This is something you could try: Ayurvedic food combining. You can skip the text and go straight to the food combining chart.

If it works, you can later try making "wrong" food combinations and see how you feel. Fruit and cheese is a bad combination according to the chart, but I eat dates with feta quite frequently without issues.

Another thing to try is to keep some space between meals. Having ~3 hours between meals is usually enough for me, but some people might need more time.

Keeping meals simple can also be helpful--if for nothing else, at least to make it easier to notice when something doesn't agree with your body. I usually have 1-3 food items per meal. For example: dates with feta, which is 2; just dark chocolate, which is 1 (yes, I have just dark chocolate as a meal); or oat bread with butter and cheese, which is 3.

It may take a few weeks to notice improvements in gut function.

@gg12 said in Gut issues but I can’t go to doctor:

However It feels impossible to get even 1500 calories because 90percent of foods irritate my gut besides berries and carrots

Does juice irritate your gut too? Drinking juice between meals--1 hour before or after--works well for me. I usually have a somewhat poor appetite, so it's a bit difficult for me to get enough calories from meals alone, without drinking juice between them.

@serotoninskeptic, gotcha. I experienced the same thing when having too little, too much and the wrong type of protein (all but dairy) for my constitution. Most people I’ve communicated with regarding health fare best long-term getting ample protein, fat and carbs at every meal so I understand. I, myself, find mixed meals way more enjoyable, which I believe to be essential for healing. Every meal of mine must elicit a happy wiggle or it’s out. 😄

96b5d553-0aa5-49b2-b237-2e97cdfbf4c9-image.gif

@healingisposs18 said in Csf leak that wont heal:

I was told by a physician many years ago I probably have ehlers danlos, which I think is contributing.

Gluten and lactose are very often poorly tolerated in EDS. Not everyone. This is likely due to the way EDS affects the gastrointestinal system, leading to increased sensitivities and intolerances.

@water-fire Primitive consciousness, I guess. With flaws but mostly right.

SR must graduate from being a "based" view of the world to a Correct one. Which was the process Ray did.

Taurine is good for bile formation

@otto said in Silicon the dietary nutrient:

Here is the brand that I chose. It claims to be a 1-year supply.

According to LLR, silicium molecule has to be small enough to be effective.
Dr. Willems has tested several sold silicium a long time ago. They are not all equal, to say the least.
Usful info:
When I type « silicium » on my forum I get 4 posts in the section « Traitements naturels et complémentaires »:

Silicium organique ou minéral ?
https://mirzoune-ciboulette.forumactif.org/t864-silicium-organique-ou-mineral?highlight=silicium Silicium organique et arthrose. Dr JM Dupuis
https://mirzoune-ciboulette.forumactif.org/t866-silicium-organique-et-arthrose-jm-dupuis?highlight=silicium Test silicium. Dr Willems
https://mirzoune-ciboulette.forumactif.org/t865-test-silicium-dr-willems?highlight=silicium

Extraits en Français (Translator needed) :
Extrait 1 :
Le corps humain contient de 6 à 10 grammes de silice selon l'âge, et 1 mg par 100 ml de sang. Le silicium est en concentration supérieure (7g) à celles du fer (Fe) ou du cuivre (Cu) chez l’homme ; il potentialise l'action du zinc (Zn) et du cuivre (Cu) et permet la fixation du calcium (Ca).
La quantité de silicium diminue de façon irréversible, chez l'homme comme chez l'animal.
On le trouve essentiellement dans le tissu conjonctif, dans la peau, les cheveux, les ongles et les dents, dans les os et le sang.
Un traitement à base de silicium organique peut d'ailleurs faire régresser ces lésions athéromateuses (travaux de LOEPER, Académie de Médecine). Il restaure également la synthèse de l'élastine, tout en diminuant la calcification et la rigidité des artères vieillissantes. Il est frappant de constater que ces tissus (peau, artères, thymus) sont ceux dont le vieillissement est le plus constant et le plus marquant (ainsi rides, amincissement, perte d'élasticité et d'hydratation pour la peau)."
http://www.esculape.com/bricabrac/silicium.htm
Extrait 2 : Organique ou minéral ?

Le silicium organique : Taux d’absorption élevé (70%)

Le silicium minéral : problème de biodisponibilité (3%)

Le silicium végétal : champignons, graminées, agrumes, olives, argile verte, prêle, gélatine, eau, etc.
NB : La biodisponibilité sera faible, comparée à une plante, sauf si …
Extrait 3 : Conditions liées à l’assimilation

Le pH du silicium ainsi que sa charge ionique. Le titrage du silicium (0,2 % est l’idéal selon LLR ; 0.4 % est un maximum pour l’assimilation => biodisponibilité).

Besoin d'une protéine qui lui sert de transporteur, pour passer la barrière digestive, il est limité à un seuil de saturation dans les applications thérapeutiques. Voilà pourquoi il est conseillé de l’ingérer 15’ avant le début d’un repas.
Extrait 4
Le silicium organique se différencie du minéral par la présence d’un (ou plusieurs) atome(s) de carbone associé(s) à de l’hydrogène. Sous cette forme, c’est un des éléments essentiels de la matière vivante (plantes, animaux et humains).
Liens intéressants :

Silicium organique : Présentation. Connaissez-vous le G5 ?
Applications, revendications du silicium organique en thérapeutique.
Source: Dr Janet, gastro-entérologue et cancérologue.
http://www.nature-et-forme.info/article-739693.html (blog temporairement indisponible)
https://sante-vivante.fr/wp-content/uploads/2018/07/SV-SILICIUM-3.pdf

7 siliciums au banc d’essai
Test du Dr WILLEMS
Le silicium : produit mythique de la médecine naturelle
Samedi 17 février 2007 • Pratiques de santé. Le Journal de la Médecine naturelle. N° 64 Hors-série n° 1. Dr Jean-Pierre WILLEM. Epuisé.
https://mirzoune-ciboulette.forumactif.org/t865-test-silicium-dr-willems#8167
Résumé du test:
Si l’on cumule l’ensemble des résultats obtenus, le classement final est le suivant :
1 - G5
2 - Dynasil +
3 - Ortie-Silice
4 - Eau de silice
4 - Siliplex
6 - Silicea Universel
7 - Vita Sil.
Seul 3 1ers sont recommandables.
NDLR: Il existe peut-être d'autres produits apparus ensuite sur le marché, non testés ...
Translation : Only the first three are recommended.
Editor's note: There may be other products that appeared on the market later, but haven't been tested...
I use G5.

@hainsloy in case you hadn’t seen, I posted some discussions about dht from Ray Peat email exchanges at this thread:

https://bioenergetic.forum/topic/6745/androsterone-source-in-eu

Rule of three | Wikipedia

Ray was into linguistics, likely preventing him from overusing this triad pattern. Yet, you can still find it in many of his titles, making them appear well-rounded and memorable.

Adaptive substance, creative regeneration: Mainstream science, repression, and creativity Aging Eyes, Infant Eyes, and Excitable Tissues Aging, estrogen, and progesterone Aspirin, brain and cancer Bleeding, clotting, cancer Diabetes, scleroderma, oils and hormones Estrogen, memory and heredity: Imprinting and the stress response Estrogen, progesterone, and cancer: Conflicts of interest in regulation and product promotion Fatigue, aging, and recuperation Gelatin, stress, longevity Genes, Carbon Dioxide and Adaptation Glycemia, starch, and sugar in context Growth hormone: Hormone of Stress, Aging, and Death? Hot flashes, energy, and aging How do you know? Students, patients, and discovery Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer Leakiness, aging, and cancer Meat physiology, stress, and degenerative physiology Membranes, plasma membranes, and surfaces Milk in context: allergies, ecology, and some myths Osteoporosis, harmful calcification, and nerve/muscle malfunctions Phosphate, activation, and aging Rosacea, inflammation, and aging: The inefficiency of stress Serotonin, depression, and aggression: The problem of brain energy Serotonin: Effects in disease, aging and inflammation Stem cells, cell culture, and culture: Issues in regeneration Thyroid, insomnia, and the insanities: Commonalities in disease Thyroid: Therapies, Confusion, and Fraud Tryptophan, serotonin, and aging Vitamin E: Estrogen antagonist, energy promoter, and anti-inflammatory

It's one of the reasons why the "perceive, feel, think, and act" gained acceptance and popularized.

@Brunus I personally have bought vitalundfit100, a German company, and it fulfills the following list better than all competitors. But generally, just buy the cheapest, best rated powder (capsules are 99% of the time overpriced) for every product you can (CoA optional and helpful)

Miguel Favo released a video titled:

"The Randle Cycle Masterclass"

He runs with core misconceptions that are widespread and worth addressing, appearing to closely adhere to the 'new head, old hat' publication.

"[..]you're basically storing electrons in [NAD and FAD]. Now, [NADH and FADH2] are then brought into the electron transport chain, which is second part of the mitochondria you need to know."

"Now, as I mentioned, NADH goes to Complex I. Well, FADH2 goes to Complex II. When you start to have a lot more electrons flow to FADH2, which you see in fats, because you have only a 2:1 ratio of NADH/FADH2 versus carbs where you have a 5:1 ratio of NADH/FADH2, Complex II starts to hog CoQ10 and steal it from Complex I."

"[..]when you inhibit the fatty acid oxidation and you basically lead to a circumstance where you don't have all the FADH2 going to Complex II and over reducing co-enzyme Q[..]"

The reduced form of FAD in question is not "brought into" or "going to" the Electron-transfer System (ETS), as FAD already belongs to it bound to stationary respiratory complexes.

The intention of highlighting select coenzymes—NAD and FAD—is to differentiate the catabolic yields based on reduction potentials, not to specify the particular electron entry-points, as many respiratory complexes have coenzymes in common. It's important to acknowledge this to avoid limiting FAD to SDH (Complex II), for example.

d9af554b-2331-4a62-adb6-8c0d95b16357-image.png

(The reduction potential should vary depending on the flavoprotein, to be compatible with the preceding reaction.)

Each respiratory complex listed below is a flavoprotein:

Mobile e⁻ donor Respiratory complex Contains NAD Complex I FMN Succinate SDH FAD ETF ETFDH FAD Proline PRODH FAD Choline CHODH FAD Sulfide SULDH FAD Glycerol phosphate GPDH FAD Dihydroorotate DHODH FMN

Dehydrogenase abbreviations here refer to whole and functional complexes.

For a comparison that specifies the respiratory chain entry-points, yet separated by similarities in reduction potentials:

Dehydrogenases NAD FAD ⠀ Glucose ⠀ Glycolysis GAPDH (→ MAS) Complex I {GADPH (→ GPS)} {GPDH} ⠀ Pyruvate oxidation PDHc Complex I ⠀ TCA cycle IDH Complex I KGDHc Complex I SDH (Cx-II) SDH MDH Complex I ⠀ Total Glucose with MAS 5 1 Glucose with GPS 4 2 2 1 ⠀ Fatty acids ⠀ β-oxidation (standard) ACADHs ETFDH HADH Complex I ⠀ TCA cycle IDH Complex I KGDHc Complex I SDH (Cx-II) SDH MDH Complex I ⠀ Total Fatty acid oxidation 4 2 2 1 ⠀ Ketones ⠀ Ketolysis HBDH Complex I ⠀ TCA cycle (as above) 3×Complex I SDH ⠀ Total Acetoacetate 3 1 Hydroxybutyrate 4 1

Summary (still with rounded values):

Complex I (NDH) Complex II (SDH) Complex IIS* (ETFDH) Glucose 5 1 - Fatty acid 4 1 1

*Doing a fun with Complex 2.5.

It's their grouping that gives the usual ratios:

NAD 5:1 FAD -- Glucose NAD 2:1 FAD -- Fatty acids [4:(1+1)]

Therefore, the main change responsible for the marked decrease in the NAD/FAD ratio is the inclusion of ETFDH associated with β-oxidation, making it unreasonable to neglect ETFDH and misattribute its involvement to SDH. ETFDH and SDH differ in their capacity to produce ROS, but to compare them takes the recognition that we're dealing with different respiratory complexes and electron routes. Their particularities invalidate any attempt to suggest that it's fine to treat them as one, without the need to differentiate.

Moreover, observe in the video that the simplified NAD/FAD ratio with glucose ended up right (5:1) only because the missing PDH was compensated for by GAPDH quantified erroneously twice.

Electrons that are pulled off in glycolysis (via GAPDH) commonly reach mitochondria through the malate-aspartate shuttle (MAS), where each imported pyruvate can bring a malate molecule along. Those electrons are then recovered from malate in a NAD-dependent reaction, which is why they're expected to contribute to the NAD-linked respiration.

However, in situations where electrons reach mitochondria through the alternative glycerol-phosphate shuttle (GPS), they enter the respiratory chain on a lower level through a FAD-linked pathway, and the NAD/FAD ratio difference between glucose and fatty acid catabolism disappears.

NAD 5:1 FAD -- Glucose with MAS NAD 2:1 FAD -- Glucose with GPS NAD 2:1 FAD -- Fatty acids

Yet, ratios don't mean much on their own. To get to the principle in question, consider these simplified paths:

NAD → [FMN → FeS]Cx-I → UQ Suc → [FAD → FeS]SDH → UQ ETF → [FeS → FAD]ETFDH → UQ

If the reduction potential differences happened to be equal, a mere rerouting of electrons (after a partial shift from NAD-linked to FAD-linked respiration) wouldn't be an issue because one route would increase at the expense of the other, without perturbing the ubiquinone pool. Example:

Situation Aː 65 NAD + 13 FAD → 78 UQ Situation Bː ↓52 NAD + ↑26 FAD → 78 UQ

However, it is Complex I, III, and IV that are directly responsible for driving respiratory phosphorylation. FAD-linked substrates have less reducing power, so they enter the 'Electron-transfer System' bypassing Complex I. As a consequence, fewer protons are extruded, leading to a decreased ATP yield per electron or oxygen consumed.

It can be useful to identify respiratory complexes based on their ability to drive proton translocation, either directly (middle column) or indirectly (middle row):

Matrix DHs ↳ NAD ↘ Complex I PRODH, ETFDH, SDH → ↳ UQ ↴ ← GPDH, DHODH, SULDH, CHODH Complex III ↳ Cyt c ↴ Complex IV

(Funky arrows render automatically.)

Now stacking them:

Enzyme Proton (H⁺) translocation Concentrators Complex I 4H⁺/2e⁻ ↴ SDH - ↴ ETFDH - ↴ PRODH - ↴ SULDH - ↴ CHODH - ↴ GPDH - ↴ DHODH - Complex III 4H⁺/2e⁻ Complex IV 2H⁺/2e⁻ Total NAD-linked respiration (w/ Complex I) 10H⁺/NAD FAD-linked respiration (w/o Complex I) 6H⁺/FAD Dissipators Complex V (w/ ATP)* −8H⁺/3ATP PTP-ANT (w/o ATP) −3H⁺/3ATP UCP, NNT, leakage, etc. (w/o ATP) −?H⁺/3ATP Total −11H⁺/3ATP Per each ATP −3.7H⁺/1ATP For each H⁺ −1H⁺/0.27ATP Simplified (−12H⁺/3ATP) −1H⁺/0.25ATP

*Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria

Complex V

"Each 360° rotation of the central stalk takes each catalytic site through [..] conformations in which substrates bind, and 3 ATP molecules are made and released."

"The turning of the rotor is impelled by protons, driven across the inner membrane into the mitochondrial matrix by the transmembrane proton-motive force."

"According to current models based on structures, the number of translocated protons for generation of each 360° rotation is the same as the number of c-subunits in the ring, as each c-subunit carries a carboxylate involved in protonation and deprotonation events. In the yeast F-ATPase, the ring has ten c-subunits, and so 10 protons are translocated per 3 ATP molecules made during a 360° cycle; therefore, the bioenergetic cost to the enzyme is 3.3 protons per ATP (9). However, the c-ring sizes differ between species; c10–c15 rings have been found in yeast, eubacterial, and plant chloroplast F-ATPases (10–13)."

"The most important inference from the presence of the c8-ring in bovine F-ATP synthase, is that 8 protons are translocated across the inner mitochondrial membranes per 360° rotation of its rotor. As each 360° rotation produces 3 ATP molecules from the F1-domain, the bioenergetic cost of the enzyme making an ATP is 2.7 protons [from 8H⁺/3ATP]."

Dissipators that don't generate ATP reduce the efficiency of its synthesis, making the process more costly. Relating them in terms of ATP production remains useful, for being the primary purpose of cellular respiration.

Phosphate translocase protein (PTP) can lead to the dissipation of a H⁺ for every Pi imported (with ADP) and ATP synthesized: −1H⁺/1ATP. As shown below:

dd2f12dd-66e4-4b81-a2f7-0feaba64e3fa-image.png

We can also compare their contribution to the cost of respiration. For example:

8H⁺ + 3H⁺ = 11H⁺ (100%) 3H⁺/11H⁺ = 27% of H⁺ dissipated without ATP synthesis

Given that respiratory complexes prevail in mitochondrial cristae, it's unclear to me how PTP could dissipate H⁺ from an isolated compartment as ADP and Pi return from the cytosol to the matrix of mitochondria. Nevertheless, once these factors are taken into account, it becomes easy to make future adjustments.

From the table:

0.25 ATP produced per 1 H⁺ consumed (dissipated): 0.25ATP/H⁺

Then:

NAD ⇝ 10H⁺ 10H⁺/NAD × 0.25ATP/H⁺ = 2.5 ATP/NAD FAD ⇝ 6H⁺ 6H⁺/FAD × 0.25ATP/H⁺ = 1.5 ATP/FAD

Because of variation and uncertainties, the values are often given in ranges:

2–3 ATP/NAD 1–2 ATP/FAD

When cells increase reliance on substrates that depend more on FAD-linked respiration, they have to compensate for the inefficiency by oxidizing more molecules to produce the same amount of ATP. This compensation is what's expected to perturb the ubiquinone pool, where respiratory complexes converge. Reworked example:

Situation Aː 65 NAD + 13 FAD → 78 UQ Situation Bː ↓52 NAD + ↑26 FAD → 78 UQ Situation Cː ↓56 NAD + ↑28 FAD → 84 UQ

But now both situations yielding similar amounts of ATP while demanding different amounts of UQ.

If we focus on FAD changes, we may expect a dramatic perturbation on UQ, but not all of this change will always represent FAD- competing with NAD-linked respiration, as more than half of FAD dependence can increase at the expense of NAD. Decreasing the involvement of Complex I could free up a fraction of UQ for other complexes. From the example:

NAD

56 RE − 65 RE = −9 RE

FAD

28 RE − 13 RE = +15 RE

Impact on UQ

−9 RE + 15 RE = +6 UQ

If UQ occurs as a single and shared pool, eventual perturbations would be minimized from this partial Complex I disuse.

Some aspects to consider beyond NAD/FAD ratios:

Fatty acids may have a H⁺-dissipating effect that's independent of their catabolism, which diverts H⁺ from ATP synthesis. Activation of fatty acids consumes the equivalent of 2 ATP molecules, regardless of whether fatty acids are catabolized or stored. Given the extensive lipid cycling in the body, if every fatty acid activation expends 2 ATP molecules, part of the ATP synthesized is being wasted, calling for additional ATP synthesis with H⁺ dissipation to make up for it. Lipid cycling isn't all futile

These processes should occur whether fats are eaten or not, but they might intensify with eating. Both situations above would also demand oxidizing more molecules, increasing the involvement of NAD- and FAD-linked respiration proportionally, and counting on UQ to follow along.

This elevated need implies additional succinate processing by SDH as well, that's part of the TCA cycle.

Glucose and fatty acid differ in how they're decarboxylated (↝CO₂). With glucose, decarboxylation occurs only partially in the TCA cycle (2/3); with fatty acids, it occurs entirely (3/3).

Glucose

⅓ decarboxylations @ PDHc ⅓ decarboxylations @ IDH ⅓ decarboxylations @ KGDHc

Fatty acids and ketones

½ decarboxylations @ IDH ½ decarboxylations @ KGDHc

No carbons are left behind in either case, which can confuse those who assume that glucose oxidation releases additional CO₂ judging solely by the PDHc reaction. They treat PDHc decarboxylations as extra steps, rather than substitutions to the TCA cycle decarboxylations. The effect in question can't be concluded from an excerpt of whole cellular respiration.

In shifting from glucose to fatty acid oxidation, we have the following points to recap concerning SDH.

What may generate..

More succinate for SDH:

Complete TCA cycle dependence for decarboxylation. As just mentioned, glucose oxidation spares SDH by eliminating ⅓ of carbons before the TCA cycle, whereas the full TCA cycle dependence in fatty acid oxidation must increase succinate synthesis for SDH. Lower reducing potential from the catabolic yield. FAD-linked respiration is a less efficient way to derive ATP. The need for more oxygen as a proxy for electrons consumed is a marker of the inefficiency (lower ATP/O), and part of the additional electrons will come from succinate. Proton-dissipating effect. Fatty acids may dissipate some of the H+ concentrated through respiration. To replenish the losses, cells have to perform more oxidation, including that of succinate. Energy-consuming lipid cycling. Repeated fatty acid activation consumes ATP wastefully, which is counteracted by further oxidation, again involving more succinate.

Less succinate for SDH:

Higher yield of reducing equivalents per molecule catabolized. The elimination of ⅓ of carbons outside of the TCA cycle in glucose oxidation is one of the reasons for its lower ATP yield on a carbon basis, which opposes its higher ATP yield on an electron or oxygen basis. Decreasing some of its advantage means less need for succinate oxidation than anticipated in fatty acid oxidation.

Whether the shift from glucose to common fatty acids will burden or relieve a respiratory route depends on how much their catabolism deviates from theoretical values. A refined version of a comparison uploaded before:

24c88e0b-cca8-48f4-bdd8-fcc31ac49116-image.png

The stearic acid column on the left is identical to the one on the right, except for the amount of ATP produced in each, accounting for the inefficiencies discussed so far. The adjustment to 2 ATP/O (left) from ~2.3 ATP/O (right) is exaggerated, admittedly sourced from the Annals of Human Anatomy (formerly Acta Buttologica).

Bringing back the early table:

Complex I (NDH) Complex II (SDH) Complex IIS (ETFDH) CO₂ Glucose 5 1 - 3 Fatty acid 4 1 1 2 NAD 5:1 FAD -- Glucose NAD 2:1 FAD -- Fatty acids

However, a more intuitive way to relate them and represent the high-everything situation that we may run into with fatty acids could be (as contrasted by the first two columns of the image):

Complex I (NDH) Complex II (SDH) Complex IIS (ETFDH) CO₂ Glucose 5 1 - 3 Fatty acid 6 1.5 1.5 3 NAD 5:1 FAD -- Glucose NAD 6:3 FAD -- Fatty acids

Putting them together to further illustrate possible scenarios that we may encounter in practice:

Complex I (NDH) Complex II (SDH) Complex IIS (ETFDH) CO₂ Glucose 5 1 - 3 Fatty acid (efficient) 4 1 1 2 Fatty acid (inefficient) 5 1.25 1.25 2.5 Fatty acid (very inefficient) 6 1.5 1.5 3

Glucose → Fatty acid (efficient use)

↓Complex I ≈SDH ↑ETFDH [↓↓CO₂]

Glucose → Fatty acid (inefficient use)

≈Complex I ↑SDH ↑↑ETFDH [↓CO₂]

Glucose → Fatty acid (very inefficient use)

↑Complex I ↑↑SDH ↑↑↑ETFDH [≈CO₂]

Alternating from glucose to fatty acids may barely perturb a respiratory route ('≈' cases) depending on the efficiency of their oxidation. Scenarios range from sparing NAD-linked respiration while minimally affecting SDH-linked respiration (first case) to a high-everything situation that evens out CO₂ production (last case). It remains applicable that ETFDH-linked respiration is the most affected route in these scenarios that are varying proportionally.

One final thing for now:

The lower ATP yield per oxygen consumed (↓ATP/O) with fatty acids raises an issue. If cells that are actively respiring tend to produce less ROS (as pointed out in the original post), the need for further respiration with fatty acid makes us wonder to what extent it recreates the same protective conditions. Fatty acid prevalence could work in effect similar to the use of proton dissipators (oxidative phosphorylation uncouplers), those that keep being praised as therapeutic.

Oxygenated,

You're making one categorical affirmation after another with a conviction that contrasts with the attitude of authors in this field, who are conservative for being aware of the volume of unreliable or contradictory information on the topic.

Already in the title, you declared that fat oxidation is the main source of cellular ROS, but how did you conclude this?

029bee82-cd38-4ff1-aeb7-28846684e250-image.png
⠀(10.1242/jeb.221606)

In pink are the major sources:

dac6e475-a2b8-42a9-babc-92ed6b2fc234-image.png
⠀(10.1038/s41580-020-0230-3)

da7b76ab-128b-4dfb-8524-02fee5516ac3-image.png
⠀(10.1038/s41580-020-0230-3)

It would be worth clarifying how each of these H₂O₂ is generated, as we could have yet another statement put to question: that ROS formation involves unpaired electrons. Example:

"[..]complex I could mediate one- or two-electron reduction of oxygen[..]" (10.1016/j.bbabio.2013.01.002)

786c9b7d-f263-4d02-ad31-1196acfc643a-image.png
⠀(10.1146/annurev.arplant.55.031903.141701)

We know that oxidases generate H₂O₂, which already challenges the exclusive association of ROS with one-electron reactions.

Nevertheless, even if we relax the criteria to include other ROS sources related to fatty acids (peroxidation and eicosanoid metabolism as examples), we would still be left with comparable alternatives to consider, such as NADPH oxidases (NOX).

7c318a3d-f274-44da-9199-9fa83e96b037-image.png
⠀(10.1016/j.redox.2020.101722)

2f9790b8-96fe-438d-81f6-21dbb7593dd7-image.png
⠀(10.1242/jeb.221606)

You can tell that a fraction is attributed to mitochondria. Then, only part of this mitochondrial (and peroxisomal) ROS will come from fatty acid oxidation in normal conditions.

Cellular ROS > Mitochondrial ROS > Fatty acid oxidation ROS

With conclusive information about the contribution of each compartment, we would have to discount all ROS sources unrelated to the oxidation of fatty acids, our latest carcinogens on the block.

Funnily, with glucose oxidation, every opportunity to maximize ROS production is taken as a room for cancer therapy. With fatty acids, when the opportunity appears, the picture is carcinogenic and let's leave the interpretation at that, without conceiving exploiting this "massive" burst of ROS to potentiate eradication therapies.

Different from many doctors, most researchers in the field are well-aware of the association of stimulated oxidative phosphorylation with lower ROS production, an observation that has been circulating since early publications:

"Addition of succinate speeds up H₂O₂ production by a factor of six and, after that, the addition of ADP (state 4 → state 3 transition) (Chance & Williams, 1956) decreases it to a value similar to that in the absence of substrate. When all the added ADP is phosphorylated, there is an acceleration paralleling the changes in the mitochondrial metabolic state. A further addition of ADP produces the transition to the active state, with the corresponding slow rate of H₂O₂ production." (10.1042/bj1280617)

But a higher metabolic rate doesn't inherently lower ROS production. It's a matter of electron availability around susceptible sites. Oxygen consumption is usually tied to ATP production, and increasing the need for ATP tends to increase the rate of respiration. Then, with a higher metabolic rate, the demand for electrons tends to decrease their availability, clearing the way for an orderly electron movement while reducing the chances of leakage. Likewise, a low metabolic rate with accompanying low rate of substrates oxidation must be able to get respiratory ROS production under control.
⠀

"Not only does reverse flow result in a dramatic shift of the redox status towards reduction, but the build-up of ROS leads to direct structural damage to various cell proteins, as well as any intracellular structure containing polyunsaturated lipids."

More like the other way around: an abnormal change of the redox status in favor of reduction results in reverse electron flow. Electron accumulation precedes the redistribution.
⠀

"What has not been widely acknowledged is that in the absence of exogenous agents capable of blocking or more of the ETC complexes (e.g rotenone, metformin, etc), reverse electron flow happens quite easily and is in fact responsible for the majority of ROS production simply as a result of shifting the metabolic substrate from glucose to fat (Randle Cycle). Namely, if the Randle Cycle (RC) shifts sufficiently in favor of fat oxidation, that results in depletion of the FAD co-factor, and thus a block at ETC Complex II. In other words, all that is needed for massive generation of ROS is to switch from oxidizing primarily glucose to oxidizing primarily fat. That sounds shocking and counter-intuitive, considering the world (and medicine) has gone crazy over low-carb diets lately, but it is well-known and undisputed biochemical fact."

Putting aside the authoritative "undisputed biochemical fact", you have constructed the argument concerned with ROS overproduction from acute substrate alternation ("to switch"), only to then abruptly invoke chronic fatty acid oxidation ("low-carb diets"). These are different scenarios that can't be lumped together.

Why the need for alarmism? The term "massive" might be more suitable for describing Kvothe's reproductive organ (..I've heard) or the overwhelming ROS production that often occurs when blood flow is restored after a period of interruption, leading to severe tissue damage. However, reverse electron flow can also occur in a controlled, transient fashion, serving to induce beneficial adaptations.

It's odd that you reduced the problem to SDH 'blockage' from FAD depletion. If this was the case, why would it trouble cells that are primed to metabolize fatty acids as an adaptation to frequent exposure? Once the body synthesizes enough flavins to meet predictable needs (including everyday perturbations), it's a matter of maintenance to replenish obligatory losses from flavoproteins, and these are modest in relation to their extensive recycling in reactions. Fatty acid metabolism has to remain dependable in stressful conditions, and these are associated with micronutrient shortage.

Also, how do you explain the ability of mitochondria to oxidize copious amounts of plain succinate when incubated with it? Not only in isolation, but especially in the presence of other substrates that help to clear inhibitory oxaloacetate. If other substrates can enhance the oxidation capacity, it becomes questionable to argue in terms of flavins repurposing.

For succinate to become a SDH inhibitor itself, levels have to get extremely high while possibly involving an inability to wash it out, as when local blood circulation stops. Nevertheless, FAD should remain intact in SDH, which is why succinate can be readily oxidized when oxygen levels are restored in the tissue. In some situations, the purported SDH blockage could actually be protective, such as when SDH is intentionally inhibited by malonate to prevent ROS overproduction in classical reverse electron flow.

Complex I 💥 ← UQ ← SDH ← Succinate Complex I ← UQ ← SDH ↚ Succinate

If you had in mind reverse electron flow in the broad sense, the immediate concern in the respiratory chain for upstream processes would be impaired Complex I activity due to competition for available ubiquinone. Complex I is responsible for reoxidizing NAD for matrix dehydrogenases dependent on it, that in turn are overlooked sources of ROS.

Altogether, it's a peculiar approach. What to make of it?

@NoeticJuice said in Kanna, OCD + other:

maybe it's just the left hemisphere of my brain that is fatigued; what I was experiencing was because it tried to hold on, to maintain some level of control, even though it lacked energy.

So, I decided to let go--to let the left hemisphere rest, even fall asleep if it needed to, and to let the right hemisphere take over.

"Letting go," as in opposition to "holding on."

@NoeticJuice said in Kanna, OCD + other:

When I do feel fatigued, I can let it go, and the fatigue disappears.

Also in opposition to "pushing away"/fighting/resisting.

In a way, it takes effort, but it leads to increased energy. It doesn't feel like what effort usually feels like.

By the way

@NoeticJuice said in Kanna, OCD + other:

When I did this, I didn't feel fatigued anymore. I also experienced other changes

Internal speech also decreased, although it's still present to some degree most of the time. There seems to be some negative correlation between internal speech and the degree of the other changes.

Ai

Key Strategies to Improve Your Microbiome

1. Increase Dietary Fiber

Benefits: Fiber acts as a prebiotic, feeding beneficial gut bacteria.

Sources: Aim for 21 to 38 grams of fiber daily from:

Legumes (beans, lentils)

Whole grains (oats, quinoa)

Fruits (berries, apples)

Vegetables (leafy greens, sweet potatoes)

Nuts and seeds

>2. Stay Hydrated

Importance: Water supports digestion and nutrient absorption.

Recommendation: Drink enough water to prevent dehydration and maintain gut health.

>3. Incorporate Fermented Foods

Examples: Yogurt, kefir, sauerkraut, kimchi, and kombucha.

Benefits: These foods contain probiotics, which can enhance gut diversity.

>4. Limit Processed Foods

Impact: Ultra-processed foods can negatively affect gut health.

Advice: Focus on whole, unprocessed foods to support a healthy microbiome.

>5. Manage Stress

Connection: Stress can disrupt gut health.

Techniques: Practice relaxation methods like meditation, yoga, or deep breathing.

>6. Regular Exercise

Effect: Physical activity promotes a diverse microbiome.

Goal: Aim for at least 150 minutes of moderate exercise weekly.

>7. Get Enough Sleep

Recommendation: Aim for 7 to 9 hours of quality sleep each night.

Benefit: Good sleep supports overall health, including gut health.

Conclusion

Improving your microbiome involves a combination of dietary changes, hydration, stress management, exercise, and sleep. By adopting these practices, you can enhance your gut health and overall well-being.

ae915d57-17ee-4535-9bac-8004ad73cdca-image.png

@lobotomize-me

I don’t have any of the problems I listed from before but thanks for the advice. I don’t like taking supplements anymore it distracts me from tackling other problems in my life.

@Mauritio have been taking sr 9011 for a week or so which is a strong agonist of reverb/Clock haven't been feeling much other than increased base bpm and easier time changing my sleep schedule (which is helpful as I usually go to sleep late and now it gives me the motivation to go to sleep early)

You didn't see graphite. You didn't. Because it's not there.

did anyone try this?