Serotonin Causes Obesity, Diabetes, Fibrosis,liver Damage ,increases Endotoxin And NO

Mauritio

Member
Joined
Feb 26, 2018
Messages
5,669
Inspired by this thread Serotonin/endotoxin/PUFA As Primary Causes Of Depression And Diabetes; Can Be Easily Blocked
I was reading a few more recent studies on the detrimental effect of serotonin on ones health. It seems clear that by now it is known in medicine, that blocking it is highly therapeutic for many diseases.
Here we go:



Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance. - PubMed - NCBI
In line with haiduts post ,when mice are lacking TPH , the enzyme that converts tryptophan to serotonin , it prevents obesity and insulin resistance .
And it also increases uncoupling (UCP1), which is highly therapeutic of it's own.

"These data suggest that therapies aimed at inhibiting mast cell Tph1 may represent a therapeutic approach for the treatment of obesity and type 2 diabetes."



Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase-A/5-Hydroxytryptamine/5-Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Pro... - PubMed - NCBI
This is is another of the serotonin "modulation" studies which is the new word for antagonism. This a very recent study, so it really seems like it might be that we will read the term serotonin modulation more often than the term serotonin antagonism ,which they ironically do use in the actual study but not the in the headline.

"...treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls."




The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice. - PubMed - NCBI

This is a great one as it shows serotonin as the fundamental initiator of disease/ stress hormones:It increases liver enzymes, induces cell death in liver cells ,increases NO and activates the TLR4 Receptor.
Ketanserine was actually therapeutic of that liver damage.

Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.
 
Last edited:
OP
Mauritio

Mauritio

Member
Joined
Feb 26, 2018
Messages
5,669
German government founds development of a TPH inhibtor to treat fibrosis . 500 000 € for 2020-2022 .


From Google translate:
Fibrotic diseases of various tissues such as the lungs, liver, kidneys, heart and skin are a serious health problem with insufficient therapeutic options. These diseases are major contributors to all-cause mortality worldwide. Serotonin and its receptors have been shown to be involved in the pathogenesis of fibrotic diseases, but these findings have not yet been translated into novel therapies. This project aims to test whether the serotonin-synthesizing enzyme tryptophan hydroxylase (TPH) 1 is a valid therapeutic target for the treatment of fibrosis diseases. TPH inhibition is a new type of clinical concept which, in contrast to the drugs currently used, aims not only at reducing symptoms, but also at treating the cause of the disease. In the project, highly efficient TPH inhibitors are to be developed as novel therapeutics for fibrotic diseases, which are to be transferred to clinical application after successful completion of the project.

 
OP
Mauritio

Mauritio

Member
Joined
Feb 26, 2018
Messages
5,669
Here's another one. TPH inhibitors for pulmonary hypertension.
1,6 Million € from 2020-23 .

"Pulmonary hypertension is a complex disease that, once diagnosed, leads to heart failure and death within five years in 25-60% of affected patients. The messenger substance serotonin, which among other things plays a key role in the formation and development of pulmonary hypertension, is involved. is formed locally in the lungs. Reducing serotonin in the lungs is therefore a key to treating pulmonary hypertension. The aim of the project is to validate a class of new inhibitors of the serotonin-generating enzyme tryptophan hydroxylase (TPH) found by the Max Delbrück Center for Molecular Medicine (MDC) as an inhalation application for pulmonary hypertension. The reduction of serotonin in the lungs could significantly increase the long-term survival of patients. At the MDC, the TPH-inhibiting substances are to be tested for the best candidates. At the ITEM, nebulization methods for two of these substances are to be developed and validated in animal models together with the MHH. Utilization can take place via a license sale or the implementation of clinical studies."


 
OP
Mauritio

Mauritio

Member
Joined
Feb 26, 2018
Messages
5,669
Here's another study showing TPH knockout mice are almost resistant to weight gain on a high fat diet . And even on standard diet they lost weight and gained lean mass.
Interestingly some of the downsides of serotonin seem to be mediated through the 5ht2a receptor .

They also showed TPH1 knockout and thus lower serotonin, leads to increased O2 consumption , CO2 production and heat production .

"Tph1 FKO mice fed HFD exhibited reduced lipid accumulation, increased thermogenesis, and resistance to obesity. In addition, Htr2a FKO mice fed HFD showed reduced lipid accumulation in white adipose tissue and resistance to obesity."

1628023579661.png




1628024234644.png

(KoreaMed Synapse)
 
Last edited:
OP
Mauritio

Mauritio

Member
Joined
Feb 26, 2018
Messages
5,669
A list of current clinical trials for TPH-inhibitors
Screenshot_20210804-113637_Drive.jpg
 

Dr. B

Member
Joined
Mar 16, 2021
Messages
4,316
Inspired by this thread Serotonin/endotoxin/PUFA As Primary Causes Of Depression And Diabetes; Can Be Easily Blocked
I was reading a few more recent studies on the detrimental effect of serotonin on ones health. It seems clear that by now it is known in medicine, that blocking it is highly therapeutic for many diseases.
Here we go:



Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance. - PubMed - NCBI
In line with haiduts post ,when mice are lacking TPH , the enzyme that converts tryptophan to serotonin , it prevents obesity and insulin resistance .
And it also increases uncoupling (UCP1), which is highly therapeutic of it's own.

"These data suggest that therapies aimed at inhibiting mast cell Tph1 may represent a therapeutic approach for the treatment of obesity and type 2 diabetes."



Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase-A/5-Hydroxytryptamine/5-Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Pro... - PubMed - NCBI
This is is another of the serotonin "modulation" studies which is the new word for antagonism. This a very recent study, so it really seems like it might be that we will read the term serotonin modulation more often than the term serotonin antagonism ,which they ironically do use in the actual study but not the in the headline.

"...treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls."




The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice. - PubMed - NCBI

This is a great one as it shows serotonin as the fundamental initiator of disease/ stress hormones:It increases liver enzymes, induces cell death in liver cells ,increases NO and activates the TLR4 Receptor.
Ketanserine was actually therapeutic of that liver damage.

Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.
IME, taking something to attempt to artificially drop serotonin doesnt work and causes more side effects. the only thing that worked was finding what was raising serotonin and removing the stressor. for some it could be pufa, for some anti depressant or some other prescription medicine or supplement. in my case it was vitamin D3. have you looked into vitamin D3 apparently it upregulates that TPH enzyme a lot...? that uncoupling protein goes up from vitamin A too doesnt it, and vitamin D oral supps mess with that. everything you mentioned there is spot on but in my case I literally dropped all D3 supps, continued a whole grass fed milk + fruit juice diet and its only been a bit over a week but there's drastic changes in me.
 
OP
Mauritio

Mauritio

Member
Joined
Feb 26, 2018
Messages
5,669
IME, taking something to attempt to artificially drop serotonin doesnt work and causes more side effects. the only thing that worked was finding what was raising serotonin and removing the stressor. for some it could be pufa, for some anti depressant or some other prescription medicine or supplement. in my case it was vitamin D3. have you looked into vitamin D3 apparently it upregulates that TPH enzyme a lot...? that uncoupling protein goes up from vitamin A too doesnt it, and vitamin D oral supps mess with that. everything you mentioned there is spot on but in my case I literally dropped all D3 supps, continued a whole grass fed milk + fruit juice diet and its only been a bit over a week but there's drastic changes in me.
For me anti-serotonin chemicals definitely work , at least to some extent.

I havent looked into that much but IRRC vitamin D increases brain serotonin.
Have you taken vitamin K and magnesium with it ?
I think that's very important. I have stopped taking vitamin K for like 10 days and continued vitamin D and calcium and I get strong teeth sensitivity from it.
So for me peats saying '10k IU never hurt somebody' isnt really true. At least without the necessary cofactors.
 

Dr. B

Member
Joined
Mar 16, 2021
Messages
4,316
For me anti-serotonin chemicals definitely work , at least to some extent.

I havent looked into that much but IRRC vitamin D increases brain serotonin.
Have you taken vitamin K and magnesium with it ?
I think that's very important. I have stopped taking vitamin K for like 10 days and continued vitamin D and calcium and I get strong teeth sensitivity from it.
So for me peats saying '10k IU never hurt somebody' isnt really true. At least without the necessary cofactors.
did he say that just for a couple winter months to use 10k IU

i have taken vitamin K and magnesium. I think the K as a vitamin has issues of its own. im doing the best I ever have on a milk fruit juice diet with no supplements besides 500mg black seed oil. the lack of soda and fluoride/tap water also likely helps a lot.
 

Similar threads

Back
Top Bottom