Terma, The Most Underrated Member

[Amazoniac]

The guy knows a lot and his writing isn't too technical to justify him not getting the attention that he deserves.

I've witnessed charlatans being harassed for opinions and interviews when he's around and accessible. Don't be intimidated by shine and tanka, they're friendly bodyguards and on their way to mastery.

If you have questions, obtain your answers, and if you have a condition, get your diagnosis and protocol below (just kidding, legals):

 

[Jam]

Agreed

 

[Terma]

Thanks, but I already had a thread, since I found you can just take them

 

[Terma]

You went there so I decided to write this. It's not a regular thing because I'm not Travis or Ray and long posts are gay***. GSH or whatever effects of NAC seem important to prevent sometimes break biofilms and fight pathogens in general (take no action on anything here):
In vitro effects of N-acetyl cysteine alone and in combination with antibiotics on Prevotella intermedia. - PubMed - NCBI

N-acetyl cysteine (NAC) is an antioxidant that possesses anti-inflammatory activities in tissues. In the field of dentistry, NAC was demonstrated to prevent the expression of LPS-induced inflammatory mediators in phagocytic cells and gingival fibroblasts during the inflammatory process, but the effect of NAC on oral pathogens has been rarely studied. Here, we examined the effect of NAC against planktonic and biofilm cells of Prevotella intermedia, a major oral pathogen. NAC showed antibacterial activity against the planktonic P. intermedia with MIC value of 3 mg/ml and significantly decreased biofilm formation by the bacterium even at sub MIC. NAC did not affect the antibiotic susceptibility of planktonic P. intermedia, showing indifference (fractional inhibitory concentration index of 0.5-4) results against the bacterium in combination with ampicillin, ciprofloxacin, tetracycline or metronidazole. On the other hand, viability of the pre-established bacterial biofilm exposed to the antibiotics except metronidazole was increased in the presence of NAC. Collectively, NAC may be used for prevention of the biofilm formation by P. intermedia rather than eradication of the pre-established bacterial biofilm. Further studies are required to explore antibacterial and anti-biofilm activity of NAC against mixed population of oral bacteria and its modulatory effect on antibiotics used for oral infectious diseases.

N-acetylcysteine as powerful molecule to destroy bacterial biofilms. A systematic review. - PubMed - NCBI

For a lot of people except cancer and some infections (although NAC itself has at least in vitro anti-cancer effects in some studies like below - and NADPH which happens NAC has some ability to spare can act through NOX with pros and cons) it's safer to assume what study above suggests: once biofilms are established GSH is no longer effective, though might still have general antibacterial effects even on other strains present - so lower overall burden on the immune system plus stronger somatic cells. I'm not sure how much faith I put in these but some of the results/ideas were surprising. But NOX was always a major defensive weapon so it makes sense NADPH could be used to defeat some types of cancers/pathogens - in cancer only if properly targeted by restoring the arms of the immune system concomitantly - including HSP70 and other immune markers - metabolism, fatty acids synthesis, methylation, polyamine high synthesis/low catabolism (related to acetyl groups for SSAT, and otherwise seems controlled) and other factors. The body has ways to turn antioxidants into prooxidants as asborbate/oxalate and lipoic acid already show, and NOX allowing this for NADPH is damaging but necessary evil I think can be healed from, even fibrosis together with TGF-beta, theoretically. During sleep, when intestines and lungs can relax more.
NADPH accumulation is responsible for apoptosis in breast cancer cells induced by fatty acid synthase inhibition
N-Acetylcysteine
Expression of polyamine and SSAT (spermidine/spermine N-1 acetyl transferase) levels following surgical trauma and sepsis. - PubMed - NCBI

This suggests regular high GSH is desirable to prevent oral biofilms - probably at times of day you're consuming food, then exercising, at least when you're likely to be stressed and exposed to pathogens (general def.) or sexually active - in time with digestion and buffering effects.

But circadian rhythm suggests sleep affords the body periods of lower GSH precursor synthesis at least certain parts or prioritize cells that need it most, if such system exists. Health is highly cyclical. Melatonin might lower the need for GSH in some ways? Cysteine floats around picked up as needed, even if it has side-effects, and is produced endogenously by transsulfuration from homocysteine along with taurine. Some of that inflammatory damage should be preventable by GSH and taurine synthesized with sufficient serine and P5P. Eating seafood with pre-formed taurine, presumably you significantly increase it or otherwise divert toward cysteine/GSH synthesis with help of glycine/serine/P5P, with minerals needed to balance/use sulfur, important in joint health.

NADPH-dependent KMO enzyme in kynurenine pathway as well highly important in immunity and some B3 synthesis (KMO relieved by NAC since despite NAC supposedly lowering NADPH recycling - there's a reference somewhere in NAC studies - it seems to supply enough de-novo GSH for therapeutic effects regardless and should recycle ascorbate so it recruits soldiers to compensate for NADPH one way or another). L-serine production by kidneys even though limited shows our dependency on it, but it can increase NAD+, GABA signaling, D-serine, glycine, NMDA, cysteine, taurine, methylenetetrahydrofolate through SHMT (also enabling methylation and limiting folate acid precursors from accumulating - it's all about flux) logically NADPH through MTHFD, and more I forget; it lowers homocysteine and processes folate. I'm not sure what creates SHMT silencing during aging or causes it to become problematic (outside cancer/pathogens), but I've imagined it could theoretically be a mechanism to limit use of a small serine pool by epigenetically methylating away serine-consuming enzymes like SHMT - only a theoretical mechanism I'm not following up.
l-Serine induces sedative and hypnotic effects acting at GABA(A) receptors in neonatal chicks. - PubMed - NCBI
Sci-Hub | Amino acids in the regulation of aging and aging-related diseases. Translational Medicine of Aging | 10.1016/j.tma.2019.09.001

It probably applies to other pathogens but considering how sensitive the lungs, studies like this tell me I'm doing better because I eat high protein and B3/NAD (even a little pre-formed with possible intact absorption as some researchers reported, though may get broken down in the extracellular milieu) - scallops/shrimp/turkey, choline, 1-3tsp serine and sometimes NAC. So far no coronavirus, still joint problems but fewer than with dairy and less strict diet (oxalates? not sure), and I remember no fever for a long time (I know), and I doubt my liver has serious problems, mainly gut and brain. Sugar seems handled fine, and adding Mg2+/K+/glycine/taurine fixes a lot of problems even without GSH. Best place for glutamate is GSH - except in enemy/rogue cells - but you only have to outcompete them and our cells have a better support network. Melatonin might help do this if it affected bacteria the way it does our cells:
Melatonin as an antibiotic: new insights into the actions of this ubiquitous molecule. - PubMed - NCBI

Everybody this side supplements glycine and gelatin = GSH (Glycine restores glutathione and protects against oxidative stress in vascular tissue from sucrose-fed rats. - PubMed - NCBI) and even arginine (but that goes a bit to creatine with glycine, and some needed for immunity - maybe arginine partly compensates for tryptophan? maybe not). Gelatin has both protective use with meals but theoretically might be useful to support GH at night though methionine is needed. I found this to not work out. But you recharge GSH before activity using daily circadian and feeding cycles unless you want to push your tissues to oxidation (must be a safe limit). 99% sure Ray's brain is high GSH unless he sabotages it, says eats shellfish (and risking the o-6 and o-3 of eggs). Most people are protein deficient and it's only a third of their problems. Haven't read but:
Sci-Hub | Cysteine, glutathione (GSH) and zinc and copper ions together are effective, natural, intracellular inhibitors of (AIDS) viruses. Medical Hypotheses, 52(6), 529–538 | 10.1054/mehy.1997.0689

Glycine/serine/NAC/GSH is useful to counter (arguably) copper/glutamate/immune/iron/methylglyoxal/NOX/PUFA damage, fight some infections and lung issues and more especially if digestion's impaired. I've taken probably upwards of 4g NAC at a time (with glycine up to ~20g or about as much well-advertised gelatin iirc - but suffered issues, even though people take 60g - better with sarcosine and serine) to no ill effect. But one guy on another forum took it for an extended period and seemed to have cardiac palpitations of sorts? - maybe its mucolytic ability and unstabilizing effect on mineral levels (arguments to refrain from extended use). Note sure what point to use upon symptoms, depends on alternatives.
Medical and Dietary Uses of N-Acetylcysteine
Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for a... - PubMed - NCBI
N-acetylcysteine overdose after acetaminophen poisoning
29 NAC Benefits & Uses (N-Acetyl Cysteine) - SelfHacked
What is NAC? Side Effects, Dosage, Mechanism, Reviews - SelfHacked
Role of Combined Lipoic Acid and Vitamin D3 on Astrocytes as a Way to Prevent Brain Ageing by Induced Oxidative Stress and Iron Accumulation
N-Acetylcysteine interacts with copper to generate hydrogen peroxide and selectively induce cancer cell death

NAC could handle or help recover from cancer treatment cisplatin's oxalate damage (perhaps in cycles of treatment, with short NAC exposures and circadian timing? Not sure this drug is worth it):
Thermo-Sensitive TRP Channels: Novel Targets for Treating Chemotherapy-Induced Peripheral Pain
N-acetylcysteine as salvage therapy in cisplatin nephrotoxicity. - PubMed - NCBI
N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models. - PubMed - NCBI
Speaking of which, I guess I could attribute my quick recovery from tinnitus by minerals like Zn and things like NAC, unprovable now.

I'm OCD about NAC due to OCD, but it helps that in sufficient dose seems a clinically-approved safer treatment than SSRIs, though I think you need breaks off NAC so alternating therapies seems prudent, because NAC will affect metals and may preference to certain pathogens/gut bacteria, 2,400–3,000 mg/day of NAC:
N-Acetyl Cysteine in the Treatment of Obsessive Compulsive and Related Disorders: A Systematic Review

Worth mentioning potential disaster scenario with high NAC described by Freddd from ME/CFS sites who warns against it, which might be more than one thing but might include compromised NADPH recycling at high doses (in some study). But this might theoretically be counteracted by other agents anyway, like B1, mito-Q maybe supports G6PD/NADPH (iirc CoQ10 and even folate could stimulate AMPK, a little like lipoic acid):
High Concentration of Antioxidants N-Acetylcysteine and Mitoquinone-Q Induces Intercellular Adhesion Molecule 1 and Oxidative Stress by Increasing Intracellular Glutathione

To further examine how mito-Q affected the GSH/GSSG cycle, we determined the expression and activity of G6PD, a rate-limiting enzyme of the pentose phosphate pathway that generates cytosolic NADPH, a cofactor utilized by GR. A moderate level induction of G6PD expression and activity was observed by TNF-α (Fig. 3⇓, lane 2) or TNF-α-treated cells pretreated with mito-Q (Fig. 3⇓, lanes 5 and 6). At low concentrations, while mito-Q significantly induced G6PD expression it did not reflect in increased G6PD activity (Fig. 3⇓, lane 5). At high concentrations, mito-Q induced both expression and activity of G6PD (Fig. 3⇓, lane 6). Enhancement of G6PD expression and activity by mito-Q, a mitochondria-specific antioxidant, indicates that mito-Q activity is not limited to mitochondria but also influences the cytosol. Of note, mito-Q also increased isocitrate dehydrogenase activity, an enzyme responsible for mitochondrial NADPH production (data not shown). In contrast to mito-Q, although 3 mM NAC-pretreated cells showed no significant alteration of G6PD expression and activity, 30 mM NAC significantly attenuated TNF-α-dependent G6PD expression and activity (Fig. 3⇓, lanes 3 and 4). Increased expression and activity of NADPH-generating enzymes is reflected in increased generation of NADPH (data not shown).

The present investigation on the effects of antioxidants on the GSH/GSSG cycle show that NAC or mito-Q dose-dependently increase cellular GSH levels (Fig. 1⇑) by GSH synthesis and recycling, respectively (Fig. 2⇑). Moreover, they do so by controlling the activity (Fig. 2⇑), but not the expression of different enzymes involved in this cycle (data not shown). The predominant action of NAC is mediated by enhancing GCS activity that is responsible for increased de novo synthesis of GSH (Fig. 2⇑A). In contras, the predominant action of mito-Q is mediated by enhanced recycling of GSH by increasing GR activity (Fig. 2⇑C). Increased GR activity by mito-Q is mediated by enhancing the activity of G6PD, a rate-limiting enzyme of the pentose phosphate pathway that is responsible for increased supply of NADPH, a cofactor of GR activity (Fig. 3⇑). Therefore, the results indicate that NAC or mito-Q use different mechanisms to enhance the levels of GSH.

Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARα induction in 3T3-L1 preadipocytes. - PubMed - NCBI

These are highly clinically useful supplements and with ascorbate, lipoic acid, vit E, astaxanthin, methylenetetrahydrofolate, thiamine, ribose and others form a flux to ensure the right NADPH levels for the NAD+ pool, to allow the cell ultimate adaptability to stressors. If NAC compromised NADPH recycling (compensated by de-novo GSH) you might suspect G6PD deficiency to be contraindicated, but in practice NAC even seems beneficial there and can be balanced somehow with methylene blue:
N-acetylcysteine reduces methemoglobin in an in-vitro model of glucose-6-phosphate dehydrogenase deficiency. - PubMed - NCBI

I'm not sure if Freddd's negative experiences with NAC really has to do that much with NADPH, but still curious because those guys take up to 30mg methylfolate (2x deplin) that can probably be expected to generate significant NADPH especially with sufficient serine/P5P (SHMT).
Quantitative flux analysis reveals folate-dependent NADPH production
Afaik 800-1600mcg L-methylfolate is place to start, avoiding folic acid (bad form to avoid explicitly to avoid impeding DHFR for some people - yet they force this synthetic drug in the food supply even in pregnancy, which might at the extreme worsening anemia-like symptoms for some - throwing inorganic iron into fortification ripe for misuse and promoting infection).
Folate
From the Cover: The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake
Seafood has a bit of B12 but probably not enough for 30mg methylfolate and poorly-absorbed methylcobalamin becomes necessary up to i.v. for some people. Combined with copper/B2/R5P/P5P/GH/T3 deficiency precipitates anemia and liver dysfunction followed by brain.

NAC increases "tolerance" to some metals:
Cadmium-induced oxidative damage and protective effects of N-acetyl-L-cysteine against cadmium toxicity in Solanum nigrum L. - PubMed - NCBI

The effects of cadmium (Cd) on the accumulation of hydrogen peroxide (H(2)O(2)) and antioxidant enzyme activities in roots of Solanum nigrum L. and the role of N-acetyl-l-cysteine (NAC) as a cysteine (Cys) donor against Cd toxicity were investigated. Cd at 50 and 200 microM significantly increased the contents of thiobarbituric acid-reactive substances (TBARS), the production of H(2)O(2) and superoxide anion (O(2)(-)), and the activities of catalase, guaiacol peroxidase, ascorbate peroxidase, glutathione peroxidase (GSH-Px), glutathione reductase, and superoxide dismutase. Experiments with diphenylene iodonium as an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and NaN(3) as an inhibitor of peroxidase showed that the major source of Cd-induced reactive oxygen species in the roots may include plasma membrane-bound NADPH oxidase and peroxidase. In addition, the effects of NAC on plant growth, antioxidant enzyme activity, and non-protein thiol content were analyzed. Under Cd stress, the addition of 500 microM NAC decreased the contents of TBARS and production of H(2)O(2) and O(2)(-), but increased levels of Cys and reduced glutathione (GSH), phytochelatins, and activity of GSH-Px in roots. These results suggest that NAC could protect plants from oxidative stress damage, and this protection seems to be performed via increased GSH biosynthesis. Furthermore, NAC treatment also increased the contents of protein thiols in S. nigrum roots. By using size-exclusion chromatography, we found involvement of NAC in the Cd tolerance mechanism through increased biosynthesis of Cd-binding proteins.

but maybe this suggests you sometimes need an oxidative state to help stimulate movement of heavy metals for excretion (coincidentally lipoic acid being a therapy) or "pulse" their movements, but there are tons more therapeutic uses for NAC/glycine/serine all over this forum and some probably missed. It can involve metallothionein/zinc, mercury:
Zinc and N-acetylcysteine modify mercury distribution and promote increase in hepatic metallothionein levels. - PubMed - NCBI
Zinc is quite important and again abundant in some seafood. All this suggests alternating NAC and minerals somehow for safe therapeutic effects, but quality seafood might already substitute for part of that effect, even if dietary protein doesn't increase cysteine for GSH as much as NAC.

Best option when sick or lowering calories, carbs or fat sounds like a diet of: high cholesterol, choline (acetylcholine/phosphatidylcholine for intelligence/cellular health), non-methionine amino acids and sat/mono phospholipids but including phosphatidylserine (PS) even with o-3 - important to cell/mitochondrial membranes [Travis] and cell signaling. Also distinct effects for alpha-linolenic acid (o-3 ALA, not lipoic acid) could be desirable biased by presence in vegetables and some of their benefits such as polarizing macrophages, while not being quite as fragile as EPA/DHA and even preferentially burned:
Anti-inflammatory effects of α-linolenic acid in M1-like macrophages are associated with enhanced production of oxylipins from α-linolenic and lino... - PubMed - NCBI
Sci-Hub | The rates of oxidation of unsaturated fatty acids and esters. Journal of the American Oil Chemists Society, 24(4), 127–129 | 10.1007/bf02643258
α-Linolenic acid–derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40
I think enough T3/GSH/factors mitigates some risks of o-3 ALA. But huge doses don't seem essential and why bother if you can have stearic acid (needed for 18:0-22:6(n-3)-PS anyway) and acetoacetate instead.

GSH supports the immune system and cellular defense, which just has to be supported with sleep to recover. Otherwise brain and liver risk things like high cortisol promoting degeneration. There might be enough in seafood to handle the o-3 and methionine and put them to use, though the metal burden is probably significant.

That's why seafood works for weight loss: it has all factors to increase survival on lower calories, large survival advantage. Maybe increase glycogen levels, especially if uridine, although dairy can also do that (orotate/pre-formed). It could be how fishing helped us develop intelligence (tools + patience) - more than the o-3 (18:0-22:6(n-3)-PS). Some forms of fishing (maybe not deep-sea) allowed stress-free relaxation as opposed to stressful hunting. More than carbs, helps exploit/manage/spare carbs and generate ketones. o-3 is only needed in small quantities as excess is volatile, maybe not needed or damages/risks exceeds (projected) benefits. Seafood gave GSH to survive its PUFA/methionine - even toxins (GSH, especially for the brain) - balanced food sources, even Ca2+/vit D from bones, coral and calcium carbonate. Maybe GSH helped allow fishing underwater since you can't deny GSH in cancer and ascorbate recycling - it helps cells sustain ultimate survival mode - like drowning.

Linoleate a small minimum might be desirable for life outside a house to some extent for its role in immunity/pathogen signaling/etc - conditionally essential for survival in harsh environments.

Shellfish = glycine (GSH), taurine to counter high methionine in seafood and lower its absorption, so seafood already contains antidotes to aging, it's a key to tissue recovery. Only bad if SAMe not used together with ALLO/DHEA/DHT/GABA/GH/IGF-1/IGF-BP/mTorC1 (SAMTOR)T/T3/etc which work during sleep to restore collagen and sensitive tissues (where are our gums going?) but work repairs can only happen during extended consorted rest or paralysis. The loss of any leads to healing defects; GH declines with age - in youth it lowers GNMT with a permissive effect for more SAMe in the earlier night and GH keep T3 high in connective/pheripheral tissues during paralysis - cartilage and sensitive tissues that are difficult to rebuild. SAMe is restorative if it produces important compounds when used well and works in regeneration - putting its power to good use (CoQ10, neurostransmitters, collagen, GABA, melatonin, sarcosine (NMDA - together with acetylcholine, dopamine, intelligence under pressure = survival), etc). Directed the right places not clogging arteries for various reasons including inflammation - that's what Ray's worried about for collagen - but part of that is already fixed by better controlled inflammation and GSH (I'd risk it to survive). Despite their volatility nature found way to make the best of o-3 to couter o-6 inflammation.

T3's also thought to be able to lower GNMT (counteract retinoic acid (RA)) making more SAMe available, in concert with GH (other study):
New Insights into the Regulation of Methyl Group and Homocysteine Metabolism

In rats, it is well known that thyroid status alters the activity of 5,10-methylenetetrahydrofolate reductase (MTHFR), which would be expected to result in an alteration of GNMT activity via allosteric regulation by 5-CH3-THF (24). In support of this, recent studies have found that triiodothyronine reversed retinoic acid-mediated elevations in GNMT activity but was without effect on abundance, suggesting post-translational regulation of GNMT in the hyperthyroid state (25).

How could SAMe not be increasing at night unless the needed doses were way too high? It's usually some hours following the largest protein meal of the day.

Later RA would come into play to restore GNMT and produce more homocysteine for transsulfuration toward GSH and taurine and other protective compounds for the daytime. Since caretonoids seem like a logical visual daytime marker, I guess their active forms might help signal the memory of when they last occurred - RA is involved in circadian rhythm, steroids and more. Of course it helps regulate cortisol and requires NAD+ to synthesize, so it's prime for morning synthesis, I think. Furthermore it tissue-dependently (? how much) promotes differentiation more than proliferation in adulthood to complement GH/SAMe/etc.

Scallops for example have high B12/choline to support healthy parts of methylation and prevent accumulation of methionine and homocysteine (latter also lowered by serine/B6, present in these foods): Scallops

Again choline promotes the Kennedy pathway and so the biggest risk of PUFA incorporation into phospholipids is from the PEMT enzyme:
https://raypeatforum.com/community/threads/incomprehensive-ble-notes-on-choline.23228
Incomprehensive/ble Notes On Choline
Incomprehensive/ble Notes On Choline
Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes
So the biggest risk from PUFA is actually high estrogen (PEMT promoter), high methionine (egg whites) and o-6 (egg yolks). You pay for cholesterol and vit A but without appeal to authority several prominent figures agree it's worth the risk despite studies with inflammatory concerns not sure all attributed to the whites: haidut, Jaminet, Ray, ... Jaminet argued 5 egg yolks during pregnancy, just add saturated fat in that case, maybe stearate. Meanwhile Amazoniac posted studies suggesting overall preference of the lower-PUFA Kennedy pathway, and afaik PEMT is not necessarily increased by choline (alpha-GPC) itself, presumably until methyl groups deplete, in which case choline can help prevent damage and help ensure production of carnitine, creatine, etc. to better survive lower protein (as Jaminet advocated compared to Ray or me).

I read at least one story of someone with side-effects of accutane improving on scallops and rice. Certainly seemed low caretenoids/retinoids too. Maybe improved methylation may help reset the system, affect epigenetics, but there's everything else. DNA methylation + some histone methylation may be undesirable so the point is to not drive methyl groups there, and again the upregulating effect of RA on GNMT counter to SAMe although I thought that temporary.

You can get very low o-6 sardines, but mine made me hate eating, while ones marked with 0.8g+ o-6 tasted like tuna, tolerable. If you're trying to lower cortisol/dynorphin/serotonin, why evoke the disgust response? Some side effects, I had started to wonder if the high o-3 low o-6 was messing with blood flow.

Using a seafood+plain+supplement(Mg2+) carb diet you can lower oxalate burden for a period to see if it makes any difference. I'm not sure what to make of oxalate dumping, but the high purine (uric acid) content of seafood is reported to influence kidney health and gout for some, so their side effects might get confused. Metal handling notably copper and zinc and production of ceruloplasmin might be expected to start up, and ceruloplasmin oxidizes ascorbate - toward oxalic acid - so GSH becomes essential to prevent damage from ascorbate and copper (especially when consuming poor sources of copper since copper can be even worse). Not enough GSH to chaperone copper, ascorbate oxidation to oxalic acid in the presence of Ca2+, too high methylglyoxal. I guess in theory any of these might explain negative symptoms after starting a low-irritant diet, and more, and minimum Ca2+/Mg2+ essential regardless which diet, in part due to high phosphate.
Proof for the Ascorbate Oxidase Activity of Ceruloplasmin
Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1

High phosphate but it's full of iodine plus the selenium (GSH) to balance it, tyrosine, zinc for immunity, cholesterol and thyroid substrates. Scallops are decent source of potassium I guess with liquids recovered. Everything in seafood supports dopamine synthesis, and maybe at some level of dosage limiting vitamin C levels might(?) restrict the dopamine->norepinephrine conversion although it might cost you oxytocin/vasopressin? - I don't know at what level each happens - relative to each other compared with a lower-vitamin C high seafood diet normal production. Since this is all steroid- and amino acid-effect-supported - with glucose regulation improvements you recycle ascorbate with GSH efficiently to keep ascorbate levels optimal and less variable during supply disruptions - prevent dips into oxalate synthesis when dangerous. Without disruption of intestines or affecting mineral absorption, which after chronic exposure to excessive ascorbate or zinc can affect metabolism by losing copper. Finally steroid production supported by seafood, liver, eggs, saturated fats help produce allopregnanolone, GABA agonists, which generally help stabilize neurotransmitter levels and filter signals (maybe especially for sounds?). Glycine and taurine serve in all these roles.

Meanwhile NADPH supports steroid synthesis and in my best estimate too low NADPH would be expected to lead to depression, one indicator being the possible role of methylfolate generation of NADPH through MTHFD together with methylation. Expected to be what makes deplin an effective anti-depressive adjunct people risk despite associations of folate with cancer - some people's cells need the opposite.

Not sure but some seafoods or associated water sources might have a little lithium, might become significant if magnesium were low, where small compensatory effects by other substances are more noticeable.

Besides pre-formed PS, seafood should encourage de-novo phospholipid synthesis of all forms (choline, ethanolamine, serine). This implies strong need for B3/NAD which is abundant in seafood but requires metabolism to support membrane/phospholipid integrity. Mainly misses some Mg2+, more uridine but can't have too much uridine due to the purine content.

Uric acid (from purines/xanthine oxidase) acts as antioxidant expected to lower need for vitamin C though it can be undesirable, and I suspect it might have the power to prevent liver/brain damage from fluoroquinolone antibiotics, highly promoted by brewer's yeast, which also has uridine. It might have contributed to one person's recovery along with all the B vitamins, protein, some minerals. Sardines in particular are a very high source of purines including high uric acid producer hypoxanthine, but also guanine, which is related to GTP used in de-novo BH4 synthesis. Many seafood items are high in different purines. The Japanese surely benefit, and altogether everything in seafood might even help glucose regulation enough that you can omit fructose, but they eat some fructose and acetic acid to help glucose regulation.
Sci-Hub | Levels of Purines in Foods and Their Metabolic Effects in Rats. The Journal of Nutrition, 106(3), 435–442 | 10.1093/jn/106.3.435

Of course since we know urea and salt explain water conservation, there's a clear tie to human survival in saltwater/seafood environments, probably stronger than arid lands given limited protein supply in some and frozen environments if clean/glacier ice can be melted. Scurvy is easily fixed and part of the problem of survival would be catch diversity and pressure on gluconeogenesis/ketogenesis, which however naturally integrates with high salt. Seafaring requires patience and salt helps calm down aldosterone/angiotensin/glucocorticoids/serotonin and generate oxytocin/vasopressin, related to (social) rationing and increasing patience although serotonin's still involved.
More Dietary Salt Increases Urea Synthesis And Energy Requirements

I didn't touch on bile acids but together with taurine might stimulate T3 in liver given TUDCA and other numerous benefits. Supported by cholesterol and phospholipids, glycine and taurine. This is maybe one way digestive/liver harm from harsh pharmaceuticals like accutane/pfs can be healed.
Bile acid - Wikipedia

Seafood was nature's perfect food and could easily have kept us lean healthy until dioxins, Hg, PCBs, oil, oils, seasonings, breadenings, deep-frying in volatile chemicals. Dioxins, polychlorinated biphenyls, methyl mercury and omega-3 polyunsaturated fatty acids as biomarkers of fish consumption. - PubMed - NCBI I guess I'd advocate for pescetarianism against biofilms and coronavirus - 100% not advice. Felt like writing down these thoughts, thought Travis might hate them - SAMe-synthesized polyamines from arginine. But you have to use them somewhere and arginine/ornithine ties polyamines to the urea cycle related to nighttime water conservation (oxytocin/vasopressin/salt). Night is a form of survival mode, so some semblance to cancer would be natural through shared pathways, but sleep is not meant to be like drowning in lactate, and your brain suffers if either astrocytes or neurons interdependently can't manage it, or liver.
Ornithine transcarbamylase deficiency:diagnostic and management challenges in the ICU (polyuria)
Is there an astrocyte-neuron ketone body shuttle? - PubMed - NCBI

Maybe I'll find time to cite all this later. I've already cited resources for many of these claims across these forums and others. I know intelligent people agree with me on points, and Ray eats sardines - top source Phosphatidylserine - Wikipedia if right species. Jaminet was highly inspired by the Japanese diet both seafood and rice, acknowledging a pescetarian version of his diet was possible and put ideal levels of o-3 around 1g/day at some point (also used to suggest iodine up to 1mg/day or so but stopped).

I used to eat revolting sardines (+ uridine) known to be offspring of Atlantic Herring (afaik) trying to reach 3g/day o-3 for years with potatoes. There were good moments, more at peace in normal circumstances, calmer, superior for some anxiety/OCD disorders. Problems: in-can cooking (same as canned salmon last checked? Except salmon was a closed can, less oxidation maybe?) meaning risks of aluminum/leeching, some iron, PUFA oxidation/presence and resulting poor phospholipid composition for cell membranes (rather have tryglycerides, which when burned in stressful situations can be handled by things like GSH in an appropriate organelle - remedy included). But species of herring/sardines alone have PS, protein, selenium (GSH), Ca2+, vit D, T3?, etc. Potatoes seem like insulin generators when lowering fat, while the right type of rice with acetic acid and sugar should be kinder. Nigiri would appear easier on the body than potatoes + sardines.

But with that and seafood fat attracting dangerous toxins I stopped eating them years ago (even though it was only 1.5g/can o-3 much lower o-6 already, Atlantic Herring) along with tuna. Drainable canned seafood is ultimate survival food, especially if they used real salt, oysters. But I had a shopping experience where one of the few people I've seen buy sardines of that brand looked badly aged. Parasite-free (at least frozen) sashimi may be better even if you have to eat very high o-3 salmon/other sashimi and less of it. Still, sardines have rare properties and packaging.

This is what I suggest to people in general as a diet strategy to consider as a possibility when nothing else works, maybe preventative strategy or part of low irritant diets. Soft alternative to carnivore if you don't need the saturated-fat-backed steroid synthesis as much (sufficient androgens). Instead you switch to pre-formed cholesterol and steroid-promoting nutrients.

But part of the power of eggs lies in cooking them in saturated fat and after more weight loss I plan to simply re-add cooking fat to eggs to counter their o-6, since that seems like the best use of saturated fat - promoting steroid synthesis. I could see some people surviving low-carb by recovering their steroids and encouraging ketones. Includes possibly acetylcholine- and acetylcarnitine-stimulated ketogenesis in astrocytes (together with acetoacetate and polyamines (SSAT) demonstrate the importance of acetyl groups in brain function), but at least surely in liver - with high NAD+ from serine, low carb/calories and healing promoting acetoacetate over hydroxybutyrate:
3-Hydroxybutyrate dehydrogenase - Wikipedia
with ketogenesis promoted by things like PPARalpha and carnitine/lysine.
Peroxisome proliferator‐activated receptor alpha and the ketogenic diet
Combine with melatonin it seems you could survive low-carb or keep your brain quite functional without resorting to frequent fasting.
Sci-Hub | Ketogenic Diet Combined With Melatonin Overcomes Cisplatin and Vincrisitne Drug Resistance in Breast Carcinoma Syngraft. Nutrition, 110659 | 10.1016/j.nut.2019.110659

All this with PPARalpha promotes allopregnanolone, ketones with their anti-glutamate effects, probably cannabinoids (for TRP channels). High salt antagonizes stress response and paleos along with Jaminet are known for suggestings Na+ around 3g/day dependent on carb intake. Just misses Mg2+, maybe more lithium, but even without carbs seems potentially easier on the system than pure carnivore, even when it's effects from compounds like o-3.
Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes: involvement of peroxisome-proliferator act... - PubMed - NCBI

In contrast to Travis I still eat meat (not ideal) but I think the best place is in between, if you can source quality ethical seafood that covers most benefits of meat (exception: liver). Some people on the web reported improvements with rice and seafood diets especially scallops (eggs/shrimp for cholesterol, more), but same works with sugar which seafood has the nutrients to handle (glycine/taurine/everything) - even though PUFA+sugar didn't look great (maybe needs coordination, not immediately fatal) so in that case lower fat.

There are also exotic components such as asthaxanthin in krill so nigiri/sashimi seems worth it on occasion - for phosphatidylserine and others in their most possible bioavailable/unprocessed/safe form (without the anti-nutrients of plants). Yes parasites, but the ones I eat seemed frozen.

This is why I decided not to worry my friend about omega-3 pills too much. I'm sure they're part rancid but the rest can go toward lowering cortisol/stress and overactive immunity, despite the membrane/peroxidation damage they create (The rates of oxidation of unsaturated fatty acids and esters). That said it's garbage compared to real seafood and I think it's dangerous to take o-3 pills with insufficient protein/vit E/selenium/etc. Seafood even contains asthaxanthin in krill oil and a bit in salmon, which rivals vit E, so becomes an obvious choice:
Sci-Hub | Production of High-Value Products by Marine Microalgae Thraustochytrids. Bioprocessing for Value-Added Products from Renewable Resources, 293–323 | 10.1016/b978-044452114-9/50012-8

Astaxanthin (3,3’-dihydroxy-ß,-ß,carotene 4,4’-dione), a ketocarotenoid, is widely distributed in nature and is responsible for imparting the distinctive orange-red coloration in animals, particularly in shrimp, crabs, lobster, and salmonids of marine origin [6].

Astaxanthin Supplement — Health Benefits, Dosage, Side Effects

Astaxanthin appears to be recommended in the dosage range of 6-8mg daily, which is low enough that an enriched salmon oil or krill oil supplement may contain adequate levels. Doses of up to 20-50mg astaxanthin have been tolerated, although the exact toxicity and upper limit is not known.

Astaxanthin is known to be a more potent antioxidant than Vitamin E in regards to sequestering singlet oxygen (dioxide; O2) in particular[51][52] which is known to produce superoxide (O2-) that can sequester nitric oxide by forming peroxynitrate (ONOO-);[53] as high superoxide concentrations are known to impair blood flow by interfering with nitric oxide signalling, it is thought that astaxanthin could preserve signalling by nitric oxide.[7]

Travis wrote at length about ONOO- and gamma vit E so I won't bother.

Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. - PubMed - NCBI

Nitric oxide contrasts with most intercellular messengers because it diffuses rapidly and isotropically through most tissues with little reaction but cannot be transported through the vasculature due to rapid destruction by oxyhemoglobin. The rapid diffusion of nitric oxide between cells allows it to locally integrate the responses of blood vessels to turbulence, modulate synaptic plasticity in neurons, and control the oscillatory behavior of neuronal networks. Nitric oxide is not necessarily short lived and is intrinsically no more reactive than oxygen. The reactivity of nitric oxide per se has been greatly overestimated in vitro because no drain is provided to remove nitric oxide. Nitric oxide persists in solution for several minutes in micromolar concentrations before it reacts with oxygen to form much stronger oxidants like nitrogen dioxide. Nitric oxide is removed within seconds in vivo by diffusion over 100 microns through tissues to enter red blood cells and react with oxyhemoglobin. The direct toxicity of nitric oxide is modest but is greatly enhanced by reacting with superoxide to form peroxynitrite (ONOO-). Nitric oxide is the only biological molecule produced in high enough concentrations to out-compete superoxide dismutase for superoxide. Peroxynitrite reacts relatively slowly with most biological molecules, making peroxynitrite a selective oxidant. Peroxynitrite modifies tyrosine in proteins to create nitrotyrosines, leaving a footprint detectable in vivo. Nitration of structural proteins, including neurofilaments and actin, can disrupt filament assembly with major pathological consequences. Antibodies to nitrotyrosine have revealed nitration in human atherosclerosis, myocardial ischemia, septic and distressed lung, inflammatory bowel disease, and amyotrophic lateral sclerosis.

NO in low levels produced by eNOS by even progesterone should help nutrients penetrate harder to reach tissues like joints and cartilage, so may be important to get some eNOS at night through progesterone, GH/T3 and maybe muscarinic receptor activation which seemed to be promoted at least in the brain by DHEA/estrone (sulfate) . T/DHT also, dose-dependently. As melatonin both restricts NO while restricting metabolism itself, these other substances like DHEA/progesterone can be increased, and methylation can both produce melatonin and exploit the actions of NO and GH/T3 to help heal sensitive tissues during paralysis. It's a matter of having optimal levels of each. Carnosine can also restrict NO effects. * However it looks like in some studies it increased eNOS. Carnosine/beta-alanine could have dramatic benefits.
Carnosine interaction with nitric oxide and astroglial cell protection. - PubMed - NCBI
Carnosine facilitates nitric oxide production in endothelial f-2 cells. - PubMed - NCBI
Endothelial regulation of eNOS, PAI-1 and t-PA by testosterone and dihydrotestosterone in vitro and in vivo. - PubMed - NCBI
Dehydroepiandrosterone sulfate and estrone sulfate reduce GABA-recurrent inhibition in the hippocampus via muscarinic acetylcholine receptors. - PubMed - NCBI
Caveolins and the regulation of endothelial nitric oxide synthase in the heart

The muscarinic cholinergic m2 receptor was the first GPCR found to mediate an agonist-induced disruption of the caveolin–eNOS heterocomplex [10].

The Endothelial Nitric-oxide Synthase-Caveolin Regulatory Cycle
M(2) and M(4) muscarinic receptor subtypes couple to activation of endothelial nitric oxide synthase. - PubMed - NCBI

Some people on reddit (rarely read) shared my thoughts: carnosine - notably as an NO mopper within muscle and maybe consuming histidine and antagonizing PUFA - might help control immune/histamine reactions like those of coronavirus. Beta-alanine helps breathing somewhat. Of course, like I just wrote some NO is needed, so beta-alanine is best if NO already or pushed high, otherwise morning with some limit. I'm not sure anyone's investigating it for coronavirus, but as an effective sports supplement it's well-placed. I think it could help control not just iNOS but - in part based on my experience - excessive NO production through other means like nNOS when you stack a bunch of drugs. ** It looks like carnosine might have a specific nitrite-NO binding-converting ability, see extract below. But together with high dose methylene blue and lysine supplements might be overkill. I prefer carnosine (beta-alanine+carnosine) to either in personal experience and even on paper e.g. AGEs for fructose/PUFA/ribose + subjective effects.
Carnosine modulates nitric oxide in stimulated murine RAW 264.7 macrophages

This is in agreement with previous studies in which antioxidants were found to alter M2 polarization through ROS modulation [26]. When cells were pre-incubated with Car and stimulated with LPS + IFN-γ, a lower amount of IL-6 in supernatants was detected compared to that in ells stimulated in the absence of Car (Fig. 6e). Il-6 has recently been described as an important cytokine for alternate macrophage activation [39]. This observation could provide an explanation for the reduction in M2 polarization indicated by the flow cytometric results, although further in vitro and in vivo studies with models of inflammation are certainly needed. This provides a rationale to investigate the role of Car in modulating IL-6 signaling in macrophages under conditions, such as atherosclerosis, obesity and cancer, where alternative macrophages activation is of critical importance. Car pre-treatment also decreased the production of other pro-inflammatory markers, including IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12, and IFN-γ, although to a lesser extent. These results are in agreement with those obtained by Ooi et al. showing the ability of Zn-Car conjugates to inhibit inflammatory mediators production in LPS-activated RAW 264.7 cells [40]. Interestingly, TNF-α levels obtained from cells treated with LPS + IFN-γ in the presence of Car were comparable with those found in the supernatants of stimulated cells treated in the absence of Car. Nevertheless, a decreasing concentration of TNF-α was observed when cells were pre-treated with increasing concentrations (5, 10, and 20 mM) of Car (Online Resource 6), suggesting that, different from the other pro-inflammatory markers, higher concentrations of Car (> 20 mM) are necessary to produce significantly lower TNF-α levels than those found in supernatants of cells treated with LPS + IFN-γ in the absence of Car.

The results of the present study strongly suggest that Car, rather than decreasing the overall amount of NO formation, is directly interacting with NO by favoring oxidation of NO to its low toxic endproduct nitrite. Thus, it does not inhibit NO production in activated RAW 264.7 macrophages, according to preliminary data reported by Karabay et al. [41]. These results indicate an alternative mechanism for the hypothesized influence of Car on iNOS gene expression [32, 33]. In fact, it is evident that, under our experimental conditions of iNOS activation, a faster removal of NO from the cell environment (transformed by Car into nitrite) reduces the possibility of RNS formation (including peroxynitrite) [42]. This then limits oxidative damage to macromolecules with relevant beneficial effects for cell health and survival [30]. Although previous studies have indicated that Car might decrease NO production through the formation of stable Car–NO adducts [20], our results led us to hypothesize that Car somehow intervenes by accelerating the conversion of NO into nitrite via a still-unknown mechanism. It may also be possible that part of the beneficial effects of Car are due to just an increase in nitrite, since it has been demonstrated that nitrite can alleviate the effects of cerebral vasospasms [43] and can attenuate ischemia-reperfusion injury in the heart and liver [43, 44]. These beneficial effects of nitrite are very relevant under hypoxic conditions, where it has been suggested that it functions as an important source of NO for vasoregulation [45].

Although further experiments are needed to determine the exact mechanism, our findings show, for the first time to the best of our knowledge, that Car (but not its constituent amino acids) caused an increase in the amount of NO converted into nitrite by directly interacting with NO, thereby strongly suggesting a novel mechanism through which Car decreases apparent NO formation in stimulated murine RAW 264.7 macrophages. It may explain in part the beneficial effects of Car in reducing cell damage due to the overproduction of ROS and RNS.

Sports supplements might make sense in general - if not exploited by dangerous bacteria - but not sure about creatine since seems to act as an amplifier in general including immune reactions - whereas beta-alanine/carnosine might be expected to do the opposite, so might be required to protect tissues from ATP/other:
Creatine Supplementation Exacerbates Allergic Lung Inflammation and Airway Remodeling in Mice
Beta-Alanine Supplement — Health Benefits, Dosage, Side Effects
Maybe beta-alanine might help protect tissue while creatine allows a more powerful immune response as well as ATP for immunity, signaling and tissue integrity. Healthy, well-buffered lean tissue means everything, tissue damage/loss needs to be replaced or your chances of recovery from reinfection/injury might fall every time. You'd expect the outcome to depend on cholesterol and phospholipids at least.

This is meant to list theoretical ideas to counter the bull**** the media spews how no diet will save you. Essential part of the solution, especially to lower dependence on glucocorticoids, and compounds in seafood have numerous pharmacological effects expected to protect from effects of pharmaceutical drugs, fortunate since it probably contains traces of them.

I think sustainable seafood is the best compromise between human health, ethics and environment - avoiding most cows/beef entirely and focusing only on liver, emphasis raising those animals on healthy stock. A healthier population should be more able to take responsibility for those problems. Some of the most impressive civilizations valued seafood to raw extremes, and you expect it to promote intelligence, with carbs. Even religious significance (not an appeal, observation). The mainstream writes these but it's so much more than o-3 and carbs:

Since healthier plants contain o-3 to o-6 ratios toward linolenic acid (C18:3) and it can fill basic requirements - like Travis argued iirc and you can say he demonstrated - the evolutionary advantages from seafood seem maybe even less from its EPA/DHA content and toward the rest.
By Land or by Sea: How Did Early Humans Access Key Brain-Building Nutrients?

He suggests that it was not just omega-3s but a cluster of nutrients found in fish (including iodine, iron, zinc, copper and selenium) that contributed to our big brain. “I think DHA was hugely important to our evolution and brain health, but I don't think it was a magic bullet all by itself,” Crawford says.

Evolution of the Human Brain: the key roles of DHA(omega-3 fatty acid) andD6-desaturase gene

I'm sure fruits and starches played significant parts as also thought. But seafood fills in for inability to tolerate gelatin, glycine or serine due to problem foods like egg whites, providing cholesterol and compounds limited in fruits/vegetables. I'm sure fruitarianism/veganism/vegetarianism can work for temporary low-protein periods therapeutically, as well as carnivore with carbs, but they can't do it as well or allow making significant diet+supplement restrictions with less risk. Like Travis suggested pre-formed retinol doesn't seem essential or beneficial for everyone so liver can be replaced by fruits/vegetables to an extent, until worse stress/disorders.

May contain inaccuracies (feel free to correct) and these studies occasionally have conflicting ones, but there are enough arguments for temporary and even permanent (ovo-)pescetarianism the idea regenerates itself from endless studies.

Edit: corrected some mistakes, didn't realize there were so many lol

*** "gay" is a ubiquitous expression in my life and symbolizes the extent to which I do not wish to expand on that part of the conversation

 

[Terma]

Microplastic contamination in Penaeid shrimp from the Northern Bay of Bengal - ScienceDirect
https://www.researchgate.net/public...rs_of_the_Southern_North_Sea_and_Channel_area

 

[Terma]

These are not suggestions to anyone, there are certainly risks: for example I don't know these interactions in practice (yet), thus concern about accumulation/flux, and it's difficult to tell what your methylation cycle liver/brain is doing. It's theoretically possible to create dangerously high levels of uridine in cancer or promote it some way:
Leflunomide - Wikipedia
and folate/methylation is required to convert uridine into thymidine along with B6/serine to recycle it (that's why you want SHMT so you must prevent its silencing with aging - even if you only think you want glycine). This is a part of the pathway you also want to avoid artificial folic acid, for DHFR. So this is full of caveats but the main takeaway is you can achieve a best-bet diet for prominent conditions using only safe supplements as extras if no allergies/intolerances, with huge focus on circadian rhythm. Paul especially suggests germs but this can already improves immunity, inflammation, high ROS, stress resistance, and can lower/protect against Fe and PUFA if the fats are reasonable.

***

If thyroid is huge player in intelligence which it clearly matters then selenium is great survival advantage, especially out at sea, sometimes wikipedia manages:
Selenium - Wikipedia

Selenium salts are toxic in large amounts, but trace amounts are necessary for cellular function in many organisms, including all animals. Selenium is an ingredient in many multivitamins and other dietary supplements, including infant formula. It is a component of the antioxidant enzymes glutathione peroxidase and thioredoxin reductase (which indirectly reduce certain oxidized molecules in animals and some plants). It is also found in three deiodinase enzymes, which convert one thyroid hormone to another. Selenium requirements in plants differ by species, with some plants requiring relatively large amounts and others apparently requiring none.[5]

So if Se is less than optimal both thyroid and GSH, plus others like gene transcription and immunity suffer, meaning a more available supply raises the bar for higher metabolism, immunity and genetic integrity. I imagine sub-clinical deficiency compromises them especially in times of stress. Add iodine, glycine, aminos, all above. If there's any one mineral you'd want to be on the upper end of safe of (depending on the side-effects of course) is Se.

***

A few years back people were worried fluoroquinolones caused adducts: Does a role for selenium in DNA damage repair explain apparent controversies in its use in chemoprevention? - PubMed - NCBI

My (only) personal non-medical thought when taking fluoroquinolones by force if you can't take any supplements or are contraindicated is eat lower o-3 seafood like shrimp, scallops, oysters, because you will be under greater oxidative stress and need all the help you can get from glycine/taurine plus cholesterol for immunity.

They contain a little copper but not amount high enough for oxidative stress, and you can find some of these with low Fe - this is probably a good way to both prevent fluoroquinolone damage and lower risk of infection, plus Zn to antagonize absorption. However it's possible for manganese in fruits to cause problems like that iirc...
Dietary manganese promotes staphylococcal infection of the heart

But you don't want any immunosuppressive effects which o-3 can give, because if you're going to take one of these things, at least make it count - medical professionals aren't taking any such precautions.

Uric acid from purines in seafood acts as an antioxidant that could help control the ROS from fluoroquinolones, but cysteine, glycine, Se, serine may be instrumental in maintaining GSH, SOD, Cu, Zn levels to prevent ROS damage from fluoroquinolones (though there might be NOX?).

Mg2+ and NAC have the known potential to help/prevent damage from fluoroquinolones, but Mg2+ has to be timed apart carefully if risked and NAC can weaken its effect on bacteria, so doxycycline is a possible alternative for its ROS-scavenging effects. I've recommended other things in the past like MB but I would not want to risk compromising NADPH recycling further while taking a fluoroquinolone antibiotic.

This document recommends taking ALA (lipioc acid) with it, which seems intelligent to me as song as it doesn't affect the bactericidal effects negatively:
https://www.ema.europa.eu/en/docume...-fluoroquinolone-written-interventions_en.pdf

Your question 3: FQ should only be given to patients that are stationary in hospital under strong supervision and no other Doctor should be allowed to prescribe FQ. If FQ are given as a last resort to apatient, these Doctors should have a special training and they should also make sure, that the patient is getting with his FQ intake Alpha Lipoic Acid R Form to protect the cells.

Again you can make a strong case for ALA's Fe handling, maybe hemoglobin/NOX even PUFA; people had concerns about mercury from seafood, but ALA could maybe heal handle volatile o-3.

Once the damage is done it's much more difficult to reverse and you maybe be talking about NAD+ therapy, GH, BPC-157?, steroids/VGCC/GABA together with Mg2+, vit C, protein.

Rebuilding tissues can take years, so medical recommendations seem geared to inflicted maximum damage on bacteria regardless of collateral damage, it's totally wreckless, ruins lives.

***

Note:
Science: Copper and cholesterol make a lethal cocktail

After they had eliminated the effects of smoking and age, Salonen and
his colleagues found three factors which contributed to thickening of the
arterial wall: a high level of ‘low-density lipoprotein’ (LDL) cholesterol
in the blood; a high level of copper; and a low concentration of selenium.

If you acknowledge that GSH chaperones copper, Se is at least involved with Cu.

If you consume high Se it seems likely you could more safely tolerate higher levels of iodine, maybe copper. It's not necessarily ideal for the thyroid as an isolated effect I assume but it might promote stronger immunity and fluoride excretion so the animal is exposed to less inflammation and lower levels of poison accumulation over its life. Iodine is powerful so the organism that exploits it has a distinct advantage.

***

This is maybe a very large evolutionary advantage with regard to thyroid: you only need a small amount of daily iodine, but cultures often had periods of famine and seasonal variation - sometimes enforced for sustainability - so it would have been an advantage to have access to a food supply naturally higher to compensate for times of scarcity (where you also need Se and glycine for ROS from FAO). There's naturally seaweed that can be preserved.

***

Originally Paul had recommended around 1mg/day iodine but withdrew it due to concerns of variability in Se in food iirc (correct if wrong) settling on the current RDA? There was a period I was doing 1mg/day and several aspects of health were better than doing 300mcg/day, by coincidence. This was despite consuming fluoridated water, only back then. In fact I wonder if that effect doesn't help antagonize the extra fluoride in fruits and juices accumulated from water/soils? I'm not sure exactly but I won't go under 400mcg/day extra potassium iodide anymore, even though you must get quite a bit or well enough from seafood and eggs (Se).

I think the original suggestion of 1mg/day makes sense for our environment if you eat sufficient seafood variety and eggs. Some countries tolerate these levels or more. If you believe thyroid is at the core of problems and intelligence, then the supply of these minerals should have raised the bar. Or at least if you want to antagonize fluoride rise in food/water and find better antibiotics, fight infection, prevent needless antibiotic exposure. NaCl also makes sense for this.

***

So with a keto seafood diet you get potentially higher thyroid potential overall from minerals, aminos and overall nutrition without the confines of low-carb. Probably increased growth hormone at night, at same time as improved ketogenesis both in astrocytes and liver (in part helped by factors in seafood) and proper handling of o-3/PS lipids from precisely things like higher Se supply, then NAD+ in morning.

That sounds like the way to develop intelligence. Ketogenesis could have been evolutionarily pressured by survival at sea + high salt intake + high oxytocin/vasopressin (water conservation). This seems like a very powerful set of circumstances.

Fish may have methionine but the selenium makes up by helping against cancer:
Selenium: from cancer prevention to DNA damage. - PubMed - NCBI

Methylation's involved in promoting cancer for sure, but it has circadian aspect and many beneficial properties including producing melatonin for restoration (it's almost as if the cancer cells hog the methyl groups!) and methylating histamine. But cancers must be half NK cell and immune system/signaling defects (HSP70) which maybe could be prevented with higher baseline Se/I and even melatonin.

Carnitine synthesis is essential for keto and as studies further above suggest for the health of astrocytes.

***

Since SAMe converts serotonin to melatonin:
Acetylserotonin O-methyltransferase - Wikipedia

On this forum dedicated to Ray Peat there are numerous beneficial effects of melatonin despite lowering metabolism, I guess because it's appropriate for sleep and nature exploits the calm to repair?

But really it's because SAMe (usable methionine) increases the melatonin:serotonin and methylhistamine:histamine ratios that you know it has to be worth having at that time; adrenaline as emergency or natural wake-up signal.

SAMe seems worth ensuring sufficiency (meaning abundance in uncertainty) as various hormones do, despite ambiguous risks of DNA methylation, I guess traditionally posed by dietary methionine + B12 supply abundant in seafood (but in fact Travis argued for glutamate for DNA methylation - well with enough cystine/glycine/methione it goes toward GSH and other productive purposes).

***

However fruits/vegetables were the crucial sources of folate - more than vitamin C or K1 maybe? Package deal
folate
This lends credence to humans most benefiting from coastal environments due to availability of both seafood and fruits/vegetables. On top of that some cultures had access to bird eggs, plus birds from forests/jungles.

Fruits especially must have provided nevermind vitamin C and manganese for MnSOD and tissues but especially folate and sugar, a good combination whether for daytime or early nighttime recovery processes - unless they disturb the intestines, which is a major issue for myself.

If T3/thyroid can lower GNMT it may help to have the most SAMe available to make the best of it at the same time, whether night or even day to some extent (reflecting pheripheral vs other tissues I suppose).

However I think that respecting the role of SAMe in nighttime processes is probably the prudent approach to avoiding cancer.

So in the morning and lunch you'd eat alpha-GPC/CDP-choline, eggs, fruits/vegetables, tyrosine, histidine. The retinol in eggs is nicely timed for increased retinoic acid signaling during the day (converted using NAD+ in the morning in the right tissues, it seems - together with calorie-restriction enzymes likes SIRT), all without getting into worrying levels. Lutein (eggs/veg) might have relevance.

In the evening you have the protein-dominated seafood and fruits/starches. If you're dieting you sometimes have to increase protein intake in the morning instead for satiety especially. But I find free aminos work excellent, with lysine last resort.

***

Sugar simply gives us and kidneys/liver a metabolic/ROS break during the day. Like Ray says it encourages CO2.

I think it simply works like this: during the day you want CO2 with carbs especially while during the night you want the metabolic flexibility to shift to well-controlled longer-chain fatty acid oxidation on top of ketones.

At night the CO2 drops with the shift to FAO and you compensate CO2 with eNOS increased by various hormones.

This inhibits the organism clearly, but seems to help tissue healing of sensitive tissues, helping deliver nutrients to tissues with lower blood flow. This is why studies like this remain plausible (there were several more including some demonstrating nitrates vs arginine as substrates for NO synthesis):
Using nitric oxide to treat tendinopathy

eNOS is something progesterone and thyroid tend to do as well:
https://www.researchgate.net/figure...ntrationdependent-effects-of-T-3_fig5_6823609
Thyroid hormone affects both endothelial and vascular smooth muscle cells in rat arteries. - PubMed - NCBI
Thyroid hormones stimulate L-arginine transport in human endothelial cells in: Journal of Endocrinology Volume 239 Issue 1 (2018)
Thyroid hormone stimulates NO production via activation of the PI3K/Akt pathway in vascular myocytes
There GH comes into play with T3 conversion at night so timing matches up well with the concept of the FAO-eNOS association: progesterone/thyroid drive the nutrient pool. GH becomes a problem mainly together with cortisol, I think.

I want the metabolic flexibility for daytime acetylcholine/carbs/CO2/DHEA/DHT/dopamine/histamine/pregnenolone/T versus nightime allopregnanolone/eNOS/FAO/GH/ketogenesis/methylation/melatonin/progesterone/serine.

In my non-expert opinion, this reflects Jaminet's ideas especially in the sense that this cycle should be expected to potentiate the circadian rhythm, GH, kidney health, NAD+ levels, thyroid health and several health parameters. It's an important factor in aging. However you can implement it using only Ray-approved sustances if you wanted (I'd only push for choline, but you could use acetylcholine antagonists).

***

At the same time fruits/vegetables provide high folate. It permits proper functioning of the methylation cycle, for nighttime regeneration especially? Of course you had associations of folate with cancer.

Folate can also be used to make purines and NADPH (requiring serine and B6) and even activates AMPK so it's an extremely valuable vitamin. It's more versatile than glucose and broader in purpose than vit K except mitochondria. Glucose has to be balanced with folate:
Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome. - PubMed - NCBI

Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome.
Buettner R1, Bettermann I, Hechtl C, Gäbele E, Hellerbrand C, Schölmerich J, Bollheimer LC.
Author information
Abstract

The AMP activated kinase plays an important role in metabolic control, and pharmacologic enhancement of AMPK activity is used to improve insulin resistance. We hypothesized that high dose of folic acid supplementation might improve insulin sensitivity and hepatic inflammation and examined this by a dietary intervention in (a) the high fat fed rat model of the metabolic syndrome, which shows sole hepatic steatosis as well as (b) in rats fed with a high cholesterol, high cholate diet inducing nonalcoholic steatohepatitis (NASH). Male Wistar rats were fed with folic acid supplemented (40 mg/kg) high fat diet [based on lard, fat content 25% (wt/wt)] or NASH inducing diet (containing 15% fat, 1.25% cholesterol, 0.5% sodium cholate). Metabolic profiling was performed by measuring the animals' visceral fat pads, fasting plasma glucose, insulin, and adipokines as well as in vivo insulin tolerance tests. Hepatic steatosis and inflammation were analyzed semiquantitatively by histological analysis. Folic acid supplementation reduced visceral obesity and improved plasma adiponectin levels. In vivo insulin sensitivity was improved, and in HF-FA rats folic acid increased activation of hepatic AMPK. Further, folic acid supplementation improved hepatic inflammation in animals fed with NASH-inducing diet. Dietary folic acid improved parameters of insulin resistance and hepatic inflammation in rodent models. This might be due to an increased AMK activation.

Folic acid supplementation during high-fat diet feeding restores AMPK activation via an AMP-LKB1-dependent mechanism

It could however lower cholesterol synthesis in the liver - but you could count this against the arguments commonly made about natural folate-containing carbohydrate sources:
https://www.fasebj.org/doi/abs/10.1096/fasebj.30.1_supplement.870.3

Non-alcoholic fatty liver disease (NAFLD) is a worldwide epidemic associated with obesity and type 2 diabetes. Chronic high-fat diet consumption promotes NAFLD which is characterized by hepatic lipid accumulation, hyperglycemia and hyperlipidemia. Emerging evidence suggests that metabolic aberration during NAFLD may be related to dysregulation of AMP-activated protein kinase (AMPK). AMPK is an endogenous energy sensor involved in regulating lipid and glucose metabolism, which has been proposed as a potential therapeutic target in NAFLD and its associated metabolic disorders. Folic acid is an essential B vitamin that has been implicated in NAFLD through improvement of liver function. The aim of our study was to investigate the mechanisms by which folic acid supplementation regulated hepatic AMPK and its impact on cholesterol and glucose metabolism. Male C57BL/6J mice were fed a control diet (10% kcals fat), a high-fat diet (60% kcals fat) or a high-fat diet supplemented with folic acid for 5 weeks. Mice fed a high-fat diet exhibited fatty liver, hyperglycemia, elevated activity of hepatic HMG-CoA reductase and lower AMPK activity. Folic acid supplementation restored AMPK activity, attenuated hepatic lipid accumulation and reduced blood glucose levels. Activation of AMPK by folic acid was mediated, in part, through activation of its upstream kinase LKB1. Folic acid-induced AMPK activation could attenuate HMG-CoA reductase activity via AMPK-dependent phosphorylation of the reductase and hence reduce hepatic cholesterol biosynthesis. Our results suggest that folic acid supplementation can improve cholesterol and glucose metabolism through restoration of AMPK activation in the liver, which may have a therapeutic implication in mitigating hepatic lipid accumulation and hyperglycemia in NAFLD.

On the other paw it's a good thing to know?

What else is known to affect STK11 - Wikipedia

Testosterone and DHT treatment of murine 3T3-L1 or human SGBS adipocytes for 24 h significantly decreased the mRNA expression of LKB1 via the androgen receptor and consequently reduced the activation of AMPK by phosphorylation. In contrast, 17β-estradiol treatment increased LKB1 mRNA, an effect mediated by oestrogen receptor alpha.[6]

Conclusion: high folate might be expected to require sufficient blood glucose and could act in some ways opposite to T or DHT for healing or feedback signaling, maybe, considering SAMTor and the several points they could converge? Then again androgens are more about mTorC1/mTorC2 activation there might be antagonism with folate AMPK, suggesting folate to help with some high androgen symtoms? However, that might only apply if it's not converted to methylfolate for SAMe (SAMTor).

***

Even better:
Effects of testosterone on the metabolism of folate coenzymes in the rat

1. The effects of castration and testosterone treatment on enzymic activities involved in folate coenzyme metabolism in the liver and in accessory sex organs of male adult rats were studied. 2. In the liver of castrated rats the concentration of 10-formyltetrahydrofolate (10-HCO-H4folate) synthetase and tetrahydrofolate (H4folate) dehydrogenase were significantly decreased whereas that of 5,10-methylenetetrahydrofolate dehydrogenase increased; the treatment with five doses of testosterone caused a return to normal values of these activities. 3. In the prostate of castrated rats a pronounced decrease in H4folate dehydrogenase, serine hydroxymethyltransferase and 10-HCO-H4folate synthetase activities was observed. The administration of testosterone restored the enzymic activities to normal values. 4. In the seminal vesicles of castrated rats only 10-HCO-H4folate synthetase was markedly depressed; testosterone treatment not only restored activity to normal values but raised it to higher than normal values. The slight changes observed in other enzymic activities also returned to normal values with the hormone treatment. 5. These results are discussed in relation to a possible control mechanism of folate metabolism by testosterone.

Superficially this study suggests an increase in valuable methylene-THF in castrate rats and lower formyl-THF synthetase; administering T meanwhile seemed to drive it toward ATP production:
5-formyltetrahydrofolate cyclo-ligase - Wikipedia

But this also means that lower folate intake during maritime ketogenesis could theoretically have had glucose usage modulating effects (AMPK/etc.). I think you could add folate restrictions to important evolutionary pressures.
folate

At the same time these guys reported breast cancer could be related to low folate status while simultaneously while T or maybe androgens:
Do Higher Testosterone and Folate Deficiency Conspire to Increase Breast Cancer Risk?
If you consider DNA, methylation/SAMe, polyamines, purines, ATP, NADPH, it's guaranteed folate must work together with androgens, possibly estrogen and steroids in general - maybe countering in other ways like AMPK. If you place methyl groups in the right places at night you can eat high methione/glutamate/B12 like Travis warned but my hope is they get invested properly into healing during nighttime.

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Perhaps that's part of how folate recycling might have improved evolutionarily? SHMT creates useful methylene-THF from THF (basic folate) using B6 and serine.

Where are B6 and serine? Seafood, eggs. Speeding up transamination?
vitamin B6 - pyridoxine

In other words: just like this diet could have encouraged ketogenesis, it also would have provided more cofactors for efficient folate recycling during folate restriction, so it works out, at the expense of some extra work by the kidneys in a few different ways.

That's a major thing you can do eating a scallop and rice diet: limited folate intake. This could maybe encourage hormetic effects - or rather I'd suggest - impact histone and/or gene expression, since (I've posted the links earlier on this board) folate is involved in maintaining gene expession beyond GSH (NADPH/cysteine), methylation, purines and thymidine synthesis, which already seems like a number, but then it might help prevent formaldehyde:

So folate deficiency maybe might have quite some effects on the maintenance of gene expression or I'd suggest prioritization. At the same time, some warnings required for 30mg deplin doses maybe? Might be worse with folinic acid? According to this:
Folate and formaldehyde: from vitamin to genotoxin to DNA building block - MRC Laboratory of Molecular Biology

Previous work from KJ Patel’s lab had shown that mammals are continuously producing the toxin formaldehyde. They further showed that when the protection against this molecule is removed in mice then the levels of endogenous formaldehyde rise leading to overwhelming DNA damage and rapid death. Our cells possess two tiers of protection against this endogenously produced formaldehyde: the first tier consists of an enzyme called alcohol dehydrogenase 5 (ADH5) that detoxifies it, the second tier or essential backup is DNA repair which fixes the damage done to chromosomes by formaldehyde. In this most recent work the scientists uncover where and how in our bodies some of this formaldehyde comes from. They further show that as the cell processes formaldehyde using tier 1 protection, it essentially converts this violent reactive chemical into a molecule that is eventually used to make DNA.

I guess it's true if you for some reason your formyl-THF or formaldehyde production is too high, you might be tempted to go on a pure seafood low-folate diet, like someone once said.

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At the same time you don't want too low B9 and Fe at the same time, low Cu and high Zn because it maybe become a recipe for anemia, maybe more depending on sex, but eggs and vegetable can fill in unless you need liver or red meat.

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Note that ADH5 - Wikipedia is also used to convert retinol:

This gene encodes glutathione-dependent formaldehyde dehydrogenase or the class III alcohol dehydrogenase chi subunit, which is a member of the alcohol dehydrogenase family. Members of this family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Class III alcohol dehydrogenase is a homodimer composed of 2 chi subunits. It has virtually no activity for ethanol oxidation, but exhibits high activity for oxidation of long-chain primary alcohols and for oxidation of S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione.

So I suppose very theoretically excessive (free?) retinol might impede formaldehyde detoxification?

So I think that probably folinic acid isn't a good idea, because - the optimal amount - of oral methylfolate (~200mcg - ?) for long life could be bound by a dose that produces DNA damage. Ultimately you need the seafood specifically to balance folate with methionine and B12, but serine/glycine/B6 could additionally enhance folate recycling.

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Another way to see it is that during the day you load up on the folate or methylfolate. Notably your body can *probably* use larger doses to generate NADPH for defense and steroid synthesis. Later in the night after a meal of fish/scallops you get arginine/B6/B12/glycine/methionine/serine/taurine and usually lysine. All these are hunger-controlling amino acids and with cholesterol and choline/phospholipids bile acid-promoting so digestion is well-supported and you get the most out of your meal especially targeting GH release in the early night.

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The seafood and fruits/vegetables combo if no allergies/kidney problems (even then if you find lower uric acid options) might be the healthiest way to achieve all the nutrients for healthy nighttime methylation, plus the glycine/taurine in seafood for both sedative effect and helping of handling methylation and volatile amino acids in a healthy way.

Eggs meanwhile are high in cholesterol and choline. Choline is especially for membrane lipids but eating choline in the evening could be problematic if acetylcholine increases, some people seem sensitive. But with cholesterol, choline, phospholipids, selenium, vitamin A, etc., eggs make the best brain food in the morning, something people naturally crave. Sardines as well but you'd have to convince people to swap their bacon for it and I already tried eating it for breakfast for extended periods. It works but you dread eating.

Basically ovo-pesceterianism especially with fruits/vegetables covers the basic nutrients required for healthy circadian rhythm - both daytime and nighttime - and therefore has to delay aging, in my opinion. There are other healthy foods like cheese and liver but a lot of people reach forums through google and desperate and have to eliminate problematic foods for awhile.

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Based on my own research and experience I think people probably had real success on things like the grapefruit and egg diet to an extent - so you could also exclude seafood and eat only egg yolks and fruits/vegs as a low-protein alternative for awhile - maybe with extra amino acids and supplements for some with kidney issues who can't tolerate either more protein or uric acid? Eggs in fact have no uric acid so you can make a gout-elimination diet like this with optional dairy.

But the point is I think it's possible to create relatively healthy extremely restrictive diets that can be used therapeutically against brain/gut/liver disorders, since we built and sailed ships on such diets, to my knowledge. Pickling of seafood must have forced increased salt intake, but also great survival tool if attainable.

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Folate is critical but my opinion is that betaine/TMG is best avoided - instead encourage the B9/B12 remethylation route.

This is because this is a known positive role of B12 so it's good to consume it this way - as well as make good use of B9 and methionine. Seafood is full of B12 - it means you can take full advantage of the methionine. I think it might be the SAMe:methionine or SAMe:homocysteine and similar ratios that determine the efficiency of use of methionine toward healthy purposes. Of course it also goes to creatine synthesis. Apparently the more creatine you can synthesize, the less absolutely sleep needed to function.

Increased methionine and SAMe can be used to synthesize creatine means they can be used to lower the need for sleep, especially in times of stress, I'd suggest times of cold, too.

Creatine is a form of investment: it costs ATP to synthesize SAMe (S-adenosylmethionine synthetase enzyme - Wikipedia), but later on creatine helps buffer ATP. This way you turn methionine into a metabolic or power advantage, and help preserve lean tissue. I guess that's one reason to eat muscle meat or whey for methionine (with option to avoid the extra TMAO from dietary carnitine), but they're lower in arginine and glycine, so in fact seafood provides the best-rounded packages for creatine synthesis unless you include collagen/gelatin. Add to that cholesterol content (best in ghee for strict diets?) to increase androgens/IGF-1/T/DHT/etc. and it sounds like a food source designed for lean tissue preservation.

It's arginine that becomes all of: polyamines, NO, creatine, urea cycle... whereas SAMe participates in highly desirable reactions and a few less, especially in the absence of estrogen.

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In my opinion choline (from alpha-GPC, CDP-choline, eggs) is healthier than betaine/TMG because it does not necessarily encourage the PEMT enzyme to incorporate PUFA excessively into membranes/phospholipids. TMG on the other hand is processed especially locally to the liver by BHMT, so you generate a load of methionine in the liver. Since PEMT is a known high consuming of methyl groups in the liver and stimulated there by estrogen, it seems like the best way to to send PUFA into your membranes is high estrogen combined with high betaine/TMG/BHMT.

This might be worsened if deficient in L-serine or P5P so if kidney or liver function is compromised in general. Glucocorticoids and possibly other stressors induce BHMT along with estrogen, so there's a cooperation between cortisol and estrogen to store PUFA into phospholipids:
Sci-Hub | Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Cellular and Molecular Life Sciences, 63(23), 2792–2803 | 10.1007/s00018-006-6249-6

Increases in BHMT activity and mRNA levels were observed by the action of hydrocortisone, cortisol and triamcinolone, whereas growth hormone only induced BHMT mRNA [18, 34, 65, 70–76].

Note again GH increases remethylation so along with lowering GNMT (together with T3) in theory this should increase the availability of SAMe. This is during high ALLO, GABA, oxytocin, melatonin, progesterone or some balance with others.

So in times of extra stress cortisol can alter methylation. Helps further explain associations between glucocorticoids and cancer, by promoting SAMe (polyamines/SAMTor/carnitine/etc.) during stress at the same time as causing immunosuppression; then estrogen provides proliferation and survival mode with FAO/FAS.
Glucocorticoids promote breast cancer metastasis
Glucocorticoids and Cancer

So if hormones like cortisol and estrogen drive cancer, you don't have to worry as much at night about methylation as long as those aren't high, and unless you take too much DHEA or T or don't sleep you could likely avoid the major risk factors with strong NAD+, circadian rhythm and immunity.

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I suppose if GR receptors desensitize in the hypothalamus you get cortisol release; but if liver GR lost sensitity you'd get compromised ability to promote SAMe via BHMT and/or other effects [along with the usual insulin resistance - I wrote this backword earlier]. This might translate further into higher homocysteine, which kidneys/P5P/serine can somewhat compensate, until they succumb... maybe not necessarily all from tissue catabolism, but/also from extra inflammation if the receptors on the right cells desensitize? Just thinking out loud, but GR sensitivity loss could work several ways to impede healing; not only for catabolism but preventing healing. But this is a reason you may have to restore methylation as part of healing.

From that angle carnitine can be a relative improvement even if it activated GR receptors as long as it were an equal or weaker agonist as cortisol, because it can help solve ROS and problems with fatty acid or propionic acid overload. For seafood helps lower absolute need for vit E, I'd imagine.

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The advantage of having PEMT would be properly packaged o-3 PC/PS in liver - handling the seafood properly, or as best possible - unless you'd prefer to burn it or excrede it immediately and leave smallest amount possible in membranes. I guess it depends on brain o-3 levels? But choline encourages more mono/sat phospholipids.
Dietary docosahexaenoic acid supplementation modulates hippocampal development in the Pemt-/- mouse. - PubMed - NCBI

The development of fetal brain is influenced by nutrients such as docosahexaenoic acid (DHA, 22:6) and choline. Phosphatidylethanolamine-N-methyltransferase (PEMT) catalyzes the biosynthesis of phosphatidylcholine from phosphatidylethanolamine enriched in DHA and many humans have functional genetic polymorphisms in the PEMT gene. Previously, it was reported that Pemt(-/-) mice have altered hippocampal development. The present study explores whether abnormal phosphatidylcholine biosynthesis causes altered incorporation of DHA into membranes, thereby influencing brain development, and determines whether supplemental dietary DHA can reverse some of these changes. Pregnant C57BL/6 wild type (WT) and Pemt(-/-) mice were fed a control diet, or a diet supplemented with 3 g/kg of DHA, from gestational day 11 to 17. Brains from embryonic day 17 fetuses derived from Pemt(-/-) dams fed the control diet had 25-50% less phospholipid-DHA as compared with WT (p < 0.05). Also, they had 60% more neural progenitor cell proliferation (p < 0.05), 60% more neuronal apoptosis (p < 0.01), and 30% less calretinin expression (p < 0.05; a marker of neuronal differentiation) in the hippocampus compared with WT. The DHA-supplemented diet increased fetal brain Pemt(-/-) phospholipid-DHA to WT levels, and abrogated the neural progenitor cell proliferation and apoptosis differences. Although this diet did not change proliferation in the WT group, it halved the rate of apoptosis (p < 0.05). In both genotypes, the DHA-supplemented diet increased calretinin expression 2-fold (p < 0.05). These results suggest that the changes in hippocampal development in the Pemt(-/-) mouse could be mediated by altered DHA incorporation into membrane phospholipids, and that maternal dietary DHA can influence fetal brain development.

I would suggest this explanation for our tolerance of o-3s: maybe PEMT important to help us package o-3 as safely as possible (3 methyl groups?) as phospholipids at least outside the brain with contribution from BHMT, and this might highlight the value of seafood during an ice age (during which our populations presumably declined, allowing some proliferation and later nutrients with melting glaciers)? But it's a fragile compound maybe already degraded and a long road so you don't want an overload of o-3 causing high peroxidation or immune suppression. The higher cortisol + estrogen.

So the key is especially to avoid that combo. There's no way I know of completely around a morning cortisol peak, but you could possibly avoid estrogen and serotonin.

In the evening you might get end up with serotonin, but methylation helps convert it to melatonin and histamine to methylhistamine (again - this is getting long). You need to do this to avoid triggering cortisol release.

But you need all these major things for this to function:
1. Aminos (glycine, methionine, serine, taurine, for carnitine, creatine...; tyrosine for dopamine and morning (nor)adrenaline)
2. Fatty acids (ketogenesis and ATP)
3. Minerals (Mg2+, K+, right level Na+/Cl- + vit C for angiotensin/oxytocin/vasopressin balance, Ca2+ to offset dietary phosphate and at nighttime works together with active vitamin D to build bones and like Ray says keept PTH low - but some people seem highly sensitive to TRP/Ca2+ channels, I guess at least in certain neurons, bladder, etc.)
4. Cholesterol for pregnenolone and ultimate GH and DHEA synthesis, along with the minimum required for morning cortisol.

It seems conceivable to me that GH helps orchestrate the anabolic effects of (active) vitamin D with T3, IGF-1 and the others, probably healing effects of ALLO/oxytocin/etc., with inhibition implemented by cannabinoids/GABA(A/B)/melatonin, later in morning heading toward DHEA, NAD+, retinoic acid (unless you're full of aldehydes?) and cortisol.

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Meanwhile serotonin synthesis during nighttime might help implement nighttime vigilance, so its synthesis or sensitivity resembles a threat level.

Methylation can increase adrenaline as mentioned, so too much SAMe or PNMT/NMT and the system's always ready to jump at the sign of danger.

But there's also post-synaptic 5-HT1a. Maybe it might get activated more in the evening, and stressed people with chronically stimulated sustainable 5-HT2/3 signaling are more easily stressed and vasoconstricted (with 5-HT3 interacting with TRP channels and probably other Ca2+ chanels in general) before factoring in angiotensin. This would speak to the importance of avoiding stimulation in the evening.

On top of that kynurenic acid has known inhibitory effects on neurotransmission (Mg2+ + KYNA might help counteract quinolinic acid/glytamate/glycine/sarcosine NMDA agonism).

Fluoxetine is known to increase KYNA, I could imagine that KYNA on top of ALLO might allow SSRIs to offset or tolerate their pro-serotonergic effects (transient or not), it almost seems like a deliberate mechanism (you could also consider GSH/NADPH levels affecting KMO):
New insight into the antidepressants action: modulation of kynurenine pathway by increasing the kynurenic acid/3-hydroxykynurenine ratio. - PubMed - NCBI
Prolonged therapy with antidepressants increases hippocampal level of kynurenic acid and expression of Kat1 and Kat2 genes. - PubMed - NCBI
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So to me antagonizing receptors like 5-HT2c + KYNA + ALLO altogether I could see how someone might benefit from fluoxetine in particular. It even has anti-viral effects according to some sources? But personally I would never consider it more than a temporary therapy, and post-synaptic 5-HT1a can't last forever if it's that since it releases cortisol. I find unlikely cortisol would be an absolute requirement for oxytocin release since you have ERbeta, promiscuous for several steroids - there exist some that stimulate less ERalpha. Retinoic acid also plays into the expression of these receptors.

But there seem to be yet other mechanisms, maybe through histamine and/or cannabinoids, salt, acetylcholine (muscarinic receptors - see DHEA/estrogen sulfate study on M2 receptors and others iirc on adrenals) to help trigger oxytocin, some of which may work at nighttime. Vasopressin is essential for quality sleep and oxytocin seems to have regenerative properties and else.

All post-synaptic 5HT-1 agonists including CBD (iirc applicable) can come at the cost of degenerative cortisol, unless it's prevented, say by a different transcription/translation mechanism or 11 beta-HSD2.

But there are enough resources to derive safe drug/nootropic/nutrient protocols giving twice the anti-anxiety/depressive benefits (thanks to steroids especially - the right ones should promote patience and stability, GABAA, opposite the suicide period of SSRIs) and avoiding pretty much all the risks. Simple natural compounds like CDP-choline and several amino acids, generally safer than increases in serotonin on cardiac function and cortisol release.

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CDP-choline (choline + uridine) is found in some sources of carbs and seems to promote dopamine and acetylcholine function in general:

CDP-choline administration was also found to stimulate the synthesis and release of a family of neurotransmitters derived from tyrosine (i.e., the catecholamines, including noradrenaline, adrenaline, and dopamine) (5). Of note, non-neuronal cells of various tissues and organ systems also synthesize and release acetylcholine, which then binds and stimulates cholinergic receptors on target cells (reviewed in 6).

But especially, CDP-choline should promote the Kennedy pathway long-term, over PEMT and PUFA incorporation into phospholipids.

Simultaneously, oral CDP-choline should provide uridine for glycogen synthesis. Theoretically CDP-choline should help shunt PUFA toward either excretion (ideal) or triglycerides (manageable - especially for shorter-chain ones like linolenic acid - Travis was never worried about that in his kale). In cases of methyl group insufficiency, however, it would donate methyl groups. But if you believe SAMe is a critical nighttime healing factor, then choline/uridine must be tissue-saving compounds in low-B6/B9/B12/serine/methionine/serine situations, which I would imagine might be diets that could increase cortisol/estrogen.

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If it's true coronavirus patients could benefit from nicotine, I'm personally taking CDP-choline or alpha-GPC at least.

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You can consider acetylcholine's role in intelligence other regulation as maybe a stressor, but it compensates by increasing eNOS (along with maybe T3) during the daytime. Progesterone might take over some of that during the night?

If acetylcholine goes way too high, it seems like people can overdo choline supplements and end up with anxiety and depression. So it's a question of balance and form and I guess a balance with CO2. It's hard to get around eNOS. But it already sounded in one article that acetylcholine and insulin might cooperate, indeed to increase eNOS, so while I don't doubt some effect of CO2 I find it hard to get around eNOS at any time of day:
Defective Insulin and Acetylcholine Induction of Endothelial Cell–Nitric Oxide Synthase Through Insulin Receptor Substrate/Akt Signaling Pathway in Aorta of Obese Rats

The actions of acetylcholine (ACh) on endothelium mainly are mediated through muscarinic receptors, which are members of the G protein–coupled receptor family. In the present study, we show that ACh induces rapid tyrosine phosphorylation and activation of Janus kinase 2 (JAK2) in rat aorta. Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell–nitric oxide synthase (eNOS), and extracellular signal–regulated kinase (ERK)-1/2. The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyperactivated ERK/mitogen-activated protein kinase pathway. These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS.

Acetylcholine and insulin cooperate throught the IRS-1/PI3k/Akt pathway which leads to eNOS activation at least here. Since sunlight is likely to lead to NO synthesis even in some cases destructive iNOS (UVB afaik) it's hard to damn acetylcholine for it unless it were over-expressing nNOS - but according to some people's ideas nNOS sounded like it could have value in healthy sexuality, as you'd expect from the nervous system that seems to influence control apetite for fluids and oxytocin release through possibly more than one receptor, together with dopamine release and sensations? Add cholesterol/histidine/salt/tyrosine/zinc and that's probably building blocks of a sex life, with serotonin and vasopressin maybe inserting anxiety, dominance, fear and quirks.

In a sense acetylcholine might focus NO production from arginine toward nNOS instead of the immune arm, iNOS. If arginine becomes deficient it might make H2O2 instead, and you get over-vasoconstriction together with high angiotension and NADPH oxidase.

As the immune response continues Trp drives toward serotonin, KYNA and KYN metabolites.

Because of CDP-choline and intelligence acetylcholine seems like an important "evil" that's overwhelmingly helpful during the daytime. Histamine has serious issues but carnosine/histidine improve tissues and seems desirable in socialization/sexuality.

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Very high caffeine intake might acutely increase glutamate/histamine release or affect histamine receptors:
Caffeine promotes glutamate and histamine release in the posterior hypothalamus

Together with blood-pressure and catecholamine-raising effects, I prefer taking serine/other to increase NAD+ levels more softly over the night, because although Mg2+ goes well with caffeine high niacinamide is not tolerated by everyone...

If any substance increases histamine synthesis from histidine, that could leave tissues with less carnosine available to handle NO, AGEs and even partly fill in for histamine. So it has to be worth the experience and gentler signaling levels.

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So this is what someone could try if they were *really* careful and took small doses:

cyproheptadine, diphenhydramine, H2 antagonists combined with: L-histidine, beta-alanine, B6, minerals - all to ensure synthesis of carnosine and availability of histidine without unwanted or exaggerated effects of histamine, with receptors antagonized.

Also you'd have to ensure SAMe/methylation precursors for breakdown of histamine produced by HNMT using SAMe - so its synthesis risks less building up - that is especially you accidentally or intentionally (sex) stimulate histamine synthesis - unless you want them to build up I suppose. Maybe high levels are exploitable with the right histamine receptor antagonists.

Lowered acetylcholine/cortisol/serotonin synthesis make cypro theoretical great choice for night-time combining with high protein/seafood and carb/fruit/veg dinners a few hours before bed. The choline/methyl/folate/B12 should produce melatonin, using less the stress-associated BHMT/PEMT hopefully. It provides potassium but especially salt for oxytocin/vasopressin and to contribute to serotonin reuptake and more goes to melatonin simultaneously and the histamine, so everything can be antagonized while the correct levels are determines to feed anabolic and pro-metabolic pathways.

Ofc B3 and Mg2+ are needed to support phospholipid synthesis, cell integrity, NMDA, ATP and important conversions. One way or other it helps to counter quinolinic acid, although you can use D-ribose maybe instead of B3 to encourage its conversion to B3 instead.

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You also need phospholipids and many of these things for complex sphingolipid and sphingomyelin synthesis - something Freddd once referred to as well - as well as preventing ceramide overload (some role for carnitine, stearic acid?).

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Basically I think you could exploit cyproheptadine to simultaneously increase CDP-choline pathway with fewer effects from acetylcholine - while improving carnosine/histidine stores without the negative effects of histamine.

It could be CDP-choline as a supplement is enough to generate mono/sat phospholipids and increase carnosine/histidine tissue reserves with histidine and beta-alanine

SAMe/methylation is probably important to avoid buildup in case synthesis of either continues, up to the point it starts making adrenaline too easy to synthesize.

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CDP-choline has other been noted in other coronavirus thread in conjunction with bacterial/viral infection and nicotinic receptors, and at least extremely important to maintain somatic and immune cell integrity.

But simultaneously during the day, administration with carbs of CDP-choline (uridine) should help build/maintain glycogen. Toward the evening you could use uridine without choline (UMP, triacetyluridine). It seems to improve sleep quality even with crappy cereal:
Improving the quality of infant sleep through the inclusion at supper of cereals enriched with tryptophan, adenosine-5'-phosphate, and uridine-5'-p... - PubMed - NCBI

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But basically seafood + CDP-choline + carbs/eggs/fruit/veg sounds like a safe place to start for an array of health issues, but you could add cypro and at the same time help prevent risk of fibrosis from these infections, increase survival and lean tissue, lower PUFA in membranes and consume a high Se/I/Zn/Mg/Na/Cl/K+ diet.

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But you'd want to limit Ca2+ because you could need acuse or chronic high-dose vitamin A/D/K, and as other people posted, damage can happen through TRP/Ca2+ channels with influence from Ca2+/Na+ exchangers if a hormone like calcitriol increase Ca2+ absorption/retaining - or if it increases bone resorption so you still want a minimum somewhere at or below 1000mg/day probably. At the other end is phosphate and PTH.

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Considering the value of glycogen stores during sickness, it seems like loading on glucose and oral low-dose uridine during the day seems sensible (a little bit as lithium orotate as well and in milk) with choline during the morning at least, necessity dependent on protein/amino intake. Uridine helps balance/buffer reliance on ketones, choline helps cell integrity and protein deficiency. Phospholipids and bile inter-depend, especially phosphatidylcholine.

I imagine you want mostly mono/sat PC and phospholipids in the bile, since this would leave less linoleic acid available to gut inflammation and reabsorption? Just guessing.
Fatty acid composition of phospholipids in bile in man: promoting effect of deoxycholate on arachidonate. - PubMed - NCBI

Ninety-five percent of phospholipids (PLs) in bile is secreted as phosphatidylcholine or lecithin. The study of fatty acid patterns of phospholipids present in gallbladder bile could help clarify whether a preponderance of certain fatty acids could play a role in cholesterol gallstone formation in man. In acute bile acid-exchange experiments, it was found that more hydrophobic bile acids did promote the excretion in bile of PL rich in arachidonic acid (a prostaglandin precursor) and stearic acid. We studied, therefore, bile acid, cholesterol and phospholipid fatty acid patterns (measured by gas chromatography) in gallbladder bile, obtained by duodenal intubation and cholecystokinin-stimulation of 24 healthy volunteers with normal liver/gallbladder function (ultrasound). PL-fatty acid composition (mean % +/- SD) was 41.40 (+/- 1.41) for palmitic acid, 2.68 (+/- 0.82) for palmitoleic acid, 5.50 (+/- 1.55) for stearic acid, 12.09 (+/- 0.98) for oleic acid, 32.83 (+/- 3.04) for linoleic acid and 5.64 (+/- 1.59) for arachidonic acid. The proportion of biliary deoxycholate was positively correlated with arachidonic acid (r = 0.71; p less than 0.01), whereas chenodeoxycholate was inversely correlated with arachidonic acid (r = -0.53; p less than 0.01). There was a positive correlation between biliary chenodeoxycholate and linoleic acid (r = 0.48; p less than 0.05) and a negative correlation between biliary deoxycholate and linoleic acid composition (r = 0.68; p less than 0.01). Also a correlation was found between palmitic acid and cholesterol saturation index (r = 0.49; p less than 0.05). We conclude that the hydrophobic bile acid deoxycholate, which does not desaturate cholesterol in bile, promotes the biliary excretion of arachidonic acid. Since arachidonic acid could induce the gallbladder mucosa to produce prostaglandins and mucus, increased biliary PL-arachidonic acid composition might be a factor in cholesterol gallstone disease.

According to that palmitic acid is the predominant fatty acid in biliary PC followed by linoleic acid even before oleic acid by several-fold? In other words, PUFA/PEMT/BHMT restriction should help composition of bile, unless you want them there for some reason maybe signaling.

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If needed (at the expense of some Cu/Zn) you can avoid Fe using the right species/quality of scallops, shrimp and fish. Basically a scallops or very low Fe seafood diet + safe carbs might be a powerful way to lower Fe safely with extra vit C. The small amount in eggs and sardines can at least prevent deficiency despite the combination with o-6 and o-3.
Bioavailability of Iron in Cooked Egg Yolk for Maintenance of Hemoglobin Levels in Growing Rats

Cholesterol/choline/aminos/vitamins seem like decent reasons to think egg yolks and seafood should help heal bile, brain, gallbladder, gut, immunity, liver, lungs, steroids, with some compounds compensating kidneys but some dependency on vegetables - though egg yolks do contain B9/biotin/retinol/Se/I already despite binders.

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I've cut up my thinking into small posts like divide and conquer to try to come out with a more complete picture. I've cited almost nothing, it's all just to give examples where top-down or bottom-up the parts all fit. Egg yolks/CDP/aminos in the morning, seafood at night; carbs/fruit/sugar/veg every meal except occasional 16-hour fasts. This strikes a balance between Jaminet and Peat, skips meat (Fe needs might be best met by liver), has a future, and you can tweak it by the time of last carb+CDP-containing meal, 5-11pm, based on priorities, basically justifications like before. It can be done relatively safely I think even with less variety. It's what I plan to do long-term for awhile but it would help if someone brought down the cost down and improved the feed.

I guess I had nothing I wanted better to do than write a bunch of uncited claims, but pretty much every part of this first perfectly into the circadian rhythm. Our bodies learned to exploit night and darkness to heal and give brain, cartilage, gut, lungs healing time while kidneys/liver sustain them. At the first meal you load with sugar + NAD+ to relieve load off kidneys - including cortisol - and especially regenerate liver glycogen, with whatever uridine you can synthesize or consume to keep glycogen stores topped as possible and support the CDP pathway.

Not for the sake of contrarianism but to me in the case of life-threatening disease ovo-pescetarianism appears safer approach than dairy (except butter/ghee) - allows higher vitamin D exposure or intake or it can focus on its non-Ca2+ beneficial effects. Quality sources of casein tend to provide an excess of calcium compared to their protein content, less so whey, and if you have trouble absorbing or retaining Mg2+ in the first place that should probably be your priority, to echo what people sometimes report in practice.

For these purposes the choices are kind of obvious, I'm sure cheese/milk is healthy for someone but sometimes might be best seen as alternative for people with seafood or egg allergies or lack access/variety, if you sum all this up. It has iodine/selenium/minerals/tyrosine but possibly unwanted growth factors. Though I can see the value of slow-release casein at night - if calcium handled otherwise it might interfere with sleep or contribute to disorders like nocturia. More to the point, Travis warned of the effects of casein including opioid-like effects and apparent folate receptor antibodies - and I think in particular folate function shouldn't be compromised but improved. Whey even has a place for temporary use and lean tissue, and it was recommended all over the place anecdotally for things like fluoroquinolone antibiotics as a general way to increase GSH and prevent damage, though it could share some risks with NAC. Maybe by lowering Ca2+ the risk you take is lowering oxalate binding, but alternatively you can take care of those during times of lower stress. Still, scallops seem like much higher quality natural protein aimed toward metabolism rather than specifically growth.

This still fails to cover a bunch of aspects about this type of diet, I guess you have to write a book or review article to justify it but no such plans, only trying to imagine the ultimate healthiest half salt preserved seafood buffet.

 

[ampersand]

I'm OCD about NAC due to OCD

Thank you for doing the work of posting all of this for all of us. I especially appreciate the little flashes of humor and character throughout.

 

[S-VV]

@Terma great and innovative writing. Exactly what this forum needs.

Just don’t pull a Travis on us:)

 

[mrchibbs]

+1 follower, really good content @Terma

 

[Memento]

trouble absorbing or retaining Mg2+ in the first place that should probably be your priority

Got any tips for a chronicly hypothyroid person with glucose handling issues? I used to eat a lot of spinach but that got old, now I supplement with Mg citrate every now and then.

Whats your opinion on Alaskan Pollock as main protein source?

Thanks a bunch for the writeup, got to read it multiple times to understand the connections.

 

[Terma]

Hell of a thread title to try to live up to, let me tell you

Hard to find info about non-Atlantic pollock, but looks edible and low-fat. Atlantic pollock has usable nutritional profile but more mercury(?). I'd eat some tilapia to stay alive.

This was a part I skipped last time. So the biggest immediate problem with methylation is adrenaline:

The catecholamine epinephrine is physiologically important in cardiac function and blood pressure regulation. Phenylethanolamine N-methyltransferase (PNMT) is the terminal enzyme in the catecholamine biosynthetic pathway, responsible for epinephrine biosynthesis, and is primarily localized in the adrenal gland. In hypertensive rats, adrenal PNMT mRNA, protein and enzyme activity are elevated along with elevated levels of epinephrine, suggesting that increased expression of PNMT in the adrenal gland results in the increased adrenergic function associated with hypertension. Genetic mapping studies performed in hypertensive rats and humans have investigated the possibility that the PNMT gene may be a candidate gene for hypertension; their findings suggest that differences in expression in PNMT in hypertension are not attributed to polymorphisms within the PNMT gene. It is proposed that increased PNMT in hypertension is likely due to altered transcriptional regulation of the gene. The PNMT gene is highly regulated by key transcription factors including: Egr-1, Sp1, AP-2 and the glucocorticoid receptor. The aim of this study was to investigate the molecular mechanisms involved in the dysregulation of adrenal PNMT in a genetic model of hypertension, by examining expression of transcriptional regulators in the spontaneous hypertensive rat (SHR) in comparison to Wistar-Kyoto (WKY) normotensive controls. Results demonstrate changes in key transcription factors regulating PNMT expression within the SHR adrenal gland, coincident with elevated adrenal PNMT expression. This study suggests altered transcriptional regulation of PNMT is a contributing factor to altered adrenergic function in hypertension.

Phenylethanolamine N-methyltransferase - Wikipedia

Elevated PNMT expression is one of the ways that the stress response positively feeds back on itself. An increase in stress hormones or nerve impulses due to stress can cause PNMT to convert more norepinephrine into epinephrine. This increases the potency of the catecholamine response system, increasing the sympathetic output and making the stress response more profound.[14]

PNMT is known to be regulated by glucocorticoids made in the adrenal gland. One way that it can regulate PNMT expression is by corticosterone's positive influence on the maintenance of PNMT mRNA.[15] Glucocorticoids have also been shown to increase the biological half life of the enzyme in vitro.[16] In animals who have had their pituitary gland removed, the addition of glucocorticoids significantly lengthens the half life of PNMT enzymes.[16]

Elevated PNMT levels can also be triggered by splanchnic nerve impulses. Nerve impulses increase the synthesis of PNMT mRNA by affecting certain promoter sequences.[16]

Stress immobilization for a few hours has also been shown to increase PNMT activity in rats. This treatment takes about one week to manifest a difference in PNMT levels.[17]

SAM not only acts as a cofactor for PNMT, but also helps to stabilize the enzyme and increase the half life by making it more resistant to being cut by trypsin protease.[16]

So lowering cortisol becomes the goal so SAMe gets spent on the right enzymes. Except we were already trying to do that.

Cortisol at night could tangibly encourage a defective or aberrant methylation cycle:
Serum homocysteine: relationship with circulating levels of cortisol and ascorbate. - PubMed - NCBI

Serum homocysteine levels correlate positively with cortisol (r = 0.36, p <0.01) and age (r = 0.49, p < 0.001), and negatively with ascorbate (r = -0.30, p < 0.05) and folate (r = -0.31, p < 0.05). A negative correlation between serum levels of cortisol and ascorbate (r = -0.30, p < 0.05) was also observed. Multiple linear regression analysis showed that the best independent predictors of serum homocysteine concentration were cortisol (beta = 0.319, p < 0.003), age (beta = 0.529, p < 0.001) and folate (beta = -0.338, p < 0.001). When subjects were divided into tertiles according to their homocysteine concentration, the highest tertile of homocysteine concentration has also higher cortisol (p < 0.005) and lower ascorbate (p < 0.05) concentrations compared with the lowest tertile of homocysteine concentration.

Depression, homocysteine, cortisol all go together:
Homocysteine, Cortisol, Diabetes Mellitus, and Psychopathology

The scores of uncontrolled diabetic patients showed a statistically significant relationship between libido and homocysteine. The more decreased the libido patients experienced, the higher the values of homocysteine measured (11.16 ± 2.04 versus 15.21 ± 6.17) (P = 0.002).

https://www.karger.com/Article/Abstract/158636

Ofc as before PEMT is a large homocysteine producer, so it does make me question increasing estrogen at night for sure...

***

Carnitine on the other hand will be synthesized endogenously as needed (lysine/methyl). Nobody supplements acetylcarnitine in the evening to my knowledge since it popularly thought to increase acetylcholine in doses:
Acetyl-L-carnitine enhances acetylcholine release in the striatum and hippocampus of awake freely moving rats. - PubMed - NCBI

Carnitine fumarate and some derivatives exist, occasionally I've had symptom relief from - notably cardiovascular - which actually improved rest with no sign of adrenaline - but notably blood flow. But some people complain of getting wired on it iirc.

Modulatory effects of L-carnitine on glucocorticoid receptor activity. - PubMed - NCBI

L-carnitine (3-hydroxy-4-N,N,N-trimethylaminobutyrate) is a conditionally essential nutrient with a major role in cellular energy metabolism. It is available in the United States as both a prescription drug and an over-the-counter nutritional supplement. Accumulating evidence from both animal and human studies indicates that pharmacologic doses of L-carnitine (LCAR) have immunomodulatory effects resembling those of glucocorticoids (GC). On the other hand, in contrast to GC, which cause bone loss, LCAR seems to have positive effects on bone metabolism.

Elsewhere in the literature in places I've linked, forms of carnitine appear to help bone:

Sci-Hub | L-Carnitine and Isovaleryl L-Carnitine Fumarate Positively Affect Human Osteoblast Proliferation and Differentiation In Vitro. Calcified Tissue International, 76(6), 458–465 | 10.1007/s00223-004-0147-4
Sci-Hub | l-Carnitine Fumarate and Isovaleryl-l-Carnitine Fumarate Accelerate the Recovery of Bone Volume/Total Volume Ratio after Experimetally Induced Osteoporosis in Pregnant Mice. Calcified Tissue International, 82(3), 221–228 | 10.1007/s00223-008-9109-6

This would seem logical for bone growth at night fueled by fatty acids preferably mono/sat. So even if carn can agonize GR it somehow manages to fuel anabolism normally ascribed to things like vitamin D. Meanwhile by supporting ketogenesis it can have anti-glutamate/stress effects. The point of circadian rhythm is net higher capacity for anabolism/regeneration over catabolic processes or not catabolize any one tissue disproportionately in a too short period. Others already reported its associations with androgens. It seems to me like carnitine might simply replace cortisol at GH's side at nighttime, under rest not stress, simply a different 'hormone'. But I'm not sure about the magnitudes of these responses:
L-carnitine: A nutritional modulator of glucocorticoid receptor functions. - PubMed - NCBI

Finally, similarly to glucocorticoids, L-carnitine suppressed tumor necrosis factor-alpha (TNFalpha) and interleukin-12 release by human primary monocytes stimulated with lipopolysaccharide ex vivo.

Addition of either 1 μM of DEX or 50 mM of L-carnitine to the cell medium triggered translocation of the chimeric receptor from the cytosol to the nucleus within 15 min (Fig. 2, B and E). After 30 min, GFP-GRα was entirely localized in the nucleus (Fig. 3, Cand F). This effect of L-carnitine was dose dependent, because L-carnitine doses of 25 and 10 mM produced slower translocation of GFP-GRα, which was completed in 120 and 240 min, respectively (data not shown).

So according to that one the effect is dose-dependent with interestingly a delayed effect.

Taken together, these results suggest that L-carnitine, a nutrient structurally entirely different from the classic glucocorticoid DEX (Fig. 7), may stimulate GRα-mediated transactivation by functioning as an allosteric regulator of this steroid receptor.

In fact, the decreased affinity of GRα for DEX in the presence of L-carnitine might be explained by the ability of this nutrient to interact with a portion of the receptor outside the glucocorticoid binding pocket and modify the allosteric structure of the latter. This structural modification would, at the same time, reduce the affinity of the binding pocket for DEX and create conformational changes similar to those induced by the native ligand, ultimately resulting in GRα activation. Our hypothesis is also supported by the ability of L-carnitine to trigger nuclear translocation of the receptor in the absence of glucocorticoids. However, we cannot exclude an indirect effect of L-carnitine on GRαactivation by other mechanisms that have yet to be elucidated. The ability of L-carnitine to reduce GRα affinity for DEX, combined with its weaker transactivating effect compared with DEX, brings up the possibility that this compound may act as a partial glucocorticoid agonist/antagonist, able to both transactivate GRα in the absence of the native ligand and antagonize GRα activation in its presence. The agonist/antagonist effect may depend on the responsive promoter and be cell specific.

Role of carnitine in disease

I guess besides this complex set of effects it helps to know cortisol has non-genomic effects:
https://joe.bioscientifica.com/view/journals/joe/209/2/153.xml

In response to a stressful encounter, the brain activates a comprehensive stress system that engages the organism in an adaptive response to the threatening situation. This stress system acts on multiple peripheral tissues and feeds back to the brain; one of its key players is the family of corticosteroid hormones. Corticosteroids affect brain functioning through both delayed, genomic and rapid, non-genomic mechanisms. The latter mode of action has long been known, but it is only in recent years that the physiological basis in the brain is beginning to be unravelled. We now know that corticosteroids exert rapid, non-genomic effects on the excitability and activation of neurons in (amongst others) the hypothalamus, hippocampus, amygdala and prefrontal cortex. In addition, corticosteroids affect cognition, adaptive behaviour and neuroendocrine output within minutes. Knowledge on the identity of the receptors and secondary pathways mediating the non-genomic effects of corticosteroids on a cellular level is accumulating. Interestingly, in many cases, an essential role for the ‘classical’ mineralocorticoid and glucocorticoid receptors in a novel membrane-associated mechanism is found. Here, we systematically review the recent literature on non-genomic actions of corticosteroids on neuronal activity and functioning in selected limbic brain targets. Further, we discuss the relevance of these permissive effects for cognition and neuroendocrine control, and the integration of this novel mode of action into the complex balanced pattern of stress effects in the brain.

In practice it's not like you won't notice if you get adrenaline.

 

[Terma]

Got any tips for a chronicly hypothyroid person with glucose handling issues? I used to eat a lot of spinach but that got old, now I supplement with Mg citrate every now and then..

That sounds like half the planet lol. Gut, liver, bile first places to look if it's not a specific thyroid disorder, usually.

Edit: Oh the magnesium. In he past I had to high-dose Mg citrate at 800mg+/day (always with a minimum of the other 3 minerals), now MgCl topical gel (amigel).

 

[Amazoniac]

Many thanks for these, I have a lot to learn from you and Trabis. As you know, I've been following, just not commenting.


I suggested Terma to create means for donation, which is without the responsibility of having fixed supporters that expect content to be produced (although it wouldn't be a bad idea either).

If there are people like Charnathan, earning money from coaching and sales of an erotic autobiography (Ditch Portion Control) with bits of appropriated content and variations of questionable origins, I can't see why there wouldn't be money to support someone legitimate as well. Perhaps Terma is up to give you some ideas for your condition, but it's time-consuming.

If this turns into a lengthy thread, it gets to a point where it's impractical for him to stay and he suddenly disappears, I would like to mention in advance that I probably won't know where he is and how to contact him.

 

[SB4]

@Terma Did you say you have CFS? If so have you been doing anything that helped it over the last few months and have you seen the following paper by Prusty?

Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)–6 and HHV-7 are two infectious triggers for which evidence has been growing. To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic analysis was conducted by pulsed stable isotope labeling by amino acids in cell culture analysis. Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidation of fatty acid, amino acid, and glucose metabolism, including pyruvate dehydrogenase, were strongly inhibited. Adoptive transfer of U2-OS cell supernatants after reactivation of HHV-6A led to an antiviral state in A549 cells that prevented superinfection with influenza-A and HSV-1. Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the associated antiviral state in the A549 cell assay. In conclusion, HHV-6 reactivation in ME/CFS patients activates a multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metabolism.

 

[S-VV]

"Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the associated antiviral state in the A549 cell assay" <-- this is the most important part of the research.

Why the f**k won't they start stratifying the serum to identify the agent. Ron Davis kind of established it was an exosome, but things went silent after that.

 

[SB4]

@S-VV Yeah I thought once they knew it was in the serum it wouldn't take too long to track it down but I have no idea on how hard it actually is.

I think the paper is good as it relates to what I think is happening due to my experience of the illness.

They managed to show that partial activation of small non coding RNA from HHV-6 was enough to cause not only the infected cells mito to fragment, but also the surrounding uninfected cells. Not only that, all the cells went into potent antiviral mode.

This fits up with my experience and a few others. I rarely get ill with flu's ever since my tonsilitis/ulcer that started my symptoms off 9yrs ago. I have an intolerance to carbs where my heart pounding and other POTS symptoms massively increase in the hrs post carbs meal. Prustys paper shows HHV-6 transactivation causes Pyruvate Dehydrogenase Phosphatase 1 to decrease which would result in lowered glycolysis derived acetyl CoA and higher lactic acid. I get lactic acid build up from minimal activity and have done since the start of the disease.

It makes sense to me that a stealth, partially activating virus is behind this illness thanks to the sheer number of people reporting it started after coming down with the flu or similar. Perhaps the initial virus gets someplace the immune system cant find it and goes into stealth activation mode causing whatever it is to leak into serum and warn other cells of danger. Perhaps the initial virus is gone but HHV-6 etc is awakened. Apparently this happens in healthy people when sick. HHV-6/etc partially activated which causes the cell its in and sourounding cells to enter antiviral mode and stop a new virus getting in to its turf. In healthy people it switches off. Perhaps in us it stays on for some reason?

Whilst I find the paper very interesting and hopefull for moving forwards I cannot find anything in it that will change my current approach which is trying out supplements, diets, meds almost at random. There is talk off SS31 or something but its super hard to get hold of.

 

[Terma]

Alaskan pollock looks decent on some papers, better than tilapia, just missing a detailed nutrition on it (seems heavily promoted by industry), I'll probably try some, thanks:
Sci-Hub | Mercury Content in Commercially Available Finfish in the United States. Journal of Food Protection, 77(8), 1361–1366 | 10.4315/0362-028X.JFP-14-097
Sci-Hub | Fatty Acid Profiles of Commercially Available Finfish Fillets in the United States. Lipids, 49(10), 1005–1018 | 10.1007/s11745-014-3932-5

For Mg2+ I meant it was my personal experience that nothing substitutes for the right supplementation when you degrade past a certain point, and though retention is said to be improved by some things like taurine/vitamins (and thyroid) they never substituted for high Mg2+ supplementation in my experience, though I hope to refine this knowledge later and there's probably some in Amazoniac's threads. You get problems neglecting the other minerals after.

***

Appreciate the suggestion and comments above, but there's no use to involve money, or expectations.

***

I had something ME/CFS-like that improved after throwing super high dose supplements at it (agmatine, R5P, adamantane), it was too random to recommend specifics, apart from basic morals like not being riboflavin deficient. I haven't read that paper yet but yeah from the abstract you can see the relation to Davis. The fact some people didn't seem to get sick anecdotally is almost suggestive of viral competition (I always wondered about mycoplasma too, but never a lead) but I'd have to catch up to what those people are doing.

I recall one or more PR members did mention benefit from aminos such as beta-alanine as a stopgap (provided no protein deficiency because histidine deficiency is bad), given how diverse that population is I think it's one of the first things to try when you get such condition (to keep functioning) since it seems rather safe. But it's not like lactic acid is a new discussion.

 

[SQu]

I agree with Amazoniac. Thanks Terma, I look forward to working my way through this info.

 

[LLight]

@S-VV Yeah I thought once they knew it was in the serum it wouldn't take too long to track it down but I have no idea on how hard it actually is.

I think the paper is good as it relates to what I think is happening due to my experience of the illness.

They managed to show that partial activation of small non coding RNA from HHV-6 was enough to cause not only the infected cells mito to fragment, but also the surrounding uninfected cells. Not only that, all the cells went into potent antiviral mode.

This fits up with my experience and a few others. I rarely get ill with flu's ever since my tonsilitis/ulcer that started my symptoms off 9yrs ago. I have an intolerance to carbs where my heart pounding and other POTS symptoms massively increase in the hrs post carbs meal. Prustys paper shows HHV-6 transactivation causes Pyruvate Dehydrogenase Phosphatase 1 to decrease which would result in lowered glycolysis derived acetyl CoA and higher lactic acid. I get lactic acid build up from minimal activity and have done since the start of the disease.

It makes sense to me that a stealth, partially activating virus is behind this illness thanks to the sheer number of people reporting it started after coming down with the flu or similar. Perhaps the initial virus gets someplace the immune system cant find it and goes into stealth activation mode causing whatever it is to leak into serum and warn other cells of danger. Perhaps the initial virus is gone but HHV-6 etc is awakened. Apparently this happens in healthy people when sick. HHV-6/etc partially activated which causes the cell its in and sourounding cells to enter antiviral mode and stop a new virus getting in to its turf. In healthy people it switches off. Perhaps in us it stays on for some reason?

Whilst I find the paper very interesting and hopefull for moving forwards I cannot find anything in it that will change my current approach which is trying out supplements, diets, meds almost at random. There is talk off SS31 or something but its super hard to get hold of.

Didn't Davis exclude the persistent infection cause by testing cells of CFS patients?

@Terma

Why do you think about mycoplasma specifically?

It's interesting because mycoplasma is a cell wall-deficient version of mycobacteria, if I'm not mistaken.

Immune system response to tuberculosis in macrophages has been found to be involving NFAT5, a transcription factor that also is involved in the osmotic stress response (intake of osmolytes among others).

The test that Davis has developped to diagnose CFS patients from immune system cells is based on a observing eletrical properties (impedance IIRC) of these cells when they are subjected to ... hyperosmotic stress.

 

[SB4]

Didn't Davis exclude the persistent infection cause by testing cells of CFS patients?

As far as my baby level of understanding can tell the tests Davis did might not pick up partially activating viruses. Perhaps the amount of RNA is very small and mostly contained in extracellular space or perhaps D didn't test for the specific RNA strands released.