welcome back mitochondriac for another episode of cancer as a mitochondrial metabolic disease I am happy to be back with you today to discuss the next substance when it comes to glutamine and that is egcg and this is an exciting topic because this is the probably the glutamine inhibitor that most people are aware of although of course we're going to cover several others in addition to what we've already covered so far with curcumin berberine and silly benon but but most of the natural glutamine Inhibitors work on various uptake ports and channels therefore it can't be brought into the cell but egcg is one of the only that work specifically on glutamine enzymes for its utilization with inside the cell and the TCA cycle so without further Ado let's get into it so I want to start with this paper to not only talk about egcg from a 20,000 foot view but to also discuss just in general what egcg is for those who are not aware of what it is and this paper is titled targeting cancer Hallmarks with epig Gallo catagen gallate egcg mechanistic basis and therapeutic targets and what it says here is that egcg is a catechin which is a type of flavonoid found in high concentrations in green tea egcg has been studied extensively for its potential health benefits particularly in cancer EG PCG has been found to exhibit antiproliferative anti-angiogenic and proapoptotic effects and numerous cancer cell lines and animal models egcg has demonstrated the ability to interrupt various signaling Pathways associated with cellular proliferation and division for different cancer types egcg anti-cancer activity is mediated by interfering with various cancer Hallmarks this article summarizes and highlights the effect of egcg on cancer Hallmarks and focuses on the impact of egcg on these cancer related Hallmarks the studies discussed in this review enriched the understanding of egcg potential as a therapeutic tool against cancer offering a substantial foundation for scientists and medical experts to advance scientific and clinical investigations regarding possibility as a potential anti-cancer treatment so let's look at the potential Hallmarks that are affected by egcg starting from the top left here it shows that it assists with the the genomic instability the resistance of cancer cell death or the anti-apoptosis mechanisms found in cancer it helps with tumor Genesis and carcinogenic activity sustain proliferative signaling evasion of growth suppressors enabling replicative immortality deregulating cell metabolism tumor promoting inflammation induction of angiogenesis tissue Invasion and metastases and immune Invasion so egcg as you can see here given its multiple mechanisms is one of the most powerful tools we have in our tool bag against this disease and I particularly want to show some of the mechanisms in which egcg has shown in effect so for example in the adherence migration and extracellular Matrix remodeling it's shown to have activity against TGF beta and multiple signaling Pathways to do with adherence migration and proliferation it's also been shown to affect the VF vascular endothelial growth factor pathway at multiple levels to mitigate endothelial angiogenesis or the creation of new blood vessels of note you can see here that egcg works upon hif1 Alpha mtor this pi3k ATK pathway which involves NFA B which is a pro-inflammatory signal it also works upon Pat and other parts of the inflammatory Cascade here's its role within the activation proliferation and migration as well when it comes to toik receptors inflammation at various levels it's also responsible for blocking this smad which has to do with the denovo synthesis of glutathione and again involved with Pathways regarding inflammatory cyto kindes and chemokines which are chemical mediators involved in the inflammatory process pretty cool so in this paper from January 2024 and frontiers of Immunology is titled the role of egcg in the tumor micro environment metabolic reprogramming and amother capy and it says additionally egcg can suppress multiple metabolic reprogramming Pathways including glucose uptake aerobic glycolysis aka the warberg effect glutamine metabolism fatty acid metabolism and nucleotide synthesis so as we can see it doesn't just have diverse actions on multiple signaling and inflammatory Pathways but it also has to do with the nuts and bolts of metabolic pathways including glucose glutamine fatty acids and nucleotide synthesis which are all part of the metabolic approach to cancer so we're going to talk a lot more about egcg in the future when we get to an entire micro series regarding glucose uptake and Metabolism but needless to say egcg does affect on multiple levels glucose metabolism and in particular in this picture it's showing the blockade of this pfk enzyme which stands for foso fructokinase which is responsible for converting fructose 6 phosphate to fructose bif phosphate which is a key step in glycolysis and that's going to Downstream have an effect on the amount of available pyruvate which can get later converted to lactate and it's going to ultimately help us with the process of apoptosis through caspas mechanisms this is beyond a busy slide but the bottom line is that I don't know if there is a better molecule in our fight against cancer because egcg as you can see here is having diverse effects I'm going to start from the top left here it's G to help in blocking glucose uptake it's going to help in blocking glucose utilization at multiple levels lactate dehydrogenase enzymes it's also going to block the use of glucose 6 phosphate from getting put into the PPP or the pentos phosphate pathway by blocking G6PD it's going to block several areas of the folate Pathways that are responsible for improving the nucleotide synthesis so that DNA and RNA can be replicated you're going to see egcg act upon this fasn enzyme which is responsible for the creation of new fatty acids we've already talked about several of these growth Pathways like pi3k akt but also hif1 Alpha mtor erk1 and two which relate to cic if you remember right from the last video CCH at least partially responsible for the increased uptake in glutamine utilization it also has positive effects on the amp kyes pathway as we go down further if you remember right from the dawn talks this is where Don works this GLS enzyme or glutaminase enzyme where egcg works on the glutamine side of things is right here where it's blocking this glutamate dehydrogenase enzyme so that glutamate can't get utilized in the TCA cycle to further make fatty acids and it also blocks this enzyme here where alphet glutarate is being converted to this 2dhg chemical which is responsible for some important epigenetic modifications within cancer cells so as you can see egcg is a rock star when added to the foundations of metabolic therapy I just wanted to give a couple additional pictures here where egcg actually works so if you remember right glutamate is being converted into alph gluer through these glutamate dehydrogenase enzymes and this is where egcg works and again here's another picture showing that egcg is blocking this glutamate dehydrogenase 1 enzyme and again here egcg is blocking glutamate dehydrogenase enzymes and remember Don worked here some of the other things like berberine and cinin work on this particular slc15 but egcg is working on the inner workings of glutamate to ALF glutarate and that's going to essentially shut down the lipid synthesis and nucleotide synthesis it's also going to we talked about in the prior slide it's going to block enzymes responsible for converting citrate into lipids the fasn enzyme it's just almost too remarkable to believe how amazing egcg is now the question that you all might have is how does egcg compare to Dawn and in a lot of the cases of molecules that are under investigation for their inhibition of glutamine related enzymes and uptake channels we don't have a lot of head-to-head data but egcg is one of the ones that we actually do okay so we obviously have some baseline amount of utilization by cancer cells or glutamine oxidation right and what we see is when egcg is added we see a dose response curve that is pretty impressive it's a near 50% response when egcg is added and we can see that there is actually remarkable responses even at 10 Micro moles and it really kind of levels off at about 30 to 40 micro moles and then it kind of completely levels off at about 40 to 50 and you may ask well how does that compare to Dawn well Dawn was compared here and we had the same starting point about 40 and we see that with Dawn we have a lower amount of glutamine utilized but not a huge amount difference we're at 20 pea moles per hour and here even at maximum concentrations with Don and it gets down to about 10 pames per hour so that's pretty cool and then when they actually graft it here in the same units pea moles per hour we see that Don has a very slight Edge on egcg so I think this really highlights that this is a really powerful tool that we have in our tool bag and this is something that is available to almost everybody either through green tea or through the actual supplementation of egcg and I think that's pretty amazing so I really hope that I'm making the case today that egcg is a very powerful intervention that we have in our tool bag and it's cheap it's safe and it can be employed for most people now never add any intervention without discussing it with your doctor or like-minded Healthcare practitioner but it's fairly safe to say that this can be utilized by most people the dosing the scheduling the timing all of that stuff again will have to be between you and your doctor but egcg is something that I think that most people can benefit from if you like videos like this please like it if you have someone in your life who is struggling and could benefit from this information please share it with them and if you're not a subscriber yet to our 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