I have made lists from PPARG agonists and antagonists, but it looks like the effect is not dependent on the group the compound belongs to. It is also interesting to note that
among these are also the ones that enhance my POIS. I haven't achieved a perfect conclusion yet, but the most important thing for
a compound to be effective in my case is probably that it
should both inhibit FAAH and activate PPARG at the same time. Pure PPARG agonists probably all enhance my case, although they seem to help other POISers nonetheless. Pure PPARG antagonists may also help me, but some of them still has to be tested for a reliable conclusion. Pure FAAH inhibitors also seem to work without serious side effects, but their efficacy is lower than those combined with PPARG agonism.
I think this article provides the most reliable information about combined FAAH inhibitors and PPARG agonist.
It is important to note that, among NAEs, AEA, OEA, and PEA all act as PPARA agonists, while only AEA is also capable of acting as a PPARG agonist.
The pharmacological inhibition of FAAH results in an enhancement of the endocannabinoid tone, which has many potential advantages as a therapeutic strategy, since the ECS is essential to many physiological processes in the central nervous system (CNS) and is usually upregulated as a protective response to various pathological conditions, such as pain, inflammation and the expansion of neoplastic clones.
The overlap between endocannabinoid and PPAR signaling suggests that it is possible to expand the activity profile of PPAR ligands by coupling their activity with the inhibition of enzymes such as FAAH. The applications of such an activity profile would be many, including the treatment of cancer, of neurodegenerative diseases, and of alcohol withdrawal, other than metabolic syndrome. In this particular case, the anti-inflammatory effects linked to endocannabinoid activation would be particularly helpful in reducing the hyperinflammatory state of metabolic syndrome patients; it is however important to note that PPARs themselves are among the most important mediators of such effects.
The activation of PPARA mediated by a stable analog of OEA could alleviate the symptoms of nicotine abstinence and reduce the reward mechanisms linked to its consumption, while PPARG activation can reduce the reward mechanisms linked to alcohol consumption.
While most of these compounds showed no relevant activity towards FAAH, some of them showed promising results; these were compounds 4, 5, 8, and 12 (resveratrol). In particular, this last compound can interact with PPARG, albeit as an antagonist and has numerous other reported biological activities. It is worth noting that compounds 1 (Rosiglitazone), 2 (Wy 14,643), and 3 (L165,041) showed little to no activity on FAAH, demonstrating that a more specific drug design process is necessary for the obtainment of dual-acting compounds. These biological results are reported in Table 1.
Rosmarinic acid was reported in the literature as a PPARG agonist and presents some structural similarity to arylacetic acids. Although we did not find any activity of this compound on either PPARA or PPARG, in light of its positive result as an inhibitor of FAAH, we decided to synthesize a short series of new derivatives of this compound and its natural analogue clovamide.https://www.mdpi.com/1422-0067/21/19/7026/htmSo a list I had found for
PPARG agonists: arachidonic acid, several ligands like fatty acids (linoleic acid being the most common), Berberine (Berberis vulgaris), Cannabidiol, Daidzein (alfalfa), Genistein (soybean, chickpeas), Ibuprofen (only weakly), 15-HETE, biotin, taurine, curcumin, DHA, EPA, carvacrol (thyme and oregano), capsaicin (hot pepper), carnosic acid and carnosol (rosemary and sage), punicic acid (pomegrenate seed oil), citral (lemongrass), Cistus salviflius, synthetic thiazolidinediones (TZD) used to treat diabetes: troglitazone (Rezulin), pioglitazone (Actos), rosiglitazone (Avondia), tesaglitazar, chromium histidine, exercise, stilbenoid resveratrol, luteolin, epigallocatechin-3-gallate (EGCG) and others.
These may all work for one group (e.g. taurine), but I could be wrong. I also haven’t tested them all, but most of them make me more ill. I have just made some
lemongrass tea (citral) and consumed about 1 liter. After about 3 hours it gave me a severe burning flatulence, which is rather strange as citral is not only a PPARG agonist, but also a weak TRPV1 antagonist too.
To the contrary
ibuprofen [200 mg] actually seems to work, although with a weak efficacy. It didn’t give any burning pain, but it also didn’t relieve the mind fog. It takes a long time for a general effect to appear. Next time I will try a greater dose [400 mg].
Daidzein and Genistein both activate PPARG and inhibit FAAH, so they are prospective compounds.
The few
PPARG antagonists I found are: green tea, black tea, astaxanthin, rosmarinus (carnosic acid), tamoxifen (also an estrogen receptor antagonist), resveratrol, apigenin, betulinic acid.
I think both black and green tea makes me better slightly.
Astaxanthine seems to have worked for other POISers, but it is not very cost-effective. I will really have to try this.
Carnosic acid seems an odd one compared to the other list, but a paper explicitly claims that it is an antagonist, although
carnosol is still an agonist. Rosemary also contains rosmarinic acid which seems to be a pure FAAH inhibitor. It also contains betulinic acid which is another PPARG antagonist. Tamoxifen is used to treat breast cancer, so it would sound strange if I wanted a prescription for it, although I have POIS related nodules in my breasts. Resveratrol is also indicated as both an agonist and an antagonist. I think researchers should really address this issue to clarify the matter.
The papers also imply that mu opioid agonists could work in cannabinoid deprivation. Based on what I had written earlier in the Kappa agony thread it doesn't seem likely. As opioid alkaloids (probably papaverine) in poppy seed enhance my symptoms it is only logical to assume that opioid antagonists like
Low Dose Naltrexon (LDN) would help me. Naltrexon also had efficacy in the treatment of COVID-19 and it simply can't be a coincidence.
The other things I tried in the meanwhile:
Lime tea (Tilia) [kaempferol – leaves and flower combined]: I consumed more than 1 liter. It definitely has a positive effect, although rather weak. It didn't really do anything to cognitive symptoms, but it had a soothing effect on the intestine almost without any flatulence.
I took a pill of
vitamin B6 (pyridoxine) and I think it reduced POIS somewhat, but I was not feeling well (not the POIS way). I think it did something to my blood pressure, but I will have to test this out more.
Kaempferol, quercetin, and stilbenoid resveratrol are PPARG agonists.
https://link.springer.com/article/10.1007/s00894-020-04488-0The controversy of PPARG agonism or antagonism may be solved by a different approach.The consumption of dietary flavonoids has been associated with a variety of health benefits, including effects mediated by the activation of peroxisome proliferator-activated receptor-gamma (PPARG). Flavonoids are extensively metabolized during and after uptake and there is little known on the biological effects of these conjugated metabolites of flavonoids that are found in plasma. To investigate the effect of glucuronidation on the ability of flavonoids to activate PPARG we studied and compared the activity of quercetin, kaempferol and their relevant plasma conjugates quercetin-3-O-glucuronide (Q3G) and kaempferol-3-O-glucuronide (K3G) on different PPARG related endpoints.
It is concluded that flavonoids affect PPARG mediated gene transcription by a mode of action different from agonist binding. Increases in PPARG receptor mRNA expression and synergistic effects with endogenous PPARG agonists may play a role in this alternative mode of action. Glucuronidation reduced the activity of the flavonoid aglycones.https://pubs.rsc.org/en/content/articlelanding/2015/fo/c5fo00076a/unauth#!divAbstractSome information about
rosmarinic acid (FAAH inhibitor):
Although some of these enhance POIS, but it is probably caused by another compound like carnosol or carvacrol.
Rosmarinic acid accumulation is shown in hornworts, in the fern family Blechnaceae and in species of several orders of mono- and dicotyledonous angiosperms.
It is found most notably in many Lamiaceae (dicotyledons in the order Lamiales), especially in the subfamily Nepetoideae. It is found in species used commonly as culinary herbs such as Ocimum basilicum (basil), Ocimum tenuiflorum (holy basil), Melissa officinalis (lemon balm), Rosmarinus officinalis (rosemary), Origanum majorana (marjoram), Salvia officinalis (sage), thyme and peppermint. It is also found in plants in the family Marantaceae (monocotyledons in the order Zingiberales) such as species in the genera Maranta (Maranta leuconeura, Maranta depressa) and Thalia (Thalia geniculata).
Rosmarinic acid and the derivative rosmarinic acid 3'-O-?-D-glucoside can be found in Anthoceros agrestis, a hornwort (Anthocerotophyta).https://en.wikipedia.org/wiki/Rosmarinic_acidRosemary contains a number of phytochemicals, including rosmarinic acid, camphor, caffeic acid, ursolic acid, betulinic acid, carnosic acid, and carnosol. Rosemary essential oil contains 10–20% camphor.https://en.wikipedia.org/wiki/RosemaryGenistein (4',5,7-trihydroxyisoflavone) is an isoflavone. Soybean, a high protein vegetable, has been accounted for to contain the most genistein. Pint sized quantities of genistein are found in different legumes, for example, chickpeas (garbanzo beans). Soy based edibles contain genistein in variable quantity. Other plant foods that have been shown to contain genistein consist of alfalfa and clover sprouts, barley meal, broccoli, cauliflower and sunflower, caraway, and clover seeds.https://www.researchgate.net/profile/Juber-Akhtar-2/publication/329449590_An_Overview_on_Genistein_and_its_Various_Formulations/links/5ddcab44a6fdccdb44656b91/An-Overview-on-Genistein-and-its-Various-Formulations.pdfGenistein is also a proposed drug in the treatment of Alzheimer's disease.
https://content.iospress.com/articles/journal-of-alzheimers-disease/jad151020As I have a possible arachidonic acid overload PPARG is probably over-activated all the time.
Peroxisome proliferator-activated receptor-gamma (PPARG) modulates the expression of many genes actively involved in regulating the cell cycle. Specific ligands bind PPARG protein can exert inhibition on the proliferation of human breast carcinoma cells. In contrast, the persistent over-regulation of the PPARG gene can also increase the likelihood of breast carcinogenesis.https://link.springer.com/article/10.1186/s12906-019-2715-1Macamides are neuroprotective and they can activate PPARG.
The gene reporter assay was performed to test the ability of macamides to activate PPARG receptors. No PPARG activation was observed in response to MAC 18:1 exposure. However, MAC 18:2 and MAC 18:3 at 30 uM activated PPARG with EC50 values of 22.6 ± 0.1 uM and 20.4 ± 0.1 uM, respectively (p ? 0.05). Human PPARG activation was observed in the presence of RGZ, with an EC50 value of 240.8 ± 1.4 nM.
Macamides, as they are structurally similar to AEA, should activate PPAR, particularly the PPAR? receptor.
This observation is in agreement with results of a study which describes linoleic acid and linolenic acid as endogenous activators of PPARG, with EC50 values in the range of 5–20 uM. Therefore, the presence of the linoleic and linolenic acid backbones in macamides MAC 18:2 and MAC 18:3 makes these compounds suitable ligands for PPARG transactivation. This result is considered important in the study of the relationship between macamides and AEA. Moreover, it will be interesting to examine the effects of macamides that are mediated by PPARG.https://www.sciencedirect.com/science/article/pii/S0041008X17304957An extensive study about the relation of cannabinoids and PPARs
https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13497The severe adverse effects of thiazolidinediones which led to their withdrawal from the market or restricted clinical application are suggested to be a result of full PPAR? activation, contrasting the weak agonistic effect of endogenous PPARG ligands such as fatty acids and prostanoids.
Noteworthy, along with plants and mushrooms applied in traditional medicines, PPARG-ligands were often identified in plants that are common food sources, including the tea plant (Camellia sinensis), soybeans (Glycine max), palm oil (Elaeis guineensis), ginger (Zingiber officinale), grapes and wine (Vitis vinifera), and a number of culinary herbs and spices (e.g. Origanum vulgare, Rosmarinus officinalis, Salvia officinalis, Thymus vulgaris).
Although most of the agonists identified in food sources are weak PPARG agonists per se, the effects of their metabolites deserve further research to better estimate their preventive potential. While research in this direction is largely missing, a previous study reported that some main metabolites of flavonoid constituents from red clover (Trifolium pratense) have an up to 100-fold higher PPARG binding affinity than their precursors.Check out Table 1. as it lists a lot of PPARG ligands which could potentially modify POIS.
You better check the table as I only dumped this here for easier search.
The list: Amorpha fruticosa L. - Amorfrutins (in the fruits), Astragalus membranaceus Moench - Formononetin (in ethanolic extracts), Bixa orellana L. - Bixin and norbixin (in annatto extracts), Camellia sinensis - Catechin (in green tea), Cannabis sativa L. - THC, Chromolaena odorata - (9S,13R)-12-Oxo-phytodienoic acid and odarotin, Coix lacryma-jobi var. ma-yuen - Hydroxy unsaturated fatty acids, Commiphora mukul - Commipheric acid, Cornus alternifolia L.f. - Kaempferol-3-O-B-glucopyranoside, Cymbopogon citratus - Citral (in lemongrass oil), Echinacea purpurea (L.) - Alkamides, Elaeis guineensis Jacq. - Tocotrienols (in palm oil), Elephantopus scaber L. - Deoxyelephantopin, Epimedium elatum C. - Acylated flavonol glycosides, Euonymus alatus - Kaempferol and quercetin, Glycine max (L.) - Genistein (in soya beans); Glycyrrhiza glabra L. - 5?-Formylglabridin, (2R,3R)-3,4',7-trihydroxy-3'-prenylflavane, echinatin, (3R)-2',3',7-trihydroxy-4'- methoxyisoflavan, kanzonol X, kanzonol W, shinpterocarpin, licoflavanone A, glabrol, shinflavanone, gancaonin L, glabrone; Glycyrrhiza foetida Desf. - Amorfrutins (in the edible roots), Glycyrrhiza inflata Batalin - Licochalcone E (in roots), Glycyrrhiza uralensis Fisch. ex DC. - Flavonoids and 3-arylcoumarins (in ethanolic extract of the roots), Limnocitrus littoralis (Miq.) Swingle – Meranzin, Lycium chinense Mill. - Fatty acids (in root bark), Magnolia officinalis – Magnolol and honokiol, Melampyrum pratense L. - Lunularin and fatty acids, Momordica charantia L. - Cucurbitane-type triterpene glycosides, Notopterygium incisum C.T. - Polyacetylenes, Origanum vulgare L. - Biochanin A, Panax ginseng - Ginsenoside 20(S)-protopanaxatriol and ginsenoside Rb1 (in ginseng roots), Pinellia ternata - Fatty acids (in different apolar extracts from the rhizomes), Pistacia lentiscus L. - Oleanonic acid, Pseudolarix amabilis - Pseudolaric acid B, Pueraria thomsonii Benth – Daidzein, Robinia pseudoacacia var. umbraculifer DC. - Amorphastilbol, Rosmarinus officinalis L. - Carnosic acid and carnosol, Salvia officinalis L. - Carnosic acid and carnosol (in ethanolic extract of sage); as well as 12-O-methyl carnosic acid and ?-linolenic acid, Sambucus nigra L. - ?-Linolenic acid, linoleic acid, and naringenin, Saururus chinensis - Saurufuran A (in roots), Silybum marianum (L.) - Isosilybin A (in silymarin, a phenolic mixture from the fruits of the plant), Terminalia bellerica Roxb. - Gallotannins (in the fruits), Thymus vulgaris L. - Carvacrol (in thyme oil), Trifolium pratense L. - Isoflavones (in red clover extracts), Vitis vinifera L. - Ellagic acid, epicatechin gallate, flavonoids (in grapes and wine), Wolfiporia extensa - Dehydrotrametenolic acid (in dried sclerotia), Zingiber officinale Roscoe - 6-Shogaol (in ginger roots).
https://www.sciencedirect.com/science/article/pii/S0006295214004249In this study, PPAR activation by oregano (e.g., Origanum vulgare) and its components was tested. Oregano extracts bind but do not transactivate PPARG, and binding affinity differs among different oregano extracts. The extracts contain PPARG antagonists (e.g., quercetin, luteolin, rosmarinic acid, and diosmetin), selective PPARG modulators (e.g., naringenin and apigenin), and PPARG agonists (e.g., biochanin A). Oregano extract and isolated compounds in the extract antagonize rosiglitazone-mediated DRIP205/TRAP220 recruitment to PPARG, pointing to oregano extracts as putative food supplements for weight reduction. Rosmarinic acid and biochanin A, PPARA agonists, may ameliorate the lipid profile. By endothelial nitric oxide synthase activation, oregano extract could prevent atherosclerosis.https://pubs.acs.org/doi/abs/10.1021/jf802298wThe cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPARG), a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPARG also represses the inflammatory process. Similarly, the PPARG agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPARG, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPARG activation.Table 1. contains other PPARG agonists like DHA, EPA, curcumin, capsaicin, punicic acid.
https://www.mdpi.com/1420-3049/25/9/2076/htmEPA and DHA also inhibit COX!EPA and DHA provided by the diet or arising from a-linolenic acid metabolism inhibit adenylate cyclase and COX activities, presumably altering adipogenesis.
Arachidonic acid (ARA) and some of its metabolites generated through cyclo-oxygenase (COX) and lipoxygenase activities are implicated in adipogenesis as activators/ligands of PPARs. Thus ARA is a potent stimulator of adipogenesis that acts through cell-surface IP-R and nuclear PPAR in early and late events of adipogenesis, respectively.
https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/an-emerging-risk-factor-for-obesity-does-disequilibrium-of-polyunsaturated-fatty-acid-metabolism-contribute-to-excessive-adipose-tissue-development/A4390A23446AD5D3A55C0BCB50C603AFBy the way at the time I drank a lot of Cistus incantus tea (approximately 1 liter) besides heart ache or heartburn I noticed other symptoms. I also felt my chest constricted and had an inflammation at the descending colon. I will have to test it again to see if these symptoms can be reproduced.
I also bought some naproxen, but haven't tested it yet.
For those POISers who have emotional problems this may be interesting.
A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional–motivational reactivity.https://link.springer.com/article/10.1007/s00213-012-2785-yInhibition of FAAH may increase regeneration through PPARA.
https://www.sciencedirect.com/science/article/pii/S0022227520309706The beneficial effects of saffron on inhibition of serum levels nuclear transcription factor kB (NF-kB) p65 unit, tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-g) and some interleukin (IL) such as IL-1B, IL-6, IL-12, IL-17A were reported. Furthermore, saffron has been known as the antagonist of NF-kB and the agonist of peroxisome proliferator-activated receptor gamma (PPARG). In addition, saffron down-regulates the key pro-inflammatory enzymes such as myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phospholipase A2, and prostanoids.
Some studies suggested that the immunomodulatory activity of saffron may involve direct targeting of Toll-like receptors (TLRs), attributed to the regulation of various transcription factors such as nuclear factor (NF-kB), activator protein 1 (AP-1) and also their downstream signaling pathways. TLRs play a crucial role in the innate immune system by triggering pro-inflammatory signaling pathways in response to either external or internal stimuli. Moreover, NF-kB acts a vital role in producing pro-inflammatory cytokines such as IL-1, IL-2 and IFN-g in T lymphocytes. Pradere et al. showed saffron has an inhibitory effect on producing pro-inflammatory cytokines like IL-1 production by suppressing NF-kB activity via the inhibition of I kappa B kinase-a (IKK-a) phosphorylation and prevention of nuclear translocation of the NF-kB p65 subunit.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535192/Until the BIA 10–2474 case is resolved there won't be any pharmaceutical FAAH inhibitors.
It is expected that the effects of FAAH inhibitors, due to their pharmacological interaction with the endocannabinoid system, may exhibit tolerance following repeated administration. This phenomenon is called tachyphylaxis.This is probably the reason why herbal teas and other supplements lose efficacy over time.https://www.sciencedirect.com/science/article/pii/S0273230019303198Endocannabinoids have an intricate connection to helminthic infections and this may also be the reason why
ivermectin could work in parasitic infections, COVID-19 infections and possibly in POIS as well.
AEA was also reported as immunosuppressive to adaptive cells such as T and B lymphocytes. It is believed that AEA functions this way by signaling via CB2 receptor, PPARG and by inhibiting NF-kB. Similar to innate cells, AEA inhibits lymphoid cell proliferation, Th1 cytokine production and enhances Th2 responses by increasing expression of IL-4 and IL-10. Similarly, 2-AG (more precisely a 2-AG metabolite) was immunosuppressive towards T cells by impairing pro-inflammatory IL-2 cytokine expression.
Although eCBs at times play controversial roles in immune responses, in general, eCBs are immunosuppressive, with AEA being the most potent. Interestingly, the Th1 response
inhibition by eCB is coupled with enhancement of Th2 response in many immune cells types.
Moreover, Th1 cytokine production was associated with reduced FAAH (AEA degrading enzyme) activity suggesting that a self-sustaining anti-inflammatory mechanism of eCBs.
Therefore, eCBs can be exploited for their anti-inflammatory therapeutic potential.
Endocannabinoids are lipid signaling molecules that have functions in dampening Th1 immune responses and driving Th2 immunity.https://escholarship.org/content/qt3jj0r5rj/qt3jj0r5rj_noSplash_cf4ddf688073eddd42026c402db34e81.pdf#page=14Peroxisome proliferator-activated receptor gamma (PPARG), insulin receptor substrate-1 (IRS-1) and nuclear transcription factor kappa B (NF-kB) are important biomarkers involved in numerous metabolic processes. PPARG plays a key role in regulating lipid, carbohydrate, glucose and insulin metabolisms. It has been shown that exercise induced an increase in PPARG expression in liver and skeletal muscle tissues. In the current study, PPARG expression levels in the liver and muscle tissues were significantly elevated compared to the control group. Remarkably, CrHis and biotin supplementation significantly increased PPARG expression levels in sedentary and exercised rats. The efficacy of CrHis and biotin was more pronounced when used simultaneously, thus indicating a synergetic effect. Our previous findings demonstrated that CrPic and biotin, as well as their combination, increased PPARG expression in adipose tissue and improved insulin resistance in type 2 diabetes rats.https://link.springer.com/article/10.1186/s12970-018-0249-4PPARG may be an important molecule in acne vulgaris, the most frequent sebaceous dermatoses (SG)-related dermatosis with abnormal lipid storage and inflammation. Arachidonic acid (AA) markedly enhances lipid synthesis in SZ95 sebocytes, and some of this induction might be regulated via PPARG.
In summary, our study provides evidence that PPARG participates in the signaling mechanisms of sebocyte differentiation. We also demonstrated that AA-activated PPARG is involved in the regulation of major neutral lipid and phospholipid biosynthesis. Finally, we presented that PPARG is activated by AA keto-metabolites (5-KETE, 12-KETE). Taken together, our data implicate that AA-activated PPARG is an important regulator of differentiation and lipid metabolism in human sebocytes; therefore PPARG might be a potential therapeutic target molecule in sebaceous dermatoses.https://www.sciencedirect.com/science/article/pii/S0022202X15367026Ketoconazole (Nisoral) is also a FAAH inhibitor. I have been using it effectively for years as a means to control POIS induced dandruff formation. This is probably in line with the former article as I also have more acne after O. I think this also contradicts a possible fungal origin even though they may still be present. I think this is something similar to my case with dysbacteriosis.
I also have to wonder if ketoconazole pills could be effective, although they may have serious side effects on the long run. Still it would be good to know as there is a possibility that it could work very well in the treatment of COVID-19 infection.
In the present study we have demonstrated that ketoconazole (Nisoral) inhibits the uptake of the endocannabinoid AEA into a variety of cell lines, and that this effect can be most simply explanined by the ability of the compound to inhibit FAAH.
In Sweden, ketoconazole is available as a shampoo (20 mg/ml) and until recently as tablets (200 mg; the dose could be doubled if deemed necessary).
In intact rat peritoneal polymorphonucelar leukocytes, leukotriene B4 and 5-hydroxyeicosatetraenoic acid production from arachidonic acid was inhibited with IC50 values of 30 and 26 µM, respectively. These authors demonstrated further than oral pretreatment with ketoconazole (10–40 mg/kg) inhibited in a dose-dependent manner ovalbumin-induced bronchoconstriction in sensitised guinea pigs, suggesting that leukotriene synthesis could be inhibited in vivo by the compound.https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087542Carpofen (NSAID) is a FAAH inhibitor. Caprofen is a COX inhibitor too.
Membrane lipids could also modulate structure, functional activity, and subcellular localization of FAAH. Indeed, the FAAH dimer is stabilized by the lipid bilayer and shows a higher membrane-binding affinity and enzymatic activity within membranes containing both cholesterol and the FAAH substrate, AEA. In addition, the colocalization of cholesterol, AEA, and FAAH in intact cells supports a mechanism by which cholesterol can increase substrate accessibility to the active site.https://www.liebertpub.com/doi/full/10.1089/can.2018.0051Table 1 contains a lot of herbs with a high quercetin content.
https://www.researchgate.net/profile/Gabriele-Carullo/publication/326447772_Quercetin_and_its_Natural_Sources_in_Wound_Healing_Management/links/5cf24052299bf1fb184e936a/Quercetin-and-its-Natural-Sources-in-Wound-Healing-Management.pdfApigenin reduces PPAR-gamma expression.Further studies suggest that apigenin binds to non-phosphorylated STAT3, reduces STAT3 phosphorylation and transcriptional activity in VAT, and consequently reduces the expression of STAT3 target gene cluster of differentiation 36 (CD36). The reduced CD36 expression in adipocytes reduces the expression of peroxisome proliferator-activated receptor gamma (PPARG) which is the critical nuclear factor in adipogenesis. Our data show that apigenin reduces CD36 and PPARG expressions and inhibits adipocyte differentiation; overexpression of constitutive active STAT3 reverses the apigenin-inhibited adipogenesis. Taken together, our data suggest that apigenin inhibits adipogenesis via the STAT3/CD36 axis. Our study has delineated the mechanism of action underlying the anti-visceral obesity effect of apigenin, and provide scientific evidence to support the development of apigenin as anti-visceral obesity therapeutic agent.https://www.sciencedirect.com/science/article/pii/S1043661819302324Relora containing Magnolia officinalis bark also helped some POISers.https://poiscenter.com/forums/index.php?topic=3551.msg37338#msg37338https://poiscenter.com/forums/index.php?topic=1152.msg10493#msg10493In the present study, we examined whether PPARs-mediated pathways contribute to the antiplatelet activity of magnolol, a compound purified from Magnolia officinalis. Magnolol (20–60 uM) dose-dependently enhanced the activity and intracellular level of PPAR-B/G in platelets.
Additionally, magnolol significantly inhibited collagen-induced PKCa activation through a PPAR-B/G and PKCa interaction manner. The arachidonic acid (AA) or collagen-induced thromboxane B2 formation and elevation of COX-1 activity caused by AA were also markedly attenuated by magnolol.https://www.sciencedirect.com/science/article/abs/pii/S0006295212004200PPAR agonists reduce voluntary alcohol consumption in rodent models.https://onlinelibrary.wiley.com/doi/abs/10.1111/acer.12976The cardinal biologic activity of PPARG is the induction of differentiation of adipocytes, the cell type that expresses the highest levels of PPARG amongst normal tissues. Lower levels of PPARG are, however, found in other normal tissues and cell types such as skeletal muscle, liver, breast, prostate, colon, type 2 alveolar pneumocytes, some endothelial cells as well as monocytes, and B-lymphocytes.
Also, uncertainty about mechanisms of anticancer effects of PPARG ligands has resulted from variability in the classification of some compounds (e.g., bisphenol A diglycidyl ether [BADGE], which has been shown to have both agonist and antagonist activities).
Also, the observation that combinations of PPARG agonist and antagonist compounds result in additive antiproliferative effects in various cancer cell lines is consistent with this mechanism. This mechanism is plausible, as it has been shown to inhibit the NF-kB signaling pathway, which is central to inflammation and to the proliferation and survival of multiple cancer types including hepatocellular and colon carcinomas as well as multiple myeloma.https://www.hindawi.com/journals/ppar/2008/494161/As
betaine was mentioned a lot on the site I thought this may have relevance.
Our findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression.
Betaine, a methyl donor, is a naturally occurring compound in common foods, such as wheat bran, wheat germ, spinach, pretzels, shrimp and wheat bread etc. In vivo, betaine can also be produced by oxidation of choline, and it serves as an effective methyl donor for remethylating homocysteine (Hcy) into methionine (Met).https://lipidworld.biomedcentral.com/articles/10.1186/1476-511X-12-34An extensive overview of the complex relation of
cannabinoids and PPARs.
https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13497Thermogenic brown and brite adipocytes convert chemical energy from nutrients into heat.
The peroxisome proliferator-activated receptor (PPAR) family plays key roles in the maintenance of adipose tissue and in the regulation of thermogenic activity. Activation of these receptors induce browning of white adipocyte. The purpose of this work was to characterize the role of carnosic acid (CA), a compound used in traditional medicine, in the control of brown/brite adipocyte formation and function.
We used transactivation assays to show that CA has a PPARA/G antagonistic action. Our data pinpoint CA as a drug able to control PPAR activity through an antagonistic effect. These observations shed some light on the development of natural PPAR antagonists and their potential effects on thermogenic response.
Mammalian adipose organs can be divided into two distinct types of adipose tissues: white and brown. White adipose tissue (WAT) is specialized in the storage and release of fatty acids, which are required as an energy source for heart and muscles. In contrast, brown adipose tissue (BAT) dissipates energy in the form of heat by uncoupling the mitochondrial respiratory chain from ATP synthesis. Adipose tissue is the largest endocrine organ and links metabolism and immunity. It is a major actor in the regulation of energetic metabolism and represents a potential therapeutic target to combat fat mass disorders such as obesity and hypermetabolism in critical illness.
High increases in catecholamine production, such as epinephrine and norepinephrine, and pro-inflammatory factors are observed in critical illness, but pharmacologic treatments are associated with secondary effects such as gastrointestinal and cardiovascular failures. Obesity appears to be protective against death induced by critical illness, and this process is called the "obesity paradox".
Carnosic acid (CA) inhibits the browning process of human white adipocytes.
Under conditions where browning of white adipocytes is exacerbated, such as in critical illness after a severe burn injury or cachexia, CA treatment may represent a potential therapeutic option. Animal models and patients with severe burns develop hypermetabolism with massive browning of white adipose tissue, hepatic steatosis, and cachexia, which are harmful and have limited therapeutic treatments. In a similar manner, cancer-associated cachexia, a wasting syndrome, is associated with increased browning of white adipose tissue, which leads to higher thermogenesis with increased lipid mobilization and energy expenditure, further worsening the clinical situation and risk of death. Inhibition of white adipose tissue browning in burn and cancer patients represents a promising approach that can be potentially achieved with CA treatment alone or in combination with other approaches. In line with this, it has been suggested that CA is efficient against obesity-associated cancers, in particular against colon cancer. Furthermore, it is known that PPAR activation by thiazolidinediones is associated with bone fracture, and we could speculate that CA treatment has the potential to restore bone mass, given that betulinic acid, a PPARG antagonist, is known to favor osteogenesis at the expense of adipogenesis.https://www.mdpi.com/2073-4409/9/11/2433/htmBetulinic acidIt exhibits anti-HIV, antimalarial, antineoplastic and anti-inflammatory properties.
The effects of betulinic acid as an anticancer agent in breast cancer is found to be cannabinoid receptor dependent. Betulinic acid behaves as a CB1 antagonist and CB2 agonist.https://pubchem.ncbi.nlm.nih.gov/compound/Betulinic-acidhttps://en.wikipedia.org/wiki/Betulinic_acidBitter melon up-regulates PPARG.It would be interesting to test Momordica charantia also called bitter melon or bitter gourd.
It has anti-diabetic, anti-HIV, anti-ulcer, anti-inflammatory, anti-leukemic, anti-microbial, and anti-tumor effects.https://www.sciencedirect.com/science/article/abs/pii/S0378874109005595
