The bright side of estrogen

[Progecitor]

As it turns out my case is related to estrogens after all even though earlier I dismissed this theory due to controversial experiences. However recent tests forced me to reconsider my views. This became pretty evident when I realized that resveratrol is a potent activator of estrogen receptor beta (ERB). As Ecdysterone has been already implicated to act through ERB, it simply couldn't be a coincidence anymore. This motivated me to research ERB more in-depth which lead me to the discovery that my problems most likely stem from a malfunction of 5a-androstane-3B, 17B-diol (3B-Adiol) bioavailability as this steroid is the most important endogenous activator of ERB and it has a crucial role in the protection of the prostate and other organs by partly antagonizing ERa mediated downstream effects.
It is important to note that there are two forms of Adiol, namely 3a-Adiol (also 3a-diol) and 3B-Adiol (also 3B-diol). 3a-Adiol is mostly inactive and serves as a pool for DHT, while 3B-Adiol is considered an estrogen that preferentially activates ERB. They are intimately connected to DHT and testosterone metabolism and it is a wonder that they have been quite neglected so far as there are only a few mention of them on the site.
Of particular note is a post by a post finasteride syndrome patient who actually mentioned that they had low levels of "3 adiol g", although unfortunately he didn't specify this further.
https://poiscenter.com/forums/index.php?topic=1397.msg12889#msg12889
In this case 5a-reductase is probably dysfunctional which would result in a reduction of both 3a-Adiol and 3B-Adiol levels. Of course it may yet turn out that finasteride is also capable of disabling other enzymes as well so it is really only a guesswork. Even so the body would not only lose a potent androgen, but also a kind of "good" estrogen that compensates for the effects of estradiol.

An excess of "3adiol" as a causative was also proposed before.
https://poiscenter.com/forums/index.php?topic=3733.20
I guess this actually meant 5a-androstane-3a,17B-diol (3a-Adiol), which may be possible if the conversion to 3B-Adiol is inhibited or prohibited and 5a-DHT can only be transformed towards 3a-Adiol. However insufficient activation of ERB is definitely the more important issue based on the supplements I have trialed so far. It is true though that 5a-reductase inhibitors also benefit me to a lesser extent, which is contradictory, but this may not have much of an effect on 3B-Adiol synthesis if it has been already inhibited. Unfortunately many ERB agonists also inhibit (biofeedback?) the enzymes that would increase 3B-Adiol (AKR1C1 (HSD17B1), 3B-HSD and 3a-HSD) and should be ideally avoided, however if either of them is really dysfunctional this may not amount to much and the overall effect of exogenous ERB activation may be positive still. CYP7B1 activity also has to be considered as it inactivates 3B-Adiol and may contribute to the issue.

Regardless the main metabolic issue is evidently that the ESR1 (ERa) : ESR2 (ERB) ratio is high even though the level of estradiol could be normal. ESR1 dominance would lead to a downward signaling cascade that seems to somewhat parallel the metabolic syndrome model discussed earlier.
https://poiscenter.com/forums/index.php?topic=3986.0
So a more ideal approach would not only manage these issues separately, but act through the rebalancing of ESR1: ESR2 by the use of ERB agonists.

I haven't yet figured out aromatase inhibitors either, but they are probably beneficial to some extent as estradiol is more preferential towards ERa activation compared to ERB and more (or a normal amount of) estradiol would only keep the system unbalanced. Increasing free testosterone seems to be beneficial, but it is probably not due to any effect on ERB, however some effects of testosterone seem to parallel ERB downward signaling (e.g. PPARG downregulation) and thus their overall effect on health may actually converge. This is possibly the reason why some supplements have a testosterone boosting-like effect even though they don't actually increase testosterone.

Besides deficient 3B-adiol an other possibility I could think of is either the downregulation or outright destruction of ERB due to some compounds released at orgasm. Examples for this could be antibodies or bacterial LPS. Nevertheless even in such a case preventive overactivation of ERB would prohibit ligand binding of these toxic compounds and subsequent loss of ERB activity.

The issue of detrimental foods and supplements is more of a mystery as it is unlikely that many of them would have a potent ERa agonist or ERB antagonist activity. They probably potentiate downstream signaling effects, but the specifics have yet to be uncovered.

In the following posts I am going to provide more detail on this theory. First I am going to highlight a number of supplements with ERB agonist activity that me and other POISers use. There is also a need to discuss the ERa : ERB balance as an emerging theory for many other diseases besides POIS. Later I wish to uncover possible ways to increase 3B-Adiol.

Actually the following study is a must read as it discusses most of what I said and it also indicates supplements that increase 3B-Adiol. Needless to say many of these are also popular with POISers.

These include NAD, lithium, Triiodothyronine (T3), zinc, vitamin A, olive oil and coconut oil. These agents could have a beneficial effect in supporting the synthesis of 3B-Adiol in the prostate gland.
https://www.meridianvalleylab.com/an-assessment-of-testosterone-and-its-essential-metabolites-for-prostate-cancer-risk/

[Progecitor]

I am sorry for the long post, but I managed to find even more evidence than I thought I would. At least this mostly proves the involvement of estrogen receptor beta.

Supplements that preferentially modulate estrogen receptor beta (ERB)

We found opposite androgen regulation of ERa mRNA compared to ERB mRNA where ERa mRNA was down-regulated by DHT and ERB mRNA was up-regulated by testosterone and DHT. When co-expressed with ERa, via heterodimerization with ERa, ERB can exert an inhibitory effect on ERa-mediated gene expression and in many instances opposes the actions of ERa. Our results suggest that testosterone may co-ordinate simultaneous changes in sex-steroid receptors to increase responsiveness to testosterone through AR and ERB and reduce responsiveness through ERa via decreased ERa and increased ERB mRNAs.
Studies in ERB knockout mice show morphological abnormalities including neuronal shrinkage and neuronal loss in the substantia nigra indicating ERB is important for midbrain neuronal survival. Testosterone increased ERB mRNA in our study, implying that testosterone can potentially contribute to ERB mediated effects such as neuron survival and maturation.
In summary, treatment with exogenous sex steroids, be it T, DHT or E, shifted the adolescent male rat midbrain to a more androgen responsive state. In addition, increasing levels of circulating testosterone in male adolescence could be anticipated to increase AR mRNA, decrease ERa mRNA and increase ERB mRNA. The underlying susceptibility to schizophrenia may involve the inability of the brain to respond appropriately to sex steroids, which is unmasked at adolescence. For example, either lower endogenous ERa and/or increased AR signaling could be exaggerated by adolescent testosterone and thus, testosterone could shift the individual toward a dysregulated dopaminergic state.
https://link.springer.com/article/10.1186/1471-2202-13-95

The present study showed that intragastric treatment of crocin prevented weight gain, fat accumulation, and insulin resistance in OVX mice by increasing energy expenditure and fat oxidation. Mechanistically, crocin (saffron) influenced adipose tissue homeostasis by regulating adipogenic and lipolytic factors, which was strongly associated with the restoration of the downregulated ERB function in white adipose tissue (WAT). In vitro, crocetin facilitated lipid metabolism in an ERB-dependent manner.
https://pubs.acs.org/doi/abs/10.1021/acs.jafc.1c04570

There is increasing evidence that a plethora of plant-derived nutraceuticals including resveratrol, saw palmetto, maca, curcumin, tocotrienols, ashwagandha, horsetail, astaxanthin, kelp, annurca apple fruits, safflower and ginseng, can have beneficial effects on hair growth.
Nutraceuticals with beneficial effects on hair growth, including curcumin, tocotrienols, kelp and resveratrol, also exert an anti-proliferative effect on breast cancer cells.
The predominant ER in the human hair follicle is ERB, while in breast cancer cells it is ERa.
There is some evidence that some plant polyphenol nutraceuticals can downregulate ERa while stabilizing the anti-proliferative ERB, resulting in an altered ERa:ERB ratio.
The ability of the following nutraceuticals: kelp, astaxanthin, saw palmetto, tocotrienol, maca, horsetail, resveratrol, curcumin, ashwagandha, alternative curcumin, to stimulate proliferation of all three breast cancer cell lines was assessed either on an individual basis, or in combination.
Incubation of breast cancer cells with the combined nutraceuticals, except acumin-curcumin, induced a shift in the ratio of ERa:ERB protein expression in favour of ERB.
An interesting observation was the change in the cellular localisation of ERs following incubation with combined nutraceuticals, to a specific area around the periphery of the nucleus, which was observed in all three cell lines. Recently it has been demonstrated that cellular redistribution of mitochondria during the mitochondrial retrograde response (MRR) can be facilitated by contact sites with the nucleus; coined nucleus associated mitochondria (NAM). It has also been reported that mitochondria express ERa and ERB that regulate oxidative stress originating in the mitochondria.
https://assets.researchsquare.com/files/rs-1167112/v1_covered.pdf?c=1639668824

Of the plant food sources assessed, only spinach leaves/petioles and quinoa grain contained significant amounts of ecdysterone (20E), while virtually all other samples contained no detectable 20E. The spinach sample was found to contain 236 ug 20E/g dw, while a sample of commercial quinoa grain contained 138 ug 20E/g dw, which was reduced to 98 ug/g dw after heating at 100 C degrees in 10 volumes of water for 15 min (i.e., 32% of the 20E was lost to, and recovered in, the cooking water).
Table 5! Ecdysteroids and ecdysteroid related compounds in mushrooms.
Ganoderma lucidum Ergosta-4,7,22-triene-3,6-dione (314 mg from 5.32 kg fw)
Hericium erinaceus (Lion’s mane) Cerevisterol (73 mg from 3.8 kg dw), cerevisterol-3-glucoside (29 mg), 3B,5a,9atrihydroxyergosta-7,22-dien-6-one (32 mg).
https://www.researchgate.net/profile/Nilufar-Mamadalieva/publication/343541713_Dietary_Phytoecdysteroids/links/5f30544fa6fdcccc43bb289a/Dietary-Phytoecdysteroids.pdf

Treatments with red maca extract and its n-butanol but not aqueous fraction reduced prostate weight similar to finasteride. All maca treated groups restored the expression of ERB, but only the aqueous fraction increased androgen receptors and ERa. In conclusion, butanol fraction of red maca reduced prostate size in BPH by restoring expression of ERB without affecting androgen receptors and ERa. This effect was not observed with aqueous fraction of methanolic extract of red maca.
In summary, red maca methanolic extract and its butanol and aqueous fractions have a favorable estrogenic effect by reestablishing ERa and ERB levels; nonetheless, in the case of the aqueous fraction, its androgenic effect counteracts this beneficial effect, not only by promoting cell growth via AR activation, but also by increasing ERa levels, in which mixed actions would interfere with both ERB expression and signaling pathways.
Perhaps, it is due to its content of beta-sitosterol, a component with antiandrogenic effects by inhibiting 5a-reductase isoforms, found also in saw palmetto (Serenoa repens), plant that is widely reported to reduce BPH.
https://www.hindawi.com/journals/ecam/2017/9124240/

We report that resveratrol exhibits E2 antagonist activity for ERa with select EREs. In contrast, resveratrol shows no E2 antagonist activity with ERB.
While both ER isoforms bind E2 with comparable affinity, some phytoestrogens, e.g. genistein and coumestrol, show higher affinity for ERB than ERa, suggesting that resveratrol may show selectivity for ERB.
https://academic.oup.com/endo/article/141/10/3657/2987553?login=true

Piperine, a compound found in black pepper, can inhibit glucuronidation of resveratrol. In mice, piperine significantly increased the serum levels of resveratrol after oral administration of both compounds.
https://pdfs.nutramedix.ec/Reveratrol%20-%20Cancer%20(preclinical).pdf

Our previous work with the phytoestrogen resveratrol (RES) revealed that its ability to slow cell growth and increase stress resistance is dependent on an increase in the antioxidant enzyme manganese superoxide dismutase (MnSOD). This effect can be inhibited with an estrogen receptor antagonist and mimicked with an estrogen receptor beta (ERB) agonist. Both MnSOD and ERB activation are associated with slower rates of cell proliferation and increased stress resistance in a number of experimental contexts. We hypothesize that RES's effects are mediated through ERB and MnSOD, and that the same mechanism is shared by other phytoestrogens and RES derivatives.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=Estrogen+Receptors+and+the+Mitochondrial+Antioxidant+Enzyme+Manganese+Superoxide+Dismutase+Are+Two+Key+Players+in+the+Cellular+Activities+of+Phytoestrogens&btnG=

Reduced ERa expression and its associated anti-proliferative effect upon artemisinin is reported. As orphan nuclear receptors ERRa, ERRB, ERRg and PgR are significantly involved in increased cancer cell proliferation, we studied their possible contribution in anti-cancerous effects of artemisinin. Reduced expression of ERRa, ERRB, ERRg and PgR was observed in artemisinin treated MCF-7 cells. At the same time increased expression of tumor suppressor ERB was found.
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3863-7

In oestrogen-responsive breast cancer cells, a biologically significant response to artemisinin is the transcriptional downregulation of ERa. In MCF-7 cells, treatment with artemisinin strongly inhibited ESR1 promoter activity without any effects on ESR2 expression or activity, which accounted for the potent effects of artemisinin on oestrogen-responsive proliferation.
ERa is a potential target for drug therapy in oestrogen-sensitive breast cancer, and artemisinin can be considered a selective ER downregulator (SERD) because of its selective downregulation of ERa expression (without affecting ERB expression levels). In addition to artemisinin, other phytochemical SERDs that disrupt ERa expression are kaempferol and indole-3-carbinol, suggesting a common feature in their mechanism of action.
https://lavierebelle.org/IMG/pdf/2009_anticancer_activities_of_artemisinin_and_its_bioactive_derivatives.pdf

Moreover, luteolin treatment upregulated the expression of ERB and p-ERK1/2, whereas fulvestrant blocked the expression of p-ERK1/2. The study showed that luteolin could activate the ER/ERK/MAPK signalling pathway to protect PC-12 cells against AB25-35-induced cell apoptosis via selectively acting on ERB. Thus, luteolin may be considered as a potential novel therapeutic strategy for Alzheimer’s disease.
Luteolin is a kind of flavonoid that is found widely in edible plants such as carrot, broccoli, and Perilla leaf.
In addition, study has found that the combination of L-theanine and luteolin may prevent AD-like symptoms, possibly by improving norepinephrine metabolisms and hippocampal insulin signalling and decreasing neuroinflammation.
Surprisingly, we found that luteolin showed a significant toxic side effect at a dose of 10?umol/L, which reminded us that high doses of luteolin may have potential toxicity. The present study showed that luteolin at the concentration of 10?4?umol/L could significantly prevent AB25-35-induced decrease in cell viability.
In the present study, we found that luteolin significantly upregulated the expression of ERB, whereas no ERa proteins were detected in any group.
https://www.hindawi.com/journals/ecam/2020/2861978/

In contrast to the increase in ERB, beta-D-glucan reduced ESR1 (ERa) mRNA transcript levels in MCF-7 cells and increased ERa mRNA expression in LCC9 cells. ERa protein expression was unaffected (change <10%) by beta-D-glucan treatment in MCF-7 cells and increased ?17% in LCC9 cells. Likewise, the increase in ERB mRNA in LCC9 cells treated with beta-D-glucan is another logical follow-up for this study to further characterize the mechanisms by which beta-D-glucan inhibits breast cancer cell proliferation in vitro.
https://www.spandidos-publications.com/10.3892/ijo.2014.2294?text=abstract

In this study, the estrogenic effect of GL-1, a component of the Ganoderma lucidum, was studied, and the possible mechanism was discussed preliminarily.
The results showed that GL-1 has a good binding ability to estrogen receptor beta, and has estrogen-like effect, which might be related to secretion of estrogen and expression of ERB by binding to ERs.
https://www.tandfonline.com/doi/abs/10.1080/14786419.2020.1819270

Chrysin (5,7-dihydroxyflavone) is an important natural dietary phytochemical flavonoid that be extant in various foods and plants, such as passion flower, mushroom, chamomile, propolis, and honey.
When chrysin was co-treated with ERB antagonist PHTPP, it had weak neuroprotective effects in I/R rats; thus, it was hypothesized that chrysin might bind preferentially to ERB.
The current work's data showed that chrysin alone or when combined with ERa MPP antagonists diminished the MDA production and enhanced GPx activity in I/R rats. These results suggest that chrysin may ameliorate the abnormality of the free radical system and compensate the antioxidant ability secondary to hypoperfusion and reperfusion insult in vivo and in the presence of ERB.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114856/

Two flavonoids, genistein and apigenin, have been implicated as chemopreventive agents against prostate and breast cancers. It was found that both genistein and apigenin, although not 17B-estradiol, exhibited anti proliferative effects and proapoptotic activities through caspase-3 activation in these two cell lines. In yeast transcription assays, both flavonoids displayed high specificity toward ERB transactivation, particularly at lower concentrations. However, in mammalian assay, apigenin was found to be more ERB-selective than genistein, which has equal potency in inducing transactivation through ERa and ERB.
https://www.sciencedirect.com/science/article/pii/S1476558606800734

Chrysin, a phytochemical from Morinda citrifolia (Noni), in combination with apigenin synergistically inhibits breast cancer (BC) in vitro and in vivo MDA-MB-231 mice xenografts models of BC. In the same study, chrysin and apigenin decreased extracellular matrix degrader proteins such as MMP9 and MMP2, and EMT markers like fibronectin, slug, vimentin, snail and TWIST to a greater extent in combination than as single agents.
https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.31085

Recently it has been shown, that an extract of Silybum marianum (SM) has an estrogenic, anti-osteoporotic effect. 4 flavonoids were isolated from SM. None of the isolated compounds interacted with ERa. In contrast, the flavonoids displaced E2 from the ERB in the order silydianin > silibinin > isosilybinin. SM proved to be a selective ERB agonist with no adverse on the uterus or thyroid. Since it is known that estrogenic compounds which reduce LH levels also ameliorate menopausal symptoms like hot flushes, SM may be considered as an organ specific phytoestrogen suitable as alternative treatment for hormone replacement therapy.
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2006-932965

In this study, we investigated the mechanism underlying the antitumor effect of 3B,7B-dihydroxy-25-methoxycucurbita-5,23-diene-19-al (DMC), a cucurbitane triterpenoid isolated from wild bitter gourd with antileukemic activity. We obtained first evidence that DMC induced apoptotic death in breast cancer cells, at least in part, through a PPARG-dependent mechanism.
Second, DMC suppressed the expression of a series of PPARG-targeted signaling effectors that govern cell cycle progression, proliferation, and survival, including cyclin D1, CDK6, Bcl-2, XIAP, COX-2, NF-?B, and ERa. Particularly, the downregulation of ERa expression is noteworthy since ERa has been shown to bind to PPRE and negatively interfere with PPARG signaling in breast cancer cells.
https://www.hindawi.com/journals/ecam/2013/935675/

The antitumor activity of 3B,7B,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated.
The result showed that TCD increased the ratio of ERB to ERa expression in MCF-7 cells. In ERa-null MDA-MB-231 cells, TCD increased the expression of ERB.
Interestingly, we found that TCD induced HDAC inhibition as evidenced by increased acetyl histone H3 expression in a concentration-dependent manner as well as the HDAC activity in MCF-7 cells.
Interestingly, curcumin and sulforaphane, ingredients of tumeric and green tea polyphenols, showed antiproliferative activities in breast cancer through modulation of HDACs.
https://www.nature.com/articles/srep22419

We found that aqueous mangosteen rind extract (MRE) inhibited growth of MCF-7 and altered the transcript levels of ERa, ERB, and EGFR genes.
In this study, MRE treatment reduced the mRNA expression of ERa, but upregulated ERB. This finding correlates with a study wherein a-mangostin treatment of MCF-7 cells resulted in a suppression of ERa. On the contrary, another researcher showed that 70% ethanolic extract of mangosteen pericarp induced MCF-7 cytotoxicity without altering ER expression. It is known that ERa is expressed in most of breast cancers and hence used as a marker of survival in human breast cancers. The reduced viability of MCF-7 cells observed in this study could be due to decrease in the levels of ERa. On the other hand, it is known that ERB is associated with low tumor grade.
https://fjps.springeropen.com/articles/10.1186/s43094-021-00368-3

Pomegranate (Punica granatum) seed linolenic acid isomers were evaluated as selective estrogen receptor modulators (SERMs) in vitro. Punicic acid (PA) inhibited (IC50) ERa at 7.2 mM, ERB at 8.8 mM; a-eleostearic acid (AEA) inhibited ERa/ERB at 6.5/7.8 mM. PA (not AEA) agonized ERa/ERB (EC50) at 1.8/2 mM, antagonizing at 101/80 mM. AEA antagonized ERa/ERB at 150/140 mM. PA and AEA induced ERa and ERB mRNA expression in MCF-7, but not in MDA-MB-231. Overall, the results show PA and AEA are SERMs.
https://www.tandfonline.com/doi/abs/10.3109/07435800903524161

Linoleic acid also stimulated mRNA ERB expression in T47D:A18 cells, progesterone receptor expression in Ishikawa cells, but not alkaline phosphatase activity in Ishikawa cells. These data suggest that linoleic acid from the fruits of Vitex agnus-castus can bind to estrogen receptors and induce certain estrogen inducible genes.
https://www.sciencedirect.com/science/article/abs/pii/S0944711304702901

However, in the olive oil treated group, this increase was associated to an enhanced expression of ERa, whereas in the omega-3 PUFAs-treated group a reduction of ERa protein expression was observed. In addition, ERB/ERa ratio increased 3-fold and 2-fold in mice treated with omega-3 PUFAs and olive oil, respectively, compared with the ST group.
https://academic.oup.com/carcin/article/35/7/1613/379053?login=true

We have previously reported that royal jelly (RJ) from honeybees (Apis mellifera) has weak estrogenic activity mediated by interaction with estrogen receptors that leads to changes in gene expression and cell proliferation. In this study, we isolated four compounds from RJ that exhibit estrogenic activity as evaluated by a ligand-binding assay for the ERB. All these compounds inhibited binding of 17B-estradiol to ERB, although more weakly than diethylstilbestrol or phytoestrogens. However, these compounds had little or no effect on the binding of 17B-estradiol to ERa. Expression assays suggested that these compounds activated ER.
https://www.hindawi.com/journals/ecam/2008/938757/

An in vitro study of the effects of Rhodiola rosea constituents on estrogen receptors ERa and ERB identified strongly docking flavonoids, gossypetin, herbacetin, and rhodiolin. The lignan (+)-lariciresinol also strongly docked to both ERa and ERB.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0944711315003682

"Masculine" contains ethanol extract from seeds and 50% water-ethanol root of asafoetida. Extracts of asafoetida contain volatile oil, resin and gum. The resinous constituents include asaresinol ferulate, free ferulic and umbellic acids as well as sesquiterpene coumarines identified as asafetidnol A and B. Asafoetida sesquiterpene coumarines may act similar to those present in Ferula hermonis sesquiterpenes (ferutinin, teferdin, and tenuferidine) that have been shown to have estrogenic activity, and may contribute to its aphrodisiac activity. It also contains ferulic acid that is present in other plants such as Angelica sinensis that is used for female tonic effects.
https://benthamopen.com/contents/pdf/TOALTMEDJ/TOALTMEDJ-1-102.pdf

Estrogen binding equivalents (EBE) of plant extracts with recombinant estrogen receptor alpha and beta:
Extract            n         EBE
                     (ng/g)+-SD
               ERB            ERa
Red Raspberry leaf      6   23.8+-11.1         8.1+-3.0
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369323/

Our data show that curcumin activates estrogen receptor B (ERB) selectively and the activation of ERB directly effects on the upstream factors of the NFkB signaling pathway. The above results indicate that curcumin reduces BACE1 expression through ERB and NF?B pathway, providing a novel mechanism for curcumin as a candidate for AD therapy.
https://link.springer.com/article/10.1007/s11010-019-03638-0

In the initial stages, human prostate cancer (PC) is an androgen-sensitive disease, which can be pharmacologically controlled by androgen blockade. This therapy often induces selection of androgen-independent PC cells with increased invasiveness. We recently demonstrated, both in cells and mice, that a testosterone metabolite locally synthetized in prostate, the 5a-androstane-3B, 17B-diol (3B-Adiol), inhibits PC cell proliferation, migration and invasion, acting as an anti-proliferative/anti-metastatic agent. 3B-Adiol is unable to bind androgen receptor (AR), but exerts its protection against PC by specifically interacting with estrogen receptor beta (ERB).
Because of its potential retro-conversion to androgenic steroids, 3B-Adiol cannot be used "in vivo", thus, the aims of this study were to investigate the capability of four ligands of ERB (raloxifen, tamoxifen, genistein and curcumin) to counteract PC progression by mimicking the 3B-Adiol activity.
In conclusion, these data demonstrate that by selectively activating the ERB, raloxifen, tamoxifen, genistein and curcumin inhibit human PC cells proliferation and migration favoring cell adesion.
https://www.sciencedirect.com/science/article/abs/pii/S1043661813001709

A method using human recombinant estrogen receptors alpha and beta (ERa and ERB) was adapted for pure isoflavone compounds: glycitein, glycitin, biochanin A and formononetin; and extracts from chaste tree, Queen-Anne's lace, Cyperus rhizome, dong quai, flaxseed, black cohosh, Siberian ginseng, saw palmetto, hops, licorice, red clover and alfalfa. Estrogen binding equivalents (EBE) for extracts binding with ERa were: black cohosh < Queen-Anne's Lace < saw palmetto < hops concentrate < licorice < red clover < alfalfa. Extracts from Cyperus, flaxseed, Siberian ginseng, chaste tree and dong quai had no detectable binding to ERa. For ERB the estrogen binding equivalents were: chaste tree berry < hops concentrate < Cyperus rhizome < black cohosh < Siberian ginseng < dong quai < Queen-Anne's Lace seed < flaxseed < saw palmetto berry < licorice < red clover < alfalfa. The relative binding affinity (RBA) of isoflavone standards for ERa and ERB was compared to that of estradiol. At ERa, the RBA for isoflavone standards were as follows: glycitein > glycitin > biochanin A > formononetin and at ERB the RBA were: biochanin A > glycitein > glycitin > formononetin.
The estrogen receptors, ERa and ERB, are the focus of this research. ERB has been called the phytoestrogen receptor and differs from ERa in ligand selectivity, tissue expression and regulation.
ERa showed significantly less affinity for the phytoestrogens than ERB. Based on EBE concentrations, the most potent ERa binding extracts were that from alfalfa which approached that of kudzu (Pueraria montana var. lobata).
The EBE concentrations in the ERB binding test were 3-fold higher for alfalfa, 7-fold higher for licorice, and 33-fold higher for red clover than for ERa.
Licorice root extract and two of its novel estrogenic compounds, glabrine and isoliquiritigenin, have estrogenic activity in cell proliferation and transactivation assays.
A novel mechanism of cellular protection by these phytoestrogens may involve ERB mediated induction of manganese superoxide dismutase.
Korean ginseng had insignificant receptor binding in the assay; however, red ginseng, a reddishbrown root obtained by hot water treatment of scraped Korean ginseng roots, had 70 times higher EBE concentration in the ERB assay.
Table1 and Table2! (Phytoestrogen_binding)
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S2210803318300629

Kudzu root extract displayed the highest affinity for ERB with an IC50 value of 22 ug/mL, followed by red clover blossom (37 ug/mL), soybean (100 ug/mL), red clover sprout (130 ug/mL), and alfalfa sprout (198 ug/ mL). Only kudzu root showed significant binding affinity for ERa (110 ug/mL), with all other extracts displaying only weak binding affinity.
Both green bean and mung bean sprout extracts showed weak binding affinity (> 200 ug/mL) for both ER receptor subtypes. Of the seven extracts analyzed, kudzu root showed the highest level of cell proliferation. Red clover extracts (blossom and clover), mung bean sprout, and alfalfa sprout extracts all induced MCF-7 cell growth above levels observed using estradiol. All of the extracts examined in ER-binding experiments indicated preferential binding for ERB except for mung bean sprout and
green bean extracts, which were not active at the concentrations tested.
https://sci-hub.se/https://pubs.acs.org/doi/abs/10.1021/jf021114s

The profile of ERa-mediated transactivation is similar to the result of the BG1Luc4E(2) cell experiment, suggesting that ERa-mediated estrogenic activity is dominant in the extracts of soybean seeds. The profile of ERB-mediated transactivation is similar to the result of the BG1Luc4E(2) cell experiment, suggesting that ERB-mediated estrogenic activity is dominant in the extracts of soybean sprouts. These findings imply that phytoestrogenic substances differ between soybean seeds and sprouts.
https://link.springer.com/article/10.1186/1471-2202-13-95

Some phytoestrogens such as coumestrol, genistein, apigenin, naringenin, and kaempferol compete stronger with E2 for binding to ERB than to ERa.
The ranking of the estrogenic potency of phytoestrogens for both ER subtypes in the transactivation assay is different; that is, E2 >> zearalenone = coumestrol > genistein > daidzein > apigenin = phloretin > biochanin A = kaempferol = naringenin> formononetin = ipriflavone = quercetin = chrysin for ERa and E2>> genistein = coumestrol > zearalenone > daidzein > biochanin A = apigenin = kaempferol = naringenin > phloretin = quercetin = ipriflavone = formononetin = chrysin for ERB. Antiestrogenic activity of the phytoestrogens could not be detected, except for zearalenone which is a full agonist for ERa and a mixed agonist-antagonist for ERB.
In the rat and mouse prostate, ERB messenger RNA (mRNA) is highly expressed in the secretory epithelial cells, and it has been shown that fetal or neonatal exposure to E2/DES or estrogenic chemicals causes not only permanent changes in the size of the prostate but also in the expression level of certain genes.
The binding affinity of coumestrol to ERB is 7-fold higher in comparison to ERa. Several flavonoids, especially genistein, apigenin and kaempferol have a higher binding affinity (20- to 30-fold more) for ERB in the solid-phase binding assay.
https://academic.oup.com/endo/article/139/10/4252/2987100?itm_medium=sidebar&itm_content=endo&itm_source=trendmd-widget&itm_campaign=trendmd-pilot

Regarding aromatase, this is where the lignans in whole flaxseed come into play. Flax seed is the highest source of the plant lignan secoisolariciresinol diglucoside (SDG0), a type of phytoestrogen that's similar in structure to endogenous sex hormones.
Once ingested, the bacterial flora in the colon metabolizes SDG to enterodiol (ED) and enterolactone (EL), which are commonly referred to as mammalian lignans. There's research showing that ED and EL both inhibit aromatase.
https://biotest.t-nation.com/articles/flax-oil-vs-fish-oil

Ellagic acid can be easily isolated from pomegranate or strawberries.
ERa and ERB responded differently to ellagic acid, which displayed a low but significant estrogenic activity on ERa and complete antagonist activity on ERB at low concentrations (10-7 to 10-9 M). This is similar to the estrogen agonist/antagonists activities of tamoxifen, 4-OH-tamoxifen, and raloxifen, which display low but significant estrogenic activity in hERa- but only antagonism in hERB-reporter cell systems.
For example, some tea catechins, particularly epigallocatechin gallate (EGCG), were antiestrogenic for ERa at high doses (5 × 10-6 M) and estrogenic for ERa at low doses (5 × 10-7 to 10-9 M) in the presence of E2.
Resveratrol, a polyphenol found naturally in grapes, binds ERa and ERB with comparable affinity, but it transactivates ERa and ERB differently in an ERE sequence-dependent manner. The phytochemical polyphenol lindleyin, on the other hand, transactivates ERB with a higher potency than ERa, whereas glabrene, a polyphenol isolated from the licorice root, is a natural estrogen agonist that activates ERa-mediated transcription in vitro. Recently, it was reported that phytochemical glyceollins exerted antihormonal effects through ERa and ERB.
The divergent biologic activities of ellagic acid, being an agonist in bone cells, but an antagonist in breast cancer cells, may be attributed to the recruitment of tissue-specific ERa or ERB coactivators or corepressors, as well as to varying proportions of tissue ERa and ERB levels.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=Evaluation+of+Estrogenic%2FAntiestrogenic+Activity+of+Ellagic+Acid+via+the+Estrogen+Receptor+Subtypes+ERr+and+ER%C3%A2&btnG=

Natural sources of tocotrienols are from amaranth, annatto, barley, berry, coconut, flax seed, grape fruit seed, grape seed, hazel nut, maize, oat, olive, palm, poppy seed, pumpkin seed, rice bran, rye, safflower, sun flower, and wheat germ. Tocotrienols have also been present in human milk. The richest sources of tocotrienols are rice bran, palm, and annatto oils.
The comparative anticancer activities of four isomers of tocotrienol have proved that delta-tocotrienol is the most potent bioactive tocotrienol against cancer.
In silico simulations and in vitro binding analyses showed high affinity of tocotrienols (gamma and delta) for the estrogen receptor-beta (ERB), but not for the ERa. The binding of tocotrienol to ERB resulted in caspase-3 activation, DNA fragmentation, and apoptosis. Tocotrienols target and inhibit the pro-inflammatory enzyme cyclooxygenase-2 (COX-2), which is aberrantly activated in gastric, hepatocellular, esophageal, pancreatic, colorectal, breast, bladder, cervical, endometrial, skin, and lung cancers and is involved in promoting cell survival, angiogenesis, and metastasis. Gamma-Tocotrienol has been shown to induce apoptosis and autophagy in prostate and breast cancer cells.
https://sci-hub.se/https://www.sciencedirect.com/science/article/pii/B9780128123737000048

Calycosin showed weak agonistic activities at both ERa and ERB (maximum activity was 14.6% and 8.6%, respectively). In contrast, the antagonistic activities of calycosin against E2 at ERa and ERB were significant (maximum inhibition was 46% and 82%, respectively). Thus, our results suggest that calycosin is a partial agonist/antagonist for both ERa and ERB.
Calycosin from Radix Astragali acts as a novel SERM, since calycosin was shown to competitively bind with ERa and ERB, as well as selectively modulate ER transcriptional activities.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011822

Pycnogenol (PYC), a family of flavonoids isolated from French maritime pine bark (Pinus pinaster Aiton., synonym Pinus maritima Mill.), catechin with potent antioxidant and ROS scavenging properties. Cells in the control group showed no expression of ERB, but cells in the presence of B-glycerophosphate and L-ascorbic acid expressed ERB. PYC activated the expression of ERB about 2.8-fold. PYC activated the expression of ERB 2.6- fold higher than the differentiated osteoblasts.
We showed that PYC could cause proliferation and mineralization via the activation of ERB. These results suggest that PYC stimulates osteoblastic differentiation via ROS scavenging properties and the expression of ERB. These findings suggest that PYC is useful in preventing osteoporosis in postmenopausal women.
http://inforesights.com/phytopharmacology/files/pp4v3i7.pdf

After the identification and characterization of two ERs (a and B), optimal SERMs would be those that selectively block the ERa but not the ERB.
Unlike the "classic" antiestrogens such as tamoxifen and its derivates, melatonin neither binds to the ER nor interferes with the binding of estrogens to its receptor. What melatonin seems to do is to decrease the expression of ERa and to inhibit the binding of the E2-ER complex to the estrogen response element (ERE) on DNA.
Thus, melatonin behaves as an antiestrogen which does not bind to ER but to its own membrane receptors, and via this binding to its specific receptors it is able to interact with the ER-signaling pathway.
Interestingly, only ERa, but not ERB, interacts with CaM stimulating the phosphorylation of the receptor, thus facilitating the binding of estrogen as well as that of the E2–ER complex to the ERE. In this context, melatonin is known to exert modulatory effects on the Ca2+/CaM-signaling pathway.
Recently, it was demonstrated that whereas melatonin is a specific inhibitor of E2-induced ERa-mediated transcriptional activation, it does not inhibit ERB-mediated transactivation.
We recently demonstrated, by using MCF-7 cells, which express aromatase and MT1 melatonin receptors, that melatonin, at physiological concentrations, reduces aromatase activity in these cells both under basal conditions and when aromatase activity is stimulated by cAMP or cortisol.
https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-079X.2004.00207.x

Check the table that says "Affinities of estrogen receptor ligands for the ERa and ERB"
Catechol estrogens may also alter ERa:ERB ratio.
https://en.wikipedia.org/wiki/Catechol_estrogen

Tumor-induced myeloid-derived suppressor cell (MDSC) expansion negatively regulates the immune response by inhibiting T cell function through signal transducer and activator of transcription 3 (STAT3) activation, thereby facilitating tumor escape from host immune surveillance. Thus MDSC is an attractive target for cancer immunotherapy to enhance cytotoxic T cell responses.
Since up-regulation of ESR2 expression was reported to activate STAT3 to improve the expansion and activation of MDSC during pregnancy, we detected the levels of phosphorylated STAT3 (pSTAT3) in human and mouse-derived MDSC after quercetin treatment. These results demonstrated that quercetin activated MDSC via ESR2/pSTAT3 signaling.
https://www.sciencedirect.com/science/article/pii/S0753332220301128

Icariin (ICA), the principal Epimedium (Horny Goat Weed) prenylflavonoid, significantly inhibits human phosphodiesterase-5 and induces nitric oxide synthase expression in corpus cavernosum smooth muscle. Icaritin (ICT), the aglycon of ICA, has estrogenic properties and stimulates estrogen-driven cells. In conclusion, the Epi ext, ICT, and quercetin exhibited in vitro ERa- and ERB-mediated estrogenic activity with more specific action to ERB. From these results, phytoestrogens interfere with endogenous estrogen action either by acting as agonists at low endogenous estrogen levels or by acting as antagonists at higher endogenous estrogen levels.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0278691512003584

In the spleen, we were not able to identify a major factor per se, but the three generated networks gave a hint into the molecular events being modulated by lavender oil treatment. In the top-ranking network 1, some of the key molecules were albumin (Alb), prolactin receptor (Prlr), and estrogen receptor 2 beta (Esr2).
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129951

I couldn't find direct evidence for tree tea oil, but I suspect it to preferentially activate ERB.

I can't deny some controversies exist like soy and kudzu, but this may stem from their potent activation of ERa, although I mostly had success with alfalfa (coumestrol) and red clover.

It is rather perplexing that both linoleic acid and omega-3 PUFAs increase ERB given their supposed role in cancer development.

Also linoleic acid and gamma tocotrienols still don't explain the safflower - poppy seed dilemma as they can be found in both.

[Progecitor]

Drugs that modulate estrogen receptor beta (ERB)

Moreover, our in vivo study showed that while endometrial ERB expression was no different between non-PCOS and PCOS patients regardless of whether or not hyperplasia was present, ERa and AR protein expression was gradually increased in women with PCOS following the onset of endometrial hyperplasia. Our in vitro study showed that treatment with metformin inhibited ERa expression without affecting ERB expression. Our findings suggest that decreased glycolysis and increased mitochondrial activity might contribute to the onset of ERa-dependent endometrial hyperplasia and that metformin might directly reverse impaired glycolysis and normalize mitochondrial function in PCOS patients with endometrial hyperplasia.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367580/

By real-time FQ-PCR tested, the expression levels of c-fos and c-myc in both cell lines gradually declined subsequent to metformin treatment at different concentrations (1, 5 and 15 mmol/L). Western blot analyses showed that with the increasing concentrations of metformin, the ERa expression was markedly down-regulated, while ERB expression was up-regulated in the metformin group at the concentrations of 5 mmol/L and 15 mmol/L, compared to those at the control group, there were significant differences between them, respectively.
https://europepmc.org/article/med/25608995

Traconazole was a dual-profile compound, which showed agonistic activity with EC50 of 200 nM on ERa but a higher antagonistic activity with IC50 of 280 nM on ERB than tamoxifen, a classical anti-breast cancer drug.
In this study, simvastatin was validated to have antagonistic effects on ERB with IC50 value at 3.12 uM and showed good antiproliferative activity on human MDA-MB-231 breast cancer cell line with IC50 value of 1.49 uM.
In last decades, tissue- or subtype-selective ER modulators (SERM) showed great advantages in clinic due to less adverse side effects. Ketoconazole selectively inhibit ERB with IC50?=?0.79 uM, and it did not show any antagonistic or agonistic activity to ERa. However, itraconazole was a dual-profile compound, which showed agonistic activity on ERa but a higher antagonistic activity on ERB than the classical anti-breast cancer drug tamoxifen.
Diclofenac is an acetic acid nonsteroidal antiinflammatory drug (NSAID) with analgesic and antipyretic properties, and widely used to treat pain, dysmenorrhea, ocular inflammation, and so on. In the past decades, the anti-inflammatory effects of diclofenac were thought to be linked with inhibition of both leukocyte migration and cyclooxygenase (COX-1 and COX-2), leading to the peripheral inhibition of prostaglandin synthesis. Herein, we reported that diclofenac targeted ERa and ERB with IC50 values of 7.59 and 2.32 uM, respectively for the first time. There were a few similar examples to show NSAIDs targeting nuclear receptors recently. Zhou et al. reported that sulindac could induce apoptosis by binding to retinoid X receptor a (RXRa), while Lehmann et al. found that indomethacin could activate the peroxisome proliferator-activated receptors A and B. There were also several reports to show that oral administration of ER ligands had neuroprotective and anti-inflammatory effects.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349722/

Donepezil mediates oligodendrocyte differentiation by activating both ERa and ERB. Western blotting revealed that the donepezil-mediated increased expression of MAG and MBP was inhibited following treatment with antagonists of ERa and ERB. These findings demonstrated that ERa and ERB play important roles in donepezil-induced oligodendrocyte differentiation as indicated by the expression of myelin-associated protein.
https://onlinelibrary.wiley.com/doi/full/10.1111/jnc.14927

Upon binding of a ligand to a nuclear receptor, the receptor homo- or heterodimerizes and is translocated in the cell nucleus where it acts as a transcription factor regulating a vast number of genes and eliciting numerous physiological responses. Among such receptors are androgen receptor (AR); estrogen receptors a (ERa) and B (ERB); glucocorticoid receptor (GR); liver X receptors a (LXRa) and B (LXRB); peroxisome proliferator-activated receptors a (PPARa), B (PPARB), and gamma (PPARG); retinoid X receptor a (RXRa); and thyroid receptors a (TRa) and B (TRB). Activation of those receptors regulates processes important for reproductive and developmental health, behavior, and the immune system.

This is practically a treasure-trove. I think POISers should really dig into this to see if they can relate.
Identification of Drugs with Strong Binding to Nuclear Receptors:
Check Table 1 for the full list!

Name 1 Nuclear Receptor 2 Binding Free Energy (kcal/mol)
ERB agonists:
Artemether AR; ERB -8.7(an); -9.6
Celecoxib ERa; ERB -9.6 and -9.9(an); -9.3
Conivaptan ERB; GR -9.5; -10.9 and -11.1(an)
Lorazepam ERB -9.6
Morphine ERa; ERB -9.4; -9.5
Naftifine AR; ERB -8.7(an); -9.5
Oxazepam ERB -9.4
Trihexyphenidyl AR; ERB -9.0(an); -9.3

ERB antagonists:
Amitriptyline ERB -9.2(an)
Azilsartan ERB; GR -9.8(an); -9.9(an)
Benzatropine ERa; ERB -9.6; -9.6(an)
Butenafine ERB -9.6(an)
Cabozantinib ERB; GR -9.1(an); -10.2(an)
Candesartan ERB -9.6(an)
Carbamazepine AR; ERa; ERB -8.8(an); -9.6; -9.8(an)
Ceritinib ERB -9.2(an)
Cinacalcet AR; ERa; ERB; TRa -8.5(an); -10.0; -9.7 and -9.2(an); -10.3
Clonazepam ERB -9.4(an)
Cyclobenzaprine AR; ERa; ERB -8.6(an); -9.9; -9.6(an)
Cyproheptadine ERa; ERB -10.2; -9.3(an)
Dabrafenib ERB -9.7(an)
Deacetylbisacodyl ERa; ERB -9.5; -9.4(an)
Dihydroergotamine ERa; ERB; GR -11.6(an); -10.6(an); -11.6(an)
Duvelisib ERB; LXRa; LXRB -9.2(an); -12.5; -12.5
Estazolam ERB -9.1(an)
Ezetimibe ERa; ERB; PPARG -10.5 and -9.8(an); -9.7(an); -10.7
Fluorescein ERB -9.7(an)
Hydromorphone AR; ERa; ERB -9.2(an); -9.8; -9.4 and -9.5(an)
Irbesartan ERa; ERB -10.0(an); -9.4(an)
Irinotecan ERa; ERB; GR -9.4(an); -9.7(an); -11.1(an)
Ketoconazole ERa; ERB -9.5 and -9.9(an); -9.3(an)
Larotrectinib ERB; LXRB -9.1(an); -12.2
Levorphanol AR; ERa; ERB -9.1 and -8.9(an); -9.5; -9.5 and -9.1(an
Lumacaftor ERB; GR; LXRB -9.9(an); -10.3(an); -12.7
Lurasidone ERB; GR; LXRa; LXRB -9.2(an); -10.0(an); -12.1; -12.6
Maraviroc ERa; ERB -9.4(an); -9.7(an)
Meclizine ERB -9.3(an)
Mefloquine AR; ERB; TRa -9.8(an); -9.4(an); -10.5
Montelukast ERa; ERB; PPARG -10.2(an); -9.5(an); -10.4
Naldemedine ERB; GR -9.2(an); -10.8(an)
Nelfinavir ERa; ERB; GR; PPARG -10.5(an); -9.6(an); -10.9(an); -11.5
Nortriptyline ERB -9.1(an)
Oxymorphone AR; ERB -9.0(an); -9.4 and -9.2(an)
Perampanel ERB -9.6(an)
Phenindamine ERa; ERB -9.6; -9.5 and -9.7(an)
Pimozide ERa; ERB; GR; LXRa; LXRB; PPARG -9.9; -9.9(an); -10.6(an); -12.1; -12.8; -11.2
Plerixafor ERa; ERB -10.8(an); -10.9(an)
Protriptyline ERB -9.1(an)
Regorafenib ERa; ERB -10.0; -9.7(an)
Revefenacin ERB; GR; PPARG -9.7(an); -10.2(an); -10.7
Risperidone ERa; ERB; LXRB -9.7(an); -9.5(an); -12.3
Rolapitant ERB; PPARG; TRB -10.5(an); -10.5; -10.8
Solifenacin ERB -9.6(an)
Sonidegib ERB -9.5(an)
Tadalafil ERa; ERB -9.7(an); -9.6(an)
Telmisartan ERa; ERB; PPARG -10.0(an); -10.1(an); -10.6
Tolvaptan ERB; GR -9.6(an); -10.3(an)
Triazolam ERB -9.1(an)
Vorapaxar ERB; GR -9.7(an); -10.6(an)
Zafirlukast ERB; PPARG -9.7(an); -10.9

There were some more that seemed important for POISers:
Amoxicillin AR -8.5(an)
Cocaine AR -8.4(an)
Codeine AR -9.1 and -8.7(an)
Diazepam ERa -9.5
Fluoxetine AR -8.5(an)
Imatinib ERa -9.8(an)
Naltrexone AR -8.7(an)
Paroxetine ERa -9.5
Penicillin g/benzylpenicillin AR -8.5(an)
Piroxicam AR -9.3 and -9.0(an)
Sertraline ERa -9.5
Vortioxetine AR -8.5(an)
Warfarin ERa -9.4(an)
https://www.mdpi.com/1420-3049/25/7/1616/htm

Needless to say clonazepam having an ERB antagonist property is a major finding for me as I had taken Rivotril for several year and even though it was not recently I am still quite sure that clonazepam increased my brain fog, photophobia and made me even more forgetful. It also induced a very deep slumber where I could hardly arouse and hardly had any dreams. I am not sure about bloodshot eyes or gut issues, but as I took Rivotril along with almost all the anti-psychotics I was prescribed it may have substantially deteriorated their effects even though there were no ERB agonists among them. This also proves that at least these symptoms are ERB mediated in my case.
As other POISers had success with Celecoxib and Lorazepam I can only guess they would be beneficial for me too.
I have already discussed my controversial experiences with sertraline, but it was more similar to L-Tryptophan which would make me think that these effects were more related to serotonin than to ERa.

[Progecitor]

Even more supplements with a preferential activation of estrogen receptor beta.

Angelica sinensis
Dong quai (Angelica sinensis root) has been used in Chinese traditional medicine for thousands of years for various female health conditions (e.g., dysmenorrhea, pelvic pain, symptoms of menopause).  In fact, dong quai has been shown to stimulate the growth of MCF-7 (ER+ human mammary carcinoma) cells, but does not bind either ERa or ERB. The plant contains several miscellaneous phytochemicals, only two of which have notable docking energies, 10-angeloylbutylphthalide (?107.1 kJ/mol with ERB) and angeliferulate (?110.7 and ?121.5 kJ/mol with ERa and ERB, respectively).

Centella asiatica
Centella asiatica (gotu kola) has been used in Ayurvedic traditional medicine for cognitive enhancement to alleviate symptoms of anxiety and promote relaxation as well as for headache, body ache, asthma, ulcers, and wound healing. Animal studies have revealed cognitive enhancement and anxiolytic effects. To our knowledge, there have been no reports on the estrogenic activity of C. asiatica.
Both quercetin and asiaticin had notable exothermic docking energies with ERB (?106.0 and ?109.0 kJ/mol, respectively). Quercetin has shown preferential binding to ERB.

Cimicifuga racemosa (syn. Actaea racemosa)
Although black cohosh extracts have demonstrated clinical efficacy against some symptoms of menopause, several studies have demonstrated little or no estrogenic activity. The efficacy of C. racemosa extracts on post-menopausal symptoms has been attributed to partial agonism of the serotonin receptor and the mu-opiate receptor.
C. racemosa extracts have revealed several triterpenoids, phenylpropanoids and caffeic acid derivatives. Several C. racemosa phenolic compounds did show remarkable docking affinities for both ERa and ERB: cimicifugic acid A, cimicifugic acid B, cimicifugic acid G, cimiciphenol, cimiciphenone, cimiracemate A, cimiracemate B, cimiracemate C, cimiracemate D, and fukinolic acid. It is likely that any estrogenic activity of C. racemosa extract is due to the presence of phenolic components rather than triterpenoids.

Dioscorea villosa
The rhizomes of wild yam, Dioscorea villosa, have been used to treat symptoms associated with menopause and premenstrual syndrome (PMS) as well as to relieve labor pains and sooth dysmenorrhea. The genus contains numerous steroidal glycosides. In this work, we have carried out in-silico screening of phytochemicals from the genus Dioscorea. Of these, the diosbulbins D, F, H, J, K, and L (diterpenoids from D. bulbifera) gave remarkable docking energies with both ERa and ERB while the pregnane steroids 3,16-dihydroxypregn-5-en-20-one, 3,21-dihydroxypregna-5,16-dien-20-one, ergost-5-ene-3,26-diol, and pregnadienolone, showed selective docking with ERB. Interestingly, neither furostane nor the spirostane steroids, common in Dioscorea spp. docked well with the estrogen receptors. It is worth noting that clinical studies have shown D. villosa to have little effect on menopausal symptoms.

Echinacea spp.
Echinacea (E. angustifolia, E. pallida, and E. purpurea) is one of the most popular herbal supplements sold in the United States and has been used as a treatment for the common cold, coughs, bronchitis, upper respiratory infections, and inflammatory conditions. Recent studies have demonstrated Echinacea to exhibit immune-system-stimulating activity. Phytochemicals that have been isolated from Echinacea spp. include chicoric acid and monomethyl and dimethyl ethers, trichocarpinine, cinnamoylechinadiol, cinnamoylechinaxanthol, cinnamoylepoxyechinadiol, cinnamoyldihydroxynardol, caftaric acid, caffeoyl-p-coumaroyltartaric acid, burkinabin A, burkinabin B, kaempferol, luteolin, and quercetin. Six phytochemicals were identified in this docking study that showed strong docking to the estrogen receptor: the flavonoid quercetin; the phenolic compounds caffeoyl-p-coumaroyltartaric acid, caftaric acid, and chicoric acid; and the sesquiterpenoids cinnamoylechinadiol and cinnamoylepoxyechinadiol.

Gingko biloba
G. biloba is commonly used as a supplement to improve cognitive abilities and for women specifically, it has been used to treat some of the side effects accompanying menopause. The extracts of G. biloba have previously been shown to exhibit feeble estrogenic effects, and act as selective estrogen receptor modulators (SERMs) with the alpha and beta estrogen receptors.
Of these, quercetin, tricetin, and sesamin gave large negative docking energies. Sesamin, in particular, docked strongly with ERB.

Glycyrrhiza glabra
The phytochemistry of Glycyrrhiza glabra has been well studied and numerous compounds have been isolated and identified.
Licorice (Glycyrrhiza glabra) root has been used for thousands of years by different cultures and for a variety of reasons. Although licorice root has been suggested as a treatment for symptoms of menopause, G. glabra root extracts have been shown to be inactive in terms of ERa or ERB binding. Nevertheless, however, fractionation of G. glabra extracts has revealed several ER-modulating components. Glabrene binds to human ER and shows estrogenic activity. Our in-silico docking study shows glabrene to be a strongly docking ligand to both ERa and ERB (?104.8 and ?114.9 kJ/mol, respectively). Glabridin, on the other hand, displayed ERa-selective antagonism, in contrast to the docking results that showed glabridin to have ERB docking selectivity (?15.8 and ?92.9 kJ/mol, respectively). The chalcones isoliquiritigenin and licochalcone A, the flavonoid quercetin and the isoflavonoid genistein also bind to human ERa and show estrogenic activity. These ligands all show negative docking energies with ERa (range from ?93.2 to ?99.9 kJ/mol) and ERB (?98.9 to ?107.8 kJ/mol).

Lepidium meyenii
Maca (Lepidium meyenii) is native to the central Andes of Peru (3500–4500 m asl). The root has been used by native Amerindians to improve fertility, as an aphrodisiac for both men and women. Maca was found to increase sperm counts and gonadal mass in a rat model to improve copulatory performance of male mice and rats and to increase litter size and pregnancy rates in female mice. In adult human males, maca treatment led to increased semen volume and sperm count and increased sexual desire. In addition, maca reduced sexual dysfunction in postmenopausal women and inhibited estrogen-deficient osteoporosis in ovariectomized rats, but maca extracts have not shown estrogenic activity. None of the L. meyenii phytochemicals investigated in this in-silico study showed remarkable docking energies, consistent with the non-estrogenic activity previously reported.

Ptychopetalum olacoides, P. uncinatum
Muira puama (bark and root extracts of P. olacoides or P. uncinatum) has been used in Amazonian Brazil during highly stressful periods, to treat CNS-related ailments, neuromuscular problems, "nervous weakness", sexual debility, frigidity, impotence, and rheumatism. Consistent with these traditional uses, P. olacoides ethanol root extract has shown memory retrieval improvement in young and aging mice, in-vitro acetylcholine esterase inhibitory activity and prevention of stress-induced hypothalamic-pituitary-adrenal hyperactivity. In addition, Muira puama formulations have demonstrated efficacy in treating male erectile dysfunction and low libido and low sex drive in women. A number of clerodane diterpenoids have been isolated from P. olacoides bark. Several of these have given excellent docking energies with the estrogen receptor, but two in particular, ptycho-6a,7a-diol and ptycholide IV had remarkable docking to ERB (?122.9 and ?114.7 kJ/mol, respectively). To our knowledge, the estrogenic effects of Muira puama have not been investigated.

Rhodiola rosea
R. rosea is reputed to strengthen the nervous system, fight depression, enhance memory, and improve energy levels, which has been attributed to adaptogenic properties of the herb. The flavonoids gossypetin, herbacetin, and rhodiolin, and the lignan (+)-lariciresinol, have been identified in R. rosea. Lariciresinol showed strong docking to both ERa and ERB. There are conflicting reports on the potential estrogenic effects of R. rosea, however.

Sambucus nigra
The bark, leaves, flowers, fruit, and root extracts of black elderberry (Sambucus nigra) have been used traditionally to treat respiratory ailments such as bronchitis, cough, influenza, and upper respiratory infections. Of these, only the flavonoid quercetin showed good docking to the estrogen receptor. To our knowledge, there are no reports on the estrogenic activity of S. nigra extracts.

Silybum marianum
Milk thistle, Silybum marianum, extracts (silymarin) have been used for centuries to treat liver diseases. Silybin B (also called silibinin) has been shown to selectively bind to the ERB receptor rather than ERa and previous docking studies have shown selective docking to ERB over ERa. In contrast, our current docking study revealed that neither silybin A nor silybin B gave negative docking energies with either ERa or ERB. Quercetin and taxifolin, on the other hand, gave docking energies comparable to zearalenone with ERB (?106.0, ?104.6, and ?104.5 kJ/mol, respectively), and these flavonoids have also shown estrogenic activity. Silymarin modulation of ERB may be responsible for the estrogenic effects of the extract.

Tribulus terrestris
Tribulus terrestris has been used to contribute to physical and sexual strength. The plant is rich in steroidal glycosides and T. terrestris extracts have shown androgenic effects in animal models, but had no influence on androgen production or gains in strength or muscle mass in young men. To our knowledge, there have been no reports on the estrogenic effects of T. terrestris.
In-silico molecular docking has shown that N-trans-feruloyltyramine docks strongly to both ERa and ERB, perlolyrine docks strongly to ERB, terrestribisamide docks strongly to ERa, quercetin docks strongly to ERB, and the steroid 2,3-dihydroxypregn-16-en-20-one docks strongly to both ERa and ERB.

Trifolium pratense
The alkaloids cis- and trans-clovamide, several coumarins, flavonoids, and isoflavonoids have been identified in red clover (Trifolium pratense). Although there have been no ethnobotanical reports to support it, the presence of isoflavones has led to suggest that red clover may serve as a phytochemical alternative to post-menopausal hormone replacement therapy. Red clover extract has been shown to exhibit weakly estrogenic effects in a rat model and does show in-vitro ERa and ERB binding ability.
Biochanin A, daidzein, formononetin, and genistein have been identified as T. pratense isoflavonoids with ERa and ERB binding activity and these compounds did show a binding preference for ERB. Molecular docking of these ligands also showed preference for ERB. They were not, however, the best docking ligands of T. pratense phytochemicals. The alkaloids cis- and trans-clovamide, and the coumarin pratenol B showed good docking to both ERa and ERB. Of the T. pratense isoflavonoids, calycosin and pseudobaptigenin had more exothermic docking energies to ERB than did biochanin A, daidzein, formononetin, or genistein.

Trigonella foenum-graecum
Fenugreek (Trigonella foenum-graecum) is used as an antidiabetic and for lowering blood lipid and cholesterol levels. Quercetin and 3',5,7-trihydroxy-5'-methoxyisoflavone were the strongest docking ligands for ERB. Fenugreek seed extract has shown estrogenic activity.

Turnera aphrodisiaca (syn. T. diffusa)
Damiana leaf has been used in traditional medicine in Neotropical cultures as a stimulant and aphrodisiac and the herb is marketed as a sexual enhancer for men and women. Extracts of T. aphrodisiaca have shown aphrodisiac activity in mouse and rat models, as well as anxiolytic activity in mice. Phytochemical investigations have revealed damiana to be rich in flavonoids, including acacetin, apigenin, gonzalitosin, laricitrin, luteolin-8-propenoic acid, orientin, orientin-3"-ketone, pinocembrin, and syringetin. The extract has shown anti-aromatase (due primarily to acacetin and pinocembrin) and estrogenic activity (due primarily to apigenin, Z-echinacin, and pinocembrin). In contrast to these experimental results, molecular docking revealed the strongest docking Turnera compound to be luteolin-8-propenoic acid (?113.1, ?123.1 kJ/mol for ERa and ERB, respectively) but this compound was inactive in the aromatase and estrogen assays. In contrast, pinocembrin, which was active in both experimental assays, had ERa and ERB docking energies of ?81.4 and ?87.9 kJ/mol, respectively.

Vitex agnus-castus
Vitex agnus-castus, "chaste tree", has been used as a tonic for female reproductive disorders, including menstrual disorders (amenorrhea, dysmenorrhea), premenstrual syndrome (PMS, corpus luteum insufficiency, hyperprolactinemia, infertility, menopause, and disrupted lactation. Based upon docking energies with ERB, casticin, santin, vitexcarpan, and the aglycones of agnucastoside C and agnuside, could be expected to exhibit ER modulation. Indeed, V. agnus-castus extracts have been shown to bind to ERa and ERB. It has been suggested that V. agnus-castus is a source of 3-ketosteroids with progesterone-like activity.

This molecular docking study has revealed that almost all popular herbal supplements contain phytochemical components that may bind to the human estrogen receptor and exhibit selective estrogen receptor modulation. As such, these herbal supplements may cause unwanted side effects related to estrogenic activity. For example, estrogenic agents may be effective and potent growth stimulators of estrogen-receptor positive tumors and pose a hazard to patients with breast cancer who have ER-positive tumors and who are being treated with antiestrogens.
There are several limitations to these docking results:
Some of the herbal phytochemicals examined may not be bioavailable due to limited solubility, membrane permeability;
This docking study has only examined docking of the natural ligands (or their aglycones) and does not take into account in-vivo hydrolysis or other metabolic derivatization;
The docking studies do not account for synergism in the estrogen receptor binding;
Docking energies do not provide information about whether strongly binding ligands may function as agonists or antagonists of the estrogen receptor.
https://link.springer.com/article/10.1186/s40203-015-0008-z

Delphinidin-3-glucoside is a major anthocyanin present in pigmented fruits and vegetables.
In our experiments, pelargonidin-3-glucoside showed affinity for both receptors, with a relatively higher affinity for ERa (61.3 lM +/- 0.7) than for ERB (93.0 lM +/- 0.8 ), whereas peonidin-3-glucoside only demonstrated affinity for ERa (64.4 lM +/- 0.9) and delphinidin-3-glucoside only reasonable affinity for ERB (63.2 lM +/- 0.8 ). We also assayed the breakdown metabolites deriving from anthocyanins. Among the phenolic acid metabolites assayed, gallic acid showed affinity for ERB (100.3 lM +/- 0.9) but did not show affinity for ERa. It is interesting to note that delphinidin-3-glucoside and gallic acid, with similar structural features in the hydroxylation pattern of their B ring, showed affinity for ERB, but not for ERa. Moreover, delphinidin-3-glucoside demonstrated a binding affinity for ERB that is approximately 2-fold higher than that of gallic acid.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S000398611400143X

Baicalein and wogonin can be found in Chinese skullcap (Scutellaria baicalensis).
Although baicalein and wogonin were relatively weaker agonists in transactivation through ERa, they exhibited clear ERB selectivity as they induced significantly higher transactivation through ERB than through ERa.
Blood vessels express ERs, and ERB plays an essential role in the regulation of vascular function and blood pressure. Activating ERs reenforces their anti-hypertensive effect. Our study is first to show that one iridoids (aucubin) could increase luciferase activity in ERs.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0308814611006583

We examined 17 black raspberry constituents and metabolites (10 uM or 10 ug/mL, 48 h) for their ability to prevent endometrial cancer cells from proliferating. Urolithin A (UA) was most able to suppress proliferation in a time- and dose-dependent manner. It arrested the G2/M phase of the cell cycle by upregulating cyclin-B1, cyclin-E2, p21, phospho-cdc2, and CDC25B. UA also acted as an estrogen agonist by modulating estrogen receptor-a (ERa) dependent gene expression in ER-positive endometrial cancer cells. UA enhanced the expression of ERB, PGR, pS2, GREB1 while inhibiting the expression of ERa and GRIP1.
https://onlinelibrary.wiley.com/doi/abs/10.1002/mnfr.201600048

Triphala-derived polyphenols such as chebulinic acid are transformed by the human gut microbiota into metabolites such as urolithins, which have the potential to prevent oxidative damage. The authors speculate that the bioactivity of Triphala is elicited by the gut microbiome to generate a widened spectrum and abundance of anti-inflammatory compounds.
https://www.liebertpub.com/doi/pdfplus/10.1089/acm.2017.0083

Table 1 lists a good number of natural estrogen modulators with some not mentioned before. This study mostly suggest an antagonist role for phytoestrogens. However if this was true than it would not explain my terrible experiences with clonazepam which also has an ERB antagonistic effect.
https://www.sciencedirect.com/science/article/pii/S2005290116000388

This is all I could find for now. As a further possibility I have a suspicion that the MCF-7 breast cancer model due to its altered ERa:ERB ratio may serve as a good model for my case and could lead to the identification of additional prospective compounds. I know this may sound stupid as I don't have breast cancer, but the hardened lumps in the breast could be precancerous formations that came about due to the persistently altered estrogenic ratio induced by POIS. This may be supported by the fact that some very potent activators of ERB can reduce this symptom or even make it disappear temporary.

[hurray]

What is the connection between your posts in this thread and POIS?

Sometimes using fewer words can make your posts more effective 

[Progecitor]

What is the connection between your posts in this thread and POIS?

Sometimes using fewer words can make your posts more effective 

Well thanks for the inquiry! I was actually moving in that direction, but it takes a lot of time to put these posts together. In the first post I have already laid out the general theory and I am currently expanding on that with more details. At first I wanted to provide evidence that this theory could be sound, especially considering that I erred earlier with my reasoning about FAAH inhibitors which was almost solely built upon my success with saffron. I didn't want to make the same mistake again. In the past year I had done a good amount of experimenting with different supplements which gave rise to other theories. So far I have tested about one hundred things and at the moment I find this the only plausible explanation taking into account everything.
https://poiscenter.com/forums/index.php?topic=3798.msg40769#msg40769
(ctrl+F: alfalfa)
It is true that several of these supplements could increase testosterone, but I think it is plain to see that alone can't explain everything. There are also other theories on the forum, but I can't see any that would easily explain all my experiences. This doesn't mean that some of them can't be correct, but there is a need for a unifying theory that would at least connect some of the known facts. Unfortunately there seems to be several types of POIS which often contradict each other and this makes it even harder to draw any definite conclusions. For now at least I can say that I had partly figured out my case and this serves as a rather solid base to make any further advancement.

[Progecitor]

Safflower oil (contains linoleic acid, oleic acid, palmitic acid and stearic acid) [Daily dose is 2 ml (1 coffeespoon) which contains 340 mg of MUFAs from which 340 mg is oleic acid and 1462 mg of PUFAs of which 1462 mg are omega-6 fatty acids]: I took 1.5 (3 x 0.5) teaspoon per day which is about 4-5 times the recommended daily dose. This turned out surprisingly good. The overall effect somehow reminded me to that of passionflower. It doesn't seem like it turns POIS any worse, so it is quite unlikely that linoleic acid would be detrimental. I had an O and while it can't prevent POIS onset the symptoms in the following days were generally weaker, so it helps with recovery. The stool was noticeably yellowish and looser, but the burning pain was still present somewhat. Generally it had about a moderate efficiency in POIS management.

What if Safflower oil (= mostly linoleic acid)
"elevates the endocannabinoids 2-AG and anandamide"
which helps you somehow?
Source: http://yelling-stop.blogspot.com/2021/11/does-linoleic-acid-induce-obesity.html "Essentially, we are eating a diet that is giving us the munchies, the effect that marijuana has on those that consume it."

This somehow relates to the thought that I'm self-medicating with Pizza (cheese casomorphin etc) on the day after orgasm.
Others had success with CBD.

But how would this interfact with your caipiscin like theory?

I am sorry for the late response, but earlier I didn't really know what to say. I still haven't figured out whether linoleic acid is purely beneficial or not, but recently I have found an amazing study which not only details the intricacies of endocannabinoids in my case, but also provides the major clue that unifies my other theories. At first I wanted to savor this for later when I have already provided some info on the estrogenic balance, however given its importance I guess it is only appropriate to provide this now. Based on the supplementation topography I have built so far it became rather evident that the two major factors that positively affect my symptoms are estrogen receptor beta agonists, as discussed above, and PDE4 inhibitors. As it surprisingly turns out the two are connected by activator protein 1 (AP-1), which was shown in the earlier metabolic syndrome model to be a key element. In more detail ERa agonists tend to activate AP-1, while ERB agonists inhibit AP-1. I guess the reverse is true for the antagonists. As AP-1 inhibition leads to the inhibition of PDE4 this means that the estrogen balance has a major impact on this pathway. To my delight this gives a rather detailed systemic view over my whole POIS case and serves as a solid base for any further research and treatment considerations.
Thus supplements and drugs that increase ERB:ERa ratio, inhibit AP-1 and/or PDE4 can potentially benefit my case. It is really interesting that many other diseases (e.g. sepsis, multiple sclerosis, Alzheimer, breast cancer, prostate cancer, covid-19, etc.) are involved in this pathway. This of course makes it rather difficult to identify the exact origin of POIS. I haven't researched AP-1 that much yet, but I can provide two interesting examples for AP-1 inhibition.
- honokiol (Relora):
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0006295205005344
- imatinib:
https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.23029

I am going into more detail about this later, but for now I wanted to outline the possible involvement of endocannabinoids in this matter as to answer the original question. Actually the issue is more complex than anything I could have imagined earlier as the ECS has both pro- and contra-activities on this model which makes it rather difficult to make any straight and simple conclusions.

Cannabinoid-estrogen relation:
- The activation of ERa activates AP-1-dependent transcription, whereas the activation of ERB inhibits AP-1-dependent transcription. Cannabinoid agonists inhibit AP-1-mediated transcriptional activities.
- ERB activates FAAH transcription, thus reducing anandamide, this is also the first step of spermatogenesis.
- Increased levels of AEA induce ERB transcription.
- A high AEA level may impair the expression of key steroidogenesis enzymes (i.e., Cyp17 and 3B-HSD) causing a drop in intratesticular testosterone level and also increases the expression of Cyp19, causing the increase of intratesticular estradiol levels.
- One study states that THC doesn't affect ERa, but disrupts ERB signaling, although another study claims the opposite.
- CBD doesn't seem to effect ERs, but inhibits aromatase which is in favor of ERB signaling.
- Estrogen (ERa) can stimulate anandamide release and also inhibits FAAH activity, thus increase AEA.
- Estrogen stimulates also AEA synthesis via NAPE-PLD and inhibits nongenomically AEA degradation via FAAH, overall increasing the endogenous level of endothelial AEA.
- Another study claims the opposite: Estrogens and progesterone downregulate N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) enzyme expression.
- Cannabinoid receptor agonists may inhibit the adenylate cyclase and PKA pathways.
- Cannabinoids reduce epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF).
- Estrogens activate ATF-1/CREB, while cannabinoids inhibit cAMP and decrease CREB.
- ERa activates p38/MAPK, extracellular-signal-regulated kinase (ERK)/MAPK and (PI3K)/protein kinase B (Akt), while ERB only activates p38/MAPK.
- Cannabinoids also activate the p38/MAPK pathway, downregulate PI3K-Akt and ERK1/2 kinase signaling.
- Gut microbes exquisitely control the ECS.
- ERB activation can suppress TRPV1.
- Cannabinoids may modulate CB1, CB2, TRPV1-4 and 8, PPARA and PPARG.
- AEA can also inhibit T-type Ca2+ channels (Cav3s).
- Endocannabinoids can act intracellularly on mitochondrial CB1 receptors to regulate energy metabolism, with increased in situ endocannabinoids leading to decreased cellular respiration.
- In right amounts AEA is anti-inflammatory, however if FAAH inhibition leads to increased AEA then it may be oxidized alternatively by cyclooxygenase-2 (COX-2), lipoxygenase (LOX) or p450 that drives inflammation.
- Bacterial LPS inhibits FAAH and promotes COX-2 expression and these data suggest that endocannabinoids increase gut permeability in a positive, pro-inflammatory feedback loop.
- Most studies implicate AEA and CB1 activity in intestinal hypomotility.
- CB1 receptor densities are generally higher in males and CB1 receptor density is probably controlled by estrogen expression.
- AEA abundance has been shown to elicit increased ghrelin production, which is the hunger hormone.
- Dietary-introduced n-3 LCPUFAs may alleviate metabolic syndrome by reducing the bioavailability of endocannabinoid precursors (e.g. linoleic acid).
- Probiotic Lactobacillus and prebiotic oligofructose (inulin) supplementation can decrease AEA synthesis.

Taken these facts together I suspect a high endocannabinoid tone in my case, however it is not clear how much this contributes to POIS actually. It is unlikely that FAAH inhibition would be majorly detrimental as most of the time they help somewhat, but many other supplements also help without a direct relation to the ECS. It is rather perplexing though that several supplements (saffron, maca, Echinacea, genistein (red clover), apigenin, quercetin, kaempferol, etc.) simultaneously activate ERB and inhibit FAAH which should exhibit opposing effects on spermatogenesis, but convergence on AP-1 inhibition. A high level of anandamide could impair 3B-HSD, which would decrease 3B-Adiol and the ERB tone as well. As marijuana (THC) use contributed to POIS development in some cases both its impact on steroidogenic enzymes and its anti-estrogenic property has to be considered. The aromatase inhibitory effect of CBD should lead to an increased testosterone and ERB preference, but of course it also inhibits FAAH, so it should increase AEA as well, which shows how complex this is. Linoleic acid also has mixed effects in this relation as acutely it could activate ERB, but as a precursor for endocannabinoids and arachidonic acid, it would serve to upkeep a high ECS tone in the long run.
So while the ECS certainly plays some role in my POIS, currently I can't label it as something black or white. Still it is good to keep in mind these facts while testing different supplements as it could lead to interesting realizations regarding POIS pharmacology.

Sources (The first three are probably the most enlightening):
https://www.spandidos-publications.com/ijmm/38/6/1642
https://www.mdpi.com/1422-0067/22/2/972/htm
https://www.tandfonline.com/doi/full/10.1080/19490976.2021.1911572
https://link.springer.com/article/10.1007/s00018-012-1074-6
https://link.springer.com/article/10.1186/s13293-021-00364-5
https://ashpublications.org/blood/article/100/12/4040/88263
https://onlinelibrary.wiley.com/doi/full/10.1111/andr.12785
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0890623820300058
https://www.sciencedirect.com/science/article/abs/pii/S037811190200598X
https://ashpublications.org/blood/article/100/12/4040/88263/Estrogen-stimulates-arachidonoylethanolamide

[Progecitor]

The 5-HT2A serotonin receptor is likely involved in POIS related depression.

Most importantly 5-HT2A has a role in sexual motivation and arousal, thus it could be also viewed from this aspect.
In the past I had a positive experience with Venlafaxine, but it was such a long time ago that I can't recall the details. Unfortunately I don't have any experience with Milnacipran, so I can't relate to that. Nevertheless I think these facts should be considered as a possible mechanism for their action.
Tryptophan and SSRIs were also anti-depressive, however they also increase POIS in other ways, which may mean that activation of some monoamine receptors could result in differential effects.
Some facts seem controversial, however ERB agonists, testosterone boosters are experimentally beneficial for me, although only some of them have a clear anti-depressive effect. Inhibition of 5-HT2A is usually considered anti-depressive, however in my case the opposite may be true. Even more interestingly PDE4 inhibitors also seem to be anti-depressive, which may be due to an increase in BDNF and/or decrease in pro-inflammatory cytokine (e.g. TNF-a) production.

The role of 5-HT2A and 5-HT2C subtypes of serotonergic receptors in the control of sexual behavior and plasma testosterone regulation was studied in male CBA mice exposed to a sexually receptive female separated by a transparent partition.
Administration of 5-HT2A receptor antagonists ketanserin (1.0 and 2.0 mg/kg i.p.) or cyproheptadine (1.0 and 2.0 mg/kg i.p.) diminished the behavioral components and prevented the hormonal components of male sexual arousal.
Administration of ritanserin – a nonselective 5-HT2A/2C antagonist and, to a smaller degree, 5-HT2B antagonist – at doses of 0.1 and 0.5 mg/kg did not significantly influence male behavior and the activating effect of the presence of a female on the hypothalamo-pituitary-testicular system, although it increased resting testosterone levels.
The present findings suggest that 5-HT2A/5-HT2C receptors may be involved in the neural control of male sexual motivation and arousal, presumably by exerting reciprocal facilitative (5-HT2A) or suppressive (5-HT2C) influences.
https://www.karger.com/Article/Abstract/63681

Herein, we report on an NDPH patient who failed to find relief from over 20 different treatments, but found resolution with Venlafaxine, a known TNF-a inhibitor. Venlafaxine is traditionally used for major depressive disorder (MDD) patients, but its binding to 5-HT2A receptor allows for downstream inhibition of TNF-a.
https://journals.sagepub.com/doi/full/10.1177/2050313X19847804

Milnacipran (MIL) is a representative of a new class of antidepressants (SNRIs) which inhibit selectively the reuptake of serotonin and noradrenaline but, in contrast to tricyclics, show no affinity for neurotransmitter receptors. MIL was administered at a dose of 10 or 30 mg/kg p.o. once or repeatedly (twice daily for 14 days). MIL did not change the number or affinity (Bmax and KD) of a1-adrenergic receptors in the cerebral cortex for [3H]prazonsin, however, the ability of the a1-adrenoceptor agonist phenylephrine to compete for these sites was significantly enhanced. MIL given repeatedly (but not acutely) inhibited both the head twitch reaction induced by L-5-HTP or (+-)DOI, the effects mediated by serotonergic 5-HT2A receptors. The above results indicate that repeated MIL administration increases the responsiveness of a1-adrenergic system (behavioural and biochemical changes) and decreases the responsiveness of the serotonergic 5-HT2A receptors (especially behavioural changes) as tricyclics do. It may be concluded that the lack of MIL affinity for neurotransmitter receptors is of no importance to the development of adaptive changes in the studied systems, observed after repeated treatment with antidepressants.
https://link.springer.com/article/10.1007/s007020070022

Estrogen has a complex connection with 5-HT2A.

In addition, depression and depressive symptoms are common in individuals diagnosed with Late-onset Alzheimer disease (LOAD) and it is now well-established that a significant association exists between depression and LOAD. The human apolipoprotein E (APOE) gene exists as three major isoforms (eps2, eps3, and eps4) and the eps4 allele has been independently associated with a greater incidence for both depression and AD.
Further analyses in primary hippocampal neurons indicated that ERB agonism significantly enhanced BDNF-TrkB signaling and the downstream signaling cascades involved in neurogenesis and synaptic plasticity. Our subsequent analysis in the hippocampus of ERB-/- rats demonstrated that ERB deficiency was associated with significantly elevated expression levels of 5HT2A receptor but not 5HT1A receptor. Moreover, our analyses in primary hippocampal neurons revealed that BDNF/TrkB signaling is likely an upstream regulator of the 5HT2A pathway. Collectively, these findings suggest that ERB signaling dyshomeostasis during perimenopause results in the dysregulation of the BDNF-5HT2A network. These perturbations along with weakened synaptic plasticity may contribute to the overall female susceptibility for depression. Therefore, we hypothesize that timely intervention with an ERB-targeted modulator could potentially attenuate this susceptibility and reduce the risk or ameliorate the clinical manifestation of depression.
Our analyses in 6-month-old female humanized APOE mice (ApoE2, ApoE3, and ApoE4) demonstrated that BDNF and 5HT2A receptor expression levels were regulated in a genotype-depended manner with ApoE4 brain exhibiting the lowest level of BDNF and the highest level of 5HT2A. Moreover, we find that chronic administration of an ERB-targeted phytoestrogenic diet induced a number of changes in ApoE2 and ApoE3 brains, including a significant decrease in the expression of 5HT2A receptor and an increase in BDNF/TrkB and synaptic proteins whereas, in contrast, ApoE4 brain was largely unresponsive to the treatment.
https://kuscholarworks.ku.edu/handle/1808/25357

The 5-HT2A receptor has shown to importantly decrease pain when estrogen levels are high, and its blockage by a 5-HT2A antagonist tends to decrease the estrogen-induced pain release. Estrogen receptors alpha and beta respond differently to estrogen concentrations, with high hormone levels inducing an increase in the expression of ERB compared with ERa. This cycle promotes an increased tone in 5-HT2A and uncoupling of the 5-HT1A with subsequent abolition of the negative feedback system. In pain, estrogen has an important role in the modulation of the central serotonergic system. Some authors have hypothesized that the 5-HT2A receptor plays an important role, and that administration of 5-HT2A receptor antagonists would decrease the estrogen induced pain relief effect. High concentrations of estrogen promote an increase in estrogen receptor (ER)B and downregulation of ERa. In general, ERB upregulates the effect of 5-HT2A activation, while ERa increases the effect of 5-HT1A via nuclear factor kappa B (NFkB). Therefore, a high concentration of estrogen increases the density of 5-HT2A receptors, which stimulates intracellular calcium (Ca) release and protein kinase C (PKC) activation, with cell-dependent effects. One common effect of the PKC is the negative feedback and uncoupling of the 5-HT1A auto-receptors, decreasing the amount and effect of these receptors, and increasing the serotonin concentration through the inability of the system to produce negative feedback. This specific modification in the pathway promotes vasodilation and has been associated with migraine and other headaches. The understanding of visceral pain pathways is important in recognizing the serotonin relation and influence of it in pain modulation in IBS. Pain regulation pathways in visceral pain include vagal and spinal afferents that project into the CNS, both facilitating and/or inhibiting the sensory transmission to the spinal cord. Specifically, in visceral pain, there is an antinociceptive action of estrogen on the serotoninergic system due to afferent-driven vagal inhibition of the pain. On the other hand, the pro-nociceptive action occurs because of the enhancement of serotonin secretion in the intestinal mucosal mast cells (IMMCs); cells in which estrogen receptors have been found and that have been associated with its degranulation, increasing the visceral motor response and spinal or supraspinal processing of visceral nociception, mainly in IBS. Furthermore, as described previously, the interference of serotonin in pain modulation depends on the receptors, route of administration, type of pain, and influence of other substances on the release of this neurotransmitter.
Vasodilation in the brain may be the cause of the headache. The activation of the 5-HT1B receptor induces vasodilation, normally balanced by the activation of the 5-HT2A receptor, which leads
to vasoconstriction. Unlike the 5-HT1A receptor, 5-HT1B is not downregulated or uncoupled by estrogen. Therefore, the estrogen-induced increase in serotonin results in vasodilation without the
capacity to appropriately compensate using the 5-HT2A receptor.
Additionally, it is believed that trigeminal neurons are hyper-sensitized during this disease, increasing pro-nociceptive substance expression as calcitonin gene-related peptide (CGRP) and transient vanilloid receptor 1 (TrpV1), a nonselective capsaicin-binding cation channel. Hormone fluctuations may change the expression level of those peptides, and newer studies have shown an inverse correlation between estrogens and CGRP, which may explain the peri-menstrual sensitization of the trigeminovascular system. Sex hormones can have an important role in modifying the c-Fos protein pathway, regulating gene transcription, and causing an increase in the transmission of neurotransmitters such as serotonin and norepinephrine. These neurotransmitters are responsible for the development of neurogenic inflammation and vasodilation through the sensory afferents between intracranial vessels and the trigeminal system.
Serotonin plays an important role in migraine. An increase in its transmission in the central nervous system in patients with migraine and the induction of headache with serotonin agonists in
experimental studies support this idea. Some experiments have shown the effect on serotonin synthesis in trigeminal ganglion neurons due to local increases in the rate-limiting enzymes such
as TPH, and demonstrate that this synthesis can be modulated by ovarian estrogens. However, the influence and effects of serotonin in the sensory system are complex, modulating the activity of a variety of receptors including potassium channels, calcium channels, tetrodotoxin-resistant sodium channels, TRPV1, and intracellular calcium, which in conjunction regulate the excitability of the sensory neurons. Alosetron is a selective 5-HT3 receptor antagonist that is the only FDA-approved drug for IBS. Studies have demonstrated more efficacy in women with diarrhea-type predominance IBS. These disparities could be explained by differences in drug metabolism by CYP2C19 between the sexes, SERT gene polymorphisms, or limbic system activation with higher limbic activity in women during pain production. The exact mechanism of action of alosetron is unknown; however, studies have demonstrated an inhibition of expression of c-Fos genes, which are related to pain generation, and suggest that this drug can exert its effects at a spinal level to block the visceral afferent nociceptive signaling.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=An+Association+of+Serotonin+with+Pain+Disorders+and+Its+Modulation+by+Estrogens&btnG=

Testosterone increases 5-HT2A expression.

Subcutaneous injection of testosterone (25 mg/kg) may induce anxiogenic-like behavior in male mice. In addition, immunohistochemical data reveal reduced expression of 5-HT2A serotonergic receptor after gonadectomy in all areas of the hippocampus. However, treatment with testosterone could increase the mean number of dark neurons as well as immunoreactive neurons in CA1 and CA3 area, dose dependently. The density of 5-HT2A receptor-immunoreactive neurons may play a crucial role in the induction of anxiety like behavior. As reduction in such receptor expression have shown to significantly enhance anxiety behaviors. However, replacement of testosterone dose dependently enhances the number of 5-HT2A receptor-immunoreactive neurons and interestingly also reduced anxiety like behaviors.
The results of immunohistochemistry demonstrated that castration of male mice reduced the number of 5-HT2A serotonergic receptor-immunoreactive neurons in the CA1, CA3, and DG regions of the hippocampus. Chronic treatment with testosterone also increases the number of 5-HT2A serotonergic receptor-immunoreactive neurons in the hippocampus in all testosterone-treated groups. It seems that these increases at the 5-HT2A receptor-immunoreactive neurons are related to the dose of testosterone.
In agreement with our results, other studies demonstrated that gonadectomy in female and male rats decreased, while testosterone or estrogen increased 5-HT2A receptor mRNA levels in frontal cortex and dorsal raphe nucleus. Gonadectomized female and male rats demonstrated reduced density of 5-HT2A receptor binding sites and or 5-HT2A receptor density in frontal, cingulate and primary olfactory cortex and nucleus accumbens and this could be increased by testosterone or estrogen treatment.
In addition, the estrogen receptor beta is expressed on serotonergic neurons that are therefore targets of testosterone converted to estrogen by aromatase (e.g., 5-HT2A receptor). As well as, throughout the hippocampus of rodents express aromatase in a steroid- and sex-independent manner. Given that the hippocampal formation is rich in both androgen and estrogen receptors, it is possible that testosterone may exert anxiolytic effects via both androgen-dependent and estrogen-dependent mechanisms within this brain region. As reduction in such receptor expression have shown to significantly enhanced anxiety behaviors. However, replacement of testosterone dose dependently enhances the number of 5-HT2A receptors–immunoreactive neurons and interestingly also reduced anxiety like behaviors.
https://synapse.koreamed.org/articles/1071869

Saffron and silymarin definitely have a direct anti-depressive effect in my case and resveratrol improves my mood. Their anti-depressive effect is related to DA, 5-HT and NE reuptake and/or an increase in BDNF, however they are also ERB agonists as shown before.

Tian et al. found that adhyperforin, a newly-identified active component of H. perforatum exerts strong antidepressant effects by binding to 5-HT and NE transporter and inhibiting their reabsorption. Zirak et al. showed that the anti-depressant effects of hypericin may be related to reduction of NE and 5-HT in the brain. Further, Ji et al. demonstrated that the essential oil from Perilla frutescens (EOPF) relieved depression-like behaviors in UCMS rats, likely through reversing changes in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. The antidepressant effect of saffron is attributed to the activities of safranal and crocin through the re-uptake of DA, 5-HT, and NE from neurons.
V. bracteatum exerted antidepressant-like effects through regulation of monoaminergic systems and glucocorticoids with neuroprotective effects, alongside antagonism of the 5-HT2A receptor. The antidepressant effects of silymarin may also be due to the decrease of monoamine synthesis (5-HT, NE, etc.) in the hippocampus and cerebral cortex of mice with UCMS-induced depression-like behavior.
Geniposide, saikosaponin D, resveratrol, paeonol, ginsenosides, geniposide, naringenin, Perilla seed oil, the water extract of saffron, catalpol, extract of C. tubulosa, Rehmannia glutinosa, silymarin, Xiaoyao San, Chaihu Shugan San, Yueju, etc. could prevent depression-like behaviors through increasing BDNF expression. Interestingly, most of botanicals and active components facilitate BDNF expression through promoting cAMP/PKA/CREB signaling way.
https://link.springer.com/article/10.1186/s13020-019-0246-9

I can't remember much about olanzapine besides making me gain weight. Quetiapine surely knocked me out as I was sleeping practically all the time. It also made me more anxious, however I was supposedly thinking more clearly. I also have two pills of mirtazapine lying in the drawer, but this is probably not enough for an appropriate test.

The 5-HT2A receptor is known primarily to couple to the Gaq signal transduction pathway. Upon receptor stimulation with agonist, Gaq and beta-gamma subunits dissociate to initiate downstream effector pathways. Gaq stimulates phospholipase C (PLC) activity, which subsequently promotes the release of diacylglycerol (DAG) and inositol triphosphate (IP3), which in turn stimulate protein kinase C (PKC) activity and Ca2+ release.
Agonists
Activation of the 5-HT2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT2A agonists, the ergolines, tryptamines and phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched. Agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity. Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT2A–mGlu2 and not by monomeric 5-HT2A receptors. Agonists enhance dopamine in PFC, enhance memory and play an active role in attention and learning.
Antagonists
Mirtazapine is a 5-HT2A, 5-HT2C, and 5-HT3 antagonist. Mirtazapine also has an antagonistic effect on H1 histamine receptors. Because of its wide spectrum of serotonergic receptor inhibition, Mirtazapine exhibits an agonistic effect on 5-HT1A receptors by funneling more serotonin to them. Mirtazapine is used as an antidepressant in patients dealing with insomnia and weight loss.
The discovery of ketanserin was a landmark in the pharmacology of 5-HT2 receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well-known antihypertensive action through 5-HT2 receptor family, but through its high affinity for alpha1 adrenergic receptors. It also has high affinity for H1 histaminergic receptors equal to that at 5-HT2A receptors. Compounds chemically related to ketanserin such as ritanserin are more selective 5-HT2A receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT2A receptor antagonists, also potently inhibits 5-HT2C receptors.
Atypical antipsychotic drugs like clozapine, olanzapine, quetiapine, risperidone and asenapine are relatively potent antagonists of 5-HT2A as are some of the lower potency old generation/typical antipsychotics. Another antagonist is cyproheptadine.
Probable role in fibromyalgia as the T102C polymorphisms of the gene 5HT2A were common in fibromyalgia patients.
https://en.wikipedia.org/wiki/5-HT2A_receptor

I can't remember much good about Zeldox (ziprasidone), but it is another antagonist of 5-HT2A.

Ziprasidone mostly affects the receptors of dopamine (D2), serotonin (5-HT2A, partially 5-HT1A, 5-HT2C, and 5-HT1D) and epinephrine/norepinephrine (alpha1) to a high degree, while of histamine (H1) - moderately. It also somewhat inhibits reuptake of serotonin and norepinephrine, though not dopamine.
Ziprasidone's efficacy in treating the positive symptoms of schizophrenia is believed to be mediated primarily via antagonism of the dopamine receptors, specifically D2. Blockade of the 5-HT2A receptor may also play a role in its effectiveness against positive symptoms, though the significance of this property in antipsychotic drugs is still debated among researchers. Blockade of 5-HT2A and 5-HT2C and activation of 5-HT1A as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms. The relatively weak antagonistic actions of ziprasidone on the alpha1-adrenergic receptor likely in part explains some of its side effects, such as orthostatic hypotension. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks any anticholinergic side effects. Like most other antipsychotics, ziprasidone is sedating due primarily to serotonin and dopamine blockade.
https://en.wikipedia.org/wiki/Ziprasidone

Acetaminophen has been already discussed as an other way to reduce 5HT2A receptor activity and some POISer benefit from paracetamol treatment.

Dynorphin antagonists already exist in the form of acetaminophen and mu-opioid agonists, but they are hardly panaceas. High doses of acetaminophen raise brain 5-HT levels and inhibit the 5HT2A receptor. Acetaminophen is also a COX-3 antagonist.
https://poiscenter.com/forums/index.php?topic=17.msg38737#msg38737

It is interesting though that I have a quite severe reaction to acetaminophen (aka paracetamol), however it may be due to my particular problem with TRPV1 activation.

The second mechanism centers around the paracetamol metabolite AM404. This metabolite has been detected in the brains of animals and cerebrospinal fluid of humans taking paracetamol. Apparently, it is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase. AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor. This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.
https://en.wikipedia.org/wiki/Paracetamol

Another discussion on 5-HT2A and 5-HT1A.
https://poiscenter.com/forums/index.php?topic=2409.msg24630#msg24630

LSD and psilocybin proved anti-depressive for some POISers, but of course they are not a recommended treatment.

The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Psi binds with high affinity to 5-HT1A, 5-HT2A/C, 5-HT6, and 5-HT7 receptors. In humans, Psi is rapidly dephosphorylated to psilocin (4-N,N-dimethyltryptamine), which acts as a partial agonist at 5-HT2A and 5-HT1A receptors. Furthermore, given that 5-HT1A receptor stimulation has been associated with decreased, and 5-HT2A receptor stimulation has been associated with both decreased and increased, neuronal excitation of medial prefrontal neurons at rest. Interestingly, the structurally related psychotropic 5-HT2A/1A agonist lysergic acid diethylamide (LSD) increases extracellular medial prefrontal Glu release and prefrontal pyramidal cell activity in rodents.
https://www.pnas.org/content/pnas/113/18/5119.full.pdf

Interestingly PDE4 inhibitors (mostly drotaverine and tongkat ali) also seem to have an anti-depressive effect in my case. I couldn't find a direct connection between PDE4 and 5-HT2A, however PDE4 inhibitors have a major role in TNF-a suppression, which may mean that the major benefit of 5-HT2A is also TNF-a reduction.

Inhibitors of cyclic nucleotide phosphodiesterases are known to suppress lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-a) production in vitro in human monocytes. The most potent of these have selectivity for type IV PDEs, suggesting that this class of PDE is the major type involved in the regulation of human TNF-a production.
These data are consistent with a major role for PDE-IV in regulation of TNF-a production and inflammatory responses in murine systems. It suggests a potential therapeutic use for PDE-IV-specific inhibitors in inflammatory disease such as rheumatoid arthritis, septic shock and other inflammatory diseases where TNF-a has been postulated to be a contributing factor in the pathology of the disease.
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2249.1995.tb03613.x

Elevation of cAMP downregulates certain functions of inflammatory cells, including the release of TNF alpha and IL-1 beta by macrophages. Intracellular cAMP levels can be modulated pharmacologically by adding cell-permeable cAMP analogs, by stimulating adenylate cyclase or by inhibiting degradation of cAMP by cAMP-phosphodiesterases (cAMP-PDE).
Our results demonstrate that selective inhibitors of type IV cAMP-PDE, such as rolipram and Ro20-1724, are clearly the most effective compounds at enhancing cAMP levels and inhibiting the release of TNF alpha and IL-1 beta in these cells.
https://jpet.aspetjournals.org/content/272/3/1313.short

Cannabinoids may be also involved, however the activation of AP-1 is surely bad for me regardless of any effect on depression.

We have recently reported that selective cannabinoid 2 (CB2) receptor agonists upregulate 5-HT2A receptors by enhancing ERK1/2 signaling in prefrontal cortex (PFCx). Increased activity of cortical 5-HT2A receptors has been associated with several neuropsychiatric disorders such as anxiety and schizophrenia.
Our results suggest that sustained activation of CB2 receptors would enhance beta-Arrestin 2 expression possibly contributing to its increased interaction with ERK1/2, thereby driving the upregulation of 5-HT2A receptors. The CB2 receptor-mediated upregulation of beta-Arrestin 2 would be mediated, at least in part, by an ERK1/2-dependent activation of AP-1. These data could provide the rationale for some of the adverse effects associated with repeated cannabinoid exposure and shed light on some CB2 receptor agonists that could represent an alternative therapeutic because of their minimal effect on serotonergic neurotransmission. Our results suggest that inhibition of AP-1, but not CREB, significantly decreased the GP1a-induced upregulation of 5-HT2A receptors.
https://www.sciencedirect.com/science/article/abs/pii/S1043661812002216

[Progecitor]

Recently I came upon the epidrug concept, which really grabbed my attention and urged me to learn about this area. As it turns out this may be actually the root of my POIS. This is nothing new of course as others on the forum have already proposed this many years ago and methylation issues were extensively discussed as well. Still I believe this issue was not adequately addressed and mostly undermethylation was considered as a possible source. However studying this problem with more scrutiny I have come to the conclusion that in my case hypermethylation must be the underlying cause. This also makes it clear why I had the most success with anti-cancer supplements and at least partly resolves the similarities with prostate or breast cancer, multiple sclerosis, Alzheimer, COVID-19 and possibly a number of other diseases as well.
The simple notion that POIS may be acquired secondarily should imply of its epigenetic origin at least in a number of cases. I haven't read everything about methylation on the site, but I simply can't understand why the two key factors in this regard were not even mentioned before. These are DNA methyl transferases (DNMTs) and histone deacetylases (HDACs). DNMTs are classified as maintenance (Dnmt1) and de novo methyltransferases (Dnmt3a, Dnmt3b) and for the time being DNMT1 was the focus of my research. Insufficient methylation can cause problems of its own and could explain why many POISers had success with methylation support. However hypermethylation was mostly the focus of cancer research so far, even though researchers are beginning to realize that it may contribute to the development of many other diseases as well. Hypermethylation may occur due to prolonged inflammation that upregulates DNMT1 and leads to gene promoter (CpG islands) methylation, which causes specific genes to become inactive or silent. Many of these genes code cancer suppressive functions, so their loss could easily lead to development of malignancy. It is true that I don't have cancer, though I may be prone to it. Nevertheless other genes could be also silenced this way, which could lead to metabolic dysfunction. Most importantly this hypermethylation (gene silencing) could occur tissue or organ specifically which could explain different types of cancer or why our disease is different from CFS/FM or asthma even though particular treatments could apparently have the same benefit. I can't deny the possibility that some POIS start in the brain as some believe, however I am practically convinced that for me it is the genital region and the prostate being the most likely culprit. Hypermethylation may silence both ERB and SRD5A2. As DHT is a precursor of 3B-Adiol this could lead to both receptor and ligand insufficiency. POIS was also associated with a possible loss of 5a-reductase function which may be caused by hypermethyaltion of prostatic SRD5A2.

Regarding my own case the most enlightening revelation came from a study which concludes that inhibition of DNMT1 and HDAC lead to the restoration of estrogen receptor beta function and expression. What is even better the combination of such inhibitors have an even greater effect and this was actually proven on prostate cancer cells as an addition. I think it is needless to say how this translates to my own particular case given my success with ERB agonists. Gene silencing may also impair DNA repair and hormonal response and the involvement of 3beta-Adiol is even implied in this study. ERB itself upregulates quinone reductase and glutathione-S-reductase thereby confers anti-oxidative support. It is also proposed that ERB may antagonize the proliferative and pro-oxidant actions of both ERa and AR. This could be interesting if we consider that ERa antagonists (e.g. artemisinin) or AR antagonists (e.g. silodosin) also proved useful for some POISer, though I also had success with testosterone boosters.
Histone acetylation could be also targeted as it can activate transcription. The re-expression of ERB probably involves the upregulation of E-cadherin expression.
http://irep.ntu.ac.uk/id/eprint/22538/1/192797_1177%20Mcardle%20PostPrint.pdf

Resveratrol can inhibit both DNMT1 and HDAC1 which protects against breast cancer. In this respect synergistic effects were seen with melatonin, tea polyphenols (EGCG), quercetin and gamma-tocotrienol.
https://pdfs.nutramedix.ec/Reveratrol%20-%20Cancer%20(preclinical).pdf

Through SIRT-1 activation resveratrol may decrease viral replication and hyper-inflammation in viral infections. It is proposed that antiviral drugs could be combined with epidrugs (DNMTi and HDACi) combating viral infections like SARS-CoV. For example, various antiviral drugs such as remdesivir, ribavirin, favipiravir, and galidesivir could be combined with DNMT inhibitors such as decitabine, azacitidine or HDAC inhibitors, including vorinostat, belinostat, panobinostat, TSA.
In silico study on the combination of vitamin C, curcumin and glycyrrhizic acid (VCG Plus) revealed strong immunoprotection against SARS-CoV-2 infection by inhibiting the inflammatory response and cytokine storm.
https://www.sciencedirect.com/science/article/pii/S0753332221008787

SIRT3, a class III HDAC, restricted HBV cccDNA transcription. RNA viruses can also recruit host DNA methyltransferases (DNMTs) to methylate and decrease gene expression of specific genes including those for shaping innate and adaptive immune responses. Inhibition of DNMTs will reactivate the immunity-related gene function responsible for combating viral infection.
The most important compound of Nigella Sativa is Thymoquinone (TQ) which is known for epigenetic action. Thymoquinone can suppress UHRF1 and, thus, might be able to repair epigenetic aberrations in cancer cells through a DNA demethylating process, most likely through the downregulation of DNMT 1.
https://www.ffhdj.com/index.php/ffhd/article/view/707/1259
 
Age-related macular degeneration (AMD) patients exhibited up-regulation of DNMT1 and DNMT3B expression compared to healthy peers.
Sirtuin1 (SIRT1) is a NAD+ dependent HDAC, which makes the action of resveratrol perplexing in view of other research. DNMT1 and LINE-1 are positively correlated. LINE-1 methylation was also higher in Alzheimer’s disease (AD) and other similarities were also found with AMD. Resveratrol is also recommended for the treatment for both AMD and AD in different studies.
https://www.mdpi.com/2077-0383/8/2/159/htm

It has to be noted that in human retinal pigment epithelial cells resveratrol had an opposite effect as it increased DNMT1. This contradiction may be due to different tissues examined or a general balancing effect of resveratrol in this regard. Nevertheless resveratrol proved the best treatment for my photophobia so this has to be mentioned. Bacterial LPS may also reduce DNMT1 and LINE-1 in this setting, although as shown later inflammatory processes usually enhance DNMT1.
https://www.mdpi.com/1422-0067/19/7/2118/htm

Deletion of DNMT3b gene in a colorectal cancer cell line led to less than 3% loss of global DNA methylation, however concomitant distruption of DNMT1 and DNMT3b reduced genomic DNA methylation by greater than 95%.
https://www.nature.com/articles/416552a

S-adenosyl-L-methionine (SAMe) serves as an effective methyl donor while S-adenosyl-L-homocysteine (SAH) is a potent modulator of DNMTs and HNMTs activity. Dietary folic acid (200 mg/day) and vitamin B1 (0.8–1 mg/day) are essential for conversion of homocysteine (hyc) to methionine. Low levels of folic acid and high levels of serum hyc have been related to hypermethylation in patients.
Histone tails acetylation mediated by histone acetyltransferases (HATs) leads to euchromatin, whereas histone deacetylation by deacetylases (HDACs) leads to heterochromatin with reduced DNA accessibility. This makes it likely that increasing euchromatin compared to heterochromatin is beneficial for me.
Alpha-ketoglutarate (aKG), succinate and fumarate are products of acetyl coenzyme A (acetyl-CoA) and a low aKG hampers demethylation. Acetyl-CoA is known to activate HATs. Barley beta-glucan and beta-hydroxybutyrate inhibit HDAC1 and increases histone acetylation that induces antioxidant genes.
Polyphenols are potent inhibitors of DNMTs and regulate genes encoding important enzymes including sirtuin-type deacetylases and transcription factors in in vitro and in vivo models.
Dietary compounds may regulate HATs (i.e. curcumin, catechin, genistein, diallyl disulfide) and HDACs (i.e. b-glucan, sulforaphane, curcumin, butyrate, resveratrol, quercetin) activity.
NAD+ regulates Class III HDACs, also termed sirtuins (Sirts). The sirtuins that rely on NAD+ activity are generally cardioprotective in both animal models and humans. Nicotinamide riboside, a NAD+ precursor abundant in cow milk, stimulates Sirt1 preventing cardiac injury in septic mice and arterial stiffness in older humans.
Resveratrol and PUFAs differentially up- and down-regulate miRNAs. Beta-glucan affects gut microbiota composition as it increases propionate (HDACs inhibitor) producing Bacteriodes while reducing Firmicutes.
The coffee polyphenols (caffeic and chlorogenic acids) are potent inhibitors of DNMTs in humans.
Figure 1. Epigenetic_mechanisms
Figure 2. FeedingTheEpigenome
http://statics.drvoice.cn/uploadfile/2019/0217/20190217055754211.pdf

SAM is possibly detrimental for me, while SAH could be beneficial as a DNMT inhibitor.
In this mouse model, folate supplementation led to a reduction in tumor numbers if administered prior to tumor development; in contrast, folate deficiency conferred protection after tumor formation. Folate deficiency resulted in a significant decrease in SAM levels in almost all groups. In the group in which the decreased SAM was not statistically significant, a significant increase in SAH was observed. The observed alterations in SAM or SAH are characteristic of folate deficiency and indicate the effectiveness of the folate-deficient diet. It is postulated that lower levels of SAM can result in DNA hypomethylation.
https://academic.oup.com/carcin/article/24/1/39/2608348?login=true

Could this be the reason for my problems with zinc?
Sarcosine is an epigenetic modifier that can induce DNA hypermethylation in combination with SAMe excess. Sarcosine did not increase spermidine and spermine in this study, although elsewhere it is indicated that they are positively correlated. Sarcosine is also upregulated in some breast tumours. High intracellular zinc levels could be responsible for sarcosine-induced effects as DNA methylation is depressed in zinc deficiency. Zinc deficiency does not impair the synthesis of SAMe and SAH, but slowed SAMe activity.
https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1878-0261.12439

EGCG inhibits DNMT, but increases SAM, which may explain my negative experiences with it. In a different study creatine supplementation also increased SAM, which may associate SAM to my lymphatic issues.
SAM serves as the endogenous co-substrate and binds to the SET domain of EZH2. Although EZH2-mediated methylation also contributes as a potential independent mechanism for epigenetic gene silencing, it also cooperates with other enzymes that participate in epigenetic gene silencing. A physical and functional relationship between EZH2 and DNMTs has been recently documented.
A dose-dependent inhibition of DNMT activity was observed with each flavone in the order Luteolin>Apigenin>Chrysin
In our study, DNMT inhibition by plant flavones seems to be due to the binding of flavones at the catalytic binding pocket of DNMTs. These might be different from catechol-containing polyphenols, such as epigallocatechic-3-gallate, in which the noncompetitive inhibition of DNA methylation catalyzed by DNMTs is majorly due to the higher levels of SAM resulting from the catechol-O-methyltransferase-mediated O-methylation of these compounds.
Together, our study demonstrated the dual potential of flavones in targeting DNMTs and EZH2, which is better than targeting a single silencing enzyme.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162956

This may imply that even primary POIS could be epigenetic in origin.
DNA methylation typically regulates gene expression by repressing transcription but in some cases DNA methylation can be transcriptionally activating.
These studies provide evidence that early life exposure to endocrine disruptors, and potentially endogenous hormones, do not necessarily elicit immediately detectable changes in DNA methylation or gene expression. In some cases, these responses are not detectable until later in life-puberty or in response to a 'second hit' stimulus such as changes in hormone levels.
It has been proposed that a reawakening of developmental signals drives inappropriate growth in prostate cancer and BPH.
https://sci-hub.se/https://www.futuremedicine.com/doi/abs/10.2217/EPI.15.8

Recently, interplay between DNA methylation and prostate-associated diseases has been found. The most studied 5-alpha reductase, SRD5A2, has CpG regions, and its expression, which is varied in adulthood, is regulated by Dnmt1. Increased methylation of the SRD5A2 promoter is associated with increasing age in humans and with decreased expression. Thus, DNA methylation could be a personalized medical target for the management of BPH patients resistant to 5-alpha reductase inhibitor therapy.
Epithelial-mesenchymal transition (EMT) can lead to prostatic malignancies like benign prostatic hyperplasia (BPH) or prostate cancer. During EMT E-cadherin (Cdh1) is decreased.
Inflammation is regarded as one of the potential inducers of EMT. Indeed, our results showed that IL-6 and TGF-B1 decreased E-cadherin expression and increased the expression and activity of DNMT1, which in turn induced DNA hypermethylation in the promoter region of Cdh1. Moreover, we found that the combination of the DNMT1 inhibitor 5-Aza and TGF-B1 antibody significantly rescued E-cadherin expression, providing a promising strategy for the treatment of BPH. Cdh1 expression is inappropriately silenced by DNA methylation in breast cancers and prostate cancer. In the present study of BPH, our results showed that the expression of Dnmt1 was higher in BPH cells. It was found that three key downstream mediators in TGF-B signaling (Smad3, Snail, and Slug) were up-regulated in BPH tissue.
Chen et al. showed that TGF-B1 induced EMT through non-canonical PI3K/AKT and MAPK/ERK1/2 signaling pathways. The canonical Smad pathway of TGF-B1 signaling can be enhanced by LPS/TLR4 signaling through the down-regulation of a member of the TGF-B type I receptor family. In prostate cancers, TGF-B1 was identified as activating Erk and therefore Dnmts, which could result in promoter DNA hypermethylation of its own receptors.
Other EMT features, such as N-cadherin, Vimentin and MMP9, should also be fully assessed. Second, the role of other factors, such as IL-8 and TNF-a, should also be investigated in inducing EMT because it has been shown that EMT could be induced by TNF-a through the NF-kB signaling pathway.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432940/

Imatinib is a potent TNF-a inhibitor that cured some POISers. Suppressing TNF-a downregulates methylation and restores prostatic SRD5A2. However it has to be noted that another study claims imatinib as a DNMT1 inducer, which makes it difficult to make a straight conclusion (see below).
Artificial induction of inflammation in prostate primary epithelial cells leads to hypermethylation of the SRD5A2 promoter and silencing of SRD5A2, whereas inhibition with TNF-a inhibitor reactivates SRD5A2 expression.
We have shown that the SRD5A2 gene contains a promoter with a rich CpG island capable of being methylated. Because epigenetic factors can regulate the expression of genes, we hypothesized that methylation of SRD5A2 leads to reduced SRD5A2 gene expression and protein production during adulthood in benign prostatic tissues. We show that members of the DNA methyltransferase (DNMT) family regulate methylation of SRD5A2. Specifically, we show that DNMT1, and not DNMT3a or DNMT3b, regulates methylation of the SRD5A2 gene promoter.
We found that at baseline, DNMT1 was expressed in BPH-1 cells, however, on exposure to AZA (demethylating compound), there was a significant reduction in DNMT1 levels that was accompanied by increased SRD5A2 expression. These data suggest that DNMT1 plays an important role in silencing SRD5A2 expression.
The results suggest that cytokines including TNF-a and transcriptional factors such as NF-kB (p65) contribute to silencing of SRD5A2 by regulating DNMT1 activity. Therefore, NF-kB/p65 plays a central role not only in increasing the expression of DNMT1, but also in facilitating binding of DNMT1 to the SRD5A2 promoter region, leading to methylation and suppression of the SRD5A2 gene.
By suppressing p65 we found significant down-regulation of IL-6, p-STAT3, and DNMT1, in addition to a significant reduction in DNMT1 activity. However, simultaneous ectopic expression of IL-6 in p65-suppressed cells led to re-expression of DNMT1 protein levels. These results show that NF-kB/p65 regulates DNMT1 binding to the SRD5A2 promoter via an IL-6–dependent pathway.
These results from our patient cohort suggest that increasing age is associated strongly with increased methylation of the SRD5A2 promoter region and reduced SRD5A2 protein expression.
Combined, these results show that increased expression of DMNT1, methylation of the SRD5A2 promoter, and reduced expression of SRD5A2 protein are associated strongly with increased inflammatory mediators with aging.
For example, histone deacetylation, nucleosome occupancy, or gene modifications all can account for other mechanisms that may modulate the expression of SRD5A2.
Although methylation of tumor-suppressor genes and their role in initiation and progression in neoplasia is well studied, the idea that epigenetic changes may be involved in benign disease models is less appreciated. Because the prostate gland is the only solid organ that grows during adulthood, we postulated that epigenetic modifications may play an important role in mediating expression of SRD5A2 in a manner similar to that observed in tumor growth. In this study, we show for the first time that epigenetic modifications of SRD5A2 exist and are regulated by DNMT1.
https://www.sciencedirect.com/science/article/pii/S0002944014006907

Given the list TGFB downregulation should be beneficial for POISers, though some of them were detrimental for me.
Upregulated transforming growth factor-beta (TGFB) signalling, driving mesenchymal cells to increase their production of ground substance and undergo a transition to a myofibroblast phenotype, is believed to play a pathogenic role in diverse fibrotic disorders, including benign prostatic hyperplasia, scleroderma, pulmonary fibrosis, glomerulosclerosis, tubulointerstial fibrosis, hepatic fibrosis, open angle glaucoma, Peyronie’s disease and the cardiac fibrosis associated with cardiac hypertrophy and heart failure. This issue is now of particular interest, as pulmonary fibrosis is emerging as a not-uncommon long-term complication of COVID-19.
However, the Smad2/3-Smad4 heterodimer quite frequently functions in concert with an AP-1 complex to mediate TGF?-induced transcription. Activation of AP-1 reflects concurrent TGFB-mediated activation of the mitogen-activated protein (MAP) kinases ERK, JNK and p38.
Activated ERK1/2, JNK and p38 MAP kinase can collaborate to boost c-Fos expression and confer a serine phosphorylation on c-Jun which boosts its transactivational activity. As a result, AP-1 activity is markedly induced, and this collaborates with Smad2/3-Smad4 heterodimers to promote TGFB-mediated transcription.
TGFB signalling can be opposed by cGMP, the ligand-bound oestrogen receptor-B (ERB), activation of the nrf2 transcription factor and the Sirt1 deacetylase.
Ligand-bound activated ERB has been found to downregulate TGFB-mediated transcription by a direct interaction with AP-1 complexes that blocks their transactivational activity. This interaction does not involve binding of ERB to oestrogen response elements on DNA, but rather to c-Jun. This may rationalise preclinical and epidemiological evidence that endogenous or therapeutic oestrogen provides protection from cardiac hypertrophy, hepatic fibrosis, glomerulosclerosis and primary open-angle glaucoma (POAG). Pertinently, ERB is expressed in hepatic stellate cells, mesangial cells, cardiac fibroblasts and prostate stroma. Moreover, polymorphisms of the ERB gene (but not that of the ERa gene) have been linked to increased risk for POAG.
In summary, spirulina/PhyCB, phase II inducers such as lipoic acid, ferulic acid or broccoli sprout powder, melatonin, berberine, high-dose biotin, soy isoflavones, taurine and NAC may have potential for downregulating TGFB signalling, and thereby decreasing risk for, or improving clinical control of, a wide range of pro-fibrotic pathologies. Suggested dose schedules for these agents are presented in box 1. With regard to post-COVID-19 syndrome specifically, the antioxidant/anti-inflammatory effects of PhyCB, phase II inducers, melatonin and NAC might address neurological aspects of this syndrome thought likely to reflect chronic inflammation of cerebrovascular endothelial cells and microglia.
A more complete list for TGFB downregulation: spirulina/phycocyanin/phycocyanobilin (PhyCB), biliverdin/bilirubin, lipoic acid, ferulic acid, broccoli sprout extracts (sulforaphane), melatonin, NAD+, berberine, metformin, citrulline and/or high-dose folate, sodium nitrate or of nitrate-rich beetroot juice, soy isoflavones, equol, genistein, hydrogen sulfide (H2S), taurine, high-dose biotin, N-acetylcysteine (NAC).
Spirulina also protects E-cadherin.
https://openheart.bmj.com/content/8/1/e001663.full

Fulvestrant and decitabine are DNMT inhibitors that increase ERB expression.
Fulvestrant inhibits growth of triple negative breast cancer and synergizes with tamoxifen in ERa positive breast cancer by up-regulation of ERB. Inhibition of DNA methyltransferase (DNMT) increased the levels of ERB and fulvestrant exerted similar potency on DNMT activity as the DNMT inhibitor decitabine. ERB expression may be regulated by methylation of the promoter region of ERB. This process is dependent on DNA methyltransferase (DNMT). Here we report that the pure anti-ERa drug fulvestrant increased ERB expression both at mRNA and protein levels in ERa+/ERB+ as well as in ERa-/ERB+ breast cancers.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302959/

Imatinib increases EZH2 and DNMT3A. It is likely that imatinib both increases and decreases methylation of certain genes.
Imatinib causes epigenetic alterations of PTEN gene via upregulation of DNA methyltransferases and polycomb group proteins. Histone-methyltransferase enhancer of zeste homolog 2 (EZH2) is essential for DNMTs to bind to the EZH2-target promoters such as MYT1, KCNA1 and cannabinoid receptor 1 (CNR1), and silences expression of these genes. Imatinib-induced DNMT3A formed a complex with EZH2, which facilitated their binding to the PTEN promoter and induced DNA hypermethylation of this region, leading to downregulation of PTEN. Imatinib increased levels of both EZH2 and DNMT3A in leukemia cells, which probably caused global epigenetic aberrations and downregulated the expression of important genes involved in regulation of cell growth, apoptosis and drug metabolism, which could relate to acquisition of drug resistance.
The drug resistance against tyrosine kinase inhibitors could be overcome by treatment with an anti-epigenetic agent histone deacetylase inhibitor, highlighting a potential therapeutic strategy. In fact, we previously showed that histone deacetylase inhibitor successfully overcame imatinib resistance in EOL-1R cells in association with restoration of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression.
https://www.nature.com/articles/bcj201133.pdf?origin=ppub

Some POISer had success with a high-fat diet (HFD).
We showed a lower expression of Dnmt1 in colon with HFD with no changes due to vitamin E supplementation, although in CD animals an increase with supplementation was noted.
Vitamin E reduced DNA damage and showed organ-specific effects on MLH1 and Dnmt1 gene expression and methylation. The repair protein MutL homolog 1 (MLH1) is part of the DNA mismatch repair (MMR) system. Microsatellite instability (MSI) is often associated with promoter hypermethylation, resulting in inactivation of MLH1.
In mice with diet induced obesity (DIO), the binding of HDACs is increased at the leptin promoter. In another DIO mouse model, Dnmt1 expression and enzymatic activity were elevated in adipocytes, leading to promoter hypermethylation and following decreased adiponectin expression.
https://www.mdpi.com/2072-6643/9/6/607/htm

Our study suggests that curcumin may represent an effective antioxidant compound against diabetic retinopathy (DR), via restoring oxidative stress and DNMT functions, though further studies are recommended.
There are different types of repetitive sequences scattered throughout the genome (e.g., satellite repeat, short interspersed nuclear element, and long interspersed nuclear element-1 (LINE-1)). LINE-1 sequences, accounting for about 18% of human genome, are widely used as a surrogate marker of global DNA methylation.
Consistently, the high glucose-induced effect on DNMT expression was evident after 48 hours from the insult, with the upregulation of DNMT1. These changes persisted even when the glucose level is normalized, indicating that DNA methylation is probably involved in the metabolic memory of DR.
The early effect results in decreasing DNMT activity, accompanied by the highest ROS production, while long-term oxidative stress increases DNMT activity and DNMT1 expression.
https://www.hindawi.com/journals/omcl/2018/5407482/

Genistein (2–20 umol/l) was found to inhibit DNMT, reverse DNA hypermethylation and reactivate RARB, p16, and O6-methylguanine methyltransferase (MGMT) in esophageal squamous carcinoma and prostate and mammary cancer cells in vitro. In theory, prevention or reversal of hypermethylation-induced inactivation of key tumor suppressor or receptor genes by DNMT inhibitors such as genistein and daidzein could be an effective approach for cancer prevention, but little is known about the methylation effects of these compounds in humans.
https://sci-hub.se/https://www.tandfonline.com/doi/abs/10.1080/01635580802404196

Vitamin D is popular amongst POISers and drug resistance was an issue for some.
These data suggest that 1,25(OH)2D3 treatment reduces expression and activity of DNMT1 and DNMT3B and may lead to reduced DNA methylation.
Our results suggest that long-term 1,25(OH)2D3 treatment induces hypomethylation and overexpression of specific genes that may contribute to vitamin D resistance.
Overall, these hypomethylated/upregulated genes are involved in long-term vitamin D treatment-induced upregulation of the mTOR signaling axis. In a recent animal study, suppressed mTOR signaling is observed in the rat model of chronic vitamin D deficiency, and restoring vitamin D in rats reverses the effect. The mTOR pathway inhibitor metformin has been reported to increase the growth-inhibitory effects of vitamin D. In addition, the combination of vitamin D and metformin synergistically prevents colon carcinogenesis in both rat and mouse colon neoplasia models. Since long-term 1,25(OH)2D3 treatment is confirmed to induce hypomethylation and overexpression of genes that lead to overactivation of the mTOR pathway, future combinations of mTOR inhibitors with vitamin D therapy may be useful in preventing vitamin D resistance.
https://journals.physiology.org/doi/full/10.1152/ajpcell.00522.2019

Curcumin's ability to inhibit HAT could be one reason why it doesn't work for me.
Several vitamin Bs, especially folic acid and vitamin B12, may have roles in DNA synthesis, repair, and methylation in which methylenetetrahydrofolate reductase (MTHFR) plays a critical key of catalyzing the synthesis of 5-methyltetrahydrofolate, therefore, regulating the utility of diet folate in DNA metabolism pathways.
In addition to the classic dietary HDAC inhibitor, butyric acid, more recently there are a number of dietary HDAC inhibitors being discovered including diallyl disulfite and sulforaphane. Diallyl disulfite is a garlic compound and sulforaphane is a major isothiocyanate found in broccoli and cauliflowers.
Interestingly instead of themselves, their metabolites, S-allylmercaptocysteine, and sulforaphane-cysteine respectively have been identified as the true HDAC inhibitors.
On the other hand, it was reported that a dietary polyphenol, curcumin, can induce histone hypoacetylation in vitro and in vivo by inhibiting histone acetylase (HAT) instead of HDAC. The reactive oxygen species generated by curcumin may be involved in the inactivation of HAT. Folate, vitamin B12, selenium may have certain critical roles in DNA methyl metabolism pathways. Flavonoids (dietary catechols) like caffeic acid, chlorogenic acid, quercetin, myricetin, tea catechins and others seem to show an indirect mechanism to inhibit DNMT activity to achieve reactivation of silenced genes in cancer cells. COMT in mammalian cells can catalyze SAM (also the substrate of DNMT) mediated O-methylation of the above dietary catechols and the other product, SAH (a potent inhibitor for DNMT), thus, by competing the same substrate (i.e., SAM) and producing a potent inhibitor, SAH, the DNMT activities can be effectively inhibited by the above phytochemicals.
https://sci-hub.se/https://www.ingentaconnect.com/content/ben/ccdt/2007/00000007/00000007/art00010

A vitamin A derivate used in acne therapy (isotretinoin) has been inconsistently associated with the onset of IBD. However, what needs to be considered is the previous treatment of acne patients with antibiotics that are also associated with the development of IBD, thus representing a crucial confounding factor. Here, we studied whether doxycycline (acne therapy), metronidazole (IBD therapy) or isotretinoin are able to induce alterations in DNA methylation and microRNA expression patterns in murine colonic intestinal epithelial cells (IECs).
As for changes in DNA methylation, we found isotretinoin to have strong demethylating effects, while antibiotic treatment had only a moderate impact.
Regarding microRNA and mRNA expression, isotretinoin and doxycycline, but not metronidazole, potentially induce long-term changes in microRNA/mRNA expression profiles towards the down-regulation of immune responses.
In contrast, isotretinoin had a strong impact on DNA methylation with 234 hypomethylated targets compared to the vehicle. Previous treatment with isotretinoin resulted in eight hypermethylated targets, indicating a resolution of the direct effect on demethylation, and thereby pointing to a short-term effect of isotretinoin on DNA methylation. In total, 308 mRNAs were up-regulated and 136 mRNAs down-regulated after isotretinoin-washout, while treatment with metronidazole and doxycycline up-regulated the expression of 23 and 59 mRNAs, respectively, and down-regulated the expression of 59 and 91 mRNAs, respectively. These results point to possible long-term changes on mRNA expression levels after isotretinoin treatment in murine colonic IECs.
Treatment with the vitamin A derivate isotretinoin led to the demethylation of targets that were involved in IL-12 signaling and developmental processes, including the hypomethylated target IL-12rb1 and the corresponding up-regulated IL-12-dependent pathway in the transcriptome analysis directly after isotretinoin treatment in IECs. Although epigenetic marks such as DNA methylation are long-lasting and inheritable modifications, isotretinoin-induced demethylation was resolved after the washout phase of 4 weeks, indicating short-term effects on IL-12rb1. Furthermore, isotretinoin did not affect IBD-associated microRNAs in IECs neither directly after treatment cessation nor after the washout phase.
https://www.mdpi.com/2075-4655/1/3/24/htm

HDAC1 is overexpressed in prostate, gastric, colon, and breast cancers, and HDAC2 is overexpressed in colorectal, cervical, and gastric cancers.
Direct effects may be caused by drugs that affect chromatin architecture or DNA methylation, whereas indirect effects may be caused by drugs that affect transcription. For example, hydralazine directly affects the epigenome by inhibiting DNA methylation, and isotretinoin indirectly affects the epigenome by altering transcription factor activity. Drugs that indirectly affect the epigenome initially influence signaling pathways, thereby altering transcription factor activity at gene promoters and subsequently altering expression of receptors, signaling molecules, and other proteins. One study postulated that cells will ultimately adopt more permanent modifications to DNA methylation and chromatin structure, leading to enduring epigenetic changes. Thus these effects could persist after the drug is discontinued.
https://sci-hub.se/https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.1408

In the meanwhile I tested a Magnolia bark supplement and it provided a moderate benefit for me.
Honokiol is a phytochemical that can be found in Magnolia species. Honokiol could prevent tumorigenesis. Honokiol could significantly inhibit DNMT activity and reduced Dnmt1, Dnmt3a and Dnmt3b proteins expression. Honokiol could also reactivate and restore the levels of TET proteins suppressed by UVB radiation. Indomethacin can also inhibit DNA methylation. Honokiol application induced persisting effects.
Honokiol application also inhibited UVB-induced DNA hypermethylation and its elevation of the levels of TET enzyme, which is responsible for DNA demethylation in UVB-exposed skin.
Collectively, these data suggest that PGE2 promotes UVB-induced immunosuppression and that the PGE2 may act to suppress the immune reactivity by promoting DNA methylation in UVB-exposed skin.
It has been shown that the ten eleven translocation (TET) enzymes that catalyze demethylation of 5-methyl cytosine (5-mC) and promote locus-specific reversal of DNA hypermethylation.
Furthermore, honokiol inhibits the transcription regulators of Dnmt activity, Sp1 and Sp3, which have been implicated in DNA demethylation. In addition to blocking the addition of extra methyl groups to the 5th position of cytosine through inhibiting Dnmt activity, honokiol treatment also promotes DNA demethylation of existing DNA hypermethylation through activation of the TET enzyme and expression of TET proteins. Active DNA demethylation by TET proteins has been shown to play critical roles in T cell functions and particularly cytokine expression. This is consistent with the literature indicating that epigenetic modifications in general, and especially aberrant DNA methylation, play important role in the regulation of cytokines in malignancies.
https://www.nature.com/articles/s41598-017-01774-5

T-cells are implicated in POIS.
Perhaps consistent with such antagonism between DNMT1 and TET in Treg cells, knockdown of DNMT1 activity induces the expression of Foxp3 in conventional CD4 T cells whereas loss of TET protein activity leads to unstable Foxp3 expression.
Both DNMT1 and TET enzymatic activities are highly sensitive to the metabolic state of T cells. Unlike T effector (Teff) cells that rely heavily on aerobic glycolysis for energy generation, stable Foxp3 + Treg cells generate little lactate in the presence of glucose and instead make use of lipid and glucose oxidative phosphorylation (OXPHOS) and mitochondrial electron transport for ATP synthesis.
One long-standing question in the investigation of anergy as a peripheral immune tolerance mechanism has been its purpose. Why should the immune system actively promote the survival of potentially dangerous self-reactive T cells when mechanisms exist to delete such cells from the repertoire? One attractive hypothesis is that anergy reversal can at times be protective—either to facilitate aggressive immunity against particular tissue-specific self-antigens during intracellular infection or cancer or to augment antigen-specific suppression in the face of immunopathology.
Therefore, we now hypothesize that partial demethylation of the Foxp3 CNS2 region is a key feature of anergic Treg progenitor cells.
Therefore, DNMT1 activity and Foxp3 CNS2 maintenance methylation may destabilize Foxp3 expression in the setting of T-cell lymphopenia.
Thus, we hypothesize that high DNMT1 and SAM-e levels, chromosomal replication, and Foxp3 CNS2 remethylation promote the differentiation of dangerous conventional CD4 Teff cells following the reversal of anergy. This is particularly true when an anergic T cell has accumulated only a modest number of hydroxymethylated and demethylated CpG nucleotides at the CNS2 locus.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305231/

The above information could mean that taking a combination of DNMT1 and HDAC inhibitors for a prolonged time may actually cure POIS for at least a group of us. Some case reports show that Relora (honokiol) was capable of curing at least one POISer. Medicinal mushrooms (beta-glucan) could also result in sustained symptom amelioration. Thus a combination like beta-glucan (medicinal mushrooms, barley, oat straw), honokiol (Magnolia/Relora), resveratrol, chrysin (passion flower/noni), etc. can potentially cause permanent effects on disease severity or complete resolution over time, though primary cases may not benefit as much as secondary ones. Other POIS cases could be caused by hypomethylated genes and such a therapy may be detrimental for them, although more information would be required to properly differentiate POIS types.
Some other opportunities for treatment of this type could be an increase of E-cadherin, inhibition of TGFbeta, increase of TET, inhibition of TGF-a and IL6, decreasing EZH2 and many more options can be derived from the above. Needless to say this is not only a treatment model for POIS, but a number of cancers, neurodegenerative diseases, viral infections and a number of other ailments. Researchers have already realized this, it just hasn't become common knowledge so far.

[Progecitor]

Many years ago an interim general practitioner told me that I may have Ankylosing spondylitis (AS). I read about it at the time, but came to the conclusion that it would not explain everything about my case. It is true though that I also have a lightly hunched posture that developed during adolescent years and remained unchanged afterwards. However I don't usually have back pain and even when I have it is usually a result of overexertion at work. It is rather interesting though that uveitis, eye pain and photophobia are also symptoms of AS. Thus it was rather surprising to find that DNMT1 hypermethylation also has a role in AS, which could establish the connection between the two as a result of an ERB insufficiency or antagonism driven inflammation, although in different tissues.

Ankylosing spondylitis symptoms:
https://www.mayoclinic.org/diseases-conditions/ankylosing-spondylitis/symptoms-causes/syc-20354808

At least two other POISers suspected a connection between the two diseases.
https://poiscenter.com/forums/index.php?topic=2628.msg28608#msg28608

We observed an inverse correlation between plasma homocysteine and DNMT1 methylation levels.
In this regard, increased DNMT1 promoter methylation resulting in decreased gene expression levels was observed in blood DNA of individuals with ankylosing spondylitis, a chronic inflammatory autoimmune disease.
Increased DNMT1 expression was observed in blood DNA from patients with psoriasis.
Hypermethylation of the Dnmt1 promoter was also responsible for reduced gene expression levels in various tissues of animal models of asthma.
Observing an inter-individual variability in DNMT1 promoter methylation levels, which ranged from 0% to 15% in the studied cohort, a significant inverse correlation with plasma Hcy levels, and a trend for a positive correlation with vitamin B12 levels.
Elevated plasma Hcy levels in the Alzheimer's disease subjects were linked to reduced methylation levels of several genes in blood DNA, including DNMT1.
https://www.mdpi.com/2218-1989/9/12/298/htm

Unfortunately my homocysteine level has never been measured, but usually only a high level is considered pathogenic. Given the above information a low homocysteine could be equally detrimental as SAH is an important endogenous DNMT1 inhibitor and its insufficiency could lead to gene promoter hypermethylation making it potentially pro-carcinogenic. As hypermethylation is also involved in several autoimmune diseases (ankylosing spondylitis, psoriasis, asthma, etc.), the similarities can be easily understood.

Folic acid supplementation (FAS) has been known to be protective in early pregnancy, however new evidences suggest that folate overload can increase the risk of adverse health effects (i.e., immune diseases, autism, lipid disorders).
As such, folic acid plays a double-edged sword role in offspring health via mediating DNA methylation.
In humans, low serum folate has been found to correlate with lower sperm counts.
Recently, a randomized control trial revealed that insufficient amounts of B vitamins were associated with higher levels of neural inflammation and oxidative stress, as marked by increased plasma homocysteine. Decreased serum B vitamins may contribute to impaired cognitive by hypermethylation of redox-related genes NUDT15 and TXNRD1. These results have demonstrated that disruption of the homeostasis of one-carbon metabolism could affect DNA methylation patterns, which in turn leading to increased oxidative stress.
The optimal pH for intestinal folate transport is between 5.5 and 6.0; thus antacids appear to reduce folate absorption.
Another recent study has shown maternal FAS throughout gestation and lactation improved learning and memory behaviors in mouse offspring. Specifically, hypomethylation of glucocorticoid receptor (GR) promoters promotes GR, PCNA, and BDNF expression in hippocampus to activate BDNF/AKT/ERK1/2 signaling. Periconceptional FAS is beneficial for the early development of sensorymotor function by enhancing methylation potential, global DNA 5mC, DNA methyltransferase expression, and activity.
FA Overload Related Diseases
Maternal folic acid supplementation and/or folate concentration during pregnancy have shown correlations with allergic diseases. Periconceptional and first trimester FAS has increased the risk of atopic dermatitis in children up to 4 years old, although another study has found that prenatal FAS was an independent and protective factor for atopic dermatitis in children in the first 6 years of life. FA intake after 12 weeks of pregnancy has also presented as a risk factor of wheeze in children at 18 months. Maternal FAS has shown associations with wheeze at 1 year of age, but not with wheeze at later ages, sensitization, and bronchial hyperresponsiveness. In addition, FAS during late pregnancy (after 12 weeks) has been suggested to be associated with susceptibility of asthma at ~ 3 years of age, and high dose of FAS (> 500 ug/day) during this period had a positive correlation with eczema. A mouse model study has revealed that FAS during pregnancy affected airway remodeling and allergic reactions in offspring after ovalbumin stimulation, and the effect size was dose- and time-dependent. By contrast, FAS has no significant effect or a beneficial effect on children allergic diseases. Recently, blood DNA methylation biomarkers and differential methylation in CD4+ T cells have shown the potential of predicting clinical reactivity for food-sensitized infants. The cow’s milk allergy has been believed to be linked with methylation of TH2(IL-4, IL-5)- and TH1(IL-10, IFN)-associated cytokine genes.
A prospective study has demonstrated that maternal high plasma folate levels at delivery were associated with an increased risk of ASD in offspring. Another study has reported that pregnant women who had multivitamin-containing folate either at a low or a high dose predisposed their offsprings to ASD.
FAS was also reported to have a plausible association with lipid metabolic disorders. Some studies have indicated that high folate levels in maternal plasma had adverse impact on offspring health, such as high risk of insulin resistance, colitis susceptibility, increased body weight and food intake, and impaired glucose response to insulin. A recent Sprague-Dawley rat study has revealed that maternal FAS resulted in an increase of 5mC within the promoter and/or first exon region of hepatic adipose triglyceride lipase (ATGL) and adipose lipoprotein lipase (LPL) genes, which induced persistent downregulation of ATGL and LPL.
Similarly, maternal FAS during pregnancy seems to have dual effects on offspring health, both beneficial and potential detrimental influences.
https://sci-hub.se/https://link.springer.com/article/10.1007/s43032-020-00161-2

Bitter melon also inhibits HDACs.
The antitumor activity of 3B,7B,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD), a triterpenoid isolated from wild bitter gourd, in breast cancer cells was investigated.
It has been reported that ERB antagonized ERa-induced cell proliferation. Additionally, HDACs participate in gene regulation mediated by nuclear receptors including ER. For example, HDAC1 interacts with ERa and suppresses its transcriptional activity in vitro and in vivo and HDAC inhibitors can reverse the resistance of antiestrogen therapies in breast cancer. Therefore, we evaluated the influence of TCD on the expression of estrogen receptor and HDACs in breast cancer cells. The result showed that TCD increased the ratio of ERB to ERa expression in MCF-7 cells. In ERa-null MDA-MB-231 cells, TCD increased the expression of ERB. Interestingly, we found that TCD induced HDAC inhibition as evidenced by increased acetyl histone H3 expression in a concentration-dependent manner as well as the HDAC activity in MCF-7 cells. Compatible with the finding was the down-regulation of HDAC1, HDAC2, HDAC3 and HDAC4 protein expression.
It has been reported that triterpenoids isolated from wild bitter gourd and bitter gourd crude extracts down-regulate Akt and NF-kB and inhibit HDAC activity.
Interestingly, curcumin and sulforaphane, ingredients of tumeric and green tea polyphenols, showed antiproliferative activities in breast cancer through modulation of HDACs.
https://www.nature.com/articles/srep22419

Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor—estrogen receptor beta. Disulfiram (DSF), an antabuse drug, inhibits DNMT and prevents proliferation of cells in prostate and other cancers, plausibly through the re-expression of tumor suppressors like ERB.
https://onlinelibrary.wiley.com/doi/abs/10.1002/mc.22433

These results indicate that hinokitiol may exert DNA demethylation by inhibiting the expression of DNMT1 and UHRF1 in colon cancer cells.
Several DNMT inhibitors, including 5-aza-2'-deoxycytidine (5-aza-dC), zebularine, and (-)-epigallocatechin-3-gallate (EGCG), reduce DNA methylation and re-express silenced genes.
Hinokitiol is a natural tropolone-based monoterpenoid which is found in cupressacceous plants (cypress family).
On the other hand, several studies reported that various chemical agents such as GSH, vitamin B1, and vitamin E, appeared not to affect 5mC oxidation patterns despite DNA demethylation effects via an increase of 5hmC level in cultured cells.
https://bmcmolcellbiol.biomedcentral.com/articles/10.1186/s12860-017-0130-3

Our data indicate that DNMT1 inhibitor AZA and HDAC inhibitor TSA play important roles in restoring sensitivity of the ERa negative breast cancer cells to endocrine therapy in vitro and in vivo.
https://link.springer.com/article/10.1007/s00432-008-0354-x

Although most cancers could benefit from a reduction of DNMT1 activity, lung adenocarcinoma may not. SAM-e was also depleted and LKB-1 lost in this case.
https://etd.ohiolink.edu/apexprod/rws_olink/r/1501/10?clear=10&p10_accession_num=osu1555503848137523

Dnmt1 is itself associated with HDAC1 activity. HDAC1 may repress Dnmt1 as a regulatory mechanism.
The DNA methyltransferase Dnmt1 is responsible for cytosine methylation in mammals and has a role in gene silencing. DNA methylation represses genes partly by recruitment of the methyl-CpG-binding protein MeCP2, which in turn recruits a histone deacetylase activity. Here we show that Dnmt1 is itself associated with histone deacetylase activity in vivo. Consistent with this association, we find that one of the known histone deacetylases, HDAC1, has the ability to bind Dnmt1 and can purify methyltransferase activity from nuclear extracts. We have identified a transcriptional repression domain in Dnmt1 that functions, at least partly, by recruiting histone deacetylase activity and shows homology to the repressor domain of the trithorax-related protein HRX (also known as MLL and ALL-1). Our data show a more direct connection between DNA methylation and histone deacetylation than was previously considered. We suggest that the process of DNA methylation, mediated by Dnmt1, may depend on or generate an altered chromatin state via histone deacetylase activity.
https://www.nature.com/articles/ng0100_88

[Progecitor]

I have already associated my disease to asthma even though in my case it doesn’t seem to be an issue, however treatments for asthma consistently proved to be effective for me as well.

Some supplements for asthma also proved beneficial for me. (Not a complete listing, just some earlier findings.):
- Wild yam
https://www.frontiersin.org/articles/10.3389/fphar.2020.00496/full
https://sci-hub.se/https://www.tandfonline.com/doi/abs/10.1080/J157v03n04_08
- Ganoderma
https://www.spandidos-publications.com/10.3892/mmr.2017.7904
- Allantoin (yam, lungwort)
https://www.mdpi.com/1420-3049/23/8/2023/htm
- Saffron
https://www.sciencedirect.com/science/article/pii/S2589936821000359
- Triphala (quercetin)
https://www.researchgate.net/profile/Ankit-Gupta-23/publication/276293748_Hepatoprotective_Activities_of_Triphala_and_Its_Constituents/links/5556442908ae6943a8733a18/Hepatoprotective-Activities-of-Triphala-and-Its-Constituents.pdf
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=pharmacological+benefits+of+triphala+a+perspective+for+allergic+rhinitis&btnG=
- Asafoetida
http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.1060.1982&rep=rep1&type=pdf
- Gotu Kola
https://link.springer.com/article/10.1186/s40203-015-0008-z
- Astaxanthin
https://www.mdpi.com/1420-3049/22/11/2019
- L-theanine
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0278691516304501?via%3Dihub
- Honokiol
https://www.spandidos-publications.com/mmr/13/2/1353

Interestingly Capsicum could exacerbate asthma.
http://s3.amazonaws.com/EliteCME_WebSite_2013/f/pdf/RPAZ04GTI14.pdf

L-theanine is also a plausible treatment for asthma.
In this study, we investigated the protective effects of L-theanine on asthmatic responses, particularly airway inflammation and oxidative stress modulation in an ovalbumin (OVA)-induced murine model of asthma. Treatment with L-theanine dramatically attenuated the extensive trafficking of inflammatory cells into bronchoalveolar lavage fluid (BALF).
L-theanine administration also significantly decreased the production of IgE, monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-alpha (TNF-a), and interferon-gamma (INF-g) in BALF. The lung weight decreased with L-theanine administration.
Together, these results suggest that L-theanine alleviates airway inflammation in asthma, which likely occurs via the oxidative stress-responsive NF-kB pathway, highlighting its potential as a useful therapeutic agent for asthma management.
Thus far, a variety of drugs such as Beta2 adrenergic agonists, steroids, leukotriene inhibitors, and mast-cell stabilizers have been developed to treat allergic asthma.
L-theanine is a biologically active ingredient in green tea and a widely used pharmacological agent in cell biology, with reported antioxidant, anti-inflammatory, relaxant, and anxiolytic properties.
Furthermore, activated Th2 cells increase the secretion of IgE from B cells, and activate mast cells.
The OVA-induced secretion of Th2 (IL-4, IL-5, and IL-13) and Th1 cytokines (TNF-a and IFN-g), decreased following L-theanine treatment. In addition, treatment with L-theanine resulted in a
significant reduction of ROS generation and proinflammatory related proteins, including NFkB and MMP-9.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0278691516304501?via%3Dihub

ERB agonists seem to be beneficial for asthma.
Our recent work showed the differential expression of ERa and ERB in asthmatic and non-asthmatic ASM, and found ERB expression is significantly greater in asthmatic ASM in both males and females, but the downstream signaling has not been elucidated.
Consistent with reported data we observed increased phosphorylation of ERK 1/2, and p38 MAPK upon PDGF exposure. These signaling pathways were inhibited by ERB activation, particularly in asthmatic ASM. These effects of ERB are consistent with data from mammary epithelium and breast cancer cells.
ERB activation significantly inhibits PDGF-induced cell proliferation in non-asthmatic and asthmatic ASM cells by suppressing proliferative proteins along with MAPKs and PI3K signaling pathway.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0303720718301266?via%3Dihub

The benefit of increasing SERCA2 by CoQ10H2 was shown earlier in a metabolic syndrome model that works for me. ERB activation can increase SERCA2!
Asthma is defined as chronic inflammation of the airways and is characterized by airway remodeling, hyperresponsiveness, and acute bronchoconstriction of airway smooth muscle (ASM) cells.
In Fura-2-loaded nonasthmatic and asthmatic human ASM cells, we found that prolonged (24 h) exposure to ERa agonist (PPT) increased [Ca2+]i response to histamine, whereas ERB activation (WAY) led to decreased [Ca2+] compared with vehicle.
TNF-a alone produced a marked increase in [Ca2+]i responses to ACh, bradykinin, and histamine, as compared with the vehicle in both asthmatic and nonasthmatic ASM cells, which is consistent with our previous results. In nonasthmatic and asthmatic ASM cells, ERB agonist WAY, but not PPT, showed a reduction in the enhancing effect of TNF-a on [Ca2+]i response to all the three agonists. An interesting point to note was that the effectiveness of ERB in reducing the [Ca2+]i was much more pronounced in ERB-overexpressed cells, suggesting a regulatory role of ERB isoform under higher expression. ERa activation at baseline shows increased [Ca2+]i response and is not effective in regulating the cytokine-induced increase in [Ca2+]i responses. Whereas ERB activation tends to decrease [Ca2+]i response slightly at baseline and significantly in the inflamed conditions. ERB contributes to decreased [Ca2+]i response through increased SERCA2 function, as evident by the increased rate of sequestration of Ca2+. Furthermore, ERB also exerts its signaling through inhibition of pathways involved in activating the voltage-gated LTCC. Overall, these results suggest that estrogen signaling is maintained in the presence of inflammation, and indeed, more enhanced via ERB activation, providing a potential avenue to blunt effects of inflammation on [Ca2+]i in ASM.
https://journals.physiology.org/doi/full/10.1152/ajplung.00206.2019

Bradykinin and AP-1 activation are involved in Asthma.
Because bradykinin (BK) and interleukin (IL)-6 may play important roles in the regulation of airway inflammation, we tested whether BK induces IL-6 expression from human ASM cells.
Curcumin, an inhibitor of AP-1, also reduced BK-induced IL-6 expression.
The nature of the cell types involved remains unknown, but BK does stimulate the production of IL-1B, IL-6, IL-8, and eotaxin from cultured human lung fibroblasts. BK may also stimulate sensory (C-fibers) and cholinergic nerves to release neuropeptides such as tachykinins with contractile and inflammatory properties. We have shown that the activation of B2 receptor induced calcium mobilization in human and guinea pig ASM cells. More recently, Pang and colleagues showed that BK, via B2 receptor activation, stimulated the release of PGE2, IL-8, and vascular endothelial growth factor from human ASM cells.
Interleukin (IL)-6 is a pleiotropic cytokine that has an important physiologic effect in B-cell differentiation, T-cell activation, and inducing acute-phase proteins.
We report that BK stimulates IL-6 expression in human ASM cells by activating the B2 receptor, ERK1/2, and p38 MAPKs. BK effect on IL-6 expression involves the transcription factor AP-1.
AP-1, c-Fos/c-Jun is another class of transcription factors that regulate inflammatory genes expression that involve IL-6. Using cells transfected with an AP-1 luciferase reporter, we found that BK induces AP-1–dependent gene expression.
The current study demonstrates that BK stimulated IL-6 expression in cultured ASM cells in a B2 receptor-dependent manner by activating ERK1/2 and p38 MAPK.
The effect of BK on IL-6 expression also involves the transcription factor AP-1, whose activation is modulated by steroids and indomethacin.
https://www.atsjournals.org/doi/full/10.1165/rcmb.2002-0040OC

AP-1 is also involved in SARS-CoV-2 and other studies indicated bradykinin as well.
We found that activities against autophagy and AP-1 significantly correlated with anti-SARS-CoV-2 activity. Activator protein 1 (AP-1) is a dimeric transcription factor composed of proteins belonging to the Jun, Fos, ATF, and JDP families, and it regulates a range of cellular processes. The AP-1 transcription factor family can be activated by different stimuli, such as cytokines, stress, bacterial, and viral infections. The AP-1 signaling pathway has been shown to be activated by the SARS-CoV viral particle, spike protein, nucleocapsid protein, and accessory protein 3b. In a recent study, the AP-1 protein Jun was identified as one of the top hub host proteins, which can either be directly targeted by coronavirus proteins or indirectly involved in the coronavirus infection. The activation of AP-1 signaling may serve as an immune response for the host to fight viral infections. One hypothesis that can be drawn from this observation is that the coronavirus hijacks the AP-1 pathway, which leads to the mediation of the CPE process. Therefore, disruption of the AP-1 pathway could offset this process.
Psychoactive drugs have been reported to be active against SARS-CoV-2. In this study, we found that the neurology/psychiatry class of drugs, in contrast to other classes of drugs, was significantly enriched in anti-SARS-CoV-2 activity. It is interesting to note that among the active compounds in both the AP-1 and SARS-CoV-2 CPE assays, we found a more pronounced enrichment of neurology/psychiatry drugs (3.76-fold), suggesting that this class of drugs may also act through the AP-1 pathway to inhibit SARS-CoV-2.
Supplementary Table 1! (Compounds with reported anti-SARS-CoV-2 activity.)
https://www.nature.com/articles/s41598-021-86110-8

AP-1 is probably involved in post-COVID-19 syndrome.
Our epigenetic, gene expression and integrative SDA analyses have all identified the AP-1 p38 MAPK pathway upregulation as a specific feature of COVID-19 disease across different immune subsets. Combined with evidence of proliferation and cytokine response in these populations, this supports systemic immune activation and proliferation as a hallmark specific to COVID-19.
Moreover, AP-1 is a pioneer transcription factor that reversibly imprints the senescence enhancer landscape following stress and can be modulated to reverse T cell exhaustion. This suggests a possible role for AP-1 in inappropriate chromatin remodelling and cellular activation/senescence in multiple cell types, with evidence of persisting differential chromatin accessibility, gene expression signatures and cell protein markers of activation that may contribute to both acute disease and post-COVID-19 syndrome. Our findings are in keeping with recent evidence of efficacy for baricitinib (Janus Kinase inhibitor) in improving recovery of hospitalised patients. Baricitinib acts upstream of AP-1 and controls macrophage inflammation and neutrophil recruitment in COVID-19.
We note that COVID-19 induced down regulation of ACE2 may be involved in the modulation of both the renin-angiotensin system and activation of AP-1/p38MAPK signaling.
We further found extensive sharing of pathways and networks including modules involving JAK-STAT and zinc finger proteins, as well as differences, most notably the enrichment of AP-1/MAPK specifically in COVID-19.
https://www.medrxiv.org/content/medrxiv/early/2021/05/11/2021.05.11.21256877.full.pdf

EMT was indicated for prostatic diseases.
Epithelial/mesenchymal transition also develops in chronic asthma with great impact on the bronchial functions. Bronchial epithelial cells of the human lineage 16HBE-14, induced to fibrosis by TGFB1, were prevented from developing it by adding DHEA to their cultivation.
https://www.scielo.br/j/abd/a/dgNpDgTZwzPdwNSnwRMNPhD/?format=html&lang=en

Asthma and psoriasis are further associated.
Asthma, chronic obstructive pulmonary disease (COPD), and autoimmune diseases of the lung also display enhanced activation of the Th17 pathway. IL-23/Th17 pathway is also considered a major perpetuator of skin disorders such as psoriasis and atopic dermatitis.
https://journals.physiology.org/doi/full/10.1152/ajpcell.00141.2016

AR activation is beneficial in asthma.
Activation of androgen receptor (AR) using 5a-dihydrotestosterone (5a-DHT, AR agonist) resulted in decreased Th2/Th17 inflammation and remodeling-associated changes, resulting in improved lung function compared with mixed allergen (MA) alone challenged mice. Overall, we show that AR exerts a significant and beneficial role in asthma by regulating airway hyperresponsiveness (AHR) and inflammation.
https://journals.physiology.org/doi/full/10.1152/ajplung.00441.2020

Testosterone is protective for asthma.
Epidemiological studies describe sex disparities in asthma which fluctuate throughout life. During childhood, asthma prevalence and morbidity are higher among males than females. A reversal occurs during adolescence whereby asthma prevalence and morbidity decrease in males and increase in females. This sex disparity remains so until menopause. Asthma prevalence and morbidity increase again in males after the fifth decade, when testosterone levels coincidentally decrease. These observations suggest that sex hormones play a pivotal role in asthma pathobiology.
Male sex hormones (i.e. androgens) seem to attenuate type 2 airway inflammation, which is present in most asthmatic patients. These findings suggest that androgens have effects on cellular targets that may attenuate asthmatic pathobiology.
In summary, we have found in a nationally-representative cohort that serum testosterone inversely associates with current asthma prevalence, and with better lung function among asthmatic patients, regardless of sex.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S2213219820305146

[Progecitor]

I have already tested four sources of resveratrol and had to conclude that only the first one worked really well. I was wondering why this could be when I realized that the answer may be a synergy between resveratrol and emodin. The best resveratrol product was extracted from Polygonum cuspidatum which is a known source of emodin.
Emodin also proved beneficial for at least nanna1, although he used a different source (Aloe vera gel drink).
https://poiscenter.com/forums/index.php?topic=2597.msg24971#msg24971

Numerous benefits are indicated for emodin, but from my personal view I think it must be its property as an estrogen receptor beta agonist.

When characterizing the ER specificity in biological activity of rhodoeosein and emodin, rhodoeosein was able to exhibit a four-fold greater relative estrogenic potency (REP) in breast cells transiently-transfected with ERB as compared to those transfected with ERa, and emodin exhibited a six-fold greater REP in ERB-transfected breast cells.
This study is the first to characterize the novel flavan-3-ol compound, rhodoeosein, and its ability to induce estrogenic activity in human cell lines. Rhodoeosein and emodin may have potential therapeutic applications as natural products activating ERB, and further characterization of rhodoeosein is necessary to evaluate its selectivity as a cell type-specific ER agonist.
https://link.springer.com/article/10.1186/1472-6882-13-133

Furthermore in line with previous findings emodin also inhibits AP-1 and downregulates TRPV1. I have already tested the highlighted sources of emodin and have either reported about them in my personal thread or will do so soon. My current recommendation would be Polygonum cuspidatum (Resveratrol extract) and Scutellaria baicalensis (Chinese skullcap) as they were rather good without major side-effects.

Numerous researchers have reported the use of phytochemical compounds such as anthraquinone emodin extracts from traditional Chinese medicines (TCM), including Polygonum multiflorum, P Cuspidatum, Rumex patientia, Rhamnus catharticus, Rhamnus orbiculatus, Aloe vera, Acorus tatarinowii, Cassia obtusifolia, Cassia occidentalis, Rheum palmatum, Rheum officinale, Eriocaulon buergerianum, Dendrobium thyrsiflorum, Fibraurea tinctoria, Coptis chinensis, Scutellaria baicalensis, Isatis indigotica, and Rumex chalepensis.
Treatment of menopausal symptoms using an extract from the roots of Rhapontic rhubarb (plus the results of in vitro and in vivo experiments) indicate estrogenic actions, especially estrogen receptor beta (ERB)-mediated effects. Oligostilbenes from rhubarb also inhibit low-density lipoprotein and high-density lipoprotein oxidation in humans, suggesting a pivotal role in the prevention of lipoprotein oxidation.
It has been reported that emodin and docosahexaenoic acid (DHA) increase arsenic trioxide interferon–alpha-induced cell death in human T-cell leukemia virus type 1 (HTLV-I)–transformed cells via ROS generation and the inhibition of Akt and activator protein 1 (AP-1). Emodin not only successfully suppresses acute graft rejection in vivo, thereby prolonging the survival of the recipient rats by inhibiting hepatocellular apoptosis and modulating Th1/Th2 balance, but also mediates protection against acute myocardial infarction in local ischemic myocardium.
Emodin downregulates the expression of transient receptor potential vanilloid 1 (TRPV1) ion channel protein mRNA and its functions in Dorsal root ganglion (DRG) neurons in vitro, thereby inhibiting inflammatory stimuli-induced hyperalgesia.
It can sequester and negatively regulate c-jun N-terminal kinase (JNK). Emodin reportedly induces neuroprotective effects in rat cortical neurons against beta-amyloid–induced neurotoxicity. Likewise, emodin effectively suppresses hyaluronic acid (HA)-induced matrix metalloproteinase (MMP) secretion and the invasion of glioma through the inhibition of focal adhesion kinase (FAK), extracellular regulated protein kinase (ERK)1/2, and Akt/protein kinase B (PKB) activation and the partial inhibition of the transcriptional activities of activator protein-1 (AP-1) and nuclear factor-kB (NF-kB).
https://www.sciencedirect.com/science/article/pii/S2211802012000241

[Progecitor]

After trying to find a possible connection between some plausible cures (Imatinib and Relora) another potential solution arose. Besides epigenetic modifications telomerase activity can also result in long term changes. This is mostly controlled by human telomerase reverse transcriptase (hTERT) activity. Several POIS treatments or "cures" inhibit hTERT, which at first seems controversial. Increased hTERT activity is pro-cancerous as it can lead to cell immortalisation, however decreased hTERT activity leads to telomere shortening which is an aging process that results in cell senescence. Interestingly several clues indicate that tissue specific senescence (e.g. prostate) could be a potential cause of POIS. The most interesting aspect of senescence is the senescence induced secretory phenotype (SASP), which sounds exactly like what is going in our bodies. There is no distinct SASP, but numerous unique manifestations which may reflect the diversity of our cases. Theoretically using hTERT inhibitors could further aggravate problems by telomere erosion, however the exact same compounds are often considered as senolytics which over time may clear senescent cells possibly through inducing apoptosis. Several of these have been already in use by POISers, but we should also know about the associated risks and opportunities these compounds carry.
I would have put this theory in a separate thread, but it is clear that hTERT activity is at least partially under estrogenic control and HDAC is also involved, so it is better to see the whole in a context. The specific involvement of estrogen receptor beta is not clear as different studies claim that it may either up-regulate, down-regulate or doesn't effect hTERT activity. Still considering that most hTERT inhibitors are also known ERB agonists there may be some correlation yet. Remarkably AP-1 is also involved in hTERT control which also implies a role for senescence and SASP in the postcovid phenomenon.

Telomerase is most active in proliferating cells like male sperm cells, epidermal cells and activated T cell and B cell lymphocytes. Psychological stress could increase telomerase activity, but mediation may also do so.
https://en.wikipedia.org/wiki/Telomerase

Senescence is a functional alternative to apoptosis that serves as a strategy for protection against cancer.
https://en.wikipedia.org/wiki/DNA_repair

Senescence is a process related to the stopping of divisions and changes leading the cell to the SASP phenotype. Dysfunctional telomeres are responsible for triggering the signaling of DNA damage response (DDR). Telomerase is a nucleoprotein reverse transcriptase whose main task is to counteract telomere shortening and senescence. In most human somatic cells, telomerase is inactive due to the strict repression of the hTERT gene, which encodes its protein catalytic portion. It is activated in cells with a high proliferative potential, in stem cells, activated lymphocytes and cancer cells. The non-canonical role of telomerase is to suppress ROS generation, protect mtDNA, increase respiratory chain activity, which helps maintain mitochondrial function and prevents the SASP phenotype. Cells with the SASP phenotype release a number of proteins. These include growth factors, chemokines, cytokines and metalloproteases (MMPs), including pro-inflammatory factors such as IL-6, IL-8 or monocyte chemotactic protein (MCP). Chronic presence of many cells with the SASP phenotype leads to pathological changes associated with the persistence of inflammation state referred to as "inflammaging", which is believed to cause aging-related diseases. Moreover, senescent cells are more resistant to factors that induce apoptosis. Akt1 kinase, involved in the control of cell growth, metabolism, survival, apoptosis and proliferation phosphorylates nitric oxide synthase as well as TERT, which leads to elevated activity of both proteins. In this manner, telomerase and nitric oxide synthase mutually enhance their activity in the endothelium by inhibiting senescence and preventing apoptosis. Similarly, TERT plays a protective role in nerve cells by interacting with mitochondria. The lack of this protein results in increased ROS production and oxidative damage in neurons. Mitochondrial disorders cause telomere shortening, while telomere damage leads to mitochondrial dysfunction. In cells overexpressing TERT, increased mitochondrial membrane potential was observed, accompanied by a decrease in the production and level of peroxides, while TERT deficiency in mice inhibited major regulators of mitochondrial transcription and biogenesis, such as PGC (peroxisome proliferator-activated gamma receptor) and changed metabolic pathways. Epigenetic modifications of TERT lead to interactions with key signaling pathways such as DNMT3B, PI3K-AKT and WNT/B-catenin pathways.
https://www.sciencedirect.com/science/article/pii/S1568786420302056

Cell senescence is involved in the occurrence or aggravation of neurodegenerative diseases and cognitive impairments. Senolytic approaches that eliminate both senescent cells and the accompanying SASP may represent novel therapeutic strategies for treating neurodegenerative diseases.
Senescent cells also display widespread changes in gene expression and secrete extensive inflammation mediators, such as chemokines, cytokines, growth factors, and proteases, which are referred to as senescence-associated secretory phenotype (SASP). It has been demonstrated that the pro-inflammatory microenvironment caused by pro-inflammatory SASP can also damage neighboring cells. Numerous recent reports have established multiple factors that can trigger cells to enter a senescent state, including telomere shortening, mitochondrial dysfunction, DNA damage, oncogene activation, inflammation and metabolic dysfunction. Additionally, various other stimuli or stressors, such as autophagy impairment, DNA damage, oxidative stress, stalled DNA replication, strong mitogenic/oncogenic signaling, hyperoxia, chromatin disruption, mitotic stress, radiation, proteasome inhibition, and loss of certain tumor suppressors, among others, are capable of inducing telomere attrition and senescence program.
It has been emphasized that global DNA hypomethylation and focal hypermethylation can be detected in replicative senescence.
Depending on the cell type and stimuli, SASP signifies diametrically opposite effects. The positive effects include embryonic tissue remodeling, anticancer effect, activation of the immune system, tissue regeneration, and wound healing. While the detrimental effects include chronic inflammation, angiogenesis, tissue dysfunction and disruption, elevated tumor growth and proliferation induction, differentiation and epithelium?mesenchymal transition, age-related illnesses, and neurodegenerative diseases.
Based on the recent findings, SASP production can be detected almost 6-10 days of cell induction after senescence. However, other pathways must be involved to verify this particular state.
The p38/MAPK pathway has been found to control SASP secretion, which can be activated by phosphorylation in a few minutes after a stimulus. This pathway can also upregulate multiple cytokines, for instance, TNF-a, IL-6, and IL-8. Furthermore, numerous reports have detailed that the p38/MAPK pathway plays a critical role in sustaining cell cycle arrest by activating pRB/ p16INK4a and p53 signaling pathways. IL-1a is a vital component in SASP that can regulate the activation of NF-kB. A critical feature of IL-1a is to regulate its own expression in an autocrine way, as well as promotes the expression of IL-6 and IL-8. Moreover, the activation of the JAK/STAT pathway has been shown to regulate phosphatases and kinases that are involved in SASP regulation.
In senescent cells, mitochondria are dysfunctional with increased proton leak, elevated mass, reduced membrane potential, enhanced enzyme release, and more metabolites of the tricarboxylic acid (TCA) cycle. It has been observed that the number of mitochondria increases in cells that undergo a senescent state. Despite the elevated number, mitochondria generally harbor an impaired ability to produce ATP in senescent cells and tend to produce more ROS, leading to the activation of DDR, damage of proteins and lipids, and shortened telomeres. Cell senescence can be prevented or triggered via targeting mitochondria activities or components, including mitochondrial fission rates, mitochondrial sirtuin molecules, complex I assembly, disruption of the TCA cycle, electron transport chain (etc), and biogenesis process. In addition, the cell cycle has been reported to change via regulating the ratio of ADP: ATP and AMP: ATP in senescent cells by activating the AMPK pathway. The senescent cells with dysfunctional mitochondria show reduced NAD+/NADH ratios and lead to metabolic reprogramming, resulting from AMPK-mediated activation of p53. The decreased NAD+/NADH ratio can regulate sirtuins activity, which alters NF-kB activation in SASP components.
It has been shown that neurons in AD patients harbored senescent phenotypes, such as increased p38/MAPK activity, TGF-B mRNA expression, IL-6 expression, and p16/CDKN2A expression, while the elevated activity of SASP can induce nearby cells into senescence in a paracrine manner.
Premature senescence is also found in T cells and B cells in peripheral blood of MS patients.
"Senolytic" approaches (target mouse models and therapy for senescent cells) eliminate both senescent cells and the accompanying SASP and may exert beneficial effects on neurodegenerative brains. Recent studies have demonstrated that metformin can inhibit cell senescence in AD and PD by activating microRNA-processing proteins and ultimately prevent amyloid plaque deposition in AD and suppress alpha-synuclein phosphorylation in PD. Notably, mTOR has been shown to promote the secretion of SASP and play a significant role in cell senescence. Potentially senolytic molecules and strategies such as ABT-737, ABT-263 (navitoclax), dasatinib, UBX0101, HSP90 inhibitors, piperlongumine, quercetin, FOXO4 peptide have also been identified as possible treatment options for senescent cell removal in aging and diseases, which are likely demonstrating bioavailability in neurological conditions.
https://www.sciencedirect.com/science/article/pii/S0753332221001128

This is a very comprehensive and up to date review on cellular senescence that also describes many factors that contribute to its modification. Some noteworthy excerpts though:
Senescence is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Senescent cells remain viable with alterations in metabolic activity and are usually resistant to apoptosis. One characteristic feature of senescent cells is increased lysosomal activity, macromolecular damage and a temporal cascade in the development of the complex senescence-associated secretory phenotype (SASP). Cellular senescence is different from another form of growth arrest known as quiescence, in that senescence occurs in G1 and possibly G2 phase of the cell cycle as opposed to quiescence which happens in G0. Another crucial difference is that quiescent cells can resume proliferation in response to appropriate signals such as stimulation by growth factors or mitogenic signals whereas senescent cells cannot. Cells with persistent activation of mTOR undergo a stable senescent growth arrest, whereas cells undergo quiescence when mTOR is inhibited. Prolonged overexpression of any of these four critical components (p53, pRB, p16INK4A, p21WAF1/CIP1) is sufficient to induce senescence. p21WAF1/CIP1 can also be activated by p53 independent mechanisms by other stimulators such as nuclear receptors including androgen, vitamin D and retinoid receptors. In contrast p16INK4A is required to maintain the senescent state.
Transient stress leads to induction of p53 which activates DNA repair and leads to quiescence. Cells can resume proliferation upon resolution of the stress. Additional signals and persistent stress can lead to sustained expression of p53 and activation of p16INK4A contributing to a long lasting cell cycle arrest. Cells undergoing senescence demonstrate significant changes in their secretome and exhibit a hyper secretory phenotype called the Senescence Associated Secretory Phenotype (SASP) or Senescence-Messaging Secretome (SMS). However, NF-kB dependent pro-inflammatory factors are the key components of SASP with IL-6 and IL-8 being the most conserved and robustly expressed cytokines. DNA damage is an essential driver of SASP. It was demonstrated that p38MAPK induced SASP mainly by inducing NF-kB activity. SASP has been described as a temporally regulated dynamic program that can be divided into an initial rapid DDR-associated phase followed by an early self-amplification phase eventually leading to a late ‘mature’ phase. Recently a multi-marker, three-step workflow which allows accurate detection of senescent cells has been proposed. The first step includes assessing senescence-associated-beta-galactosidase (SA-beta-gal) activity and/or lipofuscin accumulation (GL-13 or SBB). The second step examines frequently observed markers of senescent cells including transcriptional signatures linked to the cell-cycle arrest and SASP such as increased expression of the cyclin-dependent kinase inhibitors and a subset of SASP genes, along with decreased expression of proliferation markers such as cyclins, CCNA2 and CCNE2 and LMNB1. The third step consists of identification of factors that are anticipated to be altered in the specific context. They demonstrated that a hierarchical transcription factor network defines the senescence transcriptional program and identified activator protein 1 (AP-1) as a master regulator that drives the transcriptional program of senescent cells thereby revealing promising pathways with therapeutic implications for modulation of senescence in vivo. Targeting senescence using senolytics to selectively eliminate senescent cells or modulate SASP using small molecules or antibodies will not only aid in treatment of senescence related diseases but may contribute toward improving the health span of individuals.
Check out the figures!
https://www.frontiersin.org/articles/10.3389/fcell.2021.645593/full

Studies have shown that resveratrol significantly increases the telomerase activity by increasing the expression of the catalytic subunit of human telomerase reverse transcriptase (hTRET) in a dose-dependent manner.
Zhang et al. reported that apart from shortened and dysfunctional telomeres, cells undergoing senescence are also associated with increased activity of transcription factor NF-kB and increased expression of inflammatory cytokines such as TNF-a, IL-6, and IFN-g in circulating macrophages.
According to Yegorov et al. accelerated shortening of telomeres in all cell types is seen in people exposed to chronic stress, and they age rapidly; inflammation is a major feature of stress, along with aging, together causing the phenomenon of inflammaging.
They noted that many longevity treatments are related to the induction of autophagy, activation of the Sirtuin pathway, AMPK Activation, inhibition of mTOR (mechanistic target of rapamycin). Such treatments focus on calorie restriction (CR) and drugs like resveratrol, metformin, rapamycin, aspirin. According to Shimizu et al. senescent cells are pro-inflammatory and cause chronic sterile inflammation.
Human trials have shown that CR improves cardiovascular function and causes regression of cardiac senescence. Known mediators of CR are AMP-activated PK, sirtuins, adiponectin, and NO. The CR-mimetic drug resveratrol has cardiovascular protective effects. Tousian et al. reviewed 52 articles in their study regarding cellular senescence and protective effects of natural substances and found resveratrol and ginseng are the safest and most studied agents in phytotherapy for preventing stem cell senescence and cardiovascular aging.
They found that metformin or resveratrol prevented senescent-memory by regulating the SIRT1/p300/p53/p21 pathway. Treatment with resveratrol or metformin enhanced SIRT1 mediated signaling and was protective against senescent-memory, resveratrol or metformin are therefore promising anti-senescence drugs.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735524/

Telomere shortening has been emerging as a potential contributor in the pathogenesis of several neurological disorders including autism spectrum disorders (ASD), schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD) and depression. The rate of telomere attrition in the brain is slower than that of other tissues owing to the low rate of cell proliferation in brain. Telomerase activation is now being considered as a potential therapeutic strategy for neurological disorders.
https://www.sciencedirect.com/science/article/abs/pii/S0065242319300034

Moreover, in patients drinking at least four cups of coffee per day, we demonstrated a reduction in collagen synthesis and oxidative DNA damage and an increase in telomere length and circulating apoptotic markers.
https://hrjournal.net/article/view/3989

Using yeast as a model organism, we show that stresses may have very different outcomes: alcohol and acetic acid elongate telomeres, whereas caffeine and high temperatures shorten telomeres. Additional treatments, such as oxidative stress, show no effect.
https://journals.plos.org/plosgenetics/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003721

ER-alpha and/or ER beta are reported to be implicated in regulating TERT gene transcription in both cancer and healthy adult cells including human primary hematopoietic cells. Estrogen deficiency could lead to telomerase inhibition, telomere shorting and reduced cell proliferation and lower longevity in animal models as well as arresting proliferation of human cancer cells.
https://www.sciencedirect.com/science/article/pii/S1568163714001159

Similarly, ligand-independent phosphorylation of ERB is associated with increased promoter occupancy and gene expression of hTERT, a major determinant in telomerase activity, preventing apoptosis of pancreatic cancer cells. Among the possible mechanisms involved in ligand-independent activation of ERB is the selective recruitment of steroid receptor coactivator-1 (SRC-1) and histone acetyl transferase CREB binding protein (CBP), following AF-1 phosphorylation in response to EGF.
https://www.sciencedirect.com/science/article/abs/pii/S1043276009001581

In the presence of E2, transient expression of ERa but not ERB remarkably increased hTERT promoter activity, and mutation of the ERE significantly reduced this effect. Recent findings are consistent with the hypothesis that telomerase activity is potentially under hormonal control in some estrogen-targeted tissues, such as the endometrium, the prostate and in epithelial cells with high renewing potential from estrogen-regulated tissues.
Overall, these results demonstrate that distinct and cell-type specific remodelling of chromatin takes place over the hTERT ERE upon hormonal induction and that the expression of ERa is required for this effect. Moreover, treatment with tamoxifen (TAM), which is reported to activate ERB via an AP1 binding site did not elicit a promoter response. As expected, the addition of TAM virtually abrogated ERa transactivation.
https://journals.asm.org/doi/full/10.1128/MCB.20.11.3764-3771.2000

When ERB was knocked down by siRNA, the expression of prostate derived Ets factor, prostate-specific antigen, prostate cancer–specific indicator gene DD3PCA3, insulin-like growth factor-1 receptor, the catalytic subunit of the telomerase and ERa was up-regulated and the tectorigenin effects were abrogated. ERB levels were diminished in prostate cancer and loss of ERB was associated with proliferation. In addition, we show that one prominent result of treatment with VPA or tectorigenin is the up-regulation of ERB resulting in anti-proliferative effects.
In addition, tectorigenin diminished the expression of androgen receptor, DD3, IGF-1 receptor, and hTERT. siRNA silencing of ERB without tectorigenin induced ERa expression and markedly increased the expression of PDEF, PSA, DD3, IGF-1 receptor, and hTERT.
https://aacrjournals.org/mct/article/6/10/2626/234842/The-relevance-of-estrogen-receptor-expression-to

The maintenance of hTERT expression by ERB was inhibited in a dose-dependent manner by the natural PPARG ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) to induce cancer cell death. Thus, induction of telomerase activity by estrogen-bound ERa or ERB might facilitate hormone-dependent tumorigenesis in a number of tissues and conditions.
https://www.sciencedirect.com/science/article/pii/S1568163710000243

Prior studies demonstrated that targeting senescent RGCs for removal (i.e., a senolytic approach) protected healthy RGCs and preserved visual function in a mouse ocular hypertension model. The most common senolytics were tocilizumab (n=20) and imatinib (n=19).
Among these 32,414 patients, we identified 111 patients with orders for the following senolytic drugs: imatinib, dasatinib, venetoclax, nilotinib, tocilizumab, and quercetin.
https://www.nature.com/articles/s41598-020-78802-4

When given in combination, the tyrosine kinase inhibitor dasatinib and quercetin depleted senescent cells and improved lung function and fibrotic markers following bleomycin injury. Different preclinical and clinical trials testing the senolytic cocktail dasatinib plus quercetin has shown both positive outcomes and negative ones. Other senolytics with positive preclinical studies are curcumin, fisetin and fisetin-loaded mesoporous carbon nanoparticles and navitoclax.
Decosahexanoic acid- and omega-3 eicosapentanoic acid-derived resolvins D1 and E1 also mitigate inflammation, preventing chemotaxis and promoting clearance of apoptotic neutrophils.
https://www.mdpi.com/1422-0067/21/23/9317/htm

Some natural plant derived telomerase inhibitors: Quercetin, Genistein, Resveratrol, gambogic acid, berberine, epigallocatechin-3-gallate (EGCG) from green tea, garlic (allicin, E- and Z-ajoene), coralyne (a planar synthetic analogue of berberine), Berbamine (also found in Berberis vulgaris (barberry)), Cryptolepine, tanshinones isolated from danshen (Chinese red-rooted sage Salvia miltiorrhiza), Helenalin (Arnica montana), Costunolide (Saussurea lappa), Oleic acid and related long chain fatty acids (e.g. petroselinic acid, vaccenic acid).
https://pubs.rsc.org/en/content/articlehtml/2011/md/c0md00241k

TCM indicated to be able to change senescence.
- HTERT inhibitors: Ginger (6-paradol, 6-shogaol), Pterostilbene, S. baicalensis (Baicalin, baicalein),  Triptolide (Tripterygium wilfordii), Paclitaxel, Papaverine (Papaverine somnifrum), Harmine (Peganum harmala L. and Banisteriopsis caapi), Tianshengyuan-1 (mangnolia officinalis, schisandra Chinensis, pericarpium citri reticulatae viride and almond) - can both induce and inhibit hTERT, 
- DNA damage induced cell senescence: Icaritin (Epimedium brevicornu Maxim. (Berberidaceae)), Berberine, Hinokitiol (Calocedrus formosana heartwood), Acetyl-11-keto-b-boswellic acid (Boswellia serrata), gallotannin (green tea), Curcumin
- oncogene-induced senescence: Chansu (bufalin from skin of giant toads), Baicalin, Avenanthramide A (Avena sativa L.), punicalagin (pomegranate), Marchantin C (liverworts Marchantia polymorpha)
- others: 1, 8-cineole (eucalyptus essential oil), Artemisinin, Gypenoside L (Jiaogulan), Magnolin (Magnolia fargesii)
Also: Germ cells and hematopoietic stem cells can express certain levels of telomerase activity, and telomerase inhibitors may have adverse effects on these tissues. Chronic senescence-induced inflammation can lead to systemic immunosuppression.
Check out the figures!
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cpr.12894

Honokiol and several of the synthetic biphenyl derivatives were able to inhibiting hTERT gene expression to levels below 50% of the control (45% for honokiol).
https://sci-hub.se/https://onlinelibrary.wiley.com/doi/abs/10.1111/cbdd.12880

Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines.
Imatinib mesylate caused a dose-dependent inhibition of telomerase activity (TA) (up to 90% at a concentration of 15?uM IM). Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. In another study, histone deacetylase inhibitors, which suppress hTERT expression in prostate cancer cells, also inhibited cell proliferation inhibition with no cell cycle arrest, apoptosis or cell differentiation. The results of our study show that IM inhibits proliferation by cell cycle arrest and not by apoptosis.
We detected two phases of TA inhibition. Immediately after the drug addition, there was a moderate decrease (?15%), which lasted 3 days. At days 4 and 5, the inhibition reached its maximal level, that is, 75–80%. These results attest to multiple levels of telomerase inhibition. Decreased expression of telomerase post-translational modifying enzymes (AKT 1) and the slight increase in telomerase dephosphorylating enzyme, PP2A, should be effective during 24?h after drug addition. However, downregulation of the phosphorylated form of AKT, which will eventually decrease the phosphorylated form of telomerase, should be detected only after 3 days, due to the long half-life of the enzyme.
Two concerns have been mentioned regarding telomerase inhibition. Firstly, it may result in damage to normal stem cells. However, the length of telomeres in these cells compared to malignant cells may protect them from that apparent damage. Secondly, inhibiting TA might result in genomic instability, thereby leading to increased neoplasia.
https://www.nature.com/articles/6602592

Fenugreek extract diosgenin and pure diosgenin inhibit the hTERT gene expression in A549 lung cancer cell line.
https://link.springer.com/article/10.1007/s11033-014-3505-y

Sulforaphane (SFN) treatment dose- and time-dependently inhibited human telomerase reverse transcriptase (hTERT), the catalytic regulatory subunit of telomerase, in both MCF-7 and MDA-MB-231 human breast cancer cells. DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3a, were also decreased in SFN-treated breast cancer cells suggesting that SFN may repress hTERT by impacting epigenetic pathways. SFN-induced hyperacetylation facilitated the binding of many hTERT repressor proteins. In addition, down-regulation of hTERT expression facilitated the induction of cellular apoptosis in human breast cancer cells.
hTERT regulatory region hypermethylation has been associated with increased hTERT expression, whereas demethylation of this region inhibits hTERT transcription. This phenomenon is opposite to the general model of gene activation, in which the presence of methylated cytosines in a promoter typically inhibits gene transcription.
Many studies have also shown that HDAC inhibitors suppress hTERT expression in various cancer cells including prostate, leukemic and oral squamous cell carcinoma. Reports on telomerase inhibition by HDAC inhibitors are controversial.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011457

Downregulation of the telomerase and c-myc has been linked to interactive effects of tocotrienols in cancer cells.
https://sci-hub.se/https://www.sciencedirect.com/science/article/pii/B9780128123737000048

It was further elucidated that tannic acid was more effective than resveratrol and quercetin in potentiating tamoxifen against MCF-7 cells by downregulating telomerase activity.
https://pdfs.nutramedix.ec/Reveratrol%20-%20Cancer%20(preclinical).pdf

Finally, the inhibitory effect of melatonin on telomerase activity in MCF-7 human breast cancer cells has been considered as the basis for its antitumor action, but also in this case, the antiestrogenic effects of melatonin could be the link to its effects on telomerase, as recently it has been demonstrated that estrogens possess the ability to up-regulate telomerase activity.
https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-079X.2004.00207.x

Here, we show that genistein inhibits the transcription of hTERT, the catalytic subunit of the human telomerase enzyme, in breast MCF10AT benign cells and MCF-7 cancer cells in a time- and dose-dependent manner. Three major DNA methyltransferases (DNMT1, 3a and 3b) were also decreased in genistein-treated breast cancer cells suggesting that genistein may repress hTERT by impacting epigenetic pathways.
https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.24398

Telomerase activity in MCF-7 cells is 6.9-fold higher than that of human mammary epithelial cells. In MCF-7 cells, telomerase activity decreased with increasing concentrations of curcumin, inhibiting about 93.4% activity at 100 uM concentration. The inhibition of telomerase activity in MCF-7 cells may be due to down-regulation of hTERT expression. Increasing concentrations of curcumin caused a steady decrease in the level of hTERT mRNA in MCF-7 cells whereas the level of hTER and c-myc mRNAs remained the same.
https://www.sciencedirect.com/science/article/abs/pii/S0304383502001921

Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) from Brassica plants are regarded as promising anticancer phytochemicals. A relevance of ERa/B-AP1 signalling for telomerase inhibition on enzyme activity, but not transcription level became evident indicating a non-classical mode for ER regulation of telomerase by DIM. Although desired in cancer cells, this study identified a potential adverse impact of I3C and DIM on telomerase action in normal human immune cells, partly mediated by an ER dependent mechanism. For I3C it was found that cell cycle arrest of indole-sensitive human cancer cells was associated with the downregulation of cellular telomerase expression and/or activity.
Telomerase loss contributes to alterations in the T-cell compartment leading to a decline in humoral and cell-mediated responses and the waning protective function of the immune system. DIM - which was 10-fold more potent compared to its parent compound I3C - significantly blocked telomerase enzyme activity at 3 uM in normal cells and 10 uM in cancer cells. Several studies linked low levels of telomerase activity and short telomere length in leukocytes to age-related diseases like coronary heart disease, chronic asthma, cancer and premature lethality. However, upon long-term treatment we found reduced cell proliferation in lymphocytes and also elevated levels in DNA damage frequency besides telomerase reduction.
https://sci-hub.se/https://onlinelibrary.wiley.com/doi/abs/10.1002/mnfr.201600524

Previous research suggests increased in Ca2+ dependent signaling causes downstream changes in telomerase activity. Eventually, this causes uncontrolled cell proliferation normally prevented in non-neoplastic cells. Overall calcium channels create high sensitivity to mitogen and growth factor secretion.
https://www.irjmets.com/uploadedfiles/paper/volume2/issue_7_july_2020/2288/1628083084.pdf

Excessive HPA activation results in reduced blood levels of growth hormone (GH), which has an effect on telomere maintenance.
https://www.sciencedirect.com/science/article/abs/pii/S0166223614000265

[Progecitor]

ERB/ERa ratio plays a role in prostatitis.
Conclusion Guizhi fuling pills can mitigate the prostatitis and alleviate bladder overactivity induced by CNP probably by activating the ERbeta and increasing the ERB/ERa ratio in the prostate.
http://www.xinyixue.cn/EN/10.3969/j.issn.0253-9802.2019.06.011

Dutasteride may help in POIS treatment, but can also potentially lead to POIS development if irreversible inhibition of 5a-reductase occurs.
Estrogen receptor beta (ERB) stimulation can improve local inflammation whereas ERalpha stimulation could induce local inflammation. It has been reported that dutasteride, which not only inhibits 5alpha-reductase, but also stimulates ERB, might have anti-inflammatory effects in the prostate of patients with lower urinary tract symptoms. Therefore, dutasteride might be effective via ERB for the treatment of nonbacterial prostatic inflammation in addition to benign prostatic hyperplasia.
https://www.auajournals.org/doi/full/10.1016/j.juro.2016.02.1649

3alpha-Adiol can be low due to finasteride or isotretinoin that were both implicated as possible causes of POIS.
There is increasing evidence showing that chronic non-bacterial prostatic inflammation is involved in the pathogenesis of benign prostatic hyperplasia (BPH) and male lower urinary tract symptoms (LUTS). It has also been reported that estrogen receptor beta (ERB) could have an immunoprotective role in prostatic tissue. These results indicate that ERB activation by 3alpha-Adiol administration, which normalized the ERbeta/ERalpha expression ratio in the prostate, can improve not only prostatic inflammation, but also bladder overactivity. Therefore, ERB agonists might be useful for treating irritative bladder symptoms in patients with symptomatic BPH associated with prostatic inflammation.
https://onlinelibrary.wiley.com/doi/abs/10.1002/pros.23320

3alpha-Adiol and 3beta-Adiol are both DHT metabolites and also serve as endogenous estrogen receptor beta agonists.
In the prostate, ERB is highly expressed in the epithelium and appears to participate in the regulation of cell proliferation, apoptosis and differentiation. Evidence shows that ERB is decreased in malignant prostate, suggesting that it plays an important role in protecting this tissue. The decrease in ERB reactivity occurred in a hormonal milieu characterized by a constant concentration of estradiol and decreased plasmatic and tissue DHT. A reduction in androgen and increase or maintenance of the estradiol levels in the plasma and tissue has long been postulated as a risk factor for pathological changes in the prostate, thus corroborating our findings. The reduction in ERB without changes in the local estradiol levels indicates that the receptor does not appear to be modulated by estradiol. Others have also found that estrogens do not autoregulate ERB in the rat prostate. On the other hand, evidence suggests that estradiol is not the only estrogen acting in the prostate. In fact, the most abundant estrogenic steroid in this tissue is 5a-androstane, 3B,17B-diol (3B-diol), a DHT metabolite that acts by paracrine and autocrine mechanisms. The decrease in DHT may have resulted in a decrease in 3B-diol, which has been shown to modulate the expression of ERB in the rat prostate. In contrast to 3B-diol, the cognate ligand of ERB, estradiol, had minor effects on the ERB levels. In addition, ERB autoregulation by 3B-diol has also been found in other organs. Therefore, an investigation of the prostate 3B-diol levels during aging is warranted to clarify the composition of the hormonal milieu that leads to local alterations in this gland.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131901

Aging leads to a decrease of ERbeta expression and I think premature aging also does the same.
The role of ERB in opposing AR signaling, proliferation, and inflammation suggests that ERB-selective agonists may be used to prevent progression of prostate cancer, prevent fibrosis and development of benign prostatic hyperplasia, and treat prostatitis. Several ERB-selective agonists have been synthesized and they have been found to be antiinflammatory in the brain and the gastrointestinal tract and antiproliferative in cell lines and cancer models. Down-regulation of ERB expression with age suggests that the aging prostate may be more susceptible to diseases related to excessive AR signaling. Regulation by ERB of PTEN, NFkB, and TGFB suggests wide-spread effects of this receptor in cells in which it is expressed. ERB is not ubiquitously expressed. In addition to the prostate epithelium and stroma, ERB is expressed in several organs where it has profound physiological effects: to name a few, the immune system, the sympathetic nervous system, in blood vessels where its loss leads to hypertension, the urinary bladder where its loss leads to interstitial cystitis and in the lung where its loss leads to general hypoxia because of a decrease in elasticity. In addition, development of BPH is related to inflammation, and ERB has powerful antiinflammatory actions by down-regulating activated NFkB, iNOS, IL-6, and CXCL14, -16, and -17. Cytokines stimulate production of chemokines by stromal cells, leading to proliferation and development of BPH. These two pathways (TGFB and NFkB) regulated by ERB suggest that ERB ligands should be effective in preventing development of BPH, but perhaps not in the treatment of BPH. Treatment with ERB agonists does not cause chemical castration because ERB is not expressed in the pituitary and does not influence gonadotropin secretion from the pituitary. In addition, the antiinflammatory actions of ERB ligands may be useful in treatment of prostatitis, a painful, distressing condition for which there is no adequate treatment. ERB agonists have the advantage over glucocorticoids, the most powerful and effective antiinflammatory agents available, because they do not cause bone loss, a severe side effect of use of glucocorticoids. It is possible that there is no endogenous ligand present because androgen ablation will lead to the absence of dihydrotestosterone (DHT) and its metabolite, 5a-androstane-3B,17B-diol (3B-Adiol), the endogenous ERB ligand in the prostate. If there is absence of an endogenous ERB ligand, ERB agonists should be useful in treating metastatic PCa. Overall, our data confirm a key role for ERB in prostatic homeostasis and suggest that ERB agonists should be useful in controlling prostate cancer, BPH, and prostatitis.
https://www.pnas.org/doi/full/10.1073/pnas.1702211114

[Progecitor]

Lycopene turned out to be relatively useful for me as well. The most likely reason is an increase in both testosterone and 3beta-Adiol.

Although vitamin E did not alter the expression of steroid 5alpha-reductase 1, the expression of the same set of androgen target genes was downregulated as in the lycopene-treated groups. Moreover, vitamin E alone or together with lycopene reduced aromatase expression (0.57- and 0.65-fold). Lycopene and vitamin E cotreatment downregulated androgen target genes in an additive manner. In addition to the effects on steroid metabolism and signaling, lycopene alone inhibited local IL-6 expression. Furthermore, the prostate-specific expression of IGF-I was substantially downregulated by lycopene both alone and in combination with vitamin E.
The expression profiles of 3 major enzymes of androgen metabolism [5alpha-reductase 2, 17beta-hydroxysteroid-dehydrogenases (17beta-HSD), Cyp7B1] suggest that lycopene supplementation reduced the activation of androgens in normal prostate tissue. 5alpha-Reductase 2 was mildly, but consistently, downregulated by lycopene in both lobes [0.66-fold change in the dorsal lobe (d); 0.81-fold in the lateral lobe (l)], indicating reduced androgen activation. In line with this, androgen targets were also downregulated by lycopene (prostatic steroid binding proteins C1 and C3, cystatin-related protein 2, and seminal vesicle secretion protein IV). 17beta-HSD type IV is responsible for dehydroepiandrosterone (DHEA) generation, whereas Cyp7B1 regulates 3beta-Adiol catabolism. Both DHEA and 3beta-Adiol are ligands for the estrogen receptor beta (ERbeta). Upregulation of 17beta-HSD type IV [1.55-fold (d)] as well as downregulation of Cyp7B1 [0.66-fold (d); 0.74-fold (l)] by lycopene suggests increased formation of both ERbeta ligands, presumably at the expense of 5alpha-DHT.
https://academic.oup.com/jn/article/135/8/2050S/4664017

[Progecitor]

I wanted to make these posts several months ago, but then I was a bit lazy and got carried away. Nevertheless I felt this was necessary, so that the role of estrogen can be adequately appreciated in the etiology of our disease. It also serves to establish context to a later post where I am going to discuss, how this may be related to senescence and also outline a possible cure that could be evidence based.

Estrogen receptor localization and distribution with a focus on estrogen receptor beta (ERB)

The potential interplay between several factors, including inherently lower estradiol (E2) and slightly higher ERB levels in males, with inflammatory mediators are described. Physiologically, the ERa:ERB composition ratio in the human lung does not differ significantly between males and females, although the expression of ERB is slightly higher in males.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126387/

ERa is localized in the prostate stroma while ERB is present in both epithelia and stroma.
https://www.sciencedirect.com/science/article/pii/S1110570418300055

In the prostate, ERB is highly expressed in the epithelium and appears to participate in the regulation of cell proliferation, apoptosis and differentiation.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131901

3B-adiol, as an alternative ligand to estradiol of ERB (the concentration of 3B-adiol in prostate is 100-fold higher than that of estradiol). ERB expression has been revealed to be greatly decreased in malignant prostate tissue, reaching nearly undetectable levels with tumor progression in more than 75% of cases.
https://lmreview.com/bio-identical-hormone-replacement-selecting-the-right-hormone-tests-for-your-male-patient/

The present studies found ERB mRNA in two major cellular compartments of the testis (germ and Sertoli cells in the seminiferous tubules). Since the Sertoli and granulosa cells develop from the same precursor cells during the ontogeny of these organs, the presence of ERB mRNA in both these cell types may reflect the similar origin of these cells. In contrast, the presence of ERB mRNA in spermatocytes was surprising. It is interesting to note that the ERB mRNA-containing cells are rather sparse, with only scattered germ cells (primarily large secondary spermatocytes) and Sertoli cells containing the signal. Regardless of the method of detection or species investigated, all studies have found a high level of ERB mRNA in the prostate. In situ hybridization studies have shown that the ERB mRNA is concentrated in the epithelial cells of the intact rat prostate, with little or no specific signal seen in the other cell types. The expression of ERB was very sensitive to changes in hormonal conditions.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0039128X98000543

The medial preoptic area of the hypothalamus is involved in the control of libido and ejaculation, the locus coeruleus in the mediation of sexual arousal, and the nucleus paragigantocellularis and the paraventricular nucleus of hypothalamus in ejaculation control. Interestingly, the ERB protein is detectable in the preoptic area, the paraventricular nucleus of the hypothalamus, the dorsal raphe, and locus coeruleus. Moreover, ERB protein is present in the preoptic area and the bed nucleus of stria terminalis that are important for processing of pheromone-induced signals.
https://www.pnas.org/doi/pdf/10.1073/pnas.1217668109

Sperm are able to synthesize estrogen. In ejaculated sperm, E2 stimulates various sperm functions including motility, longevity, capacitation, and acrosome reaction. In varicocele a strong reduction of the ERB was observed, while the ERa was almost absent. In human sperm, ERs were found differently located being both receptors in the midpiece, while ERB continues to be expressed in the flagellum. ERB appears to be also present in sperm membranes. In "varicocele" sperm, the ERB was absent in the head and a strong reduction of the labeling was noticed along the midpiece and the tail. From an overview of the ERs localization and abundance in the male genital tract, ERB seems to be the predominant ER subtype in male reproductive system, conversely ERa appears to be very weakly expressed, as we found in our study. Intriguingly, in "varicocele" sperm, a strong reduction of the ERB labeling was noticed while the ERa was almost absent. The massive presence of ERB in the flagellum may indicate an important role in the sperm motility.
https://www.researchgate.net/profile/Stefania-Marsico/publication/49857930_Human_sperm_physiology_Estrogen_receptor_alpha_ERa_and_estrogen_receptor_beta_ERb_influence_sperm_metabolism_and_may_be_involved_in_the_pathophysiology_of_varicocele-associated_male_infertility/links/5cdd31f6299bf14d959cecdc/Human-sperm-physiology-Estrogen-receptor-alpha-ERa-and-estrogen-receptor-beta-ERb-influence-sperm-metabolism-and-may-be-involved-in-the-pathophysiology-of-varicocele-associated-male-infertility.pdf

While ERB mRNA could not be detected by in situ hybridization, weak staining for ERB was localized in epithelial cells of seminal vesicles. In the ovary, both ERa and ERB were found to be expressed. ERB mRNA was found in granulosa cells of growing follicles.
https://www.researchgate.net/profile/Georges-Pelletier-2/publication/12508136_Localization_of_oestrogen_receptor_a_oestrogen_receptor_b_and_androgen_receptors_in_the_rat_reproductive_organs/links/02bfe50cf283bbf4ff000000/Localization-of-oestrogen-receptor-a-oestrogen-receptor-b-and-androgen-receptors-in-the-rat-reproductive-organs.pdf

In addition to the prostate epithelium and stroma, ERB is expressed in several organs where it has profound physiological effects: to name a few, the immune system, the sympathetic nervous system, in blood vessels where its loss leads to hypertension, the urinary bladder where its loss leads to interstitial cystitis, and in the lung where its loss leads to general hypoxia because of a decrease in elasticity.
https://www.pnas.org/doi/full/10.1073/pnas.1702211114

ERB is expressed prominently in tissues such as the brain and urinary tract, and apparently also in breast cells.
https://www.degruyter.com/document/doi/10.1351/pac199870091759/html

ERa is the major ER in neoplastic breast epithelium, whereas ERB is the predominant ER in normal breast tissue. GPR30, the plasma membrane ER, is expressed in pain-relevant areas of the rat central nervous system, and the expression levels are similar in the male and female.
https://journals.sagepub.com/doi/10.1186/1744-8069-9-45

ERa is mainly expressed in immune cells, reproductive tissues, breast, bone, kidney, liver, and white adipose tissue, while ERB is found in the immune cells, lung, central nervous system, cardiovascular system, ovary, prostate, male reproductive organs, colon, and kidney. GPER1 is also expressed in the immune, central nervous, reproductive, renal and cardiovascular systems.
https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.2290

ERB is widely expressed in most tissues across the body including the immune system, prostate, mammary gland, adipose tissue, cardiovascular system, digestive system, central nervous system, skeletal and smooth muscle, white and brown adipose tissue, lung, ovary, and uterus.
ERB is not expressed in the heart. ERB is highly expressed in immune cells and is an important regulator of the immune system. ERB is the primary estrogen receptor expressed in the prostate and is normally present in high levels. Also, ERB levels in clinical prostate cancer samples decrease with increasing Gleason grade and ERB is usually absent from prostate cancer cells in culture.
https://uh-ir.tdl.org/bitstream/handle/10657/956/BUTLER-DISSERTATION-2013.pdf?sequence=1&isAllowed=y

ERB is expressed in hepatic stellate cells, mesangial cells, cardiac fibroblasts and prostate stroma.
https://openheart.bmj.com/content/8/1/e001663.full

The main ER expressed in both normal lymphocytes as well in lymphoma cells is ERB while ERa levels are very low or undetectable. ERa mainly has a stimulatory effect on cell proliferation and has been shown to be a tumor promoter in, for example, breast cancer, whereas ERB mainly acts in the opposite way by exerting anti-proliferative and pro-apoptotic effects on multiple healthy and tumor cell types, such as in breast, prostate and ovarian cancer. We have previously demonstrated this also to be the case for several subtypes of lymphomas. Lymphocytes and lymphoma cells mainly express ERB.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991487/

Moreover, they have distinct expression patterns in tissues: ERa is primarily involved in reproductive functions and it is abundant in mammary glands, uterus and vagina, while ERB is almost ubiquitous in the central nervous system, in the cardiovascular system, in the immunity system, in the urogenital apparatus, in the gastroenteric apparatus, in the kidney and the lung.
The results of several biochemical and microscopic analyses have suggested the existence of different pools of ER in the cellular environment, including the plasma membrane, the mitochondria, and the endoplasmic reticulum. In general, about 80% of ERs localizes in the nucleus in absence of estrogen.
https://www3.med.unipmn.it/Dottorato/Medicina_Molecolare/tesi-2011/I_sessione/DiVito_Clara_Tesi_dottorato.pdf

Both ERB1 mRNA and protein expression increased from the G1 to the S phase and decreased before entering the G2/M phase, whereas ERB2 levels decreased during the S phase and increased in the G2/M phase. ERB1 protein was detected in both the nuclear and non-nuclear fractions, and ERB2 was found exclusively in the nucleus.
https://www.hindawi.com/journals/acp/2008/129726/

ERB has been found in the cardiovascular system, urogenital tract, and GI tract. Interestingly, the incidence of cardiovascular disease differs significantly between men and women, this suggests that, in part, estrogen levels might influence the risk factor of cardiovascular disease.
In addition, the fact that ERB is the predominant ER isoform in the GI tract (e.g., epithelium, vascular smooth muscle, and endothelium) draws more attention to the potential interaction between ERB and GI physiology.
https://ir.canterbury.ac.nz/handle/10092/16577

These data were supported by the higher expression levels of ERB in the gastric cancer than those in the gastric epithelial cell lines, and consistent with preventive effects of ERB on digestive system carcinogenesis.
https://www.nature.com/articles/s41416-018-0008-y

The ERB isoform is predominantly found in the brain, which makes it a promising drug target for memory consolidation.
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fasebj.2021.35.S1.01501

Importantly, ERB are abundantly expressed in the hippocampus, a brain region which subserves learning, memory and neurodevelopmental processes, while ERa are predominantly located in the basal forebrain, which coordinates information processing and attentional function.
https://www.mdpi.com/2072-6643/8/3/150/htm

In the brain, especially in the hippocampus the ERB expression is more than ERa although ERa and ERB are both expressed there. Memory function regulation including cholinergic system is through ERa, while ERB modulates ERa activity.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Black+Cummin+Extract+%28Nigella+sativa+Linn%29&btnG=

ERa and ERB were widely distributed in the stellate ganglion, and ERa and ERB immunoreactive substances were distributed in neurons, supporting cells, and passing fiber. ERa and ERB were mainly distributed in neurons. In neurons, ERa and ERB were mainly distributed in cell membrane and cytoplasm, and the nuclear was weak positive. The relative expression level of ERa was significantly higher than that of non-neurons and ERB was very significantly higher than that of non-neurons.
https://www.cabdirect.org/cabdirect/abstract/20153025331

Detailed immunohistochemical studies, performed in rat and mouse, demonstrated the presence of ERa and ERB within the DRN serotoninergic neurons of both sexes, whereas the ARs are visible only in male neurons adjacent to 5-HT elements.
https://sci-hub.se/https://link.springer.com/article/10.1007/s12020-018-1593-5

Immunopositive ERB protein (?50–55 kDa) can be detected in several of the samples, including normal pituitary and several gonadotropin tumors, but not in the prolactinoma. This tumor contained detectable ERa protein and was positive for ERa, but not ERB, mRNA.
https://academic.oup.com/jcem/article/83/11/3965/2865580?login=true

It has also been reported that mitochondria express ERa and ERB that regulate oxidative stress originating in the mitochondria.
https://assets.researchsquare.com/files/rs-1167112/v1_covered.pdf?c=1639668824

Oestrogen receptor beta is the predominant oestrogen receptor in human scalp skin. ERB was the major steroid receptor expressed in human skin. It was highly expressed in epidermis, blood vessels and dermal fibroblasts, in contrast to ERa and AR. In the hair follicle, ERB expression was localized to nuclei of outer root sheath, epithelial matrix and dermal papilla cells, in contrast to ERa, and the AR, which was only expressed in dermal papilla cells. Serial sections also showed strong nuclear expression of ERB in the cells of the bulge, while neither ERa nor AR was expressed. In the sebaceous gland, ERB was expressed in both basal and partially differentiated sebocytes. There was no obvious difference in the expression of either oestrogen receptor in male or female skin. The wide distribution of ERB in human skin suggests that oestrogens may play an important role in the maintenance of skin and in the regulation of the pilosebaceous unit, and provides further evidence for oestrogen action in non-classic target tissues.
https://onlinelibrary.wiley.com/doi/abs/10.1034/j.1600-0625.2003.120209.x

Both receptors (ERa, ERB) have been identified in osteoblasts and osteoclasts as well as in their
precursors.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0024320516300261

In our study, we showed that strong diffuse nuclear ERB immunohistochemical staining was present in normal pancreatic acinar cells, ductal epithelium and islets of Langerhans and 30% of pancreatic neuroendocrine tumors (PanNETs), low positivity was seen in 66% of PanNETs while only 4% of PanNETs had no nuclear staining for ERB. Our results are compatible with the high frequency of ERB staining previously reported in insulinomas.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628823/

[Progecitor]

Estrogen receptor function with a focus on estrogen receptor beta (ERB)

ERB serving largely as a brake on ERa-driven proliferation. As we observed in breast cancer cells here, in target tissues such as the prostate, which contain both ERa and ERB, estrogen action through ERB appears to mute the hyperproliferative effect of ERa.
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.13-234617

ERa promotes inflammation and hyperplasia while ERB serves to exert antiproliferative and proapoptotic effect in the prostate.
https://www.sciencedirect.com/science/article/pii/S1110570418300055

3B-Adiol is the natural ligand for ERB, which is highly expressed in adult prostatic epithelium. 3B-Adiol has no androgenic activity. ERB expression is significantly decreased in malignant prostate tissue. Activation of ERB can suppress proliferation and promote differentiation of the prostatic epithelium, counteracting the physiological action of androgen receptor activation.
https://www.meridianvalleylab.com/an-assessment-of-testosterone-and-its-essential-metabolites-for-prostate-cancer-risk/

TGF-B can induce Epithelial-to-mesenchymal transition (EMT)-like states in various prostate cancer cell lines. The effects of both hypoxia and TGF-B on an EMT-like state might be mediated by ERB. In cultured prostate cells, both hypoxia and TGF-B lead to concomitant downregulation of ERB expression and changes in EMT markers. ERB, in response to its endogenous ligand 3B-Adiol, normally enforces an epithelial phenotype via multiple repressive effects on hypoxia inducible factor 1a (HIF-1a) and its target gene, vascular endothelial growth factor A (VEGF-A).
https://sci-hub.se/https://www.nature.com/articles/nrurol.2011.85

This finding is consistent with several reports on the anti-PCa action of ERB, such as inhibition of EMT, downregulation of VEGF-A and TMPRSS2-ERG, reduction of PC3 cell migration and invasion in vitro, and growth of DU145 and PC3 xenografts in nude mice.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098037

This indicates that normal primary stromal cells (PSC) generates more 3B-diol than 3a-diol. The AKR1C1:AKR1C2 ratio decreased in diseased PSC to 13 in prostate adenocarcinoma (CaP) and to eight in BPH and indicates that the 3B-diol signal will be attenuated in this disease. Additional fates exist for DHT in normal primary epithelial cells (PEC) are that it can be converted to 3B-diol by AKR1C1 to activate ERB or it can be converted to the inactive androgen 3a-diol by AKR1C2. Furthermore, P4507B1 could eliminate 3B-diol by metabolizing it to 5a-androstane-3B,7a,17B-triol that is excreted. P4507B1 regulates the local concentration of 3B-diol, a ligand for the ERB.
https://academic.oup.com/endo/article/147/12/5806/2500950?login=true

Western blot analysis showed that CYP7B1 expression was high in the ventral prostate before puberty (4-week-old rats), and decreased postpubertally (between 6 and 18 weeks of age). At the peak of proliferation, the proliferating epithelial cells in the ventral prostate expressed high levels of CYP7B1 but had no detectable ERB, whereas in nonproliferating cells the level of ERB was high and that of CYP7B1 was low. Even though 3BAdiol has been shown to bind to estrogen receptor in pituitary cytosol, the high level of 3BAdiol hydroxylase (CYP7B1) in the pituitary makes this gland resistant to the estrogenic actions of 3BAdiol.
https://www.pnas.org/content/99/21/13589.long

Since Sertoli cells contain the aromatase enzyme, it is possible that testosterone, converted into estrogen, acts via the ERB receptor to modify spermiohistogenesis by Sertoli cells. Testosterone and/or estrogen may also regulate the maturation of germ cells. The expression of ERB was very sensitive to changes in hormonal conditions.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0039128X98000543

Oestrogen action is important for the regulation of spermatogenesis; E2 is involved in the regulation of the somatotropic axis, it mediates epiphyseal closure in bones, improves bone mineralization and bone microarchitecture, decreases fat mass, thereby favouring lean body mass. In addition, it positively affects glucose metabolism by enhancing insulin sensitivity and conveys vasomotor stability.
https://onlinelibrary.wiley.com/doi/full/10.1111/cen.14324

Experimentally, prostatitis induced by E2 alone increased the prostatic levels of the inflammatory markers TNF-a, COX-2 and MIP-1a. As signs of antiestrogenic actions, androgens dose-dependently decreased the expression of TNF-a, COX-2 and MIP-1a. Testosterone was anti-inflammatory at the doses which normalized or over stimulated the growth of the prostate and seminal vesicles.
https://sci-hub.se/https://link.springer.com/article/10.1007/s11255-014-0845-4

ERBKO mice treated with T+E2 developed large bladders with urinary retention, detrusor hypertrophy and prostate growth.
https://www.proquest.com/openview/147c694c1e6e49955f701bfd87082db6/1?pq-origsite=gscholar&cbl=18750

Patients with low estradiol below 42.6 pg/ml had more patients complaining of low libido. Patients with higher estradiol levels above 42.6 pg/ml had less sexual dysfunction problems identified by their providers. E2 appears to play a key role in the negative feedback control of testosterone.
https://journals.sagepub.com/doi/pdf/10.1177/1557988314539000

The reported synergism between androgens and estrogens in restoring libido and ejaculation after postpuberal castration of male pigs or establishing libido and ejaculation after prepuberal castration suggests that mating behavior might be adversely affected by reduced endogenous estrogens resulting from inhibition of testicular aromatase.
https://www.sciencedirect.com/science/article/abs/pii/S0093691X1400260X

Activation of ERa increased the expression of appetitive aspects of male behavior while both ERa and ERB agonists, separately, enhanced the performance of the initial behavior patterns in the copulatory sequence. Male sexual behavior can be divided into an appetitive and a consummatory component.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018627

ERa-null males exhibit severely reduced numbers of mounts, thrusts and intromissions, and very few ejaculate. ERB appeared to be a major determinant of antianxiety behaviors in female mice, and, in a transient manner, of aggressive behaviors in male mice. ERB was also reported to be involved in male mouse brain defeminization. We found that ERB is required for a normal sexual behavior in males that display delayed ejaculation, and in females that exhibit decreased receptivity and attractivity. However, the medial preoptic area and the paraventricular nucleus of hypothalamus appear to have excitatory influences on ejaculation. The neurotransmitters in these pathways are dopamine and oxytocin, respectively. Several pieces of evidence suggest an involvement of ERB in the regulation of dopamine D2 receptor, dopamine transporters (DAT), and oxytocin.
https://www.pnas.org/doi/pdf/10.1073/pnas.1217668109

ERa interacts with and influences the activity of other transcription factors, such as stimulating protein-1 (SP-1), AP-1, NF-kB and c-jun.
https://ir.nsfc.gov.cn//paperDownload/1000009071255.pdf

ERs may also follow a tethered signaling pathway, interacting with other transcription factor complexes and binding to non-ERE sequences. The transcription factor complexes include activator protein 1 (AP-1), STATs, activation transcription factor 2 (ATF-2), NF-kB, specificity protein 1 (SP1), which are bound to their cognate DNA binding sites.
https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.2290

Our findings support the therapeutic role for E2 in promoting resolution of lung inflammation after pneumonia via ERB Tregs. Treg ERB contributes to suppression of macrophage-generated proinflammatory cytokines. E2 was not bactericidal and did not affect bacterial burden, but rather targets enhanced prorepair mechanisms.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934849/

ERB-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease. Homeostatic expression of ERB normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression.
https://www.researchgate.net/publication/342743502_Impaired_estrogen_signaling_underlies_regulatory_T_cell_loss-of-function_in_the_chronically_inflamed_intestine

AhR ubiquitin ligase activity is responsible for the degradation of several proteins like ERa, AR, beta-catenin and possibly ERB. Some AhR ligands are cAMP, kynurenine, FICZ and bilirubin. Quercetin and curcumin also activates AhR through FICZ. AhR may activate Treg cells, induce Foxp3, Th17 cells. By activating the inhibitory cells (Tregs), AhR may protect against an overactive immune system. ERB is tethered to Fos/Jun (AP-1) and SP-1 activity. ERB can be activated by phosphorylation even without ligands. ERB signaling can also occur through a rapid, nongenomic mechanism. Rapid effects of ERB may increase NO or activate kinases. A lack of ERB may lead to a myeloproliferative disorder which is similar to chronic myeloid leukemia. ERB agonists appear to be anti-inflammatory in macrophages and leukocytes. ERB has a role in controlling aggression, anxiety and feeding behavior. ERB-selective ligands could be used in the treatment of depression.
ERB is required to help control the immune system by decreasing proliferation and regulating differentiation of hematopoietic progenitor cells. ERB also has an anti-inflammatory function in microglia of the brain and in Th17 T cells. ERB can alter TGF-B signaling by increasing inhibin and the inhibin receptor TGF-B receptor 3. We also found that breast density is not affected by hormone replacement therapy but is in fact reflective of breast fibrosis which can be visualized by histochemical stain for collagen.
https://uh-ir.tdl.org/bitstream/handle/10657/956/BUTLER-DISSERTATION-2013.pdf?sequence=1&isAllowed=y

Conjugation and hydrolysis of sulfates or glucuronides may reduce estrogen. Oxidative estrogen metabolism produces ROS that may directly affect the redox-sensitive transcription factors such as Nrf2, AP-1 or NF-kB and also facilitates JNK activation. The exact mechanism of estrogen-mediated Akt activation is unclear; however, it is possible that the reversible inactivation of Cdc25A or PTEN by estrogen-induced ROS plays a key role in the activation of Akt.
https://www.koreascience.or.kr/article/JAKO201123163432838.pdf

SULT1E1 is responsible for sulfating active 17B-estradiol (E2) into an inactive form. Carcinogenesis process reduces SULT1E1. NRF2 pathway creates an environment that favors the survival of normal as well as malignant cells, protecting them against oxidative stress.
https://cancerci.biomedcentral.com/articles/10.1186/s12935-019-0826-x

Reduction of ADIOL or ERB expression results in exaggerated inflammatory responses to TLR4 agonists. Conversely, the administration of ADIOL or synthetic ERB-specific ligands that promote CtBP recruitment prevents experimental autoimmune encephalomyelitis in an ERB-dependent manner.
HSD17B14 converts DHEA to ADIOL, and the expression of HSD17B14 itself is controlled by inducers and inhibitors of inflammatory responses. Lack of this enzyme or ERB results in exaggerated inflammatory responses in microglia and astrocytes. The ERB pathway functions as a negative feedback mechanism to attenuate transcription from active promoters.
The findings that HSD17B14 and HSD3Bs are reciprocally regulated by LPS and that HSD17B14 is positively regulated by the anti-inflammatory cytokine IL-10 suggests that in the setting of acute infection or injury, the ADIOL pathway is rapidly downregulated to allow an effective inflammatory response to occur. Upon eradication of the inciting stimulus, anti-inflammatory cytokines such as IL-10 induce expression of HSD17B14, which by activating the ERB/CtBP pathway, could promote resolution of inflammation and re-establishment of the de-activated phenotypes of microglia and astrocytes, in concert with other resolution pathways. The finding that 17B-estradiol can antagonize the anti-inflammatory activities of ADIOL provides another level by which the ADIOL pathway might be controlled, and could help explain some of the complexity of estrogen activity in the brain and the increased susceptibility of females to Multiple Sclerosis.
https://www.sciencedirect.com/science/article/pii/S0092867411004272

ERB binding preferential (83 times) Phyto-B-SERM proved neuroprotective, prevented menopause symptoms, prolonged survival, improved spatial recognition memory and reduced cerebral amyloid-B plaque deposition, modulated glycogen synthase kinase 3 (GSK3B).
https://www.frontiersin.org/articles/10.3389/fphar.2021.644103/full?fbclid=IwAR0rU0SHCCgCZFTzt__yOkQa0uqkbFTOVT4r2C5nDo2Ok9FTnuxGF4VSb5c

Chhibber et al. found in knockout mice with estrogen receptor subtype ERB -/- to exert a downregulation effect on BDNF, with a 40% decrease in BDNF protein expression found in the
hippocampus, while not significant in the cortex and hypothalamus.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0165032719307402

Decreased estrogen causes the role of estrogen in inducing choline acetyltransferase (ChAT) in basal forebrain and hippocampus down. The decrease in ChAT activity in the hippocampus causes the production of acetylcholine (ACh) in the hippocampus to fall, this may be marked by the decrease of several cholinergic markers, including AChE levels.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Black+Cummin+Extract+%28Nigella+sativa+Linn%29&btnG=

SRC1 (steroid receptor coactivator-1), SRC1-4, was identified to be the most favorable brain-relevant peptide for ERB.
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fasebj.2021.35.S1.01501

The mesencephalic dopaminergic neurons are chiefly under the control of testosterone via ARs or, to a minor extent, estradiol via ERB. The hypothalamic dopaminergic neurons are chiefly under the control of ERa and dopamine may cooperate with the kisspeptin system.
https://sci-hub.se/https://link.springer.com/article/10.1007/s12020-018-1593-5

3B-adiol has lately also been revealed to be a key means through which the neuroendocrine response to stress is modulated in males. 3B-adiol suppresses excessive hypothalamic-pituitary-adrenal (HPA) axis activation, which would otherwise promote depression and neurodegeneration.
https://lmreview.com/bio-identical-hormone-replacement-selecting-the-right-hormone-tests-for-your-male-patient/

The stellate ganglion was the network node that estrogen regulated cardiovascular system via the endocrine pathway and autonomic nerve pathway.
https://www.cabdirect.org/cabdirect/abstract/20153025331

- Chronic isolation (CPSI) decreased ERB and increased phospho-pERB in hippocampal mitochondria of both sexes.
- Reduced ERB paralleled with cyt c oxidase in males and Bax in females.
Impaired behaviour induced by CPSI was followed by decreased corticosterone (CORT) in both sexes and downregulation of cyt c oxidase in males. CPSI did not affect the ERa in either of sexes, but it decreased mitochondrial ERB and increased pERB in both sexes. Stress-reduced ERB is associated with a decrease in mitochondrial energetic processes in males and with apoptotic mechanisms in females.
https://www.sciencedirect.com/science/article/abs/pii/S0006899317302974

ERB controls ERa by inhibiting SP-1. ERB in adipose tissue differentiate toward the brown adipocyte phenotype, increases thermogenic capacity, increases mitochondria biogenesis and mitochondrial function, enhances fat/lipid burning process, inhibits ligand-mediated PPARG activation.
ERa increases adipogenesis and lipid deposition, activates PPARG, decreases lipolysis, induced glucose uptake via enhanced insulin stimulated GLUT4, increases angiogenesis via VEGF, reduces mitochondriogenesis and mitochondrial function.
https://www.mdpi.com/1422-0067/22/21/11720/htm

In MCF-7 cells, tamoxifen activates mitochondrial ERB as an antagonist to inactivate manganese superoxide dismutase which upregulates superoxide induced apoptosis.
https://assets.researchsquare.com/files/rs-1167112/v1_covered.pdf?c=1639668824

ERB can increase MnSOD expression.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Fish+Oil+and+Astaxanthin+Modulates+Lymphocyte&btnG=

Both MnSOD and ERB activation are associated with slower rates of cell proliferation and increased stress resistance.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Estrogen+Receptors+and+the+Mitochondrial+Antioxidant&btnG=

These data were supported by the higher expression levels of ERB in the gastric cancer than those in the gastric epithelial cell lines, and consistent with preventive effects of ERB on digestive system carcinogenesis.
https://www.nature.com/articles/s41416-018-0008-y

For example, the female/male ratio for slow-transit constipation is approximately 9:1; which suggests this might be linked to the higher prevalence of irritable bowel syndrome in women than in men because of the important role of the estrogen regulation in the GI tract. An increase in colonic permeability is associated with a decrease in ERB mRNA, this may lead directly to gut diseases (e.g., colon cancer, inflammatory bowel disease).
https://ir.canterbury.ac.nz/handle/10092/16577

Impairment of intestinal barrier function is linked to certain pathologies and to aging, and can be a cause of bacterial infections, systemic and hepatic inflammation, food allergies, and autoimmune disorders. The formation and maintenance of intestinal tight junctions is supported by glucagon-like peptide-2 (GLP-2), which boosts PI3K/Akt/mTORC1 signaling in enterocytes. AMPK activity as well as ERB activity are also protective in this regard. Conversely, activation of mitogen-activated protein kinases (MAPKs) and cellular Src (c-Src) under inflammatory conditions can induce dissociation of tight junctions.
https://academic.oup.com/advances/article-abstract/12/2/316/5944125

These findings indicate that targeted activation of ERB may represent a novel clinical approach for management of colorectal adenomatous polyps and prevention of colorectal carcinoma in patients at risk for this condition. We found that the antitumorigenic effect of ERB across different cell lines may be a combined result of cell cycle regulation; anti-inflammatory response regulation; increased DNA repair capacity and downregulation of oncogenes (PROX1, MYC, and MYB) and of the microRNAs cluster miR-17-92.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S030438351500748X

An interesting finding is that ERB was able to regulate the expression of cellular adhesion molecules, such as a-catenin and plectin, and likewise cytokeratin 20, a marker of differentiation. The study suggested lignans as possible regulators for maintenance of the normal colonic crypt-villus architecture in the inflamed bowel, through their ERB-agonism activity.
https://sci-hub.se/https://www.ingentaconnect.com/content/ben/cmc/2011/00000018/00000031/art00009

ESR2 is the predominant ER type in intestinal tract which inhibits A-type K+ currents of intestines smooth muscle cells and regulates the excitability of smooth muscle.
https://www.frontiersin.org/articles/10.3389/fphar.2018.01448/full

In conclusion, DHT appears to be protective against the progression of vascular inflammation through metabolism to 3B-diol and activation of ERB.
https://www.sciencedirect.com/science/article/abs/pii/S0039128X12001390

3B-Adiol reverts in vitro the TNF-a and LPS induced pro-inflammatory activation of endothelial cells and macrophages. 3B-Adiol in vivo modulates the inflammatory response induced by LPS in the arterial vascular wall.
https://www.sciencedirect.com/science/article/abs/pii/S002191501000393X

ERB-mediated antioxidative mechanisms may also contribute to antiapoptotic effects on cardiomyocytes by the reduction of calcium influx, and inhibition of apoptosis signal-regulating kinase 1 activity and its downstream targets including c-Jun N-terminal kinase and p38 mitogen-activated protein kinase.
https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Estrogen+receptor+%CE%B1+supports+cardiomyocytes+indirectly+through+post-infarct+cardiac+c-kit%2B+cells&btnG=

Here we show that estrogen can dose-dependently promote megakaryocyte (MK) polyploidization and maturation via activation of ERB, accompanied by a significant upregulation of GATA1, and ERB-mediated GATA1 upregulation subsequently enhances NFR2 expression, thereby promoting proplatelet formation and platelet release. Deficiency of ERB may cause myeloproliferative disease resembling chronic myeloid leukemia. In this study, for the first time, we demonstrate that estrogen can promote MK polyploidization via ERB-mediated upregulation of GATA1 and signal transducer and activator of transcription 1 (STAT1) activation. Estrogen can also repress the transcription of GATA1 through ERa, thereby inhibiting erythropoiesis.
https://www.nature.com/articles/leu2016285

ERB agonists might have clinical value in the treatment of leukemia. All female and male ERB–/– mice by 1.5 years of age developed a profound splenomegaly and lymphadenopathy. Spleen and bone marrow histology in ERB–/– mice revealed a significant increase in the number of megakaryocytes and in total cellularity.
https://www.pnas.org/doi/full/10.1073/pnas.0731830100

ERB agonists were successfully utilized to slow lymphoma growth and inhibiting lymphoma vascularization and dissemination. Lymphocytes and lymphoma cells mainly express ERB.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991487/

Chemotherapy-induced neuropathic pain (CINP) remains a major unmet medical need. We confirmed that ERB-selective agonists have antiallodynic effects in the spinal nerve ligation model of neuropathic pain. The efficacy and potency of ERB-agonists was greater in male rats than females.
https://pubs.acs.org/doi/abs/10.1021/acschemneuro.6b00183

There is a cross-talk between estrogen and opioid receptors. Naloxone modulates ERa activity directly as well as indirectly via MOR. Additionally, ERB is expressed in human vascular endothelial cells, and morphine down-regulates this receptor. ERa, but not ERB, is required for estrogen-induced MOR internalization, suggesting that ERa can mediate rapid actions of estrogen. GPR30 activation leads to hyperalgesia in rats and spinal nociception in mice, and is involved in mediating the rapid pronociceptive effects of E2. The downstream mechanisms involve cytosolic calcium increase, ROS accumulation, and neuronal membrane depolarization.
https://journals.sagepub.com/doi/10.1186/1744-8069-9-45

For example, 17B-estradiol (E2) facilitates heterodimerization of kappa and mu opioid receptors via a membrane estrogen receptor (ER)-dependent process. Opioid peptides exert antiestrogenic effects by interfering with AP-1-driven transcription. Thus, ERa and B could explain, at least in part, sex differences in pain sensitivity. GPER has an indisputable role in nociception via rapid steroid hormone signaling pathways.
https://www.frontiersin.org/articles/10.3389/fendo.2021.578250/full

The estrogen receptor antagonism predictions identified 9/14 drugs as moderate or strong estrogen receptor antagonists, including desvenlafaxine and most opioid receptor (OR) ligands.
The OR ligands have been reported to share structural similarities with ERa ligands and the cannabinoid d9?tetrahydrocannabinol has conflicting data in the literature related to interaction with ERs in vitro. OR agonists and cannabinoids are known to induce hypogonadism due to the central suppression of hypothalamic secretion of gonadotropin?releasing hormone, leading to decreased luteinizing hormone/follicle?stimulating hormone release and reduced gonadal hormone synthesis.
https://sci-hub.se/https://setac.onlinelibrary.wiley.com/doi/abs/10.1002/etc.4533

In tissues with low intracellular pH (more acidic), such as in cells of bone tissues, a greater activation of ERB would be expected. In neutral to basic intracellular pH, such as in tumor cells our results predict lower activation of ERB by E2.
https://www.nature.com/articles/s41598-017-03774-x

Estrogens play an important role in coordinating activities of osteoblasts and osteoclasts in bone homeostasis and preventing postmenopausal bone loss. Multiple lines of evidence suggest that activation of the tyrosine kinase c-Src represents one of the initial steps in ERa-mediated cell signaling.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0024320516300261

It is believed that the major action of estrogen on the skeleton in vivo is through the inhibition of bone resorption.
https://sci-hub.se/https://www.sciencedirect.com/science/article/abs/pii/S0024320516300261

ERB is protective for bone loss.
https://www.frontiersin.org/articles/10.3389/fimmu.2018.02279/full

Loading-induced increases in bone formation involve osteoblastic cell proliferation and down-regulation of Sost/sclerostin, a glycoprotein secreted primarily by osteocytes. Although increased ERB activity down-regulates basal Sost, the decreased ERB activity does not increase it. The effects of acute changes in strain or estradiol are mediated primarily by ERB. The functions of ERB may relate to the formation of post-proliferative matrix-secreting cells.
https://www.sciencedirect.com/science/article/pii/S0021925819350641

Thus, it appears that the pharmacology of ER ligands is reversed at an AP1 element with ERB: with ERB-AP1, the antiestrogens act as transcription activators, and the estrogens act as transcription inhibitors. Thus, when ERB is bound by the estrogen hormone E2 or the synthetic estrogen DES, it may function as a negative regulator of genes controlled by an ER-dependent AP1 element. Moreover, the ligand-induced responses with ERB at an AP1 site provide an example of negative transcriptional regulation by the natural hormone and strong positive regulation by synthetic antiestrogens.
http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.874.2182&rep=rep1&type=pdf

ERB inhibits cell cycle progression by increasing the expression of p21 in MCF-7 cells. The authors also reported that ERB inactivates Cdc2 by inducing it inhibitors, GADD45A and BTG2.
https://www.frontiersin.org/articles/10.3389/fphar.2016.00128/full

Over-expression of either wild type ERB1 or ERB1 mutated in the DNA-binding domain caused an arrest in early G1. This arrest was accompanied by the interaction of over-expressed ERB1 with c-Jun N-terminal protein kinase 1 (JNK1) and a decrease in c-Jun phosphorylation and cyclin D1 expression. Our results demonstrate that, in LNCaP prostate cancer cells, both ERB isoforms are differentially expressed during the cell cycle and that ERB regulates the G1 phase by a non-genomic mechanism.
https://www.hindawi.com/journals/acp/2008/129726/

Non-genomic signaling of estrogen involves a series of events that include mobilization of second messengers, interaction with membrane receptors, such as insulin like growth factor-1-receptor and epidermal growth factor receptor, and stimulation of effector molecules, such as the tyrosine kinase Src, PI3-K, Akt and MAPKs in various cell types.
https://www3.med.unipmn.it/Dottorato/Medicina_Molecolare/tesi-2011/I_sessione/DiVito_Clara_Tesi_dottorato.pdf

These data indicate that exposure to estrogen causes prostatic inflammation and directly links estrogen and prostatitis. AROM+ VPs revealed increased expression of ERa throughout the epithelial cells. AR, ERB, CKH and smooth muscle alpha-actin expression was unaltered. Chronic inflammation was found to emerge in the VP’s of the aromatase overexpression (AROM+) mice with aging and was characterized by a number of pathological patterns, including mononuclear lymphocyte-like cells and granulocytes throughout the stroma, as well as extensive infiltration and collection of macrophages, plasma cells, neutrophils, and some cellular debris within the lumen itself. This inflammation increased in incidence and severity with age. Mast cells are known to express ERa and are estrogen responsive. Mast cells have specifically been reported to mediate the recruitment of neutrophils and macrophages as well as the activation of T-lymphocytes, all of which were significantly increased in the chronic inflammation observed in the AROM+ animals.
https://www.sciencedirect.com/science/article/pii/S0002944010606281

Hormonally induced prostatitis in the rat may be an autoimmune disease. E2 -treated animals presented evidence of inflammation in terms of lymphocytic infiltration and presence of degranulated mast cells. Furthermore, we observed in these animals an increase in histamine-releasing peptide (HRP) levels, an indication of plasma extravasation. Our results demonstrate that hormonal imbalance and autoimmunity in male rats produce the symptoms of nonbacterial prostatitis.
https://www.auajournals.org/doi/abs/10.1016/S0022-5347%2801%2965548-4

17B-estradiol exhibits a tendency to increase COX-2 expression and prostaglandin E2 synthesis in primary human uterine microvascular endothelial cells.
https://www.spandidos-publications.com/ijmm/38/6/1642

Under hypoxic in vitro conditions, human prostate stromal cells in culture secrete increased levels of growth factors (such as FGF7 and TGF-B) than normoxic cells. The co-localization of ERB2 (ERBcx) and wild-type ERB1 in BPH tissues suggests that ERB2 might regulate ERB signaling in prostate cells. Suggesting that ERB-mediated apoptosis is mediated by TNF-a. Recently, aromatase mrna expression in prostate stromal cells derived from BPH tissues was found to be inducible by prostaglandin E2. These effects were abrogated by a CoX-2 specific inhibitor, suggesting that epithelial cells regulate aromatase expression in stromal cells via a paracrine mechanism that involves the secretion of prostaglandin E2. Prostaglandin E2-mediated regulation of aromatase in stromal cells has been further confirmed by another study demonstrating that ER-related receptor a (ERRa), an orphan nuclear receptor, upregulated aromatase expression in response to prostaglandin E2 in the prostate stromal cell line wPmY-1.
https://www.researchgate.net/profile/Fouad-Habib/publication/49749484_Estrogen_and_androgen_signaling_in_the_pathogenesis_of_BPH/links/5966a2380f7e9b80917ff59f/Estrogen-and-androgen-signaling-in-the-pathogenesis-of-BPH.pdf

Previous studies suggest a role for ERB in beta–cell function. ERB inhibited cell proliferation by decreasing the proportion of cells in S phase and increasing the proportion of cells in G2/M phase by inhibiting Akt phosphorylation thereby reducing cyclin D1 expression, and in turn downregulating phosphorylation of Rb. In breast cancer cell lines, ERB induced G2 cell cycle arrest by downregulating cyclin D1, cyclin A and c-myc expression thereby upregulating expression of p21 and p27, in a ligand-independent mechanism. In summary, we found that a subset of pancreatic neuroendocrine tumors, those with indolent behavior, have upregulated progesterone receptor and EIG121 mRNA expression, which may be regulated by ERB.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628823/

In COV434 cells stimulated with follicular fluid from post COVID-19 patients, steroidogenic acute regulatory protein (StAR), ERB, and VEGF expression were significantly decreased, whereas estrogen-receptor alpha and 3B-HSD did not change.
https://www.sciencedirect.com/science/article/pii/S0925443921002283

[Progecitor]

A POISer on reddit had great success with Oxazepam. This is clearly another proof that estrogen receptor beta agonists are the real way to treat POIS.
https://www.reddit.com/r/POIS/comments/12vu3dw/oxazepam_cured_my_case/

Drugs that modulate estrogen receptor beta (ERB)

Name 1 Nuclear Receptor 2 Binding Free Energy (kcal/mol)
ERB agonists:
Artemether AR; ERB -8.7(an); -9.6
Celecoxib ERa; ERB -9.6 and -9.9(an); -9.3
Conivaptan ERB; GR -9.5; -10.9 and -11.1(an)
Lorazepam ERB -9.6
Morphine ERa; ERB -9.4; -9.5
Naftifine AR; ERB -8.7(an); -9.5
Oxazepam ERB -9.4
Trihexyphenidyl AR; ERB -9.0(an); -9.3
https://www.mdpi.com/1420-3049/25/7/1616/htm

[Progecitor]

Additional phytoestrogens:

Research in this area is just beginning, but it appears that boron-containing compounds may beneficially modulate estrogen receptors, selectively binding to ER-beta.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712861/

ERa is known to be present in the uterus whereas ERB is predominantly present in bone. Genistein, which is one of the most typical isoflavones and is thought to have properties similar to those of ipriflavone, binds weakly with ERa but complexes with ERB nearly as well as estrogens. Arjmandi et al. speculated that ipriflavone binds to ERB and has positive effects on bone. The report of Kuiper et al. indicating that the estrogenic potency of phytoestrogens is significant, and more so for ERB than for ERa, supports this explanation. Ipriflavone may act in a fashion analogous to SERMs and has antiestrogenic effects on uterus, resulting in similar rates of reduction of uterine myoma node volumes with or without ipriflavone treatment. Effects of ipriflavone on bone mass, lipid metabolism, and menopausal symptoms may be estrogenic, and this SERM-like property may be the reason why ipriflavone has not affected observed reduction of myoma node volume, whereas it causes differences in bone mass, lipid metabolism, and menopausal symptoms.
https://academic.oup.com/jcem/article/86/7/3202/2848851

The results of this in silico study revealed that raloxifene and 23 compounds displayed agonist interaction toward ERB, and two of these compounds, namely catechin and epicatechin, were predicted agonist to ERB with binding values of -5.6 and -5.9 kcal/mol, respectively. These two compounds also showed the lowest toxicity.
Phytoestrogen can be found in several plants, such as Glycine max (soybean), Marsilea crenata, Pueraria montana (kudzu), Humulus lupulus (hops), Glycyrrhiza glabra (liquorice), Ipomoea batatas (sweet potato), Rheum rhabarbarum (rhubarb), and Vitex agnus-castus (chasteberry/monk's pepper).
According to literature studies, there are at least 39 compounds that can be classified as phytoestrogen, including catechin, epicatechin, genistein, kaempferol, luteolin, myricetin, naringenin, and quercetin.
The result of the molecular docking also revealed that raloxifene and the 23 compounds showed agonist interaction to ERB.
The molecular docking results of catechin and epicatechin were predicted to have the most potential to be developed into antiosteoporosis agent, not only because it has low toxicity, but also due to the similarity with 17B-estradiol.
Phytoestrogens that can bind to ERB will reduce the production of osteoclastogenic cytokines including TNF-a, IL-1, and IL-6. If the production of cytokines decreased, it can inhibit the occurrence of osteoclast differentiation process and become mature osteoclast, resulting in the inhibition of the bone resorption process. On the other hand, the bonding phytoestrogen with ERB can increase the production of OPG, which may inhibit the occurrence of RANKL-RANK bonds.
Catechin and epicatechin are the most potent and non-toxic antiosteoporosis compounds among the 39 phytoestrogens that act through an ER-dependent mechanism.
http://repository.uin-malang.ac.id/9528/1/9528.pdf

These results suggest that caffeic acid phenethyl ester (CAPE) induces pacemaker potential depolarization through ERB in a G protein, NSCC, Cl– channel, MAPK- and PI3 kinase dependent manner via intracellular and extracellular Ca2+ regulation in the murine small intestine. CAPE may therefore modulate GI motility by acting on ICCs in the murine small intestine.
https://cdnsciencepub.com/doi/abs/10.1139/cjpp-2019-0452

As estrogen signaling can be initiated by the binding of estrogenic chemicals with either ERa or ERB, there are cases in which preference or selectivity was observed: 17B-estradiol (E2) and diazene motifs exhibit preferential binding to ERa, whereas caffeic acid phenethyl ester, chlorogenic acid and gamma/delta-tocotrienol prefer ERB.
For example, caffeic acid phenethyl ester exhibited an affinity for ERB and increased ERE-dependent transcription, although no estrogenic activity was observed in cell or uterotrophic assays, suggesting the chemical to be a potential SERM.
https://www.mdpi.com/2072-6643/11/6/1401

Phytoestrogens in Chaste-berry are ERB-selective. Chaste-berry (Vitex) is a multifunctional herb belonging to the Verbenaceae family with phytoestrogenic properties. Also, Vitex is known for its antifungal, anti-androgenic, antibacterial, anticancer, antiseptic, and various biological activities such as antimicrobial and antioxidant properties.
Vitex consists of compounds such as vitexin, apigenin, and pendoltin, which are the most active phytoestrogen in Vitex fruits and mostly affect estrogen receptor beta (ERB). It also contains small amounts of linoleic acid, which can bind to alpha and beta estrogen receptors and stimulate ERB mRNA expression.
https://www.ivj.ir/article_172721_cfa20c42c472a5ac873e7de11e7b7e3f.pdf?lang=en

According to the study findings, Aloe vera, Foeniculum vulgare (fennel), Anethum graveolens (dill), Portulaca oleracea L (common purslane), Phoenix dactylifera (date palm) and Allium sativum (garlic) were effective on estrogen, A. graveolens, and P. dactylifera, on progesterone, and F. vulgare, and Vitex agnus-castus L. on prolactin. Out of these plants, A. graveolens, F. vulgare, and P. dactylifera exerted more pronounced effects on female hormones.
V. agnus-castus contains certain effective compounds including flavone-c-glycoside, casticin, omoorientin, orientin, isoorientin, isovitexina, isovitexin-glucoside, isovitexin-xiloside, and luteolin-7-glycoside. Indeed, anatole is the main constituent of F. vulgare plant that exhibits estrogenic properties.
https://www.researchgate.net/profile/Majid-Asadi-Samani/publication/309103717_The_medicinal_plants_effective_on_female_hormones_A_review_of_the_native_medicinal_plants_of_Iran_effective_on_estrogen_progesterone_and_prolactin/links/58357beb08ae004f74cc3d99/The-medicinal-plants-effective-on-female-hormones-A-review-of-the-native-medicinal-plants-of-Iran-effective-on-estrogen-progesterone-and-prolactin.pdf

Arctium lappa L. (common name-burdock) root is high in phenols, saponins, lignans, tannin, and flavonoids, according to phytochemical studies. The primary active compounds identified from this plant include arctigenin (ARG), tanin, arctiin, chlorogenic acid, caffeic acid, beta-eudesmol, trachelogenin, inulin, sitosterol-beta-D-glucopyranoside, diarctigenin and lappaol. Among them, two important lignans present in the roots, ARG and arctiin, are known to have anti-inflammatory, anti-allergic, anticancer, and anti-metastatic activities. Burdock leaves, fruit/seeds, and burdock roots are also used for various medicinal purposes. Arctigenin showed anti- depression and anti-anxiety-like properties in male ICR mice at 10 and 30 mg/kg which might possible to have protective action towards central nervous system. Arctigenin reduced infarct volume, neurological score, and brain water content and attenuated ischemic stroke induced neuroinflammation and NLRP3 inflammasome activation via the SIRT1 pathway.
https://www.researchgate.net/profile/Shalini-Singh-96/publication/366524547_Arctigenin_A_Potential_Component_with_Multifaceted_Therapeutic_Properties/links/63a962f9c3c99660eba7041a/Arctigenin-A-Potential-Component-with-Multifaceted-Therapeutic-Properties.pdf

Pharmacological activation of ERB by arctigenin maintains the integrity of intestinal epithelial barrier in inflammatory bowel diseases.
Arctigenin maintained the integrity of the intestinal epithelial barrier under IBD by upregulating the expression of tight junction proteins through the ERB-MLCK/MLC pathway.
https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.201901638RR

Through numerous preclinical studies (in vitro and in vivo), burdock has been found to exhibit a plethora of biological activities and pharmacological functions, including anti-inflammatory, anti-constipation, anti-cancer, management of male erectile dysfunction, angiogenic, antioxidant, ameliorating cerebral ischemia, and proapoptotic and antiangiogenic effects against breast cancer cells. These effects are mostly ascribed to its richness of arctiin, arctigenin, pectin, fructooligosaccharides, inulin, dicaffeoyl acids and fructofuranan, chlorogenic acid, cynarin, and flavonoids: rutin, myricetin, quercetin, apigenin, and kaempferol.
The European Medicines Agency (EMA) recommends the roots of Arctium lappa as adjunct therapy for seborrheic skin conditions and urinary tract infections.
As a component in the Chinese pharmacopoeia, Arctiin exerts traditional therapeutic actions, to “ease the throat, dissipate nodules, remove toxic materials, expel wind and heat”.
Arctigenin significantly decreased both total and nuclear AR (a key modulator of growth and progression of prostate cancer) expression as well as reduced the expression of multiple growth factors (VEGF, EGF, NGF-B, TNF-a, FGF-B, and PDGF-BB) in tumor tissues, leading to downregulation of proliferative signaling and upregulation of apoptotic signaling in tumors.
https://www.sciencedirect.com/science/article/pii/S0753332222014937

Among the 18 hits, 8 hits viz. berberine, cimicifugic acid G, cyanidin-3-glucoside, delphinidin-3-glucoside, epigallocatechin-3-gallate, flavopiridol, fangochinoline and flemingin C were found to putatively belong to SERM class.
Berberine - a benzyl isoquinoline alkaloid abundantly present in Goldenseal (Hydrastis canadensis) and flavopiridol – a flavo-alkaloid type of natural product possessed high docking scores (~ -60.00) than the threshold dock score for SERMs, owing to the interaction with CYS530, which is observed in fulvestrant. Similarly fangochinoline, a benzylisoquinoline alkaloid obtained from the roots of Stephaniae tetrandrine (Menispermaceae) showed a high dock score due to the absence of hydrogen bonding with ARG394. On the contrary, cyanidin-3-glucoside - an anthocyanin found commonly in the Roselle plant (Hibiscus sabdariffa, Malvaceae), the green tea polyphenol epigallocatechin-3-gallate and flemingin C - the prenylated chalcone from the Sarawak rainforest plant Desmodium congestum showed hydrogen bonding interactions with ARG394 and ASP351 and exhibited the dock scores at par with the SERMs. Likewise, cimifugic acid C, a dimeric phenylpropanoic acid derivative from Cimicifuga racemosa (Ranunculaceae) showed similar hydrogen bonding interactions and docking scores in the range of SERMs, with the only difference of showing an interaction with CYS530.
In this pursuit, 4 hits were found to belong in the ERa antagonist class including broussoflavonol B, sceptrin, silibinin, and soranjidiol. Amongst these, only soranjidiol - the photocytotoxic compound from Heterophyllaea pustulata showed a docking score close to that of fulvestrant. The hits silibinin - a major flavonolignan of the fruits of Silybum marianum, sceptrin - a bioactive marine isolate from the sponge Agelas conifera and broussaflavanol B – a flavanoid obtained from the bark of the Paper Mulberry tree (Broussonetia papyrifera) showed lower docking scores than fulvestrant.
Only one hit Arctigenin - a lignan found in the seeds of Arctium lappa showed a docking score and interactions exactly similar to that of letrozole.
Furthermore, Unkila proposed a lignan composition containing arctigenin, to inhibit the aromatase enzyme. These studies show that arctigenin can act in both ways – modulate the ER and inhibit aromatase; although clinical AIs still need to be proven for ER modulatory activity.
https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0039128X18300011

Studies have found that estradiol primarily improves memory deficits via activating ERbeta instead of ERalpha. On the other hand, activation of ERalpha is the main risk factor for cancer.
Royal jelly (RJ) contains fatty acids and sterols, including 10-hydroxy-trans-2-decenoic acid, 10-hydroxydecanoic acid, trans-2-decenoic acid, and 24-methylenecholesterol. These components have estrogenic activity and bind to ERB more selectively rather than ERa.
The various components of RJ have estrogen-like effects, such as 10-hydroxy-2-olenoic acid, 10-hydroxy succinic acid, trans-2-ylenic acid, and 24-methylene cholesterol.
Moreover, since RJ contains fatty acids and sterols with estrogenic activity acting on ERB, the beneficial effects of RJ on behavioral deficits may be caused via ERB activation.
https://www.mdpi.com/1420-3049/24/6/1149

Osthole can be also found in the Angelica herb. Of note Cnidium is regarded as an aphrodisiac.
To investigate the effects of osthole, a natural coumarin first derived from the Cnidium plant, on learning and memory, physiological and pathological changes, and expression of estrogen receptor (ER) alpha and beta in the brain of ovariectomized (OVX) rats of Alzheimer's disease (AD) models.
Effects on the estrogen pathway in the brain: the level of estradiol in the serum and expression of ERB in the hippocampus in the OVX alone were significantly lower, while the expression of ERa was higher, relative to the sham operation control; osthole at 25 mg/kg reversed the OVX-induced changes in expression of ERa and ERB. Therefore, osthole is potent in delaying the development of female neurodegenerative diseases, which provides a potential, new approach to treatment of female AD.
http://actanp.hebeinu.edu.cn/CN/abstract/abstract530.shtml

The two compounds were found to strongly stimulate the proliferation of MCF-7 cells. The estrogen receptor-regulated ERa, progesterone receptor (PR) and PS2 mRNA levels were increased by treatment with osthole and imperatorin. These results suggested that osthole and imperatorin could stimulate osteoblastic activity by displaying estrogenic properties or through the ER pathway.
https://www.sciencedirect.com/science/article/abs/pii/S1875536416300371

We found 18 plants (ashitaba, avocados, chinese mustard, chinese chive (yellow), chrysanthemum, dokudami, shantung greens, green soybeans, soybean seeds, soybean sprouts, hop, japanese pepper, kidney beans, kuromame, perilla, peas (immature), plantain, and pomegranate juice) expressing estrogenic activity in BG1Luc4E(2) cells.
We found that several plants (ashitaba, chrysanthemum, chinese mustard, chinese chive (yellow), Japanese pepper, perilla, and shantung greens) had weak estrogenic activity and ERa- and ERB-mediated transcription is equivalent in these plants. ERa-mediated estrogenic activity is dominant in the extracts of soybean seeds. ERB-mediated estrogenic activity is dominant in the extracts of soybean sprouts. These findings imply that phytoestrogenic substances differ between soybean seeds and sprouts.
https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0308814607002609

Acteoside (also a testosterone booster):
According to the Chinese Comprehensive Pharmaceutical Dictionary, it supplements renal function, increases sexual power, and smoothes the intestines. The extract has activities to improve brain functions, prevent aging or fatigue, and boost immune strength from test data accumulated in their long-term study. The main effective ingredients of Cistanche Tubulosa extract are phenylethanoid glycosides, especially echinacoside and acteoside. Although echinacoside is known as the main component of the herb Echinacea, Cistanche Tubulosa contains a higher amount of echinacoside than any other plant. Acteoside (a type of polyphenols) has an extremely strong antioxidative property which is reported to be 15 times stronger than resveratrol (polyphenols contained in grapes) and 5 times stronger than vitamin C). In recent study, new compounds (kankanoside and others) have been isolated) and vasorelaxing activity has been reported as a pharmacological action of the new compounds, echinacoside, and acteoside).
http://www.oryza.co.jp/html/english/pdf/Cistanche%20tubulosa%20ver1.0.pdf

Acteoside (AC, also named as verbascoside or kusagin), is abundant in many dicotyledonous plants, such as Oleaceae, Bignoniaceae, Verbenaceae, and Labiatae. AC has been reported to exhibit estrogenic effects, and it inhibits melanoma growth and inflammation by mediating ERB/Ras/Raf-1/STAT3 signaling. AC exhibits anti-estrogenic effects in ERa- and ERB-transfected HeLa cells. In addition, AC can reverse the effects of E2 by ERa.
Other plants mentioned to contain acteoside: Duranta erecta Linn., Plantago asiatica, TLR (leaves of Rehmannia) and DTG (Dihuangye total glycoside capsule) extracts, Abeliophyllum distichum, Callicarpa dichotoma, Ligustrum vulgare, Fufang Shatai Heji, Clerodendrum trichotomum, Stachytarpheta cayennensis, Pedicularis densispica, Ligustrum purpurascens kudingcha tea, Aloysia polystachya.
https://www.sciencedirect.com/science/article/pii/S0753332222006850

Compound Verbascoside can be found in S. cayennensis, Buddleja davidii, and Phlomis brunneogaleata as well as in olive oil mill wastewater.
https://sci-hub.st/https://pubs.acs.org/doi/abs/10.1021/acs.jnatprod.5b00875

Previous research established that the mechanisms of varicocele-induced (VCL-induced) testicular dysfunction include increased temperature, inflammatory cytokines, oxidative stress, endoplasmic reticulum stress, hormonal imbalance, and apoptosis. Verbascoside (VB), also known as acteoside, was first isolated from mullein (Verbascum sinuatum L.), and 23 other plant families. Concomitantly, compared with the VCL-vehicle group, all VB groups showed a marked increase in testosterone levels, while LH, FH, and GnRH levels exhibited significant reductions. After treatment with 50, 100, and 200?mg/kg VB, the LH, FH, and GnRH levels were significantly decreased while testosterone levels were increased. The testosterone, LH, FH, and GnRH levels in the group treated with VB at 200?mg/kg were close to those of the control group. The present study demonstrated the ability of VB to protect against VCL-induced testicular damage and dysregulation of the HPG axis in a VCL rat model.
https://www.tandfonline.com/doi/full/10.1080/13880209.2021.1933085

The results showed that acteoside inhibited melanoma growth, alleviated inflammation levels in mice, attenuated ROS and apoptosis levels in the spleen, downregulated the levels of CD31, survivin, Ras, Raf1, p-STAT3, and Bcl-2, and upregulated the levels of ERB, Bax, cleaved caspase-3, and cleaved caspase-9. Moreover, the effect of acteoside was blocked by ICI182,780.
Acteoside is a water-soluble phenylpropanoid glycoside which can be extracted from Chinese herbal medicines such as Rehmannia glutinosa, Cistanche cistanche, and Pedicularia gansuensis.
Acteoside and docetaxel promoted the expression of ERB and inhibited the expression of p-STAT3.
The estrogen receptor beta (ERB), as a member of the nuclear receptor superfamily, has shown potent tumor-suppressive activity in many cancers. Clinical studies have shown that ERB, but not ERa, is the predominant ER subtype in melanoma tissues and its expression decreases as melanoma progresses, supporting its role as a tumor suppressor. Therefore, natural compounds with estrogenic activity may have an inhibitory effect on melanoma. This indicated that acteoside may activate the apoptotic pathway through the ERB-Ras/Raf1-STAT3 axis and promote tumor cell apoptosis.
https://www.sciencedirect.com/science/article/abs/pii/S0003986121002277

Acteoside and martynoside exhibit estrogenic/antiestrogenic properties. Its antiproliferative effect on endometrial cells suggests that martynoside may be an important natural SERM. Acteoside was an antiestrogen in breast cancer cells and osteoblasts, without any effect on endometrial cells. Our results indicate that the phenylpropanoid glycosides acteoside and martynoside may act as estrogen antagonists mainly via ERalpha. In light of the above, we hypothesize that the coexistence of various compounds in plant extracts acting either as agonists via the ERB pathway or antagonists via the ERa pathway, may result in combined/synergistic actions in preventing breast cancer. Similar to our results, novel plant-derived compounds, different from the known phytoestrogens have also been reported to act via the ERa and ERB subtypes. For example, a component of ginseng saponin (a ginsenoside), a 4-ethoxymethylphenol, some catechins, and the phytochemical lindleyin may act as agonists/antagonists of estrogens via the ERa and ERB pathway, depending on their concentration and tissue type.
https://www.sciencedirect.com/science/article/abs/pii/S0960076005003675

The results indicated that verbascoside and martynoside have the potential of antagonizing sports anaemia, the mechanism of this effect might be related to preventing RBC from free radical damage. Moreover, verbascoside was found to be more active than martynoside.
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0030-1254115

The major isolates in lemon verbena oil are citral (30–35%), nerol, and geraniol. Extracts of lemon verbena also contain verbascoside.
https://en.wikipedia.org/wiki/Aloysia_citrodora

White dead nettle expresses a wide spectrum of therapeutic activities which are attributed to a variety of biologically active substances such as iridoids, flavonoids, phenolic acids, isoscutellarein derivatives, terpenes, phytoecdysteroids and essential oils. In the aerial part of L. album three phenylethanoid glycosides, verbascoside (acteoside), isoverbascoside and lamalboside were identified.
Investigations on plant phytoecdysteroids in aerial part of L. album revealed four ecdysteroids: abutasterone, inokosterone, polypodine B and pterosterone. Phytoecdysteroids display a wide array of beneficial pharmacological effects on vertebrates. These compounds stimulate protein synthesis and immune response, reduce the concentration of cholesterol and glucose in blood vessels and have antimutagenic, antioxidant and wound healing activity. The cytoprotective effect of L. album ethanol extract seems related to the presence of the major phenol compound verbascoside (50 lg/ml) that counteracted by 49 % the decrease in cell reducing activity induced by 200 lM potassium dichromate. The involved mechanism of cytoprotection of verbascoside is rather independent from its ROS scavenging action whereas other polyphenols as naringenin, apigenin and luteolin dominate with higher antioxidant potential.
https://sci-hub.st/https://link.springer.com/article/10.1007/s11101-014-9356-2

The major components of dill are flavonoids, phenolic compounds and essential oil. This herb also consist kaempferol, trans-anethole and limonene which show phytoestrogenic properties.
A. graveolens extract both in low dose and high dose increased estrous cycle duration and progesterone concentration and induced infertility. This indicates that the estrogenic property of dill is high enough to suppress the normal estrous cycle. Dill essence or estradiol both showed beneficial effects on memory performance.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852659/

Aucubin is an iridoid glycoside. Iridoids are commonly found in plants and function as defensive compounds. Iridoids decrease the growth rates of many generalist herbivores. Aucubin, as other iridoids, is found in asterids such as Aucuba japonica (Garryaceae), Eucommia ulmoides (Eucommiaceae), Plantago asiatica, Plantago major, Plantago lanceolata (Plantaginaceae), Galium aparine (Rubiaceae) and others. These plants are used in traditional Chinese and folk medicine.
Agnuside is composed of aucubin and p-hydroxybenzoic acid. Aucubin was found to protect against liver damage induced by carbon tetrachloride or alpha-amanitin in mice and rats when 80 mg/kg was dosed intraperitoneally.
https://en.wikipedia.org/wiki/Aucubin

The Chinese yam and two main compounds, adenosine and arbutin, have estrogen-like effects. The mechanism of the yam which plays a role in its estrogen-like effects was mainly mediated by the estrogen receptors ERa, ERB, and GPR30; that of adenosine was mainly mediated by estrogen receptors ERa and ERB, and that of arbutin was mainly mediated by estrogen receptors ERB and GPR30. Arbutin—which is mainly extracted from leaves of the Bearberry and is also found in some fruits and other plants— is a hydroquinone glycoside.
https://www.mdpi.com/1420-3049/23/2/11

Arbutin has been found in species of several plant families, for example in the Rosaceae (Pyrus communis L., Lamiaceae (Origanum majorana L., Myrothamnaceae (Myrothamnus flabellifolia Welw.) and Ericaceae (e.g. Vaccinium spp. or Arctostaphylos uva-ursi L.. Although in plants the content of arbutin can reach considerable amounts, up to 25% of the dry weight in leaves of M. flabellifolia or up to 17% in the widely used A. uva-ursi, its physiological and ecological functions are still under discussion. The arbutin-rich leaves of A. uva-ursi (bearberry) are internally used for moderate inflammatory conditions of the urinary tract and bladder. In both cases the active principle is hydroquinone, a metabolite of arbutin. Arbutin, however, could also exhibit adverse effects, as its metabolites showed hepatotoxic, nephrotoxic, mutagenic and carcinogenic potentials in animal studies. Furthermore, a hypothesis was published linking phenol and hydroquinone as causal factors for leukaemia. For this reason the therapeutic use of A. uva-ursii is always restricted to a short period.
Within the genus Origanum the formation of arbutin seems to be polymorphic, with arbutin present in considerable amounts (O. majorana) or completely absent (O. vulgare).
https://www.sciencedirect.com/science/article/abs/pii/S0308814609014319

Chlorogenic acid is an ester of caffeic acid and quinic acid, and was found to exhibit estrogenic activity, although weak or too weak to be detected by other assays. In contrast to quinic acid, which is a cyclic polyol unlikely to have estrogenic activity, caffeic acid is likely estrogenic, although this has not been confirmed. Estrogen-dependent activities can sometimes appear as anti-estrogenic activity or modulator activities, as with selective estrogen receptor degraders (SERDs) and selective estrogen receptor modulators (SERMs), which are shown by a cinnamic acid ester/moiety or caffeic acid phenethyl ester.
Similarly, other acids found in coffee, such as ferulic acid/isoferulic acid, hippuric acid, sinapic acid, and vanillic acid, exhibited estrogenic/anti-estrogenic activity. Gallic acid is a phenolic acid with three hydroxyl groups and may therefore function in the estrogenicity, as observed for octyl gallate; however, because of its simple structure, its estrogenic activity was unclear.
Humic substances are mainly composed of humic and fulvic acids, and lead to a decrease in estrogenic activity, as demonstrated in ER-dependent assays.
Its degradation products thus may have estrogenic activity through ER-binding, whereas lignin was demonstrated to have anti-estrogenic activity through direct binding to estrogens, like humic acids (see above), by inhibiting the reabsorption of estrogens in the intestine, thereby decreasing plasma estrogen levels.
Caffeine is a well-known constituent in coffee and is known for its health benefits due to its estrogenic effects; neuroprotective effects by estrogenic activity and cancer chemopreventive effects by anti-estrogenic activity, for example. Other nitrogenous compounds, including their derivatives, such as nicotinic acid (niacin), serotonin amides, theophylline, and trigonelline, are also estrogenic/anti-estrogenic and may function in cardioprotection, neuroprotection, cancer chemoprevention, and bone protection.
Terpenes and terpenoids are an important category of components of coffee oil, and are associated with estrogenic activity. Sterols were reported to exhibit estrogenic/anti-estrogenic activity, such as beta-sitosterol and stigmasterol. Other types of terpenes included in coffee, such as gamma/delta-tocopherol and gamma/delta-tocotrienol, are also estrogenic/anti-estrogenic. Lecithin is an important component of coffee and may exhibit numerous biological effects, although, due to its complex chemical composition, it has not been well-studied. Soy lecithin was found to be estrogenic and leads to the estrogenic activity of chocolate.
17B-estradiol (E2) and diazene motifs exhibit preferential binding to ERa, whereas caffeic acid phenethyl ester, chlorogenic acid and gamma/delta-tocotrienol prefer ERB.
Note that some chemicals demonstrated biphasic effects, such as beta-sitosterol, which is estrogenic at low doses and anti-estrogenic at high doses.
For example, caffeic acid phenethyl ester exhibited an affinity for ERB and increased ERE-dependent transcription, although no estrogenic activity was observed in cell or uterotrophic assays, suggesting the chemical to be a potential SERM. Among phenolic acids and phenolic esters found in the plant black cohosh, which has been used for the treatment of menopausal syndromes, ferulic and isoferulic acids were found to be slightly estrogenic. Due to strong estrogenic activity without mutagenic activity, stigmasterol was considered to be a good candidate for estrogen replacement therapy.
Several coffee constituents were reported to act as SERMs, such as caffeic acid phenethyl ester, cinnamic acid (moiety), and diazenes (motifs). SERDs, on the other hand, are a class of substances that inhibit ER functions by binding to and degrading the ER. Cinnamic acid (moiety) was also reported among SERDs.
https://www.mdpi.com/2072-6643/11/6/1401

One of these is trigonelline (Trig), a niacin-related compound. After caffeine, Trig is the second most abundant alkaloid compound in raw coffee beans and makes up ?1% of the dry matter of roasted coffee beans. Trig induced the reporter, suggesting that not only can it activate the receptor, but it also induces the molecular action of ERa, the predominant form of the receptor in MCF-7 cells.
https://academic.oup.com/jn/article/139/10/1833/4670305

Apigenin (4‘,5,7-trihydroxyflavone), a naturally occurring flavone, is widely distributed in many fruits and vegetables, such as parsley, chamomile, celery and kumquats.
Dried parsley is the richest source of apigenin, containing 4503.5 mg/100 g, respectively. Other sources such as chamomile (dried flower) contain 300-500 mg/100 g, celery seed 78.65 mg/100 g, vine spinach 62.2 mg/100 g, and Chinese celery 24.02 mg/100 g. Other than apigenin, various glycosylated derivatives (e.g., apiin and apigetrin) and dimers of apigenin such as amentoflavone (3?,8??-biapigenin) have been found in natural sources.
Other popular and ample sources include grapefruits, onions, oranges, parsley, chamomile tea. It is also found at high levels in celery, yarrow, tarragon, cilantro, passion flower, horehound, basil, foxglove, oregano, licorice, flax, coneflower, Chinese cabbage, bell pepper, garlic, and guava. It is also found in red wine, beer, wheat sprouts and is an active ingredient in the memory herb Ginkgo biloba.
Apigenin can also inhibit the estrogen receptor-alpha (ERa)-dependent pathway through downregulating protein levels of ERa and ‘amplified in breast cancer-1’ (AIB1).
https://www.researchgate.net/profile/Ramesh-Pandey-2/publication/270824089_Dietary_Sources_Bioavailability_and_Biological_Activities_of_Naringenin_and_its_Derivatives/links/5641440b08aec448fa607288/Dietary-Sources-Bioavailability-and-Biological-Activities-of-Naringenin-and-its-Derivatives.pdf#page=87

Tibolone Reduces Oxidative Damage and Inflammation in Microglia Stimulated with Palmitic Acid through Mechanisms Involving Estrogen Receptor Beta Estrogen receptor beta (ERB) inhibition partially dampened tibolone’s protective actions in BV-2 cells stimulated with palmitic acid. In conclusion, tibolone protects BV-2 cells by a mechanism involving ERB and upregulation of neuroglobin.
https://link.springer.com/article/10.1007/s12035-017-0777-y

Ecdysteroids (EDs) are a group of steroid hormones that occur naturally in plants and insects. Nowadays, more than 550 EDs have been identified and classified on the basis of their natural origin as phyto-, zoo-, and myco-ecdysteroids. Certain plant families such as Asteraceae, Liliaceae, Lamiaceae, Magnoliaceae, Basellaceae, Podocarpaceae, Commelinaceae, Ranunculaceae, etc. contain phytoecdysteroids (PEs), including species such as Rhaponticum carthamoides Willd. (R. carthamoides), Podocarpus nakaii, Serratula coronate, Ajuga turkestanica (Regel) Briq. (A. turkestanica), Cyanotis arachnoidea C.B.Clarke (C. arachnoidea), etc.
These plants have been used since ancient times for their adaptogenic and tonifying effects, to promote muscle growth, and for their antioxidant properties. Among the complex of PEs found in these plants are 20-hydroxyecdysterone (ecdysterone), turkesterone, ponasterones A, B, and C, ajugasterone C, polypodine B, etc. The dominant PEs in R. carthamoides, A. turkestanica, and C. arachnoidea are 20-hydroxyecdysterone and turkesterone. Guibolt et al. reported that A. turkestanica contains approximately 70% of all isolated PEs as turkesterone, while the amount of ecdysterone is about 10 times less. In R. carthamoides, the content of 20-hydroxyecdysterone is in the range of 0.04–1.51% of the plant dry matter. These PEs—ecdysterone and turkesterone—have been associated with several biological effects, such as anabolic, neuroprotective, antidiabetic, and antihyperlipidemic. Ecdysteroids have been recognized for their pharmacological properties, particularly their ability to enhance physical performance through beneficial changes in body composition and anabolic effects, mediated by the activation of beta-estrogen receptors.
https://www.mdpi.com/2227-9717/11/6/1786

Moreover, Radix rehmanniae extract (RRE) restored and even enhanced ERB expression levels in uterus and brain without affecting uterine, hippocampal and cortical ERa.
This study demonstrated the antidepressant and anxiolytic effects of RRE in OVX mice, which were possibly mediated via their modulation of brain neurotransmitters, and regulation of neurotrophins and activation of ERB.
https://www.sciencedirect.com/science/article/abs/pii/S0944711319301783

These results suggest that alpha-lipoic acid may up-regulate the expression of ERa and ERB that was diminished during the development of atherosclerosis.
https://karger.com/cpb/article/47/6/2261/75613/Alpha-Lipoic-Acid-Protects-Human-Aortic

(The lower the Ki value the stronger the binding.)
Based on in silico study, orientin had the lowest deltaG and Ki values compared to 17-? estradiol and tamoxifen. Orientin and galactomannan showed similar features according to pharmacophore fit results and modeling. In conclusion, orientin and galactomannan perform the best synergistic activity with ERa and ERB.
Fenugreek has also performed an antidiabetic activity due to a huge amount of galactomannan fibre in its seeds. Fenugreek is a natural source of iron, sodium, thiamine. The primary biologically active ingredients of fenugreek are steroidal sapogenins (diosgenin, yamogenin, gitogenin, tigogenin), alkaloid (trigonelline), flavonoid (quercetin, vitexin, isovitexin, orientin, isoorientin) and a nonproteinogenic amino acid '4-hydroxyisoleucine'. Some ingredients i.e., trigonelline and 4-hydroxyisoleucine, are believed to able to bind to the estrogen receptors.
https://www.proquest.com/openview/f7db60a90621cc21029068d43880b456/1?pq-origsite=gscholar&cbl=54977

Orientin is a glycosyl flavonoid found in rooibos tea and passion fruits, bamboo leaf and basil herb.
https://scholar.google.com/scholar?hl=hu&as_sdt=0%2C5&q=Orientin+inhibits+invasion+by+suppressing+MMP-9+and+IL-8+expression&btnG=

Salvia miltiorrhiza bunge at 10 ug/mL induced a 2.58-fold increase in ERa and a 20.31-fold increase in ERB luciferase activity.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310662/

Taken together, the results show that Salvia miltiorrhiza induces pacemaker potential depolarization through ERB in a G protein-dependent manner via extracellular Ca2+ and Na+ regulation in the murine small intestine in vitro.
https://www.spandidos-publications.com/10.3892/mmr.2021.11987

Poplar buds and their secretions (resins) are plant materials very rich in phenolic compounds. For this reason, studies on bioactive compounds of poplars focus on the raw material of buds.
The bioactive phenols in extracts were p-coumaric acid, pinocembrin, galangin, pinostrobin, pinobanksin and chrysin. Among the identified flavonoids in ethanol–water extracts from P. nigra resins, chrysin (15.2–28.9 mg/L) and pinocembrin (19.7–23.5 mg/L) occurred at the highest concentration.
https://link.springer.com/article/10.1007/s00468-019-01837-2

[sartre02]

are you implying that SERMS like arimidex is the solution?!!