ROS responses to palmitate oxidation Back to the previous figure, but now with simplified routes shown on top and red circles marking the assigned sites: [image: 1770058205159-560e4ec7-0608-400b-805d-cad9e86e26c2-image.png] ⠀(10.1016/j.freeradbiomed.2016.04.001) Based on the ROS contribution profile for palmitoyl-carnitine: Overall rate is relatively low Complex I is not the dominant source Forward electron transfer through Complex I (otherwise site Iq would also appear) Complex III and SDH are the main contributors Complex III is often overlooked (not by researchers, but by bioenergetic quantum coaches) and SDH is even more ignored as a direct ROS source. When fatty acids are oxidized in mitochondria, additional potential contributors tend to be neglected as well: KGDHc, ETF, and ACADHs. We'll first go through how metabolic inhibitors influence the overall ROS production from palmitoyl-carnitine, and then discuss each of the sources mentioned above individually. Palmitoyl-carnitine: metabolic inhibitors, ROS responses, and some influencing factors The earlier figure becomes useful again, showing where standard inhibitors act (red text): [image: 1770058267421-2db2e9d1-95d9-4dd4-abda-e727df441c48-image.png] ⠀(10.1016/j.freeradbiomed.2016.04.001) Site Standard inhibitor Iq ⊢ Rotenone IIf (Sf) ⊢ Malonate IIq (Sq) ⊢ Atpenin IIIqo ⊢ Myxothiazol/stigmatellin IIIqi ⊢ Antimycin Vo ⊢ Oligomycin kvothe.de None (unstoppable) (Palmitate → palmitoyl-CoA :: Malonate → malonyl-CoA) These inhibitors disrupt electron flow, causing a redistribution that can confound interpretation. Martin and colleagues once more did a great job determining ROS contributors through deduction. However, they now favor molecules that prevent electron leakage at target sites without disrupting the flow (green text ⇈). Nevertheless, standard inhibitors remain valuable and widely used. Their presence mirrors aspects of metabolic impairments and changes the overall ROS production rate from palmitoyl-carnitine: [image: 1770058302338-cec5af7d-3953-413f-a06f-5b8d9f9480d3-image.png] ⠀(10.1016/j.freeradbiomed.2009.02.008) ⠀50 μM palmitoyl-carnitine ⠀ [image: 1770058575988-3adc3168-8e6b-4443-908d-b2e970bab4be-image.png] ⠀(10.1074/jbc.M109.026203) ⠀18 μM palmitoyl-carnitine ⠀ [image: 1770058344861-83d07613-79e4-4de4-be92-8a61e246588a-image.png] ⠀(10.1074/jbc.M207217200) ⠀60 μM palmitoyl-carnitine (+ 2 mM carnitine) ⠀ [image: 1770058420815-7d909147-d6e8-4264-aa82-e7705b2a6e16-image.png] ⠀(10.2337/db11-1437) ⠀40 μM palmitoyl-carnitine (+ 5 mM malate) These experiments used mitochondria isolated from rat muscle in resting state ("state 4") induced by oligomycin or minimal ADP, and were run under supraphysiological oxygen levels. In isolated mitochondria, added superoxide dismutase (SOD) compensates for losses of surface SOD, helping to detect part of superoxide released outward (~50% of that generated by Complex III, which may first pass through the lumen of cristae). In the presence of antimycin, palmitoyl-carnitine generated far more ROS than succinate, especially surprising when rotenone (suppressor of succinate-derived ROS) was absent. Conversely, in the presence of rotenone, palmitoyl-carnitine produced ROS at similar or even lower rates than pyruvate + malate. Concentration matters [image: 1770059289753-2fb2b2a3-b6f2-495e-b4e6-48adcafde18d-image.png] ⠀(10.1074/jbc.M109.026203) H₂O₂ production peaked at 60 pmol H₂O₂/min/mg with 18 μM palmitoyl-carnitine and lowered at higher concentrations, possibly because excess fatty acids can dissipate built-up protons (H⁺), promoting electron consumption and lowering ROS formation. The dissipating effect can be direct (probable with free fatty acids rather than their esterified forms) or indirect (triggered by ROS and derivatives). Fatty acids as natural uncouplers preventing generation of O₂•⁻ and H₂O₂ by mitochondria in the resting state Induction of Endogenous Uncoupling Protein 3 Suppresses Mitochondrial Oxidant Emission during Fatty Acid-supported Respiration Fatty acid type matters [image: 1770059328688-ab9df908-09c7-4a6b-9b6f-127dcc918dbf-image.png] ⠀(10.1016/j.bbabio.2007.04.005) Tissue specificity matters A site with relatively low ROS-producing capacity can occur more frequently in a tissue, increasing the contribution to the overall rate. For example, compare the production rate for Iq (higher capacity) in muscle with Gq (lower capacity) in brown adipose tissue. [image: 1770059354108-7520bcf7-dd04-4ace-b808-7d3ed7636434-image.png] ⠀(10.1016/j.freeradbiomed.2016.04.001) Multiple factors result in different responses depending on the tissue: [image: 1770059386905-8483bd61-97a1-4253-829d-e4e7a4aca3c8-image.png] ⠀(10.1016/j.freeradbiomed.2009.02.008) Medium-chain fatty acids bypass the carnitine-dependent transport, so they enter mitochondria avoiding this regulatory step. But their metabolism concentrates in the liver, where excess acetyl-CoA from β-oxidation can convert into ketone bodies. Ketogenesis helps to export carbons, recover CoA, and (with further conversion of acetoacetate into hydroxybutyrate) reoxidize NAD, preventing local burden. Ketogenesis therefore lifts oxidation constraints by regenerating CoA and eventually reoxidizing NAD. When ROS production is excessive, depletion of these cofactors can limit electron supply and curb further ROS generation. Mitochondrial state matters A shift from a resting to stimulated state ("state 4" → "state 3") increases electron demand relative to supply, decreasing their availability at susceptible sites, and minimizing leakage. Individuals with higher metabolic rates have lower levels of reactive oxygen species in vivo Decreased mitochondrial metabolic requirements in fasting animals carry an oxidative cost Cellular oxidative damage is more sensitive to biosynthetic rate than to metabolic rate: A test of the theoretical model on hornworms (Manduca sexta larvae) Exercise-mimicking conditions decrease ROS production from cellular respiration: [image: 1770059418480-cec8a58d-c0c5-456d-b567-8aca1c6f8c31-image.png] ⠀(10.1074/jbc.M114.619072) But that also calls for alternative explanations for the exercise-induced ROS increase. Redefining the major contributors to superoxide production in contracting skeletal muscle. The role of NAD(P)H oxidases Pre-condition matters The following experiments relied on: Permeabilized muscle strips High-fat intervention diets (~60% fat) for pre-conditioning 25 μM palmitoyl-carnitine + 2 mM malate as the challenge A single high-fat meal markedly changes the response of muscle strips from lean individuals to palmitoyl-carnitine + malate. The same effect is noticed after 5 days on a high-fat diet followed by a 12-hour fast before the challenge. [image: 1770059457753-d4b72fef-1c32-4afc-a73c-1c75d46c53ff-image.png] ⠀(10.1172/JCI37048) After 6 weeks on a high-fat diet, rat muscle strips still show an unexpected response to a substrate that they should have adjusted to, suggesting that lipid overload prevents proper adaptation. [image: 1770059549244-ba1c2aca-1b1b-42cf-9be5-21078bd1cb40-image.png] ⠀(10.1172/JCI37048) Muscle strips from lean versus obese individuals also respond much differently to the same challenge: [image: 1770059572073-2eb7528f-e59f-4edf-bbfe-18762f5ba8b9-image.png] ⠀(10.1172/JCI37048) Sex matters [image: 1770059591608-f1dbd037-cdd9-4f0f-8b4b-46f9298396c2-image.png] ⠀(10.1016/j.jbc.2024.107159) Oxygen availability also matters Since respiratory complexes function at O₂ levels that already exceed their saturation, supraphysiological O₂ levels in experiments have little effect on ROS production. However, ROS generation decreases as O₂ levels become critically low, and enzymes differ in O₂ affinity, giving them varying sensitivities to hypoxia. Palmitoyl-carnitine at a low concentration: [image: 1770059614780-7f1f352c-d1fa-404f-81f9-76428ef12e10-image.png] ⠀(10.1074/jbc.M809512200) [image: 1770059640674-14d6298f-6d89-4f9d-ac4d-c1e959d55340-image.png] ⠀(10.1155/2018/8238459) In the absence of O₂, enzymes can't produce ROS because the substrate is missing. Hypoxia decreases mitochondrial ROS production in cells Oxygen Sensitivity of Mitochondrial Reactive Oxygen Species Generation Depends on Metabolic Conditions How Supraphysiological Oxygen Levels in Standard Cell Culture Affect Oxygen-Consuming Reactions Fatty acid oxidation demands more O₂ than glucose oxidation to compensate for metabolic inefficiencies. This need is easily met by modest increases in delivery, but may deplete O₂ further when delivery is impaired. Uncouplers of oxidative phosphorylation control ROS production The limited efficacy of CCCP ("mitochondrial uncoupler") in normalizing ROS production deserves a few comments. [image: 1770059680813-57f7ab58-9ec4-4cd0-ba13-ddfec9b89528-image.png] ⠀(10.1016/j.freeradbiomed.2009.02.008) The primary purpose of respiration is ATP synthesis. Protons concentrated by respiration dissipate back into mitochondrial matrix through Complex V (ATP synthase), but some return via alternative dissipation pathways as well. Mitochondrial uncouplers increase the relative contribution of those alternative pathways, making oxidation less tied to phosphorylation, allowing oxidation to continue without being limited by the need for ATP. Uncouplers (acting as dissipators) increase the rate of electron consumption to compensate for the energetic inefficiency. Before the electron supply catches up, the respiratory chain becomes more oxidized, decreasing the electron availability at susceptible sites, preventing leakage, and lowering ROS. Uncouplers counteract the tendency for ROS to rise as the 'membrane potential' ("Δψ") increases: [image: 1770059704114-054cd32b-4938-4e44-ab70-50ff0bf67f1c-image.png] ⠀(10.1016/S0014-5793(97)01159-9) However, with palmitoyl-carnitine, ROS production continues to increase when the potential is already maximized. [image: 1770059771049-4b1c215d-da85-4e3f-a517-19b0198c03dd-image.png] ⠀(10.1074/jbc.M109.026203) Maximal ψₘ occurs at ≥2.5 μM palmitoyl-carnitine; Maximal H₂O₂ occurs at 18 μM palmitoyl-carnitine. Keeping 18 μM palmitoyl-carnitine constant and lowering the membrane potential with FCCP (another mitochondrial uncoupler; black bars) produces the expected moderate suppression: [image: 1770059793166-a010ac2a-67e3-45aa-b613-e339cef372ca-image.png] ⠀(10.1074/jbc.M109.026203) The decrease reflects the ROS fraction that depends on membrane potential. Uncoupling suppressed ROS from glutamate + malate (NAD-oriented substrates) far more effectively than from palmitoyl-carnitine. This suggests that a substantial portion of ROS generated with palmitoyl-carnitine is independent of the state of the respiratory chain, so uncouplers can't affect that portion (the remaining 55%). Interestingly, stimulating the respiratory chain drains more electrons from the UQ pool than from the NAD pool. [image: 1770059823638-8d69f5ee-1c17-4cc0-a5b0-bd79f4f6454b-image.png] ⠀(10.1074/jbc.M114.619072) Cyt b566 (also called cyt bL) is one of the redox centers of Complex III that interacts and equilibrates with UQ, serving as a proxy for the local UQ redox state. Supplementary carnitine and malate disinhibit fatty acid oxidation Regarding the addition of free carnitine (+ L-carn) in one of the graphs, it's common in experiments to combine palmitoyl-carnitine with extra carnitine or malate because sustaining high rates of plain palmitoyl-carnitine oxidation is difficult, as reflected in low rates of oxygen consumption regardless of interventions (such as added ADP) that would normally change the rate: [image: 1770059846561-c664a17c-6d02-4582-a584-939205873e9d-image.png] ⠀(10.1016/j.freeradbiomed.2013.04.006) Additional carnitine or malate (an importable oxaloacetate precursor) overcomes that limitation. [image: 1770059926858-031b0d85-04a7-4e86-a8d7-97d4a3e7d418-image.png] ⠀(10.1074/jbc.M113.545301) When acetyl-CoA production exceeds oxaloacetate regeneration, acetyl-CoA accumulates and sequesters CoA, impairing β-oxidation but also other CoA-dependent processes (PDHc, KGDHc, etc.). β-oxidation impairment (as from insufficient CoA) can result in accumulation of intermediate metabolites. Compared with malate/oxaloacetate, carnitine has the advantage of exporting these incomplete β-oxidation intermediates, preventing their buildup, that would otherwise risk further perturbations and more ROS. Unlike fatty acids, pyruvate can divert from acetyl-CoA into oxaloacetate (dashed line), restoring the acetyl-oxaloacetate balance and freeing CoA; excess acetyl groups can then be exported as citrate if needed. Substrate overload: Glucose oxidation in human myotubes conquers palmitate oxidation through anaplerosis As an interesting side note, it's possible with fatty acids to sustain respiration with minimal decarboxylation (↝CO₂). That's because β-oxidation (first stage) channels electrons into the respiratory chain (via ETF and NAD) independently of the TCA cycle (second stage, where decarboxylation occurs). [image: 1770059978066-9e0eb453-2558-44f1-a315-50916850a7a9-image.png] ⠀(10.1074/jbc.M109.026203) Altogether, those reasons explain the three compositions tested for each scenario ahead: Palmitoyl-carnitine alone Palmitoyl-carnitine + extra carnitine Palmitoyl-carnitine + malate Palmitoyl-carnitine: ROS contribution profiles and their response to inhibitors Returning to inhibitors, their presence not only affects the overall ROS production rate, but also changes the contribution profile: [image: 1770060140483-23c299cd-84e4-4d6f-99cc-ea5d0e46de0a-image.png] ⠀(10.1016/j.freeradbiomed.2013.04.006) ⠀15 μM palmitoyl-carnitine (+ 2 mM carnitine or + 5 mM malate) [Still using mitochondria isolated from rat muscle in resting state ("state 4") induced by oligomycin or minimal ADP, under supraphysiological oxygen levels.] With palmitoyl-carnitine + carnitine as reference, we had: Scenario Detected H₂O₂ (pmol/min/mg) Contributors "Native" (uninhibited) ~140 ▸IIIqo + ▸IIf + ▸If + ▸Kf? + ▸Ef? Antimycin (⊣IIIqi) ~2150 ▸IIIqo + IIf◃ Myxothiazol (⊣IIIqo) ~250 IIf◃ + ▸If + ▸Ef? ▸ Forward electron flow ◃ Reverse electron flow The following sections will address each of the overlooked ROS contributors with the depth of a conversation with drunk Spring Break Britney. To put them in context: [image: 1770060190462-e8f4f0dc-dd85-4bff-aa7a-59ba9ccb715a-image-resized.png]

@CurmudgeonApple Bro blocked me?? @sunsunsun please forward this messsage: "I don't care what studies the authors cited or what their subjective opinion is. The objective fact, we know in humans, is that in this subset of patients, prolactin was lowered by 66%. Vitamin E doesn't need to directly interact with the pituarity to exert it's effects. It blocks the production of fatty acid metabolites, and their metabolites, and the encompossing effects of them all. This directly can reduce serotonin/prolactin. So instead of asking the involvement of vitamin E in prolactin, ask your self what do these fatty acid metabolites do? for example; Omega 3 metabolite blocked by vitamin E, increases prolactin https://pubmed.ncbi.nlm.nih.gov/3921344/ "

@lykos I'm guessing your mom is a narcissist and didnt' love you

[image: 1770028991469-53ef2a7d-4f24-4e35-8985-9cf1a137176a-image.png]

https://www.youtube.com/watch?v=F_CLYkVSb6E

Here are some of the side effects of eating too many. The Shiitake Mushroom Overload: What Happens When You Eat Too Many?

@lobotomize Very good.  You must've gone to the Chuck Norris school of Buteyko Breathing.

@PissBoy this seems to be common among the other reporters with TRT, I can only guess why but the most likely explanation seems to be unbridled aromatase conversion into estrogen while they're none the wiser because they never learned how estrogen is actually made. If only they took some kind, any kind, of AI!

@Mauritio If you're talking about XI-KT then that could work just as an experiment. Actually, a bottle is only $70, no different than what we'd pay for Idealabs, so I might try it too.

Phytol "...PHY efficiently interacts with COX-1 and 2, NF-κB, and IL-1β. In conclusion, PHY exhibits anti-inflammatory activity, possibly via COX-1 and 2, NF-κB, and IL-1β dependent pathways." https://pubmed.ncbi.nlm.nih.gov/32583784/ Phytol, Produces Antihyperalgesic, Anti-inflammatory, and Antiarthritic Effects https://pubmed.ncbi.nlm.nih.gov/32091204/ Phytol seems to be a GABA-A receptor agonist, lengthening sleep time https://pubmed.ncbi.nlm.nih.gov/39357640/ Again, it binds to GABA-A receptor, but also to 5HT1A. Not sure if it agonizes or antagonizes it. https://pmc.ncbi.nlm.nih.gov/articles/PMC11926570/ Phytol drastically inhibits gastric ulcers https://pubmed.ncbi.nlm.nih.gov/38717706/ Could be a dopamine d2 antagonist based on its antiemetic properties. But could also be due to possible 5ht3 antagonism (similar to ondansetron) . https://pmc.ncbi.nlm.nih.gov/articles/PMC10008523/

https://www.youtube.com/watch?v=3JwC4pCukHc

#BIOENERGETICFRIDAY[image: 1769807397165-img_2571.jpeg]

@heyman Yes it is

@Insr just to give you the full rabbit hole… https://www.dancingwithwater.com/ I’m not affiliated with that company. I’m just a gardener that’s gone down the water rabbit whole for many years! I’m very wet! Ha! JK. For thousands of years people have made reference to living water. It has spiritual as well as philosophical and scientific connotations. The fact that the term has survived so many generations is an indication of deeper significance. It implies there is living water AND that there is something other than living water. Can water lose its life? If so, can the life be returned to water? These are powerful questions that deserve more than philosophical answers. Dancing with Water: The New Science of Water is an investigation into water’s liquid crystalline phase where water molecules exist in a repeating geometric array similar to the molecular pattern found in a solid crystal. Although the molecules remain independently mobile, they respond as a coherent “whole.” This is living water–an organized network that responds to its environment carrying signals and supportive vibratory information to the life forms it supports. Living water has existed on Earth for millions of years. As the foundation of life, it is one of Mother Earth’s finest creations. But the degree to which water can support life depends on the degree of life force in the water. Water can be vibrantly alive or it can be barely alive, just like the inhabitants of the Earth. Although much of the water on the planet today has been mistreated to the point that its life hangs by a drop, understanding a few simple concepts can return water’s life force. The first step is to restore the liquid crystalline network. Then, the addition of frequencies/information completes the task. The term, full-spectrum living water is a phrase used by the authors of Dancing with Water to refer to living water that carries the full spectrum of life supporting frequencies. Several factors contribute to the overall process. Movement or turbulence – which creates vortices. Some form of gentle, organizing energy (this can be supplied by magnets and paramagnetic materials some geometric shapes and many methods of concentrating life force (for example, orgone energy devices Mineral ions (salts). These anchor the life force in water and help water to hold vibratory information. Stillness — a period following movement during which water develops coherence. Vibratory information — frequency-based input, including the very important resonance of the Earth. When these elements come together (and they can do so in many ways) water becomes a living, liquid crystal with the full spectrum of life supporting enhancements. The process is outlined in the book, Dancing with Water, with instructions for providing these elements in such a way that they result in full-spectrum living water—Earth’s finest gift—water that supports life to its fullest. That’s all from her website… great stuff. Investigate your own local water before you go slamming too much of it. And look at the pipes in your home. Hard water (like my town) has tons of great minerals in it but lots of fluoride too. Thyroid crusher! You may be able to set a two liter of your tap water out over night and off gas a lot of the chlorine gasses and get pretty decent water. Drip coffee is a good way to filter water and transform it into food! Yay! ️

top 20 anti fibrotics Pirfenidone - 100% Nintedanib - 98% Nerandomilast - 96% Losartan - 90% Spironolactone - 85% Rapamycin (Sirolimus) - 82% Curcumin (high-bioavailability forms) - 75% Gotu Kola (Centella asiatica standardized extract) - 74% Frankincense/Boswellia (standardized) - 72% Pentoxifylline - 70% Berberine - 68% Resveratrol - 65% Quercetin - 60% EGCG (Epigallocatechin gallate) - 58% Silymarin (Milk Thistle) - 55% Colchicine - 52% Metformin - 48% N-Acetylcysteine (NAC) - 45% Sulforaphane - 42% Apigenin - 40%

nobody commented on my schizopoll so I have to agree or disagree idk

@mag-me said in Refined beet sugar: I just tried these jams from Turkey, SOMEHOW BEAT SUGAR FROM HIGH UP IN THE MOUNTAINS LISTED https://garisar.com/?srsltid=AfmBOopElE9pHgWQQku6G4GGIyJGRzTVLOJ7px4pAlOa5kqRumClL6w- Ingredients: Wild Rosehip (80 %), Sugar, Lemon Juice It is produced using only beet sugar and real lemon juice with the traditional method, without additives, without preservatives; from mountain rosehip that grow wild in the high altitude of the Gumushane plateaus. Sounds incredible! Roses hips are super high in vitamin c! 🫜

@Sitaruim are you practising print pushing looking at things at the point they just become blurry not too clear not too blurry the point of blur glasses are actually safe for distance, for example looking at the moon, you should use your glasses. but for reading a book you shouldn;t

@Ecstatic_Hamster did you recieve it?