@Milk-Destroyer - Evidently, the study has its limitations.

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? [image: 1754347668994-029bee82-cd38-4ff1-aeb7-28846684e250-image.png] ⠀(10.1242/jeb.221606) In pink are the major sources: [image: 1754347697643-dac6e475-a2b8-42a9-babc-92ed6b2fc234-image.png] ⠀(10.1038/s41580-020-0230-3) [image: 1754347722481-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) [image: 1754347771554-786c9b7d-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). [image: 1754347859260-7c318a3d-f274-44da-9199-9fa83e96b037-image.png] ⠀(10.1016/j.redox.2020.101722) [image: 1754347869418-2f9790b8-96fe-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?

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.

Defining a vitamin A5/X specific deficiency – vitamin A5/X as a critical dietary factor for mental Health Abstract: A healthy and balanced diet is an important factor to assure a good functioning of the central and peripheral nervous system. Retinoid X receptor (RXR)-mediated signaling was identified as an important mechanism of transmitting major diet-dependent physiological and nutritional signaling such as the control of myelination and dopamine signaling. Recently, vitamin A5/X, mainly present in vegetables as provitamin A5/X, was identified as a new concept of a vitamin which functions as the nutritional precursor for enabling RXR-mediated signaling. The active form of vitamin A5/X, 9-cis-13,14-dehydroretinoic acid (9CDHRA), induces RXR-activation, thereby acting as the central switch for enabling various heterodimer-RXR-signaling cascades involving various partner heterodimers like the fatty acid and eicosanoid receptors/peroxisome proliferator–activated receptors (PPARs), the cholesterol receptors/liver X receptors (LXRs), the vitamin D receptor(VDR), and the vitamin A(1) receptors/retinoic acid receptors (RARs). Thus, nutritional supply of vitamin A5/X might be a general nutritional-dependent switch for enabling this large cascade of hormonal signaling pathways and thus appears important to guarantee an overall organism homeostasis. RXR-mediated signaling was shown to be dependent on vitamin A5/X with direct effects for beneficial physiological and neuro-protective functions mediated systemically or directly in the brain. In summary, through control of dopamine signaling, amyloid β-clearance, neuro-protection and neuro-inflammation, the vitamin A5/X – RXR – RAR – vitamin A(1)-signaling might be “one of” or even “the” critical factor(s) necessary for good mental health, healthy brain aging, as well as for preventing drug addiction and prevention of a large array of nervous system diseases. Likewise, vitamin A5/X – RXR – non-RAR-dependent signaling relevant for myelination/re-myelination and phagocytosis/brain cleanup will contribute to such regulations too. In this review we discuss the basic scientific background, logical connections and nutritional/pharmacological expert recommendations for the nervous system especially considering the ageing brain. [image: 1753642620660-195305d5-1b58-4f65-a688-e795b5b0457c-image.png] [image: 1753642742365-868bf21c-c9f8-4fdc-b2bb-754445da7072-image.png]

@LucH Thanks for the info! There are some animal studies on restricting only omega-6, and the effect is to increase the metabolism of omega-3 and decrease that of omega-6: Fifteen weeks of n-6 PUFA deprivation compared with adequate diet decreased the mean unesterified plasma concentration of n-6 PUFAs by 84% (Table 1). The change in the total unesterified n-3 PUFA concentration was statistically insignificant, although unesterified DHA and EPA concentrations were increased by 53% and 79% The total n-3 PUFA concentration in brain was increased by 15%, reflecting largely an 11% increased DHA concentration (Igarashi et al. 2009). Expression of enzymes of the 20:4n-6 cascade, cPLA2-IVA and COX-2, was downregulated, whereas expression of DHA-preferring calcium independent iPLA2-VIA (Garcia and Kim 1997; Strokin et al. 2004; Ramadan et al. 2010; Basselin et al. 2011) and of 15-lipoxygenase (LOX) was up-regulated (Kim et al. 2011). COX-2 mRNA was decreased significantly (−23%, p b0.05) (Fig. 3A) in the n-6 PUFA deprived rats compared with adequate rats, as was COX-2 protein (−32%, pb0.05) (Fig. 3B). The deficient diet did not change COX-1 or mRNA significantly

@Hando-Jin oh yeah. Now psychedelic therapy is in vogue and I think legal in several us states. Mind-body relations. Bessel van der Kolk also mentions psychoactives for ptsd therapy.

"Green tea inhibits Helicobacter growth in vivo and in vitro" https://pmc.ncbi.nlm.nih.gov/articles/PMC2694061/ Mice were infected with H. pylori and given either tea or water. The group that was given tea had both greatly reduced inflammation and H. pylori population. In fact, mice that were given tea both before and after the infection had no inflammation and no H. pylori population at all. I suspect it is the L-Theanine in the tea but nobody has studied that so I have no proof. I think so because high dose L-Theanine completely suppresses H. pylori symptoms for me.

@springsnow haiduts arguments are that most of the benefit comes from restricting inflammatory amino acids like methionine. This seems to be in line with studies that show all the benefits of calorie restriction just with protein restriction.

@DavidPS the satiety one is interesting since milk has been traditionally considered a breakfast item. Another piece of evidence as to why people used to be much leaner.

See the reference 3 Glutathione Depletion Prevents Diet-Induced Obesity and Enhances Insulin Sensitivity Hannes M. Findeisen et al. 2012 https://doi.org/10.1038/oby.2011.298 Abstract Excessive accumulation of reactive oxygen species (ROS) in adipose tissue has been implicated in the development of insulin resistance and type 2 diabetes. However, emerging evidence suggests a physiologic role of ROS in cellular signaling and insulin sensitivity. In this study, we demonstrate that pharmacologic depletion of the antioxidant glutathione in mice prevents diet-induced obesity, increases energy expenditure and locomotor activity, and enhances insulin sensitivity. These observations support a beneficial role of ROS in glucose homeostasis and warrant further research to define the regulation of metabolism and energy balance by ROS. Excerpt (…) Since glutathione peroxidase (GPx) constitutes the principal antioxidant defense system to scavenge physiological concentrations of H2O2 in mammals (6), we investigated in this study the role of pharmacological glutathione depletion on diet-induced obesity and insulin sensitivity. Surprisingly, depletion of endogenous glutathione protected mice from obesity, preserved insulin sensitivity, and increased energy expenditure, pointing to a more complex role of endogenous ROS in diabetes and energy balance than previously anticipated. => There is a contradiction and a bias in the title as well in the abstract. To be reminded: too much of a good thing is bad. No need for more than 2x/wk 100 mcg. Diet with meat and eggs brings +/ 50 % of the RDA. Supplement is only bioavailable at +/ 60%. More info (In French, translator needed) https://mirzoune-ciboulette.forumactif.org/t1953-selenium-too-much-of-a-good-thing-is-bad#27971 => Selenium forms, bioavailability, enzymatic functions, synergy with other antioxidants, Sources and References.