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Message Subject CREB: The Transcription Factor That Thirsts After Your Soul! (Propped Up by the Pillars of Illness)
Poster Handle deluded_dawn_drizzle
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And so it comes together. Licorice root can gradually lay an anhedonic framework (as in my case) by temporarily inhibiting CREB phosphorylation through its phytoestrogenic activity.

Predictably, phytoestrogens are generally calcium antagonistic. [link to content.onlinejacc.org]

Cocaine, as an indirect dopamine agonist, induces selective behavioral and physiological events such as hyperlocomotion and dopamine release. These changes are considered as consequences of cocaine-induced molecular adaptation such as CREB and c-Fos. Recently, methanolic extracts from licorice was reported to decrease cocaine-induced dopamine release and c-Fos expression in the nucleus accumbens. In the present study, we investigated the effects of liquiritigenin (LQ), a main compound of licorice, on acute cocaine-induced behavioral and molecular changes in rats. LQ attenuated acute cocaine-induced hyperlocomotion in dose-dependent manner. In addition, LQ inhibited CREB phosphorylation and c-Fos expression in the striatum and the nucleus accumbens induced by acute cocaine. Results provide strong evidence that LQ effectively attenuates the acute behavioral effects of cocaine exposure and prevents the induction of selective neuroadaptive changes in dopaminergic signaling pathways. Further investigation of LQ from licorice extract might provide a novel therapeutic strategy for the treatment of cocaine addiction.
 Quoting: [link to citeseerx.ist.psu.edu]


This study shows the same phytoestrogen inhibiting COX-2 expression [link to www.ncbi.nlm.nih.gov] by "modulating" ERK1/2 signaling, which activates CREB (which is how cortisol upregulates COX-2). [link to www.ncbi.nlm.nih.gov]

Isoliquiritigenin is also an NMDAR antagonist [link to www.researchgate.net] - a property which would potentiate its ability to inhibit calcium influx.

Phytoestrogens Inhibit Growth and MAP Kinase Activity in Human Aortic Smooth Muscle Cells
[link to hyper.ahajournals.org]

All of this sounds nice, but the price is inevitably enhanced signaling of these CREB-supporting pathways (as I've felt first hand).

CREB activation/calcium influx increases nitric oxide production. [link to www.pnas.org]
Not only does the phytoestrogen genistein directly activate cAMP signaling, the role of the cAMP messenger system in estrogen's facilitation of calcium influx activating CREB suggests that this is not the only mechanism by which it upregulates NO production [link to jn.nutrition.org] (i.e. estrogen receptor upregulation).

Other xenoestrogens though, like BPA, appear to be outright estrogenic and thus provide some blatantly undesirable effects.

Xenoestrogens are potent activators of nongenomic estrogenic responses
[link to www.ncbi.nlm.nih.gov]

Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-alpha-mediated Ca2+ fluxes and prolactin release in GH3/B6 pituitary tumor cells.
[link to www.ncbi.nlm.nih.gov]

Bisphenol A stimulates human lung cancer cell migration via upregulation of matrix metalloproteinases by GPER/EGFR/ERK1/2 signal pathway.
[link to www.ncbi.nlm.nih.gov]

MAPK and NF-KB Pathways Are Involved in Bisphenol A-Induced TNF-a and IL-6 Production in BV2 Microglial Cells.
[link to www.researchgate.net]

Moral of the story?

Certain xenoestrogens are unapologetic haymakers, and phytoestrogens are insidious little devils to avoid resolutely if you value your health & hedonic resonance.
 
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