by that histamine. So I just want to point out that we can't pigeonhole histamine into watery eyes and runny nose. And then here's the study on excessive glutamate stimulation and pairs the ACE2 activity. Bottom line here, the study reveals a strong relationship between excessive glutamate stimulation and Adam 17 mediated impairment in ACE2 activity, suggesting a crosstalk between glutamate-induced excitotoxicity and dysregulated RAS. Wow. So therein, Dr. Jill is the mind-body connection. Yeah, and again, in the patients that we see, of course, any neurodegenerative disease, this is one of the pathways that's most of the time activated, but we also see this in patients with Lyme or mold chronic infection, chronic exposures, where especially when the brain is affected, I find that to be relevant. Absolutely. Now, what I want to go through is help everyone understand all these epigenetic factors that will stimulate NOx. One of them is homocysteine. So let's talk a little bit about homocysteine. So I'm going to bring a map over here. And a lot of people are familiar with the methylation map. The MTHFR enzyme makes your methyl folate. Your MTR is what puts a methyl group on B12. And that takes your homocysteine back into methionine that makes your SAMI, acidental methionine. Then there's also the middle pathway where trimethylglycine combines with BHMT to turn homocysteine back into methionine. Just as a side note, SAMI does a lot, but it's needed by the COMT enzyme to clear dopamine. And if we don't have enough SAMI, we're going to have high dopamine. Histamine and methyl transferase needs SAMI to take out histamine. So if you have perfect genetics on HNMT, no problems at all, but you don't have enough SAMI, your HNMT is not going to clear the histamine. So this is a very important cycle. And if this doesn't work, the homocysteine goes high. And there's a lot that can go wrong in here, even the folate receptor sites, the DHFR. A lot of people talk about MTHFR and it's important, but there's a lot upstream from that here as well. And interestingly, in our first video, we spoke about the Fenton reaction making hydroxyl radicals. Hydroxyl radicals will impede the methyl transferase enzyme that puts your methionine into SAMI. So talk about 3D, just came here, Dr. Jill, so many ways that things can get messed up. And I often, of course, high homocysteine is known. I'm always looking for ways to bring that down with the methyl donors and all of the things we talked about here on the pathway. But would you like to comment just a moment on low homocysteine? Because that can be the opposite side of the coin, I think as well. And it can cause its own set of issues when we have a homocysteine of three or four, something very, very low. Sure, well, look at our chart here. You see homocysteine comes down into cysteine. Then that combines with glutamate and glycine to make your glutathione. So not enough homocysteine is not going to allow you to make glutathione. But also let's look down here where homocysteine comes down, turns into cystothionone, and then cysteine. And we're going to talk about this in a little bit. CBS is what I was looking for there. Because CBS, rapid CBS, can be one of those factors that pulls it. Is that correct? Yes, right here. Here's CBS. So rapid CBS can pull it down through. And then we can have too many sulfates. And these are the people that say, I can't do sulfur foods. And their sulfur are sensitive. And what we need to do is figure out why they can't use them, not just totally not consume them. So there's a lot that can go wrong here. And we'll talk about this a little bit, sulfation, a very important phase 2 detox. We take out our catecholamines, our hormones, our xenobotics, and many of our toxins through sulfation. And if that is not running properly, then these toxins once again build up inside the body. And in a couple of minutes here, we're going to talk about the Suox enzyme. I saw recently on your Facebook page that you had articles on glyphosate. We're going to get into that in a moment as to how glyphosate can impact the Suox enzyme. So bottom line, it's important to have homocysteine that is not too high, not too low, just right, as we said. And then there's an interesting book out there called The H Factor. It's written for the general public. And it talks about the higher the homocysteine, the sooner you die from all causes. And there might be multiple mechanisms. But if this is stimulating the NOx enzyme, well, it is. But if there's other mechanisms besides that I'm not aware of, but just stimulating that NOx enzyme could certainly be enough to cause many of the problems that we're seeing today by high homocysteine. Now let's move on to oxalates. Now one of the interesting things that people do is they're not feeling well. And they decide, well, I think I'm going to eat healthy. So they start juicing. And they get their beets. And they get their spinach. And they get their kale. And they start juicing, feeling good about themselves that they're doing something good. Can that be excellent? You betcha. Can it backfire? Well, you know the answer. Yeah, it can. So what can happen inside the body is here's your glyoxalate. And there's actually genes, the AGXT, the GRHPR. And it's not on here, the Hoga1 and SPP1. And if you get a leaky gut, what can happen is that these healthy foods, spinach, kale, beets, if you look at them very closely under a microscope, you'll see what are called little oxalates. They're like little razor blades. And normally, if your gut is doing well, they pass through the stool. They pass out. But if you maybe had a histamine issue, if you had other issues with the gut, gluten issue, you get what's called a leaky gut. And those oxalates leak in. And when those oxalates get in the tissue, people hurt. And this is why you just grab them on the arm and they yell, ouch, is implicated in fibromyalgia. Yeah, I was just going to say that fibromyalgia, and even interstitial cystitis, there's been some implication with oxalate levels. Pain, in general, almost anywhere in the body can be exacerbated by oxalates. And one of the things I see back to my favorite topic, but aspergillus and candida and different mold species will actually contribute. So I'm always looking at load as well, because the food can be part of it if they have any aspergillus colonization in the sinuses or exposure if they have candida. Those things will all raise oxalates. So it's actually not just a low oxalate diet that can help, because I don't want them forever to be off these really good health foods. But I would have to deal with those fungal contributing factors. And clostridia, I believe, can also contribute to oxalates. So there's a bunch of different sources. And if we can bring those levels down, there's also something to be cautious about, because if someone has a normal oxalate diet or a high oxalate diet. And all of a sudden, one day they say, OK, this is a problem. I go to zero oxalates. There's a dumping effect that happens that can really exacerbate their symptoms. So I really recommend someone to go totally off oxalates, cold turkey, unless they know what they're doing, because they can really get into trouble. Absolutely. We've seen that happen. We usually recommend you reduce them by about 10% per week. That's perfect. Agree totally. Take your time. Now, we're going to talk about mTORM, a million target of rapamycin. So we showed this chart before, but it's probably worth looking at again. mTORM, a million target of rapamycin, is a very important process. When the sperm and the egg come together, they need mTOR to grow into the baby. We need mTOR to grow new cells. If we don't have mTOR, we wouldn't have a new cell growth. However, there's a lot of interest going into autophagy, the cleaning of the cells. And there needs to be a balance between mTOR and autophagy. So autophagy takes that old dead cell, either recycles it, or clears it out of the body. And if we don't have this happening, this is where you'll see people that have age spots much more quickly, because they're not cleaning out the cells. The sun oxidizes them. And when you see people in their mid-upper 40s and a lot of age spots, could be other things going on. But many times, their mTOR is excessive, their autophagy is weak. And we can see genetic factors that will weaken the autophagy. And back to epigenetics, xenoestrogens. What are we doing? Plastics everywhere, Dr. Jill. Even our polyester clothing is now getting into our water supply. Some people, we spoke about this before, that some people are doing too many amino acids that like bodybuilders that stimulate mTOR. One of the things we're going to look back on some day is we give our animals growth hormones. Well, they'll get fatter faster, and we can make more money. Well, great, but that stimulates the mTOR. High glucose, high iron, even methionine and saline will stimulate mTOR. Uh-oh, glutamate. So that's why I'm concerned that too many functional medicine doctors are giving too much glutamine powders under some circumstances, inadvertently up-regulating mTOR. Same with folate. Do we need folate? Do pregnant women need folate? You betcha. That's why if they don't have enough, they'll neither not get pregnant, have miscarriage, or a deformed baby. But once again, an excess can stimulate the mTOR. So that's why I get concerned if someone says, oh, I've got mTHFRC677. I better take a couple of milligrams of folate, maybe. It suppresses uretophagy. And then what does it do? It stimulates the NOx enzyme. Allergens, air pollution, all of those things will also stimulate the NOx enzyme. So, Bob, I want to comment real quick, because anyone in my listening area or California has known the air quality has been horrendous, probably the worst I've seen it in 10 years. And I have two Austin air filters going on in my home. I have five of them. So we have actually indoors right now, pretty good air quality. But I see so many patients right now really struggling. And what they look like is someone who's had a mast cell reaction or a mold exposure, but it's not either one of those things. It's actually the outdoor air quality from the smoke. And so this is a very real thing for those of you listening. If you're struggling, like, what is going on here? If you don't have a good HEPA air filter with a VOC filter inside your home, I highly recommend it. Just such a great thing for us to have, because it really does make a difference. Absolutely. Now, let's talk about dopamine. Dopamine is one of the catecholamines. We already pointed out it stimulates renin. And it all stimulates NOx. So once again, do I think we're seeing high dopamine in individuals? Yeah, that's just. And as we pointed out earlier, clastridia will inhibit what's called the DBH enzyme that takes your dopamine, turns it into norepinephrine. And then also, you can have genetic mutations on the DBH enzyme itself. And one of the telltale signs is people who get irritated quickly. Least little thing sets them off. And it's not just the emotional thing that's happening. It is stimulating their NOx enzyme. And there's clear evidence for neurodegeneration and chronically high dopamine. So that's another reason. I'll tell you what, Bob, I like my dopamine. I've done rock climbing. I have a motorcycle. So I do get it. But there's some really detrimental effects to the brain for high dopamine long term. So we kind of got to break that addiction and fix the gut. Absolutely. All right. Back to sulfites and sulfates. Interestingly, sulfites will stimulate the NOx enzyme. That's why in our clinic, when people come in, we actually use those little strips and we measure the sulfites and sulfates to make sure that that conversion is happening OK. Is that a urine or saliva test? That's just urine. Yes, just urine. And you can buy them strips on Amazon. And so when you've got high sulfites and low sulfates, you know that this is not converting. Very, very simple test. So the Suox enzyme, sulfur oxidase, takes sulfites, turns them into sulfates. Why is that important? Because we then go over to a very important phase two detox. Phase one is where we take toxins and put them into fat soluble. Phase two puts them in water soluble. And then we excrete them. Here you can see this is excreted in the urine. And this is a very important detox process. We all, again, hear about methylation. You don't hear too many people talking about sulfation. But it really is an important detox process. It deactivates xenobotics, inactivation of catecholamines, structure and function of the macromolecules, elimination of the end products of catabolism. So if this isn't working, we have these toxins building up. And not only that, but sulfites stimulate NOx. The catecholamines and some of these xenobotics stimulate NOx. Now, how can this get messed up? Well, we can have genetic mutations in the Suox enzyme. There's a mineral that many people have not heard about, melendimum. And that is a cofactor for Suox. But here's what's not well known. Heme is a cofactor. And this is an area that, you know, we've been taught quite a bit by one of our researchers, Dr. Michael Herra, and I want to go back over here and show everybody what happens. In your mitochondria, of course, everybody knows, we take fats, carbohydrates and proteins. There's your fats, carbohydrates, proteins. They come down through and they make something called succinal COA. That succinal COA combines with glycine. And that's an amino acid. And I know you've heard many of the things from Stephanie Seneff, brilliant woman, who, by the way, is going to be speaking at our conference, that how glyphosate is impacting our glycine. It's controversial. You know, there's people that agree with her, people that disagree, but my personal opinion is, I think it's going to turn out that she was correct. That the glyphosate impacts the glycine, then affects what's called the heme cycle, where through eight steps, we make heme. Now, there can be genetic mutations in any of these. Epigenetic factors, lead will inhibit these two. So that's why lead can be so insidious. So if we don't have enough heme, look at what heme does. We tend to think of hemoglobin, but myoglobin, neuroglobin, phase one detox, it's a health factor, peroxidase, catalase, cofactor for NADPH, for tryptophan, nitric oxide synthase, and suox. Not too many people are looking at this. To make matters worse, if these porphyrins build up, they'll block the GABA receptor sites. And when this isn't working properly, this is where people get what's called hangry. Yes. Where they're all of a sudden feeling fearful, worried, frustrated. They gotta have some food and then they feel better after they eat. These are the folks that when they try ketogenic diet, it feels miserable because they can't handle not having carbohydrates coming in on a regular basis. And this is so important, because again, diets have to be individualized. Not everybody should be on a keto diet. There are a lot of people who actually do not do well. Love that you mentioned Stephanie Seneff. I was thinking about her when you were around the sulfation pathways because she is putting this all together and the effects of glyphosate, again, hypothesizing. One other thing is the molybdenin. I love that. I remember years ago, I had lots of pain and lots of CBS up regulation. So lots of cysteine and tarin in my urine. I took molybdenin, just a milligram and all of a sudden the pain went away. And for me, that was like an aha moment. For me, I probably have a suox mutation and the molybdenin and the B2, the riboflavin, completely took away that pain. Absolutely. You know, one of the things that we just put into our software, Dr. Gill, that's fascinating is there are actually enzymes that make the cofactors that helps molybdenum be used. Wow. And for some of these people that, you know, they just can't seem to get to the root of their problem, we're finding they've got problems with their molybdenum cofactors. Yeah, wow. So the sulfites don't turn into sulfates. Now a good way to know is if this is a problem for you, is if you take a couple of sips of red wine and all of a sudden they're flushed and feel horrible. Yes. That means these sulfites are not converted. And again, oh, just one little quick, little interesting. For people who have this problem, one of their favorite foods is ice cream because glycine, carbohydrate and a tablespoon of ice cream every couple of hours just really balances them out. Now that's not the long-term solution, but that's why intermittent fasting in our keto is disastrous when somebody's got this pathway not working properly. So that's how we can have some problems with sulfites. Now, to make things that's a little bit more complicated, the H-mox enzyme breaks down the heme. If this is not working, the iron from the heme gets dumped to be a free radical. And then here's where your iron goes into ferritin, your storage. So if this isn't working, you're gonna have low ferritin, a well-meaning practitioner says, let me give you more iron. If this is just dumping, you can make more inflammation. And look up here, NADPH. Whoa, NADPH cofactor for H-mox. Makes the biliverdin and bilirubin. And guess what bilirubin does? It inhibits mast cells. And then it makes the carbon monoxide that stimulates keep one and nerf two, which is what controls the production of your antioxidants. So H-mox one, really, really important. My son and I just did a paper, a poster that's gonna be at the ILADS conference talking about the importance of H-mox in COVID, how it gets up-regulated. And we'll be presenting at that medical conference. I can't wait to hear that, Bob. Look forward to hearing from you. One question for you, this may or may not have an answer, but Gil Baer's syndrome, I see a lot of, which is a genetically predisposed to elevated bilirubin. Does that affect that pathway? Cause it looks like bilirubin has a good role, but I'm assuming it's the breakdown of bilirubin that's impaired. I don't know for sure off the top. I don't either, but I think it is the breakdown rather than overproduction. But it could be. I mean, it could be if H-mox gets up-regulated, that there could be, that'd be an interesting research project to see if H-mox is actually up-regulated in those people. We'll have to bring the answer in episode four, so stay tuned. How about 34 on that one? Yeah, exactly. That's a little too much pressure. I know, I know me too. No promises. All right, well, air pollution, we talked about that. Glutamate. Now, this is again, one of my favorite subjects. Glutamate makes you very intelligent, highly motivated, go-getter. However, in excess, it's a problem. It's a big problem. So look what happens here. Glutamate is really a multifactorial molecule. It will turn into glutamine, which is part of the healing of the gut. And then glutamine needs to turn into glutamate. However, inflammation or infection will inhibit the enzyme that turns the glutamate into glutamine. So that means you can be high-end glutamate. Also, glutamate turns into alpha-key to glutamate and susanol-CoA. I remember we just talked about that being in the heme cycle. If we don't have enough NAD+, and there's more enzymes in here that I do not have listed, there's the God enzyme and the God II, mutations here will again inhibit the glutamate to alpha-key to glutamate. So you're not gonna have energy, and you're gonna have more excitatory glutamate. And again, we just learned two days ago, glutamate inhibits ACE2, it stimulates aldosterone. Gat enzyme, along with B6 and magnesium, turns glutamate into GABA. So don't worry, relax, be happy. But as we just pointed out, if the heme cycle's not working, those porphyrins will block the GABA receptor sites. And that's where we get hangry. Then glutamate comes over and makes glutathione. And again, ATP-dependent. So if we're energy not being produced, or if we have genetic mutations on GCLM or GCLC, the glutamate doesn't come over here, and therefore we don't make our glutathione. So there's a lot that can go wrong with glutamate. And possibly this is why when people get ill, like with Lyme or other conditions, and they've got the infection and the inflammation, they become more anxious because their glutamate is going high. And without glutamate, we don't have intuition. People that are high in glutamate are usually very intuitive, go getters. But on the other hand, they're sensitive to light and sound, sometimes a little paranoid. High enough, you start having visual hallucinations where you think you see something off in the corner that's not there. And of course, as it goes higher, that's where you get your bipolar and schizophrenia. So again, Goldilocks and the three bears, we need to keep it balanced. One of my favorite herbs is Hanokial. Hanokial reduces glutamate and supports glutamate to GABA conversion. Oh, I love it. Magnolia is another name for that, I think, right? Yes, uh-huh, yep. Yep, Magnolia bark, Hanokial. Now, we wanna talk a little bit about mycotoxins. And you and I have had this discussion multiple times, how we believe that mycotoxins is more of a serious issue than we realize, but look where the mycotoxins are. They stimulate the mast cells. They're going to stimulate the histamine and the cytokines, stimulate the glutamate. Then that's going to come back, stimulate renin, stimulate aldosterone, stimulate IL-6 and NOx and just keep spinning around and around and around. So that's why the mycotoxins can be so insidious. And then unfortunately, as you know, when someone has mycotoxins, they're around allergens and they get Lyme disease and possibly EMF, they're in serious trouble. It's a perfect storm and sadly we're seeing more and more of that where there's not just one factor. Exactly. And then EMF, and we spoke about that in our peroxynitrite, so we won't go into a lot of detail on that, but basically the EMF causes the CACNA1C gene to put more calcium in. That can stimulate more superoxide, combines with nitric oxide, makes peroxynitrite. And that's why we see some individuals who are very EMF sensitive. And unfortunately, sometimes people will make fun of them and say, oh, come on, you're making this up, this cell phone, this wifi can't hurt you. But in some individuals, it does. And then of course, the Lyme disease. Now I'm not going to read these. Somebody can pause the video if they really want to look at these. But these are the genes that would cause overstimulation of the NOx enzyme. So sometimes to get to the root cause of it, we've got to dig into the functional genomics and see where it is. For example, ABP1 is what makes the dinamine oxidase that breaks down histamine. HNMT breaks down the histamine. So 3D chess game played underwater. Here's more genetic factors overstimulating the NOx. If someone watching this is a health professional and wants to learn this, we do have an online certification course that trains people on this. So it's about 35, 40 hours of instruction that helps you understand all the places you have to look to try to find why this is upregulated. Yeah, and I just want to plug that, Bob. But you've got great educational materials. And where can they find? What website can they find that they're a health professional? Well, if all they have to do is go to dnsupplementation.com, dnsupplementation.com. And there's a link there for the online certification course. And what we do is we give the first couple of modules for free because I'll be the first to admit this isn't for everybody. This is not for the faint of heart. This is for the serious practitioner because if they're looking for a piece of paper that says, do these three things, they won't get that. They've got to really dig in, learn, look at it. So that's why it's not for everybody. That's why we give opportunity to try it. And some people are like, this is the coolest thing I've ever looked at. And others say, too much work. No, sorry. And that's okay, you know. So this is for the faint of heart. So these are all the genetic factors that could over-stimulate NOx. If someone would like these maps, just go to NeutrogenicResearch.org slash research and they can download those PDFs. I have them there free for anybody who wants them. So there's that vicious cycle once again. So what do we have to do? Well, we have to see if there's genetic issues with any of the NAD plus and NADPH pathways because that NADPH steel is using your NADPH up excessively. And if you have some issues that you don't make enough, that's when you're in a serious issue. Modulate and calm NOx. Easier said than done because we showed so many. Support production and usage of NAD. Support glutamate to GABA. Reduce oxalates. Support the proper use of iron. Limit EMF exposure. I just recently had a physician whose wife was not doing very well. And she was literally in the office sitting next to their Wi-Fi. I mean, literally two feet away from their Wi-Fi. Moved her away from that dramatic improvement. Support sulfite to sulfate conversion. Get that homocysteine where you want it. Get the dopamine where you want it and then make sure you've got adequate nerve two and glutathione activity. Is that a lot? Yeah, yeah. So do we have a pill for the ill? No, that's a lot of things. So to sum it up, let's just look at one other chart here. And this is one of the things that people can download. I put on that website, the actual nutrient that will help either suppress, like here's suppress the histamine, here's help clear the histamine. So these are all the nutrients that could provide support to those enzymes that could be out of whack. And then if someone wants to know what are the genetic mutations that could contribute to that, these two charts are on the website. They're free, we don't sell anything. They're there for you to download. And you can actually see which genes when they're mutated could contribute it. Here's for example, the enzymes that if they're mutated will relate to more oxalates. This would make more iron. The DAO and GAD would make more glutamate. ULK1, ULK2, ATG13 would weaken autophagy strength and mTOR. And I just have fun with this. The reninase, the reninase genes will cause more ox will create more aldosterone. And if anybody really wants to geek out on these charts, there they are. So bottom line, I believe we've discovered this hypothetical but I think we've discovered something very significant, epigenetic factors. We weren't exposed to 50 to 75 years ago, stimulate superoxide, peroxanitrite, hydrogen peroxide, mast cells, histamine, glutamate, and we just start a positive feedback loop that feeds it and keeps it going. And I believe as we learn more about this, do more research on this, we're gonna be able to help some people that we weren't able to help before. Finally, wanna mention, coming up very, very soon, October 18 to 20, a three-day conference for health professionals, but since it's streaming, if someone's not a health professional and just wants to listen in, they certainly can. By the way, thank you, Dr. Jill, for being a speaker and I'm not gonna read these, but the who's who of a functional medicine, particularly as it relates to mycotoxins, and we're gonna spend three days, three long days on mycotoxins. And we're hoping that the doctors, when they leave this conference, they're gonna have some tools that they didn't have before, because we're going into some really unique angles, how it affects the adrenals, how it affects interleukin-13 and nitric oxide, how the mass cell relationship. And we'll be talking about some of the things that I just spoke about here today, the how this thing feeds upon itself. So if someone's a health professional, they want to attend nutrogenicresearch.org, same website for the maps, and you can click or just put in 2020 conference. So it should be a lot of fun. We're looking forward to it. Yeah, go ahead. And I was just gonna say, there's our website, toolhealth.com. If you're a health professional and want to look in at studying this and learning how to do it, there's the website, dnsupplementation.com. Bob, as always, this information is so important. I really believe it's the kind of stuff that's gonna take us to the next level in functional and integrative medicine. And we are all so grateful for you and your team for continuing to bring the research. I always learn something new when I talk to you. And I am all on board to help get the word out for you, as you well know, because I really believe in the work that you're doing. I believe in you. And what I love is I also heard some things in how you give away the free documents, how you give away the first three modules or whatever. You are a man of a generous heart because I know your heart, as far as getting the research out to people is in the right place. So I hope that if you've listened to this, enjoy this. Come back and listen to episode one and episode two. If you're a professional wanna join the conference or a layperson that wants to get really deep join the conference and be sure and support Bob because he's just doing a great work and I am so grateful for all that you do for us, Bob. Well, it's my pleasure. Our whole mission is to be a benefit to humanity. That's what we do. And to me, just what a blessing that for someone who's just a traditional naturopath has this opportunity to bring this information to the functional medicine world. And we're just hoping that it improves the lives of a lot of people. So that's our mission. I know you already have. So thanks again for joining us and stay tuned cause I'm sure Bob will be setting up maybe the next three episodes for the fall. Take care. Okay, we're looking forward to it.