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Diverse effects of ketogenic and ketogenic diets first, Ketone bodies that are naturally present in the body what kind of work does it have? In recent years, researchers have reported various effects. In papers and patents on the Ketogenic diet Emerging physiology of ketone bodies As The main ones are: (1) (2) Suppression of oxidative stress (3) (4) (5) (6) Suppression of inflammatory response (7) improving kidney function and so on. ** However, most of these papers are data obtained from mice, other animals and I don't know yet if it applies to humans. ** Clarified in patents and papers on the ketogenic diet The main physiological functions of ketone bodies are as follows. (1) Decrease in blood sugar level (2) Suppression of oxidative stress (3) anticancer effect (4) Protective effect on nerve cells (inhibition of epileptic seizures, etc.) (5) Reduction of blood fatty acids (6) suppression of inflammatory response (7) improvement of kidney function "Blood sugar level spike suppression effect" Diabetes is chronically high blood glucose levels caused by excessive glucose in the blood. If left untreated, arteriosclerosis progresses and blood vessels become more susceptible to damage. My blood sugar fluctuates all the time and I was diagnosed with diabetes. It is not uncommon for postprandial blood glucose levels to be 140 mg/dL or higher, even in people who do not. This rise in blood sugar level for about 1 to 2 hours after eating before falling into a state of constant high blood sugar level is called "blood sugar level spike". Controlling "blood sugar level spikes," in which blood sugar levels rise sharply in a short period of time after meals, is the basis of dietary habits to prevent diabetes. Ketone bodies are It is known to strongly suppress blood sugar level spikes. That is, ketone bodies are known to activate their receptor HCAR2 and promote the uptake of glucose into tissues (eg, skeletal muscles of the arms and legs). “Acquisition of resistance to oxidative stress (active oxygen)” Cell survival depends on mitochondrial energy metabolism, but at the same time, it is thought that it is endangered by reactive oxygen species generated from this. Almost all cells have enzymes that remove active oxygen by themselves. Their expression is regulated at the gene level. One such regulation that occurs at the gene level is histone acetylation. When histones are acetylated, enzymes that scavenge active oxygen are produced more and more, and resistance to oxidative stress can be acquired. The presence of ketone bodies at this time promotes acetylation and can further enhance resistance to active oxygen. A group from the University of Tokyo School of Medicine clarified the mechanism (published in 2013 / US scientific journal Science), and found that ketone bodies bind to histone deacetylase and inhibit it (release the inhibition of histone acetylation). rice field. "Protection of nerve cells" Direct administration of ketone bodies to cultured rat hippocampal cells reduced cell death caused by addition of amyloid-β, and similarly, in cultured midbrain cells, it prevented cell destruction by free radicals produced by Parkinson's disease (PK) causative agents. understood. Ketone bodies have the effect of activating gene expression by inhibiting histone deacetylase, a nuclear protein that binds to DNA and regulates gene expression. Ketone bodies act as regulators of gene expression and induce a group of enzymes that remove active oxygen. Ketone bodies thus protect nerve cells. The ketogenic diet may be one of the mechanisms by which neurodegenerative diseases associated with oxidative stress such as Parkinson's disease and Alzheimer's disease are effective. “Neural cell membrane stabilization effect” Ketone bodies have the effect of stabilizing the membrane potential of nerve cells and suppressing abnormal excitation. Ketone bodies activate ATP-dependent potassium channels, lower membrane potential, and suppress neuronal abnormal excitation. This is the molecular mechanism by which the ketogenic diet suppresses epileptic seizures. However, the membrane potential stabilizing effect of ketone bodies on nerve cells requires an increase in concentration to at least the mM order, and a thorough ketogenic diet is required. It has been known for more than 100 years that the ketogenic diet is highly effective against intractable epilepsy, but the reason why it is not widely used in clinical practice is that this thorough ketogenic diet is necessary. There is a cause. However, since ketone bodies have the function of maintaining a wide variety of brain functions normally, a ketogenic diet that can increase ketone bodies to the mM order is effective in preventing or treating various neurodegenerative diseases. It is believed that there is. "Cancer suppression effect" Ketone bodies suppress the growth of cancer cells and have the effect of regressing cancer. Cancer cells use only glycolysis to proliferate (Warburg effect). In other words, even if mitochondria exist in cancer cells, they are hardly utilized, and most of the energy substrates they need use glycolysis. mitochond Cancer cells are known to undergo apoptosis or stop growing under conditions where ketone bodies and other organic acids, which can act directly on the rear, predominate. In addition to acting as an energy substrate for ketone bodies, it has been suggested that ketone bodies may inhibit cancer cell growth through activation of the HCAR2 receptor, inhibiting the growth of many types of cancer cells. reported to do. "Adjuvant action" Of particular interest in the cancer-suppressing action of ketone bodies are gliomas. Gliomas are characterized by the following two characteristics. One is that radiotherapy is possible due to its low invasiveness. The other is that most anticancer drugs cannot pass through the blood-brain barrier, so they have little effect on gliomas. On the other hand, ketone bodies are highly transmissible to the brain, and 20-30% of ketone bodies are translocated to the brain. In this sense, the combination of radiotherapy and ketone bodies is a combination with high clinical expectations. Against this background, cancer adjuvant action has attracted attention as a prominent action of the ketogenic diet. We found that irradiation of mouse gliomas significantly improved mouse survival, but radiation plus a ketogenic diet improved mouse survival even more. The effect of ketone bodies on inhibiting the growth of cancer cells is not limited to gliomas, but is observed in many cancer cells, so this report is noteworthy in terms of the effective use of ketone bodies as food in the medical science field. It can be said that the ketogenic diet is effective as a means for significantly enhancing the therapeutic effects of 1) chemotherapy, 2) radiation therapy and 3) surgical therapy, which are the most basic therapies for cancer. Focusing on this adjuvant action, clinical trials for cancer treatment are being conducted in various countries. " Neutral fat lowering effect" When a healthy person follows a ketogenic diet, the concentration of ketone bodies in the blood increases. It activates mitochondrial metabolism throughout the body (especially in skeletal muscle). Therefore, in skeletal muscle, the function shifts in the direction of producing energy (by decomposing fat). The amount of triglycerides taken up from the blood by skeletal muscles is increased, and blood glycerol (triglycerides) is significantly reduced. metabolism like this The shift in is an energy shift to permanently eliminate obesity. Conceivable. "Anti-inflammatory action" Ketone bodies suppress chronic inflammation. That is, ketone bodies It suppresses the function of the protein NLRP3, which is a component of the protein complex necessary to continuously promote sexual inflammation, and suppresses chronic inflammation. In addition, ketone bodies have the ability to activate HCAR2, a receptor for some organic acids, suppress various inflammatory reactions, and consequently suppress cancer. From these basic studies, it can be easily inferred that ketone bodies have inhibitory effects on pathological conditions involving inflammatory reactions such as ulcerative colitis, colon cancer, rheumatism, arteriosclerosis, and obesity. “Renal function improving effect” A group at Shiga University of Medical Science has revealed that ketone bodies activate autophagy and suppress diabetic nephropathy. (Published in July 2020 / American scientific journal Cell Metabolism) In experiments with mice, administration of a ketone body precursor (1,3-butanediol: 1,3-BD) ameliorated the increase in serum cystatin C and tissue damage, which indicate increased renal dysfunction in a diabetes model. Feeding a substance (butanediol *1) that converts to ketone bodies in the liver decreases the protein cystatin C in the blood, which indicates a decline in renal function. Therefore, it can be expected to improve the symptoms of diabetic nephropathy in humans as well. 　　　　　　　　　　　　　　　　　　　　　 *For citation sources, please refer to the references below. *1 / Explain butanediol. 1,3-butanediol (a ketone body precursor) is oxidized in the liver to produce 3-hydroxybutyrate (a ketone body), which enters the systemic circulation. Physiological functions of ketone esters "Lipolysis by ketone ester diet" David Veech et al. tested mice on synthetic keto 60% of their regular diet carbohydrates. (2012) observed the effects of feeding mice on a ketone ester diet replaced with amine esters. The effect of the ketone ester diet on mice is remarkable, blood ketone body concentration increases 5-3 times compared to the ketone diet, and the mitochondria of brown adipose tissue develop and show a clear internal structure after 1 month of breeding. become. In other words, it was shown that ketone esters increase the concentration of ketone bodies, induce the decomposition of visceral fat, and markedly suppress obesity. Increased uncoupling proteins that promote mitochondrial thermogenesis and accelerated breakdown of intracellular lipids. Uncoupling proteins also increase in subcutaneous adipose tissue, contributing to fat loss. “Anti-dementia effect of ketone ester diet” David Veech and colleagues found that feeding mice with Alzheimer's disease a ketone ester diet improved cognitive function. Amyloid-β and phosphorylated tau protein, which are said to be involved in neuronal degeneration, are reduced. Although it is an animal experiment, since ketone bodies improve cognitive behavioral lesions in Alzheimer's disease A, ketone bodies are expected to have similar effects in Alzheimer's disease in humans. “Improving endurance with a ketone ester diet” A study of ketone esters by Kieren Clark et al. It can be said that it is the biggest breakthrough in several years. Drinking Ketone Ester Beverages Therefore, it was reported that the athlete's endurance and record were significantly improved. Historically, carb-loading has been used before endurance training for athletes. Although it was normal to ingest carbohydrates, this actually lowered the record, Only the ketone ester intake group showed significant improvement in recording. Moreover, this effect is immediate Effective and detectable tens of minutes after ingestion. In addition, intake of ketone esters Therefore, it was also found that the decomposition of visceral fat is rapidly promoted. until then ketones There have been many reports that the functions of the body have an immediate effect on the brain, but this report Thus, it was shown for the first time that athletes' endurance also improved rapidly. References [Prior art documents] [Patent document] [Patent document 1] JP 2018-166481 [Patent document 2] JP 2018-000073 [Patent Document 3] JP 2017-071644 [Patent Document 4] JP 2018-138549 [Patent Document 5] Special table 2015-514104 [Patent Document 6] W2005/021013 [Patent Document 7] WO2019035486A1 [Patent Document 8] JP 2010-168595 [Patent Document 9] JP 2012-72148 [Patent Document 10] W2008/120778 [Non-Patent Literature] Nakatani T, Yasuda K, Ozawa K, Tobe T. Changes in blood glucose levels in relation to blood ketone body ratio following hypertonic glucose infusion in 70% hepatectomized rabbits. Eur Surg Res. 1984;16(5):303-311. doi : 10.1159/000128423 [Non-Patent Literature] Shimazu T, Hirschey MD, Newman J, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. 2013;339(6116):211-214. doi:10.1126/science.1227166 [Non-Patent Literature] Tomita I, Kume S, Sugahara S, et al. SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition [published online ahead of print, 2020 Jul 19]. Cell Metab. 2020;S1550-4131(20 )30358-2. doi:10.1016/j.cmet.2020.06.020 [Non-Patent Literature] Fery F, Bourdoux P, Christophe J, Balasse EO. Hormonal and metabolic changes induced by an isocaloric isoproteinic ketogenic diet in healthy subjects. Diabete Metab. 1982;8(4):299-305. [Non-Patent Document 1] Evidence that supports the prescription of low-carbohydrate high-fat diets: a narrative review. Noakes TD, Windt J. Br J Sports Med. 2017 Jan;51(2):133-139. [Non-Patent Document 2] Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome. Gershuni VM, Yan SL, Medici V. Curr Nutr Rep. 2018 Sep;7(3):97-106. [Non-Patent Document 3] Analysis of energy restriction and physical activity on brain function: the role of ketone body and brain-derived neurotrophic factor. Park CH, Kwak YS. J Exerc Rehabil. 2017 Aug 29;13(4):378- 380. [Non-Patent Document 4] How Can a Ketogenic Diet Improve Motor Function? Veyrat-Durebex C, Reynier P, Procaccio V, Hergesheimer R, Corcia P, Andres CR, Blasco H. Front Mol Neurosci. 2018 Jan 26;11:15. [Non-Patent Document 5] Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease). Włodarek D. Nutrients. 2019 Jan 15;11(1). [Non-Patent Document 6] The ketogenic diet as a potential treatment and prevention strategy for Alzheimer's disease. Broom GM, Shaw IC, Rucklidge JJ. Nutrition. [Non-Patent Document 7] Ketogenic dietary therapies for epilepsy and beyond. deCampo DM, Kossoff EH. Curr Opin Clin Nutr Metab Care. 2019 Apr 24. [Non-Patent Document 8] 2-Deoxyglucose and Beta-Hydroxybutyrate: Metabolic Agents for Seizure Control. Rho JM, Shao LR, Stafstrom CE. Front Cell Neurosci. 2019 Apr 30;13:172. [Non-Patent Document 9] Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Nutr Metab (Lond). 2009 Aug 10;6:31. [Non-Patent Document 10] Medical foods for Alzheimer's disease. Shah RC. Drugs Aging. 2011 Jun 1;28(6):421-8. [Non-Patent Document 11] Potential Synergies of β-Hydroxybutyrate and Butyrate on the Modulation of Metabolism, Inflammation, Cognition, and General Health. Cavaleri F, Bashar E. J Nutr Metab. 2018 Apr 1. [Non-Patent Document 12] β-Hydroxybutyrate: A Signaling Metabolite. Newman JC, Verdin E. Annu Rev Nutr. 2017 Aug 21;37:51-76. [Non-Patent Document 13] Biomarkers, ketone bodies, and the prevention of Alzheimer's disease. VanItallie TB. Metabolism. 2015 Mar;64(3 Suppl 1):S51-7. [Non-Patent Document 14] Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E. Science. 2013 Jan 11;339(6116):211-4. [Non-Patent Document 15] Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Sada N, Lee S, Katsu T, Otsuki T, Inoue T. Science. 2015 Mar 20;347(6228):1362-7. [Non-Patent Document 16] Ketone Bodies as Anti-Seizure Agents. Simeone TA, Simeone KA, Rho JM. Neurochem Res. 2017 Jul;42(7):2011-2018 [Non-Patent Document 17] Tumor Metabolism, the Ketogenic Diet and βHydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy. Woolf EC, Syed N, Scheck AC. Front Mol Neurosci. 2016 Nov 16;9:122. [Non-Patent Document 18] The influence of ketogenic therapy on the 5 R's of radiobiology. Klement RJ. Int J Radiat Biol. 2019 Apr;95(4):394-407. [Non-Patent Document 19] The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, Scheck AC. PLoS One. 2012;7 (5): e36197. [Non-Patent Document 20] Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to AdjuvantBrain Tumor Therapy. Woolf EC, Syed N, Scheck AC. Front Mol Neurosci. 2016 Nov 16;9:122. [Non-Patent Document 21] The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD. Nat Med. 2015 Mar;21(3):263-9. [Non-Patent Document 22] The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Müller-Fielitz H, Pokorná B, Vollbrandt T, Stölting I, Nadrowitz R 2014 May 21;5:3944. [Non-Patent Document 23] Ketone esters increase brown fat in mice and overcome insulin resistance in other tissues in the rat. Veech RL. Ann NY Acad Sci. 2013 Oct;1302:42-48. [Non-Patent Document 24] A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Kashiwaya Y, Bergman C, Lee JH, Wan R, King MT, Mughal MR, Okun E, Clarke K, Mattson MP, Veech RL. Neurobiol Aging. 2013 Jun;34(6):1530-9. [Non-Patent Document 25] Nutritional Ketosis Alters Fuel Preference and Adverse Endurance Performance in Athletes. Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT , Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Cell Metab. 2016 Aug 9;24(2):256-68. [Non-Patent Document 26] Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet. Srivastava S, Kashiwaya Y, King MT, Baxa U, Tam J, Niu G, Chen X, Clarke K, Veech RL. FASEB J. 2012 Jun;26(6):2351-62. [Non-Patent Document 27] Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype? Pinckaers PJ, Churchward-Venne TA, Bailey D, van Loon LJ. Sports Med. 2017 Mar;47(3):383-391. [Non-Patent Document 28] Ketone body metabolism and cardiovascular disease. Cotter DG, Schugar RC, Crawford PA. Am J Physiol Heart Circ Physiol. 2013 Apr 15;304(8):H1060-76. [Non-Patent Document 29] Ketoacids? Good medicine? Cahill GF Jr, Veech RL. Trans Am Clin Climatol Assoc. 2003;114:149-6. 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About P HB for pet therapy food This is a kind of “New-Prebiotics”. We call it "Ketobiotics". Our commitment is to be “Beyond Science”. Polyhydroxybutyrate (PHB) made from a bacteria which originally live in the sea and salt lake.From a chemical point of view, PHB is a simple compound, a polymer of ketone bodies.PHB is known as an energy substrate for hunger saved in the bacteria and has been regarded as a candidate of biodegradable plastic. However, because it is too fragile to be used as a substrate of tissue engineering, it has not been realized as a bioplastic up to the present time. use of this compound in another biological field. Since this is hydrolyzed and primarily used as an energy substrate in the enterobacteria, it may affect and modulate the composition of intestinal microbial flora. This is a kind of “New-Prebiotics”. We call it "Ketobiotics". Beyond Science Ltd. has been aiming at the industrialization of this compound as an effector of prebiotics. This is the straightforward way for realization of “Eatable Ketone body” according to social demand for pet health. And we believe that this method is a useful tool to practice easy keto diet and ketogenic life for dogs, cats and so on. PHBs metabolized by enterobacteria PHB is a beta-hydroxybutyrate (ketone body)-polymerized compound, in which ketone body connects with each other by an ester bond(1-2). small intestine and reaches large intestine. Just enterobacteria can digest this compound by their own enzymes(2-3). As a result, enterobacteria produce ketone body in their bodies and metabolize it through a chain of chemical reactions for energy production. Thus, PHB can significantly improve microbiological environment of large intestine and this is the physiological basis of health benefits of PHB . PHB and the improvement of the environment of large intestine can induce various health benefits and we call these mechanisms as “New-Prebiotics”, which is a novel mode of “Prebiotics”. body can be diffused into the space of large intestine as well as consumption inside bacterial body. References Obruca S, Sedlacek P, Krzyzanek V, et al. Accumulation of Poly(3-hydroxybutyrate) Helps Bacterial Cells to Survive Freezing. PLoS One. 2016;11(6):e0157778. Published 2016 Jun 17. doi:10.1371/journal. pone.0157778 Gowda USV, Shivakumar S. Poly(-β-hydroxybutyrate) (PHB) depolymerase PHAZ Pen from Penicillium expansum: purification, characterization and kinetic studies. 3 Biotech. 2015;5(6):901–909. doi:10.1007/s13205- 015-0287-4 Tseng CL, Chen HJ, Shaw GC. Identification and characterization of the Bacillus thuringiensis phaZ gene, encoding new intracellular poly-3-hydroxybutyrate depolymerase. J Bacteriol. 2006;188(21):7592–7599. doi:10.1128/JB.00729 -06 Various bacteria can save polyhydroxybutyrate (PHB) into granule-like shaped body inside the bacteria for energy substate(4). This is supposed to be a sort of bacterial insurance against their food crisis. Beyond Science Ltd. makes use of a peculiar strain, in which PHB often occupies over 80% of all space of the bacterial body. In this bacterial culture, PHB can be refined as pure powder by a simple method (Patent: WO2019/035486) (5-6). Since PHB is almost tasteless and odorless, this is one of the best ingredients of pet food for dogs and cats. References 4. Wang X, Jiang XR, Wu F, Ma Y, Che X, Chen X, Liu P, Zhang W, Ma X, Chen GQ.Microbial Poly-3-Hydroxybutyrate (PHB) as a Feed Additive for Fishes and Piglets. Biotechnol J. 2019 Dec;14(12):e1900132. doi: 10.1002/biot.201900132. Epub 2019 Jun 27. 5. Yu LP, Yan X, Zhang X, Chen XB, Wu Q, Jiang XR, Chen GQ.Biosynthesis of functional polyhydroxyalkanoates by engineered Halomonas bluephagenesis. Metab Eng. 2020 May;59:119-130. doi: 10.1016/j.ymben.2020.02.005. Epub 2020 Feb 29. 6. Yokaryo H, Teruya M, Hanashiro R, Goda M, Tokiwa Y.Direct Production of (R)-3-Hydroxybutyric Acid of High Optical Purity by Halomonas sp. OITC1261 Under Aerobic conditions. Biotechnol J. 2018 Feb;13(2). doi: 10.1002/biot.201700343. Epub 2017 Oct 30. Activation of regulatory T cells (7) PHB makes enterobacteria produce ketone body inside bacterial body and activates the growth of various enterobacteria through energy production due to increase in ketone body. Good enterobacteria are supposed to activate regulatory T cells and suppress unnecessary immunological reactions(8-9). increase in good enterobacteria, regulatory T cells are activated through macrophages of Payer board of the large intestine. Regulatory T cells can suppress excess symptoms of various inflammations such as allergy and autoimmunity and return to the basal line of the reaction. References 7. Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N.Regulatory T Cells and Human Diseases. 2020 Feb 4. doi: 10.1146/annurev-immunol-042718-041717. 8. Ladinsky MS, Araujo LP, Zhang X, Veltri J, Galan-Diez M, Soualhi S, Lee C, Irie K, Pinker EY, Narushima S, Bandyopadhyay S, Nagayama M, Elhenawy W, Coombes BK, Ferraris RP, Honda K, Iliev ID, Gao N, Bjorkman PJ, Ivanov II.Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science. 2019 Mar 8;363(6431). pii: eaat4042. doi: 10.1126/science.aat4042. 9. Narushima S, Sugiura Y, Oshima K, Atarashi K, Hattori M, Suematsu M, Honda K.Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes. 2014 May-Jun;5(3):333-9. doi: 10.4161/gmic.28572. Epub 2014 Mar 18. Sustained increase in ketone body by PHB (10) PHB can induce the sustained increase the concentrations of blood ketone body, which is in a sharp contrast to that of ketone ester, another type of ketone donor. 5 hours(11-12). In contrast, PHB needs 5 hours to begin the increase, but induces the sustained increase at least over 10 hours. This may be due to digestion just by enterobacteria, but not to digestive enzymes of small intestine. Further, this sustained increase in ketone body is the biological key to the preventive effects against various lifestyle-related diseases. References 10. Patent number: WO2019/035486 11. Abdul Kadir A, Clarke K, Evans RD.Cardiac ketone body metabolism. Biochim Biophys Acta Mol Basis Dis. 2020 Jun 1;1866(6):165739. doi: 10.1016/j.bbadis.2020.165739. Epub 2020 Feb 19 12. Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014;25(1):42–52. doi:10.1016/j.tem.2013.09.002 A novel type of prebiotics The first biological target of PHB may be enterobacteria, already suggested by a prior art (patent: WO2005/021013). Pigs, kept for 5 days or 4 weeks and fed with PHB5%, increased the amount of excrement and defecation frequency(13) These results suggest that the number of enterobacteria is increased. In addition, PHB significantly decreased the amount of odor ingredients. Previous reports suggested that PHB can be digested by enzymes of enterobacteria. Thus, PHB can increase the ketone body and activate the growth of the bacteria. References 13. Patent number: WO2005/021013 Ketone body as a promising molecule of anti-aging Ketone body, which produces energy within mitochondria of the cells, is a simple C4 organic acid composed of carboxylic acid and hydroxyl group and thus two ketone bodies can form a connection through an ester bond. When great number of ketone bodies exist, they can form Ketone body is no longer regarded as a metabolic intermediate, as it regulates a broad range of physiological events at cellular and systemic levels. Importantly, ketone body functions as a stress response to maintain redox homeostasis in response to environmental and metabolic challenges(14-15). References 14. Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT.Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 2017 May;69(5):305-314. doi: 10.1002 /iub.1627. Epub 2017 Apr 3. 15. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, Perez G, Gutierrez-Casado E, Koike S, Knotts TA, Imai DM, Griffey SM, Kim K, Hagopian K, McMackin MZ, Haj FG, Baar K, Cortopassi GA, Ramsey JJ, Lopez-Dominguez JA.A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab. 2017 Sep 5;26(3):539-546.e5. doi: 10.1016/j.cmet.2017.08.005.2018 May 1;27(5):1156 . References 16. Patent number: WO2015/072456 17.Patent number: WO2008/120778 Three types of ketone donors ketone donor is defined as substance which produces ketone body by enzymes of the small and large intestine. The most prominent feature is the production of ketone body under no influence of insulin. types of ketone donors. One is ketone body salt, for example, sodium salt of ketone body(16-17). The second is ketone ester, which ketone body is connected to alcohol through an ester bond(11-12). is PHB, which is a polymer of ketone body(10). I have focused on PHB as a mammals' supplement for these three years. Ketone body and ketone ester is hydrolyzed by enzymes of the small intestine and PHB is hydrolyzed by those of the This difference makes a big difference of physiological effects by them in the point that just PHB can induce a sustained increase in ketone body concentration. Beyond Science Ltd. A new ketogenic diet for pet therapy food beyondscience( A T. )polyhydroxyphb.com _cc781905-5cde-3194-bb 3b-136bad5cf58d_ _cc781905-5cde-3194 -bb3b-136bad5cf58d_ _cc7 81905-5cde-3194-bb3b-136bad5cf58d_ _cc781905 -5cde-3194-bb3b-136bad5cf58d_ Toky o / JAPAN BACK シェア

PR Office A new methodology called "Ketobiotics", a new prebiotic We aim to go beyond ketogenic for our pets. Protect your pets' health A new methodology called "Ketobiotics", new prebiotics for maintaining the health of dogs and cats. As a pet supplement and pet food. ペットたちの健康を守りたい。 ペットたちに、ずっと健康でいてほしい。 PHB が、 お役に立てるかも知れません。 シェア

Mitochondria and anti-aging Mitochondria are small organelles inside cells that have DNA because they were originally bacteria. Therefore, it can divide and multiply autonomously. That is why it has a decisive role in controlling the life and death of cells in the human body. Impaired mitochondrial energy metabolism releases factors that induce cell death. If the mitochondria are actively working, the cells are also lively and anti-aging effects can be expected. Cells make energy in two places: the cytoplasm and the mitochondria. The energy metabolism pathway in the cytoplasm is called "glycolysis", which mainly decomposes glucose and converts it into an energy source that is easy to use in the body. However, this route cannot be said to have good metabolic efficiency because part of the glucose changes to lactic acid during decomposition and is not completely oxidized. Mitochondrial energy metabolism is very efficient. This is because the compounds called ketone bodies and pyruvate reach directly and are completely oxidized and everything becomes energy. Therefore, the key to healthy longevity is how to use these highly energy-efficient mitochondria. The reason that carbohydrate restriction is good for the body is that lowering carbohydrates suppresses insulin spikes and increases the concentration of ketone bodies, which become an energy source in mitochondria and improve metabolic efficiency. This is because mitochondria are activated. シェア

Mechanism of “longevity bacteria” Why does butyric acid provide longevity? This is because when the concentration of butyric acid increases in the large intestine, it changes the entire mammalian immune system. In other words, a butyric acid-dominant intestinal environment has a great positive effect on the whole body. An increase in butyric acid concentration in the large intestine affects the immune system of mammals. This Peyer's patch differs greatly in structure and function from other colonic epithelia. 1) It can pass butyric acid in the large intestine. 2) Concentrated antigen-presenting cells (macrophages) and immunocompetent cells (T cells) These two points. This allows colonic butyrate to directly impact macrophage and T-cell function. So what are the implications? This is what promotes the differentiation of regulatory T cells. Due to the presence of Peyer's patches, increased butyrate concentrations result in an increased number of regulatory T cells. These regulatory T cells have the effect of suppressing excessive immune responses in mammals and restoring them to a normal state. For example, Philippe Langella's group found that Faecalibacterium prausnitzii cultured and reintroduced into the gut of mice with ulcerative colitis and Crohn's disease ameliorated these conditions. This effect has been shown to be mediated by an increase in regulatory T cells. Many immune disorders involve excessive activation of helper T cells. Regulatory T cells suppress this abnormal activation. It is said that this suppresses excessive immunity and improves the disease condition. Longevity village and butyric acid bacteria Mr. Metchnikoff researched longevity villages, extracted their common eating habits, and found that they ate yogurt almost every day. was over 100 years ago. Since then, many scholars have speculated that gut bacteria may be the key to healthy longevity. Analysis using the latest technology such as the microbiome has revealed that butyric acid bacteria are also very important for maintaining a healthy intestinal environment. The microbiome revealed that Faecalibacterium prausnitzii, one of the butyric bacteria, was greatly reduced in patients with Crohn's disease. Butyric acid bacteria and Treg cells acetic acid, lactic acid, propionic acid The ideal environment in the intestine is slightly acidic. In order to maintain weak acidity, it is necessary to produce acidic substances (lower fatty acids) from intestinal bacteria, and there are mainly 4 types of lower fatty acids. That is, acetic acid (carbon number C=2), lactic acid (C=3), propionic acid (C=3), butyric acid (C=4). A ketone body is a hydroxylated carbon at the 3-position of butyric acid. Many intestinal bacteria have the ability to produce these lower fatty acids, but which lower fatty acids are preferentially produced and released outside the bacterial body is determined by the type of intestinal bacteria. Intestinal bacteria that predominantly produce acetic acid, lactic acid, propionic acid, and butyric acid are called acetic acid bacteria, lactic acid bacteria, propionic acid bacteria, and butyric acid bacteria, respectively. Butyric acid bacteria are “longevity bacteria” This pioneering work was followed by a series of reports on the health benefits of butyric acid bacteria. At the 22nd Annual Meeting of the Society of Enterobacteriology held in 2018, it was reported that ``a large amount of butyric acid bacteria was detected when analyzing the intestinal bacteria of elderly people living in areas with many longevity''. It was reported that there was a difference when comparing the intestinal microflora of Kyoto City (control) residents and Kyotango City residents (there are significantly more long-lived people). (From research by Dr. Yuji Naito, Kyoto Prefectural University of Medicine) In other words, residents of Kyotango City have significantly more butyric acid bacteria such as Rosebria and Lactococcus. Based on this report, it was proposed to call butyric acid bacteria "longevity bacteria". In other words, creating a butyric acid-dominant intestinal environment may be one of the basics of anti-aging. [reference paper] Naito Y, Takagi T, Inoue R, Kashiwagi S, Mizushima K, Tsuchiya S, Itoh Y, Okuda K, Tsujimoto Y, Adachi A, Maruyama N, Oda Y, Matoba S. Gut microbiota differences in elderly subjects between rural city Kyoto and urban city Kyoto: an age-gender-matched study. J Clin Biochem Nutr. 2019 Sep;65(2):125-131.

Ketone bodies as energy substrates chemical formula of ketone bodies Carboxylic acid at the α (alpha) position A hydroxyl group at the β (beta) position The carbon at the β (beta) position is an asymmetric carbon and produces stereoisomers, and organisms produce only the D form. A derivative of butyric acid and a kind of organic acid. Energy substrate for mitochondria. Ketone bodies (formal name / β-hydroxybutyric acid) are also included in food ingredients, It is also produced by the liver using neutral fat as a raw material. Normally, the human body breaks down the sugars ingested in the diet and uses them as an energy source. When it runs out, it breaks down fat in the body and produces ketone bodies. 　 Ketone bodies belong to the group of organic acids and are characterized by having a hydroxyl group at the β position. The presence of this hydroxyl group increases the water solubility. In other words, it can circulate in the body while being dissolved in the blood at a high concentration. Its physiological role is called "energy substrate", which is synthesized from fat in the liver, enters the blood circulation, is completely oxidized in skeletal muscle, etc., and becomes the intracellular energy currency adenosine 3-phosphate (ATP). It is transformed and consumed in various physiological processes.

腸内細菌叢と脳の関係 幸せホルモンとして知られるセロトニンは以下のように合成されます。 トリプトファン→①→水酸化トリプトファン→②→セロトニン トリプトファンは腸内で蛋白質が加水分解して生成しますが、これが小腸上皮から吸収されて、その上皮細胞が水酸化して水酸化トリプトファンを作るとされています。すなわち幸せホルモンは腸内で水酸化トリプトファンが生成することが前提となります。トリプトファン水酸化は腸内環境の影響を受けやすく、強いストレスがかかると腸内環境が悪化し、水酸化トリプトファンの生成量が十分ではなくなります。従って腸内環境が悪化すると脳で十分な量の幸せホルモンが生産できないことになります。さらに糞便移植（FMT）で腸内細菌を移植するとうつ病が改善されるという報告があり、この仮説はかなりの支持を得ています。 文献 O'Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015 Jan 15;277:32-48. Roth W, Zadeh K, Vekariya R, Ge Y, Mohamadzadeh M. Tryptophan Metabolism and Gut-Brain Homeostasis. Int J Mol Sci. 2021 Mar 15;22(6):2973. Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients. 2016 Jan 20;8(1):56.

Detailed description of poly-hydroxybutyrate (PHB) PHBとは、ケトン体が鎖状に繋がった天然の化合物 poly-hydroxybutyrate(PHB) is accumulated as an energy substrate material in the cells of bacteria that live in seas and lakes. It seems that bacteria are like insurance when they run out of energy. of the volume of bacteria 80 %More than PHBs can be purified by a relatively simple operation. History as a biodegradable plastic PHBs teeth For a long time, its potential as a raw material for biodegradable plastics has been pointed out. However, the structure is very fragile, and the practical application as a plastic is still limited. Potential as a prebiotic However, in recent years, it is expected to be applied in other fields. It is possible that this substance may have a positive effect on the intestinal flora because it is degraded by bacteria, ie as a "prebiotic". We are aiming for this "prebiotics with ketone bodies". Because it is almost tasteless and odorless (it tastes slightly like milk) and has fine particles, it is thought to be suitable as a pet food material that satisfies the palatability of dogs and cats. 腸内細菌に届く poly-hydroxybutyrate ( PHB ) is a polymerized compound of ketone bodies. mammals are PHBs Because it cannot be decomposed, it passes through the small intestine and reaches the large intestine, where it is taken up by intestinal bacteria living in the mucous membrane that covers the large intestine epithelium and is hydrolyzed by the enzymes inside. Ketone bodies are released in the intestinal flora, and short-chain fatty acids such as butyric acid, acetic acid, and propionic acid increase in the intestinal flora, thereby helping to maintain optimal colon health. In addition, ketone bodies that are not utilized by intestinal bacteria diffuse into the colon lumen and enter the blood circulation of mammals through colon epithelial cells, contributing to health maintenance. アンカー 1 ケトバイオティクスとして働く １、腸内細菌叢の酪酸・酢酸・プロピオン酸といった短鎖脂肪酸を維持して、腸内細菌たちのための理想的な環境をキープするお手伝いが可能です。 （生後90日齢のマイクロミニブタに2%のPHBを40日間混餌で与えたデータ） ケトン供与体として働く ２、さらにケトン供与体として、腸内細菌叢でのケトン体（エネルギー基質）が充足した状態を保つお手伝いが可能なため、哺乳類の免疫力の維持にも貢献できます。 毒性試験に合格 ★急性毒性試験 ★亜急性毒性試験　において合格（問題なし）でした。 安全性試験の結果　　 　　　はこちら 非常に安定した物質 まず酸化還元されることがほぼ無いため、 腐敗などの心配が少ないとされる物質です。 実際、安定性試験（加速試験）においては、 4 年に値する期間を経過しても、分子量の変化がほとんど見られませんでした。 分子量10000以上の割合（％） サンプル0 　スタ ート時 99.4 サンプル3 　3ヵ月40℃保存後 99.0 サンプル6　 6ヵ月40℃保存後 99.1 サンプル8　 8ヵ月40℃保存後 99.2 （加速条件(40℃)における試験において、 少なくとも常温で48か月の安定性が推定された。） Patented PHBs (Polyhydroxybutyric acid) is patented. patent 7138391 Patent 6571298 Paper presentation In recent years,PHBs Researchers around the world are paying attention to its role as a prebiotic. Here are some of the papers published as the result of their research. Literature: Fernández J, Saettone P, Franchini MC, Villar CJ, Lombó F. Antitumor bioactivity and gut microbiota modulation of polyhydroxybutyrate (PHB) in a rat animal model for colorectal cancer. Int J Biol Macromol. 2022 Apr 1;203:638- 649. doi: 10.1016/j.ijbiomac.2022.01.112. Epub 2022 Jan 25. PMID: 35090944. Reference: Ma, N., Guo, P., Chen, J. et al. Poly-β-hydroxybutyrate alleviated diarrhea and colitis via Lactobacillus johnsonii biofilm-mediated maturation of sulfomucin. Sci. China Life Sci. (2022). //doi.org/10.1007/s11427-022-2213-6 Literature: Suzuki R, Mishima M, Nagane M, Mizugaki H, Suzuki T, Komuro M, Shimizu T, Fukuyama T, Takeda S, Ogata M, Miyamoto T, Aihara N, Kamiie J, Kamisuki S, Yokaryo H, Yamashita T, Satoh T. The novel sustained 3-hydroxybutyrate donor poly-D-3-hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T-cells. FASEB J. 2023 Jan;37(1):e22708. Literature: Satoh T. New prebiotics by ketone donation. Trends Endocrinol Metab. 2023 Jul;34(7):414-425. doi: 10.1016/j.tem.2023.05.001. Epub 2023 Jun 2. PMID: 37271711. Trends in Endocrinology and Metabolism 2023 in press の 表紙に採用されたポリヒドロキシ酪酸と酪酸菌のイメージ図 【酪酸菌を活性化する次世代プレバイオティクスの論文発表　ジャーナル表紙に採用】として一部のニュースサイトで掲載されています ★ミニ情報 １★ PHBが腸内細菌たちに届くと。。。 腸内細菌でエネルギー基質であるケトン体が放出され、腸内細菌叢で利用されます。 ★ミニ情報 ２★ エネルギーが十分で腸内細菌たちが元気でいてくれれば。。。 ★ 好ましい割合の善玉菌を維持して腸内細菌叢の理想的な状態を保ち、良好な便通を保つことが可能になります 。 ★ 腸内細菌叢で短鎖脂肪酸や制御性T細胞の理想的な量を維持できるため、免疫力を保つことが可能になります。 ★ 脳腸相関により健康的な脳の状態を維持することが可能になります。 ★ 腸腎相関により健康的な腎臓の状態を維持することが可能になります。 *PHB is planned to be sold as pet food, pet supplement, pet therapeutic food, or feed additive. Human approval is not currently available. シェア

Ketone bodies and receptors Reevaluation of ketone bodies Ketone bodies have been discovered as substances for more than 100 years, but it is only in the last 20 years that we have begun to understand their physiological effects. During that time, countless papers have been published among researchers, and the various effects of ketone bodies have been highly evaluated. Two of them are particularly interesting here. First, unlike other organic acids, ketone bodies have specific receptors on the cell membrane. The two main proposed receptors for ketone bodies are: HCR2 (H car two) With the discovery of HCAR2, ketone bodies have come to be recognized as molecules with special physiological effects that differ from other organic acids. HCAR2 can be activated by organic acids with hydroxyl groups, but it is particularly strongly activated by ketone bodies, and is involved in many physiological activities such as anti-inflammatory action and lipolysis. GPR43 (GP 43) The most prominent physiological effect caused by an increase in ketone bodies is the decomposition of fat. Many researchers thought that there might be a special receptor for this, but last year (September 2019) it was discovered that it was a protein called GPR43. When carbohydrates are restricted, the concentration of ketone bodies increases and GPR43 is activated, so fat is preferentially broken down. (* References 1 ) Graff EC, Fang H, Wanders D, Judd RL. Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metabolism. 2016 Feb;65(2):102-13. doi: 10.1016/j.metabol.2015.10.001. Epub 2015 Nov 13. PMID: 26773933. (* References 2 ) Miyamoto J, Ohue-Kitano R, Mukouyama H, Nishida A, Watanabe K, Igarashi M, Irie J, Tsujimoto G, Satoh-Asahara N, Itoh H, Kimura I. Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions. Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23813-23821. doi: 10.1073/pnas.1912573116. Epub 2019 Nov 4. PMID: 31685604; When ketone bodies bind to receptor proteins such as HCAR2 in immune cells and GPR43 in adipocytes, they amplify signals within immune cells and adipocytes. The paper suggests that by amplifying intracellular signals, it suppresses inflammatory responses and inhibits fat synthesis.