@DavidPS I've thought along the same lines but struggled to fit those concepts coherently together. expression of Hmgcs2, the gene encoding rate-limiting enzyme of ketogenesis, decreases significantly in Leydig cells from aged mice. Additionally, the concentrations of ketone bodies β-hydroxybutyric acid and acetoacetic acid in young testes are substantially higher than that in serum, but significantly diminish in aged testes. Silencing of Hmgcs2 in young Leydig cells drives cell senescence and accelerated testicular aging. So what I'll do is shower you and the others with my open questions: First in line for me is the question: Why is (testicular) Hmgcs2 being downregulated in aging? Obviously feeding BHB as the end product of ketogenesis increased testosterone. Therefore the underlying mechanism can't be about sex hormone substrate availability (cholesterol). Rather, it's about a decline in ketogenesis, i.e. a tissue energy depletion: "suppression of ketogenesis impairs steroidogenic function of LCs" Is it locally or systemically/predominantly hepatically? --> The study tells us it's locally, because testicular tissue concentrations are higher than serum and "BHB andAcAc concentrations in serum were comparable between the young and the aged group (Fig. 2k, l)." "Remarkably, the concentration of ketone bodies in the testes were more than tenfold higher than that in serum (Fig. 2i–l), implying ketone bodies might have testis-specific functions" Is there a decline in peripheral fatty acid circulation as a reason for declining tissue ketogenesis? In contrast to ketone bodies, free fatty acids don't really cross the blood--brain-barrier. Do they significantly cross the blood-testis-barrier? If it's not about fatty acids as a ketogenesis substrate, is it about peripheral protein circulation levels? If it's about neither upstream substrates, is there perhaps a tissue-specific decrease of utilization to Acetyl-CoA? Is the HMGGCS2-decreasing cause founded in a lack of carnitine or a lack of CoA? Will supplementation of carnitine or stimulation of CoA then attain similar results to exogenously supplying BHB for that matter? --> The authors have followed this strain of thought and injected AAV vectors to deliver and overexpress the Hmgcs2 gene, demonstrating "that Hmgcs2 overexpression increased the levels of H3K9ac and FOXO3a in aged testicular tissue, similar to the levels in young testes" --> So it's not immediately about any substrate levels but HMGCS2 activity itself. Does this lead back to epigenetic downregulation of bodily functions, in this case HMGCS2, and the concepts of DNMTi and HDACi? --> Clearly there's a positive association between acetylation of H3K9 and HMGSC2 expression in rats in that HMGSC2 induced higher H3K9ac. Is this reciprocal, i.e. would H3K9ac also induce HMGCS2? Or does H3K9ac come about by increased concentrations of the products of HMGCS2, like BHB, and the cellular energy abundance provided by it? --> The authors followed this and found: "Consistent with in vitro results, Western blot analysis revealed that BHB increased the levels of H3K9ac and FOXO3a in aged testicular tissue, similar to the levels observed in young testes (Fig. 7d, e)." Is this then a course of gradual decline, wherein a decrease of testicular ketone energy in turn decreases its own synthesis? Just as the observation that more BHB increases its own synthesis? I.e. a positive / negative feedback loop? Would, therefore, a one time course of exogenous BHB or induced Hmgcs2 overexpression "reset" testicular ketogenesis back to a youthful level, wherefrom it may once again gradually decline? --> Well, the authors fed exogenous BHB in addition to the control diet to 18-months old rats for a duration of 2 months. Those were then 20-months old rats. Unfortunately, no subgroup to follow up on wrt to their physical activity and testicular findings has been kept and reported on beyond that. "Last, we validated the changes in FOXO3a-related inflammation genes through quantitative RT-PCR analysis, revealing that inflammation-related genes were significantly upregulated in aged mice, and Hmgcs2 overexpression reduced the expression of these genes (Supplementary Fig. 9b–e). Overall, these data suggest that enhancing ketogenesis is sufficient to alleviate LCs senescence and testicular aging in aged mice."

@yerrag Wow. Those are some additional challenges. Coincidentally, my brother just survived a 4 day hospital stay for congestive heart failure. I think your perspective of leaning on Peat and alternative counterculture, as a defense against status quo medical pathology, is the general perspective of most of us. But, just as you say, it's challenging, and can be daunting, because we are limited. I hope more alternative and naturopathic doctors adopt bioenergetic and similar principles to help those like us to bridge the gap, so we don't have to play doctor. There does seem to be a trend of some going that way. My thought is that it really won't be at its best until it's local, so we can have real-doctor support.

This is the fatty acid composition of the three fats. Margarine actually only has slightly higher PUFA content than olive oil and less MUFA than it. So overall margarine contains less unsaturated fats than olive oil does. One reason olive oil performs so well despite its high UFA content, might be its polyphenol content, containing oleocanthal, hydroxytyrosol or even small amounts of policosanol. I've talked about their pro-metabolic, testosterone enhancing effects here: https://bioenergetic.forum/topic/3624/olive-leaf-extract-increases-t3-t4-lowers-tsh?_=1748111089619 [image: 1748110991784-1000015133.png]

Canadian rancher Maggie is laughing at this study [image: 479882288_122215646534203038_8548433945113970019_n.jpg?_nc_cat=110&ccb=1-7&_nc_sid=aa7b47&_nc_eui2=AeEONy5dG5Kx5-34XHtxhRQBt5ClT8lPVV63kKVPyU9VXjMr1mkTi5uagTB2CxAehkeMCdDBREO5RBO6pNTE93Mh&_nc_ohc=46Rx1dxfwK4Q7kNvwHmX991&_nc_oc=AdmQT2HphoIoZDS5BY83m388IDQ46DPQi6doYYGDnPlUdOM_9e35SSXFjPrvkAF8swp6HaOwxtxUB8czLyOGK_S4&_nc_zt=23&_nc_ht=scontent.faep14-2.fna&_nc_gid=WOU-dhxC1Pp9RB-E-Ol0oA&oh=00_AfLaHX6bWJHfDaQa_ouMnc4b-wYLn9Thp0GkPwaUIA7U-Q&oe=68368F06]

Maybe something to do with tonicity, vascular tone and everything thereafter. Onset in reverse, I wonder what causes that. https://pmc.ncbi.nlm.nih.gov/articles/PMC11293686/ (Only a sample.) If "the next pandemic" had an energy mandate as or opposed to a vaccine mandate. I wonder what would happen.

the study in women athletes had them taking ridiculously high doses, something like 1g a day of TTFD iirc. it is dopamingeric, the first time i took a 25mg alinamin f tablet i got pronounced euphoria. it’s popular in japan.

@haidut I remember the announcement and recruiting for this study in 2020 iirc. Then everything vanished and reportedly the project's budget was cut and the study shelved. WTF was going on there. How did they finish it anyway? Who allowed them to now release their results? Too many polito-economic-corruptory questions.

@haidut Wow no surprise the SSRIS are really from the bad guys. Do you have a recommendations for what a person with PSSD should do? (Post ssri sexual dysfunction) Would love to hear your thoughts……. Thanks

@CrumblingCookie I wouldn't call it anti-serotonergic , the mood lift felt more like a neurosteroid boost. Which is a little different from a dopamine boost. Both are good though. Not sure about it's androgenicity , I didn't experience any detrimental effects . But I only tried it twice and I was also sick with a cold so not the best test run. I certainly would be willing to try it again if it wasn't for the constipation, but I'm sure I'll give it another go. Ive tried the old version of gonadin today with phytol in it. that was quite nice . I'm also having great results with diosgenin in the last months.

Mailloux, R. J., Gardiner, D., & O’Brien, M. (2016). 2-Oxoglutarate dehydrogenase is a more significant source of O2·−/H2O2 than pyruvate dehydrogenase in cardiac and liver tissue. Free Radical Biology and Medicine, 97, 501–512. https://doi.org/10.1016/j.freeradbiomed.2016.06.014 Maj, M. C., Cameron, J. M., & Robinson, B. H. (2006). Pyruvate dehydrogenase phosphatase deficiency: Orphan disease or an under-diagnosed condition? Molecular and Cellular Endocrinology, 249(1–2), 1–9. https://doi.org/10.1016/j.mce.2006.02.003 Masini, T., Birkaya, B., Van Dijk, S., Mondal, M., Hekelaar, J., Jäger, M., Terwisscha Van Scheltinga, A. C., Patel, M. S., Hirsch, A. K. H., & Moman, E. (2016). Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(sup4), 170–175. https://doi.org/10.1080/14756366.2016.1201812 Mathias, R. A., Greco, T. M., Oberstein, A., Budayeva, H. G., Chakrabarti, R., Rowland, E. A., Kang, Y., Shenk, T., & Cristea, I. M. (2014). Sirtuin 4 Is a Lipoamidase Regulating Pyruvate Dehydrogenase Complex Activity. Cell, 159(7), 1615–1625. https://doi.org/10.1016/j.cell.2014.11.046 Mayr, J. A., Feichtinger, R. G., Tort, F., Ribes, A., & Sperl, W. (2014). Lipoic acid biosynthesis defects. Journal of Inherited Metabolic Disease, 37(4), 553–563. https://doi.org/10.1007/s10545-014-9705-8 McFate, T., Mohyeldin, A., Lu, H., Thakar, J., Henriques, J., Halim, N. D., Wu, H., Schell, M. J., Tsang, T. M., Teahan, O., Zhou, S., Califano, J. A., Jeoung, N. H., Harris, R. A., & Verma, A. (2008). Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells. Journal of Biological Chemistry, 283(33), 22700–22708. https://doi.org/10.1074/jbc.M801765200 McKelvey, K. J., Wilson, E. B., Short, S., Melcher, A. A., Biggs, M., Diakos, C. I., & Howell, V. M. (2021). Glycolysis and Fatty Acid Oxidation Inhibition Improves Survival in Glioblastoma. Frontiers in Oncology, 11, 633210. https://doi.org/10.3389/fonc.2021.633210 McLean, P., Kunjara, S., Greenbaum, A. L., Gumaa, K., López-Prados, J., Martin-Lomas, M., & Rademacher, T. W. (2008). Reciprocal Control of Pyruvate Dehydrogenase Kinase and Phosphatase by Inositol Phosphoglycans: Dynamic State Set by “Push-Pull” System. Journal of Biological Chemistry, 283(48), 33428–33436. https://doi.org/10.1074/jbc.M801781200 Mehr, A. (2023). Structural interrogation of enzyme mechanism and dynamics [Georg-August-University Göttingen]. https://doi.org/10.53846/goediss-9875 Milne, J. L. S. (2002). Molecular architecture and mechanism of an icosahedral pyruvate dehydrogenase complex: A multifunctional catalytic machine. The EMBO Journal, 21(21), 5587–5598. https://doi.org/10.1093/emboj/cdf574 Milne, J. L. S., Wu, X., Borgnia, M. J., Lengyel, J. S., Brooks, B. R., Shi, D., Perham, R. N., & Subramaniam, S. (2006). Molecular Structure of a 9-MDa Icosahedral Pyruvate Dehydrogenase Subcomplex Containing the E2 and E3 Enzymes Using Cryoelectron Microscopy. Journal of Biological Chemistry, 281(7), 4364–4370. https://doi.org/10.1074/jbc.M504363200 Moore, J. D., Staniszewska, A., Shaw, T., D’Alessandro, J., Davis, B., Surgenor, A., Baker, L., Matassova, N., Murray, J., Brough, P., Wood, M., & Mahon, P. C. (n.d.). VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells. Motojima, K., & Seto, K. (2003). Fibrates and Statins Rapidly and Synergistically Induce Pyruvate Dehydrogenase Kinase 4 mRNA in the Liver and Muscles of Mice. Biological and Pharmaceutical Bulletin, 26(7), 954–958. https://doi.org/10.1248/bpb.26.954 Nemeria, N., Arjunan, P., Brunskill, A., Sheibani, F., Wei, W., Yan, Zhang, S., Jordan, F., & Furey, W. (2002). Histidine 407, a Phantom Residue in the E1 Subunit of the Escherichia coli Pyruvate Dehydrogenase Complex, Activates Reductive Acetylation of Lipoamide on the E2 Subunit. An Explanation for Conservation of Active Sites between the E1 Subunit and Transketolase. Biochemistry, 41(52), 15459–15467. https://doi.org/10.1021/bi0205909 Nemeria, N. S., Ambrus, A., Patel, H., Gerfen, G., Adam-Vizi, V., Tretter, L., Zhou, J., Wang, J., & Jordan, F. (2014). Human 2-Oxoglutarate Dehydrogenase Complex E1 Component Forms a Thiamin-derived Radical by Aerobic Oxidation of the Enamine Intermediate. Journal of Biological Chemistry, 289(43), 29859–29873. https://doi.org/10.1074/jbc.M114.591073 Nemeria, N. S., Chakraborty, S., Balakrishnan, A., & Jordan, F. (2009). Reaction mechanisms of thiamin diphosphate enzymes: Defining states of ionization and tautomerization of the cofactor at individual steps. The FEBS Journal, 276(9), 2432–3446. https://doi.org/10.1111/j.1742-4658.2009.06964.x Norton, L., & DeFronzo, R. (2014). Skeletal Muscle Glucose Metabolism and Insulin Resistance. In Pathobiology of Human Disease (pp. 477–487). Elsevier. https://doi.org/10.1016/B978-0-12-386456-7.02003-7 Olson, M. S., Hampson, R. K., & Craig, F. (1986). Regulation of the hepatic glycine-cleavage system. Biochemical Society Transactions, 14(6), 1004–1005. https://doi.org/10.1042/bst0141004 O’Reilly, F. J., Graziadei, A., Forbrig, C., Bremenkamp, R., Charles, K., Lenz, S., Elfmann, C., Fischer, L., Stülke, J., & Rappsilber, J. (2023). Protein complexes in cells by AI‐assisted structural proteomics. Molecular Systems Biology, 19(4), e11544. https://doi.org/10.15252/msb.202311544 Orfali, K. A., Fryer, L. G. D., Holness, M. J., & Sugden, M. C. (1993). Long‐term regulation of pyruvate dehydrogenase kinase by high‐fat feeding: Experiments in vivo and in cultured cardiomyocytes. FEBS Letters, 336(3), 501–505. https://doi.org/10.1016/0014-5793(93)80864-Q Patel, K. P., O’Brien, T. W., Subramony, S. H., Shuster, J., & Stacpoole, P. W. (2012). The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients. Molecular Genetics and Metabolism, 105(1), 34–43. https://doi.org/10.1016/j.ymgme.2011.09.032 Patel, M. S., & Korotchkina, L. G. (n.d.). Regulation of the pyruvate dehydrogenase complex. Patel, M. S., & Korotchkina, L. G. (2001). Regulation of mammalian pyruvate dehydrogenase complex by phosphorylation: Complexity of multiple phosphorylation sites and kinases. Experimental & Molecular Medicine, 33(4), 191–197. https://doi.org/10.1038/emm.2001.32 Patel, M. S., Nemeria, N. S., Furey, W., & Jordan, F. (2014). The Pyruvate Dehydrogenase Complexes: Structure-based Function and Regulation. Journal of Biological Chemistry, 289(24), 16615–16623. https://doi.org/10.1074/jbc.R114.563148 Patel, M. S., & Roche, T. E. (1990). Molecular biology and biochemistry of pyruvate dehydrogenase complexes. The FASEB Journal, 4(14), 3224–3233. https://doi.org/10.1096/fasebj.4.14.2227213 Pavlu-Pereira, H., Lousa, D., Tomé, C. S., Florindo, C., Silva, M. J., De Almeida, I. T., Leandro, P., Rivera, I., & Vicente, J. B. (2021). Structural and functional impact of clinically relevant E1α variants causing pyruvate dehydrogenase complex deficiency. Biochimie, 183, 78–88. https://doi.org/10.1016/j.biochi.2021.02.007 Pawelczyk, T., & Olson, M. S. (1995). Changes in the structure of pyruvate dehydrogenase complex induced by mono- and divalent ions. The International Journal of Biochemistry & Cell Biology, 27(5), 513–521. https://doi.org/10.1016/1357-2725(95)00006-B Paxton, R., Scislowski, P. W., Davis, E. J., & Harris, R. A. (1986). Role of branched-chain 2-oxo acid dehydrogenase and pyruvate dehydrogenase in 2-oxobutyrate metabolism. Biochemical Journal, 234(2), 295–303. https://doi.org/10.1042/bj2340295 Pei, X. Y., Titman, C. M., Frank, R. A. W., Leeper, F. J., & Luisi, B. F. (2008). Snapshots of Catalysis in the E1 Subunit of the Pyruvate Dehydrogenase Multienzyme Complex. Structure, 16(12), 1860–1872. https://doi.org/10.1016/j.str.2008.10.009 Perham, R. N. (2000). Swinging Arms and Swinging Domains in Multifunctional Enzymes: Catalytic Machines for Multistep Reactions. Annual Review of Biochemistry, 69(1), 961–1004. https://doi.org/10.1146/annurev.biochem.69.1.961 Peters, S. J., & LeBlanc, P. J. (2004). Metabolic aspects of low carbohydrate diets and exercise. Nutrition & Metabolism, 1(1), 7. https://doi.org/10.1186/1743-7075-1-7 Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O’Connell, T. M., & Bonetto, A. (2019). PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia. The FASEB Journal, 33(6), 7778–7790. https://doi.org/10.1096/fj.201802799R Prabhu, A., Sarcar, B., Miller, C. R., Kim, S.-H., Nakano, I., Forsyth, P., & Chinnaiyan, P. (2015). Ras-mediated modulation of pyruvate dehydrogenase activity regulates mitochondrial reserve capacity and contributes to glioblastoma tumorigenesis. Neuro-Oncology, 17(9), 1220–1230. https://doi.org/10.1093/neuonc/nou369 Prajapati, S., Haselbach, D., Wittig, S., Patel, M. S., Chari, A., Schmidt, C., Stark, H., & Tittmann, K. (2019). Structural and Functional Analyses of the Human PDH Complex Suggest a “Division-of-Labor” Mechanism by Local E1 and E3 Clusters. Structure, 27(7), 1124-1136.e4. https://doi.org/10.1016/j.str.2019.04.009 Prajapati, S., Rabe Von Pappenheim, F., & Tittmann, K. (2022). Frontiers in the enzymology of thiamin diphosphate-dependent enzymes. Current Opinion in Structural Biology, 76, 102441. https://doi.org/10.1016/j.sbi.2022.102441 Priestman, D. A., Orfali, K. A., & Sugden, M. C. (1996). Pyruvate inhibition of pyruvate dehydrogenase kinase: Effects of progressive starvation and hyperthyroidism in vivo, and of dibutyryl cyclic AMP and fatty acids in cultured cardiac myocytes. FEBS Letters, 393(2–3), 174–178. https://doi.org/10.1016/0014-5793(96)00877-0 Prochownik, E. V., & Wang, H. (2021). The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells. Cells, 10(4), 762. https://doi.org/10.3390/cells10040762 Quinlan, C. L., Goncalves, R. L. S., Hey-Mogensen, M., Yadava, N., Bunik, V. I., & Brand, M. D. (2014). The 2-Oxoacid Dehydrogenase Complexes in Mitochondria Can Produce Superoxide/Hydrogen Peroxide at Much Higher Rates Than Complex I. Journal of Biological Chemistry, 289(12), 8312–8325. https://doi.org/10.1074/jbc.M113.545301 Roche, T. E., Baker, J. C., Yan, X., Hiromasa, Y., Gong, X., Peng, T., Dong, J., Turkan, A., & Kasten, S. A. (2001). Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. In Progress in Nucleic Acid Research and Molecular Biology (Vol. 70, pp. 33–75). Elsevier. https://doi.org/10.1016/S0079-6603(01)70013-X Roche, T. E., & Hiromasa, Y. (2007). Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cellular and Molecular Life Sciences, 64(7–8), 830–849. https://doi.org/10.1007/s00018-007-6380-z Roche, T. E., Hiromasa, Y., Turkan, A., Gong, X., Peng, T., Yan, X., Kasten, S. A., Bao, H., & Dong, J. (2003). Essential roles of lipoyl domains in the activated function and control of pyruvate dehydrogenase kinases and phosphatase isoform 1. European Journal of Biochemistry, 270(6), 1050–1056. https://doi.org/10.1046/j.1432-1033.2003.03468.x Roche, T. E., & Reed, L. J. (1974). Monovalent cation requirement for ADP inhibition of pyruvate dehydrogenase kinase. Biochemical and Biophysical Research Communications, 59(4), 1341–1348. https://doi.org/10.1016/0006-291X(74)90461-6 Roosterman, D., Meyerhof, W., & Cottrell, G. S. (2018). Proton Transport Chains in Glucose Metabolism: Mind the Proton. Frontiers in Neuroscience, 12, 404. https://doi.org/10.3389/fnins.2018.00404 Sale, G. J., & Randle, P. J. (1982). Occupancy of phosphorylation sites in pyruvate dehydrogenase phosphate complex in rat heart in vivo. Relation to proportion of inactive complex and rate of re-activation by phosphatase. Biochemical Journal, 206(2), 221–229. https://doi.org/10.1042/bj2060221 Sattler, U. G. A., & Mueller-Klieser, W. (2009). The anti-oxidant capacity of tumour glycolysis. International Journal of Radiation Biology, 85(11), 963–971. https://doi.org/10.3109/09553000903258889 Saunier, E., Benelli, C., & Bortoli, S. (2016). The pyruvate dehydrogenase complex in cancer: An old metabolic gatekeeper regulated by new pathways and pharmacological agents. International Journal of Cancer, 138(4), 809–817. https://doi.org/10.1002/ijc.29564 Schell, J. C., Olson, K. A., Jiang, L., Hawkins, A. J., Van Vranken, J. G., Xie, J., Egnatchik, R. A., Earl, E. G., DeBerardinis, R. J., & Rutter, J. (2014). A Role for the Mitochondrial Pyruvate Carrier as a Repressor of the Warburg Effect and Colon Cancer Cell Growth. Molecular Cell, 56(3), 400–413. https://doi.org/10.1016/j.molcel.2014.09.026 Schell, J. C., Wisidagama, D. R., Bensard, C., Zhao, H., Wei, P., Tanner, J., Flores, A., Mohlman, J., Sorensen, L. K., Earl, C. S., Olson, K. A., Miao, R., Waller, T. C., Delker, D., Kanth, P., Jiang, L., DeBerardinis, R. J., Bronner, M. P., Li, D. Y., … Rutter, J. (2017). Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nature Cell Biology, 19(9), 1027–1036. https://doi.org/10.1038/ncb3593 Schoonjans, C. A., Joudiou, N., Brusa, D., Corbet, C., Feron, O., & Gallez, B. (2020). Acidosis-induced metabolic reprogramming in tumor cells enhances the anti-proliferative activity of the PDK inhibitor dichloroacetate. Cancer Letters, 470, 18–28. https://doi.org/10.1016/j.canlet.2019.12.003 Schröder-Tittmann, K., Meyer, D., Arens, J., Wechsler, C., Tietzel, M., Golbik, R., & Tittmann, K. (2013). Alternating Sites Reactivity Is a Common Feature of Thiamin Diphosphate-Dependent Enzymes As Evidenced by Isothermal Titration Calorimetry Studies of Substrate Binding. Biochemistry, 52(15), 2505–2507. https://doi.org/10.1021/bi301591e Schulze, A., & Downward, J. (2011). Flicking the Warburg Switch—Tyrosine Phosphorylation of Pyruvate Dehydrogenase Kinase Regulates Mitochondrial Activity in Cancer Cells. Molecular Cell, 44(6), 846–848. https://doi.org/10.1016/j.molcel.2011.12.004 Schwartz. (2010). A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results. Oncology Reports, 23(5). https://doi.org/10.3892/or_00000778 Schwer, B., Eckersdorff, M., Li, Y., Silva, J. C., Fermin, D., Kurtev, M. V., Giallourakis, C., Comb, M. J., Alt, F. W., & Lombard, D. B. (2009). Calorie restriction alters mitochondrial protein acetylation. Aging Cell, 8(5), 604–606. https://doi.org/10.1111/j.1474-9726.2009.00503.x Sebastian, C., Ferrer, C., Serra, M., Choi, J.-E., Ducano, N., Mira, A., Shah, M. S., Stopka, S. A., Perciaccante, A. J., Isella, C., Moya-Rull, D., Vara-Messler, M., Giordano, S., Maldi, E., Desai, N., Capen, D. E., Medico, E., Cetinbas, M., Sadreyev, R. I., … Mostoslavsky, R. (2022). A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine. Nature Communications, 13(1), 1503. https://doi.org/10.1038/s41467-022-29085-y Seifert, F., Ciszak, E., Korotchkina, L., Golbik, R., Spinka, M., Dominiak, P., Sidhu, S., Brauer, J., Patel, M. S., & Tittmann, K. (2007). Phosphorylation of Serine 264 Impedes Active Site Accessibility in the E1 Component of the Human Pyruvate Dehydrogenase Multienzyme Complex. Biochemistry, 46(21), 6277–6287. https://doi.org/10.1021/bi700083z Seifert, F., Golbik, R., Brauer, J., Lilie, H., Schröder-Tittmann, K., Hinze, E., Korotchkina, L. G., Patel, M. S., & Tittmann, K. (2006). Direct Kinetic Evidence for Half-Of-The-Sites Reactivity in the E1 Component of the Human Pyruvate Dehydrogenase Multienzyme Complex through Alternating Sites Cofactor Activation. Biochemistry, 45(42), 12775–12785. https://doi.org/10.1021/bi061582l Seim, G. L., John, S. V., Arp, N. L., Fang, Z., Pagliarini, D. J., & Fan, J. (2023). Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases. Nature Chemical Biology, 19(3), 265–274. https://doi.org/10.1038/s41589-022-01153-w Sgrignani, J., Chen, J., Alimonti, A., & Cavalli, A. (2018). How phosphorylation influences E1 subunit pyruvate dehydrogenase: A computational study. Scientific Reports, 8(1), 14683. https://doi.org/10.1038/s41598-018-33048-z Shan, C., Kang, H.-B., Elf, S., Xie, J., Gu, T.-L., Aguiar, M., Lonning, S., Hitosugi, T., Chung, T.-W., Arellano, M., Khoury, H. J., Shin, D. M., Khuri, F. R., Boggon, T. J., & Fan, J. (2014). Tyr-94 Phosphorylation Inhibits Pyruvate Dehydrogenase Phosphatase 1 and Promotes Tumor Growth. Journal of Biological Chemistry, 289(31), 21413–21422. https://doi.org/10.1074/jbc.M114.581124 Skalidis, I., Tüting, C., & Kastritis, P. L. (2020). Unstructured regions of large enzymatic complexes control the availability of metabolites with signaling functions. Cell Communication and Signaling, 18(1), 136. https://doi.org/10.1186/s12964-020-00631-9 Škerlová, J., Berndtsson, J., Nolte, H., Ott, M., & Stenmark, P. (2021). Structure of the native pyruvate dehydrogenase complex reveals the mechanism of substrate insertion. Nature Communications, 12(1), 5277. https://doi.org/10.1038/s41467-021-25570-y Smith, E. R., & Hewitson, T. D. (2020). TGF-β1 is a regulator of the pyruvate dehydrogenase complex in fibroblasts. Scientific Reports, 10(1), 17914. https://doi.org/10.1038/s41598-020-74919-8 Smolle, M., Prior, A. E., Brown, A. E., Cooper, A., Byron, O., & Lindsay, J. G. (2006). A New Level of Architectural Complexity in the Human Pyruvate Dehydrogenase Complex. Journal of Biological Chemistry, 281(28), 19772–19780. https://doi.org/10.1074/jbc.M601140200 Solmonson, A., & DeBerardinis, R. J. (2018). Lipoic acid metabolism and mitochondrial redox regulation. Journal of Biological Chemistry, 293(20), 7522–7530. https://doi.org/10.1074/jbc.TM117.000259 Song, J., & Jordan, F. (2012). Interchain Acetyl Transfer in the E2 Component of Bacterial Pyruvate Dehydrogenase Suggests a Model with Different Roles for Each Chain in a Trimer of the Homooligomeric Component. Biochemistry, 51(13), 2795–2803. https://doi.org/10.1021/bi201614n Srivastava, N., Kollipara, R. K., Singh, D. K., Sudderth, J., Hu, Z., Nguyen, H., Wang, S., Humphries, C. G., Carstens, R., Huffman, K. E., DeBerardinis, R. J., & Kittler, R. (2014). Inhibition of Cancer Cell Proliferation by PPARγ Is Mediated by a Metabolic Switch that Increases Reactive Oxygen Species Levels. Cell Metabolism, 20(4), 650–661. https://doi.org/10.1016/j.cmet.2014.08.003 Stacpoole, P. W. (2011). The Dichloroacetate Dilemma: Environmental Hazard versus Therapeutic Goldmine—Both or Neither? Environmental Health Perspectives, 119(2), 155–158. https://doi.org/10.1289/ehp.1002554 Stacpoole, P. W. (2012). The pyruvate dehydrogenase complex as a therapeutic target for age‐related diseases. Aging Cell, 11(3), 371–377. https://doi.org/10.1111/j.1474-9726.2012.00805.x Stacpoole, P. W. (2017). Therapeutic Targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) Axis in Cancer. JNCI: Journal of the National Cancer Institute, 109(11). https://doi.org/10.1093/jnci/djx071 Stacpoole, P. W., & McCall, C. E. (2023). The pyruvate dehydrogenase complex: Life’s essential, vulnerable and druggable energy homeostat. Mitochondrion, 70, 59–102. https://doi.org/10.1016/j.mito.2023.02.007 Strowitzki, M. J., Radhakrishnan, P., Pavicevic, S., Scheer, J., Kimmer, G., Ritter, A. S., Tuffs, C., Volz, C., Vondran, F., Harnoss, J. M., Klose, J., Schmidt, T., & Schneider, M. (2019). High hepatic expression of PDK4 improves survival upon multimodal treatment of colorectal liver metastases. British Journal of Cancer, 120(7), 675–688. https://doi.org/10.1038/s41416-019-0406-9 Sugden, C. M., Fryer, G. D. L., Orfali, A. K., Priestman, A. D., Donald, E., & Holness, J. M. (1998). Studies of the long-term regulation of hepatic pyruvate dehydrogenase kinase. Biochemical Journal, 329(1), 89–94. https://doi.org/10.1042/bj3290089 Sugden, M. C. (2008). PDC deletion: The way to a man’s heart disease. American Journal of Physiology-Heart and Circulatory Physiology, 295(3), H917–H919. https://doi.org/10.1152/ajpheart.00663.2008 Sugden, M. C., & Holness, M. J. (1989). Effects of re-feeding after prolonged starvation on pyruvate dehydrogenase activities in heart, diaphragm and selected skeletal muscles of the rat. Biochemical Journal, 262(2), 669–672. https://doi.org/10.1042/bj2620669 Sugden, M. C., & Holness, M. J. (2003). Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. American Journal of Physiology-Endocrinology and Metabolism, 284(5), E855–E862. https://doi.org/10.1152/ajpendo.00526.2002 Sugden, M. C., & Holness, M. J. (2006). Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases. Archives of Physiology and Biochemistry, 112(3), 139–149. https://doi.org/10.1080/13813450600935263 Sugden, M. C., Orfali, K. A., & Holness, M. J. (1995). The Pyruvate Dehydrogenase Complex: Nutrient Control and the Pathogenesis of Insulin Resistance. The Journal of Nutrition, 125, 1746S-1752S. https://doi.org/10.1093/jn/125.suppl_6.1746S Sugden, P. H., Hutson, N. J., Kerbey, A. L., & Randle, P. J. (1978). Phosphorylation of additional sites on pyruvate dehydrogenase inhibits its re-activation by pyruvate dehydrogenase phosphate phosphatase. Biochemical Journal, 169(2), 433–435. https://doi.org/10.1042/bj1690433 Sugden, P. H., & Randle, P. J. (1978). Regulation of pig heart pyruvate dehydrogenase by phosphorylation. Studies on the subunit and phosphorylation stoicheiometries. Biochemical Journal, 173(2), 659–668. https://doi.org/10.1042/bj1730659 Sugden, P. H., & Simister, N. E. (1980). Role of multisite phosphorylation in the regulation of ox kidney pyruvate dehydrogenase complex. FEBS Letters, 111(2), 299–302. https://doi.org/10.1016/0014-5793(80)80814-3 Sutendra, G., Kinnaird, A., Dromparis, P., Paulin, R., Stenson, T. H., Haromy, A., Hashimoto, K., Zhang, N., Flaim, E., & Michelakis, E. D. (2014). A Nuclear Pyruvate Dehydrogenase Complex Is Important for the Generation of Acetyl-CoA and Histone Acetylation. Cell, 158(1), 84–97. https://doi.org/10.1016/j.cell.2014.04.046 Sutendra, G., & Michelakis, E. D. (2013). Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Frontiers in Oncology, 3. https://doi.org/10.3389/fonc.2013.00038 Takakusagi, Y., Matsumoto, S., Saito, K., Matsuo, M., Kishimoto, S., Wojtkowiak, J. W., DeGraff, W., Kesarwala, A. H., Choudhuri, R., Devasahayam, N., Subramanian, S., Munasinghe, J. P., Gillies, R. J., Mitchell, J. B., Hart, C. P., & Krishna, M. C. (2014). Pyruvate Induces Transient Tumor Hypoxia by Enhancing Mitochondrial Oxygen Consumption and Potentiates the Anti-Tumor Effect of a Hypoxia-Activated Prodrug TH-302. PLoS ONE, 9(9), e107995. https://doi.org/10.1371/journal.pone.0107995 Tovar‐Méndez, A., Miernyk, J. A., & Randall, D. D. (2003). Regulation of pyruvate dehydrogenase complex activity in plant cells. European Journal of Biochemistry, 270(6), 1043–1049. https://doi.org/10.1046/j.1432-1033.2003.03469.x Tso, S.-C., Qi, X., Gui, W.-J., Wu, C.-Y., Chuang, J. L., Wernstedt-Asterholm, I., Morlock, L. K., Owens, K. R., Scherer, P. E., Williams, N. S., Tambar, U. K., Wynn, R. M., & Chuang, D. T. (2014). Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket. Journal of Biological Chemistry, 289(7), 4432–4443. https://doi.org/10.1074/jbc.M113.533885 Tsvetkov, P., Coy, S., Petrova, B., Dreishpoon, M., Verma, A., Abdusamad, M., Rossen, J., Joesch-Cohen, L., Humeidi, R., Spangler, R. D., Eaton, J. K., Frenkel, E., Kocak, M., Corsello, S. M., Lutsenko, S., Kanarek, N., Santagata, S., & Golub, T. R. (2022). Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 375(6586), 1254–1261. https://doi.org/10.1126/science.abf0529 Turvey, E. A., Heigenhauser, G. J. F., Parolin, M., & Peters, S. J. (2005). Elevated n-3 fatty acids in a high-fat diet attenuate the increase in PDH kinase activity but not PDH activity in human skeletal muscle. J Appl Physiol, 98. Tüting, C., Kyrilis, F. L., Müller, J., Sorokina, M., Skalidis, I., Hamdi, F., Sadian, Y., & Kastritis, P. L. (2021). Cryo-EM snapshots of a native lysate provide structural insights into a metabolon-embedded transacetylase reaction. Nature Communications, 12(1), 6933. https://doi.org/10.1038/s41467-021-27287-4 Wada, H., Shintani, D., & Ohlrogge, J. (1997). Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production. Proceedings of the National Academy of Sciences, 94(4), 1591–1596. https://doi.org/10.1073/pnas.94.4.1591 Wang, C., Ma, C., Xu, Y., Chang, S., Wu, H., Yan, C., Chen, J., Wu, Y., An, S., Xu, J., Han, Q., Jiang, Y., Jiang, Z., Chu, X., Gao, H., Zhang, X., & Chang, Y. (2025). Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis. Nature Communications, 16(1), 917. https://doi.org/10.1038/s41467-025-56171-8 Wang, X., Shen, X., Yan, Y., & Li, H. (2021). Pyruvate dehydrogenase kinases (PDKs): An overview toward clinical applications. Bioscience Reports, 41(4), BSR20204402. https://doi.org/10.1042/BSR20204402 Whitley, M. J., Arjunan, P., Nemeria, N. S., Korotchkina, L. G., Park, Y.-H., Patel, M. S., Jordan, F., & Furey, W. (2018). Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the αV138M variant of human pyruvate dehydrogenase. Journal of Biological Chemistry, 293(34), 13204–13213. https://doi.org/10.1074/jbc.RA118.003996 Woolbright, B. L., & Harris, R. A. (2021). PDK2: An Underappreciated Regulator of Liver Metabolism. Livers, 1(2), 82–97. https://doi.org/10.3390/livers1020008 Woolbright, B. L., Rajendran, G., Harris, R. A., & Taylor, J. A. (2019). Metabolic Flexibility in Cancer: Targeting the Pyruvate Dehydrogenase Kinase:Pyruvate Dehydrogenase Axis. Molecular Cancer Therapeutics, 18(10), 1673–1681. https://doi.org/10.1158/1535-7163.MCT-19-0079 Wu, P., Blair, P. V., Sato, J., Jaskiewicz, J., Popov, K. M., & Harris, R. A. (2000). Starvation Increases the Amount of Pyruvate Dehydrogenase Kinase in Several Mammalian Tissues. Archives of Biochemistry and Biophysics, 381(1), 1–7. https://doi.org/10.1006/abbi.2000.1946 Wynn, R. M., Kato, M., Chuang, J. L., Tso, S.-C., Li, J., & Chuang, D. T. (2008). Pyruvate Dehydrogenase Kinase-4 Structures Reveal a Metastable Open Conformation Fostering Robust Core-free Basal Activity. Journal of Biological Chemistry, 283(37), 25305–25315. https://doi.org/10.1074/jbc.M802249200 Yang, D., Gong, X., Yakhnin, A., & Roche, T. E. (1998). Requirements for the Adaptor Protein Role of Dihydrolipoyl Acetyltransferase in the Up-regulated Function of the Pyruvate Dehydrogenase Kinase and Pyruvate Dehydrogenase Phosphatase. Journal of Biological Chemistry, 273(23), 14130–14137. https://doi.org/10.1074/jbc.273.23.14130 Yihan, L., Xiaojing, W., Ao, L., Chuanjie, Z., Haofei, W., Yan, S., & Hongchao, H. (2021). SIRT5 functions as a tumor suppressor in renal cell carcinoma by reversing the Warburg effect. Journal of Translational Medicine, 19(1), 521. https://doi.org/10.1186/s12967-021-03178-6 Yin, C., He, D., Chen, S., Tan, X., & Sang, N. (2016). Exogenous pyruvate facilitates cancer cell adaptation to hypoxia by serving as an oxygen surrogate. Oncotarget, 7(30), 47494–47510. https://doi.org/10.18632/oncotarget.10202 Zachar, Z., Marecek, J., Maturo, C., Gupta, S., Stuart, S. D., Howell, K., Schauble, A., Lem, J., Piramzadian, A., Karnik, S., Lee, K., Rodriguez, R., Shorr, R., & Bingham, P. M. (2011). Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo. Journal of Molecular Medicine, 89(11), 1137–1148. https://doi.org/10.1007/s00109-011-0785-8 Zhang, N., & Palmer, A. F. (2011). Development of a dichloroacetic acid‐hemoglobin conjugate as a potential targeted anti‐cancer therapeutic. Biotechnology and Bioengineering, 108(6), 1413–1420. https://doi.org/10.1002/bit.23071 Zhang, S., Hulver, M. W., McMillan, R. P., Cline, M. A., & Gilbert, E. R. (2014). The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility. Nutrition & Metabolism, 11(1), 10. https://doi.org/10.1186/1743-7075-11-10 Zhang, S.-L., Hu, X., Zhang, W., & Tam, K. Y. (2016). Unexpected Discovery of Dichloroacetate Derived Adenosine Triphosphate Competitors Targeting Pyruvate Dehydrogenase Kinase To Inhibit Cancer Proliferation. Journal of Medicinal Chemistry, 59(7), 3562–3568. https://doi.org/10.1021/acs.jmedchem.5b01828 Zhang, S.-L., Hu, X., Zhang, W., Yao, H., & Tam, K. Y. (2015). Development of pyruvate dehydrogenase kinase inhibitors in medicinal chemistry with particular emphasis as anticancer agents. Drug Discovery Today, 20(9), 1112–1119. https://doi.org/10.1016/j.drudis.2015.03.012 Zhou, Z. H., Liao, W., Cheng, R. H., Lawson, J. E., McCarthy, D. B., Reed, L. J., & Stoops, J. K. (2001). Direct Evidence for the Size and Conformational Variability of the Pyruvate Dehydrogenase Complex Revealed by Three-dimensional Electron Microscopy. Journal of Biological Chemistry, 276(24), 21704–21713. https://doi.org/10.1074/jbc.M101765200 Zhou, Z. H., McCarthy, D. B., O’Connor, C. M., Reed, L. J., & Stoops, J. K. (2001). The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Proceedings of the National Academy of Sciences, 98(26), 14802–14807. https://doi.org/10.1073/pnas.011597698

@CrumblingCookie said in Repairing Knee Osteoarthritis and Cartilage Degeneration with the combination of Boswellia and Celery Seed:: Both celery extract and apigenin, and flavonoids in general (?), seem to promote breakdown of calcium oxalate. Digging into this I discovered the term Chondroprotective agents. These agents "include both endogenous and synthetic chemicals." No mention of exogenous natural sources. A quick search of 2025 pulbications: Anthocyanins and Anthocyanidins in the Management of Osteoarthritis: A Scoping Review of Current Evidence Potential Chondroprotective Effect of Artemisia annua L. Water Extract on SW1353 Cell Chondroprotective effect of pomegranate seed oil in papain-induced knee osteoarthritis through animal modeling

Butchered and banned. Why China. Why.

@Mauritio Thanks

@evan-hinkle said in Visceral fat reduction by enteric-coated lactoferrin: @Ismail hey man, doing well! I was taking 500mg Jarrow freeze-dried lactoferrin. And just a general update: I’ve been taking the enteric coated for a few months now, and I actually think I prefer the ones I was taking before. I replicated the study above taking 300mg of the enteric coated, and really didn’t notice anything at all, (which is odd because I respond to most everything I try, (good or bad)). TMI: I saw an undigested enteric coated lactoferrin in my stool last week, (great, they’re making it past the stomach-bad, I’m literally shitting my money away…). Lol! I guess the enteric coating is working erm too well! Since this event I’ve begun chewing the enteric coated pills, (now we’re really defeating the purpose, lol) and this has not made any difference. Still not noticing any effect. I’ll swap back to my old brand for a month and see what I think. Yes will def be interesting to see how you respond if you go back again