Key Intracellular Doorway Revealed That Facilitates The Many Miraculous Properties Of Resveratrol
Resveratrol, the much dismissed but underused red wine molecule, purported to produce near-miracle cures, yet written off as being non-bioavailable and largely shunned in medical practice, exhibits an unparalleled range of biological activities, such as:
… that also induces a transient gas (nitric oxide) that in turn dilates (widens) constricted blood vessels.
By virtue of the above nitric oxide effect, activates internal enzymatic antioxidants (glutathione, catalase, superoxide dismutase) that limits or completely prevents damage to heart muscle and brain tissue due to lack of oxygen should a heart attack or stroke occur (called preconditioning).
To the astonishment of biologists, resveratrol simultaneously inhibits abnormal blood vessels to avert the loss of vision at the back of the eyes (retina) while activating new blood vessels in an oxygen-starved heart to produce life-saving collateral circulation.
But that is not all. There is a missing component of resveratrol that is just now being revealed.
Overlooked mechanism
Another scientifically well-established but overlooked mechanism of resveratrol as a so-called weak phyto (plant)-estrogen (1/7000th the activity of estrogen) is its ability target a cellular doorway called the ESTROGEN RECEPTOR.
As background information, living cells have receptors (proteins) on their surface that bind to molecules outside the cell and send signals to internal cellular machinery.
For example, the vitamin D receptor binds to vitamin D. (Of interest, resveratrol sensitizes/optimizes the vitamin D receptor.) There are cannabinoid receptors that facilitates the biological activity of hemp/cannabis/marijuana, which suggests an inherent place for these molecules in medical practice. (Resveratrol also molecularly tickles the cannabinoid receptor.)
Unlike cell receptors on the surface of cells, the ESTROGEN RECEPTOR is a protein binder to estrogen that is located inside cells. The estrogen receptor influences genetic machinery inside the nucleus of the cell.
Estrogen (aka estradiol) is a small molecule (molecular weight 272.38 Daltons) that can pass through cell walls to reach the cell nucleus where estrogen receptors are located. Resveratrol is also an estrogen-like small molecule (228.25 Daltons)
The estrogen receptor sends a growth signal to cells.
Levels of estrogen are very high in pregnancy when women “grow” a baby from within. After childbearing years (menopause) this growth signal facilitated by the estrogen receptor may be problematic as it could encourage the growth of tumors, particularly in breast and other female sex organs.
Anti-estrogen drugs like Tamoxifen and Raloxifene have been introduced to counter the growth signal that is sent to cells via the estrogen receptor. However, the complete blockage of estrogen would be problematic given that estrogen is essential for brain function and would result in mental disturbances.
Estrogen signaling is not only involved in disease but also in maintaining health, particularly in bone, heart, colon, brain, prostate, and female sex organs. Many women fear estrogen replacement therapy in their menopausal years because of its untoward effects. Resveratrol may be the best alternative to estrogen.
Resveratrol as super-inducer of the estrogen receptor
Resveratrol is described as a “super-inducer” of the estrogen receptor.
There are two estrogen receptors: ER-alpha and ER-beta. There is a subtle but substantial difference in the biological actions produced by these two cell receptors.
Biologists say the primary function of ER-alpha seems to be for reproduction while ER-beta is primary for mental processing. ER-alpha primarily contributes to masculinization while ER-beta is reported to contribute to the de-feminization of sexual behavior. These may be oversimplifications. When the Estrogen Receptor is experimentally knocked out of laboratory animals, aggressive behavior and mental depression arises.
There are many health benefits derived from activating/sensitizing or blunting estrogen receptors. Resveratrol seems to sort out just which direction to go.
Phyto-estrogens in lieu of estrogen
The antioxidant activity of plant estrogens (phyto-estrogens) are found to allay skin aging. However, the primary mechanism of action of these antioxidants is to activate the estrogen B receptor which in turn activates internal antioxidant enzymes. Therefore, phyto-estrogens provide a treatment option for aging skin without the potential safety issues of estrogen.
Resveratrol as super inducer of the estrogen receptor
Even though estrogen promotes tumor growth via the ER-alpha receptor, resveratrol influences the ER-alpha receptor without growth stimulation. Like estrogen, resveratrol blunts inflammation and improves metabolism (sugar/calorie burning).
The phytoestrogen resveratrol activates the heralded Sirtuin1 survival gene via the estrogen receptor.
Let’s briefly tabulate the many health properties of resveratrol as a phytoestrogen that operates via the estrogen receptor.
- Estrogen and resveratrol switch on genes by binding to a protein known as an estrogen receptor. Resveratrol has been found to produce greater activation of some estrogen-regulated genes than estrogen itself.
- Phytoestrogens and resveratrol in particular are considered safer alternatives to hormone replacement therapy.
- When eight different plant estrogens were tested, all except resveratrol exhibited the same cell growth promotion as estrogen.
- Only low-doses of resveratrol are required to activate/sensitize Estrogen Receptors.
- Resveratrol binds to ER-alpha and ER-beta at 7000-fold lower affinity than estrogen. This speaks for its safety.
- Resveratrol acts both as an activator/sensitizer for both ER-alpha and ER-beta cell receptors in the absence of estrogen; but in the presence of estrogen it is an anti-estrogen. This has been demonstrated in human breast cancer cells.
- Via the estrogen receptor, resveratrol inhibits the aromatase enzyme that converts testosterone to estrogen. Therefore resveratrol inhibits feminizing effects of estrogen or estrogen-like molecules in the environment (e.g. bisphenol A, phthalates).
- Via both ER-alpha and ER-beta, resveratrol inhibits tumor growth by virtue of its ability to increase cell die off (apoptosis) and inhibit growth factors and new blood vessel formation (angiogenesis) that facilitate the feeding of tumors.
- In the animal lab, resveratrol acts as a tumor suppressor in the prostate gland via ER-beta.
- Activation of the estrogen receptor is “crucial” for resveratrol’s ability to normalize blood sugar levels.
- Even in estrogen receptor negative breast cancer cells, resveratrol inhibits growth factors.
- Estrogen is known to relax constriction of blood vessels. An estrogen receptor inhibitor blunts but resveratrol reverses this deleterious effect.
- Estrogen and resveratrol via estrogen receptor alpha (ER-alpha) facilitate the production of nitric oxide gas that dilates (widens) blood vessels.
- Resveratrol exhibits ability to restore blood circulation to narrowed arteries (stenosis) predominantly through an estrogen receptor dependent increase in nitric oxide gas.
- Part of red wine’s ability to produce nitric oxide gas which dilates (widens) blood vessels is achieved via resveratrol’s action on Estrogen Receptors.
- Low doses of combined polyphenols (resveratrol, quercetin, catechin) inhibit breast tumor growth via modification of the estrogen receptor.
- In a laboratory dish study, resveratrol prevented the silencing of the Breast Cancer BRCA-1 tumor suppressor gene via Estrogen Receptor Alpha.
- Phytoestrogens may enhance the growth of tumor cells similar to estrogen. While resveratrol inhibits the growth of breast tumor cells, it did so even though Estrogen Receptor Alpha was silenced (negated), thus making resveratrol “a promising candidate for hormone replacement therapy … due to its inexplicable estrogenic activity yet high antitumor activity.”
- Female lab rats whose ovaries were experimentally removed and then given estrogen replacement + sugar (galactose) exhibit significant memory impairment. Resveratrol as an estrogen receptor modulator prevented this memory decline and prevented deleterious changes in the uterus as well.
- Resveratrol induces dopamine transporter in brain cells. Dopamine is a nerve transmitter responsible for memory. Estrogen receptors are involved in the increased production of dopamine via activation by resveratrol.
- In an animal study resveratrol reduced the deposition of beta amyloid plaque in the brain and reduced ER-beta while increasing ER-alpha and estrogen itself and could be used for treatment of Alzheimer’s disease.
- Both types of estrogen receptors provide maximum protection for brain cells, more so ER-beta than ER-alpha.
- Resveratrol protects the brain of lab animals that have had their ovaries surgically removed, similar to the predicament post-menopausal women find themselves in. This protective effect is mediated by Estrogen Receptors and is associated with tightening of the protective blood-brain barrier. Therefore, resveratrol is an alternative to estrogen replacement therapy.
- Resveratrol has been found to inhibit fatty liver (steatosis) through an estrogen receptor alpha pathway.
- Resveratrol, operating via the estrogen receptor, improves bone mass density as well as estrogen and is a potential remedy for osteoporosis.
- Novice investigators may discover negative lab dish studies involving resveratrol and its estrogenic effects. Lab dish (in vitro) studies differ for resveratrol from live animal studies (in vivo). Resveratrol has little or no affinity for estrogen in reproductive and non-reproductive tissues.
- In pre-menopausal women, internally produced estrogen is associated with reduced prevalence for coronary artery disease, heart attack, stroke and high blood pressure, whereas synthetic estrogen drugs adversely affect cardiovascular health. As an inhibitor of estrogen, resveratrol mitigates the adverse effects of hormone replacement therapy via Estrogen Receptors.
- Males have their own receptor for testosterone. Resveratrol represses the androgen receptor and is a suggested agent to prevent prostate cancer. Inexplicably, the protective effect of resveratrol in the androgen receptor involves biological activity separate from its degree of receptor binding. Mega-dose resveratrol has no effect on testosterone levels. In women, resveratrol inhibits testosterone.
- Of considerable interest is that the ER-beta receptor has been found to be controlled by the light-dark clock, peaking at the period of transition from light to dark.
