Aspirin suppresses "protective" prostaglandins...

[RealNeat]

I was researching the ways by which Aspirin could cause ulcers and found that it can, "... inhibits COX-1 activity in the gastric mucosa by suppressing the synthesis of protective prostaglandins. In doing so, this creates a state of propensity for the development of aspirin-associated gastrointestinal ulcers and ulcer complications." - The Effects of Aspirin and Acetaminophen on the Stomach in Healthy Volunteers - Full Text View - ClinicalTrials.gov

My understanding was that the acidity and ability of it to irritate locally was the main issue of aspirin, I wasnt aware that the stomach needed prostaglandins for proper function...

How accurate are these statements? Is there an effective way of preventing it?

Also:

Prostaglandins in peptic ulcer disease. Their postulated role in the pathogenesis and treatment - PubMed

Prostaglandins are important in the pathophysiology of peptic ulcer disease and possibly in its prevention and treatment as well. Prostaglandins have been shown to inhibit gastric secretion, stimulate bicarbonate secretion, and increase gastric blood volume. Pretreatment with prostaglandins has...

pubmed.ncbi.nlm.nih.gov

And is this why cabbage juice helps people with ulcers? "Recent research has also highlighted the fact that the protective functions of prostaglandins in the stomach can be carried out by other mediators, in particular the gaseous mediators nitric oxide and hydrogen sulfide."

https://journals.physiology.org/doi/full/10.1152/physrev.00004.2008

 

[cs3000]

there's a nice study that figured this out , ginger protects against aspirin induced ulcers ,
it works partially through reducing aspirins effect on mucosa but not via the prostaglandin (not directly anyway - low prostaglandin E2 from aspirin can increase IL-1β levels which can cause inflammation problems ironically.
"Low PGE2 levels were at least involved in the enhanced IL-1β production by Acetylsalicylic acid")

ginger reduces the increase in TNF-α and IL-1β levels in plasma which gets elevated a lot by aspirin. at least ~2 grams, not sure where the threshold is. & also reduces aspirin induced nitric oxide enzyme overexpression in the mucosa (iNOS),


~10mg human dose Shogoal gave the full effect, 5mg gives most of the effect.
i think most or all of the gingerol in ginger powder gets converted to shogoal during the drying process, so standardized products gingerol + shogaol = total shogaol content

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763798/
Ginger powder did not affect the aspirin-induced reduction in mucosal prostaglandin E2 (PGE2) content; however, it did ameliorate the aspirin-induced increases in mucosal activity of the inducible form of NO synthase (iNOS) and plasma tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels
In conclusion, ginger powder prevents the aspirin induced gastric ulcer formation by reducing mucosal iNOS activity and the plasma levels of inflammatory cytokines but does not affect gastric juice or acid production or mucosal PGE2 content. This protective effect of ginger powder against gastric ulcers may be attributable to both gingerol and shogaol


The lack of attenuation of the decrease in gastric mucosal PGE2 content after the coadministration of ginger powder also reveals that the restoration of the PGE2 level in the gastric mucosa is not the mechanism underlying the protective effects of ginger powder in this aspirin induced ulcer model. This is not unexpected because the reduction of the gastric mucosal PGE2 concentration induced by aspirin does not necessarily participate in gastric ulcer generation (Takeuchi et al., 1986; Lichtenberger et al., 2007).

One of the mechanisms by which aspirin damages the gastric mucosa is the increased production of NO due to the overexpression of iNOS (Kontureck et al., 2006). NO is a mediator not only of gastrointestinal mucosal defense (Calatayud et al., 2001), but also of its damage (Muscara and Wallace, 1999). It has been shown that different concentrations of NO have completely opposite effects in the same tissue (Wallace and Millor, 2000). In general, the mucosal and endothelial NOS isoforms produce low amounts of NO. However, the high quantity of NO produced by iNOS damages the epithelium (Piotrowski et al., 1999; Wallace and Miller, 2000). The excessive release of NO from gastric epithelial cells induced by aspirin has been reported to exert detrimental effects (Whittle, 2003; Hsu and Liu, 2004). Inhibiting aspirin-induced increases in iNOS expression in the gastric mucosa leads to a reduction in gastric mucosal damage (Konturec et al., 2006). In the present study, ginger powder reduced iNOS activity and inhibited the production of gastric ulcers, even in the presence of aspirin.
From these results, ginger powder is suggested to protect the stomach against the ulcer formation induced by aspirin by reducing iNOS activity in the gastric mucosa and inflammatory cytokine (TNF-α and IL-1β) expression. These effects of ginger powder seem to be derived from the actions of gingerol and shogaol, the main ingredients of ginger.

image of mice stomach on aspirin vs asprin+ginger. ginger was completely protective

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763798/bin/YAm-54-011-g001.jpg

but even with that i think its best to stay on low doses due to aspirins negative effect on red blood cells. unless someone's at the high end of red blood markers.

 

[RealNeat]

there's a nice study that figured this out , ginger protects against aspirin induced ulcers ,
it works partially through reducing aspirins effect on mucosa but not via the prostaglandin (not directly anyway - low prostaglandin E2 from aspirin can increase IL-1β levels which can cause inflammation problems ironically.
"Low PGE2 levels were at least involved in the enhanced IL-1β production by Acetylsalicylic acid")

ginger reduces the increase in TNF-α and IL-1β levels in plasma which gets elevated a lot by aspirin. at least ~2 grams, not sure where the threshold is. & also reduces aspirin induced nitric oxide enzyme overexpression in the mucosa (iNOS),


~10mg human dose Shogoal gave the full effect, 5mg gives most of the effect.
i think most or all of the gingerol in ginger powder gets converted to shogoal during the drying process, so standardized products gingerol + shogaol = total shogaol content

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763798/
Ginger powder did not affect the aspirin-induced reduction in mucosal prostaglandin E2 (PGE2) content; however, it did ameliorate the aspirin-induced increases in mucosal activity of the inducible form of NO synthase (iNOS) and plasma tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels
In conclusion, ginger powder prevents the aspirin induced gastric ulcer formation by reducing mucosal iNOS activity and the plasma levels of inflammatory cytokines but does not affect gastric juice or acid production or mucosal PGE2 content. This protective effect of ginger powder against gastric ulcers may be attributable to both gingerol and shogaol


The lack of attenuation of the decrease in gastric mucosal PGE2 content after the coadministration of ginger powder also reveals that the restoration of the PGE2 level in the gastric mucosa is not the mechanism underlying the protective effects of ginger powder in this aspirin induced ulcer model. This is not unexpected because the reduction of the gastric mucosal PGE2 concentration induced by aspirin does not necessarily participate in gastric ulcer generation (Takeuchi et al., 1986; Lichtenberger et al., 2007).

One of the mechanisms by which aspirin damages the gastric mucosa is the increased production of NO due to the overexpression of iNOS (Kontureck et al., 2006). NO is a mediator not only of gastrointestinal mucosal defense (Calatayud et al., 2001), but also of its damage (Muscara and Wallace, 1999). It has been shown that different concentrations of NO have completely opposite effects in the same tissue (Wallace and Millor, 2000). In general, the mucosal and endothelial NOS isoforms produce low amounts of NO. However, the high quantity of NO produced by iNOS damages the epithelium (Piotrowski et al., 1999; Wallace and Miller, 2000). The excessive release of NO from gastric epithelial cells induced by aspirin has been reported to exert detrimental effects (Whittle, 2003; Hsu and Liu, 2004). Inhibiting aspirin-induced increases in iNOS expression in the gastric mucosa leads to a reduction in gastric mucosal damage (Konturec et al., 2006). In the present study, ginger powder reduced iNOS activity and inhibited the production of gastric ulcers, even in the presence of aspirin.
From these results, ginger powder is suggested to protect the stomach against the ulcer formation induced by aspirin by reducing iNOS activity in the gastric mucosa and inflammatory cytokine (TNF-α and IL-1β) expression. These effects of ginger powder seem to be derived from the actions of gingerol and shogaol, the main ingredients of ginger.

image of mice stomach on aspirin vs asprin+ginger. ginger was completely protective

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763798/bin/YAm-54-011-g001.jpg

but even with that i think its best to stay on low doses due to aspirins negative effect on red blood cells. unless someone's at the high end of red blood markers.

I actually was reading on that yesterday, funny enough ginger seems to hurt my ulcer upon consumption, maybe it's too "hot"

And what you wrote/ cited says this;
"This is not unexpected because the reduction of the gastric mucosal PGE2 concentration induced by aspirin does not necessarily participate in gastric ulcer generation (Takeuchi et al., 1986; Lichtenberger et al., 2007)."

So they thinks it's all NO related and not PGE2?

 

[redsun]

I was researching the ways by which Aspirin could cause ulcers and found that it can, "... inhibits COX-1 activity in the gastric mucosa by suppressing the synthesis of protective prostaglandins. In doing so, this creates a state of propensity for the development of aspirin-associated gastrointestinal ulcers and ulcer complications." - The Effects of Aspirin and Acetaminophen on the Stomach in Healthy Volunteers - Full Text View - ClinicalTrials.gov

My understanding was that the acidity and ability of it to irritate locally was the main issue of aspirin, I wasnt aware that the stomach needed prostaglandins for proper function...

How accurate are these statements? Is there an effective way of preventing it?

Also:

Prostaglandins in peptic ulcer disease. Their postulated role in the pathogenesis and treatment - PubMed

Prostaglandins are important in the pathophysiology of peptic ulcer disease and possibly in its prevention and treatment as well. Prostaglandins have been shown to inhibit gastric secretion, stimulate bicarbonate secretion, and increase gastric blood volume. Pretreatment with prostaglandins has...

pubmed.ncbi.nlm.nih.gov

And is this why cabbage juice helps people with ulcers? "Recent research has also highlighted the fact that the protective functions of prostaglandins in the stomach can be carried out by other mediators, in particular the gaseous mediators nitric oxide and hydrogen sulfide."

https://journals.physiology.org/doi/full/10.1152/physrev.00004.2008

This is old news. Well known for a while. This is why its good to look at all types of medical literature. If you have an ulcer you probably shouldnt use aspirin.

I pasted a diagram from the last link in your post that summarizes some of the information in a way that is easier to comprehend to who anyone who views this thread:

 

[Peatress]

Taking aspirin with glycine or gelatine could mitigate the damage.

Aspirin Does NOT Cause Damage To Stomach Or Intestines

There has been a great deal of controversy in regards to the effects of aspirin on the GI tract. Most sources of "common" medical knowledge claim that aspirin is very bad for the GI tract, while Ray has claimed that is not true and sometimes even the opposite. This study claims that aspirin...

raypeatforum.com

 

[RealNeat]

This is old news. Well known for a while. This is why its good to look at all types of medical literature. If you have an ulcer you probably shouldnt use aspirin.

I pasted a diagram from the last link in your post that summarizes some of the information in a way that is easier to comprehend to who anyone who views this thread:

View attachment 46545

I wasn't aware that prostaglandins are a necessary mechanism of stomach lining integrity, im still unsure that that statement is accurate as @cs3000 s post states. That "old news" doesn't seem to have a consensus.

Also where in that diagram would the antagonism of prostaglandins leading to increased chance of stomach ulcer be made obvious?

 

[RealNeat]

Taking aspirin with glycine or gelatine could mitigate the damage.

Aspirin Does NOT Cause Damage To Stomach Or Intestines

There has been a great deal of controversy in regards to the effects of aspirin on the GI tract. Most sources of "common" medical knowledge claim that aspirin is very bad for the GI tract, while Ray has claimed that is not true and sometimes even the opposite. This study claims that aspirin...

raypeatforum.com

I'm aware of all the ways to theoretically minimize the chance of damage to the stomach, this thread is more so to clarify what really causes the damage.

 

[Korven]

I wasn't aware that prostaglandins are a necessary mechanism of stomach lining integrity, im still unsure that that statement is accurate as @cs3000 s post states. That "old news" doesn't seem to have a consensus.

Also where in that diagram would the antagonism of prostaglandins leading to increased chance of stomach ulcer be made obvious?

Mucus and bicarbonate secretion is really important in the gastric environment to protect against endogenous factors like stomach acid, pepsin, and external factors like H pylori, etc. As illustrated in the picture taking NSAIDS will inhibit COX enzymes and this mucus gel barrier will become thinner and risk of ulcers increase, i.e. your stomach starts "digesting itself". The other factors in the diagram such as reduced blood flow and impaired healing are also risk factors.

I'm sure a healthy stomach can adapt to aspirin intake but in a compromised state, for instance due to heavy H pylori infestation or nasty toxin producing H pylori strains, NSAID prostaglandin inhibition can become a problem.

 

[RealNeat]

Mucus and bicarbonate secretion is really important in the gastric environment to protect against endogenous factors like stomach acid, pepsin, and external factors like H pylori, etc. As illustrated in the picture taking NSAIDS will inhibit COX enzymes and this mucus gel barrier will become thinner and risk of ulcers increase, i.e. your stomach starts "digesting itself". The other factors in the diagram such as reduced blood flow and impaired healing are also risk factors.

I'm sure a healthy stomach can adapt to aspirin intake but in a compromised state, for instance due to heavy H pylori infestation or nasty toxin producing H pylori strains, NSAID prostaglandin inhibition can become a problem.

Right I understand that, but I'm having a hard time being convinced/ believing that prostanoids have a protective effect on the stomach.

If that's the way it is so be it, but there seems to be disagreement, im trying to get to the bottom of it.

In my OP I stated that I thought most of the damage to the stomach was from the acidity of aspirin, which bicarbonate depletion is a part of, so I'm not seeing where prostaglandins play an important role.

 

[Korven]

Right I understand that, but I'm having a hard time being convinced/ believing that prostanoids have a protective effect on the stomach.

If that's the way it is so be it, but there seems to be disagreement, im trying to get to the bottom of it.

In my OP I stated that I thought most of the damage to the stomach was from the acidity of aspirin, which bicarbonate depletion is a part of, so I'm not seeing where prostaglandins play an important role.

Gotcha.

Well I suppose "the science" could be wrong on prostaglandins having a protective effect ("the science" has certainly been wrong on many occasions), but in this case there have been a lot of experiments demonstrating that COX enzymes play an important role in stomach mucosa defence/inhibiting COX delays healing of ulcers, etc. See this study for example Role of cyclooxygenase-2 in gastric mucosal defense - PubMed. Ibuprofen and corticosteroids (both COX inhibitors) are also associated with stomach ulcers.

I am sure aspirin being an acidic molecule doesn't help either, could be a double whammy effect?

 

[Lejeboca]

In my OP I stated that I thought most of the damage to the stomach was from the acidity of aspirin, which bicarbonate depletion is a part of, so I'm not seeing where prostaglandins play an important role.

Apparently the following study does not see PGs being important either. [Perhaps it is superseded by newer studies?]
[PDF] Prostaglandins and cancer. | Semantic Scholar
From page 8, column 1:
"The recent demonstration that COX-2 is the inducible isoform and that its high expression occurs at sites of inflammation has spurred the development of isoform specific inhibitors. An additional impetus is the observation that inhibition of PG production, via inhibition of both COX-1 and COX-2, can lead to gastrointestinal lesions and nephrotoxicity. Thus, it was viewed as desirable to reduce the inflammatory effects of COX-2 while retaining the cytoprotective effects of COX-1 (133). As a result, a variety of COX-2 specific inhibitors have recently become available for testing One of the first inhibitors, NS-398, has an IC 50 of 3.8 x 10 -6 M in vitro for COX-2 and exerts no effect on COX-1 at 10 -4 M (134). In vivo, NS-398 blocked COX-2 expression in inflammatory cells induced by exogenous stimuli and completely inhibited PG synthesis from these cells whereas it did not not affect PG production from COX-1 in the stomach (133). NS-398 and another COX-2 selective inhibitor, DuP697, cause conformational changes in COX-2 that lead to irreversible loss of activity (135). CGP28238 and L-745,337 also exhibit a dramatic COX-2 selectivity when tested on several cell types and in in vivo models of inflammation (136, 137). Together, these pharmaceutical studies strongly support the hypothesis that COX-1 is utilized for cytoprotection and that COX-2 primarily plays a pro-inflammatory role. However, the recent generation of knockout mice for COX-1 and COX-2 suggest that this view may be too simplistic. Contrary to the prediction that COX-1 knockouts would have spontaneous gastrointestinal ulcerations, this pathology was not found. Furthermore, these mice were less sensitive than normal mice to the ulcerating effect of indomethacin (138). The COX-2 knockout mice also produced unexpected results. In these animals topical TPA treatment caused edema to the same extent as in wild type mice (139). In keeping with high PG levels, COX-2 knockouts, however, did show a reduced endotoxin-induced hepatocellular cytotoxicity (140). It is clear from these animal models that, to a large extent, the tissue specific function of COX-1 and COX-2 remains undefined."

 

[cs3000]

I actually was reading on that yesterday, funny enough ginger seems to hurt my ulcer upon consumption, maybe it's too "hot"

And what you wrote/ cited says this;
"This is not unexpected because the reduction of the gastric mucosal PGE2 concentration induced by aspirin does not necessarily participate in gastric ulcer generation (Takeuchi et al., 1986; Lichtenberger et al., 2007)."

So they thinks it's all NO related and not PGE2?

basically the damage is from combined too much Nitric oxide tipping the balance from the iNOS enzyme increase causing damage , + chronic neutrophil damage from the inflammatory dysfunction by cytokines.
which shogaol in ginger sorts out @ ~10mg human daily with a lot of the effectiveness at 5mg. it doesn't lower them from baseline control values in this study but inhibits the increase from aspirin.


It's complicated prostaglandin e2 has a dual role, can be anti-inflammatory, by inhibiting cytokines or in chronic inflammation by removing neutrophils. sometimes is induced by bacteria to lower immune response or can help viruses get into cells. but it can be pro-inflammatory in some situations too. (maybe a simplistic way of looking at it is its more anti-inflammatory in chronic inflammation & more pro-inflammatory in acute inflammation?)


so usually IL-1β increases PGE2/prostaglandin E2. probably to balance the overall pro-inflammatory effect of the IL-1b (which is seen in high levels in people with chronic gut inflammation), from the PGE2 removing accumulated neutrophils to prevent them from creating chronic inflammation and excessive oxidative stress.
https://www.nature.com/articles/s41577-020-0407-1 <- tissue damage by excess prolonged neutrophils
Aspirin-induced acute gastric mucosal injury is a neutrophil-dependent process in rats - PubMed <- neutrophils role in aspirin damage

but the lowering of PGE2 by aspirin could mean there's no countering of the IL-1b / cytokine increase. so continuous inflammatory damage.

the PGE2 reduction is proven at 325mg a day in humans Effect of aspirin on prostaglandin E2 and leukotriene B4 production in human colonic mucosa from cancer patients - PubMed


seems ginger skips the need to raise prostaglandin E2 because it lowers the IL-1b & TNF-a directly
+ small amounts of nitric oxide is protective in the gut , but elevating NO especially chronically (like with aspirin, because iNOS expression produces a lot of NO) makes gut inflammation worse, and damages the epithelium

so the ginger takes care of the nitric oxide enzyme excess + takes care of the pro-inflammatory cytokines creating chronic impairment

 

[RealNeat]

from that study its both increased Nitric Oxide enzyme expression + inflammatory dysfunction from the increase in TNF-A & IL-1β cytokines by aspirin

It's complicated prostaglandin e2 has a dual role, can be anti-inflammatory, by inhibiting cytokines or in chronic inflammation by removing neutrophils. sometimes is induced by bacteria to lower immune response or can help viruses get into cells. but it can be pro-inflammatory in some situations too. (maybe a simplistic way of looking at it is its more anti-inflammatory in chronic inflammation & more pro-inflammatory in acute inflammation?)


so usually IL-1β increases PGE2/prostaglandin E2. maybe in order to balance the overall pro-inflammatory effect of the IL-1b (which is seen in high levels in people with chronic gut inflammation), from the PGE2 removing accumulated neutrophils to prevent it from creating chronic inflammation and excessive oxidative stress.
https://www.nature.com/articles/s41577-020-0407-1 <- tissue damage by excess prolonged neutrophils

but the lowering of PGE2 by aspirin could mean there's no countering of the IL-1b / cytokine increase. so continuous inflammatory damage.

the PGE2 reduction is proven at 325mg a day in humans Effect of aspirin on prostaglandin E2 and leukotriene B4 production in human colonic mucosa from cancer patients - PubMed


seems ginger skips the need to raise prostaglandin E2 because it lowers the IL-1b directly
+ nitric oxide might have acute benefits but chronically elevating NO (like with aspirin) makes gut inflammation worse, and damages the epithelium

so the ginger takes care of the nitric oxide + takes care of the pro-inflammatory cytokines creating chronic impairment

That's an interesting take, it makes sense because it doesn't necessarily make the stomach dependent on prostanoids but rather it's in situations where things get put out of balance, like by Aspirin.

For people viewing I'm not against aspirin. Im just trying to riddle some stuff out.

Still leaves the question, is there an over emphasis on PGE2? I think so, as safer things could be deployed to prevent the Il-1B, and nitric oxide, like ginger.

However, it's still interesting how the lowering of prostanoids didn't have an effect on ulcer formation in the paper @Lejeboca cited, it even had benefits in COX2 knockout mice for endotoxin lol