Author Topic: FAAH Inhibitors  (Read 584 times)


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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.


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Re: FAAH Inhibitors
« Reply #20 on: May 02, 2021, 05:35:17 AM »
Hello Progecitor, did you see that I sent you a personal message?

I am sorry for the late response, but I haven't had much spare time. Nevertheless I put the reply here so that others may also find some benefit.
Prospero was kind enough to bring to my attention that the PPAR-allopregnanolone axis could have a connection to Gilbert's syndrome.
"In Gilbert's your hormones are not knocked down, you have problems with glucuronidation, which breaks down 3adiol. So your 3adiol is not broken down, which inhibits 5a-reductase and causes low allopregnanolone, which leads with time to GabaA downregulation and AMPA receptor upregulation. Your high glutamate leads to activation of microglia. These problems with liver also stop methylation, which will be worsened because you are homozygous for COMT, and then you have bad conversion from noradrenaline into adrenaline. And obviously problems with histamine, serotonin, etc."

I checked into it a bit, but the involvement of GABA seems controversial so far. You could be right, but I don't have any hormonal measurements and I haven't tried many GABAergic compounds either. I plan to have some hormonal tests done later this year and maybe some genetic tests next year, but the pandemic and my earnings don't make this easy. I highlighted some definitions as I am also just learning about these things and it makes this a bit easier to understand.
What I found so far:
3a-diol is a positive allosteric modulator of the GABA(A) receptor which means that it changes the receptor's response to stimulus. Positive modulators increase the response of the receptor by increasing the probability that an agonist will bind to a receptor (i.e. affinity), increasing its ability to activate the receptor (i.e. efficacy), or both.[/i]

I checked the list on wiki and the comments I can make:
GABA(A) agonists: GABA, taurine, beta-alanine, allopregnanolone
GABA: I plan to buy to buy a supplement, but it hasn't been a priority so far.
Beta-alanine didn't do anything to POIS or my depression although I took it for two months last summer. Taurine increases the burning pain I feel which is a major indicator of my POIS. It can also cause a heartburn. However I haven't noticed any effect on depression or I was just not aware enough.
GABA(A) positive modulators: benzodiazepines, apigenin, niacinamide, 3a-diol, allopregnanolone
I took clonazepam (benzodiazepine) for years and it surely made me even more depressed and forgetful, however I don't think it really affected the other aspects of POIS or I just can't remember.
Apigenin and niacinamide are actually beneficial for my POIS.
Antagonists: I couldn't find any that is readily available to check.
Negative modulators: DHEA, amentoflavone, ciprofloxacin
DHEA,: I haven't tried it yet but I want to in the future.
St. John's Wort (SJW) contains amentoflavone. I tried SJW twice, but I also took other POIS modulators at the time so I can't conclude anything yet.
Ciprofoxacin: I took some a few years ago, but I don't think it did anything to depression or I just don't remember.

I actually bought an Apigenin product that also contains taurine. I only took it once, but I don't think it did much. This should theoretically up-regulate GABA(A) quite well. I am going to test it a bit more of course, but others could do as well.

Lemon balm (Melissa officinalis) is a GABA transaminase inhibitor. Inhibition of GABA transaminase enzymes reduces the degradation of GABA, leading to increased neuronal GABA concentrations.

It is true that both apigenin and lemon balm help me, but they are also involved in FAAH inhibition.

The most potent and selective inhibitors of 5a-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoic acid derivatives, and more recognizably, polyunsaturated fatty acids (especially linolenic acid), zinc, and green tea. Riboflavin was also identified as a 5a-reductase inhibitor.[/b]
It is a fairly reasonable suspicion that linolenic acid enhances my POIS. I have other problems with zinc that may be not directly related to POIS. I had some reaction to green tea, but I don't exactly remember what and I have to retest it before I can say any more. Riboflavin is also known as vitamin B2, but I haven't tested that separately, so I am not sure.

AMPA receptors play a key role in the generation and spread of epileptic seizures.
It is true that I took Rivotril (Clonazepam) for years, but I have never had any kind of seizures in my life, so it is unlikely that AMPA is up-regulated in my case. Clonazepam is also used to treat epilepsy if someone hasn't heard about benzos.

The substances resulting from glucuronidation are known as glucuronides (or glucuronosides) and are typically much more water-soluble than the non-glucuronic acid-containing substances from which they were originally synthesised. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or feces (via bile from the liver).
Phenobarbital is an inducer of glucuronidation of both morphine and bilirubin.
Clonazepam is an inhibitor of morphine glucuronidation.
A low dose of phenobarbital may be beneficial for me as I probably have problems with both morphine and bilirubin.

Phenobarbital is occasionally prescribed in low doses to aid in the conjugation of bilirubin in people with Crigler–Najjar syndrome, type II, or in patients with Gilbert's syndrome.
It is true that the only consistently bad blood parameter I have is an increased total bilirubin, however its value is only slightly increased. I also haven't experienced typical jaundice. There might had been some rare occasion when I had some slight yellowing of the conjunctiva, but usually it is only bloodshot and nothing else.

An elevated bilirubin level also seems to be a risk factor in COVID-19 infection, even though the infection wasn't very serious for me. Based on research bilirubin actually protects the virus against the antibodies.

FAAH inhibition can affect GABA.
A selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic intracellular membrane cisternae at perisomatic GABAergic symmetrical synapses.
Together, these findings are consistent with the possibility that constitutively active CB1 receptors substantially influence perisomatic GABA release probability and indicate that the synaptic effects of tonic 2-AG release are tightly controlled by presynaptic MGL activity and also by postsynaptic endovanilloid signaling and FAAH activity.
The findings indicate that constitutive CB1 activity has pivotal function in the tonic control of hippocampal GABA release. Moreover, the endocannabinoid 2-arachidonoylglycerol (2-AG) is continuously generated postsynaptically, but its synaptic effect is regulated strictly by presynaptic monoacylglycerol lipase activity. Finally, anandamide signaling antagonizes tonic 2-AG signaling via activation of postsynaptic transient receptor potential vanilloid TRPV1 receptors. This unexpected mechanistic diversity may be necessary to fine-tune GABA release probability under various physiological and pathophysiological conditions.
Constitutively active receptor: A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse agonist.

Niacinamide is a PPARA agonist just like PEA.
Panthenol is known to improve epidermal differentiation and to be an effective anti?inflammatory agent. In these studies we demonstrated the effects of panthenol on reducing PGE2 levels and tissue damage induced by a strong inflammatory cocktail in an in vitro model. This is relevant to the clinical setting as PGE2 is known to be elevated in subjects with sensitive skin. PEA also proved effective at reducing the levels of PGE2 and IL?6 in vitro, both of which are UV?induced inflammatory biomarkers. In addition, PEA reduced the levels of thymic stromal lymphopoietin (TSLP), an inflammatory and pruritogenic biomarker, consistent with its reported itch?relief activity. PEA is also a putative PPARA agonist that may mitigate irritation via this mechanism also.
Niacinamide (NAM) was shown to enhance the expression of epidermal differentiation genes and increase cellular NAD.
The former result is contradictory to that of Blander et al. and may reflect different testing methods, but the latter result is consistent with Rovito. Moreover, topical NADH, the reduced form of beta?nicotinamide adenine dinucleotide, is reported to be effective in the treatment of rosacea and contact dermatitis. Furthermore, the current work also demonstrated NAM?induced PPARA gene expression which is known to play an important role in regulating epidermal differentiation and reducing UV?induced erythema. Although speculative at this stage, it is likely that NAM may synergise with PEA in this mechanism.

PEA was first isolated from soy lecithin, egg yolk, and peanut meal.
One way in which PEA can indirectly activate CB1 and CB2 receptors is by inhibiting the expression of fatty acid amide hydrolase (FAAH), an enzyme that degrades the CB1 agonist AEA. The transient receptor potential vanilloid receptor type 1 (TRPV1) channels, which are also endocannabinoid targets, can also be indirectly activated by PEA. From these activities, it can be surmised that PEA needs synergistic actions among several mechanisms for it to be able to produce its effects.
I took a soy lecithin supplement a few years ago and I think it helped a little at the time, so I will need to test it again.

Intracellular NAD+ (nicotinamide adenine dinucleotide) concentrations reflect a balance between biosynthesis from discrete dietary precursors and "consumption" by enzymes that cleave NAD+ to release nicotinamide. Stressors such as ischemia have been known to induce NAD+ consuming enzymes such as poly-ADP-ribose polymerases and CD38; induction of these enzymes lowers NAD+. Tran and colleagues recently reported that renal tubular cell NAD+ levels are suppressed in models of acute kidney injury (AKI) and that this reduction of NAD+ may blunt fatty acid oxidation, reduce adenosine triphosphate generation, and elevate susceptibility to AKI stressors. Unexpectedly, they found that the stress-related fall in NAD+ was not only a consequence of increased consumption but also the result of decreased biosynthesis. In seeking a mechanism of decreased NAD+ biosynthesis, this study identified a novel function of the mitochondrial biogenesis regulator PPAR-gamma-coactivator-1alpha (PGC1a) to coordinately induce the enzymes that sequentially convert the amino acid tryptophan to NAD+. This series of enzymes is collectively referred to as the "de novo" or "kynurenine" (one of the intermediates between tryptophan and NAD+) biosynthesis pathway for NAD+. This study showed that renal tubular PGC1a expression defends the nephron against unrelated stressors, and that artificial augmentation of NAD+ could effectively mimic PGC1a's salutary effects in the tubule. Hence, a common PGC1a-NAD+ "axis" was described for kidney protection across rodent models of ischemia, inflammation, and nephrotoxicity.
The authors then embarked on a clinical trial to augment NAD+ among high-risk patients. Since the de novo pathway appeared to be blocked by QPRT suppression, they chose to administer nicotinamide (also referred to as niacinamide), the base version of vitamin B3, which the team had shown to boost renal NAD+ through another biosynthetic route known as the "salvage" pathway.

This article greatly proves what Prospero said, although I still need to confirm it in my case.
Specifically, we focus on the function of the peroxisome proliferator–activated receptor (PPARA), a target for PEA, which is best known for its role in reducing inflammation by decreasing cytokines, pro-inflammatory enzymes and oxidative stress. For this, PPARA agonists act as neuroprotectants in various neurological disorders like Alzheimer's disease, Parkinson's disease, multiple sclerosis, and cerebral ischemia. However, recent literature in the field suggest that PPARA has emerged as a new target that is useful as a novel approach to treat mood disorders by engaging neurosteroid biosynthesis.
PPARA activation has been shown as a natural response to stress, having the ability to mediate and modulate the stress response. In healthy adults, PEA, an endogenous PPARA agonist, significantly increase after clinical stress tests, corresponding with increased cortisol levels. PEA levels increase when healthy individuals experience pain or a depressed mood transiently. However, the levels of PEA in PTSD are low, suggesting a significant role in emotion regulation. As such, endogenous and synthetic PPARA ligands have predictably and successfully stabilized emotions in preclinical models.
Given that allopregnanolone directly binds this receptor, a reduction of allopregnanolone levels correlate to reduced GABA(A) receptor activity and dysfunctional behavior.
Intriguingly, the allopregnanolone level in the blood and CSF are reduced in patients of major depressive disorder (MDD), impulsive aggression, premenstrual dysphoric disorder, PTSD and other disorders of mood and emotions.
As a specific example, the allopregnanolone level in the CSF of female PTSD patients were 40% lower than in controls, and the allopregnanolone/dehydroepiandrosterone (DHEA) ratio negatively correlates with PTSD re-experiencing. To this end, studies are being pursued to verify lower levels of allopregnanolone during pregnancy as a predictor of postpartum depression (PPD).
Early studies have shown that allopregnanolone levels in the brain increase to levels that can activate the GABA receptors, during acute stressful events. Subsequently, it has been further hypothesized that the enhancement of GABAergic transmission decreases HPA activity and contributes to the behavioral stress response. Protracted stress, on the other hand, downregulates allopregnanolone biosynthesis. The decrease of allopregnanolone was the result of reduced levels of 5a-reductase type I mRNA and protein following social isolation. Hence, these findings suggest that allopregnanolone, its precursors, and analogs of allopregnanolone are suitable treatments for emotional regulation. For example, exogenous allopregnanolone attenuated the contextual fear response in a dose-dependent manner. In a similar murine social isolation model of PTSD, researchers showed that allopregnanolone treatment normalized HPA responsiveness and interrupted depressive- and anxiety-like behavior, which are hallmarks of clinical PTSD.
The summaries above suggest that the role of allopregnanolone in the progression and recovery of psychiatric disorders is similar to the emerging role of PPARA. Importantly, these similarities are not limited to their function in emotion regulation. Comparable actions of PPARA and allopregnanolone have also been observed across cognition, neurogenesis, neuroinflammation, neurodegeneration, and substance use disorder. Raso et al. suggest that the PPARA and allopregnanolone are different substrates of the same mechanism, whereby PEA-induced activation of PPARA regulates the biogenesis of allopregnanolone in astrocytes. To this end, when astrocytes were treated with PEA in vitro, an increased expression of enzymes that are crucial to allopregnanolone biosynthesis [steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc)] were reported along with increased cytoplasmic concentrations of allopregnanolone. This interdependent relationship between PPARA and allopregnanolone has also been alluded to in studies of pain perception. In studies of acute and persistent pain, researchers showed that the usual anti-nociceptive activity of PEA was reduced when activity of enzyme 5a-reductase and P450scc were blocked. PEA restored enzyme expression and increased allopregnanolone level in the spinal cord. Further support for this relationship was shown when PEA was used as neuroprotector and regulator of the pentobarbital-evoked hypnotic effect. In this case, PEA increased the expression of relevant enzymes and allopregnanolone concentrations in the spinal cord.
These findings suggest that allopregnanolone functions downstream of PPARA to mediate its therapeutic effects, thus, we further hypothesize that part of the mechanism of action of PPARA includes an upregulation of the biosynthesis of neurosteroids, by upregulating the expression of crucial neurosteroidogenic enzymes. A recent study by Locci and Pinna further demonstrated the allopregnanolone-dependent effect of PPARA-activation. In this study, a single dose of a PPARA agonist, PEA or GW7647, normalized the levels of allopregnanolone in socially isolated mice, improved depressive-like and anxiolytic-like behavior, and facilitated impaired extinction of fear memory. The therapeutic-like effects of the PPARA agonists were however obstructed by genetic ablation of PPARA, antagonism of PPARA, and inhibition of neurosteroidogenic enzymes. This and previous studies further support a possible PPARA-allopregnanolone biomarker axis in PTSD, and a new therapeutic target for emotional disorders.
Given the new relationship pointed out in this opinion article, the biochemical profile of PTSD may include a PPAR–allopregnanolone biochemical axis such that subpopulations of PTSD patients may display reduced allopregnanolone levels that can be increased by PPARA activation, only in allopregnanolone-deficient patients. Other components of the profile can also include changes in GABA(A) receptor subunit expression, decreased levels of endogenous fatty acid amides such as PEA and OEA, or downregulated expression of PPARA.

Another great article about the PPAR-neurosteroid axis that also lists great PPAR modulator nutrients.
In the pathogenesis of mood disorders, including major depressive disorder (MDD) and postpartum depression (PPD), both neuroinflammation and glutamate-mediated excitotoxicity mechanisms (neuronal death through glutamate-based over-activated stimulation) have been suggested to play a key role.
Interestingly, allopregnanolone reduces calcium influx through the activation of GABA(A) receptors expressed on cerebrocortical nerve terminals leading to decreased glutamate release and glial activation, supporting neuroprotective effects.
Locally produced allopregnanolone is responsible for the fine-tuning of GABA(A) receptors in corticolimbic glutamatergic neurons, a mechanism that has been linked with improvement of behavioral dysfunction. At this level, allopregnanolone may conceivably dampen neuroinflammatory processes following activation of glial-type GABA(A) receptors. Recent evidence shows allopregnanolone, following activation of a2-containing GABA(A) receptors and subsequent inhibition of toll-like receptor 4, can regulate the immune response by inhibiting proinflammatory processes.
Endogenously produced allopregnanolone plays a neurophysiological role in the fine-tuning of the GABA(A) receptors to GABAmimetics, positive allosteric modulators, and GABA agonists.
By this mechanism, allopregnanolone also regulates emotional behavior and stress-responses.
Moreover, decreased allopregnanolone levels in the postpartum period is associated with increased inflammation likely by activated microglia, which releases pro-inflammatory biomarkers, such as IL-1, IL-6 and TNF-a via the NFkB pathway that is also regulated by PPAR. Another mechanism involves the toll-like receptor 4 (TLR4), which, once activated by different triggers such as lipopolysaccharide (LPS), pathogen-associated molecular patterns (PAMPs), alcohol, stress or decreased levels of pregnenolone, forms a complex with intracellular co-activators, such as TIR Domain-Containing Adaptor Protein (TIRAP) and TRIF-related Adaptor Molecule (TRAM) to initiate a pro-inflammatory cascade that leads to NFkB activation and pro-inflammatory cytokines release. Low levels of allopregnanolone lead to increased calcium channel activity in activated nerve terminals and increased release of glutamate that facilitates excitotoxicity mechanisms. Unhealthy diets, including high fatty diets or alcohol abuse play deleterious effects on PPAR function that fails to regulate pro-inflammatory processes and greatly contribute to the neuroinflammation mechanisms underlying the pathogenesis of major depression and, possibly, PPD.
At the same time, increased allopregnanolone levels in neurons may stimulate brain derived neurotropic factor (BDNF) and exert important neuroprotective functions. We suggest that healthy diets enriched in micronutrients that are PPAR-agonists by enhancing the PPAR-allopregnanolone axis and decreasing inflammation may offer an alternative strategy to pharmacological treatments to prevent and safely treat mood disorders, including PPD.
Brexanolone, despite its proven high efficacy, showed adverse effects such as headache, dizziness, somnolence, and, in some cases, excessive sedation, which may complicate the safety of its use.
Together with PPARG, PPARA is deeply involved in several physiological and pathological conditions, including regulation of mitochondrial and proteasomal function, neuroinflammation, oxidative stress and neurodegeneration, which are considered key pathogenetic mechanisms involved in stress-related disorders, including anxiety and depression.
Intriguingly, PPAR mediates anti-inflammatory responses under several pathophysiological conditions and can stimulate biosynthesis of neurosteroids, such as allopregnanolone, with documented anti-inflammatory actions and role in improving mood symptoms, which suggests that the PPAR-neurosteroid axis may have a pivotal function in the modulation of mood by regulating inflammatory processes.
Intriguingly, PPARA activation stimulates the biosynthesis of allopregnanolone that in addition to elevating mood, has also been associated with an anti-inflammatory effect. Indeed, allopregnanolone binds at GABA(A) receptors expressed both on microglia and astrocytes and in glutamatergic pyramidal neurons, and it mediates anti-inflmmatory effects through blocking toll-like receptor 4. This results in NFkB inhibition.
Allopregnanolone's binding at GABA(A) receptors on monocytoid cells leads to diminished production of inflammatory mediators by these cells. Further, GABA suppresses astrocytes and microglia inflammatory responses to lipopolysaccharide (LPS) and INF-g by inhibiting the NFkB activation pathway and P38 MAP kinase. This process leads to a decreased release of pro-inflammatory cytokines, such as TNF-a and IL-6 and results in an attenuation of neurotoxicity in vitro. Interesting, similar anti-inflammatory effects were observed following the administration of the GABA(A) receptor agonist, muscimol and the GABA(B) receptor agonist, baclofen, suggesting the direct role of both types of GABA receptors in reducing neuroinflammation. Interestingly, GABA(A) receptors are also expressed in macrophages and lymphocytes T cells and their activation produces anti-inflammatory effects. In addition, neuroinflammation-associated release of glutamate from activated microglia has been implicated in the progression of neurodegenerative diseases, including Alzheimer's and Parkinson's disease and recent studies have shown that PPARs can modulate neurotoxicity by inhibiting glutamate release in LPS-activated microglia.
In vitro and in vivo studies show that 17B-estradiol, progesterone, and allopregnanolone reduce microglial-mediated inflammation.
A combined therapy of pioglitazone with the SSRI antidepressant, citalopram, showed a higher pharmacological response and remission rate, and rapid onset compared to citalopram alone. In another study, a 12-week pioglitazone administration induced antidepressant effects in patients with comorbid insulin resistance, supporting a link between depression and metabolic dysregulation.
Green tea, broccoli, onions, and berries are enriched in phytonutrients, such as carotenoids, ellagic acid, flavonoids, resveratrol, glucosinolates, and phytoestrogens that help fighting oxidation and inflammation. Naringenin, quercetin, hydrocaffeic acid, procyanidins, and anthocyanidins belong to the class of flavonoids and exert anti-inflammatory effects in vivo and in vitro by inhibiting the expression of iNOS, ICAM-1, MCP-1, COX-2, TNF-a, IL-1B and IL-6 expression.
PEA is abundant in egg yolk, soy oil, peanut oil, and corn, peas and beans, tomatoes and potatoes.
In addition, zinc modulates PPARG signaling, which is impaired in zinc deficiency.
In rodents, for instance, high-fat diets alter PPAR pathway causing abnormalities in the microbiome that can be reversed by rosiglitazone, a PPARG agonist. Several natural bioactive compounds act on PPARs, including the tea plant, soybeans, palm oil, ginger, grapes and wine as well as a number of culinary herbs and spices (e.g. Origanum vulgare, Rosmarinus officinalis, Salvia officinalis, Thymus vulgaris).
Curcumin has also shown anti-inflammatory and antioxidant effects by increasing PPARG activity.
OEA, which is a natural metabolite of oleic acid, and an endogenous PPARA modulator, shows anti-inflammatory activity. Then, foods rich in oleic acid, such as olive oil, avocado and almond oil can be used as part of the anti-inflammatory dietary patterns.
In addition, omega-3 (or n-3) PUFAs and their metabolites are natural ligands for PPARG.
EPA and DHA supplementation have been shown to decrease levels of key inflammatory cytokines TNF-a, IL-1B, IL-6, and IL-8.

Dietary flavonoids found in fruits and vegetables exert anti-inflammatory effects, as well by suppressing microglia activation through the PPARG mediated pathway.
Resveratrol, which is present at high levels in red grapes, nuts, and pomegranates, exerts metabolic, antioxidant, and anti-inflammatory activities, as well as neuroprotective effects through PPAR-activation. Similarly, quercetin induced antidepressant-like effect in the unpredictable chronic mild stress animal model of depression and induces antioxidant, anti-inflammatory activities, reduces excitotoxicity and augments 5-HT levels, linking the role of inflammation to depression. Foods rich in quercetin are capers, goji berries, onions, asparagus, spinach and red grapes. Resveratrol and quercetin are polyphenolic compounds that improve metabolic syndrome by altering PPAR expression. PEA shows antidepressant effects by binding at its main target, PPARA, and may increase endogenous levels of the endocannabinoids, anandamide (AEA) and 2-arachinoylglycerol (2-AG) and exert anti-inflammatory, analgesic, and neuroprotective properties.
We propose that PPAR might work in synergism with stimulation of neurosteroid biosynthesis to exert their beneficial effects by decreasing inflammation and relieving mood symptoms. Intriguingly, PEA-induced PPARA activation engages allopregnanolone levels in frontal cortex, hippocampus and amygdala to improve behavioral abnormalities in an animal model of stress-induced mood disorders
Moreover, allopregnanolone is also involved in BDNF expression and neurogenesis. In socially isolated mice reduced levels of allopregnanolone in corticolimbic areas are associated with BDNF deficiency, reduced neurogenesis and depressive- and anxiety-like behavior, supporting a multifunctional role of allopregnanolone for depression and anxiety prevention.
Intriguingly, studies have suggested that PPARA activation by administering synthetic PPARA agonists, including fenofibrate, is associated with stimulation of BDNF signaling cascade and improvement of behavioral dysfunction.
Moreover, FDA-approved synthetic PPARA agonists, including the fibrates (e.g., fenofibrate, clofibrate), prescribed for the treatment of hypercholesterolemia, could be repurposed to treat mood disorders by targeting the PPAR-allopregnanolone axis.

Table 1. contains a list of Functional Foods rich in micronutrients that activate PPARA and PPARG and induce pharmacological effects!

I think PPARA agonists may help me, so I will have to thoroughly test them. A short list of PPARA agonists: PEA (soy lecithin, egg yolk, and peanut meal) niacinamide, oleic acid (olive oil, avocado and almond oil), fibrates (fenofibrate, clofibrate).


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Re: FAAH Inhibitors
« Reply #21 on: May 02, 2021, 05:43:32 AM »
To be precise, as I wrote you, it's not *my* argument, but someone else wrote this to me (as an hypothesis) and it made me think about what you were researching. I don't know if there is such a connection, it exceeds greatly my own competence.
Whatever, thank you for your findings on this topic.
« Last Edit: May 02, 2021, 06:12:47 AM by Prospero »


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Re: FAAH Inhibitors
« Reply #22 on: May 02, 2021, 11:50:51 AM »
To be precise, as I wrote you, it's not *my* argument, but someone else wrote this to me (as an hypothesis) and it made me think about what you were researching. I don't know if there is such a connection, it exceeds greatly my own competence.
Whatever, thank you for your findings on this topic.

The message I wanted to convey is that the theory is definitely valid as even official researchers proposed it. However as of this moment I can't clearly prove or refute it based on my personal experience and that is why I highlighted possible ways to modulate the process and check it against reality. Refuting it for one case doesn't necessarily mean that it is not true for at least some POIS cases.  At least PPARA agonists seem highly worthy to trial as many of them worked for one or another POISer. If someone has about the same experience with all of them then it is an indirect evidence for PPARA involvement in their personal POIS case be it either up- or down-regulation.


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Re: FAAH Inhibitors
« Reply #23 on: May 02, 2021, 05:28:30 PM »
Yes, I understand very well, I just wanted to make this clarification because, considering my absence of skills, members of the forum may be surprised by the assertive tone of the quote, which is not from me.
As for the specific link with bilirubin, I have still some difficulty to clarify the relation between low glucuronidation (of 3adiol) and 5a-reductase inhibition.
I also noticed that I had rather bad reactions to zinc and green tea (worsening of some of my usual Pois symptoms, notably tachycardia) but it may have nothing to do with 5a-reductase.
Lemon balm seems beneficient for me too, for my nervous symptoms. As for GABA as a supplement, some people seem to think that it can be transformed into glutamate and is not necessarily useful as a GABA receptor agonist.


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Re: FAAH Inhibitors
« Reply #24 on: May 04, 2021, 03:44:24 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.

Thank you for bringing this to my attention!
Actually I have been wondering about the possible role of acetylcholinesterase as well. However as of this moment I am almost completely sure about the beneficial involvement of FAAH inhibitors as it turns out that Echinacea also has FAAH inhibitory property. A possible explanation could be that acetylcholinesterase inhibition is also beneficial. There is a wide variance in the effective time of the advantageous compounds and saffron and lungwort seems somewhat distinct in that they take effect in a very short time. Of course this is a mere guess and more acetylcholinesterase inhibitory supplement and maybe even some prescribed medication have to be trialed before a clearer resolution can be made. It would be really lucky if someone who already had a positive experience with acetylcholinesterase inhibitors could test saffron or lungwort and could make a comparison.

I haven't read everything about lungwort (Pulmonaria officinalis), but it is good to know that it also contains Pyrrolizidine alkaloids (PA). However this is a bit worrying finding.
Pyrrolizidine alkaloids are produced by plants as a defense mechanism against insect herbivores.
Unsaturated pyrrolizidine alkaloids are hepatotoxic, that is, damaging to the liver. PAs also cause hepatic veno-occlusive disease and liver cancer. PAs are tumorigenic. Disease associated with consumption of PAs is known as pyrrolizidine alkaloidosis.
So even though it is filled with a lot of anti-cancerous compounds its excessive use could be detrimental in the long run. I still think it is a good choice for days when I want to have an O, but it doesn't seem like a good idea to use it on a daily basis.
Common centaury (Centarium umbellatum) is also available here, so I will surely try and see how it works.
Tussilago farfara, commonly known as coltsfoot is also used to treat asthmatic and flu symptoms, so I thought it would be interesting to see what it does. Unfortunately coltsfoot contains the most toxic and carcinogenic pyrrolizidine alkaloids, so it is definitely not for someone with a Gilbert's disease. Although experts have bred a variety that practically contains no detectable pyrrolizidine alkaloids.
Tussilago farfara leaves have been used in traditional Austrian medicine internally (as tea or syrup) or externally (directly applied) for treatment of disorders of the respiratory tract, skin, locomotor system, viral infections, flu, colds, fever, rheumatism and gout.
Tussilago farfara contains tumorigenic pyrrolizidine alkaloids. Senecionine and senkirkine, present in coltsfoot, have the highest mutagenetic activity of any pyrrolozidine alkaloid. In response, the German government banned the sale of coltsfoot. Clonal plants of coltsfoot free of pyrrolizidine alkaloids were then developed in Austria and Germany. This has resulted in the development of the registered variety Tussilago farfara 'Wien', which has no detectable levels of these alkaloids.

A pharmacy also sells coltsfoot here, but unfortunately not the 'Wien' variety.
I hope they soon realize that they should breed a low pyrrolizidine variety of Pulmonaria officinalis as well, as it is a truly wonderful medicinal plant otherwise.

About the chest inflammation: I am quite sure it has something to do with the lymph vessels and nodes. My chest is completely normal in appearance and I don't have any gynecomastia. After reading about mast cell activation here I wondered if it could be related. I don't frequently check it, but sometimes it seems like only minutes pass when the nodules are almost nonexistent and when hard nodules can be felt. Even when the nodules are solid they are hardly painful and they only sometimes get really inflamed. It is clear that it can't be cancer as it wouldn't appear and disappear in this way. It is also hard to believe that it is due to an infection as there is no excessive nasal pus production and the change couldn't be so rapid in such a case. The pain can develop minutes after or sometimes even before O, which is not sensible if we consider bacteria. They are still living organisms and can't proliferate this rapidly. Certainly I can't deny the possibility of some opportunistic pathogens, but then again what would be the reason they become opportunistic while in a chronic phase they are merely a nuisance.
I really think it is due to the excessive release of the capsaicin-like compound that gets there through the blood stream and for some reason this is the primary place where it clogs the lymph vessels. Fresh air is clearly beneficial when I have such a case, but that only can't resolve it on its own. If I do extended physical work outdoors it can actually become worse, so exertion is a more important factor than fresh air. In some severe cases I can feel the stabbing pain even in my back, so the lung may be at least partially involved, although radiography in one moderate case proved negative. There were several cases when I felt like I was dying, but still nobody believed that I had any problems and claimed it was all in my head. I don't even mention it anymore I just try to get through it somehow, but it is quite difficult when I have to work in such a state and also pretend that everything is alright.
The best term I found about lymph clogging is hypoperfusion of the lymphatic vessels, although without any apparent skin problems and the exact process is still a mystery.
It very rarely hurts at the sternum, but there are usually some slight red dots that are connected to acute POIS. I read it somewhere (probably on the site) that it is probably connected to histamine release and mast cell activation. Around 2009 I had a case when the site of the thymus gland was really inflamed for a few days, but this hasn't occurred since then. I didn't go to the doctor at the time as they wouldn't have believed me anyway due to the POIS controversy. The enlarged nodules are one of the best indicators of my actual POIS state besides the burning pain. They are followed by bloodshot eyes and then depression by the way.

A longer list of PPARA agonists (they can be found in this thread): fluoxetine, mulberry leaf water extract, Korean red ginseng, banaba leaf water extract, cardamom (limonene and kaempferol), Tribu Saponin from Tribulus terrestris, AEA, OEA, and PEA, rosmarinic acid and biochanin A, PEA (soy lecithin, egg yolk, and peanut meal), niacinamide, oleic acid - OEA (olive oil, avocado and almond oil), fibrates (fenofibrate, clofibrate).
Of course I will try to find more and test as many as I can to see if there is a real connection.