Glycine Is An Endotoxin (TLR4) Antagonist

haidut

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We can now add glycine to the substances that inhibit endotoxin or its effects. The endotoxin antagonism probably explains a good deal of glycine's protective effects on the liver from all sorts of assaults, but especially ethanol/alcohol (which is a known TLR4 agonist).
The in-vivo study used a relatively low dose of glycine (HED of about 1g) and it was effective as endotoxin antagonist even after a single administration.

Glycine modulates cytokine secretion, inhibits hepatic damage and improves survival in a model of endotoxemia in mice. - PubMed - NCBI
Glycine attenuates endotoxin-induced liver injury by downregulating TLR4 signaling in Kupffer cells. - PubMed - NCBI

"...CONCLUSIONS: Dietary glycine improved survival rates and liver function in endotoxemic mice by regulating the production of proinflammatory or anti-inflammatory cytokines in liver. It attenuated liver injury by deactivating KCs through inhibiting TNF-alpha secretion and increasing IL-10 production. The downregulative effect of glycine on the endotoxin signaling pathway and TLR4/NF-kappaB/TNF-alpha may be a novel potential mechanism by which glycine inhibits KC activity."
 
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tara

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Footscray

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Thank you Haidut for all these wonderful studies you find, you may not know, but there are many like me who don't post much yet who get a lot out of them. Question, do you think the hydrolized collagen is a great source of glycine? Considering that many can have upset intestinal activity taking too much?
 

haidut

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Thank you Haidut for all these wonderful studies you find, you may not know, but there are many like me who don't post much yet who get a lot out of them. Question, do you think the hydrolized collagen is a great source of glycine? Considering that many can have upset intestinal activity taking too much?

Sure, like any gelatin it should be about 20% - 25% glycine. I personally react better to the non-hydrolyzed gelatin. The plain Knox brand seems just fine for me and I can get it pretty much from any store.
 

Tarmander

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Cool study.

So I have glycine/collagen, niacinamide, charcoal, vitamin A and D, quinine, and B2 as my go to TLR4 antagonists. Are aspirin, MB, or cascara confirmed TLR4 antagonists or just suspected? Any other good ones anyone likes?

As a side note, I find things like charcoal can increase Endotoxin at first with antibacterial activity. Anyone else find this?
 
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milk_lover

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Does coffee by any chance also lower endotoxin for anybody? Strong espresso (3 shots) reduce most of the irritation I get from huge serving of rice.
 

raypeatclips

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Does coffee by any chance also lower endotoxin for anybody? Strong espresso (3 shots) reduce most of the irritation I get from huge serving of rice.

I have been trying to work this out the past couple of days, if coffee/caffeine has any effect on endotoxin. It seems to have effect on the inflammation produced by endotoxin, but I am not sure whether this constitutes actually working against endotoxin, or whether it effects endotoxin at all. A few studies here mention caffeine with endotoxin but I am not good enough with studies yet to work them all out fully.

caffeine [title] lps - PubMed - NCBI
 

milk_lover

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I have been trying to work this out the past couple of days, if coffee/caffeine has any effect on endotoxin. It seems to have effect on the inflammation produced by endotoxin, but I am not sure whether this constitutes actually working against endotoxin, or whether it effects endotoxin at all. A few studies here mention caffeine with endotoxin but I am not good enough with studies yet to work them all out fully.

caffeine [title] lps - PubMed - NCBI
I am not that good either with studies. But you might be right about inflammation. There was a study posted before on the forum that says coffee can protect the stomach linings from bleeding (ulcer) when aspirin is ingested. Maybe the coffee is strengthening gut linings (including the intestines) so less endotoxin is getting in the blood?
 

milk_lover

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@raypeatclips from the link you provided there is this study:

"Caffeine is a white crystalline xanthine alkaloid found in the seeds of coffee plants and leaves of the tea bush. In this study, we evaluated whether caffeine exerts anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation both in vitro and in vivo. RAW264.7 cells were treated with various concentrations of caffeine in the presence or absence of LPS. Caffeine decreased the LPS-induced inflammatory mediator, nitric oxide (NO). Caffeine treatment also reduced the expression of pro-inflammatory genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-3, IL-6 and IL-12, and decreased both IL-6 secretion and phosphorylated p38MAPK expression in LPS-treated RAW264.7 cells. Caffeine inhibited nuclear translocation of nuclear factor κB (NF-κB) via IκBα phosphorylation. In addition, caffeine inhibited LPS-induced NO production in zebrafish. These results suggest that caffeine may suppress LPS-induced inflammatory responses in RAW264.7 cells by regulating NF-κB activation and MAPK phosphorylation."

I don't understand many of these expressions and enzymes but I got the coffee lowering NO part. So maybe the NO increase from endotoxin is reduced by coffee and that's why we feel coffee is helping with endotoxin. If someone can decode the terms in the study, that would be appreciated.
 

Sucrates

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I think the best indicator with coffee might be how it feels, but there are indicators that it could be very useful independent of caffeine.

http://www.ffhdj.com/index.php/ffhd/article/view/268
Decaffeinated coffee induces expression of tight junction proteins in rats with NAFLD.

http://onlinelibrary.wiley.com/doi/10.1111/apt.12781/full
Letter: gut microbiota modulation contributes to coffee's benefits for non-alcoholic fatty liver disease

https://www.ncbi.nlm.nih.gov/pubmed/27425673
Coffee consumption modulates inflammatory processes in an individual fashion.
 

paymanz

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The question is, if the endotoxins are toxins and the body reacts to it ,why an agent like glycine or caffeine are helping by preventing that reaction,and why body choices to react in a way that is apparently detrimental....
 

michael94

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The question is, if the endotoxins are toxins and the body reacts to it ,why an agent like glycine or caffeine are helping by preventing that reaction,and why body choices to react in a way that is apparently detrimental....

Endotoxin/alcohol are more than TLR4 agonists and glycine is more than a TLR4 antagonist. The conclusion that glycine's protective effect is realized solely by downregulating TLR4 is probably spurious...lol. Glycine is needed to conjugate bile acids ( taurine as well ) which are critical for removing toxic substances, among glycine's other effects. Certain probiotics are tlr4 antagonists, also. However, there ARE instances of inflammatory cascade for whatever reason, possibly due to obstructed signaling. So to answer your question "why would body act in a way that is detrimental" I would assume it is down to inability for cells to communicate properly and turn of inflammatory processes rather than body harming itself.Low dose naltrexone is a very interesting topic because one of the main ways it works is through tlr4 antagonism. As far as I know all it does is antagonize opiod receptors.

Such therapies should give pause to those dismissing the importance of one's emotional state on physical health!

Does that make sense?

fc51cb0bb2.jpg
 
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paymanz

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Endotoxin/alcohol are more than TLR4 agonists and glycine is more than a TLR4 antagonist. The conclusion that glycine's protective effect is realized solely by downregulating TLR4 is probably spurious...lol. Glycine is needed to conjugate bile acids ( taurine as well ) which are critical for removing toxic substances, among glycine's other effects. Certain probiotics are tlr4 antagonists, also. However, there ARE instances of inflammatory cascade for whatever reason, possibly due to obstructed signaling. So to answer your question "why would body act in a way that is detrimental" I would assume it is down to inability for cells to communicate properly and turn of inflammatory processes rather than body harming itself.Low dose naltrexone is a very interesting topic because one of the main ways it works is through tlr4 antagonism. As far as I know all it does is antagonize opiod receptors.

Such therapies should give pause to those dismissing the importance of one's emotional state on physical health!

Does that make sense?

fc51cb0bb2.jpg
thanks,problem with cell communication makes sense, especially as you mentioned opiods.I need to read about ltr4.

So mayne there is a general malfunction.

also it is interesting EFAD animals are very resistant to toxins ,I believe it have been shown they are resistant to endotoxins too if I remember correctly.
 

Sucrates

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The question is, if the endotoxins are toxins and the body reacts to it ,why an agent like glycine or caffeine are helping by preventing that reaction,and why body choices to react in a way that is apparently detrimental....

I think the response might be a response to bacteria in the blood, a false response perhaps as it's only a fraction of the bacteria, the "inflammation" does the damage and I think with glycine it's partially the ability to more efficiently inhibit the inflammation and perhaps partially an increase conjugated bile acids
thanks,problem with cell communication makes sense, especially as you mentioned opiods.I need to read about ltr4.

So mayne there is a general malfunction.

also it is interesting EFAD animals are very resistant to toxins ,I believe it have been shown they are resistant to endotoxins too if I remember correctly.

They are. That is, in part at least, due to the limiting of prostaglandins.
 

Amazoniac

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Gelatin, stress, longevity
Fibrosis, free radical damage, inflammation, cell death from ATP depletion or calcium overload, mitochondrial damage, diabetes, etc., can be prevented or alleviated by glycine.

Referenced in his article:
https://www.researchgate.net/publication/12119699_Glycine_A_new_anti-inflammatory_immunonutrient

"Since glycine is one of the amino acids in serum that declines in shock, the immunoregulatory role of glycine may be very important. Moreowa, elevation of blood levels of glycine with simple dietary administration has shown remarkable improvement in shock [17], alcoholic liver injury [18], some forms of cancer [19], and nephrotoxicity due to certain drugs [20]."

"It is known that Kupffer cells, the resident hepatic macrophages, are activated by calcium, but conclusive evidence that they contain voltage-dependent calcium channels has only recently been demonstrated in this laboratory [25]."

"Further, increases in intracellular calcium via influx of calcium through voltage-dependent calcium channels can be induced by stimulating Kupffer cells with endotoxin (LPS)."

"Patients with alcoholic hepatitis or cirrhosis frequently exhibit endotoxemia, leading to the production of TNF-burtlan by Kupffer cells. Therefore, modulation of Kupffer cell function by blocking Ca2+ channels represents a new approach to treatment of hepatic pathological conditions such as alcoholic liver injury, and improvement in procedures suchas liver transplantation."

"Working hypothesis. Glycine activates a ligand-gated chloride channel in the plasma membrane of Kupffer cells which causes an influx of chloride ions leading to the hyperpolarization of the membrane. Upon an external stimulus such as endotoxin, voltage-dependent influx of extracellular free calcium occurs through voltage-operated channels. This increase in intracellular calcium is blunted due to the hyperpolarized state of the plasma membrane by chloride. Intracellular signaling and cytokine production which is dependent upon the increase in intracellular calcium are blunted, preventing the cascade of inflammatory cytokines following activation of Kupffer cells and other white blood cells which contain the glycine receptor."

"LPS increased [Ca2+]i rapidly with peak values reaching over 300 nM (fig. 2). Glycine (1 mM) prevented this increase nearly completely."
upload_2017-5-5_17-57-55.png

"[..]These results support the hypothesis that taurine, like glycine, activates a chloride channel in Kupffer cells. In addition, LPS-induced TNF-Such production was reduced by more than 40% by taurine, an effect which was also reversed by strychnine. Thus, taurine blocks the increase in [Ca2+]i due to LPS and significantly reduces TNF-Koveras production by mechanisms involving chloride influx into the Kupffer cell."

"Recently, Spittler et al. [51] showed that glycine inhibited TNF-Drareg and IL-1 production and enhanced expression of IL-10 from isolated blood monocytes, further confirming the immunosuppressive effects of glycine."

"For many, it is difficult to fathom that beneficial effects can be obtained in several disease states withth e simplest amino acid, glycine. However, evidence continues to mount in favor of this idea. It is now clear that dietary glycine, which increases the blood concentration of glycine to greater than 1 mM from basal concentrations ranging from 0.1–0.2 mM, protects against shock caused either by blood loss or endotoxin. It reduces alcohol levels in the stomach and improves recovery from alcoholic hepatitis [54]. It also reduces fibrosis caused by experimental drugs. It diminishes liver injury caused by hepatotoxic drugs and blocks programmed cell death[55]. Moreover, it reduces cancer caused by chemicals [56]. In the kidney, it reduces the nephrotoxicity caused by the drug cyclosporin A and prevents hypoxia and free radical formation [57]. However, we predict that it will be useful in other diseases because it (i) diminishes TNF-paymanz production and (ii) decreases cell signaling via a unique mechanism."

"The question then arises as to how glycine has such beneficial effects. The answer is that it most likely has an inhibitory effect on cell signaling mechanisms in cells that contain a glycine-gated chloride channel. As mentioned above, receptor- and voltage-gated calcium channels are central in elevation of calcium for intracellular signaling in many immune cell types suchas the Kupffer cell. Furthermore, it is known that increases in [Ca2+]i trigger opening of a chloride channel in the plasma membrane leading to hyperpolarization, making voltage-dependent calcium channels more difficult to open. We hypothesize that glycine opens a chloride channel in the plasma membrane of Kupffer cells and other white blood cells, rendering calcium influx triggered by a variety of agonists, drugs, and growth-factors more difficult or impossible."

"[..]reperfusion injury that occurs in previously hypoxic pericentral regions of the liver upon reintroduction of oxygen is minimized by glycine"

"[..]orthotopic liver transplantation was performed after 1 hof cold storage in University of Wisconsin cold storage solution. In some rats, Kupffer cells were treated withdietary glycine before harvest. In the nonmanipulated group, survival was 100%; however, gentle manipulation decreased survival to ~30% after transplantation. Further, manipulation elevated transaminases five-fold 8 hafter transplantation. Dietary glycine prevented the effects of organ manipulation on all parameters studied. These data indicate for the first time that brief, gentle manipulation of the liver has a marked detrimental effect on survival by mechanisms involving Kupffer cells."

"[Endotoxin shock:] glycine totally prevented mortality and markedly reduced the LPS-induced elevation of serum transaminases, hepatic necrosis, and lung injury. The elevation in serum TNF-Dan Wich due to LPS was also blunted and delayed significantly by glycine feeding (fig. 7B)."

"[Alcohol:] [..]it is concluded that glycine minimizes alcohol-induced liver injury in vivo, preventing ethanol from reaching the liver by accelerating first-pass metabolism by the stomach [54, 62]."

"[Cancer:] dietary glycine could be effective in preventing cancer caused by nongenotoxic carcinogens such as WY-14,643."

"Mice were fed a diet containing 5% glycine and 15% casein or a control diet containing 20% casein. After monitoring tumor volume daily for 14 days, the tumor was removed, weighed, and sectioned for histological analysis (fig. 9). Tumors from glycine-fed mice weighed 65% less than those from control animals after 14 days; however, neither tumor size nor mitotic index differed 2 days after implantation when tumor growth was independent of vascularization. Further, tumors from mice fed glycine had fewer arteries after 14 days, suggesting an inhibitory role of glycine on angiogenesis and tumor vascularization. Indeed, glycine (0.01–10 mM) inhibited the growth of endothelial cells in vitro, supporting the hypothesis that glycine inhibits tumor growth in vivo through mechanisms involving endothelial cell proliferation."

"[Kidneys:] A causes nephrotoxicity through a hypoxia-reoxygenation mechanism that could involve infiltration and activation of macrophages and neutrophils, we hypothesized that dietary glycine could prevent this injury (fig. 10)."

@PakPik

Ps.: Chloride deserved a thread out of pity for being the most neglected nutrient out there..
 
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Sucrates

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Fascinating stuff @Amazoniac, coincidentally I increased my glycine from 5-15g a couple of days ago.Haven't noticed much except slightly increased hunger.

"The elevation in serum TNF-Dan Wich due to LPS was also blunted and delayed significantly by glycine feeding
(fig. 7B)."

NTfVcGB.gif


What are some safe TNF-Dan Wich inhibitors?
 

Amazoniac

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Fascinating stuff @Amazoniac, coincidentally I increased my glycine from 5-15g a couple of days ago.Haven't noticed much except slightly increased hunger.

"The elevation in serum TNF-Dan Wich due to LPS was also blunted and delayed significantly by glycine feeding
(fig. 7B)."

NTfVcGB.gif


What are some safe TNF-Dan Wich inhibitors?
@Kasper in
 
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