[Lotus]

Ok, I'm gonna give this a shot at defining why essential fatty acids (EFA's) are important for NBE, any car buffs Lol?.

EFA's are like lubricants for car parts (e.g. molecules, steroids, DNA synthesis etc). They help help carry hormones to receptors, in other words, once they arrive at the cell membranes they (EFA's) make them more bioavailable. Soooo.....using these fat solubles supplements keep us squeaky, get it.



Figure 1: Bioactive lipid synthesis, metabolism and signaling pathways.
http://www.nature.com/nchembio/journal/v...94_F1.html

We should find how this enzyme palmitoyl-acyl-transferases works.

I think I found something that could help improve upon palmitoyl-acyl-transferases. It's called "Acetyl-L-carnitine"

Acetyl-L-carnitine or ALCAR, is an acetylated form of L-carnitine. It is naturally produced by the body, although it is often taken as a dietary supplement. Acetylcarnitine is broken down in the blood by plasmaesterases to carnitine which is used by the body to transport fatty acids into the mitochondria for breakdown.[2]
http://en.m.wikipedia.org/wiki/Acetylcarnitine

in the paper above, it says: These E2 rapid effects require a population of the ERα located at the cell plasma membrane through palmitoylation, a dynamic enzymatic modification mediated by palmitoyl-acyl-transferases.

We should find how this enzyme palmitoyl-acyl-transferases works, if you want to gain estrogen activity (and maybe is not enough, as you see our bodies are quite complicated... )
indeed from your link: "E2 reduces both ERalpha palmitoylation and its interaction with caveolin-1, in a time- and dose-dependent manner"
So, if you want you can increase estrogen receptor expression, but there is a negative feedback as well from estradiol. This is good for the body, to regulate his pathways....and try to keep some equilibrium. We just want to move some of it to favor breast growth, and if estrogen receptor is stronger than negative feedback of estradiol, than it should be worthy the way of palmitoylation.

[Lotus]

Clelia, I've included some related papers for discussion.


Long-chain acyl-CoA synthetases and fatty acid channeling
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846691/
http://www.ncbi.nlm.nih.gov/pmc/articles...179818.pdf

Cytoplasmic accumulation of long-chain coenzyme A esters activates KATP and inhibits Kir2.1 channels
http://www.researchgate.net/profile/Thomas_Baukrowitz/publication/7005678_Cytoplasmic_accumulation_of_long-chain_coenzyme_A_esters_activates_KATP_and_inhibits_Kir2.1_channels/links/02e7e52639c9abf06e000000.pdf?ev=pub_ext_doc_dl&origin=publication_detail&inViewer=true

Targeting Intermediary Metabolism in theHypothalamus as a Mechanism to Regulate Appetite http://pharmrev.aspetjournals.org/conten...7.full.pdf

[Lotus]

This is just an example of what could work, now this (or these) is brand new ideas for NBE, how does it relate?, well think of brain aromatase, or how amino acids actually should be considered part of an aromatase action. Now, add in the idea of how fatty acid synthesis improves the delivery of hormones and the Phosphorylation of enzymes (cell membrane diffusion) improving the translocation of mitochondria, am I (or is this) making any sense?.......anybody?, lol maybe I'm just crazy.

Phosphorylation is the addition of a phosphate (PO43−) group to a protein or other organic molecule (see also: organophosphate). Phosphorylation turns many protein enzymes on and off, thereby altering their function and activity. Protein phosphorylation is one type of post-translational modification.
http://wikipedia.org/wiki/Phosphorylation

Acetyl-L Carnitine Overview
http://health.howstuffworks.com/wellness...nitine.htm

Acetyl L-Carnitine
Energize the mind and promote concentration naturally with the help of Swanson Acetyl L-Carnitine! This unique formula comes from the ester of the essential amino acid L-carnitine. Muscles throughout your body need this energy as well to grow stronger as you exercise. Your brain uses this energy to maintain healthy functions like neurotransmitter production. Acetyl L-Carnitine also helps maintain healthy neurological function by delivering antioxidant protection throughout the entire nervous system. Each capsule delivers 500 mg of Acetyl L-Carnitine.
http://www.swansonvitamins.com/swanson-p...g-100-caps

* Energizes the mind and promotes concentration

* Unique form of L-Carnitine provides antioxidant protection throughout the nervous system

* Passes through the blood-brain barrier to support cognitive health & optimal brain function

Ubiquinol - (CoQ10, its Enhances Mitochondrial Support)

CoQ10 finally comes of age—with Swanson Ubiquinol! You know all about the benefits of the vitamin-like nutrient CoQ10, also known as ubiquinone, but did you know that our body has to break this nutrient down to create a useable molecule called ubiquinol? In fact, over 90% of the CoQ10 stored in the body is in the form of ubiquinol. Kaneka Nutrients, the world's leading manufacturer of pharmaceutical-quality, bio-identical CoQ10, recognized this, and after a decade of research and development, they created the first stabilized, bio-identical supplemental form of Ubiquinol. Produced from natural CoQ10 through a biological fermentation process, Kaneka's Ubiquinol achieves higher elevations of circulating CoQ10 in the bloodstream with just a fraction of the dose required when using a regular CoQ10 supplement. This is especially beneficial for individuals over 50 years of age and those who have substantially lower CoQ10 levels.
http://www.swansonvitamins.com/swanson-ultra-ubiquinol-100-mg-120-sgels?csi=LE112&csp=SWU377&otherSize=SWU377

Almost forgot

Acetyl-CoA carboxylase
Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes and in the chloroplasts of most plants and algae, whereas it is a large, multi-domain enzyme in the endoplasmic reticulum of most eukaryotes. The most important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids.[1] The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. The human genome contains the genes for two different ACCs[2] — ACACA[3] and ACACB.[4]

http://wikipedia.org/wiki/Acetyl-CoA_carboxylase

[-Clelia-]

hi there, i see that research go on, well done :-) see you soon Lotus

[Lotus]

hi there, i see that research go on, well done :-) see you soon Lotus

Hiya Clelia, my scientist friend , yes I'm plodding through, . I'll tell yeah, this new paper below just adds to this theory palmitoylation, it apparently doesn't degrade in the nucleus so fast. I wonder how long the process of degradation is, pretty sure that hormone synthesis inside the nucleus is about 30-to 60 minutes. I'm just curious as to how long it lasts?.



"We propose that rapid E2-dependent signaling could be considered as a prerequisite for ERα transcriptional activity and suggest an integrated model of ERα intracellular signaling where E2-dependent early extranuclear effects control late receptor-dependent nuclear actions."

Ok, I'm gonna give this a shot at defining why essential fatty acids (EFA's) are important for NBE, any car buffs Lol?.

EFA's are like lubricants for car parts (e.g. molecules, steroids, DNA synthesis etc). They help help carry hormones to receptors, in other words, once they arrive at the cell membranes they (EFA's) make them more bioavailable. Soooo.....using these fat solubles supplements keep us squeaky, get it.



Figure 1: Bioactive lipid synthesis, metabolism and signaling pathways.
http://www.nature.com/nchembio/journal/v...94_F1.html

We should find how this enzyme palmitoyl-acyl-transferases works.

I think I found something that could help improve upon palmitoyl-acyl-transferases. It's called "Acetyl-L-carnitine"

Acetyl-L-carnitine or ALCAR, is an acetylated form of L-carnitine. It is naturally produced by the body, although it is often taken as a dietary supplement. Acetylcarnitine is broken down in the blood by plasmaesterases to carnitine which is used by the body to transport fatty acids into the mitochondria for breakdown.[2]
http://en.m.wikipedia.org/wiki/Acetylcarnitine

in the paper above, it says: These E2 rapid effects require a population of the ERα located at the cell plasma membrane through palmitoylation, a dynamic enzymatic modification mediated by palmitoyl-acyl-transferases.

We should find how this enzyme palmitoyl-acyl-transferases works, if you want to gain estrogen activity (and maybe is not enough, as you see our bodies are quite complicated... )
indeed from your link: "E2 reduces both ERalpha palmitoylation and its interaction with caveolin-1, in a time- and dose-dependent manner"
So, if you want you can increase estrogen receptor expression, but there is a negative feedback as well from estradiol. This is good for the body, to regulate his pathways....and try to keep some equilibrium. We just want to move some of it to favor breast growth, and if estrogen receptor is stronger than negative feedback of estradiol, than it should be worthy the way of palmitoylation.

Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity.

Abstract
The estrogen receptor-α (ERα) is a transcription factor that regulates gene expression through the binding to its cognate hormone 17β-estradiol (E2). ERα transcriptional activity is regulated by E2-evoked 26S proteasome-mediated ERα degradation and ERα serine (S) residue 118 phosphorylation. Furthermore, ERα mediates fast cell responses to E2 through the activation of signaling cascades such as the MAPK/ERK and phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog 1 pathways. These E2 rapid effects require a population of the ERα located at the cell plasma membrane through palmitoylation, a dynamic enzymatic modification mediated by palmitoyl-acyl-transferases. However, whether membrane-initiated and transcriptional ERα activities integrate in a unique picture or represent parallel pathways still remains to be firmly clarified. Hence, we evaluated here the impact of ERα palmitoylation on E2-induced ERα degradation and S118 phosphorylation. The lack of palmitoylation renders ERα more susceptible to E2-dependent degradation, blocks ERα S118 phosphorylation and prevents E2-induced ERα estrogen-responsive element-containing promoter occupancy. Consequently, ERα transcriptional activity is prevented and the receptor addressed to the nuclear matrix subnuclear compartment. These data uncover a circuitry in which receptor palmitoylation links E2-dependent ERα degradation, S118 phosphorylation, and transcriptional activity in a unique molecular mechanism. We propose that rapid E2-dependent signaling could be considered as a prerequisite for ERα transcriptional activity and suggest an integrated model of ERα intracellular signaling where E2-dependent early extranuclear effects control late receptor-dependent nuclear actions.
http://www.ncbi.nlm.nih.gov/pubmed/22446104

[Lotus]

This is interesting,

Oral administration of 400 mg/ of puerarin, pretreated with or without white pepper and piperine increased the Cmax of puerarin by 1.30-fold or 1.64-fold and the AUC0–∞ by 133% or 157%, respectively.



This study attempted to explore the effects of white pepper and its major component piperine on puerarin administered to rats. Pharmacokinetic parameters of puerarin in rats were determined by oral administration (400 mg/kg) or intravenous injection (40 mg/kg) of puerarin, pretreated with or without white pepper and piperine given orally. Compared to the control group given oral puerarin only, the combined use of piperine (10 or 20 mg/kg) increased the Cmax of puerarin by 1.30-fold or 1.64-fold and the AUC0–∞ by 133% or 157%, respectively. In contrast, coadministration of white pepper (125 or 250 mg/kg) decreased oral absorption of puerarin to 83% or 74%, respectively. On the other hand, pretreatment with piperine orally did not alter the intravenous pharmacokinetics of puerarin, while the AUC of puerarin after intravenous administration was increased by pretreatment with white pepper. The results indicate that pretreatment with piperine or pepper exerts different effects on pharmacokinetics of puerarin administrated via intragastric and intravenous routes. Therefore, it is suggested that the combined application of piperine or white pepper with puerarin should be carefully monitored for potential diet-drug interactions.
http://www.ncbi.nlm.nih.gov/pmc/articles...796890.pdf

[Lotus]

I've put together some research on the effects of PM, sorry, it's complicated.


As estradiol did, deoxymiroestrol induced expression of CYP2B9 mRNA whereas those of CYP1A2 were suppressed.

CY2B9 mRNA induced testosterone in women

CYP1A2 -aromatase (suppresses)

HSD-17B2 suppressed (E2 and T pathway)

17β-HSD1 suppressed (E2 pathway)

3β-HSD suppressed (which catalyzes all steroids)

CYP17 (Human 17,20-lyase) activity is stimulated 10-fold by CYB5

CYP19 mRNA (aromatase) slightly decreased by deoxymiroestrol



____________________________

Posted research:

The backdoor pathway proceeds from 17OH-Preg to 17OH-Prog, 17OH-DHP, 17OH-Allo, androsterone, androstanediol, and then to DHT, all in the testes.


Assessment of testicular enzymes involved in sex hormone synthesis pathway showed suppression of 3β-HSD, 17β-HSD1, and CYP17 expressions with those of CYP19 mRNA was slightly decreased by deoxymiroestrol.

The pathways of androgen biosynthesis. The classic pathway and the alternative “backdoor pathway” are shown. The classic pathway proceeds from 17OH-Preg to DHEA, to androstenedione or androstenediol to testosterone in the testis, and thence to DHT in genital skin. The backdoor pathway proceeds from 17OH-Preg to 17OH-Prog, 17OH-DHP, 17OH-Allo, androsterone, androstanediol, and thence to DHT, all in the testis. The enzymes and cofactors shown in the classic pathway are: P450scc (cholesterol side-chain cleavage enzyme), StAR (steroidogenic acute regulatory protein), P450c17 (17α-hydroxylase/17,20-lyase), 3β-HSD (3β-hydroxysteroid dehydrogenase, type 2), cytochrome b5, 17β-HSD3 (17β-hydroxysteroid dehydrogenase, type 3), and 5αR2 (5α-reductase, type 2). The alternative pathway is characterized by the presence of three additional enzymes: 5αR1 (5α-reductase, type 1), reductive 3α-HSD (AKR1C2/4), and oxidative 3α-HSD (17β-HSD6, also known as RoDH and/or AKR1C4). Steroid names include: 17OH-Preg, 17-hydroxypregnenolone; 17OH-Prog, 17-hydroxyprogesterone; 17OH-DHP, 17-hydroxydihydroprogesterone (5α-pregnan-17α-ol-3,20-dione); 17OH-Allo, 17-hydroxy-allopregnanolone (5α-pregnan-3α,17α-diol-20-one); androstenediol, androsta-5-ene-3β,17β-diol; and androstanediol, 5α-androstane-3α,17β-diol.


Cytochrome P450 17A1 (zona reticularis) of the adrenal cortex suppressed steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.


Cytochrome P450 17A1, or steroid 17-alpha-monooxygenase, or 17α-hydroxylase/17,20 lyase/17,20 desmolase is an enzyme that in humans is encoded by the CYP17A1 gene. It is found in the zona reticularis of the adrenal cortex. This gene encodes a member of the cytochrome P450superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids. This protein localizes to the endoplasmic reticulum. It has both 17alpha-hydroxylase and 17,20-lyase activities, and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.

More specifically, CYP17A1 acts upon pregnenolone and progesterone to add a hydroxyl (-OH) group at carbon 17 of the steroid D ring (the hydroxylase activity), or acts upon 17-hydroxyprogesterone and 17-hydroxypregnenolone to split the side-chain off the steroid nucleus (the lyase activity).

[Lotus]

Efficacy of testosterone combined with a PDE5 inhibitor and testosterone combined with a serotonin 1A receptor agonist in women with SSRI-induced sexual dysfunction. A preliminary study

Abstract
Selective serotonin reuptake inhibitors (SSRIs) are known to cause sexual dysfunction, such as decreased sexual motivation, desire, arousal, and orgasm difficulties. These SSRI-induced sexual complaints have a high prevalence rate, while there is no approved pharmacological treatment for SSRI-induced sexual dysfunction. It is hypothesized that a polymorphisms in the androgen receptor gene, encoded by the nucleotides cysteine, adenine, and guanine (CAG), influence the effect of testosterone on sexual functioning. In an explorative, randomized, double-blind, placebo-controlled, crossover study we investigated the possible effects of sublingual testosterone combined with a serotonin (5-HT)1A receptor agonist, and of sublingual testosterone combined with a phosphodiesterase type 5 inhibitor (PDE5-i) on sexual functioning in women with SSRI-induced sexual dysfunction. Furthermore, we did an exploratory analysis to assess if the CAG polymorphism influences this effect. 21 pre- and postmenopausal women with SSRI-induced sexual dysfunction participated and underwent the following interventions: a combination of testosterone (0.5 mg) sublingually and the PDE5-i sildenafil (50 mg) and a combination of testosterone (0.5 mg) sublingually and the 5-HT1A receptor agonist buspirone (10 mg). The results show that women who use a low dose of SSRI and have relatively long CAG repeats report a marked improvement in sexual function in response to both treatments compared to placebo. This explorative study and preliminary results indicate that in women with SSRI-induced sexual dysfunction, a combination of testosterone sublingually and a PDE5-i or testosterone sublingually and a 5-HT1A receptor agonist might be promising treatments for certain subgroups of women with this condition.

[Lotus]

Dopamine and serotonin: influences on male sexual behavior
Steroid hormones regulate sexual behavior primarily by slow, genomically mediated effects. These effects are realized, in part, by enhancing the processing of relevant sensory stimuli, altering the synthesis, release, and/or receptors for neurotransmitters in integrative areas, and increasing the responsiveness of appropriate motor outputs. Dopamine has facilitative effects on sexual motivation, copulatory proficiency, and genital reflexes. Dopamine in the nigrostriatal tract influences motor activity; in the mesolimbic tract it activates numerous motivated behaviors, including copulation; in the medial preoptic area (MPOA) it controls genital reflexes, copulatory patterns, and specifically sexual motivation. Testosterone increases nitric oxide synthase in the MPOA; nitric oxide increases basal and female-stimulated dopamine release, which in turn facilitates copulation and genital reflexes. Serotonin (5-HT) is primarily inhibitory, although stimulation of 5-HT2C receptors increases erections and inhibits ejaculation, whereas stimulation of 5-HT1A receptors has the opposite effects: facilitation of ejaculation and, in some circumstances, inhibition of erection. 5-HT is released in the anterior lateral hypothalamus at the time of ejaculation. Microinjections of selective serotonin reuptake inhibitors there delay the onset of copulation and delay ejaculation after copulation begins. One means for this inhibition is a decrease in dopamine release in the mesolimbic tract.

https://psy.fsu.edu/faculty/hull/DA&5HT_pdf.pdf

[Lotus]

Interesting that SSRI's also interfere with oral contraceptives, I'm willing to say that boosting serotonin inhibits T. My goal would be to boost daily serotonin (during the day) followed by liberating dopamine at night.

Time-dependent inhibition of CYP3A4 by sertraline, a selective serotonin reuptake inhibitor.
Masubuchi Y, et al. Biopharm Drug Dispos. 2013.
Show full citation
Abstract
Drug-drug interactions associated with selective serotonin reuptake inhibitors (SSRIs) are widely known. A major interaction by SSRIs is the inhibition of cytochrome P450 (P450)-mediated hepatic drug metabolism. The SSRI, sertraline, is also reported to increase the blood concentration of co-administered drugs. The potency of sertraline directly to inhibit hepatic drug metabolism is relatively weak compared with the other SSRIs, implying that additional mechanisms are involved in the interactions. The study examined whether sertraline produces time-dependent inhibition of CYP3A4 and/or other P450 enzymes. Incubation of human liver microsomes with sertraline in the presence of NADPH resulted in marked decreases in testosterone 6β-hydroxylation activities, indicating that sertraline metabolism leads to CYP3A4 inactivation. This inactivation required NADPH and was not protected by glutathione. No significant inactivation was observed for other P450 enzymes. Spectroscopic evaluation revealed that microsomes with and without sertraline in the presence of NADPH gave a Soret peak at 455 nm, suggesting the formation of metabolic intermediate (MI) complexes of sertraline metabolite(s) with the reduced form of P450. This is the first report indicating that sertraline produced time-dependent inhibition of CYP3A4, which may be associated with MI complex formation.

Copyright © 2013 John Wiley & Sons, Ltd.
http://www.ncbi.nlm.nih.gov/m/pubmed/23929629/