Author Topic: FAAH Inhibitors  (Read 2235 times)


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FAAH Inhibitors
« on: March 01, 2021, 03:31:09 PM »
This is a direct continuation of my capsaicin-like thread, but it looks like I may have somewhat erred about anandamide, so I thought it wiser to start a new and clear thread. I also wanted to raise awareness that FAAH inhibitors are probably the best treatment for at least one POIS subtype.

It seems I may have to reevaluate my theory regarding the AEA poisoning. I bought some dried saffron and made tea from it. As I expected it to make my symptoms worse I thought it a safer option than CBD oil for a first trial. So as it turns out it doesn't enhance POIS, but actually makes me quite well, not if that was bad thing of course. :)
Unfortunately it cannot itself completely overcome POIS as the local burning still occurs, although to a  lesser degree, but at least it can prevent POIS from becoming a systemic event. Its potency is the best so far (~90% symptom reduction) and seems even greater than that of MACA and its effect is similarly at its peak after 1-3 hours of consumption, which probably indicates that they prevent the capsaicin-like compound from reaching a high concentration in the blood.
After ejaculation there is no tiredness, the eyes remain almost totally clear and there is no blurred vision. I don't have a pronounced brain-fog by the next day, but a slight blunt in focusing capability can still be felt. I also didn't notice the hypothermia effect. Muscle fatigue can still be felt and some rhinitis still occurs however, but to a smaller degree.
Side effects: Some (non-burning) flatulence occurs, which is similar to what I experienced with the other FAAH inhibitors. I have also experienced some sporadic and transient (1-2 second) stabbing pain at different places in the leg, but this is nothing serious.
It remains to be seen what happens in the long run and I will have to tinker with timings and combinations too. I can't buy CBD oil right now, but I will definitely try it when I can.

So it looks like the capsaicin-like compound is not AEA, but rather arachidonic acid and ethanolamine or another metabolite of these. If this holds true than the most likely root of POIS in my case is evidently a malfunction in the endocannabinoid signaling (e.g. FAAH over-activity or high substrate concentration (AEA or 2-AG)) related to the acrosomal reaction. So if there really is an arachidonic acid cascade than the entry point is probably not PLA2, but the conversion of anandamid to AA.
Even if I had false conclusions the information about AEA still seems very important in order to understand the exact mechanism that leads to POIS and to have a chance of cure and not only a treatment, however good it may be.

As AA involvement has been indicated in other threads on the site a broader view can be gained in combination with my theory. From my point of view the most important question is if AA is able to activate the TRPV1 channel as it is the deciding factor if it can be the capsaicin-like compound which I seek. The answer seems to be a yes, as AA and some of its lipoxygenase products  (12-(S)-HPETE, 15-(S)-HPETE, 5-(S)-HETE and leukotriene B4) are able to activate TRPV1 at fairly high concentrations. Conversely it also means that their concentrations are probably very high.

Actually I have found a recently published book that goes into detail about FAAH inhibitors. It turns out that MACA also contains FAAH inhibitors (macamides). Besides this other inhibitors can be found in nutmeg, flavones, isoflavones (soy bean, chickpeas), and some algae. Steroids also affect FAAH activity of which pregnenolone has the greatest efficacy, testosterone and cortisone were effective in higher concentrations, while hydrocortisone, estradiol and pregnenolone were better at low molar ratios.
A year ago my mother made some falafel and I remember that I felt better from it. I wanted to eat it again, but I just forgot about it. As the main ingredient of falafel is chickpeas it was probably not accidental.
I haven't eaten nutmeg since I was a child, but around the time I began to masturbate I remember that we used it frequently for spicing. Could this have been the initiator of my POIS!?

Progesterone Up-Regulates Anandamide Hydrolase in Human Lymphocytes.
Physiological concentrations of progesterone stimulate the activity of the endocannabinoid-degrading enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH) in human lymphocytes.
Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational level, and was partly mediated by the Th2 cytokines. In fact, lymphocyte treatment with IL-4 or with IL-10 had a stimulating effect on FAAH, whereas the Th1 cytokines IL-12 and IFN-? reduced the activity and the protein expression of FAAH. Human chorionic gonadotropin or cortisol had no effect on FAAH activity.

The only thing the authors forgot to mention that this article is actually about POIS! :)
Melatonin has appeared to stimulate IL-2 and IL-12 secretion and to inhibit the release of most inflammatory cytokines, namely TNF-alpha.
According to the data available up to now, it seems that melatonin may preferentially act on the lymphocyte system by stimulating IL-2 release from TH1 cells, which have been proven to express melatonin receptors, while 5-methoxytryptamine would mainly modulate the macrophage system by piloting its function in an antitumor way.
However, it has been demonstrated that the pineal gland, in addition to direct immunomodulating action through the release of its indole hormones, may also influence the immune functions by a regulation of the two major brain interneural immunoregulatory systems, consisting of brain cannabinoid and opioid systems.
The functional status of the endogenous cannabinoid system may be simply evaluated by determining the blood levels of the main enzyme involved in the metabolic degradation of cannabinoids, the so-called fatty acid amide hydrolase (FAAH). Then, the evidence of abnormally high blood concentrations of FAAH would reflect a condition of hypofunction of the endogenous cannabinoid system.

This might be so in my case!
Then, the biological response occurring during the inflammatory systemic diseases could be modulated and controlled by acting on the cannabinoid system through the administration of cannabinoid agonists, which may be considered as novel anti-inflammatory agents.
Cannabinoids may influence several cytokine secretions, but their main effect would consist of the inhibition of IL-17 secretion. Then, since the enhanced IL-17 secretion would constitute the main autoimmunity-related cytokine alteration, the inhibitory effect of cannabinoids on IL-17 secretion justifies their use in the potential treatment of all autoimmune pathologies. The pineal gland may modulate the cannabinoid system in an immunostimulatory way, then the pineal-brain cannabinoid system would constitute a fundamental functional axis responsible for the generation of an appropriate immune response. The main endogenous cannabinoid agents are arachidonoyl-ethanolamide (AEA), also called anandamide, and 2-arachidonyl-glycerol (2-AG), and they are both characterized by a circadian rhythm in their secretion, with higher levels of AEA during the night and higher levels of 2-AG during the day. On the contrary, brain opioid interneuron system would play a major immunosuppressive activity, particularly by acting on mu-opioid receptor.
From this point of view, it is interesting to observe that beta adrenergic agonists may allow apoptosis of all lymphocyte subsets, whereas the only T reg lymphocytes may be paradoxically stimulated in their functions. On the same way, all lymphocyte subsets are inhibited by the mu-opioid agonists, whereas T reg cells would be stimulated since the administration of the mu-opioid antagonist naloxone has been proven to inhibit T reg cell activity. The cytokine network and the neuroendocrine system are connected by several links, and one of the main cytokines involved in realizing a connection between the cytokine network and the neuroendocrine system is IL-12 itself, which has appeared to inhibit FAAH activity, with a consequent increase in brain endogenous cannabinoid content.

So melatonin is also a FAAH inhibitor! This could be the link to tryptophan and serotonin deprivation syndrome.

Different natural compounds are natural inhibitors of FAAH in vitro. They include some flavonoids such as kaempferol, apigenin, luteolin, quercetin, myricetin and genistein.

A combination of kaempferol and apigenin seems especially promising based on their potency.
Apigenin ca be found in parsley, celery and teas. Besides FAAH apigenin also inhibits PDE 1–3, PI3-kinasea, COX-2, PPARg. Kaempferol can be found in broccoli and endives (chicory).
Now this is rather strange as I haven't experienced anything definite with Sulforphane (broccoli extract), although I only tried it a few times, but I remember that eating broccoli cream soup made me feel better.
Other effects of kaempferol are activation of PPARg and inhibition of interleukin-4-induced STAT6 activation.
The finding that both apigenin and kaempferol activate PPARg is worthy of comment. PPARg is a ligand-activated transcription factor that, in addition to its role in adipocyte differentiation, fatty acid and lipid metabolism, and insulin sensitivity, also has potentially important roles in inflammation and cancer. There appears to be an overlap between this system and the endogenous cannabinoid (endocannabinoid) system (itself important in inflammation and cancer), as the endocannabinoid ligands anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol interact with PPARg. This overlap also includes the phytoestrogen genistein, the isoflavone analogue of apigenin, which activates PPARg at micromolar concentrations and is a potent competitive inhibitor of FAAH (Ki value 2.8 um). The related isoflavone compound daidzein (the isoflavone analogue of 4',7'-dihydroxyflavone, a flavonoid found in alfalfa roots (available as a supplement, but I haven't tried it yet) also inhibits rat brain FAAH in a competitive manner, with a Ki value of 1.7??m and activates PPAR?.
Tobacco leaves contain kaempferol glycoside, raising the possibility that a local inhibition of FAAH in the lungs occurs after cigarette consumption. Given that AEA, which is often produced at high levels following cellular damage, induces cough, a high local concentration of kaempferol would hardly be beneficial to smokers.

Kaempferol, known chemically as 3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one, can be isolated from black, green, and mate herb teas, as well as from numerous common vegetables and fruits, including beans, cabbage, grapes, broccoli, strawberries, kale, gooseberries, citrus fruits, Brussels sprouts, grapefruit, apples, dry raspberry, and tomatoes, and from plants or botanical products commonly used in traditional medicine such as mums (chrysanthemum spp.), ginkgo biloba (Ginkgo biloba L), lime trees (Tilia spp.), Chinese milkvetch (Astragalus mongholicus), field horsetail (Equisetum spp.), moringa (Moringa oleifera), and the Japanese pagoda tree (Sophora japonica).
This is interesting as I find things that make me both better or ill. As plants contain many chemicals which can be both good and bad, it seems logical that the net effect should be considered.

Unfortunately there are no FAAH inhibitor medications currently on the market, even though they were in development a few years ago, but then a major incident happened and then the clinical trials for every other prospective agents were suspended. Maybe understanding the function of FAAH in connection with POIS could lead to safer drug development and it could be especially important if it is also involved in COVID-19 infection.

Neobavaisoflavone can be found in high concentration in Psoralea corylifolia Linn. (also known as Babchi seeds, Bakuchi powder, Bakuchiol, malay tea) and it is an efficient natural inhibitor of FAAH.

Care should be taken with Psoralea corylifolia seeds as it can cause acute hepatitis. This is especially true for those like me, who also have Gilbert disease.

Psoralea corylifolia has many beneficial health effects, but some rather worrying adverse effects too.

Neobavaisoflavone is also a potential anti-COVID-19 drug agent.

Saffron (crocetin) effectively binds to the spike protein and also the main protease of COVID-19, although based on my findings it may even ameliorate the metabolic changes caused by the virus. So it could be the ultimate anti-covid-19 wonder drug and it possibly helps post-covid patients too.

If someone has trouble with sleeping after O, then it is possible that FAAH hydrolyzes oleamide, which is an endogenous sleep-inducing factor. Actually I can't sleep more than 6-7 hours since taking saffron, but at least I wake up much fresher without the usual brain fog.

I have also tried another supplement that works and it is Cordyceps [500 mg per capsule]. It has a lesser effect than the other medicinal mushroom I used, but taking about three capsules per day has a noticeable positive effect.
I suspected a FAAH inhibitory activity, but instead I found that Cordyceps is a COX-2 and iNOS inhibitor.
Cordyceps protects from oxidative stress caused by reactive oxygen species (ROS).
The results indicate that treatment with the CM extract down-regulates COX-2 and iNOS protein expression in H2O2-induced C6 glial cells, whereas H2O2 up-regulates COX-2 and iNOS expression.

I was also experimenting (once) with Cistus incanus tea which is supposed to be effective in covid.
Well I got a heart ache reminiscent of my experiences with fish oil (DHA/EPA) and Aspirin (also COX inhibitor). I am not exactly sure about it, but I suspect myocarditis as the underlying issue. Actually having an O can accelerate the disappearance of the symptom, although I haven't tested this with everything. Unfortunately I am not sure about the other effects of Cistus as I was quite well at the time anyway, so I only experienced its adverse effect.
Later I realized that Cistus incanus actually has a proven COX inhibitory property.
A don't remember if I had any heart ache from apigenin even though it is also a COX-2 inhibitor, but who knows.
This is a really unpleasant symptom, so I don't like experimenting with it, but later I might consider so.
Maybe I should test naproxen (another COX inhibitor) and see if it does something similar.

Both AEA and AA induces platelet aggregation.
Aspirin is known to inactivate cyclooxygenase irreversibly in various cell types. This leads to the complete inhibition of AA-induced platelet activation.
So is the reason why I get a heart ache from Aspirin due to platelet aggregation inhibition? Blood tests don't indicate that I would have any problem with blood coagulation even in acute state. Or this is just yet another thing that seems to work in a reverse way in my body.

Taurine depletion can cause cardiomyopathy.
As taurine supplementation in a great dosage definitely enhances POIS and can cause a heart ache it could indicate a connection (e.g. taurine overload?).

Anandamide can be metabolized by cyclooxygenase-2 (COX-2) to produce prostaglandin E2 (PGE2) ethanolamide.

Ibuprofen is also a FAAH inhibitor.

Cholesterol increases the substrate accessibility of FAAH.
This probably has something to do with vitamin D supplementation.

Women POISers should consider trialing vaginal suppositories that contain boric or boronic acid as it also has a FAAH inhibitory property and it may help after sexual activity. Boronic acid is used as a conservating agent. I will try this later to see if it does anything if taken orally. Unfortunately it keeps accumulating in the body leading to intoxication, so it can't be used on the long run.

I tried one of the vitamin-B supplements called D-Biotin (also called vitamin B7) [300 ug per capsule]. I mentioned earlier that I had bad experiences with vitamin-B complex and biotin is not an exception as it makes me very ill even when I took it in the chronic phase.
More than 10 years ago I also had bad experience with magnesium + vitamin B6 and at the time I thought it was magnesium, but a few years ago I also tried a vitamin-B complex and that is when I realized that it has to be vitamin-B that causes POIS enhancement. I want to test all vitamin-B, but unfortunately I still couldn't get my hands on niacin, which could be the most interesting.

Interestingly eating a lot of egg whites could induce biotin deficiency in a few weeks.
Unless I have a high level already how else could it induce toxicity?
Signs of frank biotin deficiency may be observed in individuals with deficiencies in biotin, HLCS, and biotinidase and in individuals consuming large amounts of raw egg white; the biotin-binding protein avidin in raw egg white causes a substantial decrease in the bioavailability of biotin.
Based on the observation that HLCS and biotinidase deficiency patients are treated with pharmacological doses of biotin for their entire life with no apparent signs of toxicity, one can assume with reasonable confidence that the toxicity of biotin is very low.

Arachidonic acid and prostaglandin deficiency is considered highly teratogenic in pregnancy just like biotin deficiency is. Cyclooxygenase inhibitors (e.g., indomethacin, aspirin, phenylbutazone) also inhibit the protective effect of arachidonic acid in this regard.

Just a few weeks ago my mother baked a cake stuffed with walnuts and I ate a whole lot of it even though I knew I was going to feel much worse. Needless to say it was burning like hell and multiple MACA capsules had a hard time pulling it down. So do walnuts contain any capsaicin? Of course they don't. What they actually contain are precursors of arachidonic acid.
Walnuts are also richer than most other nuts in polyunsaturated fats. The most abundant one is an omega-6 fatty acid called linoleic acid. They also contain a relatively high percentage of the healthy omega-3 fat alpha-linolenic acid (ALA). This makes up around 8–14% of the total fat content. (google)
Although some things still doesn’t seem right, so there is no easy solution. I consumed some chia and flax seed in the past in smaller amounts, but I didn't notice any effect. It is true that I wasn't even aware that it could have an effect, so I will try to combine the two in somewhat greater amounts and see if anything happens.
I have noticed some adverse events related to omega-6 fatty acids, however others don't seem to have any ill effects, which is rather contradictory. Actually arachidonic acid seems to be present in great amounts in meat of which I don't really have any problems. Maybe these effects only appear after prolonged consumption, but then again it doesn't seem to be the case with walnuts.
Maybe I specifically have a problem with gamma-Linolenic acid (GLA) as I think I remember something about rapeseed oil too, but it was such a long time ago, that I have to recheck that too.

Arachidonic acid induces a rapid cAMP production. Both this effect and its long-term adipogenic effect are impaired by cyclooxygenase inhibitors such as aspirin and indomethacin.

Phospholipases A2 (PLA2s) are enzymes that cleave fatty acid in position two of phospholipids, hydrolyzing the bond between the second fatty acid "tail" and the glycerol molecule. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond, releasing arachidonic acid and lysophosphatidic acid. Upon downstream modification by cyclooxygenases or lipoxygenases, arachidonic acid is modified into active compounds called eicosanoids. Eicosanoids include prostaglandins and leukotrienes, which are categorized as anti-inflammatory and inflammatory mediators.
PLA2 enzymes are commonly found in mammalian tissues as well as arachnid, insect, and snake venom. Venom from both snakes and insects is largely composed of melittin, which is a stimulant of PLA2. Due to the increased presence and activity of PLA2 resulting from a snake or insect bite, arachidonic acid is released from the phospholipid membrane disproportionately. As a result, inflammation and pain occur at the site. There are also prokaryotic A2 phospholipases.
As it seems like I get bitten in the ass by snakes or spiders every time I ejaculate I don't think I can get any more desensitizated to it. :D

A possible explanation for itching skin in relation to this.
In Langerhans cells, niacin can activate GPR109A to increase intracellular Ca2+. This Ca2+ increase triggers phospholipases, predominantly Phospholipase A2 (PLA2), to release arachidonic acid from cellular lipid stores. Free arachidonic acid serves as a precursor to the production of eicosanoids, including lipoxygenases, thromboxanes and prostaglandins.
The production of PGI2 and PGD2 decreases after repetitive administration of niacin in parallel with the development of flushing tolerance.
Another potential target would be to inhibit the ability of PLA2 to produce arachidonic acid, thereby eliminating the production of prostaglandins upstream of COX. Glucocorticoids can indirectly inhibit PLA2, but there are currently no approved therapies that specifically target this enzyme.
ctrl+f: bee venom
Plaquenil antagonizes PLA2, which leads to lesser arachidonic acid production. The active agent of Plaquenil is Hydroxychloroquine, which is of course used in COVID-19 treatment. So my problem is apparently with FAAH, but it could be still interesting to see if Hydroxychloroquine also worked.
It may be of note that honey bee venom can be both beneficial and harmful in CFS patients, which in my opinion implies a bipolarity in disease manifestation for both CFS and POIS.

It is a rather important fact that AEA can accumulate inside cells, although the exact mechanism is still not known. Even if a by-product (AA) is the cause it can still explain the rapid release of the compound, as I don't have a burning sensation either at the prostate or the testes before O. This could also explain the confusion with the allergic hypothesis.

We next examined the effects of genetic or pharmacological blockade of FAAH on NAE accumulation in mouse tissues. Anandamide (C20:4 NAE) was highly elevated (>8-fold) in brain, liver, and testis of FAAH(-/-) or PF-3845-treated mice, and was modestly elevated in some but not all of the other tissues analyzed. Curiously, the accumulation of anandamide following FAAH disruption was not correlated with the basal concentrations of this lipid or the FAAH enzyme itself. For instance, FAAH disruption caused dramatic elevations in anandamide in testis, but not kidney, despite both tissues possessing high basal anandamide concentrations and FAAH activity.
We also measured additional NAEs, including the polyunsaturated species C18:2 and C22:6 NAE, which share physicochemical properties with anandamide, and several saturated or monounsaturated NAEs (C16:0, C18:0, C18:1, and C22:0). Brain was the only organ that showed large increases (>5-fold) in all NAE species following FAAH blockade, although the C22:0 NAE was selectively elevated in FAAH(-/-) mice but not mice treated with PF-3845. In contrast, testis tissue from FAAH-disrupted animals accumulated high amounts of anandamide and C22:6 NAE, but displayed only modest changes in other NAEs. Livers from these animals selectively accumulated anandamide and C18:2 NAE, but not C22:6 NAE, and, like testis, showed more-limited accumulation of saturated and monounsaturated NAEs.
Both brain and testis appear to possess an enzymatic route to rapidly generate polyunsaturated NAEs, including anandamide. That testis can furthermore accumulate anandamide without substantial elevations in shorter chain NAEs suggests that at least two additional NAPE-PLD-independent NAE biosynthetic pathways may exist, one for polyunsaturated NAEs and the other for shorter chain saturated and mono-unsaturated NAEs.

Overall, these findings suggest that adiposomes may have a critical role in accumulating AEA, and possibly in connecting plasma membrane to internal organelles along the metabolic route of this eCB. In line with these data, depletion of a pre-existing pool of 2-arachidonoylglycerol has been recently shown as a key event in sperm activation, speaking against the on demand synthesis of this eCB much alike that of AEA.

It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1.

CBG is an inhibitor for the uptake of the endocannabinoid ligand anandamide.

Cannabinoids can suppress inflammation and cytokine storm in ARDS in relation to COVID-19.

Anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.

Recently, we have demonstrated that testosterone regulates mu-opioid receptor and cannabinoid 1 receptor (CB1) expression via transcriptional activities of androgen receptor in a trigeminal pain model.

Though opioids and cannabinoids can independently cause analgesia and respiratory depression (RD) that could be reversed by respective antagonists in monkeys and FAAH inhibition can attenuate morphine withdrawal effects in mice.

FAAH can hydrolyze other endocannabinoids, including 2-AG.
FAAH has a major role in regulating the magnitude and duration of anandamide signaling.
Western blotting analysis showed that FAAH, CNR1, and CNR2 are present in the testis and epididymis of WT mice.
In contrast, CNR2 was localized in spermatocytes and Sertoli cells encircling spermatocytes and spermatids in the testis. In the epididymis, epithelial cell surfaces demonstrated CNR2 immunostaining, whereas signals were undetectable in interstitial cells. FAAH was present in spermatocytes and spermatids, while spermatogonia had little or no positive signal. Sertoli cells and Leydig cells also showed positive staining of FAAH. The localization of FAAH was evident on cell surfaces of the epididymal epithelium.
The presence of FAAH on the testis and epididymis suggests that endocannabinoid levels are tightly regulated by FAAH in these tissues.
Our findings of the presence of FAAH, CNR1, and CNR2 in the testis and epididymis and the presence of FAAH and CNR1 in sperm suggest that endocannabinoid signaling has a role in spermatogenesis and sperm maturation.
Sertoli cells exposed to higher anandamide levels were shown to undergo apoptosis, and FAAH activity is regulated by FSH in mouse Sertoli cells. In addition, sperm fertility and the acrosome reaction were reported to be adversely affected if exposed in vitro to high anandamide levels.

This information is of course not necessarily accurate in humans.

We conclude that the serine hydrolase ABHD2 is the nongenomic progesterone (P4) receptor of sperm.
Metabolic serine hydrolases acting as monoacylglycerol lipases convert AGs into glycerol and AA. By hydrolyzing AGs in a P4-dependent manner, ABHD2 releases calcium channel (CatSper) from AG inhibition, which liberates AA. During sperm transit through the epididymis, the plasma membrane undergoes lipid remodeling, which results in reduced levels of AA and altered sperm motility, perhaps by means of modification of the ion channels’ function. Indeed, we found that application of AA briefly activates CatSper, whereas prolonged incubation in 3 uM AA results in CatSper inactivation and loss of P4 sensitivity. In accordance with our model, an overabundance of AA should negatively regulate ABHD2 activity; therefore, continuous P4 application will result in a considerable accumulation of AA in the outer leaflet of the sperm plasma membrane, which would ultimately lead to CatSper desensitization. However, prolonged P4 exposure does not cause CatSper desensitization. It is possible then, that during exposure to P4, liberated AA diffuses into the inner membrane leaflet or is released into the extracellular medium. Indeed, under our experimental conditions, any compound released from the plasma membrane will be removed by continuous perfusion. It is possible that AA removal from the outer leaflet in vivo could be achieved by either fatty acid transporters or chelation by albumin, which is abundant in the female reproductive tract.

Both murine and human CatSper are up-regulated by intracellular alkalinization; however, P4 exposure is also required for full human CatSper activation. This is explained by the fact that ejaculated human spermatozoa retain a substantial amount of 2AG; therefore, P4 activation of ABHD2 is needed for 2AG clearance. That MAFP-treated cells still respond to PGE1 points to an intriguing possibility that PGE1 may stimulate CatSper by allosteric activation of CatSper or may compete with 2AG directly for the binding site. Prostaglandins are derivatives of AA and are structurally similar to the 2AG tail; however, such a hypothesis requires additional experimental confirmation.

It is possible that the P4-ABHD2-endocannabinoid axis could also regulate female reproduction by a similar mechanism. In fact, the expression of endocannabinoid system components was previously linked with genomic steroid activity.

In addition, our model suggests that AGs are continuously produced to block CatSper, unless progesterone stimulates their hydrolysis by ABHD2 contradicting the "on-demand synthesis model" of endocannabinoid activity, whereby these lipids act only upon stimulus-dependent release from their precursors.

In a high concentration even AEA can be toxic.
Inhibition of CB1, CB2, VR1 or NMDA receptors by selective antagonists did not reduce AEA neurotoxicity. Anandamide-induced neuronal cell loss was associated with increased intracellular Ca2+, nuclear condensation and fragmentation, decreases in mitochondrial membrane potential, translocation of cytochrome c, and upregulation of caspase-3-like activity.

We hypothesize that AEA may induce either neuroprotection or neurotoxicity, depending on the balance of its action on CB1 receptors on the one hand, and VR1 receptors or calcium-mediated signal transduction pathways on the other.

I have also stumbled upon an interesting article about reductive stress. Researchers say that contrary to popular ideology not only oxidative stress, but even reductive stress can lead to reactive oxygen species (ROS) generation. Excessive amounts of antioxidants can lead to so called reductive stress or anti-oxidative stress (RS/AS). Surplus antioxidants are pathogenic for hearts and skeletal muscle. Reductive stress can be induced by hypoxia. I think that reductive stress might be involved in some cases of POIS. In my case I suspect oxidative stress, but I still don't get the whole picture, especially as there are conflicting data. Nevertheless I highlighted some information that seems interesting in this regard. I also suspect this has to do something with the connection between POIS and viral infections. Oxidative stress in theory could rebalance the redox system in the case of an ongoing reductive state. Viral infections usually cause oxidative stress, but in some cases they may also induce reductive stress (e.g. COVID-19) just to make things even more complicated.
Actually they used sulforaphane for their tests, which is also an antioxidant. I used NAC and sulforaphane together in combination for a few days. I haven't really noticed much change. Maybe my eyes were a bit clearer, but otherwise nothing substantial happened. Later I will test them in greater dosage or pair them with a glutathione (GSH) supplement when I can afford it.

A reduction in serum level of superoxide dismutase (SOD3) was observed in allergic rhinitis (AR) patients. SOD3 overexpression inhibited the release of proinflammatory cytokines including tumor necrosis factor-a, interleukin (IL)-4, and IL-6. Its overexpression also ameliorated the loss of interferon-g. An OVA-induced AR animal model study showed that taurine was efficacious in alleviating allergic inflammatory reactions by relieving behavior symptoms of AR mice and reducing eosinophilic and mast cell infiltration into the nasal cavity. In addition, taurine treatment increased the production of SOD3 and PPAR-g, which, in turn, suppressed expression of proinflammatory cytokines through phosphorylation of ERK1/2. Conclusion: Taurine could potentially serve as a therapeutic treatment for allergic disorders.

In addition, reductive stress resulting from high NADH is also associated with elevated ROS production under ambient oxygen tensions. For example, addition of exogenous complex I substrates, such as glutamate plus malate, or a-KG, significantly augmented NADH levels and mitochondrial membrane potential, which stimulated H2O2 production by ~10-fold in isolated rat brain mitochondria.
Treating rat L6 myoblasts with the antioxidant N-acetyl-l-cysteine (NAC; 1 mM for 1 h) induced reductive stress by increasing the NADH/NAD+ ratio, mitochondrial H2O2 levels, and free radical leak.
NADPH and GSH are essential for oxidative stress defense; and NADPH is indispensable for GSH recycling by GR.
However, excessive levels of cellular GSH and/or NADPH also lead to reductive stress.

Exposure of HT22 cells to H2O2 led to accumulation of intracellular ROS, and simultaneous treatment with AEA markedly reduced the generation of ROS. SOD plays a vital role in protecting cells against oxidative injury. H2O2 treatment sharply decreased SOD activity in HT22 cells, and AEA restored SOD activity. GSH is also an important cellular antioxidant. H2O2 treatment sharply decreased GSH activity in HT22 cells. Simultaneous application of AEA partially restored GSH levels. GSSG levels were increased in response to H2O2 treatment and this effect was almost entirely abolished by AEA, which reduced GSSH levels. The GSH/GSSG ratio was reduced by H2O2 treatment, and AEA partially restored this balance, increasing the ratio. The influences of AEA on intracellular ROS, SOD, GSH, GSSG, and GSH/GSSG ratio were abolished by the CB1 antagonist AM251, indicating that the antioxidative effects of AEA may be mediated via CB1 of HT22 cells.

Astrocytes play a key role regulating aspects of inflammation in the central nervous system (CNS). Several enzymes, such as the inducible nitric oxide synthase (iNOS) or the cyclooxygenase-2 (COX-2), along with different inflammatory mediators such as the free radical nitric oxide (NO) or proinflammatory cytokines, have been proposed to be involved in the cell damage associated with neuroinflammation. Cannabinoid agonists decrease neurotoxicity and release of proinflammatory factors from activated glial cells and anandamide itself is able to promote antiinflammatory responses in astrocytes via CB1 cannabinoid receptors.
« Last Edit: March 02, 2021, 12:23:31 PM by Progecitor »


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Re: FAAH Inhibitors
« Reply #1 on: March 01, 2021, 04:11:38 PM »
Can you put the font size in normal size please - you're clogging up the recent posts feed....


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Re: FAAH Inhibitors
« Reply #2 on: March 02, 2021, 01:02:10 PM »
Thank you for bringing up Saffron, it seems it was not mentioned much before in the forum.

I just ordered some extract and will report back. It sounds like a good alternative to SJW (St John's Wort) which decreased my gut motility way too much.

maybe you need a combination of saffron and something else, maybe cetirizine? (i have not read your post in full detail yet..)

FYI, I get this "caipiscin butthole burning" feeling only from masturbation, not from sex :-(
(And in general, POIS is much much worse from masturbation)
(...for people claiming POIS is a rare thing: Why do all religious text ask men to stop masturbating then?!)


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Re: FAAH Inhibitors
« Reply #3 on: March 02, 2021, 04:57:01 PM »
Kaempferol induced apoptosis in glioma cells by elevating intracellular oxidative stress. Heightened oxidative stress was characterized by an increased generation of reactive oxygen species (ROS) accompanied by a decrease in oxidant-scavenging agents such as superoxide dismutase (SOD-1) and thioredoxin (TRX-1). Knockdown of SOD-1 and TRX-1 expression by small interfering RNA (siRNA) increased ROS generation and sensitivity of glioma cells to kaempferol-induced apoptosis.
Kaempferol is one of the most important constituents in ginkgo flavonoids.
Ten adult volunteers with an average age 28 years were given a single oral dose of six tablets of Ginkgo biloba extract.The absorption half life was 1.51 hr and elimination half-life was 1.56 hr.

Lavender is another FAAH inhibitor.
Investigations into the mechanism of action showed that Lavender essential oil (LEO) markedly decreased the phosphorylation of ERK1, ERK2, and JNK1, and decreased the levels of iNOS in the spinal cord; involvement of the endocannabinoid system was also detected using in vitro inhibition of the FAAH and MALG enzymes as well as in vivo experiments with the CB1 antagonist. Conversely, no effect on P38 phosphorylation and NF-kB activation was detected. These antihyperalgesic effects appeared at the same dose able to induce antidepressant-like, anxiolytic-like, and anorexic effects. LEO was less potent than the inhibitor but was able to inhibit both enzymes, particularly FAAH.
I have just tried it by drinking a liter of lavender tea. It seems to have a weak effect that appears quite slowly about 2-3 hours after consumption. This is a preliminary trial and has to be tested much more of course.

Is the similarity just a coincidence or are the other compounds FAAH inhibitors as well?
We identify ten compounds against the SARS-CoV-2 virus: (emodin anthrone, kaempferol, quercetin, aesculin, cichoriin, luteolin, matricin, riolozatrione, monocaffeoyl tartaric acid, aucubin).
(A) emodin anthrone (Aloe vera), (B) kaempferol (Urtica dioica, Passiflora incarmata, Prunus pérsica L., Tilia mexicana and Tilia europea), (C) quercetin (Passiflora incarmata, Tilia europea, Taraxacum officinale, Matricaria recutita, Prunus pérsica L., Tilia mexicana and Urtica dioica) (D) aesculin (Taraxacum officinale), (E) cichoriin (Taraxacum officinale), (F) luteolin (Scoparia dulce L., Taraxacum offcinale and Passiflora incarmata), (G) matricin (Matricaria recutita), (H) riolozatrione (Jatropha dioica), (I) monocaffeoyl tartaric acid (Taraxacum officinale), (J) aucubin (Verbascum densiflorum).

The content of the potentially health-defensive and disease-preventive flavonoids quercetin, kaempferol, myricetin, apigenin and luteolin of 31 vegetables were determined. Quercetin levels in the edible parts of most vegetables were generally below 10 mg/kg, except for onions (67-121.5 mg/kg), lettuce (13.5-35.0 mg/kg), dill (74.5 mg/kg), broccoli (15.5 mg/kg) and spinach (272.2 mg/kg). Kaempferol was below 30 mg/kg except for parsnip (66.4 mg/kg) and leek (45.8 mg/kg). Myricetin could only be detected in lettuce, Swedish turnip, parsley and celery leaves, and dill. Detectable amount of luteolin was in radishes, some representatives of Brassica, sweet peppers, celery leaves and spinach while apigenin was only in Swedish turnip, celery root and celery leaves.

Check out Table 1. which contains a good list of medicinal plants with high quercetin content.

The other common trait for the best working FAAH inhibitors is PPARG modulation.
Looking at innovative targets, a recent paper describes Macamides, a group of secondary metabolites isolated from the plant Lepidium meyenii (Maca). These compounds are benzylamides of fatty acids, active as analogues of the endocannabinoid anandamide (AEA) and studies have demonstrated that they inhibit fatty acid amide hydrolase (FAAH), blocking AEA hydrolysis. Gugnani et al. demonstrated a neuroprotective role of macamides in vitro and in vivo. Macamides reduced Mn-induced mitochondrial toxicity in glioblastoma U-87 MG cells, probably by binding the CB1 receptor, and it could thus be useful in the treatment of neurodegenerative diseases, especially Alzheimer's Disease. Like AEA, macamides can interact with PPARG, regulating inflammation, energetic metabolism and glucose homeostasis, all important factors for the prevention of AD.

Saffron is also an agonist of PPARG and interestingly down-regulates IL-12, even tough it still has FAAH inhibitory property. Is PPARG agonism more important than FAAH inhibition?
Furthermore, the beneficial effects of saffron on inhibition of serum levels nuclear transcription factor kB (NF-kB) p65 unit, tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-g) and some interleukin (IL) such as IL-1B, IL-6, IL-12, IL-17A were reported. Furthermore, saffron has been known as the antagonist of NF-kB and the agonist of peroxisome proliferator-activated receptor gamma (PPARG). In addition, saffron down-regulates the key pro-inflammatory enzymes such as myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phospholipase A2, and prostanoids.

Some information on PPARG (google):
PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis. Low PPAR-gamma reduces the capacity of adipose tissue to store fat, resulting in increased storage of fat in nonadipose tissue (lipotoxicity).

Some other agonists of PPAR-gamma:
Arachidonic acid (seriously!?), Berberine, Cannabidiol, Daidzein, Genistein, Ibuprofen, 15-HETE and more.
Well I am rather speechless, but I haven't yet tried CBD or Ibuprofen so I can't really say anything.
PPARG increases insulin sensitivity by enhancing storage of fatty acids in fat cells (reducing lipotoxicity), by enhancing adiponectin release from fat cells, by inducing FGF21 and by enhancing nicotinic acid (niacin) adenine dinucleotide phosphate production through upregulation of the CD38 enzyme.
Muon also found a connection to CD38 and it seems that both quercetin and apigenin are CD38 inhibitors.
(At the bottom of the page click on show PPAR modulators.)
Berberine also has a connection to S-adenosyl methionine (SAM).
The alkaloid berberine has a tetracyclic skeleton derived from a benzyltetrahydroisoquinoline system with the incorporation of an extra carbon atom as a bridge. Formation of the berberine bridge is rationalized as an oxidative process in which the N-methyl group, supplied by S-adenosyl methionine (SAM), is oxidized to an iminium ion, and a cyclization to the aromatic ring occurs by virtue of the phenolic group.


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Re: FAAH Inhibitors
« Reply #4 on: March 03, 2021, 05:22:44 PM »
I swear that I have just found this!
A theory about COVID-19 infection leading to a systemic FAAH hyper-activation.
Since FAAH hyper-activation may also allow an excessive immune-inflammatory responses, coronavirus infection might induce an excessive inflammatory response by determining an ECS deficiency. In other words, viral spike glycoprotein ACE-2 interactions would allow a hyper-stimulation of FAAH activity, with a consequent failure in ECS function, which has been proven to predispose to cardiopulmonary complications.
My case probably only differs in that I have a testicular FAAH hyper-activation, which is primarily induced by sexual activity.
This of course leads to many concerns, of which vaccination is the most troubling. Does the provocation of the immune system lead to increased or decreased FAAH activity?
Do I have resistance to COVID-19 owing to an already high level of FAAH and systemic tolerance to it or is it extremely lethal for me regardless? Do I have a chance armed with loads of FAAH inhibitors or is all resistance futile?


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Re: FAAH Inhibitors
« Reply #5 on: March 04, 2021, 04:09:45 AM »
I swear that I have just found this!
A theory about COVID-19 infection leading to a systemic FAAH hyper-activation.
Since FAAH hyper-activation may also allow an excessive immune-inflammatory responses, coronavirus infection might induce an excessive inflammatory response by determining an ECS deficiency. In other words, viral spike glycoprotein ACE-2 interactions would allow a hyper-stimulation of FAAH activity, with a consequent failure in ECS function, which has been proven to predispose to cardiopulmonary complications.
My case probably only differs in that I have a testicular FAAH hyper-activation, which is primarily induced by sexual activity.
This of course leads to many concerns, of which vaccination is the most troubling. Does the provocation of the immune system lead to increased or decreased FAAH activity?
Do I have resistance to COVID-19 owing to an already high level of FAAH and systemic tolerance to it or is it extremely lethal for me regardless? Do I have a chance armed with loads of FAAH inhibitors or is all resistance futile?
When I was sick with this cold in 2020 February I had two orgasms and one nocturnal emission with zero POIS symptoms so there must be something immunity related to the POIS


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Re: FAAH Inhibitors
« Reply #6 on: March 04, 2021, 02:36:04 PM »
This could be the reason why FAAH inhibitors in themselves have a reduced effect. This pairing seems to counteract the rewarding effects of sexual activity too and I really felt reduced pleasure from masturbation. I think this could also counteract premature ejaculation (PE).
Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug addiction
Enhancing the effects of endogenously-released cannabinoid ligands in the brain might provide therapeutic effects more safely and effectively than administering drugs that act directly at the cannabinoid receptor. Inhibitors of fatty acid amide hydrolase (FAAH) prevent the breakdown of endogenous ligands for cannabinoid receptors and peroxisome proliferator-activated receptors (PPAR), prolonging and enhancing the effects of these ligands when they are naturally released. This review considers recent research on the effects of FAAH inhibitors and PPAR activators in animal models of addiction and cognition (specifically learning and memory). These studies show that FAAH inhibitors can produce potentially therapeutic effects, some through cannabinoid receptors and some through PPAR. These effects include enhancing certain forms of learning, counteracting the rewarding effects of nicotine and alcohol, relieving symptoms of withdrawal from cannabis and other drugs, and protecting against relapse-like reinstatement of drug self-administration. Since FAAH inhibition might have a wide range of therapeutic actions but might also share some of the adverse effects of cannabis, it is noteworthy that at least one FAAH-inhibiting drug (URB597) has been found to have potentially beneficial effects but no indication of liability for abuse or dependence. Although these areas of research are new, the preliminary evidence indicates that they might lead to improved therapeutic interventions and a better understanding of the brain mechanisms underlying addiction and memory.


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Re: FAAH Inhibitors
« Reply #7 on: March 07, 2021, 03:48:49 PM »
I have made lists from PPARG agonists and antagonists, but it looks like the effect is not dependent on the group the compound belongs to. It is also interesting to note that among these are also the ones that enhance my POIS. I haven't achieved a perfect conclusion yet, but the most important thing for a compound to be effective in my case is probably that it should both inhibit FAAH and activate PPARG at the same time. Pure PPARG agonists probably all enhance my case, although they seem to help other POISers nonetheless. Pure PPARG antagonists may also help me, but some of them still has to be tested for a reliable conclusion. Pure FAAH inhibitors also seem to work without serious side effects, but their efficacy is lower than those combined with PPARG agonism.

I think this article provides the most reliable information about combined FAAH inhibitors and PPARG agonist.
It is important to note that, among NAEs, AEA, OEA, and PEA all act as PPARA agonists, while only AEA is also capable of acting as a PPARG agonist.
The pharmacological inhibition of FAAH results in an enhancement of the endocannabinoid tone, which has many potential advantages as a therapeutic strategy, since the ECS is essential to many physiological processes in the central nervous system (CNS) and is usually upregulated as a protective response to various pathological conditions, such as pain, inflammation and the expansion of neoplastic clones.
The overlap between endocannabinoid and PPAR signaling suggests that it is possible to expand the activity profile of PPAR ligands by coupling their activity with the inhibition of enzymes such as FAAH. The applications of such an activity profile would be many, including the treatment of cancer, of neurodegenerative diseases, and of alcohol withdrawal, other than metabolic syndrome. In this particular case, the anti-inflammatory effects linked to endocannabinoid activation would be particularly helpful in reducing the hyperinflammatory state of metabolic syndrome patients; it is however important to note that PPARs themselves are among the most important mediators of such effects.
The activation of PPARA mediated by a stable analog of OEA could alleviate the symptoms of nicotine abstinence and reduce the reward mechanisms linked to its consumption, while PPARG activation can reduce the reward mechanisms linked to alcohol consumption.
While most of these compounds showed no relevant activity towards FAAH, some of them showed promising results; these were compounds 4, 5, 8, and 12 (resveratrol). In particular, this last compound can interact with PPARG, albeit as an antagonist and has numerous other reported biological activities. It is worth noting that compounds 1 (Rosiglitazone), 2 (Wy 14,643), and 3 (L165,041) showed little to no activity on FAAH, demonstrating that a more specific drug design process is necessary for the obtainment of dual-acting compounds. These biological results are reported in Table 1.
Rosmarinic acid was reported in the literature as a PPARG agonist and presents some structural similarity to arylacetic acids. Although we did not find any activity of this compound on either PPARA or PPARG, in light of its positive result as an inhibitor of FAAH, we decided to synthesize a short series of new derivatives of this compound and its natural analogue clovamide.

So a list I had found for PPARG agonists: arachidonic acid, several ligands like fatty acids (linoleic acid being the most common), Berberine (Berberis vulgaris), Cannabidiol, Daidzein (alfalfa), Genistein (soybean, chickpeas), Ibuprofen (only weakly), 15-HETE, biotin, taurine, curcumin, DHA, EPA, carvacrol (thyme and oregano), capsaicin (hot pepper), carnosic acid and carnosol (rosemary and sage), punicic acid (pomegrenate seed oil), citral (lemongrass), Cistus salviflius, synthetic thiazolidinediones (TZD) used to treat diabetes: troglitazone (Rezulin), pioglitazone (Actos), rosiglitazone (Avondia), tesaglitazar, chromium histidine, exercise, stilbenoid resveratrol, luteolin, epigallocatechin-3-gallate (EGCG) and others.
These may all work for one group (e.g. taurine), but I could be wrong. I also haven’t tested them all, but most of them make me more ill. I have just made some lemongrass tea (citral) and consumed about 1 liter. After about 3 hours it gave me a severe burning flatulence, which is rather strange as citral is not only a PPARG agonist, but also a weak TRPV1 antagonist too.
To the contrary ibuprofen [200 mg] actually seems to work, although with a weak efficacy. It didn’t give any burning pain, but it also didn’t relieve the mind fog. It takes a long time for a general effect to appear. Next time I will try a greater dose [400 mg].
Daidzein and Genistein both activate PPARG and inhibit FAAH, so they are prospective compounds.

The few PPARG antagonists I found are: green tea, black tea, astaxanthin, rosmarinus (carnosic acid), tamoxifen (also an estrogen receptor antagonist), resveratrol, apigenin, betulinic acid.
I think both black and green tea makes me better slightly. Astaxanthine seems to have worked for other POISers, but it is not very cost-effective. I will really have to try this. Carnosic acid seems an odd one compared to the other list, but a paper explicitly claims that it is an antagonist, although carnosol is still an agonist. Rosemary also contains rosmarinic acid which seems to be a pure FAAH inhibitor. It also contains betulinic acid which is another PPARG antagonist. Tamoxifen is used to treat breast cancer, so it would sound strange if I wanted a prescription for it, although I have POIS related nodules in my breasts. Resveratrol is also indicated as both an agonist and an antagonist. I think researchers should really address this issue to clarify the matter.

The papers also imply that mu opioid agonists could work in cannabinoid deprivation. Based on what I had written earlier in the Kappa agony thread it doesn't seem likely. As opioid alkaloids (probably papaverine) in poppy seed enhance my symptoms it is only logical to assume that opioid antagonists like Low Dose Naltrexon (LDN) would help me. Naltrexon also had efficacy in the treatment of COVID-19 and it simply can't be a coincidence.

The other things I tried in the meanwhile:
Lime tea (Tilia) [kaempferol – leaves and flower combined]: I consumed more than 1 liter. It definitely has a positive effect, although rather weak. It didn't really do anything to cognitive symptoms, but it had a soothing effect on the intestine almost without any flatulence.
I took a pill of vitamin B6 (pyridoxine) and I think it reduced POIS somewhat, but I was not feeling well (not the POIS way). I think it did something to my blood pressure, but I will have to test this out more.

Kaempferol, quercetin, and stilbenoid resveratrol are PPARG agonists.

The controversy of PPARG agonism or antagonism may be solved by a different approach.
The consumption of dietary flavonoids has been associated with a variety of health benefits, including effects mediated by the activation of peroxisome proliferator-activated receptor-gamma (PPARG). Flavonoids are extensively metabolized during and after uptake and there is little known on the biological effects of these conjugated metabolites of flavonoids that are found in plasma. To investigate the effect of glucuronidation on the ability of flavonoids to activate PPARG we studied and compared the activity of quercetin, kaempferol and their relevant plasma conjugates quercetin-3-O-glucuronide (Q3G) and kaempferol-3-O-glucuronide (K3G) on different PPARG related endpoints.
It is concluded that flavonoids affect PPARG mediated gene transcription by a mode of action different from agonist binding. Increases in PPARG receptor mRNA expression and synergistic effects with endogenous PPARG agonists may play a role in this alternative mode of action. Glucuronidation reduced the activity of the flavonoid aglycones.!divAbstract

Some information about rosmarinic acid (FAAH inhibitor):
Although some of these enhance POIS, but it is probably caused by another compound like carnosol or carvacrol.
Rosmarinic acid accumulation is shown in hornworts, in the fern family Blechnaceae and in species of several orders of mono- and dicotyledonous angiosperms.
It is found most notably in many Lamiaceae (dicotyledons in the order Lamiales), especially in the subfamily Nepetoideae. It is found in species used commonly as culinary herbs such as Ocimum basilicum (basil), Ocimum tenuiflorum (holy basil), Melissa officinalis (lemon balm), Rosmarinus officinalis (rosemary), Origanum majorana (marjoram), Salvia officinalis (sage), thyme and peppermint. It is also found in plants in the family Marantaceae (monocotyledons in the order Zingiberales) such as species in the genera Maranta (Maranta leuconeura, Maranta depressa) and Thalia (Thalia geniculata).
Rosmarinic acid and the derivative rosmarinic acid 3'-O-?-D-glucoside can be found in Anthoceros agrestis, a hornwort (Anthocerotophyta).

Rosemary contains a number of phytochemicals, including rosmarinic acid, camphor, caffeic acid, ursolic acid, betulinic acid, carnosic acid, and carnosol. Rosemary essential oil contains 10–20% camphor.

Genistein (4',5,7-trihydroxyisoflavone) is an isoflavone. Soybean, a high protein vegetable, has been accounted for to contain the most genistein. Pint sized quantities of genistein are found in different legumes, for example, chickpeas (garbanzo beans). Soy based edibles contain genistein in variable quantity. Other plant foods that have been shown to contain genistein consist of alfalfa and clover sprouts, barley meal, broccoli, cauliflower and sunflower, caraway, and clover seeds.
Genistein is also a proposed drug in the treatment of Alzheimer's disease.

As I have a possible arachidonic acid overload PPARG is probably over-activated all the time.
Peroxisome proliferator-activated receptor-gamma (PPARG) modulates the expression of many genes actively involved in regulating the cell cycle. Specific ligands bind PPARG protein can exert inhibition on the proliferation of human breast carcinoma cells. In contrast, the persistent over-regulation of the PPARG gene can also increase the likelihood of breast carcinogenesis.

Macamides are neuroprotective and they can activate PPARG.
The gene reporter assay was performed to test the ability of macamides to activate PPARG receptors. No PPARG activation was observed in response to MAC 18:1 exposure. However, MAC 18:2 and MAC 18:3 at 30 uM activated PPARG with EC50 values of 22.6 ± 0.1 uM and 20.4 ± 0.1 uM, respectively (p ? 0.05). Human PPARG activation was observed in the presence of RGZ, with an EC50 value of 240.8 ± 1.4 nM.
Macamides, as they are structurally similar to AEA, should activate PPAR, particularly the PPAR? receptor.
This observation is in agreement with results of a study which describes linoleic acid and linolenic acid as endogenous activators of PPARG, with EC50 values in the range of 5–20 uM. Therefore, the presence of the linoleic and linolenic acid backbones in macamides MAC 18:2 and MAC 18:3 makes these compounds suitable ligands for PPARG transactivation. This result is considered important in the study of the relationship between macamides and AEA. Moreover, it will be interesting to examine the effects of macamides that are mediated by PPARG.

An extensive study about the relation of cannabinoids and PPARs

The severe adverse effects of thiazolidinediones which led to their withdrawal from the market or restricted clinical application are suggested to be a result of full PPAR? activation, contrasting the weak agonistic effect of endogenous PPARG ligands such as fatty acids and prostanoids.
Noteworthy, along with plants and mushrooms applied in traditional medicines, PPARG-ligands were often identified in plants that are common food sources, including the tea plant (Camellia sinensis), soybeans (Glycine max), palm oil (Elaeis guineensis), ginger (Zingiber officinale), grapes and wine (Vitis vinifera), and a number of culinary herbs and spices (e.g. Origanum vulgare, Rosmarinus officinalis, Salvia officinalis, Thymus vulgaris).
Although most of the agonists identified in food sources are weak PPARG agonists per se, the effects of their metabolites deserve further research to better estimate their preventive potential. While research in this direction is largely missing, a previous study reported that some main metabolites of flavonoid constituents from red clover (Trifolium pratense) have an up to 100-fold higher PPARG binding affinity than their precursors.

Check out Table 1. as it lists a lot of PPARG ligands which could potentially modify POIS.
You better check the table as I only dumped this here for easier search.
The list: Amorpha fruticosa L. - Amorfrutins (in the fruits), Astragalus membranaceus Moench - Formononetin (in ethanolic extracts), Bixa orellana L. - Bixin and norbixin (in annatto extracts), Camellia sinensis - Catechin (in green tea), Cannabis sativa L. - THC, Chromolaena odorata - (9S,13R)-12-Oxo-phytodienoic acid and odarotin, Coix lacryma-jobi var. ma-yuen - Hydroxy unsaturated fatty acids, Commiphora mukul - Commipheric acid, Cornus alternifolia L.f. - Kaempferol-3-O-B-glucopyranoside, Cymbopogon citratus - Citral (in lemongrass oil), Echinacea purpurea (L.) - Alkamides, Elaeis guineensis Jacq. - Tocotrienols (in palm oil), Elephantopus scaber L. - Deoxyelephantopin, Epimedium elatum C. - Acylated flavonol glycosides, Euonymus alatus - Kaempferol and quercetin, Glycine max (L.) - Genistein (in soya beans); Glycyrrhiza glabra L. - 5?-Formylglabridin, (2R,3R)-3,4',7-trihydroxy-3'-prenylflavane, echinatin, (3R)-2',3',7-trihydroxy-4'- methoxyisoflavan, kanzonol X, kanzonol W, shinpterocarpin, licoflavanone A, glabrol, shinflavanone, gancaonin L, glabrone; Glycyrrhiza foetida Desf. - Amorfrutins (in the edible roots), Glycyrrhiza inflata Batalin - Licochalcone E (in roots), Glycyrrhiza uralensis Fisch. ex DC. - Flavonoids and 3-arylcoumarins (in ethanolic extract of the roots), Limnocitrus littoralis (Miq.) Swingle – Meranzin, Lycium chinense Mill. - Fatty acids (in root bark), Magnolia officinalis – Magnolol and honokiol, Melampyrum pratense L. - Lunularin and fatty acids, Momordica charantia L. - Cucurbitane-type triterpene glycosides, Notopterygium incisum C.T. - Polyacetylenes, Origanum vulgare L. - Biochanin A, Panax ginseng - Ginsenoside 20(S)-protopanaxatriol and ginsenoside Rb1 (in ginseng roots), Pinellia ternata - Fatty acids (in different apolar extracts from the rhizomes), Pistacia lentiscus L. - Oleanonic acid, Pseudolarix amabilis - Pseudolaric acid B, Pueraria thomsonii Benth – Daidzein, Robinia pseudoacacia var. umbraculifer DC. - Amorphastilbol, Rosmarinus officinalis L. - Carnosic acid and carnosol, Salvia officinalis L. - Carnosic acid and carnosol (in ethanolic extract of sage); as well as 12-O-methyl carnosic acid and ?-linolenic acid, Sambucus nigra L. - ?-Linolenic acid, linoleic acid, and naringenin, Saururus chinensis - Saurufuran A (in roots), Silybum marianum (L.) - Isosilybin A (in silymarin, a phenolic mixture from the fruits of the plant), Terminalia bellerica Roxb. - Gallotannins (in the fruits), Thymus vulgaris L. - Carvacrol (in thyme oil), Trifolium pratense L. - Isoflavones (in red clover extracts), Vitis vinifera L. - Ellagic acid, epicatechin gallate, flavonoids (in grapes and wine), Wolfiporia extensa - Dehydrotrametenolic acid (in dried sclerotia), Zingiber officinale Roscoe - 6-Shogaol (in ginger roots).

In this study, PPAR activation by oregano (e.g., Origanum vulgare) and its components was tested. Oregano extracts bind but do not transactivate PPARG, and binding affinity differs among different oregano extracts. The extracts contain PPARG antagonists (e.g., quercetin, luteolin, rosmarinic acid, and diosmetin), selective PPARG modulators (e.g., naringenin and apigenin), and PPARG agonists (e.g., biochanin A). Oregano extract and isolated compounds in the extract antagonize rosiglitazone-mediated DRIP205/TRAP220 recruitment to PPARG, pointing to oregano extracts as putative food supplements for weight reduction. Rosmarinic acid and biochanin A, PPARA agonists, may ameliorate the lipid profile. By endothelial nitric oxide synthase activation, oregano extract could prevent atherosclerosis.

The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPARG), a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPARG also represses the inflammatory process. Similarly, the PPARG agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPARG, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPARG activation.
Table 1. contains other PPARG agonists like DHA, EPA, curcumin, capsaicin, punicic acid.

EPA and DHA also inhibit COX!
EPA and DHA provided by the diet or arising from a-linolenic acid metabolism inhibit adenylate cyclase and COX activities, presumably altering adipogenesis.
Arachidonic acid (ARA) and some of its metabolites generated through cyclo-oxygenase (COX) and lipoxygenase activities are implicated in adipogenesis as activators/ligands of PPARs. Thus ARA is a potent stimulator of adipogenesis that acts through cell-surface IP-R and nuclear PPAR in early and late events of adipogenesis, respectively.
By the way at the time I drank a lot of Cistus incantus tea (approximately 1 liter) besides heart ache or heartburn I noticed other symptoms. I also felt my chest constricted and had an inflammation at the descending colon. I will have to test it again to see if these symptoms can be reproduced.
I also bought some naproxen, but haven't tested it yet.

For those POISers who have emotional problems this may be interesting.
A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional–motivational reactivity.

Inhibition of FAAH may increase regeneration through PPARA.

The beneficial effects of saffron on inhibition of serum levels nuclear transcription factor kB (NF-kB) p65 unit, tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-g) and some interleukin (IL) such as IL-1B, IL-6, IL-12, IL-17A were reported. Furthermore, saffron has been known as the antagonist of NF-kB and the agonist of peroxisome proliferator-activated receptor gamma (PPARG). In addition, saffron down-regulates the key pro-inflammatory enzymes such as myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phospholipase A2, and prostanoids.
Some studies suggested that the immunomodulatory activity of saffron may involve direct targeting of Toll-like receptors (TLRs), attributed to the regulation of various transcription factors such as nuclear factor (NF-kB), activator protein 1 (AP-1) and also their downstream signaling pathways. TLRs play a crucial role in the innate immune system by triggering pro-inflammatory signaling pathways in response to either external or internal stimuli. Moreover, NF-kB acts a vital role in producing pro-inflammatory cytokines such as IL-1, IL-2 and IFN-g in T lymphocytes. Pradere et al. showed saffron has an inhibitory effect on producing pro-inflammatory cytokines like IL-1 production by suppressing NF-kB activity via the inhibition of I kappa B kinase-a (IKK-a) phosphorylation and prevention of nuclear translocation of the NF-kB p65 subunit.

Until the BIA 10–2474 case is resolved there won't be any pharmaceutical FAAH inhibitors.
It is expected that the effects of FAAH inhibitors, due to their pharmacological interaction with the endocannabinoid system, may exhibit tolerance following repeated administration. This phenomenon is called tachyphylaxis.
This is probably the reason why herbal teas and other supplements lose efficacy over time.

Endocannabinoids have an intricate connection to helminthic infections and this may also be the reason why ivermectin could work in parasitic infections, COVID-19 infections and possibly in POIS as well.
AEA was also reported as immunosuppressive to adaptive cells such as T and B lymphocytes. It is believed that AEA functions this way by signaling via CB2 receptor, PPARG and by inhibiting NF-kB. Similar to innate cells, AEA inhibits lymphoid cell proliferation, Th1 cytokine production and enhances Th2 responses by increasing expression of IL-4 and IL-10. Similarly, 2-AG (more precisely a 2-AG metabolite) was immunosuppressive towards T cells by impairing pro-inflammatory IL-2 cytokine expression.
Although eCBs at times play controversial roles in immune responses, in general, eCBs are immunosuppressive, with AEA being the most potent. Interestingly, the Th1 response
inhibition by eCB is coupled with enhancement of Th2 response in many immune cells types.
Moreover, Th1 cytokine production was associated with reduced FAAH (AEA degrading enzyme) activity suggesting that a self-sustaining anti-inflammatory mechanism of eCBs.
Therefore, eCBs can be exploited for their anti-inflammatory therapeutic potential.
Endocannabinoids are lipid signaling molecules that have functions in dampening Th1 immune responses and driving Th2 immunity.

Peroxisome proliferator-activated receptor gamma (PPARG), insulin receptor substrate-1 (IRS-1) and nuclear transcription factor kappa B (NF-kB) are important biomarkers involved in numerous metabolic processes. PPARG plays a key role in regulating lipid, carbohydrate, glucose and insulin metabolisms. It has been shown that exercise induced an increase in PPARG expression in liver and skeletal muscle tissues. In the current study, PPARG expression levels in the liver and muscle tissues were significantly elevated compared to the control group. Remarkably, CrHis and biotin supplementation significantly increased PPARG expression levels in sedentary and exercised rats. The efficacy of CrHis and biotin was more pronounced when used simultaneously, thus indicating a synergetic effect. Our previous findings demonstrated that CrPic and biotin, as well as their combination, increased PPARG expression in adipose tissue and improved insulin resistance in type 2 diabetes rats.

PPARG may be an important molecule in acne vulgaris, the most frequent sebaceous dermatoses (SG)-related dermatosis with abnormal lipid storage and inflammation. Arachidonic acid (AA) markedly enhances lipid synthesis in SZ95 sebocytes, and some of this induction might be regulated via PPARG.
In summary, our study provides evidence that PPARG participates in the signaling mechanisms of sebocyte differentiation. We also demonstrated that AA-activated PPARG is involved in the regulation of major neutral lipid and phospholipid biosynthesis. Finally, we presented that PPARG is activated by AA keto-metabolites (5-KETE, 12-KETE). Taken together, our data implicate that AA-activated PPARG is an important regulator of differentiation and lipid metabolism in human sebocytes; therefore PPARG might be a potential therapeutic target molecule in sebaceous dermatoses.

Ketoconazole (Nisoral) is also a FAAH inhibitor. I have been using it effectively for years as a means to control POIS induced dandruff formation. This is probably in line with the former article as I also have more acne after O. I think this also contradicts a possible fungal origin even though they may still be present. I think this is something similar to my case with dysbacteriosis.
I also have to wonder if ketoconazole pills could be effective, although they may have serious side effects on the long run. Still it would be good to know as there is a possibility that it could work very well in the treatment of COVID-19 infection.
In the present study we have demonstrated that ketoconazole (Nisoral) inhibits the uptake of the endocannabinoid AEA into a variety of cell lines, and that this effect can be most simply explanined by the ability of the compound to inhibit FAAH.
In Sweden, ketoconazole is available as a shampoo (20 mg/ml) and until recently as tablets (200 mg; the dose could be doubled if deemed necessary).
In intact rat peritoneal polymorphonucelar leukocytes, leukotriene B4 and 5-hydroxyeicosatetraenoic acid production from arachidonic acid was inhibited with IC50 values of 30 and 26 µM, respectively. These authors demonstrated further than oral pretreatment with ketoconazole (10–40 mg/kg) inhibited in a dose-dependent manner ovalbumin-induced bronchoconstriction in sensitised guinea pigs, suggesting that leukotriene synthesis could be inhibited in vivo by the compound.

Carpofen (NSAID) is a FAAH inhibitor. Caprofen is a COX inhibitor too.
Membrane lipids could also modulate structure, functional activity, and subcellular localization of FAAH. Indeed, the FAAH dimer is stabilized by the lipid bilayer and shows a higher membrane-binding affinity and enzymatic activity within membranes containing both cholesterol and the FAAH substrate, AEA. In addition, the colocalization of cholesterol, AEA, and FAAH in intact cells supports a mechanism by which cholesterol can increase substrate accessibility to the active site.

Table 1 contains a lot of herbs with a high quercetin content.

Apigenin reduces PPAR-gamma expression.
Further studies suggest that apigenin binds to non-phosphorylated STAT3, reduces STAT3 phosphorylation and transcriptional activity in VAT, and consequently reduces the expression of STAT3 target gene cluster of differentiation 36 (CD36). The reduced CD36 expression in adipocytes reduces the expression of peroxisome proliferator-activated receptor gamma (PPARG) which is the critical nuclear factor in adipogenesis. Our data show that apigenin reduces CD36 and PPARG expressions and inhibits adipocyte differentiation; overexpression of constitutive active STAT3 reverses the apigenin-inhibited adipogenesis. Taken together, our data suggest that apigenin inhibits adipogenesis via the STAT3/CD36 axis. Our study has delineated the mechanism of action underlying the anti-visceral obesity effect of apigenin, and provide scientific evidence to support the development of apigenin as anti-visceral obesity therapeutic agent.

Relora containing Magnolia officinalis bark also helped some POISers.
In the present study, we examined whether PPARs-mediated pathways contribute to the antiplatelet activity of magnolol, a compound purified from Magnolia officinalis. Magnolol (20–60 uM) dose-dependently enhanced the activity and intracellular level of PPAR-B/G in platelets.
Additionally, magnolol significantly inhibited collagen-induced PKCa activation through a PPAR-B/G and PKCa interaction manner. The arachidonic acid (AA) or collagen-induced thromboxane B2 formation and elevation of COX-1 activity caused by AA were also markedly attenuated by magnolol.

PPAR agonists reduce voluntary alcohol consumption in rodent models.

The cardinal biologic activity of PPARG is the induction of differentiation of adipocytes, the cell type that expresses the highest levels of PPARG amongst normal tissues. Lower levels of PPARG are, however, found in other normal tissues and cell types such as skeletal muscle, liver, breast, prostate, colon, type 2 alveolar pneumocytes, some endothelial cells as well as monocytes, and B-lymphocytes.
Also, uncertainty about mechanisms of anticancer effects of PPARG ligands has resulted from variability in the classification of some compounds (e.g., bisphenol A diglycidyl ether [BADGE], which has been shown to have both agonist and antagonist activities).
Also, the observation that combinations of PPARG agonist and antagonist compounds result in additive antiproliferative effects in various cancer cell lines is consistent with this mechanism. This mechanism is plausible, as it has been shown to inhibit the NF-kB signaling pathway, which is central to inflammation and to the proliferation and survival of multiple cancer types including hepatocellular and colon carcinomas as well as multiple myeloma.

As betaine was mentioned a lot on the site I thought this may have relevance.
Our findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression.
Betaine, a methyl donor, is a naturally occurring compound in common foods, such as wheat bran, wheat germ, spinach, pretzels, shrimp and wheat bread etc. In vivo, betaine can also be produced by oxidation of choline, and it serves as an effective methyl donor for remethylating homocysteine (Hcy) into methionine (Met).

An extensive overview of the complex relation of cannabinoids and PPARs.

Thermogenic brown and brite adipocytes convert chemical energy from nutrients into heat.
The peroxisome proliferator-activated receptor (PPAR) family plays key roles in the maintenance of adipose tissue and in the regulation of thermogenic activity. Activation of these receptors induce browning of white adipocyte. The purpose of this work was to characterize the role of carnosic acid (CA), a compound used in traditional medicine, in the control of brown/brite adipocyte formation and function.
We used transactivation assays to show that CA has a PPARA/G antagonistic action. Our data pinpoint CA as a drug able to control PPAR activity through an antagonistic effect. These observations shed some light on the development of natural PPAR antagonists and their potential effects on thermogenic response.
Mammalian adipose organs can be divided into two distinct types of adipose tissues: white and brown. White adipose tissue (WAT) is specialized in the storage and release of fatty acids, which are required as an energy source for heart and muscles. In contrast, brown adipose tissue (BAT) dissipates energy in the form of heat by uncoupling the mitochondrial respiratory chain from ATP synthesis. Adipose tissue is the largest endocrine organ and links metabolism and immunity. It is a major actor in the regulation of energetic metabolism and represents a potential therapeutic target to combat fat mass disorders such as obesity and hypermetabolism in critical illness.
High increases in catecholamine production, such as epinephrine and norepinephrine, and pro-inflammatory factors are observed in critical illness, but pharmacologic treatments are associated with secondary effects such as gastrointestinal and cardiovascular failures. Obesity appears to be protective against death induced by critical illness, and this process is called the "obesity paradox".
Carnosic acid (CA) inhibits the browning process of human white adipocytes.
Under conditions where browning of white adipocytes is exacerbated, such as in critical illness after a severe burn injury or cachexia, CA treatment may represent a potential therapeutic option. Animal models and patients with severe burns develop hypermetabolism with massive browning of white adipose tissue, hepatic steatosis, and cachexia, which are harmful and have limited therapeutic treatments. In a similar manner, cancer-associated cachexia, a wasting syndrome, is associated with increased browning of white adipose tissue, which leads to higher thermogenesis with increased lipid mobilization and energy expenditure, further worsening the clinical situation and risk of death. Inhibition of white adipose tissue browning in burn and cancer patients represents a promising approach that can be potentially achieved with CA treatment alone or in combination with other approaches. In line with this, it has been suggested that CA is efficient against obesity-associated cancers, in particular against colon cancer. Furthermore, it is known that PPAR activation by thiazolidinediones is associated with bone fracture, and we could speculate that CA treatment has the potential to restore bone mass, given that betulinic acid, a PPARG antagonist, is known to favor osteogenesis at the expense of adipogenesis.

Betulinic acid
It exhibits anti-HIV, antimalarial, antineoplastic and anti-inflammatory properties.
The effects of betulinic acid as an anticancer agent in breast cancer is found to be cannabinoid receptor dependent. Betulinic acid behaves as a CB1 antagonist and CB2 agonist.

Bitter melon up-regulates PPARG.
It would be interesting to test Momordica charantia also called bitter melon or bitter gourd. It has anti-diabetic, anti-HIV, anti-ulcer, anti-inflammatory, anti-leukemic, anti-microbial, and anti-tumor effects.


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Re: FAAH Inhibitors
« Reply #8 on: April 13, 2021, 02:47:03 PM »
I wanted to do a post about the possible connection between infections and the endocannabinoid system before I caught COVID-19. Unfortunately I couldn't judge if there is a link to my POIS, however the theoretical background still seems credible.
Aberrant activation of toll-like receptors (TLR) probably have a role in post-covid syndrome and possibly in POIS as well.

Aberrant activation of toll-like receptor (TLR)s results in persistent and prolonged neuroinflammation and has been implicated in the pathogenesis and exacerbation of psychiatric and neurodegenerative disorders. TLR3 coordinates the innate immune response to viral infection and recent data have demonstrated that inhibiting fatty acid amide hydrolase (FAAH), the enzyme that primarily metabolizes anandamide, modulates TLR3-mediated neuroinflammation.
(TLR)3 activation results in the induction of type 1 interferon (IFN-A and IFN-B) and NFkB-inducible (e.g. IL-1B, IL-6 and TNF-a) inflammatory cascades which are responsible for coordinating the innate immune response to viral infection. Recent data has highlighted that FAAH inhibition attenuates the TLR3-mediated increase in the expression of IFN-inducible genes and pro-inflammatory cytokines in brain regions such as the hippocampus and hypothalamus, without altering peripheral immune responses. The behavioural and physiological consequences of TLR3 activation include the induction of sickness behaviours such as fever/hypothermia, hypoactivity, anorexia and enhanced pain sensitivity which represents a highly adaptive coping mechanism by the CNS to fight viral infection. However, aberrant activation of TLR3 can elicit adverse effects on the CNS including increased neuronal excitability and seizure susceptibility, impaired contextual and working memory, anxiety- and depressive-like behaviour and exacerbation of underlying neurodegenerative processes.
The FAAH substrates AEA, OEA and PEA have been shown to modulate TLR4-induced thermoregulatory changes and hypophagia most likely mediated via modulation of hypothalamic cytokine expression. A recent study from our group demonstrated that FAAH inhibition modulated TLR4-mediated neuroinflammatory responses in the hippocampus and frontal cortex, an effect which was accompanied by an attenuation of TLR4-mediated anhedonia, but not sickness behaviour. Furthermore, FAAH inhibition has been demonstrated to reverse TLR4-mediated mechanical allodynia, thermal hyperalgesia and paw oedema.
The results of the present study demonstrate that the systemic administration of the FAAH inhibitor URB597 (FAAH inhibitor) attenuated TLR3-mediated microglia/macrophage activation and some, but not all, associated behavioural changes in female rats.

Toll?like receptor (TLR)3 is a key component of the innate immune response to viral infection.
The data revealed that TLR3?induced expression of interferon? or NFkB?inducible genes (IFN?a/B, IP?10, or TNF?a), either peripherally (spleen) or centrally (hypothalamus), did not differ between male and female rats, with the exception of TLR3?induced IFN?a expression in the spleen of female, but not male, rats 8 hr post TLR3 activation. Furthermore, TLR3 activation increased plasma corticosterone levels, induced fever, and reduced locomotor activity and body weight — effects independent of sex.
Systemic administration of the monoacylglycerol lipase (MAGL) inhibitor MJN110 and subsequent increases in 2?AG levels did not alter the TLR3?induced increase in IP?10, IRF7, or TNF?a expression in the spleen or the hypothalamus of male or female rats. In contrast, the fatty acid amide hydrolase (FAAH) inhibitor URB597 increased levels of AEA and related N?acylethanolamines, an effect associated with the attenuation of TLR3?induced inflammatory responses in the hypothalamus, but not the spleen, of male and female rats.

Recent studies performed in animal models of acute and chronic pancreatitis have shown that the stimulation of primary afferent capsaicin-sensitive neurons or treatment with peptides (e.g., calcitonin gene-related peptide) before the exposure to harmful factors, can activate an adaptive mechanism called "preconditioning" which is able to reduce pancreatitis development. Sensory neurons are involved in gastroprotection and regulation of visceral blood flow and their stimulation by capsaicin can potentially inhibit the progression of inflammation, by improving the endogenous release of nitric oxide (NO) and thus the pancreatic blood flow. Certain psychoactive molecules can modulate the endocannabinoid system in the gut and possibly impact the pathogenesis of inflammatory bowel disease, as well as its extra intestinal manifestations such as pancreatitis. Anandamide reduces mucosal oxidative stress, inhibits the inflammatory process and preserves the integrity of gastric mucosa in stress-induced gastric ulcers.
On the contrary, the intracellular TLRs, expressed in cell endosomes, detect microbial nucleic acids, specifically viral double-strand RNAs (TLR3).
More and more studies have focused their attention on the role that TLRs may play in neurodegeneration, considering that they are extensively expressed in immune and non-immune cells and their expression can change not only during microbial infections but also in the presence of sterile inflammation when the pathogens are absent.
High levels of polyunsaturated fatty acids (PUFA), such as the omega-3 fatty acid docosahexaenoic (DHA), have been shown to induce anti-inflammatory effects and reduce mitochondrial dysfunction-mediated motor symptoms together with decreasing alpha-synuclein accumulation and inflammation in PD animal models. DHA inhibits, whereas saturated fatty acids can activate, certain TLR-mediated pro-inflammatory signaling pathways. DHA blocks the activation of TLR4 and TLR2/1 or TLR2/6 and other TLRs in an indirect manner, targeting TLRs downstream pathways during the receptor dimerization process (e.g., lipid rafts). Overall these findings highlight the involvement of diet, such as the intake of saturated fatty acids and DHA, in the modulation of TLR signaling pathways and related involvement in chronic inflammation and subsequent risk of chronic diseases. An in-vitro study has shown that an extract of Panax notoginseng was able to suppress microglial activation and decrease the release of inflammatory factors (IL-6 and TNF-a), suggesting the potential therapeutic utility in slowing down PD progression. The flavonoid silymarin, extracted from the seeds and fruit of Silybum marianum, was found to exert neuroprotective effects in 6-OHDA-induced hemi-parkinsonian rats, through the alleviation of nigral injury, the increase of anti-oxidant defenses and suppression of TLR4 activation.

PPARG is expressed in various immune cells, such as primary peritoneal macrophages, dendritic cells, and T cells. Growing evidence supports an anti-inflammatory role for PPARG. Activation of PPARG by various ligands down-regulates the synthesis and release of proinflammatory cytokines. For example, PPARG ligands inhibit the expression of iNOS and TNF-a downstream of TLRs by ligand-dependent transrepression in macrophages. Therefore, PPARG ligands may be important anti-inflammatory agents to treat inflammation related diseases. Varieties of endogenous and synthetic ligands bind to PPARG to modulate gene expression.
PPARG agonists negatively regulate TLR3- and TLR4-induced IFN-B production in macrophages.
Activation of PPARG by various ligands down-regulates the synthesis and release of many cytokines from various cell types that participate in the inflammatory processes. In macrophages, PPARG-mediated repression of LPS-induced iNOS gene expression has been demonstrated. PPARG has been reported to regulate the expression of macrophage colony-stimulating factor in alveolar macrophages. PPARG agonist has been shown to down-regulate IL-17 expression in a murine model of allergic airway inflammation. PPARG is expressed in both murine CD4 and CD8 cells, and PPARG ligands directly decrease IFN-g expression in T cells. In dendritic cells, PPARG agonists have been shown to inhibit TLR-mediated activation of dendritic cell via the MAP kinase and NF-kB pathways. However, the effect of PPARG on IFN-B production downstream of TLR signaling has not been clarified. In this study, we show that PPARG agonists inhibit LPS and poly(I:C)-induced IFN-B transcription and protein secretion in vitro and in vivo. In particular, the PPARG agonist, troglitazone, impaired LPS and poly(I:C)-induced IRF3 binding to the IFN-B promoter. As a result, LPS and poly(I:C)-induced STAT1 phosphorylation and subsequent ISRE activation are inhibited by troglitazone. Considering the involvement of IFN-B in several pathogenic autoimmune diseases, our results suggest that PPARG agonists may have therapeutic potential to cure these diseases. In accordance with our results, recent studies have shown that PPARG agonists could ameliorate murine lupus in a mouse model of SLE.
The production of type I IFNs, including IFN-a and -B is central for the innate immune responses to eliminate viral and bacterial infection. At the same time, uncontrolled expression of type I IFNs has been found in diverse pathogenic autoimmune diseases, including systemic lupus erythematosus. Several pathogen recognition receptors, such as TLR3, TLR4, RIG-I, and MDA-5, recognize highly conserved microbial components and activate the regulatory pathways to coordinate the production of type I IFNs.
A variety of PPARG agonists have been demonstrated to have anti-inflammatory functions, including endogenous ligands such as 15d-PGJ2 and synthetic ligands such as troglitazone and rosiglitazone.
In conclusion, our results show that PPARG agonists inhibited LPS and poly(I:C)-induced IFN-B transcription and secretion in vivo and in vitro. Furthermore, we show that troglitazone treatment prevented IRF3 binding to the IFN-B promoter. As a result, LPS and poly(I:C)-induced STAT1 phosphorylation and subsequent ISRE activation were inhibited by troglitazone. These results demonstrate that PPARG negatively regulates IFN-B production in TLR3- and -4-stimulated macrophages by preventing IRF3 binding to the IFN-B promoter. Our results provide a strategy to down-regulate IFN-B production downstream of pathogen recognition and suggest that PPARG agonists may have therapeutic potential in autoimmune diseases with uncontrolled IFN-B production.

We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signaling to increase cell surface expression of ACE2 facilitating entry. SARS-CoV-2 also destroys the type II alveolar cells that secrete pulmonary surfactants, which normally decrease the air/tissue surface tension and block TLR4 in the lungs thus promoting ARDS and inflammation. Furthermore, SARS-CoV-2-induced myocarditis and multiple-organ injury may be due to TLR4 activation, aberrant TLR4 signaling, and hyperinflammation in COVID-19 patients. Therefore, TLR4 contributes significantly to the pathogenesis of SARS-CoV-2, and its overactivation causes a prolonged or excessive innate immune response. TLR4 appears to be a promising therapeutic target in COVID-19, and since TLR4 antagonists have been previously trialed in sepsis and in other antiviral contexts, we propose the clinical trial testing of TLR4 antagonists in the treatment of severe COVID-19. Also, ongoing clinical trials of pulmonary surfactants in COVID-19 hold promise since they also block TLR4.
TLR4 is important in initiating inflammatory responses, and its overstimulation can be detrimental leading to hyperinflammation. Dysregulation of TLR4 signaling has been shown to play a role in the initiation and/or progression of various diseases, such as ischaemia-reperfusion injury, atherosclerosis, hypertension, cancer, and neuropsychiatric and neurodegenerative disorders. Moreover, TLR4 is also important in the induction of the host immune response against infectious diseases such as bacterial, fungal and viral infections, and malaria.
Moreover, activation of TLR4 on platelets whether by PAMPs (viraemia and LPS) or DAMPs induces a prothrombotic and proinflammatory state, which provides a potential explanation for the thrombotic events (such as MI) observed in COVID-19 patients.
Furthermore, LPS causes septic cardiomyopathy via TLR4 activation, which is of relevance since sepsis—whether viral or bacterial—is implicated in severe cases of COVID-19.
The body needs a certain amount of TLR4 stimulation to fight the virus, but not an overstimulation, especially in the later stages. However, other TLRs will be able to produce some interferons if TLR4 is antagonised.
The potential use of glycyrrhizin for COVID-19 has been reviewed in detail by Murck et al. and Andersson et al. Glycyrrhizin is an active ingredient extracted from liquorice plant and has been used in traditional Chinese medicines to control COVID-19. It gets metabolized in the human gut to the systemically active metabolite glycyrrhetinic acid. It appears to possess direct antiviral properties and was reported to inhibit in vitro replication and penetration of SARS-CoV-1. More importantly, it has an anti-inflammatory effect through downregulation of HMGB1-mediated inflammation and TLR4 antagonism. Given its dual antiviral effects and TLR4 antagonism, as well as being a natural compound, it may be a promising candidate in the treatment of COVID-19.

MERS-CoV S glycoprotein induced the expression of the negative regulator of TLR signaling IRAK-M as well as of the transcriptional repressor PPARG. Inhibition of DPP4 by its inhibitor sitagliptin or siRNA abrogated the effects of MERS-CoV S glycoprotein on IRAK-M, PPARG and IL-10, confirming that its immunosuppressive effects were mediated by DPP4 receptor. The effect was observed both in THP-1 macrophages and human primary peripheral blood monocytes.
Earlier evidence has shown that lack of PPARG resulted in increased lethality in mice infected with Influenza virus, and in H3N2 influenza virus infection PPARG was induced via Fatty Acid Binding Protein 5 (FAPB5) to suppress immune responses, supporting the crosstalk of PPARG with viral infection and innate immune responses. A PPARG polymorphism (Pro12Ala) has been associated with sustained response to Hepatitis C Virus. Interleukin-1 Receptor Associated Kinase -M (IRAK-M) levels in peripheral monocytes and macrophages regulate inflammatory responses in humans and in alveolar macrophages but the effect of viral infection on IRAK-M expression has not been previously demonstrated. Analysis of genetic variants of IRAK-M has only been performed in association with Systemic Lupus Erythematosus, but no association was found. Thus, our results provide evidence for the crosstalk of IRAK-M and viral infection and support earlier findings on the effect of influenza viruses on PPARG expression and function.
The magnitude of macrophage activation is regulated by multiple factors including the transcription factor PPARG, which is known to suppress production of cytokines and IRAK-M, an inactive IRAK kinase isoform known to suppress TLR signaling.
In the present study, we demonstrated that the DPP4-binding protein of MERS-CoV, the S glycoprotein, altered macrophage responses rendering them hypo-responsive to TLR4 stimulation. This finding indicates that interaction of MERS-CoV S protein with DPP4 initiates signals that suppress macrophage activation supporting an immunomodulatory mechanism of MERS-CoV that may allow viral replication and expansion.
Macrophage activation is regulated at different levels and factors. IRAK-M is an inactive homolog of IRAK kinases and is known to suppress macrophage activation by TLRs thus rendering them hypo-responsive to pro-inflammatory triggers. Expression levels of IRAK-M highlight their responsiveness and are regulated by various factors including lung surfactants as well as TLR ligands and adipokines.
Responsiveness of macrophages is also regulated by the transcription factor PPARG, a transcriptional repressor that can suppress transcription of pro-inflammatory cytokines such as TNF-a and IL-6. Our results showed that MERS-CoV S glycoprotein induced the expression of PPARG providing an additional molecular mechanism for its immunosuppressive action. Given the fact that PPARG is expressed not only in macrophages but also in T-cells and epithelial cells, this mechanism may not be restricted to macrophages.
Our findings demonstrated that indeed the immunosuppressive action of the S glycoprotein is mediated by Dipeptidyl-Peptidase 4 (DPP4) since inhibition of DPP4 by sitagliptin, a DPP4 inhibitor, ameliorated induction of IRAK-M and PPARG. Sitagliptin and other DPP4 inhibitors are known to act as anti-diabetic agents reversing insulin resistance. It is yet unknown whether individuals that are under treatment with sitagliptin are less susceptible to MERS-CoV infection or whether they do not produce as severe symptoms of the disease. Moreover, our findings may propose the use of sitagliptin as a potential treatment of patients with MERS-CoV infection since it may reverse the immunosuppressive actions of the virus.

Toll-like receptors (TLRs) are key players in host defense, homeostasis and response to injury. However, uncontrolled and aberrant TLR activation has been proposed to trigger the onset of certain
psychiatric and neurodegenerative disorders and elicit detrimental effects on the progression and outcome of established disease. Furthermore, TLR-induced neuroinflammation results in a constellation of behavioural changes which include altered appetite, reduced mood, cognitive changes, anxiety and anhedonia (chronic unhappiness which is a main symptom of depression). Accumulating evidence demonstrates potent immunoregulatory effects of the endogenous cannabinoid (endocannabinoid) system, suggesting that this system may represent an important therapeutic target in disorders with a neuroinflammatory component. The most widely studied endocannabinoid, N-arachidonoyl ethanolamine (AEA, also referred to as anandamide), has been shown to modulate neuroimmune responses, including those induced following TLR activation, although the effects depend on conditions under investigation. For example, several in vitro studies have demonstrated that increasing AEA tone, directly or via inhibition of the primary enzyme responsible for its metabolism, the serine hydrolase fatty acid amide hydrolase (FAAH), is associated with attenuation of TLR4-induced production of pro-inflammatory cytokines and mediators such as TNFa, IL-1b, prostaglandins and nitric oxide, while concurrently increasing anti-inflammatory mediators such as IL-10. However, data also demonstrate an augmentation of TLR4-induced pro-inflammatory mediators such as IL-6 by AEA. While some studies have demonstrated anti-inflammatory effects of AEA on TLR4-induced inflammatory responses to be mediated by cannabinoid CB1 and/or CB2 receptor activation and consequential regulation of NFjB and MAPK activation, non-CB1/CB2 receptor mediated effects of AEA on inflammatory processes in vitro have also been reported. AEA also has affinity for and activity at additional receptor targets to CB1 and CB2 receptors, namely the peroxisome proliferator-activated receptors (PPARs), the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and also the novel cannabinoid receptor, G-protein coupled receptor (GPR)55 activity at which may account for the variability in the effects of AEA on neuroinflammatory responses following TLR activation. Similar to in vitro data, in vivo studies have also revealed modulation of TLR4-induced inflammatory responses by AEA. The proposed AEA reuptake inhibitor AM404 has been shown to attenuate TLR4-induced increases in plasma levels of IL-6 and IL-1b, the latter effect mediated by CB1 receptor activation. Furthermore, AM404 or enhancing AEA tone via pharmacological inhibition of FAAH, augmented TLR4-induced increases in plasma TNFa levels, an effect at least partially mediated via activation of PPARG. In the brain, AEA activation of hypothalamic CB1 receptors has been shown to facilitate, while antagonism of the central CB1 receptors attenuates, TLR4-induced increases in plasma TNFa levels. In addition, work from our laboratory has demonstrated that enhancing AEA levels following FAAH inhibition was associated with attenuation of TLR4-induced increases in IL-1b, and increases in expression of suppressor of cytokine signaling (SOCS3), in the hypothalamus. It should be noted that in addition to AEA, related fatty acid amides, N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA), are also metabolised by (FAAH) and shown to be increased following FAAH inhibition. These N-acylethanolamines have been shown to exert potent biological effects on satiety, pain and inflammation and so it cannot be ruled out that some of the effects of FAAH inhibition may be due in part to activity of OEA or PEA, alone or in combination, with AEA. In addition to AEA, OEA has and increasing evidence supports an important physiological role for TRPV1 in the brain. Furthermore, FAAH inhibition can lead to indirect activation/desensitization of TRPV1 and subsequent analgesic effects, anti-inflammatory effects and central effects on mood.
The data demonstrate that the effect of FAAH inhibition on neuroinflammation is mediated directly within the brain and does not involve CB1 or CB2 receptor activation. Rather, a role for central TRPV1 receptors in mediating, at least partially (IL-6), the effects of increased FAAH substrate levels on TLR4-induced neuroinflammation was observed. Furthermore, despite the pronounced effects of increasing FAAH substrate levels on TLR4-induced neuroinflammation, this was not associated with a change in sickness behaviour, but rather tended to attenuate anhedonic-like behaviour. Overall these findings demonstrate an important role for FAAH substrates within the brain in the modulation of TLR4-induced inflammatory responses which may have implications in the treatment of neuroinflammatory disorders.
It is well known that TLR4-induced inflammation is associated with behavioural alterations including fever, hypolocomotion, altered appetite, anxiety and anhedonia. The current data demonstrate that while PF3845 potently attenuates TLR4-induced cytokines in the brain, this does not alter the associated sickness behaviour (hypolocomotion, fever, reduced body weight and food intake). Similarly, recent data have demonstrated that systemic administration of PF3845 does not alter LPS-induced hypothermia in mice, although effects of FAAH inhibition on other sickness-related behaviours have not been reported prior to this study.
Despite this, the data suggest that FAAH inhibition may modulate immune-mediated anhedonia, a core symptom of psychiatric disorders such as depression. A recent study has demonstrated that OEA, but not PEA, attenuates LPS-induced anhedonia, an effect associated with attenuation of cytokine and inflammatory mediators in the brain. Thus, it remains to be determined if one or a combination of the FAAH substrates enhanced following administration of PF3845 is responsible for the anti-anhedonic effects observed here-in, or modulates other immune-related behavioural and physiological responses.
Furthermore, administration of the peripherally restricted FAAH inhibitor URB937 increased FAAH substrate levels peripherally, with slight increases in OEA and PEA, but not AEA, levels in the brain; this treatment regime did not alter TLR4-induced increases in the expression of pro-inflammatory
cytokines. These data suggest that either high levels of FAAH substrates in the brain are required to modulate TLR4-induced neuroinflammatory responses or alternatively, that the increase in levels of AEA within the brain, rather than OEA or PEA, is primarily responsible for mediating the effects on TLR-induced neuroinflammatory responses. Thus, taken together the data indicate that FAAH substrates act to modulate TLR4-, in addition to TLR3-, induced neuroinflammatory responses directly within the brain, rather than via modulation of peripheral immune responses. AEA has been proposed to mediate some of its anti-inflammatory activity by increasing glial production of the anti-inflammatory cytokine IL-10.
FAAH substrates may act to down-regulate or delay glial activation under TLR4-induced neuroinflammatory conditions.
The current findings demonstrate that FAAH substrate-mediated attenuation of TLR4-induced increases in IL-1b and IL-6, is likely not mediated by central CB1 or CB2 receptors, given the lack of effect of i.c.v. administration of selective antagonists for these receptors on the immunosuppressive effect of PF3845. It should be noted that only in the presence of central CB1 or CB2 antagonism did PF3845 attenuate LPS-induced TNFa expression in this study.
However, AEA and FAAH substrates are known to also mediate effects via alternative receptors including the PPARs, TRPV1 and GPR55. For example, AEA-induced activation of PPARG has been shown to inhibit IL-2 release and PPARG was shown to mediate, at least in part, the effect of the putative AEA reuptake inhibitor AM404, on increases in plasma TNFa, induced following systemic TLR4 activation. However, the present findings demonstrated that blockade of either PPARA or PPARG, or the newly classified cannabinoid receptor GPR55, directly within the brain, does not alter FAAH substrate-mediated attenuation of IL-1b or IL-6 following LPS. In comparison, TRPV1 antagonism prevented the FAAH substrate-mediated attenuation of TLR4-induced increases in frontal cortical expression of IL-6, highlighting an important role for central TRPV1 in mediating, at least some of the effects, of FAAH substrates on TLR4-induced neuroinflammation. Several lines of evidence indicate that TRPV1 activation exerts anti-inflammatory effects under a variety of experimental conditions. However, to our knowledge this is the first study to report effects of TRPV1 in the modulation of TLR4-induced neuroinflammatory responses.
It should be noted that in addition to AEA, OEA is a potent TRPV1 agonists/desensitizer. Furthermore, several studies have demonstrated that FAAH inhibition can lead to indirect activation/desensitization of TRPV1, and thus shunting of the effect of AEA and other FAAH substrates onto other receptor targets which in turn mediate analgesic and anti-inflammatory effects. The current data demonstrate that although FAAH inhibition attenuates early neuroinflammatory responses to TLR4 activation, an effect partially mediated by TRPV1, this is not accompanied by alterations in sickness behaviour or anhedonia. Thus, while one or a combination of FAAH substrates may be responsible for the TRPV1-mediated decrease in LPS-induced IL-6 following PF3845, multiple receptors, mechanisms and circuitries are involved in mediating the behavioural responses.
Evaluating the possible receptor mechanisms revealed that the effects are independent of central cannabinoid receptors (CB1, CB2, and GPR55) or PPARs (PPARA/G) but rather demonstrate for the first time a role for central TRPV1 in partially mediating FAAH substrate-mediated modulation of TLR4-induced neuroinflammation.
In my opinion FAAH inhibitors not only reduce anhedonia and depression, but also sickness behavior even if to a lesser degree. I also think that contrary to the article FAAH works peripherally in my case.

It may be particularly interesting that Berberine [500 mg – pills] definitely works in my case even if not to the extent as saffron or MACA. This was rather unexpected, but later I found a possible explanation why this could be so. I am going to discuss this in my upcoming post.


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Re: FAAH Inhibitors
« Reply #9 on: April 13, 2021, 02:55:36 PM »
I think I have good experience with two of the things you posted :)

Saffron and Cordyceps and Maca. Thank you for bringing this clue to me.

I take it in a supplement combined with other well known things (Fenugreek, Citrullin, Ginseng, Zinc, tribulus, Selenium, Histidin).
I'll report more on this sometime later.

I remember in another thread Quantum posted that he does not want to take things which boost libido, worried that it might end up giving him POIS, but I think this might not actually be a problem.


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Re: FAAH Inhibitors
« Reply #10 on: April 15, 2021, 09:48:52 AM »
I think I have good experience with two of the things you posted :)

Saffron and Cordyceps and Maca. Thank you for bringing this clue to me.

I take it in a supplement combined with other well known things (Fenugreek, Citrullin, Ginseng, Zinc, tribulus, Selenium, Histidin).
I'll report more on this sometime later.

I remember in another thread Quantum posted that he does not want to take things which boost libido, worried that it might end up giving him POIS, but I think this might not actually be a problem.

I was also checking out your posts just the other day and I think the same even if we have slight differences. I bought a lot of stuff in the previous months (amongst them are Rhodiola rosea, fenugreek, citrulline malate and melatonin), but I didn't have the time to test out many things as I had the coronavirus for weeks and only used stuff that I had known to work. However I still got some results that may be of interest.

I haven't tested Rhodiola rosea (goldenseal) yet, but it contains berberine and Berberine pills definitely work for me even when used as an only supplement. The one I use have 500 mg berberis root extract standardized on 2 % berberine which is 10 mg per pill. The recommended daily dosage is one pill, but I used 3 pills in conjunction with an O without problems, although I don't know about the long term effects. I used it alone taking it one hour before and after O and also one before I went to sleep. Its overall effectiveness is not that great as of saffron or MACA, but nevertheless it works. It seems especially good in reducing red eye symptom. It could generally stop POIS to become systemic, but I still developed some chest pain. I could take berberine safely alongside saffron and MACA.
I was rather surprised as I expected it to enhance POIS as a PPARG agonist. Of course I haven't confirmed anything yet, so it could be my mistake to think so, but I also found out later that it actually inhibits FAAH, although indirectly through the stimulation of IL-12 release.
I can only encourage anyone to read this article by the way as it is about autoimmune diseases and looks to be highly interesting in relation to our case.
According to the knowledge available up to now, within the complexity of the neuroimmunology, it is possible to identify two major neuroendocrine functional systems involved in the psychoneuroendocrine regulation of the immune system, consisting of the brain opioid system-pituitary axis and the brain cannabinergic system-pineal axis, respectively provided by an immunosuppressive and an immunostimulatory role.
In contrast to the mu-opioid agonists, which inhibit IL-2 and IL-12 secretions and stimulate IL-10 release, CBD has been proven to stimulate IL-12 and IL-2 secretions and to inhibit that of IL-10, by improving the antitumor immunity, which is stimulated by IL-2 and IL-12, and inhibited by IL-10 and TGF-beta.
IL-2 deficiency and IL-6 high levels may be treated by MLT, while on the other side IL-12 deficiency and IL-10 enhanced secretion may be treated by CBD.
As far as the autoimmunity is concerned, the autoimmune disease-related enhanced production of IL-17 may be controlled by the cannabinoid agonists, including the endogenous ones, THC, and CBD itself, because of its inhibitory action on FAAH activity, even though it is not a direct cannabinoid agonist. Then, THC would be more effective in the treatment of autoimmune diseases, since autoimmunity-related chronic inflammation would be mainly depend on IL-17 abnormal secretion, which is inhibited by THC, whereas CBD could be particularly appropriate in cancer cure by counteracting IL-10-dependent suppression of the antitumor immunity and stimulating IL-12-dependent anticancer immunity. The secretion of IL-12 has been proven to be also stimulated by berberine. Then, the immunomodulating properties of CBD could be further enhanced by a concomitant administration of the pineal hormone MLT, because of its ability to stimulate IL-2 secretion from TH1 lymphocytes, or its direct cytotoxic effects against most cancer cell lines.
On the other hand IL-2 may either enhance or inhibit the autoimmune processes, since it may either activate the macrophage system with a following enhanced production of inflammatory cytokines, namely IL-6 itself, or stimulate T reg system in the presence of high concentrations of TGF-beta.
IL-12 may either stimulate autoimmunity-related inflammatory response by promoting TH1 differentiation and a consequent enhanced IL-2 release, or inhibit TH17 functions, with a consequent diminished production of IL-17, which has appeared to be one of the most important cytokines in determining the autoimmune reactions. Finally, the immunosuppressive effects of mu-opioid agonists, including morphine, consisting of inhibition of IL-2 and stimulation of IL-10 secretion, could be potentially therapeutic in the autoimmune diseases, but the potential stimulatory effect of mu-opioid agonists on IL-17 secretion could verify the benefit due to their inhibition on IL-2 and stimulation on IL-10.
At present, it becomes possible to interpret cancer cure as a simple reestablishment of the functions of cytokine network on the status of health, consisting of a perfect equilibrium between immunostimulatory and immunosuppressive cytokines, since a prevalence of immunostimulatory cytokines may allow autoimmune pathologies, whereas an exaggerated production of immunosuppressive cytokines may predispose to cancer development.
Unfortunately, despite the great number of experimental studies confirming the immunomodulating properties of some neurohormones or neuroactive molecules, namely MLT, CBD, THC, and mu-opioid antagonists, very few clinical studies have been performed up to now to evaluate the real effects of their possible combinations as a neuroimmune approach in the cure of systemic diseases, including cancer and autoimmune diseases, in an attempt to correct cancer and autoimmunity-related alterations in cytokine secretions by acting on the neuroendocrine regulation of cytokine network itself, instead of a direct artificial action on the immune effects of cytokines, as in the immunotherapy with monoclonal antibodies.

It is also true that saffron itself actually down-regulates IL-12, but it is still a FAAH inhibitor nevertheless.

I also had positive experiences with Tribulus terrestris, although not as much as with MACA. As I indicated earlier this could be due to the different packaging (pill vs capsule). I found a site where I can buy some empty capsules and I also plan to test berberine in a capsule form. Tribulus terrestris and MACA both enhance testosterone, but I am not sure about its role anymore so I still need to test this further.

This may explain why zinc works, although I have special problems with it. I haven't tested it much, so I don't really know how it affects my POIS.
NAPE-PLD is an enzyme that catalyzes the release of N-acylethanolamine (NAE) from N-acyl-phosphatidylethanolamine (NAPE). This is a major part of the process that converts ordinary lipids into chemical signals like anandamide (AEA) and oleoylethanolamine (OEA).
NAPE-PLD was found to have no homology to the known phospholipase D genes, but can be classed by homology to fall into the zinc metallohydrolase family of the beta-lactamase fold.
...leading the authors to propose that activity should be correlated with zinc content.
NAPE-PLD knockout mice have been reported to have wild-type levels or very reduced levels of anandamide.
Bile acids bind with high affinity to selective pockets in this cavity, enhancing dimer assembly and enabling catalysis. NAPE-PLD facilitates crosstalk between bile acid signals and lipid amide signals.

I don't have any problems with selenium and I also take it from time to time, but I haven't specifically tested it against POIS. A few years ago I bought a selenium supplement and if I remember well I felt a bit better while taking it, but it is certainly not very potent, otherwise I would have realized it at the time.

I also used a Ginseng supplement a few years ago and it also had a weak positive effect, but I stopped using it as it was nothing major and I needed the money for other things. I will retest it later, but it has a low priority on my list.

I also found another tea that works especially well. The herb is called lungwort (Pulmonariae officinalis). It may not be available everywhere, but it is rather cheap. It also contains kaempferol, quercetin, apigenin and rosmarinic acid etc, so it is filled with the good stuff.
When I first tried lungwort I even had a weak-moderate "regular" chest pain, but it appeared after an O, so it wasn't a post-covid symptom. I ate a lot of cakes with walnuts and it probably contributed too. So it turns out that lungwort works really well. I drank about 1 liter of the tea and after an hour my chest pain was greatly reduced. The concurrent depression was also blown out of my mind and I felt really great generally. After a few hours the chest pain reintensified somewhat which shows how perpetual POIS is.
The only side effect was a severe non-burning flatulence. This can be inconvenient, but still better than the other symptoms. Maybe I should try to use some simeticon in conjunction as it also helped somewhat if I remember well. I don't regularly use saffron, but its effectiveness also became weaker after several use, however this side effect was also reduced. Still I don't think it will lose its effectiveness completely as MACA capsules still work even after half a year.
Brantner and Karting, based on thin layer chromatography (TLC) identification, reported on the presence of quercetin and kaempferol glycosides. A fingerprint of methanol extract of P. officinalis obtained using micro-two-dimensional TLC, indicated the presence of chlorogenic acid, myricetin, acacetin, glycosides of apigenin, quercetin (rutin and hyperoside), hesperetin (hesperidin), and naringenin (naringin). Furthermore, based on HPLC analysis, Neagu et al. reported that rosmarinic acid was the main constituent of both aqueous and ethanolic extracts obtained from P. officinalis, moreover small amounts of rutin, hyperoside, chlorogenic, and caffeic acids were also detected. Our research revealed that P. officinalis extract contains yunnaneic acid B—a unique molecule that has been isolated so far only from Salvia yunnanensis, and also confirmed the presence of large amounts of rosmarinic acid.

I read through the Physalis thread and I ought to try that too. If anyone checks the first link Muon provided in his comment you can see that besides other compounds Physalis contains rutin, myricetin, quercetin and kaempferol.

Although I had a positive surprise with Berberine I had an unpleasant one with Kudzu.
Kudzu [500 mg per capsule] is marketed as a supplement to help in the treatment of nicotinic and alcoholic withdrawal symptoms. Research points out that this effect is mainly due to the isoflavones it contains, namely daidzin and daidzein. It also contains genistein in a smaller amount. As daidzein and genistein are FAAH inhibitors I had high hopes for it, however it turned out to be in vain.
Actually I am not really sure what Kudzu does as it is rather elusive. Two times out of five it gave me a sharp headache. One of this occasion was when I took two capsules and nothing else. The first time I took it with MACA it gave me acute POIS, but at an other time almost nothing happened. It didn't do anything to depression even when I took two capsules. I think Kudzu generally enhances my POIS (some burning pain), but it doesn't do this very apparently. I will have to try some other supplements containing daidzein and/or genistein to shed some light on the matter.
Based on the data obtained thus far, we propose that the antidipsotropic (antialcohol abuse)  isoflavones suppress ethanol intake by modulating activity of the central reward pathways through inhibiting the catabolism of monoamine neurotransmitters, such as serotonin or dopamine.

Some other teas I tried in the meanwhile:
Rosemary tea (one liter) had mixed effects, but mainly beneficial.
I found a site that sells pharmaceutical quality rosmarinic acid oil, but I am currently low on funds.
Nevertheless I need to test it as lemonbalm (Melissa officinalis) and lungwort (Pulmonariae officinalis) also contains rosmarinic acid in somewhat greater amounts.
Sage tea (one liter) had mixed effects, but mainly detrimental in regard of POIS.
Sennae tea [1 deciliter!] is quite dangerous. First I only drank 1 deciliter and soon my stomach was rumbling which is usually not a good sign so I didn't drink any more. I think this is the only reason I avoided a severe diarrhea. Besides this it gave me really smelly farts in the next 12 hours. However in my opinion it didn't actually do anything to POIS. So unless someone has a really-really severe constipation I wouldn't recommend its usage and even then one should be careful with it.
Hibiscus sabdariffa (roselle) tea (one liter) didn't seem to do much in short term although I think it caused some bowel pain later. It was one of the first days of my covid-19 infection when I tried this so I will have to test it again of course. By the way Hibiscus down-regulates PPARG activity so it is important to know if it does anything interesting. It is rather strange how it helps diabetics even though they have an already down-regulated PPARG.
Hibiscus sabdariffa with worldwide distribution is a powerhouse of phytochemicals viz. polyphenolics, especially anthocyanins. The nutritional abundance imparts it antioxidant, hypocholesterolaemic, antiobesity, hypotensive, antidiabetic, immunomodulatory, anticancer, hepatoprotective, antimicrobial, renoprotective, diuretic and anti-urolithiatic properties.
Oral administration of the extract reduced fat tissue accumulation, diminished body weight gain and normalized the glycaemic index as well as reduced dyslipidemia. Also, the extract treatment attenuated liver steatosis, downregulated sterol regulatory element-binding transcription factor 1 (SREBP-1c) and peroxisome proliferator-activated receptor-gamma (PPARG), blocked the increase of IL-1, TNF- mRNA and lipoperoxidation and increased catalase mRNA.
When combined with chrysanthemum, butterfly pea and mulberry extract, it exerted additive intestinal maltase inhibition. On the other hand, its combination with chrysanthemum and mulberry caused synergistic inhibition of pancreatic -amylase.

It may still turn out that FAAH inhibition only contributes to the reduction of POIS inflammation, but is not a requirement for it. I found a great article about the targets of some of the best working compounds and one can see clear parallelisms.
Kaempferol in itself is a real all-rounder and has many common traits with quercetin.
Kaempferol inhibits COX-1, COX-2, LOX, agonist of PPARG, Nrf2, downregulates NF-kB, modest inhibitor of FAAH and it also has anti-cholinesterase activity and lowers amyloid-B formation.
Although this table is very informative it is not complete as both apigenin and quercetin are also FAAH inhibitors.
Besides the well known factors the agonism of Nrf-2 also seems interesting as it is indicated in both inflammation and COVID-19 pathogenesis. However curcumin and sulforaphane are also Nfr2 agonists and they still don't have a major effect on my POIS. Maybe I should combine them and see what they do.
It could be that kaempferol, quercetin and apigenin works so well because they do all of these things in conjunction. The beneficial compounds probably have a cumulative effect, but synergism can't be ruled out which could really enhance the overall effect. So even though lime (Tilia) tea contains kaempferol and quercetin, it may not be enough to make it really potent.  Lungwort contains quercetin, kaempferol, apigenin, rosmarinic acid and even more which could make a real difference. The same may be true for saffron.
PPARG modulation still seems to be the only connection amongst the compounds that enhance (deteriorate) my symptoms. For one this is problematic as they can conceal and antagonise the positive effects and the official literature is also somewhat contradictory regarding some of the compounds. Probably this is the reason why rosemary is not clearly beneficial and this could be the case with Kudzu if Genistein turns out to work.

The tables detail the targets of some flavanoids amd terpenoids of interest.

« Last Edit: May 11, 2021, 01:51:42 PM by Progecitor »


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Re: FAAH Inhibitors
« Reply #11 on: April 15, 2021, 09:59:12 AM »


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Re: FAAH Inhibitors
« Reply #12 on: April 15, 2021, 03:54:23 PM »
Quercetin Phytosome (Absorption)

Thanks for the information! I plan to try some quercetin capsules, but it is not on top of my priority list. The product you recommend could be really good. It is true that a higher peak concentration would not only make the effects stronger, but it would also result in a slower concentration drop and a longer effect which is desireable as my symptoms never stop. I will keep this in mind if I can gather the funds.


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Re: FAAH Inhibitors
« Reply #13 on: April 21, 2021, 01:16:07 AM »
The endocannabinoid (eCB) system is an important regulatory system of the central nervous system that regulates neurotransmission and synaptic plasticity and plays an important role in emotional and social responses and cognitive function.
CB1R activation is important for cognition and memory and modulates other physiological activities by regulating neurohormone levels and signal transduction. CB2R, which mainly has an immunomodulatory role in the body, is distributed in peripheral immune organs or tissues such as the spleen margin and thymus.
CB1R plays an acute/short-term regulation of the growth cone signal at the neurite tip and has a long-term effect on neural gene expression that affect neuronal wiring and overall connectivity. Activated postsynaptic neurons release eCBs into the synaptic cleft; these eCBs serve as retrograde messengers by acting on presynaptic CB1R and inhibit neurotransmission by one of two mechanisms: by blocking calcium influx in the case of glutamate, gammaaminobutyric acid (GABA), monoamine, and acetylcholine; and by targeting cyclic (c)AMP-protein kinase A signaling associated with long-term depression (LTD) through inhibition of adenylate cyclase-mediated control of cAMP levels. These processes in turn affect the activation of synapses and the transmission of excitatory and inhibitory signals, which are closely related to synaptic plasticity. After entering the cell, eCBs are transported to their target by eCB intracellular transporters such as FAAH-1 cannabinoid transporter, fatty acid-binding protein, and heat shock protein 70, among others. In addition, peroxisome proliferator-activated receptors (PPARs) on the nuclear membrane belonging to the ligand-activated nuclear hormone receptor family can bind eCBs, resulting in conformational changes in the receptor that ultimately lead to repression of eCB-related genes and increased production of intracellular reactive oxygen species such as O2?.
Plasma and cerebrospinal fluid AEA levels are higher in patients with schizophrenia than in normal control.
However, other studies have arrived at the opposite conclusion: one study suggested that eCBs can be used to treat schizophrenia by alleviating white matter deficits in glial cells as well as damage resulting from glutamate toxicity.
Circulating plasma levels of eCBs are reduced in patients with mild depression and chronic post-traumatic stress syndrome.
Hyperactivation of the hypothalamic–pituitary–adrenal (HPA)-axis has been implicated in the pathophysiology of depression. Blockers of FAAH and TRPV1 that increase AEA levels were shown to normalize HPA axis function and improve depression symptoms in Wistar rat.
eCBs are an effective auxiliary treatment for epilepsy.
eCB system is associated with Fragile X Syndrome and can be a promising therapeutic target.
Generally known that the most famous explanation for Alzheimer’s disease is the dopamine hypothesis. A recent study reported an interaction between dopamine and eCBs.
ECB ligands are derived from polyunsaturated fatty acids (PUFAs) in neuronal cell membranes and act on presynaptic membrane receptors to inhibit neurotransmitter release from presynaptic neurons, thereby modulating synaptic plasticity.
The eCB system may be one of the hubs for the association of PUFA metabolism with neuronal development. Recent studies have revealed that defects in n-3 PUFAs inhibit eCB-associated synaptic plasticity in vivo.
At the same time, the deficiency of n-3 PUFAs also decreased the synaptic regulation function of CB1R in mice.

It is suggested that the lack of n-3 PUFAs diet may lead to synaptic plasticity damage and learning and memory impairment in neurons, which may be due to the decrease in the inhibitory effect of the eCB system on neurotransmitter release.
Some population experiments showed that the decrease of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and AA was related to cognitive impairment, which affected social function.
When BTBR mice—which are frequently used as an ASD model—were given selective FAAH inhibitor to increase the activity of AEA, social deficits associated with ASD were abolished.
Down regulation of PPAR and GRP55 has also been reported in VPA rats. Although it is unclear how this relates to social behavior, recent data suggest that activation of hippocampal PPAR can improve cognitive performance.
Therefore, the down regulation of PPAR may lead to decreased cognitive ability and impaired social behavioral responses in ASD.
Glutamate excitotoxicity and inflammation are thought to be involved in the development of ASD, and PEA has been shown to simultaneously prevent glutamate toxicity and inhibit inflammatory responses.

My relationship to sex is like cocaine, although I haven’t tried that.
One possible mechanism of this association was elucidated in studies that found that FAAH mutant genotype exhibit increased reward-related ventral striatal reactivity in comparison to control subjects.
Given the evidence that the FAAH gene plays a role in modulating subjective mood as well as addiction pathways, we hypothesized that the FAAH variant is associated with alterations in subjective effects produced by cocaine in the laboratory.
It is generally agreed that the initial rewarding effects of many drugs are an elevation in mood and affect. In Pro129Thr variant allele carriers, the observed overall increased subjective effects to drug administration ("Effect" and "High") may help explain why there has been an increased risk of addiction found in this population. Another possibility is that substance-induced dysphoria incites further substance use, leading subjects into a cyclic negative reinforcement model. In this cycle, the negative effects on mood (ie, "Sad") that accompany cocaine use drive users to seek out more substance as a coping mechanism to reduce this dysphoria. Such a process has been described in detail by Dr. George Koob, who hypothesized that chronic excessive DA release produces activation of dynorphin systems, which feedbacks to decrease DA release and mediate dysphoric states seen in cocaine addicts. In FAAH variant carriers, these negative mood states appear to intensify.

Marijuana and its major psychotropic component, THC, were found to stimulate appetite and increase body weight in wasting syndromes. Additionally, endocannabinoids have been involved in the control of energy balance and food intake and their effects have been described as mainly CB1–mediated, since they are antagonized by SR141716A.
They may also stimulate lipogenesis and fat accumulation. Therefore, endocannabinoids add to the list of the numerous neurotransmitters and neuropeptides involved in the physiological control of appetite and satiety. In particular, 2-AG has been described to stimulate feeding in a potent and dose-dependent manner, effect blocked in part by the action of SR141716A.
Interestingly, the neurohormone leptin, which is the main regulator of the hypothalamic orexigenic and anorectic signals, exerts a negative control on the AEA and 2-AG levels. Considering the role played by endocannabinoids in the intricate network that regulates feed control, the manipulation of their levels could offer useful approaches to the treatment of eating disorders as well as metabolic syndromes.
These effects have been linked to CB1 receptor activation, considering that CB1 is expressed in these prostate cancer cell lines as well as in the human prostate gland (at a level comparable with the CB1 expression in cerebellum) where it negatively regulates adenylyl cyclase activity.
The brain reward system constitutes another point of interest for 2-AG since it has demonstrated a remarkable capacity to attenuate the naloxone-precipitated withdrawal signs in morphine-dependent mice. This result is in agreement with the proposed upregulation of cannabinoid CB1 receptors in morphine dependence, and it supports the hypothesis that either accelerators of endocannabinoid synthesis or inhibitors of its degradation may have a therapeutic potential to treat opiate withdrawal symptoms. The profound changes that the ECS undergoes during the different phases of sensitization to morphine in rats provide a possible neurochemical basis for this cross-sensitization between opiates and cannabinoids. Moreover, 2-AG could play a role in alcohol addiction and in addictions to other drugs such as marijuana, nicotine, and cocaine by activation of the same or related reward pathways.
2-AG as well as anandamide could mediate opioid-independent stress-induced analgesia. Another aspect of interest is the presence of the CB1 receptor and both AEA and 2-AG in ocular tissues. Cannabinoids have shown capacity to reduce the ocular hypertension and, in particular, topical application of anandamide was shown to decrease the intraocular pressure in normotensive rabbits. Moreover, topical administration of 2-AG and noladin ether also decreased intraocular pressure in rabbits, reduction that has been attributed to the CB1 receptor. These effects could be of direct application in glaucoma, the disorder characterized by a pathological enhancement of the intraocular pressure. In this regard, the levels of 2-AG and N-palmitoylethanolamine have been found to be significantly decreased in the ciliary body in eyes from patients with glaucoma, further supporting the role of these endogenous compounds in the regulation of intraocular pressure.
Finally, the role of 2-AG in the immune system and in particular its effect on the motility of human natural killer cells should be noted, 2-AG induces the migration of KHYG-1 cells (a natural killer leukemia cell line) and human peripheral blood natural killer cells. This migration can be blocked by the presence of the CB2 antagonist SR144528, and interestingly, it does not occur in the case of AEA or THC. Accordingly, it has been suggested that 2-AG could contribute to the host-defense mechanism against infectious viruses and tumor cells.

An overexpression of MAGL could similarly lead to a kind of endocannabinoid depletion.

Thus, substitution of the glyceryl moiety by a thienylmethyl group as in CAY10402 abolishes MAGL activity while keeping a low FAAH inhibitory potency (IC50 = 10 ?M). Within this category fall a couple of old known compounds, N-(4-hydroxy-2-methylphenyl) arachidonamide (VDM11) and N4-(hydroxyphenyl) arachidonamide (AM404). Originally proposed as anandamide uptake inhibitors, they are also FAAH inhibitors. This work reveals that AM404 and its analogue VDM11 inhibited the metabolism of anandamide by rat brain FAAH equipotently (IC50 = 2.1 and 2.6 ?M, respectively) and to a lesser extent the degradation of 2-OG by cytosolic MAGL (IC50 = 21 and 20 ?M, respectively).

Indian mulberry may refer to Morinda citrifolia also called noni, beach mulberry, and cheese fruit. Morinda citrifolia (Noni) Fruit Juice Inhibits Endocannabinoid Degradation Enzymes.
Morinda citrifolia (noni) fruit juice has been shown to have a wide variety of potential health benefits in human clinical trials. It may also influence the endocannabinoid system of the body. Since the main ingredient of the product studied in these clinical trials was juice made from noni fruit puree from French Polynesia, it was evaluated for its ability to inhibit the two major endocannabinoid degradation enzymes in vitro. Noni fruit juice inhibited both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) in a concentration-dependent manner, suggesting that it may help maintain anandamide and 2-arachidonoylglycerol levels. Samples of the puree were also analyzed for the presence of characteristic phytochemical markers of authentic noni fruit such as scopoletin, rutin, quercetin, deacetylasperulosidic acid and asperulosidic acid, all of which were present. Also present was scandoside, which is reported for the first time as being identified in noni fruit or its juice. Some of these compounds may contribute to the FAAH and MAGL inhibiting activity of noni juice. These results reveal another set of mechanisms by which noni juice possibly supports mental health, maintains joint health, relieves discomfort and modulates the immune system.

This can probably rule out 2-AG in my case.
N-3-methoxybenzyl-linoleamide is one of the most active FAAH inhibitors from the Maca plant and was studied to evaluate and characterize its FAAH and MAGL inhibitory activity using in vitro assays. The results demonstrate a time-dependent and mixed inhibition on FAAH, while no inhibitory effect was observed on MAGL. Maca is known to contain macamides (alkamides), alkaloids, isothiocyanates, polyunsaturated fatty acids (macaenes), sterols, glucosinolates, amino acids, minerals, and vitamins. Naturally occurring and synthetic alkamides have been found to possess in vitro neuroprotective effects in rat neuroblastoma cells and in animal models of stroke.

Cyanidin-3-O-glucoside, also known as kuromanin, is one of the most important anthocyanins in nature. The scope of this paper is to discuss the potential role of this anthocyanin as therapeutic agent to prevent or treat chronic diseases in which oxidative stress may be involved through a modulation of certain enzymes.
Cyanidin-3-O-glucoside inhibited MAO-A, TYR and FAAH enzymes whereas it could not inhibit AChE activity. IC50 values for these assays were 7.6??M, 18.1??M and 152.1??M, respectively. Additionally, cyanidin-3-O-glucoside was able to inhibit ?-GLU (IC50?=?479.8??M) and DPP-4 (IC50?=?125.1??M). Finally, the antioxidant activity of cyanidin-3-O-glucoside was confirmed by the xanthine/xanthine oxidase method, being more efficient than gallic acid as superoxide radical scavenger. In conclusion, cyanidin-3-O-glucoside has demonstrated to be a candidate as enzyme inhibitor with neuroprotective, antioxidant and antidiabetic potential.

Supplementary Table 3. on the last pages contains an extensive list of plants with FAAH inhibitory property.

I have rechecked the covid-19 article about arachidonic acid (AA) for some further information.
Subjects with obesity, hypertension, type 2 diabetes mellitus (DM) and coronary heart disease have low plasma concentrations of AA, whereas elderly have decreased activity of desaturases that results in low plasma levels of AA and low LXA4 levels. This may explain why these subjects have severe COVID-19 and are more prone to cytokine storm and resultant mortality.
This implies that there are two phases in the pathobiology of COVID-19, the first one is characterized by hyperinflammation that may happen in the beginning of COVID-19 and the second phase could result in immunosuppression with little or no change in the levels of pro-inflammatory cytokines as in sepsis.

FAAH is also over-activated in DM.
As the eCB system is also involved in diabetes mellitus, some medications like tropisetron and glibenclamide may be worthwhile to test if they become available.
The CB1 receptor is widely expressed in the central nervous system and peripheral tissues such as the liver and its activation increases the level of reactive oxygen species (ROS) and inflammatory mediators.
It has been shown that in the liver of hypertensive rats an increase in the activity of FAAH is related to inflammatory conditions as well as oxidative stress.
Diabetes caused a significant reduction of CB1 receptor protein levels in the liver of male rats in comparison with the control group. Treatment with tropisetron and glibenclamide for two weeks reversed these protein levels.
Diabetes was associated with a significant decrease (p < 0.001) in CB1 receptor and a significant increase (p < 0.001) in FAAH enzyme gene expression compared to the control group.
Moreover, structural protein degradation in the target tissues of insulin in diabetic subjects is fundamentally associated with a sudden weight loss.
Rahimian et al. reported that tropisetron-induced calcineurin inhibition, a pivotal enzyme in the inflammatory process, might underlie the alteration in CB1 receptor expression.
In contrast to our study, with a lower CB1 receptor expression, increased CB1 receptor levels have previously been reported in hepatic tissues and some other organs in streptozotocin-treated rats.
Down-regulation of the CB1 receptor is accompanied by an increased level of endocannabinoids, which contributed to oxidative stress, inflammatory status, and subsequently the activation of caspase3 and apoptosis.
In addition, it seems that an increase in endocannabinoid biosynthesis enhances the activity of the main enzymes degrading endocannabinoids such as FAAH which is probably due to the feedback mechanism in response to an increased level of the anandamide (AEA).
FAAH is a major degrading enzyme of the AEA which participates in controlling tissue injury, partly mediated through the activation of cannabinoid receptors by endocannabinoids.

Linoleic acid, a common component of dietary fat, and its metabolic derivative, arachidonic acid (AA), have both been associated with prostate tumor progression.

Guineensine is a natural benzodioxole-alkenyl-N-isobutylamide derivative isolated from Piper nigrum. As described by Nicolussia and coworkers guineensine is a new nanomolar inhibitor (EC50= 290 nM) of cellular uptake of the endocannabinoid anandamide, through a mechanism of action that doesn't involve inhibition of endocannabinoid degrading enzymes such as fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL). Despite its ability to induce cannabimimetic effects in BALB/c mice, such as catalepsy, hypothermia and analgesia activity, it is not able to interact with cannabinoid receptors or fatty acid binding protein 5 (FABP5), a major cytoplasmic AEA carrier, revealing an intriguing mechanism of action that should be better elucidated.

All major ECS components have been found in female and male reproductive systems, and eCB levels in tissues and body fluids hold promise as disease biomarkers. Of note, the presence of a high concentration of AEA in follicular fluid is indicative of mature follicles, and significant differences of AEA and PEA in serum, and of OEA in follicular fluid, have been recorded between infertile and fertile women. Furthermore, dysregulation of the ECS has been observed in polycystic ovary syndrome (PCOS) onset, as well as in altered human endometrial stromal cell decidualization.
An essential role for GPR55 activation in the Ca2+-dependent regulation of human sperm motility and capacitation has been proposed.

Inhaled anandamide has been shown to attenuate leukotriene D4-induced airway obstruction in guinea pigs. Mice lacking CB1, CB2, or both, and those treated with a CB receptor antagonist displayed exacerbated T-cell-mediated allergic skin inflammation. The inflammatory response was attenuated in animals lacking the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH) and in those treated with CB receptor agonists. These observations suggest that anandamide release could serve as an inhibitory feedback mechanism restraining airway obstruction and inflammation in allergic asthma. We hypothesized that pulmonary anandamide concentration increases with experimental allergen exposure.


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Re: FAAH Inhibitors
« Reply #14 on: April 22, 2021, 02:09:54 AM »
Some thoughts on the Nrf2 inflammatory pathway. It may be involved in my case, but I don't think it is the root cause for me. However it may be important in other cases especially if both sulforaphane and curcumin prove effective.

The genes that are involved in the NF-kB signaling pathway were found to be upregulated, along with increased levels of cytokines and inflammatory markers, showcasing the involvement of this pathway in the hyperinflammatory response in patients with COVID-19. NF-kB (nuclear factor kB) is a family consisting of inducible transcription factors that regulate the genes involved in immune and inflammatory responses. These normally exist in the cytoplasm in a sequestered form by inhibitory proteins that include the IkB family and some other related proteins.
Nrf2 (nuclear factor erythroid 2 related factor-2) is a transcription factor that forms the genes coding for various enzymes that protect the cells from oxidative or electrophilic stress. It also transcriptionally represses inflammatory genes that regulate the inflammatory response. Normally, Nrf2 exists in bound form in the cytoplasm with its inhibitor, Keap1. When the cell is under stress, electrophile or ROS (reactive oxygen species) generation leads to dissociation of Nrf2-Keap1 complex and Nrf2 migrates into the nucleus to stimulate the transcription of a multitude of genes that are involved in redox homeostasis and anti-oxidant response. Biopsies in COVID-19 patients have revealed that genes associated with Nrf2 anti-oxidant response were suppressed in these patients. Also, in vitro experiments showcased that the Nrf2 inducible proteins expression was also downregulated that tells the suppression of this pathway in COVID-19 patients. A study on Nrf2 activator showed that it downregulated 36 genes that encode cytokines resulting in a decrease in the cytokine storm in COVID-19.
All the above studies point to the involvement of Nrf2 and NF-kB in the pathogenesis of COVID-19. Since one of the mechanisms of neurological complications is through immune injury by the cytokines, the involvement of these signaling pathways in these complications can be well attributed. A study on transgenic mice also revealed that when the Nrf2 pathway was activated, it suppressed oxidative stress and improved the cognitive function of mice. When the pathway was blocked, it resulted in oxidative injury and a decrease in the viability of neurons. As this pathway is reported to be downregulated in COVID-19 patients, this could be one of the possible causes of cognitive decline.

NF-kB Pathway and COVID-19
The NF-kB (nuclear factor k-light-chain-enhancer of activated B cells) transcription factor family is a pleiotropic regulator of many cellular signaling pathways which provide mechanisms for stimuli that link to inflammation. It influences the growth of axons and dendrites originating right from the earliest stages of neuron establishment. A lipopolysaccharide receptor complex is formed by toll-like receptors and the adaptor proteins present in the extracellular matrix. The signal pathway leads to activation of NF-kB. The blood–brain barrier prevents the entrance of immunogenic cells into the central nervous system. The stimulated cells will be regulated by not only the canonical but also non-canonical NF-kB pathways. Besides neurons, NF-kB transcription factors are abundant in glial cells and cerebral blood vessels, and the diverse functions of NF-kB also regulate the inflammatory reaction around the neuronal environment. NF-kB transcription factors are abundant in the brain and exhibit diverse functions. The pathogenesis of COVID-19 is similar to earlier discovered viral disorders namely cytomegalovirus, MERS, and varicella. Similarly, COVID-19 can cause activation of the NF-kB pathway which ultimately may lead to stroke or neuropathy associated with thromboembolism in the brain. The heightened immune response specially, the cytokine storm is characterized by an elevation in IL-6, IL-10, IFN-g, and TNF-a in the granulocyte colony–stimulating factor. The genetic induction of innate and adaptive immunogenic cells is influenced by NF-kB. Deregulated activation leads to activated T-cells in association with autoimmune inflammation and inflammasome release. In a preclinical study, NF-kB influenced the regulation of various proinflammatory mediating chemicals. When inhibitors of NF-kB like parthenolide were administered, a reduced infection was seen. The NF-kB transcription is unmasked by the degradation of IkB which is phosphorylated by protein kinases activated by mitogens. The upregulated proinflammatory genes result in excessive cytokine and reactive oxygen species which cause cerebellar damage and neuropathogenic dysregulation associated with neurotransmitters.

Nrf-2 and COVID-19
Nrf2 belongs to the basic leucine transcription factor and influences oxidative stress by expressing antioxidant genes. Nrf2 remains situated in the cytoplasm wherein it binds with keap1, which is a known inhibitor of Nrf2. When reactive oxygen species emerge, the Keap1-Nrf2 complex gets dissociated and as a result, Nrf2 migrates towards the nucleus leading to stimulation of target genes eliciting an antioxidant action whose activation enforces protection from inflammation. Upregulation in expressing Phase 1 and 2 drug-metabolizing enzymes in addition to the mitochondrial pathways is also a characteristic of this pathway. The upregulated target genes include glutathione S-transferase, catalase, heme oxygenase 1, and superoxide dismutase. These protect neuron function from oxidative degradation. All primary factors including oxidative degradation, inflammatory upregulation, and dysfunctional mitochondria contribute to aging of brain which exposes patients at a risk of neurodegenerative diseases. Nrf2 can prove to be beneficial in case of COVID-19 infections due to its attractive efficacy against such pathologies. To eradicate stress induced by oxidative species, Nrf2 is released, stabilized, and translocated. Nrf2 acts as an on-off switch and produces endogenous antioxidative relief. Several kinases like phosphoinositol-3 kinase, protein kinases, and pancreas enriched kinase also act as regulators of Nrf2 activity. Mitogen-activated protein kinases are enzymes that contain protein kinases regulated extracellularly. They catalyze the phosphorylated reactions on the amino acid serine, threonine residues which reside right next to the proline amino acid. The mitogen-activated protein kinase pathway works in response to oxidative stress and has been implied in the induction of the Nrf2 pathway. The signals are mediated by the extracellular regulated kinase and mitogen activated kinases which culminate in upregulation of glutamate cysteine ligase modulatory subunit gene, influencing nuclear translocation of Nrf2. While Nrf2 and Keap1 are not directly targeted, the mitogen-activated kinases are directly involved in the translocation of Nrf2 into the nucleus.

Crosstalk Between NF-kB and Nrf2 Pathways
After the virus replicates inside the host, the innate immunogenic response causes activation of many inflammatory mediators namely macrophages and dendritic cells to fight against cytokines and reactive oxygen species. The reactive oxygen species and inflammatory cytokines damage erythrocytes releasing heme and free ion. Respiratory burst generates superoxide radicals and hydrogen peroxide which ultimately, cause oxidative stress. The cytokine storm is a consequence of the upregulated cytokine expression through the NF-kB pathway. This storm is responsible for severe damage to the tissue.
In a study that induced scratch injury in astrocytes, it was found that this injury caused upregulation of NF-kB activity that resulted in overexpression of IL-6, IL-1B, TNF-a, and MMP9 (matrix metallopeptidase 9-gelatinase that aggravates inflammation process). This overexpression was found to be more aggravated in Nrf2 knockout astrocytes than the wild-type resulting in more astrocyte death. In another experiment, Nrf2-deficient mice showed greater pro-inflammatory gene expression on TNF-a stimulation. NF-kB activation after LPS (lipopolysaccharide) activation was also found to be high in the lungs, MEFs (mouse embryonic fibroblasts), and peritoneal macrophages of Nrf2 deficient mice. These also showed higher IKK Kinase activity in response to TNF-a or LPS. These studies point to the possible interplay between Nrf2 and NF-kB. It is proposed that these pathways exert an inhibitory effect on each other at the transcription level. The crosstalk can be both ways-Nrf2 inhibition of NF-kB and vice versa.
Nrf2 produces a multitude of antioxidant and cytoprotective enzymes in response to oxidative stress. One of them, HO-1 (hemoxygenase-1), is involved in the metabolism of heme by acting as a catalyst in the cleavage of porphyrin ring in heme into carbon monoxide, Fe2+, and biliverdin that converts into bilirubin. A study showed that overexpression of HO-1 in the endothelial cells inhibited TNF-a-induced proinflammatory adhesion molecule expression (E-selectin and VCAM-1 (vascular cell adhesion protein 1)). This inhibition was found to be at mRNA level by interfering with the rate of transcription. This represents one way of the crosstalk that the Nrf2 pathway inhibits NF-kB pathway activation by increasing HO-1 expression, thus reducing the cytokine release. Oxidative stress also causes IKK (IkB kinase) activation that further phosphorylates IkB which is the inhibitor of NF-kB and causes polyubiquitination mediated proteasomal degradation that releases NF-kB. It migrates to the nucleus and leads to the transcription of inflammatory genes. Nrf2 pathway inhibits degradation of IkB-a that leads to its stabilization and inhibition of NF- kB-mediated transcription. Hence, the release of pro-inflammatory cytokines is inhibited.

NF-kB can also regulate Nrf2 mediated ARE (antioxidant response element) expression.
This strengthens the view that NF-kB activation suppresses the Nrf2 pathway in case of enhanced oxidative stress or cytokine storm.

Keap1, with which Nrf2 exists in bound form in the cytoplasm, has been found to negatively regulate IKKB. HSP90 (heat shock protein 90) is a chaperone protein that assists in protein folding. It has been observed that Keap1 prevents the binding of HSP90 to IKKB which is the trigger for its autophagic degradation. Also, Keap1 reduces IKKB phosphorylation by concealing those residues that bind with the phosphate groups. The result of this entire interaction is that IkB-a is stabilized because IKKB is not phosphorylated that, as a result, reduces NF-kB signaling.
Patients with pre-existing auto-immune disorder susceptibility are at grave risk for COVID-19. Due to the administration of immunosuppressant for mitigating the virus, the interest in auto-immunity is implied. The dysfunctional regulatory T cells have been regarded as the cause of many autoimmune disorders. When Nrf2 is systemically activated by Keap1 (Kelch-like ECH-associated protein 1), tissue inflammation is enhanced. On the other hand, its knockdown reduces T cell and cytokine production. Nrf2 induction can mitigate the regulatory T cell dysfunction and alleviate auto-immune disorders especially, in the case of COVID-19 where the latter is further stressed upon. NF-kB has a role in promoting inflammation in autoimmune attacks as well as mediating immunogenic tolerance. It promotes the formation of regulatory T cells and plays a role in deleting self-reacting T cells situated in the thymus. The NF-kB thus lies centrally in preserving immune homeostasis and prevention of autoimmunity caused in COVID-19.
COVID-19 is characterized by a cytokine storm due to the attack on the patient’s immune cells. The mainstay of treatment is the use of anti-viral agents. Immunomodulatory agents both synthetic and herbal can be pertinent in catering and resolving the serious effects of the attack of the virus. These immunomodulatory agents act in synergism with the pre-existing approaches and act as adjunctive therapy or prophylaxis. The Nrf2 and NF-kB pathway are involved in the development and progress of inflammatory pathology in COVID-19. Consequently, immunomodulators targeting the crosstalk between these key signaling pathways offer an innovative approach in tackling this deadly pandemic and present a ray of shine in tackling COVID-19 associated neurological complications.
Oxidative stress and inflammatory cytokine storm are key characteristics of the pathology concerning this deadly virus. Many studies discussed point the substantial body of evidence hinting at severe neurological complications in patients.
Crosstalk between both, NF-kB and Nrf2 signaling pathway lies at the center of neurological complications in COVID-19 patients. Immuno-modulators both synthetic and natural can be promising candidates in catering to the pathologies targeted in the aforementioned pathways. Immunomodulatory agents act in synergism with the pre-existing approaches and act as adjunctive therapy or prophylaxis and outstand existing approaches by specifically targeting the oxidative stress and consequently, eradicating and undermining the pathology leading to severe neurological disorders.

Check out figure 6!

In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRPA1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.
TRP channels are polymodal channels and most of the superfamily members can be activated by a multitude of stimuli. Several Nrf2-interacting nutrients are direct TRPA1 activators. These include: (i) allyl isothiocyanates (AITC: pungent components of mustard, horseradish, and wasabi), cinnamaldehyde from cinnamon, (iii) allicin, an organosulfur compound from garlic, (iv) green tea polyphenols, and (v) 3 glucosinolates from Sisymbrium officinale (isopropylisothiocyanate and 2-buthylisothiocyanate) or Moringa oleifera (4-[(a-l-rhamnosyloxy) benzyl] isothiocyanate). Sulforaphane, an AITC and the most potent natural Nrf2 activator, does not appear to interact with TRPA1. The plant polyphenol resveratrol may have an agonist or antagonist effect. An indirect agonist effect was found via the N-methyl-D-aspartate (NMDA) receptor in vivo. TRPA1 may serve as a downstream target of pro-nociceptive ion channels such as N-methyl-D-aspartate receptors.
Many TRPV1 agonists also interact with Nrf2 and/or TRPA1. TRPV1 is a sensor stimulated by several spices including capsaicin (red pepper), piperine (black pepper), gingerol, and zingerone (ginger), pungent compounds from onion and garlic, eugenol (clove), and camphor. TRPV1 is also activated by AITC, present in mustard, horseradish, and wasabi, and by resiniferatoxin, a toxin of tropical Euphorbia plants.
There is a substantial overlap of electrophilic ligands between TRPA1 and Nrf2. However, not all Nrf2-interacting nutrients are activators of TRPA1. For example, mustard oil does not interact with Nrf2, whereas sulforaphane does not interact with TRPA1 or TRPV1.

Check out Table1!
Paracetamol (acetaminophen) has TRPA1-independent antipyretic effects and TRPA1-dependent effects on pain. The electrophilic metabolites N-acetyl-p-benzoquinone imine (NAPQI, hepatotoxic metabolite) and p-benzoquinone, but not paracetamol itself, activate TRPA1. They also activate and sensitize TRPV1 by interacting with intracellular cysteines. NAPQI also directly activates Nrf2, and benzoquinone desensitizes TRPA1.
The physiological and toxicological responses of paracetamol form a continuum coordinated by the Wnt and Nrf2 pathways. Therapeutic doses produce reactive ROS and NAPQI in the cytoplasm but result in little permanent damage. At high doses, paracetamol can induce oxidative stress-mediated hepatotoxicity which is reduced by enhancing the Nrf2 pathway.
The oxidative stress senses TRPA1 and, to a lesser extent, TRPV1. The activated TRPs are prone to be hyper-activated by various natural stimuli. Foods can activate Nrf2 and desensitize TRPs.
Reducing ROS by Nrf2 will most likely reduce TRPA1 hyperreactivity, thereby reducing TRPA1 activation by exogenous or endogenous agents.

Even though epidemiological studies have suggested that children with low dietary intake of vitamins and C, E and other antioxidants have in general more symptoms, the results of the clinical studies have been largely disappointing. Interestingly, a recent study has even suggested that vitamin supplements may increase the oxidant stress. In this study, the investigators have hypothesized that the intake of antioxidant vitamins would augment the beneficial effects of exercise in patients with type 2 diabetes. In contrast to their expectations, the results have shown that daily supplementation with vitamin C and vitamin A for 4 weeks not only failed to improve the insulin responsiveness but also decreased the expression of ROS-sensitive transcriptional regulators, molecular mediators of ROS defense (SOD 1 and 2, glutathione peroxidase). Thus, antioxidant supplement seems to have blocked endogenous defenses rather than counteract the oxidant stress. This emphasizes that exogeneous antioxidants need to block the oxidant pathways without suppressing the endogenous antioxidant mechanisms.
The Nrf2 pathway is a negative regulator of inflammation according to the hierarchical oxidative stress model. Sulforaphane is a potent Nrf2 agonist, which is found in high amounts in broccoli.
Studies using human bronchial epithelial cells confirm that sulforaphane is effective in suppressing the proinflammatory effects of diesel exhaust particles. It effectively upregulates GSTM1 and blocks interleukin (IL)-8, granulocyte-macrophage colony-stimulating factor (GMCSF), IL-1B production in the bronchial epithelial cells.
Quercetin is a flavonoid molecule found in a variety of foods especially in apples and has antioxidant and anti-inflammatory properties. Quercetin was shown to inhibit proinflammatory cytokines and NO production through MAP kinases and NF-kB pathway in lipopolysaccharide-stimulated cells.
Dietary intake of the soy isoflavone genistein was associated with reduced allergic respiratory symptoms.
In animal models, genistein blocks allergen-induced airway inflammation in ex vivo allergen-challenged guinea-pig bronchi and lung specimens. Intratracheal instillation of genistein was shown to reduce leukotriene and histamine levels. In support of these studies, asthma patients with high dietary genistein consumption had less severe airflow obstruction than those who consume little or no genistein.
a-Lipoic acid is a nonenzymatic antioxidant and is present in various foods and oral supplements. In an animal model, a-lipoic acid treatment was associated with reduced airway hyperresponsiveness, lower eosinophil counts, and IL-4 and IL-5 concentrations in BAL, improved pathology of the lungs, and lower intracellular ROS and NF-kB DNA-binding activity. Recently, Metha et al reported that choline and a-lipoic acid treatment reduces ROS production and isoprostanes in BAL fluid and thus suppresses oxidative stress.
Another food derivative, epigallocatechin 3 gallate, a component of polyphenols derived from green tea, was shown to be a potent inhibitor of IL-1B-induced MUC5AC gene expression and MUC5AC secretion and has antioxidant activity.

Prospective natural compounds in the management of the coronavirus infection.
Check out Table 1!

Other Nrf2 modulator compounds.
Check out Table 3!

This could give some ideas of some potentially effective combinations. Check the tables at the link!
The heartburn the patient (author) experienced is probably in line with mine.
For those who have a positive experience with sulforaphane, black pepper, curcumin and paracetamol the Nrf2 pathway should be seriously considered!
Antioxidants have been proposed as being effective in controlling COVID-19 symptoms. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most effective antioxidant mechanism. TRPA1 (transient receptor potential ankyrin 1) is highly sensitive to oxidative stress and induces several COVID-19 symptoms. TRPA1 and TRPV1 (transient receptor potential vanillin 1) are potential candidates for COVID-19 symptoms.
Nutrients with various Nrf2 and TRPA1/TRPV1 agonist activity were used: broccoli seeds (potent Nrf2 agonist and mild TRPA1 agonist), berberine (Nrf2 only), black pepper, curcumin, ginger, green tea, resveratrol, Zinc (potent TRPA1 activity and variable Nrf2 agonist) and red pepper (potent TRPV1 agonist).
Berberine and Zinc were not effective. All other nutrients except resveratrol were rapidly effective (1-10 minutes). The effect of green tea, curcumin + black pepper, ginger, resveratrol or red pepper disappeared in 1 to 4 hours. Broccoli had a longer duration of action (5-7 hours). The duration of the of the effect increased to around 10 hours when low doses of curcumin + black pepper or resveratrol were added to broccoli. Paracetamol low dose (its metabolite N-acetyl-p-benzoquinone imine is a TRPA1/TRPV1 agonist) increases the duration of action of combinations to over 14 hours.

Differences in COVID-19 death rates among countries may in part associated with Nrf2 and Nrf2-interacting nutrients like fermented vegetables could reduce COVID-19 severity.
TRPA1, an excitatory ion channel, plays a pivotal role in augmenting sensory or vagal nerve discharges, evoking several COVID-19 symptoms.
It is highly sensitive to oxidative stress. In COVID-19, rapid desensitization of TRPA1
and/or TRPV1 may reduce symptom severity.
It is difficult to deliver sulforaphane in an enriched and stable form for human consumption, thus glucoraphanin, the precursor of sulforaphane, is administered orally with myrosinase, the enzyme that transforms glucoraphanin into sulforaphane.
All nutrients tested have a variable Nfr2 agonist activity. Although the specificity of the different agonists is not clearcut it can be considered that curcuma and black pepper, ginger, green tea, quercetin and the plant polyphenol resveratrol are all TRPA1 agonists, whereas berberine does not appear to have such an effect. Capsaicin from red pepper is the agonist of TRPV1 but it also has some TRPA1 activity. Zinc acts on Nrf2 and TRPA1.

The electrophilic metabolites N-acetyl-pbenzoquinone imine (NAPQI, hepatotoxic metabolite) and p-benzoquinone, but not paracetamol itself, activate TRPA1 and TRPV1. NAPQI also directly activates Nrf2, and benzoquinone desensitizes TRPA1.
When the patient initially took capsules containing curcumin and black pepper, he experienced some gastro-esophageal discomfort and heartburn (VAS 2-3/10 for pain). However, when red pepper was associated with paracetamol heartburn increased (VAS 6) and required lansoprazole 30 mg. This discomfort lasted for around one to 2 hours.

Berberine (BBR) is a natural isoquinoline alkaloid with very impressive health benefits. It is one of the most effective natural supplements available. BBR supplemented either before or after methotrexate (MTX) significantly ameliorated body weight, liver function markers, TNF-a, lipid peroxidation, NO and caspase-3. BBR increased serum albumin and liver antioxidant defenses in MTX-induced rats. Histological and immunohistochemical examination showed improved histological structure and decreased expression of Bax in liver of MTX-induced rats treated with BBR. In addition, BBR up-regulated Nrf2, HO-1 and PPARG expression in the liver of MTX-induced rats. In conclusion, BBR attenuated MTX-induced oxidative stress and apoptosis, possibly through up-regulating Nrf2/HO-1 pathway and PPARG. Therefore, BBR can protect against MTX-induced liver injury.


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Re: FAAH Inhibitors
« Reply #15 on: April 23, 2021, 01:43:55 PM »
I think that PPARG is the single unifying factor that must be the root cause for almost all if not all of the POIS cases. Although most of the FAAH inhibitors work in my case, however the only common link between the enhancers is that they modulate PPARG. Other POIS cases also have a connection to PPARG most of the time. Even researchers confess that the function of PPARs is not that well known. The modulation of PPARs probably can't be reduced to mere agonism and antagonism, which may lead to some confusion. There may be dual action subtypes like PPARG (FAAH) or PPARG (Nrf2), but PPARG is still the common denominator. PPARA and PPARB/D may also have a role, but most clues still point towards PPARG.

We propose that PPARG is a key regulator in the maintenance of peroxisomal, mitochondrial and lysosomal functions. Genetic disruption of PPARG or PPARG2 signaling in mouse prostate epithelial cells resulted in dysregulated expression patterns of peroxisomal and mitochondrial genes whose products are involved in lipid transportation and oxidation pathways. Active autophagosomes and abnormally increased numbers of lysosomes were found in PPARG- and PPARG2- deficient prostatic epithelia. In vitro these phenotypes were rescued by re-expression of PPARG1 and PPARG2 isoform in mPrE-PPARG KO cells. In vivo changes consequent to loss of PPARG were associated with hyperplasia, PIN formation and progression to malignancy, which in the case of PPARG2 suppression could be rescued using high levels of the PPARG agonist Rosiglitazone.
Alterations in lipid metabolism resulting in loss of PPARG-signaling have been suggested to predispose the prostate to premalignant or malignant changes.
Reduced PPARG function was associated with increased activation of oxidative stress, autophagic activity, and activation of pro-inflammatory signaling pathways.
This establishes conditions for subsequent malignant transformation which would be expected to occur stochastically, resulting from epithelial genomic damage potentially caused by reactive oxygen species (ROS). The results described here parallel reported changes in gene expression resulting in reduced ligands for PPARG in the human prostate and provide the first direct evidence that loss of PPARG expression or function can lead to prostatic neoplasia in vivo.
Reduced activation of PPARG due to reduced formation of endogenous ligands for PPARG most likely explains its role early in human Pca development.
Disruption of PPARG-signaling results in altered fatty acid metabolism and induction of oxidative stress and hypoxia.
Early prostate cancer has been linked to a loss of enzymes including 15-lipoxygenase-2 (15-LOX-2) which is involved in the generation of 15(S)-hydroxyeicosatetraenoic acid (15-HETE). Such a scenario justifies the consideration of PPARG agonists as chemopreventive agents to inhibit the genesis of early stage prostate cancer.

Peroxisome proliferator–activated receptor (PPAR) belongs to the steroid family receptors and is also able to bind steroid hormones. In amphibians, rodents, and humans, three forms of PPAR have been described to date: PPARA, PPARB (also known as PPARD), and PPARG. PPARs target genes that encode enzymes involved in peroxisome and mitochondria function as well as those of fatty acids, apolipoproteins, and lipoprotein lipase. Little is known about PPARs in the male reproductive system.
In rat testis, PPARs are mainly expressed in Leydig and Sertoli cells. It was shown that some PPAR chemicals alter testosterone production, and their long-term administration results in Leydig cell tumor development in rats.
It is worth noting that biosynthesis of sex steroids is multilevel, controlled process. It requires the coordinated expression of number of genes, proteins of various function [receptors, e.g., lutropin receptor (LHR), enzymes, transporters, and regulators, e.g., translocator protein (TSPO), steroidogenic acute regulatory protein (StAR)], signaling molecules (e.g., protein kinase A (PKA)], and their regulators in response to LH stimulation. Moreover, for cellular steroidogenic function, global lipid homeostasis is crucial. Perilipin (PLIN), hormone sensitive lipase (HSL), and HMG-CoA synthase (HMGCS) as well as reductase (HMGCR) are members of a cell structural and enzymatic protein machinery controlling lipid homeostasis. Activation of lipid metabolism is an early event in tumorigenesis however, the precise expression pattern of lipid balance-controlling molecules and their molecular mechanism remains poorly characterized.

Expression and activation of either PPARG 1 or 2 reduced de novo lipogenesis and oxidative stress and mediated a switch from glucose to fatty acid oxidation through regulation of genes including Pdk4, Fabp4, Lpl, Acot1 and Cd36.
In confirmation of in vitro data, a PPARG agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPARG agonization increased prostatic differentiation markers, whereas HFD downregulated PPARG-regulated genes and decreased prostate differentiation.
Epidemiological links between benign prostatic hyperplasia (BPH) and diabetes have been recognized for many years and recent studies have demonstrated that the incidence and severity of BPH are correlated with obesity, atherosclerosis, diabetes mellitus, hyperinsulinemia, hyperglycemia and hypercholesterolemia. Although diabetes mellitus has a negative correlation with the incidence of multiple cancers including prostate, diabetic patients exhibit increased mortality.
These results suggest that PPARG is a major metabolic regulator in the control of mouse and human prostate differentiation.

Upon maximal lipid storage capacity of white adipose tissue (WAT), peripheral tissues begin to store lipid in excess of their natural oxidative or storage capacity resulting in lipotoxicity, inflammation and eventually insulin resistance. Recent evidence squarely positions prostatic diseases as sequelae of systemic metabolic dysfunction, including hyperinsulinemia, hyperglycemia and hypercholesterolemia; however, the underlying etiologies of such susceptibilities remain unknown largely because of the absence of a molecular understanding of the basic metabolic machinery governing prostatic function.

In recent years, it has been shown that PPARG agonists improve different CNS dysfunctions. The antidepressant-like effects of these drugs are demonstrated for the first time by pioglitazone in a 55-year-old female who had severe unresponsive depression. NP031115, a novel thiazolidinedione, exerts antidepressant-like effect in mice, likely by inhibiting glycogen synthase kinase-3 (GSK-3) and increasing PPARG activity.
A recent study shows that polymorphism in PPARG2 is involved in depression.
Nitric oxide (NO), a signaling molecule in the nervous system, is biosynthesized endogenously from l-arginine by nitric oxide synthase (NOS). NOS family has been classified to different groups including three isoforms. Two are constitutive NOS (cNOS) and the third one is inducible NOS (iNOS). iNOS has been distinguished from cNOS being calcium insensitive. NO involved in different biological functions in CNS such as learning, memory, depression and expression of pain. It has been shown that inhibition of NOS results in antidepressant-like effect and also is involved in efficacy of various antidepressant drugs.
The role of PPARG receptors is more prominent after 2 h of PPARG agonist administration, while this effect is mediated more prominently through nitric oxide system after 4 h of pioglitazone.

In these neurons the proliferation of peroxisomes mediated by a peroxisome proliferator-activated receptor-gamma (PPARG) agonist resulted in the decrease of ROS levels. ROS are a group of highly reactive molecules, such as singlet oxygen, hydroxyl radicals, superoxide, and hydrogen peroxides. Most ROS have extremely short half-lives (nanoseconds), whereas some others, such as hydrogen peroxide, have millisecond half-lives. Due to their high reactivity, ROS can oxidize cell constituents such as lipids, proteins, and DNA, thus damaging cell structures and compromising their function. Because of these potentially noxious effects, cells maintain ROS at a tolerable level by means of antioxidants such as the redox system, superoxide dismutase, and catalase. Catalase, predominantly located in peroxisomes, catalyzes the conversion of hydrogen peroxide into water and molecular oxygen. The transcription of this enzyme is regulated by PPARG. A putative functional PPAR response element was identified at the promoter region of the rat catalase gene. Activation of PPARG by a specific agonist further enhances catalase activity and protects neurons from oxidative stress. Growing evidence indicates that endocannabinoids exhibit profound anti-inflammatory and neuroprotective properties in response to harmful insults, including oxidative stress. Some of these effects appear to be mediated by PPARG activation.
These data strongly suggest that ECs may tonically inhibit leptin-induced ROS formation, at least in vitro, and that this inhibition is under the negative control of EC degrading enzymes
It is well known that PPARG regulates a large number of enzymes, including catalase, the most important enzyme for antioxidant defense.
This observation is consistent with the hypothesis that the CB1 receptor agonist controls leptin action at least in part through PPARG activation. This nuclear receptor can directly regulate the expression of a large number of antioxidant enzymes, including catalase, which is ubiquitously expressed in the CNS and is mainly located in peroxisomes. In agreement with the report that PPARG activation by a specific agonist enhances catalase activity, thereby resulting in the protection of neurons from oxidative stress, we found here that ACEA also prevented the inhibition of catalase induced by leptin in a PPARG-mediated manner.
In agreement with the present findings in neurons, the activation of CB1 receptors was previously shown to lead to overexpression of PPARG in adipocytes. The underlying mechanism of this effect has never been investigated, but it is possible that the well known CB1-induced activation of ERKs might cause phosphorylation of C/EBPb, a transcription factor that activates PPARG, thus explaining why ACEA enhances PPARG activity also in hypothalamic neurons, which express C/EBPb.
It is possible that, like AEA (as well as other cannabinoids); it also directly activates PPARG.

PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPARG agonists.
Three subtypes, designated PPARA (NR1C1), PPARD (NR1C2), and PPARG
(NR1C3) have been identified whose endogenous ligands include fatty acids and fatty acid metabolites.
PPARs form heterodimers with retinoid X receptors (RXRs) and bind to the hexanucleotidic PPAR responsive element (PPRE), thereby regulating the expression of target genes involved in lipid and carbohydrate metabolism. PPARA and PPARD agonists alone significantly reduced circulating insulin (INS) levels. The combination of the two agents not only reduced insulin but also significantly reduced triglyceride (TG) and nonesterified fatty acids (NEFAs) and elevated total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-c), and B-Hydroxybutyric acid (BHBA).
The selective PPARG agonist produced a significant reduction in circulating INS, TG, and NEFA levels. Both PPARpan agonists significantly reduced fed glucose, INS, NEFAs, and TG and increased total CHOL, HDL-c, and BHBA.
Selective activators of PPARG, such as glitazones, have been successfully used to treat T2DM for nearly a decade.
Treatment with rosiglitazone and pioglitazone induce body weight gain in mice, rats, nonhuman
primates, and humans. Weight gain is manifested as increased adiposity, total body water and plasma volume. In this report, mice treated with a potent and selective PPARG activator gained more weight than obese vehicle controls and the weight gain could be completely accounted for by increased fat mass which was equivalent to the increase in caloric intake. In addition to stimulation of
food consumption, activation of PPARG promotes triglyceride accumulation by increasing expression of genes modulating adipogenesis, lipid transport, storage, and glucose homeostasis.
In summary, PPARG agonism induces food consumption and energy storage without an effect on energy utilization resulting in net weight gain.
Activation of PPARA and PPARD receptors by PPARpan compounds may be expected to induce weight loss or provide weight maintenance while combining the beneficial insulin sensitization effects of a PPARG agonist.

Peroxisome-proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily of ligand-activated transcriptional factors, which include receptors for steroids, thyroid hormone, vitamin D, and retinoic acid. Among them, PPARG was originally characterized as a regulator of adipocyte differentiation and lipid metabolism and, more recently, of cellular turnover. Indeed, several lines of evidence indicate that PPARG profoundly affects cell cycle, differentiation and apoptosis. Thus, PPARG activation by natural or synthetic ligands such as the cyclooxygenase metabolite 15-deoxy-delta12,14 PGJ2, polyunsaturated fatty acids, different nonsteroidal anti-inflammatory drugs, and the oral antidiabetic agents thiazolidinediones favor macrophage differentiation and prevent colorectal, prostate, and breast cancer by inhibiting cell growth and accelerating apoptosis. Fibroblast, synoviocyte, macrophage, endothelial and T-cell apoptotic death in response to thiazolidinediones has also been documented.
In addition, PPARG activation downregulates the synthesis and release of immunomodulatory cytokines from various cell types.
Upregulation of PPARG expression in airway epithelium and smooth muscle of asthmatics reported in this study is reminiscent of previous observations showing an augmented PPARG immunostaining associated with the colonic epithelium in mice with an inflammatory bowel disease in rat neointima after balloon injury and in early human atheroma.
This enhanced PPARG expression may reflect an inflammatory response of different cell types and structures to natural PPARG ligands generated within the airways during the allergic reaction. Although the nature of these stimuli in the lung is unknown, it is well established that a range of naturally occurring substances, including polyunsaturated fatty acids, the 15-lipoxygenase metabolite, 15-hydroxyeicosatetranoic acid (15-HETE), or cytokines such as IL-4, are potent PPARG expression-promoting agents.
Structural abnormalities characteristic of the remodeling response in asthma involve, at least in part, a dysregulation in the proliferation and apoptosis of different cell types responsible for the maintenance of airway integrity. Of note, synthetic and naturally occurring PPARG ligands greatly ameliorate different features of tissue remodeling, including the thickening of the bowel wall in mice with inflammatory bowel diseases and arterial restenosis after endothelial injury in rats. These beneficial effects may be related to the ability of PPARG ligands to inhibit cell migration, proliferation, and proinflammatory and toxic mediator production and to promote apoptotic cell death.
Corticosteroids offer clinical improvement in airway function most likely by reducing airway inflammation, as a result of an inhibition of many transcription genes involved in the synthesis of proinflammatory lipid mediators and cytokines. Here we demonstrated that PPARG expression in the bronchial mucosa, the airway epithelium, and the smooth muscle was also downregulated in inhaled- and, to a higher extent, in oral steroid-treated asthmatics. These results indicate that the anti-inflammatory and immunomodulatory properties of these drugs may extend to the regulation of PPARG expression in target cells.
Our observations showing lower levels of PPARG in steroid-treated asthmatics are in apparent contradiction with some in vitro findings showing upregulation by dexamethasone of PPARG gene expression in human adipocytes.

In conclusion, our results identify PPARG as a new factor expressed in high levels by submucosal and structural cells during the inflammatory and remodeling response in asthma. It is difficult at this stage to anticipate a role for PPARG in human asthmatic airways. In view of the results from the literature showing the inhibitory properties of this nuclear antigen against cell differentiation, proliferation, and activation, it may be hypothesized that its upregulation in asthma would represent a self-regulatory mechanism aimed at preventing further cell activation and expansion, thus contributing to the cessation of airway inflammatory and remodeling, as proposed for other pathologic conditions. However, this classic view may be contradicted by our findings demonstrating a clear association between an augmented PPARG expression, the presence of features of airway remodeling, and the increase in bronchial obstruction. These observations, together with the efficacy of steroid therapy in downregulating PPARG expression, may lead to consider this nuclear antigen as a new mediator with proinflammatory and fibrogenic activities. This hypothesis is consistent with the expression of high levels PPARG within the atherosclerotic plaques of mice and humans and with the recent debate concerning the potential atherogenic properties of endogenously produced PPARG.

PPARs are ligand?activated receptors in the nuclear hormone receptor family. In the inflammatory response, PPARG inhibits the production of inflammatory signaling pathways and inflammatory mediators.
A previous study showed that miR?29a sufficiently suppressed the expression of CB1, which further restored PPARG signaling. The activation of PPARG, often in conjunction with the activation of CB1, could mediate the anti?inflammatory, analgesic, metabolic, neuroprotective, antitumour and cardiovascular effects of cannabinoids. However, the function and underling mechanism of CB1 in periodontal ligament stem cells (PDLSCs) in an inflammatory environment remains unclear along with its involvement in periodontal regeneration.
This study found that bacterial inflammation decreased CB1 expression in human periodontal ligament (PDL) cells. However, it has been found that CB1 seems to be upregulated during gingival wound healing in rats.
Next, we investigated the role of CB1 in PDLSCs under inflammatory conditions. The development of periodontitis is tied to the accumulation of inflammatory mediators including TNF-a and INF-g, and an increased inflammatory response develops with the destruction of periodontium tissue.
We found that the CB1 expression level in PDLSCs was decreased after stimulation with either of these inflammatory factors. A previous study found that the inflammatory factors IL?1B, IL?6 and TNF?a could enhance CB1 and CB2 expression levels in human whole blood and peripheral blood mononuclear cells (PBMCs). Upon stimulation with INF?g, no marked change was found in the expression level of CB1 in activated microglia. These findings indicate that inflammatory factors have different effects on CB1 in different cell types.
Other studies have confirmed that PPARG is a negative regulator of osteogenic differentiation. For example, a study showed that enhanced PPARG activity leads to bone loss, and reduced PPARG activity causes bone mass to increase in animal models.

We hypothesized that biosynthesis of tetrahydrobiopterin (BH4) is an important mechanism responsible for the stimulatory effects of PPARD activation on regenerative function of human EPCs. We provide compelling evidence that activation of PPARD stimulates GTPCH I expression and biosynthesis of BH4, which in turn enhances ability of EPCs to repair injured endothelium.

Cheng et al. investigated the effect of Rhodiola rosea extract on heart failure in streptozotocin-induced diabetic rats and found that both cardiac output and peroxisome proliferator-activated receptor PPARD expression level increased after treatment.
Wang et al. revealed that salidroside could promote 3 H-glucose uptake and downregulate the expression of PPARG and C/EBP-? in 3T3-L1 pre-adipocytes.
Synergistic effects of aerobic exercise and R. sacra in ameliorating skeletal and cardiac muscle damage caused by exhaustive exercise are related to the enhancement of mitochondrial quality control, partly due to the AMPK/ PPARG co-activator 1a (PGC-1a) signaling activation.
Their results showed that salidroside treatment increases the expression levels of nuclear factor (erythroidderived 2) factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and suppress NF-kB signaling, resulting in concentrationdependent decreases in reactive oxygen species (ROS) generation and increases in nitric oxide (NO) production in HUVECs exposed to AGEs.
Moreover, salidroside could alleviate high glucose induced oxidative stress and apoptosis in podocytes via the Nrf2/HO-1 signaling pathway. Additionally, as a highly inducible enzyme, HO-1 expression can be stimulated by AMPK during periods of metabolic stress.
Thus, for Rhodiola herb extract preparation, the extract solvent may determine how the extract performs, but both salidroside and other components such as phenolic compounds (tyrosol and gallic acids), flavonoid (kaempferol, proanthocyanidins, herbacetin) and polysaccharides have also been shown to protect against diabetes.
Furthermore, we found that, in HFD mice, salidroside could attenuate NAFLD via the AMPK-dependent thioredoxin-interacting protein (TXNIP)/NLRP3 pathway. Remarkably, NLRP3 infammasome is a sensor for metabolic danger and can be activated by ROS in metabolic syndrome. Once NLRP3 infammasome is activated, the active caspase-1 can process infammatory cytokine generation and exacerbate the infammatory response. We found that salidroside treatment alleviates obesity and improves the lipid proflie in serum and liver tissues as well as the ROS-triggered NLRP3 infammasome activation in the liver of HFD mice. These fndings suggested that Rhodiola and
salidroside may be suitable for the treatment of metabolic syndrome, such T2DM, atherosclerosis and NAFLD.

Taurine is abundant in the fruit of Lycium barbarum (Goji Berry).
L. barbarum extract and taurine dose-dependently enhanced the expression of PPARG mRNA and protein. In an inflammation model where ARPE-19 cells were exposed to high glucose L. barbarum extract and taurine down-regulated the mRNA of pro-inflammatory mediators encoding MMP-9, fibronectin and the protein expression of COX-2 and iNOS proteins. The predicted binding mode of taurine in the PPARG ligand binding site mimics key electrostatic interactions seen with known PPARG agonists. We conclude that PPARG activation by L. barbarum extract is associated with its taurine content and may explain at least in part its use in diabetic retinopathy progression.

The study showed anti-apoptotic activity of Lycium barbarum (Goji Berry) polysaccharides (LBP) in cultured seminiferous epithelium against hyperthermia-induced damage through the inhibition of superoxide-induced cyt c.

Tribu Saponin from Tribulus terrestris (STT) can down regulate the gene expression of ICAM-1, VCAM-1 and up regulate the gene expression of PPARA, PPARG in artery vessels of arterosclerotic rats, which may account for the anti-arteriosclerosis effects of STT.

The medicinal uses of saffron, the dried stigmas of Crocus sativus L.
Furthermore, the beneficial effects of saffron on inhibition of serum levels nuclear transcription factor kB (NF-kB) p65 unit, tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-g) and some interleukin (IL) such as IL-1?, IL-6, IL-12, IL-17A were reported. Furthermore, saffron has been known as the antagonist of NF-kB and the agonist of peroxisome proliferator-activated receptor gamma (PPARG). In addition, saffron down-regulates the key pro-inflammatory enzymes such as myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phospholipase A2, and prostanoids.
Also, some several compounds such as mineral agents, anthocyanins, glycosides, alkaloids and some flavonoids including quercetin and kaempferol not only are presents in this plant but also presents in the saffron petal. The main bioactive metabolites of the saffron spice are coming from the carotenoids.

The PPARG and -D protein levels were reduced in the SAH groups (p < 0.01). Glycyrrhizin significantly increased the expressed PPARG protein and mRNA (preconditioning) and PPARD mRNA (both treatment and preconditioning), which corresponded to the reduced IL-1? and TNF-? levels. The administration of a PPARG inhibitor, BADGE, halted the reduction of IL-1? and TNF-? in the glycyrrhizin groups. Conclusively, glycyrrhizin exerts anti-inflammatory effects on SAH-induced vasospasm and attenuates the expression of PPARs, especially PPARG, which corresponds to the severity of SAH-related inflammation. These findings also offer credit to the antivasospastic effect of glycyrrhizin and its vasculoprotective effect in animals subjected to SAH.

Quercetin and kaempferol are active components in the juice of Cape gooseberry (Physalis peruviana L.) The major phytochemical constituent’s mass spectra are kaempferol 3-O-rutinoside (1.40%), Quercetin 3,4',7-trimethyl ether (3.11%), Folic Acid (0.95%), 1,25-Dihydroxyvitamin D2 (1.27%), Lucenin-2 (1.50%), Betulin (0.62%), (5a)Pregnane-3,20-diol (0.97%). Combined treated groups marked decrease in the liver injury and collagen accumulation as compared with CCl4-treated animals.
The same mouse study found that goldenberries may increase HO-1, an antioxidant enzyme, and Nrf2, a protein that helps release defense mechanisms against tissue damage.
Besides other compounds Physalis contains rutin, myricetin, quercetin and kaempferol.

Green cardamom (Elettaria cardamomum) belongs to the ginger family, known as ‘Queen of spice’. It has anti-inflammatory and antioxidant properties. This spice is a good source of polyphenolic compounds such as quercetin, kaempferol, luteolin, pelargonidin, gallic acid, caffeic acid and limonene which have antioxidant properties. In a US patent, Pushpangadan and Prakash described a powder mixture of Piper longum fruit, Curcuma longa rhizome, Chlorophytum tuberosum and Elettaria cardamomum as an anti-diabetic herbal formulation. In an in vitro study, Ahmed et al. findings showed that by suppression of -amylase and -glucosidase activity, cardamom supplementation has anti-diabetic effects. Furthermore, some animal studies revealed that cardamom improved glycemic indices. Though, human studies that investigated the effects of cardamom are very limited. Yaghooblou et al. findings on pre-diabetic subjects showed that cardamom supplementation improved insulin sensitivity and decreased total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c).
Studies have demonstrated that limonene and kaempferol which exist in cardamom can increase the activity of PPARA. Findings of a study by Muller et al.suggested that a diet rich in spice activated PPARA might contribute to blood lipid improvement.

There are a number of different long-chain fatty acids that can bind to and activate PPARD, produced in the body, or from foods. Common fatty acids from foods include polyunsaturated fats such as arachidonic acid and linoleic acid.

Results indicated that mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, and the combination of above herbs effectively reduced blood glucose, insulin, TG, and percent HbA1c in study animals (p < 0.05). We also observed that the increased expressions of liver PPARA mRNA and adipose tissue PPARG mRNA in animals fed diets supplemented with test herbs.
These results suggest that mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, and the combination of these herbs fed at the level of 0.5% of the diet significantly increase insulin sensitivity, and improve hyperglycemia possibly through regulating PPAR-mediated lipid metabolism.

Fermentation with Cordyceps militaris enhanced anti-adipogenesis efficacy of mulberry leaves.
HPLC showed that fermentation changed the contents of cordycepin, pelargonidin, chlorogenic acid, iso-quercetin and caffeic acid. Furthermore, fermented dried mulberry leaves with 50% raw silkworm pupa had a better efficacy of anti-adipogenesis than dried mulberry leaves, fermented dried mulberry leaves and fermented silkworm pupa and inhibited triglycerides accumulation and glucose consumption. Additionally, fermented dried mulberry leaves with 50% raw silkworm pupa inhibited PPARG signaling.
The 3T3-L1 cells has been widely used to research the adipogenesis when induced with insulin, dexamethasone and rosiglitazone.;year=2020;volume=13;issue=12;spage=557;epage=565;aulast=Guo


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Re: FAAH Inhibitors
« Reply #16 on: April 23, 2021, 02:55:19 PM »
(Disclaimer: I have not read most of what you wrote)

How does your theory work with people that cured their POIS by improving their microbiome/gut bacteria/dysbiosis/fixing infections etc?


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Re: FAAH Inhibitors
« Reply #17 on: April 25, 2021, 09:06:04 AM »
There is actually a term called PPAR reprogramming which may be the singular and most important mechanism in the development of POIS.

PPARs have a role in neuroinflammation and concomitant depression!
Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and psychiatric disorders and in their respective animal models. Remarkably, administration of these endogenous or synthetic ligands improves mood and cognition, suggesting that PPARs may offer a significant pharmacological target to improve several neuropathologies. Furthermore, various neurological and psychiatric disorders reflect sustained levels of systemic inflammation. Traditionally, classical antidepressants fail to be effective, specifically in patients with inflammation. Non-steroidal anti-inflammatory drugs exert potent antidepressant effects by acting along with PPARs, thereby strongly substantiating the involvement of these receptors in the mechanisms that lead to development of several neuropathologies.
PPARs are a target for fatty acids (unsaturated, mono-unsaturated, and poly-unsaturated), for which they mediate binding and transport, as well as oligosaccharides, polyphenols, and numerous synthetic ligands. Furthermore, they are involved in a series of molecular processes, ranging from peroxisomal regulation and mitochondrial B-oxidation to thermogenesis and lipoprotein metabolism. PPAR distribution changes in different organs and tissues.
This antidepressant effect was also observed in clinical trials where administration of pioglitazone or rosiglitazone improved symptoms in patients with major depression. Importantly, the improvement in depression correlated with normalization of inflammatory biomarkers (e.g., IL-6) and insulin resistance, suggesting an intriguing link among PPARG-activation, depression, inflammation, and metabolism. It is remarkable that patients with high levels of neuroinflammation respond poorly to classical antidepressants, suggesting that targeting neuroinflammatory pathways may offer a therapeutic strategy to revert or alleviate mood symptoms as well. Intriguingly, dietary interventions have been tested in several neuropsychiatric disorders, such as multiple sclerosis (MS), anxiety, and depression. As molecular targets for various natural ligands found in a number of aliments, PPARs may shed light into the molecular mechanisms underlying the success of dietary treatments in nutritional psychiatry.
The nuclear receptors PPARA and G are gaining consistent interest as new promising targets for treating behavioral dysfunction. This is further substantiated by the recent discovery that stimulation of PPARA can enhance neurosteroid biosynthesis, which is implicated in the etiopathology of mood disorders and their treatment.
Both genetic or pharmacological inhibition of PPARA blocks the anti-depressive effects of fluoxetine, thereby suggesting its involvement in the molecular mechanisms of antidepressant drug action.
The main PPARA endogenous agonist, N-palmitoylethanolamine (PEA) is an anti-inflammatory, analgesic, and anti-allergic compound clinically tested for its neuroprotective effects in multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). PEA can be produced endogenously or acquired through plant-based food sources and it is endogenously metabolized by the fatty acid amide hydrolase (FAAH), which is an enzyme involved in the metabolism of endocannabinoids, including anandamide (AEA). As an endogenous ligand, PEA activates the G-protein coupled receptor, GPR55, while showing low affinity for the cannabinoid receptor type-1 (CB1) and type2 (CB2). However, its therapeutic behavioral effects appear to be mediated via PPARA binding and activation. PEA administration in socially isolated mice, a model of protracted stress-induced PTSD, normalized reduced brain levels of allopregnanolone, a GABAergic neurosteroid, which is found decreased in patients with depression and PTSD. In the socially isolated mouse, PEA improved contextual fear responses and facilitated contextual fear extinction and fear extinction retention, as well as ameliorated depressive-like and anxiety-like behavior by increasing corticolimbic levels of allopregnanolone. Consistently, in a cohort of Ugandan war survivors affected by PTSD, the hair levels of PEA, oleoylethanolamide (OEA), and stearoylethanolamide (SEA) were found to be decreased when compared with levels of war survivors without current or lifetime PTSD, thus suggesting a decreased PPARA signal pathway in PTSD. While it is important that these findings will be confirmed also in blood and post-mortem brain of PTSD patients, this observation provides support to the involvement of the PPAR-allopregnanolone axis dysfunction in PTSD. Together with the findings that allopregnanolone has been found decreased in cerebrospinal fluid (CSF) and plasma of both male and female PTSD and MDD patients, these clinical data provide a translational example with PTSD animal models.

In peripheral blood mononuclear cells (PBMC) extracted from chronic schizophrenic patients, a decreased expression and activity of PPARG correlated with lower plasma levels of its endogenous ligand, 15d-prostaglandin J2, which overall indicates a state of increased inflammation. Another study in patients affected by schizophrenia investigated the expression of inflammatory and metabolic genes. Expression of PPARG was increased while PPARA was decreased, suggesting a metabolic-inflammatory imbalance in schizophrenia. Pioglitazone provided benefits in reversing this metabolic condition.
Autism spectrum disorder (ASD) is also characterized by neuroinflammation, oxidative stress and depletion of glutathione in the brain. In clinical studies, pioglitazone was tested in a 16-week prospective cohort of 25 autistic children, showing good tolerability and leading to a statistically significant improvement in repetitive behaviors, social withdrawal, and externalizing behaviors.
A natural ligand of PPARG is resveratrol, which is also able to prevent social behavioral impairments in a rodent ASD model.
Consistent with a PPARA activation, neurobehavioral and biochemical benefits in an ASD animal model were observed following administration with fenofibrate that resulted in reduced oxidative stress and inflammation in several brain regions. PEA reverted the altered phenotype and improved ASD-like behavior through a PPARA activation. This effect was accompanied by decreased levels of inflammatory cytokines in serum, hippocampus, and colon. PEA administration restored the hippocampal BDNF signaling pathway in BTBR mice and improved mitochondrial dysfunction, which has been observed in ASD.
A PPARA-allopregnanolone (i.e., endocannabinoid-like/neurosteroids) cross-talk may have an impact for establishing relevant novel targets for the treatment of PTSD and major depression. Intriguingly, these newly observed link between the endocannabinoid-like system and biosynthesis of neurosteroids may additionally provide bio-signatures for the diagnosis and treatment of psychiatric disorders, which still rely on subjective measures based on the DSM-5 criteria. Furthermore, PPARG agonists, including pioglitazone, have shown promising antidepressant effects in several clinical trials. It is also remarkable that non-steroidal anti-inflammatory drugs, including ibuprofen and aspirin, whose mechanism of action includes a PPARG activation, have consistently shown potent antidepressant effects.
Wnt/beta-catenin is downregulated when PPARG is upregulated in AD. Imbalance in the Wnt/beta-catenin/PPARG regulation plays a role in physiopathology of neurological disorders owing to its involvement in oxidative stress and cell death through regulation of metabolic enzymes. Administration of pioglitazone in a genetically modified AD mouse model showed reductions in both soluble and insoluble amyloid B, while improving memory, learning deficits, and preventing neurodegeneration. However, in clinical studies, pioglitazone showed no significant effects on cognitive outcomes. indicating a role, not only for PPARG, but also for PPAR-B/D in the pathology of AD. On the other hand, activation of PPARA by PEA has proven efficacy in inhibiting amylogenesis, neuroinflammation, neurodegeneration and Tau hyperphosphorylation. The AB-induced tau protein hyperphosphorylation is also reduced by cannabidiol (CBD) administration, through the PPARG and Wtn/B-catenin stimulation, which underscores a role for this phytocannabinoid in reducing neuroinflammation and oxidative stress.
This finding suggests that resveratrol and other compounds, which act on PPARG and PGC-1a might be beneficial as therapeutic agents in PD pathophysiology and possibly in other neurological disorders.
PPARA also plays a role in the duration and occurrence of seizures (measured by a spike-wave discharges on EEG recordings) in WAG/Rij rats, one of the most used models of human absence epilepsy, where PEA attenuates seizures by binding PPARA and indirectly by activating the CB1 receptor.

Check out Figure 1!

PPARs have a considerable role in withdrawal!
Targeting peroxisome proliferator-activated receptors (PPARs) has received increasing interest as a potential strategy to treat substance use disorders due to the localization of PPARs in addiction-related brain regions and the ability of PPAR ligands to modulate dopamine neurotransmission. Robust evidence from animal models suggests that agonists at both the PPARA and PPARG isoforms can reduce both positive and negative reinforcing properties of ethanol, nicotine, opioids, and possibly psychostimulants. A reduction in the voluntary consumption of ethanol following treatment with PPAR agonists seems to be the most consistent finding.
Substance use disorders (SUDs) continue to represent a significant global public health burden.
For example, while the focus of early addictions research was the acute, positively reinforcing properties of drugs of abuse, it is now recognized that negatively reinforcing states involving anhedonia, dysphoria, and anxiety become more important in maintaining drug-taking over time. As a result, motivation to use the drug shifts from seeking pleasure to avoiding negative affect.
Agonist substitution therapies have been successful in mitigating this negative reinforcement in some SUDs, e.g., methadone or buprenorphine for managing withdrawal and craving associated with opioid use disorder and nicotine replacement therapy (NRT) for managing nicotine withdrawal. Other medications, such as naltrexone or acamprosate for alcohol use disorder and varenicline or bupropion for nicotine dependence, have demonstrated some efficacy in reducing positive and/or negative reinforcing aspects of drug use.
While PPARs were initially identified as lipid sensors, burgeoning evidence has demonstrated a role of these nuclear receptors in a wide range of physiological functions, including central nervous system (CNS) functions such as memory consolidation and modulation of pain perception.
PPAR agonists have been recently considered for their potential to treat neuropsychiatric disorders, largely due to their ability to target levels of neuroinflammation thought to be involved in the pathophysiology of these illnesses. In particular, mounting evidence of an important relationship between neuroimmune function and addiction-related processes has generated interest in investigating the role of PPARs in drug-related behaviors.
Converging lines of evidence have also suggested a more direct role of PPARs in addiction-relevant neurocircuitry. Initial evidence came from studies demonstrating that selective inhibition of fatty acid amide hydrolase (FAAH), an enzyme responsible for degradation of the endogenous cannabinoid anandamide and the endogenous PPAR ligands oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), could suppress nicotine-induced activation of dopamine neurons in rats. Importantly, this effect was mimicked by OEA and PEA, but not anandamide, suggesting the effect was due to PPAR activation specifically. Exogenous PPAR agonists have also been demonstrated to attenuate nicotine-induced and heroin-induced excitation of dopamine neurons in the ventral tegmental area (VTA) and elevations of dopamine in the nucleus accumbens (NAc) shell in rats. Further confirmatory evidence comes from rodent studies demonstrating that PPAR isoforms are indeed localized in addiction-relevant brain regions such as the VTA, an important part of the mesocorticolimbic dopaminergic system that plays a central role in drug-related reward, and that PPARG colocalizes with tyrosine-hydroxylase-positive cells in the VTA, suggesting direct expression in dopaminergic neurons.
A significant body of evidence has consistently demonstrated that PPARA agonists can attenuate voluntary consumption and operant self-administration of ethanol in rodents. Using the two-bottle choice paradigm, studies have found a decrease in voluntary consumption of ethanol following administration of the clinically useful drugs gemfibrozil and fenofibrate, the endogenous agonist OEA, the experimental agonist WY14643, and the dual PPAR-A/G agonist tesaglitazar.
Conflicting evidence exists regarding how PPARA agonists influence withdrawal from ethanol. Bilbao et al. (2016) found that i.p. injection of 5 mg/kg of the endogenous PPARA agonist OEA significantly reduced total ethanol withdrawal scores in male rats, and furthermore decreased each of the individual withdrawal signs evaluated (vocalizations, head tremor and rigidity, tail tremor, and body tremor). Blednov et al. (2016) found that oral administration of 150 mg/kg fenofibrate or 1.5 mg/kg of the dual PPAR-A/G agonist tesaglitazar actually increased withdrawal severity (handling-induced convulsions score) in male (but not female) mice. The results of these two studies are difficult to compare given the different choices of PPARA agonist, dose, and route of administration, withdrawal signs evaluated, and animal models, but do suggest some role of PPARA in modulating ethanol withdrawal.
Two studies have suggested a role of PPARA agonists in reducing nicotine withdrawal signs. Jackson et al. (2017) assessed the impact of PPARA agonists on symptoms of precipitated nicotine withdrawal. They observed that WY14643 attenuated anxiety-like behaviors, hyperalgesia, and somatic withdrawal signs, while fenofibrate attenuated only somatic withdrawal signs.
Finally, two studies have provided evidence that PPARA agonists can block reinstatement of nicotine-responding following a period of extinction. The reduction in withdrawal symptoms and the attenuation of both drug- and cue-induced reinstatement suggest that PPARA agonists may be useful in preventing relapse in nicotine-dependent smokers.
Similar to the evidence for PPARA agonists, the results of several studies support a role of PPARG agonists in attenuating voluntary consumption and operant self-administration of ethanol.
Two studies have suggested that PPARG agonists can attenuate behavioral sensitization to stimulant drugs.

However, when pioglitazone was co-administered with naltrexone, there was an attenuation of cue-induced reinstatement. These results suggest that PPARG agonists may be useful in preventing alcohol relapse, possibly to a greater extent when administered concurrently with naltrexone, a non-selective opioid receptor antagonist that is already approved by the United States Food and Drug Administration (FDA) to treat alcohol use disorder.
The majority of the preclinical behavioral evidence suggesting a role of PPAR agonists in addiction-like behaviors has focused on ethanol. Currently, the literature strongly supports a role of PPARA agonists (gemfibrozil, fenofibrate, OEA, and WY14643), and PPARG agonists (rosiglitazone and pioglitazone) or a dual PPAR-A/G agonist (tesaglitazar) to a lesser extent, in attenuating the voluntary consumption and reinforcing properties of ethanol in rodents. Limited evidence suggests that the PPARA agonist fenofibrate may additionally reduce the rewarding properties of ethanol, as assessed in the CPP paradigm. While agonists at both PPARA (OEA and fenofibrate) and PPARG (pioglitazone) seem to have some role in modulating ethanol withdrawal signs, the nature of this role is unclear. However, the evidence does suggest that PPAR agonists may be useful in reducing the likelihood of alcohol relapse after a period of abstinence. PPARA agonists (OEA and WY14643) were shown to attenuate cue-induced reinstatement of ethanol-seeking, while a PPARG agonist (pioglitazone) was shown to attenuate stress-induced reinstatement (and possibly also cue-induced reinstatement when co-administered with naltrexone).
Robust evidence from a limited number of studies strongly supports a role of PPARA (and possibly PPARG) agonists in modulating nicotine-related behaviors in both rodents and non-human primates. The PPARA agonists methyl-OEA, WY14643, and clofibrate were found to reduce the reinforcing properties of nicotine. In addition, WY14643, fenofibrate, and OlGly were found to reduce the rewarding effects of nicotine in the CPP paradigm. WY14643 was shown to decrease behavioral and somatic signs of nicotine withdrawal, while both WY14643 and clofibrate reduced drug- and cue-induced reinstatement of nicotine-seeking. Finally, the PPARG agonist pioglitazone reduced somatic and anxiety-like signs of nicotine withdrawal.
Preliminary evidence suggests that PPARG agonists may have a role in modulating opioid-related behaviors. Studies found that pioglitazone was able to reduce the reinforcing effects of heroin in an operant self-administration paradigm, decrease both drug- and stress-induced reinstatement of heroin-seeking, and reduce the development and expression of morphine tolerance and withdrawal.
Finally, there seems to be a role of PPAR agonists in psychostimulant-related behaviors, yet the evidence is mixed. The PPARG agonists ciglitazone and pioglitazone attenuated behavioral sensitization to methamphetamine, while pioglitazone attenuated behavioral sensitization to cocaine.
Additionally, the endogenous PPARA agonist OEA attenuated behavioral sensitization to cocaine and cocaine CPP, but through a PPARA-independent mechanism. However, it is important to note that studies of nicotine-related outcomes found no effect of PPARA agonists on operant self-administration of cocaine or cocaine CPP.
As discussed previously, pioglitazone was more effective in reducing reinstatement to ethanol-seeking when it was co-administered with naltrexone, an opioid receptor antagonist, suggesting some degree of synergy between PPAR activation and opioid receptor inhibition. Similarly, it has been proposed that simultaneous inhibition of FAAH and activation of PPARs may have an additive or even synergistic effect in treating cancers, and this approach may similarly hold promise in the context of addiction pharmacotherapy.

Antibiotics and changes in microbiome also modulate PPARG!
Using fecal transplant procedures we reveal that, in response to high?fat diet, the gut microbiota drives PPARG?mediated activation of newly oscillatory transcriptional programs in the liver. Moreover, antibiotics treatment prevents PPARG?driven transcription in the liver, underscoring the essential role of gut microbes in clock reprogramming and hepatic circadian homeostasis. Thus, a specific molecular signature characterizes the influence of the gut microbiome in the liver, leading to the transcriptional rewiring of hepatic metabolism.
Notably, high?fat feeding was shown to amplify the expression of PPARG and its target genes by inducing de novo cyclic recruitment of PPARG to chromatin. Our results show that gut microbial remodeling under high?fat feeding induces rhythmic activation of PPARG that in turn leads to transcriptional reprogramming in the liver.
Circadian activation of PPARG and SREBP1 expression coordinately contributes to the regulation of hepatic lipid metabolism in HF?R mice and previous evidence demonstrates that metabolites produced by gut microbes regulate host liver lipogenesis. Indeed, we observed an increase in the levels of hepatic long?chain fatty acids that are involved in both signaling pathways and in lipid accumulation in the liver. Furthermore, short?chain fatty acids (SCFA) produced by bacterial fermentation are modulators of PPARG, and PPARG signaling might be altered by different SCFA profiles depending on dietary changes.

Environmental pollutants modulate PPARG!
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that are widely involved in various physiological functions. They are widely expressed through the reproductive system. Their roles in the metabolism and function of sex steroids and thus the etiology of reproductive disorders receive great concern. Various kinds of exogenous chemicals, especially environmental pollutants, exert their adverse impact on the reproductive system through disturbing the PPAR signaling pathway. Chemicals could bind to PPARs and modulate the transcription of downstream genes containing PPRE (peroxisome proliferator response element). This will lead to altered expression of genes related to metabolism of sex steroids and thus the abnormal physiological function of sex steroids.
PPARs are detectable in various compartments of the reproductive system, including hypothalamus, pituitary, testis, ovary, uterus, and adrenal and mammary gland.
PPARs are widely involved in reproductive function, such as ovarian function, gestation, and communication between mother and fetus. Sex steroids, also named as gonadal steroids, are defined as steroid hormones that interact with receptors of androgen, estrogen, and progesterone in vertebrates. Sex steroids are produced by gonads (ovaries or testes) and adrenal glands. Further conversion could occur in other tissues such as livers and fats. PPARs are critical for the metabolism and physiological function of sex hormones.
Pollutants could bind to PPARs and then modulate the PPAR signaling pathways involved in the reproductive function.
Hydrophobic interactions are the primary driving force for the binding between pollutants and PPARs. Most of the amino acid residues are hydrophobic around the binding pocket which located inside the protein structure of PPARs. The sequences of amino acids which form the pocket are conserved across species. Results from reporter cell lines also show that environmental ligands (BPA derivatives, phthalates, and PFAAs) share similar affinity for PPARG of zebrafish and human.
Exogenous testosterone significantly inhibited the expression of PPARG in primary hepatocytes isolated from brown trout. 17B-Estradiol could regulate the expression of PPARG in human peripheral blood eosinophils. Additionally, precursors of sex steroids also interact with PPARs. For example, dehydroepiandrosterone (DHEA) induced elevated expression of both PPARA and PPARB/D in the muscle of mice. Conversely, PPARs have an important impact on sex steroids.
Peroxisome proliferators (PPs) are a group of chemicals which function through PPARs. PPs could impair the function of endocrine tissues by regulating the expression of phase I and phase II steroid metabolism enzymes, including P450 enzymes and 17B-hydroxysteroid dehydrogenase IV. Apart from their impact on metabolism, PPs could also disturb the physiological function of sex steroids. They have been reported to mimic or interfere with the action of sex steroids and then induce reproductive disorders. In addition, receptors of sex steroids were also reported to interplay with PPARs. For example, estrogen receptor alpha (ERa) binds to the PPRE sequence of PPARG and represses its transactivation in MCF-7 cells. Bidirectional interplay occurs between PPARG and ER.
Sources of PPs contain endogenous and exogenous chemicals. Endogenous essential fatty acids (FAs) and their derivative eicosanoids are able to activate the PPAR signaling pathway. 17B-Estradiol could suppress the expression of PPARA regulating genes. In addition to these endogenous chemicals, chemicals from environmental media, drugs, and other external sources are also reported to disturb the PPAR signaling pathway and then affect metabolism and function of sex steroids.
PPARs have been regarded as a bridge to link the environmental chemicals and their health impact.

Some environmental pollutants that modulate PPAR activity are phthalates, perfluoroalkyl acids (PFAAs), bisphenol A (BPA), dioxin, some pesticides etc.
In addition to individual pollutants, chemical mixtures also display reproductive toxicity through PPARs. Direct activation of AHR and transactivation of PPARs are indispensable parts in this molecular response pathway.
PPARs, especially the subtype of A and G, have important roles in mediating the toxicological outcomes caused by environmental ligands. Various kinds of environmental pollutants show impacts on the metabolism and function of sex steroids through disturbing the PPARs signaling pathways.

Arg1 induction was accompanied by enhanced expression of the nuclear receptor peroxisome proliferator?activated receptor gamma (PPARG), and by enhanced IL?10 release, known markers of pro?regenerative microglia.
The transcription factor STAT 6 accumulates in response to IL?4 and, along with its downstream effector PPARG, has a central role in the regulation of transcription of anti?inflammatory and pro?resolving genes. Additionally, IL?4 induces expression of CD36, a receptor of lipoproteins, whose uptake and metabolism may support fatty?acid oxidation, contributing to metabolic microglia reprogramming.
IL?10 drives microglia toward an alternative activated phenotype, which mainly participates in phagocytosis and removal of tissue debris.
As mentioned above, PPARs-G are nuclear receptors highly expressed in microglia, that play important roles in both the immune response and cell metabolism.
Consolidated evidence indicates that PPARG activation by both natural and synthetic agonists, including the small molecule SNU?BP, inhibits expression of surface antigen and synthesis of inflammatory mediators, while increases the expression of the anti?inflammatory genes Arg?1 and IL?4 and promotes microglial phagocytic ability.
PPARs-G have been implicated in the phenotypic switch induced in microglia by some neuroprotective natural compounds, such as malibatol A, a resveratrol agonist and galangin, a molecule abundant in honey and medicinal herbs (such as galangal!).
PPARG?dependent microglia reprogramming toward beneficial function accounts for better outcome in several preclinical models of brain pathologies. The treatment of AD mice with the PPARG agonist pioglitazone, a drug used to treat type 2 diabetes, results in enhanced capability of microglia to phagocyte AB and cognitive improvement. Moreover, pioglitazone ameliorates the disease course in both the experimental autoimmune encephalomyelitis (EAE) model of MS and in mice subjected to chronic mild stress.
PPARs-G regulate inflammatory pathway in microglia by several mechanisms. They block p?38MAPK inflammatory pathways, resulting in decreased microglia reaction and reduce the activation of the classical pro?inflammatory transcription factors STAT?1 and NF?kB, which are known to mediate both LPS and IFNg inflammatory signaling in microglia. However, the pivotal role of PPARs?G in regulating the activation state of microglia may be due to metabolic reprogramming, as recently highlighted in macrophages, where PPARG has been implicated in mTOR?dependent fatty acid uptake and lipid metabolic reprogramming, downstream activation of semaphorin 6D (Sema6D), a key regulator of alternative macrophage polarization. Indeed, through interaction with downstream transcription factors and coactivators, PPARs?G regulate the expression of genes involved in glucose metabolism in mitochondria and fatty acid oxidation. Specifically, when activated by the full agonist pioglitazone, PPARs-G increase mitochondrial biogenesis, mitochondrial DNA content and oxygen consumption through interaction with the PPARG coactivator 1?alpha (PGC1a), the nuclear factor erythroid 2–related factor 1–2 (Nrf1–2), and mitochondrial transcription factors (mtTF)A, regulating antioxidant gene expression. In addition, PPARG activation increases mithocondrial fission, which mediates removal of damaged mitochondria and plays an important role in the assembly of mitochondrial electron transport chain.
Independent of the inflammatory challenge applied (e.g., hypoxia, interferon?g, amyloid?B), cultured microglia consistently show decreased production of pro?inflammatory factors, decreased COX2 and iNOS activity while exibit typical features of anti?inflammatory microglia, like CD206 surface expression and autophagy when treated with n?3 PUFAs.
Inhibition of p38MAPK inflammatory pathway and PPARG activation are also in part responsible of protective effects of PUFAs and their products. Given the connection of NF?kB and PPARG to the bioenergetics state of microglia, also dietary lipids may likely shape microglia phenotype acting on cell metabolism. In support to this hypothesis, fasting and ketogenic diet, that lead to a sustained reduction in blood glucose levels and to an increase in circulating ketones, have been reported to have anti?inflammatory actions and suppress activation of microglia by regulating their metabolic features. These effects have been shown to rely on the activation of the metabolite receptor GPR109A by B?hydroxybutyrate, that attenuates NF?kB signaling and pro?inflammatory cytokine production.
Other groups of bioactive compounds, normally present in foods, especially in the Mediterranean diet, such as phenolic compounds, phytosterols and carotenoids (e.g., lycopene, fucoxanthin, and lutein) exhibit anti?inflammatory properties on microglia, but the mechanisms underlined their effects still remain to be defined.
(Micro RNA) MiR?223 deficiency leads to compromised pro?regenerative differentiation in response to IL?4. Importantly miR?223 has been shown to be required for PPARG function, linking the acquisition of pro?regenerative traits to mitochondrial glucose metabolism and fatty acid beta oxidation.
miR?181a targets the inflammatory genes IL?1?, TNF and the transcriptional factor C/EBPa but also suppresses Kruppel?like factor 6 (KLF6), a PPARG inhibitor, thus likely favoring PPARG?dependent energy metabolism in mitochondria and fatty acid peroxidation in microglia. This has been proven in lymphocytes where miR?181a enhances the expression of genes involved in beta oxidation while suppresses isocitrate dehydrogenase 1 (IDH1), a cytoplasmic enzyme involved in production of NADPH, the cofactor for NO and superoxide generation.
Previous findings from our group and others have shown that through their secretome mesenchymal stem cells (MSCs) re?direct microglia from detrimental toward pro?regenerative functions.
MSCs, indirectly co?cultured with microglia in vitro, directly counteract the pro?inflammatory response of cells activated with inflammatory cytokines and induce persistent pro?regenerative traits.
Pluchino and colleagues clearly showed that NPCs counteract the metabolic changes of pro?inflammatory cells and reprogram them toward an oxidative phosphorylation anti?inflammatory phenotype. Indeed NPCs restore basal oxygen consumption rate and extracellular acidification rate in pro?inflammatory macrophages. Furthermore, by performing an untargeted mass spectrometry analysis of the extracellular and intracellular metabolite content of macrophages, they identified the metabolite succinate as the main target of the pro?regenerative NPC action. Intracellular succinate is known to act as a key pro?inflammatory signal in phagocytes, by enhancing IL?1B generation and favouring mitochondrial production of ROS over ATP synthesis. Extracellular succinate also exhibits pro?inflammatory activity though interaction with its specific receptor SUCNR1 and it is emerging as a biomarker of metabolic distress and inflammatory activity.
PPARG activation is an alternative way to push oxidative metabolism in microglia, as already mentioned. PPARs?G can be activated with thiazolidinediones (e.g., pioglitazone or rosiglitazone) a class of antidiabetic drugs proven to be effective in reducing the extent of neuroinflammation in different models of brain diseases and to attenuate neurodegeneration in patients with mild?to?moderate dementia.
Starting from Resveratrol, the first SIRT1 activator described, other SIRT activators have been developed and some of them are currently in clinical trials for the treatment of age?related neuroinflammation.

Also check out the figures!

L-theanine inhibited the absorption of glutamine and large neutral amino acids (AAs, leucine, and tryptophan) into organs.
It is reported that the fatty acid accumulation in mice was suppressed by the administration of green tea powder and theanine was responsible for this suppressive effect. Although serum glucose in rats was not changed, the insulin was reduced by oral theanine. These literatures indicate that metabolism of lipid and insulin is regulated by L-theanine. Therefore, we predicted that L-theanine may target transcription factors (PER1, HNF, and PPARG) and further inhibit the expression of glucose transporters mRNA.


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Re: FAAH Inhibitors
« Reply #18 on: April 29, 2021, 08:23:51 AM »
(Disclaimer: I have not read most of what you wrote)

How does your theory work with people that cured their POIS by improving their microbiome/gut bacteria/dysbiosis/fixing infections etc?

I am sorry for not replying earlier, but I needed some break.
Regarding your question I was actually getting to that point, but I had to lay out some background information first. From the previous post it is fairly reasonable to assume that a change in microbiome can lead to sustained PPARG reprogramming. This might have happened in the case of the POISer who eradicated most of his microbiome and reestablished it with a different set. This may be similar to fecal transplantation. Actually there is no guarantee that this could work, as I also took Ciprofloxacin with a probiotic for 10 days and it hadn't resolved my POIS issue. I also had controversial experiences with probiotics. Some probiotics containing Lactobacillus actually increased the burning pain and that is why I suspected the involvement of lactic acid. Other probiotics caused severe flatulence which I considered a bad reaction at the time, although I am not so sure anymore. I haven't documented their effects at the time, but I will retest them based on the new findings.

(I read about these supposedly cured cases of POIS on the forum a few weeks ago, but I couldn't find the link right now. I also don't know how credible they were.)

The other POISer who got cured through abstinence may have undergone a similar PPAR reprogramming as PPARs also play a role in withdrawal which definitely seems to be linked to our case. However there is still no guarantee that POIS can be resolved in every case, especially if there is an underlying genetic issue.
I am at least quite certain that regular ejaculation won't lead to POIS cessation, although some degree of tolerance may develop due to it. The longest period I abstained from sexual activity was more than half a year, but that also didn't change POIS.
Maybe some prolonged change could be achievable by abstaining and still taking the best working medication. Even if this is feasible there is still the issue of enhancing foods which doesn't make this easy and a result could be ill-hoped.

Other POISers managed to resolve their case by curing a localized inflammation. This also seems to be in line with the role of PPARs in inflammation. However identifying the exact site of such an inflammation is rather problematic with current diagnostic methods.

Of course these are only possibilities and the role of PPARs is not even proven yet. I am going to continue to trial as many supplements as possible so that some further conclusions may be drawn.

However if the role of PPARs is proven some other novel treatment possibilities arise actually.
It may be possible that a stem cell treatment could also ablate the inflammation, however I think we are decades if not centuries from such a treatment.

Some experiences I had in the meanwhile:
The combination of lungwort tea and saffron is quite extraordinary. Unfortunately even this can't completely overcome POIS, but this is the best thing I have found so far. It reduces all aspects of POIS considerably. It is definitely a profound painkiller. It feels like most of my pain receptors are blocked. I can only imagine that a very high anandamide level desensitizes TRPV1 receptors. I can hardly feel the thighs and my dick feels like a limp mass. Well it probably shouldn't be used if someone actually wants to do sex, but it is a superb after-event treatment nonetheless. If any POISer doesn't have any positive reaction to this I can't imagine their case has anything to do with the endocannabinoid system or with FAAH inhibitors at least.

I bought a supplement containing Echinacea and beta glucan [Echinacea purpurea 450 mg per pill and oat (Avena sativa) extract 50 mg per pill].
I took one pill in the morning and also took some separate Echinacea drops. Then I took two pills an hour before watching porn. Interestingly porn couldn't arouse me which is rare and I had to use physical stimulation to get an erection, although I am not sure if it was due to the supplements. POIS still occurred at O, but this managed to reduce POIS symptoms noticeable. I also took one pill before going to bed. Its effectiveness is somewhat below that of Berberine, but it certainly works.
I also tried the Echinacea drops [Echinacea angustifolia and Echinacea pallida alcoholic tincture 1g containing 0.33 g Echinacea] separately on an acute day without O. I took 20-30 drops with several hours of difference 4 times a day. It definitely reduced the burning pain if nothing else, although it takes about 6 hours to have this effect. I still had bloodshot eyes however and I can only hope it wasn't due to Echinacea itself.

Niacinamide (Vitamin B3) [500 mg per pill]: It certainly has a positive effect. Although I didn't test this against an O, taking one pill certainly reduced the burning pain by next day. It didn't have any particular side effects, aside from the mild hot flash that appeared in about 40 minutes. I would put its efficacy around that of ibuprofen. Next time I will take two pills and check it against an O.

I tried Rhodiola rosea on its own without an O. I took two capsules in the afternoon then one before going to bed. However I couldn't judge if it had any particular positive or negative effect. I will need to test it further.

I took a soy lecithin supplement a few years ago, but I can't remember if it did anything profound. As lecithin is a good source of PEA (Palmitoylethanolamide) I think I should try it again and see if it works better in a combination.
PEA is a naturally occurring lipid discovered more than 50 years ago, when it was first isolated from soy lecithin, egg yolk, and peanut meal. It is a long-chain N-acylethanolamine (NAE) and analog of the endocannabinoid anandamide (AEA) that is present in animals and plants.

Actually I tested a lot of other things in the meanwhile, but the effects are not always evident especially if they are adverse or mixed.
Melatonin and bitter melon looks to be promising, but I still need to test them a bit more to say anything definite.

I also have to wonder why so many anti-cancer drugs work in my case. If nothing else this may further reinforce the role of PPARs as new research (see a previous post) highly indicate their involvement in cancer development and treatment.

Another interesting experience I had was on a chronic POIS day when in the morning I drank saffron tea and also took a berberine and MACA capsule. I was feeling rather well even in the afternoon. Then I decided to watch porn and masturbate, but I didn't take anything beforehand. It was like more than half an hour when I went to the bathroom for some water. I checked in the mirror and had completely clear (white) eyes. I went back and not another 10 minutes later (without O) suddenly there is a stinging pain in the eyes. I went to check in the mirror and I had full blown bloodshot eyes. So even if I use a well working treatment there seems to be an extent to their effect. So to put it in a different way POIS is much like the surging waves of the ocean while the treatment acts much like a dam. The problem is that the waves are incessantly eroding the dam and a fragile dam simply can't withstand the onslaught of the tsunami that comes at the moment of O. To prolong the drowning the ocean doesn't become still after the tsunami, but actually gets stormy and turbulent for a week and even the best dams I quickly put in its place are rapidly pulverized.


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Re: FAAH Inhibitors
« Reply #19 on: April 30, 2021, 02:07:39 PM »
The combination of lungwort tea and saffron is quite extraordinary. Unfortunately even this can't completely overcome POIS, but this is the best thing I have found so far. It reduces all aspects of POIS considerably. It is definitely a profound painkiller. It feels like most of my pain receptors are blocked. I can only imagine that a very high anandamide level desensitizes TRPV1 receptors. I can hardly feel the thighs and my dick feels like a limp mass. Well it probably shouldn't be used if someone actually wants to do sex, but it is a superb after-event treatment nonetheless. If any POISer doesn't have any positive reaction to this I can't imagine their case has anything to do with the endocannabinoid system or with FAAH inhibitors at least.

Random googlings because somewhere in forum it was mentioned that acetylcholinesterase inhibiton (and choline supplementation?) helps, someone with more science knowledge please confirm if relevant:

Pulmonariae officinalis (Lungwort) (Apparantely there are multiple lungworts, so NOT Lobaria pulmonaria)
The P. officinalis extracts showed slightly lower acetylcholinesterase inhibitory effects – 87.7%, tyrosinase inhibitory effects – 73.69%,

Saffron extract showed moderate AChE inhibitory activity (up to 30%),

I wonder about the chest pain you describe. I never have chest pain. Maybe the tea fixed something there for you if it claims it's for chest infections. Also claims it's for urinary tract infections

When reading Amazon reviews for teas with Lungwort, they say it really helped their breathing.
And in the forum here we sometimes discuss about breathing techniques or autonomic nervous system... hmmm very interesting.