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CREB: The Transcription Factor That Thirsts After Your Soul! (Propped Up by the Pillars of Illness)

 
deluded_dawn_drizzle
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02/12/2015 01:09 AM
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CREB: The Transcription Factor That Thirsts After Your Soul! (Propped Up by the Pillars of Illness)
In a sense.

I figured this bad boy deserved its own thread. Considering the confusion surrounding "depression," a smidge of clarity would be nice.

Okay, so first thing's first. When D1 receptors are overstimulated, well, you're on your weary way to CREB-courted catastrophe!

Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1.
[link to www.ncbi.nlm.nih.gov]

Roles of Nucleus Accumbens CREB and Dynorphin in Dysregulation of Motivation
[link to perspectivesinmedicine.cshlp.org]

Activation of CREB in the nucleus accumbens shell produces anhedonia and resistance to extinction of fear in rats.
[link to www.ncbi.nlm.nih.gov]

Cyclic AMP-mediated signaling components are upregulated in the prefrontal cortex of depressed suicide victims.
[link to www.ncbi.nlm.nih.gov]

Eventually, the disparity between CREB/dynorphin and dopamine function makes experience without the stimulus seem unbearable. CREB's prevalence in withdrawal/addiction should warrant our focus.

This is basically how it works:

devilscreb

In order to determine if CREB is responsible for the depression response, Dr. Carlezon and his colleagues did experiments to turn CREB off. This approach is used by scientists to determine if the chemical in question is the primary chemical responsible for the effect being studied. In this case, depression or addiction.

The team found that animals with a broken or mutant form of CREB have lower CREB levels, which inhibits dynorphin. Cutting down on dynorphin allows dopamine to be released, which turns on the reward system or addictive behavior in animals.

Dr. Carlezon believes his approach is unique because he is looking at causes for depression and reward (addictive behavior) in the brain. "Previously," said Dr. Carlezon, "researchers would try to figure out how antidepressant drugs work, and base their ideas about what causes depression on those findings. What we are doing is finding how the brain works, which should give us better ideas for new treatments." Possible antidepressant drugs are now being tested at prominent pharmaceutical companies. Dr. Carlezon is hopeful novel therapies will be developed from his research.
 Quoting: [link to www.whatayear.org]


... therapies like the use of l-THP, an herbal D2 antagonist that upregulates those receptors, decreasing CREB phosphorylation. [link to www.ncbi.nlm.nih.gov] [link to www.ncbi.nlm.nih.gov]

Given the hyperfluxive disposition, schizophrenia would sensically entail more D2 receptors [link to www.ncbi.nlm.nih.gov] and less CREB/glutamate activity:

Elevated dopamine D2 receptor in prefrontal cortex of CUMS rats is associated with downregulated cAMP-independent signaling pathway.
[link to www.ncbi.nlm.nih.gov]

A difference found in SCZD hiPSCs was a decreased number of neurites and synaptic protein levels. In terms of gene expression, the comparison of schizophrenia and control cells showed lower levels of adenylate cyclase (ADCY8), PKA catalytic subunits (PRKACA), and greater levels of the PKA regulatory subunits (PRKAR2A) (Brennand et al. 2011). This is all consistent with the idea that there is less cAMP signaling to regulate gene transcription in SCZD neurons.

[. . .]

With the presence of H89 and KT-5720, we were also able to mimic glutamate gene expression changes seen in patients with schizophrenia. It was previously reported that GRIK1 [glutamate receptor, ionotropic, kainate 1] showed a fold decrease of 3.9 in schizophrenic neurons relative to the control (Brennand et al., 2011). By decreasing activation of PKA with H89 and KT-5720, we were able to consistently mimic this decrease in expression. In only one set of our experiments, we saw by increasing PKA signaling, we increased expression of GRIK1. Glutamate receptors are excitatory neurotransmitter receptors and are activated in many neurophysiologic processes. It has been previously reported that there is a reduction of the GRIK1 gene in the dorsolateral prefrontal cortex of patients with schizophrenia (Hirata et al., 2012).
 Quoting: [link to deepblue.lib.umich.edu]


Glutamate's an ever-willing CREB loyalist. [link to www.ncbi.nlm.nih.gov]

These two have no shame! Some glutamate regulators for good measure:

Glycine-gated chloride channels in neutrophils attenuate calcium influx and superoxide production.
[link to www.ncbi.nlm.nih.gov]

Dopamine protects neurons against glutamate-induced excitotoxicity
[link to www.nature.com]

Thyroid hormone increases astrocytic glutamate uptake and protects astrocytes and neurons against glutamate toxicity.
[link to www.researchgate.net]

Thyroid won't have none of that! Always knows best it seems:

The thyroid hormone receptor antagonizes CREB-mediated transcription
[link to www.ncbi.nlm.nih.gov]

Magnesium also has a fair amount of skin in this game:

Magnesium levels are inversely associated with hypothyroidism [link to www.ncbi.nlm.nih.gov] and estrogen excess. [link to www.ncbi.nlm.nih.gov]
Oral contraceptives reduce magnesium. [link to www.ncbi.nlm.nih.gov]
Adequate concentrations help to normalize NMDAR function & prevent corticosteroid entry into the brain. [link to www.ncbi.nlm.nih.gov]
It also hinders the activity of protein kinase C (PKC), which stimulates CREB phosphorylation in morphine withdrawal. [link to www.ncbi.nlm.nih.gov]
It takes on an insulinogenic role. [link to www.ncbi.nlm.nih.gov]
Its deficiency increases lipid peroxidation, another characteristic of metabolic dysfunction (& ASD). [link to www.ncbi.nlm.nih.gov]

But who else is in bed with CREB? (The sheets are stained with antimetabolic matter that makes the CREB-propellors look awfully suspicious, so keep an eye out.)

Norepinephrine is (by stimulating the enzyme adenylate cyclase and elevating intracellular calcium). [link to webcache.googleusercontent.com]

And the dopamine metabolite, 3-MT, enhances the phosphorylation of CREB. [link to scholars.duke.edu (secure)]

So, not only does CREB's influence outweigh dopamine's in the (anticipatorily) anhedonic state, but wasting dopamine further fuels its fire.

Cortisol, though generally regarded as anti-inflammatory, upregulates COX-2 expression via CREB! [link to www.ncbi.nlm.nih.gov]

Huh, obese mice are more sensitive to dynorphin's provocation of insulin release (exacerbative potential for resistance). [link to www.researchgate.net]

Estrogen and BPA activate CREB (likely through glutamatergic mechanism). [link to www.ourstolenfuture.org]

The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance.
[link to www.ncbi.nlm.nih.gov]

^^^ Sound like a doozy? Thiamine & riboflavin are critically important for hepatic estradiol inactivation. [link to www.jbc.org]
Yes, estrogen is a potential "safeguard" against schizophrenia. [link to www.ncbi.nlm.nih.gov]

Increased CREB in obesity: [link to www.pubfacts.com]
ICER is a CREB-forestalling transcription factor whose impairment promotes the development of insulin resistance in obesity. [link to diabetes.diabetesjournals.org] [link to www.pubfacts.com]

The CREB-booster forskolin augmented glucose-stimulated insulin secretion by 30%. [link to www.pubfacts.com]
So, uh, beware. Our next bewarence:

Chronic SSRI use increases CREB. [link to www.jneurosci.org] - which could explain a lot.
Seems they actually work by modulating GABA (by increasing levels of allopregnanolone). [link to www.sciencedaily.com]

Omega-3s "normalize" BDNF, thus increasing CREB. [link to www.ncbi.nlm.nih.gov] [link to www.sciencedirect.com]
DHA & arachidonic acid facilitate NMDAR activity. [link to www.ncbi.nlm.nih.gov]
Omega-6 consumption is a handy path toward dysbiosis. [link to www.ncbi.nlm.nih.gov]
High corn oil diet elevates serum endotoxin. [link to ajcn.nutrition.org]
Essential fatty acid (EFA) deficiency boosts metabolic rate [link to www.functionalps.com] - which should warrant their avoidance in ASD, at least given the benefit of temporary antipurinergic therapy encouraging metabolic stability. [link to www.sciencedirect.com]
And of course, lowered PUFA is evident in schizophrenia. [link to link.springer.com]

A "high-fat [mainly saturated] sucrose diet" decreases BDNF & CREB, though. [link to www.ncbi.nlm.nih.gov]
Sucrose increases T3.

Apparently BDNF can promote anhedonia as well, only if via its control of CREB.

Now, onto LPS:

Lipopolysaccharides (endotoxin) induce CREB phosphorylation. [link to www.sciencedirect.com]
And of course they work to dysregulate thyroid function [link to www.ncbi.nlm.nih.gov] [link to www.ncbi.nlm.nih.gov]
Are inflammatory as fuck [link to www.ncbi.nlm.nih.gov]
Induce lipid peroxidation (whose effect is assuaged by selenium) [link to www.sciencedirect.com]
Promote insulin resistance & obesity [link to www.ncbi.nlm.nih.gov]
And of course make a perhaps unrivaled appearance in ASD. [link to www.microbialinfluence.com]
And part of their inflammatory effect lies in increasing parathyroid hormone-related protein. [link to www.ncbi.nlm.nih.gov]

^^^ A friend in estrogen:

HOW DOES ESTROGEN ENHANCE ENDOTOXIN TOXICITY? LET ME COUNT THE WAYS
[link to onlinelibrary.wiley.com]

Now, obviously we want to rein out intracellular calcium, whose levels are 10,000 times lower than those of extracellular calcium.

Agents that increase cellular cyclic AMP or calcium stimulate prolactin release from the 235-1 pituitary cell line
[link to www.sciencedirect.com]

Calcium deficiency paradoxically increases intracellular calcium. [link to www.ncbi.nlm.nih.gov]
This paradox likely partially constitutes how calcium supplementation can increase testosterone - forestalling prolactin release due to decreased intracellular calcium. [link to link.springer.com]

Since parathyroid hormone is signaled to keep serum calcium up, adequate dietary calcium helps prevent its inflammatory [link to www.researchgate.net] release.

PTH stimulates adenylate cyclase activity and lactic acid production. [link to www.ncbi.nlm.nih.gov]

Vitamin D and calcium both appear to be reduced in hypothyroidism. [link to www.ncbi.nlm.nih.gov]

Vitamin D, selenium & magnesium are commonly reduced in autism. [link to www.ncbi.nlm.nih.gov] [link to www.ncbi.nlm.nih.gov]
Selenium is needed for T3 generation in the liver.

Overload of intracellular calcium is associated with autism. [link to www.sciencedirect.com] [link to www.nature.com]

Higher levels of the enzyme salivary alpha-amylase (sAA) in ASD suggest a system in "overdrive." [link to www.newswise.com]
More sAA means more norepinephrine. [link to www.ncbi.nlm.nih.gov] [link to www.ncbi.nlm.nih.gov]

Research abounds linking autism spectrum disorders (and a myriad of others) to metabolic disarray, of which an elevated lactate:pyruvate ratio and rampant lipid peroxidation are common components. [link to www.mitoaction.org] [link to www.sciencedirect.com]

The decreased cellular oxygen utilization seen in hypothyroidism [link to www.ncbi.nlm.nih.gov] would contribute to the dysregulation of glutamate [link to www.jneurosci.org] and lactic acid. [link to www.ncbi.nlm.nih.gov]

Relevance to autism:
Hypoxic impairment of the NTS, which could interact with the microcirculatory effects of toxins, joins vulnerability to hydrophilic toxins as the second key element of the hypothesis. Inadequate delivery of oxygen to the NTS fits a second strong trend in the epidemiology: that ASDs are associated with perinatal hypoxia.

Fetal distress, maternal hypertension, prolonged labor, cord complications, low Apgar score, and Caesarean delivery associate with ASDs [36] and entail increased risk of fetal hypoxia. In fetal distress, for instance, progressive loss of beat-to-beat variability during labor associates with fetal asphyxia [37] and possibly reflects acute impairment of fetal NTS. Progressive fetal hypoxia is suggested to explain an observed three-fold increase of ASDs in pregnancies complicated by preeclampsia [37,38]. Low fetal pH associates significantly with increased incidence of ASDs, and implies perinatal hypoxia [39]. Newborn encephalopathy has been found to associate with a six-fold increase in ASDs [40].
 Quoting: [link to www.ncbi.nlm.nih.gov]


It's pretty clear that there's an inverse relation between compulsory responsivity and introvertive/ruminative capacity.

The states of "hyper-emotionality" might bespeak a metabolic advantage propelling dopaminergic transmission. If one had wound up in such condition to an idiosyncratically perceived fault, though, they could daringly self-inflict any of these suppressive factors in the name of balance. (Of course, I'm sure symptoms of such states are representing metabolic derangements in their own way that I cannot yet fathom.)

Either way, given the disease promoting ability of all these CREB-lovers, I think it's safe to say that the optimal existential state for humans entails brimming exploratory behavior, low latent inhibition, ramped-up (better forest view) connectivity, enhanced desire, appetite, libido - maximated flux, full throttle thriving. It isn't mere coincidence the effect these antimetabolic factors have on our "morale." Fuck them.

Well, that was fun!

Last Edited by cerebrose on 02/14/2015 09:26 PM
Without energy life would be extinguished instantaneously, and the cellular fabric would collapse. - Albert Szent-Györgyi

What the midnight creep said to the fine black sheep: Help me stir her stolen blood with the jealousy of death above... [link to musescore.com (secure)]
deluded_dawn_drizzle  (OP)

User ID: 67667907
United States
02/12/2015 08:39 PM
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Re: CREB: The Transcription Factor That Thirsts After Your Soul! (Propped Up by the Pillars of Illness)
Emodin (from Cascara sagrada) is antiproliferative [link to www.pubfacts.com] [link to www.pubfacts.com] - a property dependent on its ability to inhibit the signaling of a group of CREB-supporting kinases (MAPK) that play a part in typical diabetic issues.

At 2 months of diabetes, insulin-deficient diabetic control rats exhibited significant increases in retinal superoxide, nitric oxide (NO), cyclooxygenase (COX)-2, and leukostasis within retinal microvessels. All these abnormalities were significantly inhibited by the p38 MAPK inhibitor (25 mg/kgBW/d). At 10 months of diabetes, significant increases in the number of degenerate (acellular) capillaries and pericyte ghosts were measured in control diabetic rats versus those in nondiabetic control animals, and pharmacologic inhibition of p38 MAPK significantly inhibited all these abnormalities (all P < 0.05). This therapy also had beneficial effects outside the eye in diabetes, as evidenced by the inhibition of a diabetes-induced hypersensitivity of peripheral nerves to light touch (tactile allodynia).
 Quoting: [link to www.ncbi.nlm.nih.gov]


Apparently emodin is able to achieve this by increasing expression of the PPARG gene. [link to www.pubfacts.com]

Emodin also antagonizes the P2X7 (a purinergic) receptor. [link to www.ncbi.nlm.nih.gov]
This antipurinergic property is shared by sumarin, a drug hinted at in the OP that could benefit ASD by restabilizing metabolic function.

Berberine (from the bark of phellodendron) also ameliorates overactivation of the p38 MAPK pathway (thus reducing phospho-CREB) [link to www.pubfacts.com] and is antidiabetic/prometabolic.

RESULTS: After berberine administration, patients had a remission of 36% (P=0.037) in the presence of metabolic syndrome and a significant decrease in waist circumference in females (106±4 vs. 103±3 cm, P<0.05), systolic blood pressure (SBP) (123±7 vs. 115±9 mmHg, P<0.01), triglycerides (2.4±0.7 vs. 1.4±0.5 mmol/L, P<0.01), area under the curve (AUC) of glucose (1182.1±253.6 vs. 1069.5±172.4 mmol/l, P<0.05), AUC of insulin (92,056±72,148 vs. 67,407±46,441 pmol/L, P<0.01), and insulinogenic index (0.78±0.69 vs. 0.62±0.46, P<0.05), as well as an increase in the Matsuda index (2.1±1.0 vs. 3.1±1.6, P<0.01).

CONCLUSIONS: Administration of berberine leads to remission of metabolic syndrome and decreases in waist circumference, SBP, triglycerides, and total insulin secretion, with an increase in insulin sensitivity.
 Quoting: [link to www.ncbi.nlm.nih.gov]


To suppress NO formation & CREB activation, the mitigation of oxidative stress is crucial.

Advanced glycosylation end products induce inducible nitric oxide synthase (iNOS) expression via a p38 MAPK-dependent pathway.
[link to www.pubfacts.com]

Retinoic acid (metabolite of vitamin A) also has this ability [link to www.pubfacts.com] and is crucial for D2R mRNA expression. [link to www.ncbi.nlm.nih.gov]

More on AGEs: [link to blog.cholesterol-and-health.com]

The dysregulation of blood glucose has a key role in sustaining these vicious circles by relentlessly keeping CREB activated, perpetuating the numbness that would seek remediation through overeating & the like. Suppressing CREB is of obvious desirability.

A thirst to allay thirst.
Without energy life would be extinguished instantaneously, and the cellular fabric would collapse. - Albert Szent-Györgyi

What the midnight creep said to the fine black sheep: Help me stir her stolen blood with the jealousy of death above... [link to musescore.com (secure)]
deluded_dawn_drizzle  (OP)

User ID: 67667907
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02/14/2015 09:25 PM
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Re: CREB: The Transcription Factor That Thirsts After Your Soul! (Propped Up by the Pillars of Illness)
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.
Without energy life would be extinguished instantaneously, and the cellular fabric would collapse. - Albert Szent-Györgyi

What the midnight creep said to the fine black sheep: Help me stir her stolen blood with the jealousy of death above... [link to musescore.com (secure)]





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