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Granpa John's Optimal Journal

Discussion in 'My Optimal Journal' started by John Schumacher, Jul 18, 2019.

  1. The Peroxisome-Mitochondria Connection - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485950/ What is the current understanding of the interconnectivity between peroxisomes and mitochondria in the various metabolic and signaling pathways?

    upload_2020-9-29_16-29-34.png

    Peroxisomes and mitochondria can proliferate by fission of pre-existing organelles. A major breakthrough in the field was the discovery that these organelles share multiple components of their fission machinery (e.g., mitochondrial fission protein (FIS) 1, mitochondrial fission factor (MFF), ganglioside-induced differentiation-associated protein (GDAP) 1, and dynamin 1-like protein (DNM1L).
     
  2. Mitochondrial Dynamics in the metabolic signaling pathways

    Mitochondria separate and merge using fission and fusion processes in response to changes in energy and stress status. While many mitochondrial processes are already characterized in relation to aging, specific evidence in multicellular organisms causally linking mitochondrial dynamics to the regulation of lifespan is limited. - https://www.sciencedirect.com/science/article/pii/S0047637420300063 Mitochondrial dynamics include: TORC1-mediated longevity, AMPK-mediated longevity.

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    Mitochondria harbor a network of surveillance mechanisms encompassing (1) fusion-mediated function complementation, (2) mitochondria-derived vesicles, and (3) mitophagy processes to protect mitochondrial homeostasis from increasing degrees of damage. Specifically, fusion-mediated functional complementation and mitochondria-derived vesicles constitute the first line of defense against mild mitochondrial impairment. Upon an increase in the impairment within the mitochondria, damaged compartments are segregated from the mitochondrial network through fission and subsequently undergo mitophagy. According to the type of stress, different molecular machineries are responsible for mitophagy. For instance, PINK1/Parkin mediates mitophagy in the face of mitochondrial depolarization while, in mitophagy induced by hypoxia or during erythropoiesis, the connection of damaged mitochondria to nascent autophagosomes is built by mitochondrial receptors such as NIX, BNIP3, FUNDC1, and BCL2L13 through interaction with LC3.

    upload_2020-9-29_16-31-40.png

    The role of mitochondrial fission and fusion in metabolic signaling pathways. Generalized and simplified summary of the main pathways linking nutritional state with mitochondrial dynamics and their ultimate phenotypic outcome. AMPK, insulin/IGF, and mTOR nutrient signaling pathways constitute a core network in mammalian cells to coordinate metabolism and regulate lifespan. “Depending on the availability of nutrients,” these signaling pathways are differentially switched on or off, corresponding to specific mitochondrial morphologies. For example, under the condition of starvation, AMPK is activated, while insulin/IGF and mTOR signaling are suppressed. This change typically favors mitochondrial fusion, which is associated with major beneficial effects such as prolonged lifespan, improved insulin sensitivity, and enhanced glucose tolerance. In contrast, nutrient excess activates insulin/IGF and mTOR signaling but represses AMPK. This leads to an activation of mitochondrial fission, which is associated with a number of human pathologies such as aging, cardiomyopathy, obesity, and diabetes.
     
  3. The Lipid Transport interfaces
    o Mitochondria uses acetyl CoA
    o Peroxisome process molecules in a similar fashion but includes enzymatic steps - glyceronephosphate O-acyltransferase (GNPAT) and alkylglycerone phosphate synthase (AGPS)
    o Endoplasmic Reticulum hydroxylates and oxidizes fatty acids to dicarboxylic acids

    Mitochondrial beta-oxidation of fatty acids requires four steps, all of which occur in the mitochondrial matrix, to produce three energy storage molecules per round of oxidation, including one NADH, one FAD(H2), and one acetyl CoA molecule.

    Peroxisomal beta-oxidation is specialized in that it metabolizes very-long-chain fatty acids (VLCFAs), which are composed of 24-26 carbon units. Processing of these molecules proceeds in a similar fashion to mitochondrial beta-oxidation.

    Omega-oxidation of fatty acids in the endoplasmic reticulum primarily functions to hydroxylate and oxidize fatty acids to dicarboxylic acids to increase water solubility for excretion in the urine. This enzymatic conversion relies on the cytochrome P450 superfamily to catalyze this reaction between xenobiotic compounds and molecular oxygen. Deficiencies in some enzymes of fatty acid oxidation may result in accumulation, and thus, up-regulation of omega-oxidation, increased serum, and or urine medium-chain dicarboxylic acids. https://www.ncbi.nlm.nih.gov/books/NBK556002/

    Mitochondrial Lipid Transport at a Glance - https://jcs.biologists.org/content/joces/126/23/5317.full.pdf Leptin signaling mitochondria respiration

    upload_2020-9-29_16-33-50.png


    Mitochondria have a central role in fatty acid synthesis and metabolism. Lipid droplets are either stored for sterols or decomposition through beta-oxidation.
    Notes:
    · beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol (intercellular membrane fluid) in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA,
    · Fatty acid β-oxidation occurs in the mitochondrial matrix, and the fatty acid substrate (in the form of fatty acyl-CoA) needs to be transported across the outer and inner mitochondrial membranes that are not permeable to fatty acids or fatty acyl-CoAs with a hydrocarbon chain longer than 12 carbons.
    · Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT).

    When fatty acids are rapidly synthesized, the cytosolic (intercellular membrane fluid) concentration of malonyl-CoA is high and the mitochondrial uptake and oxidation of fatty acids are inhibited. Malonyl-CoA is a key intermediary metabolite in fatty acid synthesis. In fatty acid synthesis, malonyl-coenzyme A (CoA) is the substrate that provides the primary carbon source for the formation of palmitate (most common saturated fatty acid).

    Common saturated fats:
    Peroxisomes and mitochondria are surrounded by one and two membranes, respectively, each displaying different permeability properties: the OMM contains porin proteins that form transmembrane channels large enough to allow free passage of molecules up to 5 kDa; the inner mitochondrial membrane (IMM) is impermeable to inorganic ions and water-soluble metabolites, and transport of these compounds across the IMM requires the presence of a large set of transporters. The peroxisomal membrane contains non-selective channels (e.g., peroxisomal membrane protein 2 (PXMP2) in mammals) that allow free transmembrane movement of solutes with molecular masses up to 300–400 Da but prevent diffusion of larger molecules. Transmembrane transfer of larger molecules (e.g., fatty acids, acetyl-CoA, and ATP) across the peroxisomal membrane requires specific transporter proteins. Examples of transporters that have been identified include (i) three members (ABCD1-3) of the ATP-binding cassette half-transporters of subfamily D (ABCD), which catalyze the transmembrane transport of the substrates for peroxisomal fatty acid oxidation; (ii) the adenine nucleotide transporter SLC25A17, which functions as a transporter of CoA, flavin adenine dinucleotide (FAD), flavin mononucleotide, and adenosine monophosphate, and—to a lesser extent—of nicotinamide adenine dinucleotide (NAD+) and adenine dinucleotide phosphate (ADP); and (iii) three members (SLC16A1, SLC16A4, and SLC16A7) of the monocarboxylate transporter (MCT) family, which transport monocarboxylates such as lactate and pyruvate across peroxisomal membranes. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485950/
     
    Last edited: Sep 29, 2020
  4. Fatty acid β-oxidation metabolism between the peroxisome & mitochondria

    Fatty acid β-oxidation is a multistep process by which fatty acyl-CoA esters are stepwise shortened between carbons 2 and 3, yielding as products: a chain-shortened acyl-CoA and—depending on the presence of a 2-methyl group in the substrate—acetyl-CoA or propionyl-CoA. In mammals, this process takes place in both peroxisomes and mitochondria. Each β-oxidation cycle involves four consecutive reactions: (i) desaturation of the bond between C2 and C3; (ii) hydration of the formed 2-enoyl-CoA; (iii) dehydrogenation of 3-hydroxyacyl-CoA; and (iv) thiolytic cleavage of 3-oxoacyl-CoA [7]. While the three latter reactions are mechanistically comparable in both organelles, the first reaction is catalyzed by FAD-dependent acyl-CoA oxidases (ACOXs) in peroxisomes and FAD-dependent acyl-CoA dehydrogenases (ACADs) in mitochondria. In the ACOX-catalyzed reaction, electrons from reduced FAD (FADH2) are passed directly to molecular oxygen (O2), thereby producing heat and H2O2; in the ACAD-catalyzed reaction, the electrons from FADH2 are delivered to the respiratory chain via the electron transfer flavoprotein (ETF) and the ETF dehydrogenase (ETFDH).

    upload_2020-9-29_16-36-4.png

    Comparison and interplay of peroxisomal and mitochondrial fatty acid β-oxidation. Fatty acid β-oxidation, the NAD(H) redox shuttles, the tricarboxylic acid cycle, and the electron transfer chain are respectively depicted in blue, purple, red, and pink. 1a, acyl-CoA oxidase; 1b, acyl-CoA dehydrogenase; 2, enoyl-CoA hydratase; 3, 3-hydroxyacyl-CoA dehydrogenase; 4, 3-ketoacyl-CoA thiolase. ABCD, ATP-binding cassette transporters of subfamily D; ADP, adenine dinucleotide phosphate; BRCFA, branched-chain fatty acid; CAC, carnitine-acylcarnitine carrier; FAD, flavin adenine dinucleotide; FADH2, reduced FAD; LCFA, long-chain fatty acid; MCFA, medium-chain fatty acid; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; NRS, NAD(H) redox shuttles; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid; VLCFA, very-long-chain fatty acid.

    While peroxisomes are only able to chain-shorten their substrates, mitochondria can β-oxidize fatty acids all the way to CO2 and H2O through entry of acetyl-CoA into the tricarboxylic acid cycle (TCA) and reoxidation of NADH and FADH2 by the respiratory chain.

    Specific or general defects in peroxisome function can result in the accumulation of phytanic acid (e.g., in patients with α-oxidation defects), pristanic acid (e.g., in patients with peroxisomal β-oxidation defects) and/or VLCFAs (e.g., in X-linked adrenoleukodystrophy (X-ALD) or Zellweger syndrome spectrum (ZSS) patients), and most—if not all—of these defects have been directly or indirectly linked to mitochondrial dysfunction.

    Peroxisomal β-oxidation can only continue if the NADH formed in peroxisomes is reoxidized to NAD+, a complex process that can only be achieved in mitochondria.

    So what is the stimuli for NADH -> NAD+ transformation?

    In the matrix of the peroxisome, the alpha-oxidation machinery can only work efficiently if the NADH produced in the aldehyde dehydrogenase reaction is reoxidized back to NAD+

    Peroxisomes can also release matrix proteins into the cytosol. Interestingly, this process appears to depend on voltage-dependent anion-selective channel (VDAC) 2, a redox-sensitive outer mitochondrial membrane (OMM) protein whose primary role is to form an aqueous pore allowing the exchange of small ions and metabolites across the OMM.

    Voltage charge separation will always the name of the game current researchers do not understand - dipole oxygen behavior, etc. But, what is its stimuli? -> Is it “really” a nutrient?
     
    Last edited: Sep 29, 2020
  5. Cellular Signaling involved in Lipid Metabolism

    Peroxisomes: a Nexus of Lipid Metabolism and Cellular Signaling - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951609/ Peroxisomes carry out fatty acid oxidation and lipid synthesis.

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    The peroxisome is a single membrane-enclosed organelle that plays an important role in metabolism. The main metabolic functions of peroxisomes in mammalian cells include β-oxidation of very long chain fatty acids, α-oxidation of branched chain fatty acids, synthesis of bile acids and ether-linked phospholipids and removal of reactive oxygen species. Peroxisomes in many, but not all, cell types contain a dense crystalline core of oxidative enzymes.

    Potential stimulant -> Hypothalamic leptin signaling increases fatty acid oxidation (FAO) rates in peripheral tissues by central and peripheral signaling via leptin receptors.
     
  6. Peroxisomal plasmalogen synthesis

    Plasmalogen synthesis is initiated in peroxisomes and completed in the endoplasmic reticulum. Plasmalogens are a unique class of membrane glycerophospholipids containing a fatty alcohol with a vinyl-ether bond at the sn-1 position, and enriched in polyunsaturated fatty acids at the sn-2 position of the glycerol backbone. In animal cells, cholesterol and dolichol are synthesized in peroxisomes as well as in the endoplasmic reticulum. In the liver, peroxisomes are also involved in the synthesis of bile acids, which are derived from cholesterol. In addition, peroxisomes contain enzymes required for the synthesis of plasmalogens—a family of phospholipids in which one of the hydrocarbon chains is joined to glycerol by an ether bond rather than an ester bond.

    Peroxisomes are small, membrane-enclosed organelles that contain enzymes involved in a variety of metabolic reactions, including several aspects of energy metabolism. Peroxisomes contain at least 50 different enzymes. Peroxisomes also contain the enzyme catalase, which decomposes hydrogen peroxide either by converting it to water or by using it to oxidize another organic compound. Peroxisomal membrane proteins (PMPs) requires a completely different, less well-characterised machinery which requires the cytosolic receptor/chaperone Pex19p. Pex19p is a peroxin involved in peroxisomal membrane biogenesis and probably functions as a chaperone and/or soluble receptor specific for cargo peroxisomal membrane proteins (PMPs). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171958/

    upload_2020-9-29_16-38-12.png


    Peroxisomes can form by growth and division from pre-existing organelles and/or by de novo synthesis and further maturation from the endoplasmic reticulum.

    Peroxisomes mechanism of action include an understanding of: (i) the activity of many enzymes involved in epigenetic regulation is subject to exquisite regulation by metabolite concentrations; (ii) the intracellular levels of many of these metabolites are controlled by peroxisomal as well as mitochondrial metabolism; (iii) the cause and effect relationships between peroxisomal (dys)function and epigenetic alterations are clearly modulated by a number of complex feedforward/feedback mechanisms; and (iv) the cellular epigenetic landscape and its bidirectional relationship with peroxisomes and associated organelle function can differ significantly among cell types, tissues, organs, organisms, and disease states.

    Peroxisomes role in the biosynthesis of the primary bile acids - The enzymes catalyzing the formation of DHCA and THCA in the cytosol, endoplasmic reticulum, and mitochondrion.

    upload_2020-9-29_16-38-49.png
    https://www.frontiersin.org/articles/10.3389/fcell.2015.00083/full

    Peroxisomes’ role in amino acid metabolism notably the D-amino acids. Two different degradative enzymes D-amino acid oxidase (DAO) and D-aspartate oxidase (DDO). DAO and DDO are presumed to regulate the levels of several endogenous and exogenous D-amino acids including D-serine and D-aspartate in various organs notably the brain. D-serine for instance binds to the glycine binding site of the N-methyl-D-aspartate (NMDA) receptor and potentiates glutamatergic neurotransmission in the central nervous system. Several lines of evidence suggest that D-serine plays an important role inthe regulation of brain functions by acting as co-agonist for the NMDA receptor and perturbations in D-serine in the nervous system have recently been implicated in the pathophysiology of various neuropsychiatric disorders. Recent studies have shown that D-aspartate acts as signaling molecule in nervous and neuroendocrine systems at least in part by binding to the NMDA receptor and, thus plays an important role in the regulation of brain function.

    Peroxisome also plays a major role in cellular ROS/RNS-metabolism. Indeed, peroxisomes contain a large number of ROS-producing enzymes of which the acyl-CoA oxidases are the most abundant being present in virtually all peroxisomes independent of the tissue and cell type involved. Other H2O2 producing oxidases include D-amino acid oxidase (DAO), D-aspartate oxidase (DDO), L-pipecolate oxidase (PIPOX), 2-hydroxy acid oxidases (HAO), polyamine oxidase, and xanthine oxidase.

    Suggestion: DAO supplement - https://heartandsoil.co/products/beef-organs
     
  7. Thermogenesis in mitochondrial fission

    Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission - https://www.jci.org/articles/view/120606 Disorders of peroxisome biogenesis and peroxisomal β-oxidation, expression of enzymes can impede this process. -> Mitochondrial dysfunction in the context of peroxisome deficiency has been well documented for hepatocytes. The primary defect in adipocytes is impaired mitochondrial division, resulting in mtDNA loss, decreased expression of mitochondrially encoded components of the electron transport chain, and reduced rate of coupled and uncoupled respiration.

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    (A) Gene expression analysis in BAT, iWAT, and gWAT of WT mice kept at normal room temperature (RT) (22°C) or subjected to cold (4°C) exposure;
    Our results indicate that peroxisomes are critical for adipose tissue thermogenesis.
     
  8. Cholesterol Trafficking

    Cholesterol Trafficking defect in AGPS and GNPAT deficient CHO cells. A defect in cholesterol transport from the cell surface or endocytic compartments to the endoplasmic reticulum, where it is esterified by Acyl-CoA: cholesterol acyltransferase (ACAT). Plasmalogen deficiency reduced the pool of cholesterol available for efflux. (Cholesterol efflux is the ability of HDL to scoop up cholesterol particles from plaques in the heart's blood vessels and move those particles to the liver for disposal.) Cholesterol esterification depends on PlsEtn containing polyunsaturated fatty acids. These cells had higher total and free, but less esterified cholesterol in total cell lysates. After supplementation with 1-0-hexadecyl-2-acyl-sn-glycerol, only PlsEtn with ≥ 3 unsaturations (DHA, AA and linolenic acid) could significantly reduce free and increase esterified cholesterol. Supplementation of HEK293 cells with 1-0-hexadecyl-2-DHA-sn-glycerol resulted in increased cellular ACAT levels, thus providing a mechanism for the observed increased cholesterol esterification. Taken together these studies are consistent with a defect in the transport of LDL-derived cholesterol from the cell surface and/or endocytic compartments to the endoplasmic reticulum, resulting in accumulation of free cholesterol, reduced esterified cholesterol and less cholesterol available for HDL mediated efflux.
     
  9. Peroxisomal matrix enzymes – How their deficiencies could be mitigated and some partial interventions

    Peroxisomes control mitochondrial dynamics and the mitochondrion dependent pathway of apoptosis - https://jcs.biologists.org/content/joces/early/2019/05/08/jcs.224766.full.pdf?with-ds=yes?versioned=true Effects of peroxin genes mutations on mitochondrion-dependent apoptosis may contribute to pathogenesis of peroxisome biogenesis disorders.

    https://www.sciencedirect.com/science/article/pii/S0925443912001160#f0005
    - peroxisomal matrix enzymes, glyceronephosphate O-acyltransferase (GNPAT) and alkylglycerone phosphate synthase (AGPS)

    The brain contains the highest amounts of tissue plasmalogens. AD patients have decreased PlsEtn and PlsCho.

    Supplementation with the plasmalogen precursor, chimyl alcohol, restored both PlsEtn and DHA levels, supporting the notion that DHA is primarily targeted to PlsEtn during its biosynthesis.


    Plasmalogen precursor, chimyl alcohol - Technological approach of 1-O-alkyl-sn-glycerols separation from Berryteuthis magister squid liver oil - https://link.springer.com/article/10.1007/s13197-015-2148-x

    Plasmalogen precursor, “chimyl alcohol” – Alkyldiacylglycerols - https://www.lipidmaps.org/resources/lipidweb/index.php?page=lipids/complex/ethers/index.htm In marine invertebrates, polyunsaturated fatty acids tend to be concentrated in position sn-2.

    Plasmalogen replacement therapy - The highest amounts are found in oils of invertebrate marine animals, such as shark liver and krill oil. The average adult is estimated to consume 10–100 mg of 1-0-octadecyl-sn-glycerol (batyl alcohol) daily. Although it is the alkylglycerol content of these dietary compounds that has been more extensively studied, there is some evidence that intestinal absorption of phospholipids is superior to that of alkylglycerols.

    Ethanolamine plasmalogens (PlsEtns) are the predominant phospholipids in the brain, kidney, lungs and skeletal muscle - https://lipidworld.biomedcentral.com/articles/10.1186/s12944-019-1044-1 Plasmalogens are subclass of phospholipids characterized by the presence of a vinyl ether bond at the sn-1 position and an ester bond at the sn-2 position of a glycerol backbone. The sn-1 position consists of C16:0 (palmitic acid), C18:0 (stearic acid) or C18:1 (oleic acid) carbon chains, and the head group is usually either ethanolamine or choline, thus there are two predominant types of plasmalogens, ethanolamine plasmalogens (PlsEtns) and choline plasmalogens (PlsChos). The sn-2 position is predominately occupied by a polyunsaturated fatty acid, specifically arachidonic acid (ARA) or docosahexaenoic acid (DHA).

    Oysters contain lipids of interest, such as cardiolipin [56], plasmalogens and NMI FAs with effects against oxidative stress, n-3 PUFAS and phytosterols with cholesterol-lowering effects, anti-inflammatory properties and as useful adjuvants in the reduction of cardiovascular risk. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926063/

    Very expensive product “option”: https://prodrome.com/product/prodromeneuro-plasmalogen-capsule-supplement/ $300 for 30 days.

    Efficacy and Blood Plasmalogen Changes by Oral Administration of Plasmalogen in Patients with Mild Alzheimer's Disease and Mild Cognitive Impairment: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360580/ Patients with mild AD showed a significantly greater decrease in plasma PlsPE in the placebo group than in the treatment group.

    Improvement of Blood Plasmalogens and Clinical Symptoms in Parkinson’s Disease by Oral Administration of Ether Phospholipids: A Preliminary Report - https://www.hindawi.com/journals/pd/2020/2671070/ Conclusion. 1 mg/day of oral administration of purified ether phospholipids derived from scallop can increase ether phospholipids in peripheral blood and concomitantly improve some clinical symptoms of PD.

    Phenylbutyrate up-regulates Peroxisome function by proliferating beta-oxidation - https://biblio.ugent.be/publication/326696/file/901285.pdf it has been demonstrated that butyrate-producing probiotics (e.g. 4-phenylbutyrate) can upregulate peroxisome activity through inactivation of HDAC activity, an event that enhances the expression of PPARα. In summary, these findings suggest that HDAC activity modulators such as 4-PBA and SAHA are potential therapeutics for treatment of X-ALD. N-acetylcysteine has also been shown (i) to attenuate peroxisome dysfunction (e.g., β-oxidation, plasmalogen biosynthesis) and oxidative stress in a PPARα-dependent manner in fetal mouse brain upon exposure of the mothers to lipopolysaccharides, a major constituent of the outer membrane of Gram-negative bacteria and primary inducer of chronic inflammatory diseases and septic shock , and to scavenge VLCFA-dependent ROS generation in human X-ALD fibroblasts.

    upload_2020-9-29_17-24-2.png
    [​IMG]

    https://www.sciencedirect.com/science/article/pii/S0167488915002803#bb0275

    Potential epigenetic therapies to treat peroxisomal disease. 4-PBA, 4-phenylbutyrate; BA, bile acid; CC, chemical chaperone; DHA, docosahexaenoic acid; ERT, enzyme replacement therapy; HDAC, histone deacetylase; NAC, N-acetylcysteine; NS, nonsense; PP, plasmalogen precursor; SAHA, suberoylanilide hydroxamic acid.

    Enzyme replacement therapy (ERT) is a potentially attractive medical treatment approach in which proteins are administered to patients to compensate for the loss of a particular enzyme that is dysfunctional or absent.

    Regulation of Inflammation by Short Chain Fatty Acids – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257741/ The short chain fatty acids (SCFAs) acetate (C2), propionate (C3) and butyrate (C4) are recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function by inhibiting histone deacetylase (HDAC). In general, SCFAs, such as propionate and butyrate, inhibit stimuli-induced expression of adhesion molecules, chemokine production and consequently suppress monocyte/macrophage and neutrophil recruitment, suggesting an anti-inflammatory action.

    Butyrate, a short chain fatty acid, modulates gene expression by inhibiting histone acetyltransferase activity but its effects are far reaching in modulating inflammatory mediators, modifying lipid metabolism as it stimulates the production of resolvins / protectins and having a CNS protective aspect in neurological disease including reduction of brain infarct volume.

    Potential Synergies of β-Hydroxybutyrate and Butyrate on the Modulation of Metabolism, Inflammation, Cognition, and General Health - https://www.hindawi.com/journals/jnme/2018/7195760/

    Specialized proresolving mediators (SPM) lipoxin, resolvins, protectins and maresins - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884427/ Nutrient therapy of lipid mediators: the lipoxins resolvins, protectins and maresins.

    Phosphaticylchonline and Phosphatidylserine https://examine.com/supplements/phosphatidylserine/ & https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508628/ - a triple cell membrane synergy of Phosphatidylserine, DHA & EPA showed improvements in cognitive function. Also, Astaxanthin and palm oil-derived tocotrienol may also be involved in the present results. Astaxanthin can cross the brain-blood barrier and is strongly suggested to be effective against oxidative neurodegeneration. Palm oil-derived tocotrienol is natural vitamin E and current studies demonstrate that tocotrienol has neuroprotective properties. Arachidonic acid, one of the most abundant polyunsaturated fatty acids, is highly susceptible to oxidative metabolism under pathologic conditions and tocotrienol at nanomolar concentrations was shown to attenuate arachidonic acid metabolism and neurodegeneration; therefore, it seems that elements in addition to PS and omega 3-fatty acids are also important.

    Linoleic Acid – Avocado Seed oil - fatty acid profile in linoleic acid (48.77%) and linolenic acid (12.17%). Avocado seed presents, in its composition, a large number of extractable polyphenols, which have attracted attention due to their high antioxidant capacity. Avocados “flesh / fruit” contain a monounsaturated fatty acids (MUFA)-rich fruit oil with 71% MUFA, 13% polyunsaturated fatty acids (PUFA), and 16% saturated fatty acids (SFA). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600360/.


    Stearic Acid - https://www.nature.com/articles/s41467-018-05614-6 stearic acid (C18:0) signals via a dedicated pathway to regulate mitofusin activity and thereby mitochondrial morphology and function, increasing fatty acid beta-oxidation C18:0 ingestion causes mitochondrial fusion. Mitochondrial fusion enables content mixing within a mitochondrial population, thereby preventing permanent loss of essential components.



    Acylcarnitines are fatty acids coupled to carnitine that are ready for mitochondrial import for beta-oxidation. When beta-oxidation is impaired relative to the fatty acid supply, these long chain acylcarnitines accumulate and are released into the blood where they can be detected.

    A diet rich in C16:0 (Palmitic acid) could be particularly bad because it provides lipids to the body without activating the mitochondrial response that C18:0 does.

    Human liver microsomal phospholipid is composed of 49% phosphatidylcholine, 31% phosphatidylethanolamine, 14% phosphatidylserine + phosphatidylinositol and 6% sphingomyelin, very similar to the phospholipid composition of rat liver microsomes.

    Cardiolipin mtDNA -> Mitochndrial pathway for biosynthesis of lipid mediators - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201180/ Here we report that a range of diversified polyunsaturated molecular species derived from a mitochondria-specific phospholipid, cardiolipin, are oxidized by the intermembrane space hemoprotein, cytochrome c. We show that an assortment of oxygenated cardiolipin species undergoes phospholipase A2-catalyzed hydrolysis thus generating multiple oxygenated fatty acids, including well known lipid mediators. This represents a new biosynthetic pathway for lipid mediators. We demonstrate that this pathway including oxidation of polyunsaturated cardiolipins and accumulation of their hydrolysis products – oxygenated linoleic, arachidonic acids and monolyso-cardiolipins.

    Note: The amounts of DHA, AA and LA decreased almost 20-, 5- and 0.3-fold, respectively. The energies for H-abstraction in α-position to bis-allylic double-bonds for different FA with multiple double bonds decrease in the order LA<AA<DHA. Accordingly, the propagation rate constants for FA oxidation determined for LA (one bis-allylic group), AA (3 bis-allylic groups), EPA (4 bis-allylic groups) and DHA (5 bis-allylic groups) increase at ratios of 1, 3.2, 4.0, and 5.4.

    Cardiolipin (IUPAC name 1,3-bis(sn-3'-phosphatidyl)-sn-glycerol, also known as Calcutta antigen) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. The cardiolipin is only found in the inner mitochondrial membrane. The cardiolipin molecule depends on linoleic acid, and linoleic acid is the primary omega-6 in our diets. However, in a high-linoleic acid diet, the linoleic acid in the cardiolipin molecule ends up being destroyed.

    Increased levels of cardiolipin and ubiquinone may help to preserve mitochondrial function - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168306/ We also found a negative association between hepatic odd-chain phosphatidylcholine and Nonalcoholic fatty liver disease (NAFLD).

    Omega-3 fatty acids are associated with decreased levels of inflammatory markers, such as CRP, TNFα, NFkB, IL-1 and IL-6.

    We hypothesized that leptin, like insulin, could boost liver lipid export and protect from NAFLD via receptors expressed in the CNS. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586634/ After recovery from the surgery, fasted and freely moving rats were intracerebroventricularly (ICV) infused with leptin. An intracerebroventricularly ICV leptin infusion activated the leptin receptor signaling cascade as assessed by phosphorylation of the signal transducer and activator of transcription (STAT) 3 in protein lysates of punch biopsies in several periventricular brain regions, i.e. the mediobasal hypothalamus (MBH), the paraventricular nucleus of the hypothalamus (PVN) and the dorsal vagal complex (DVC). Brain leptin increased STAT3 phosphorylation at Tyr705 in all three examined brain regions 2 to 3-fold.

    Ketone bodies release by the liver and cross the blood-brain barrier-> However, elevated triglycerides and decreased the transport of leptin across the Blood Brain Barrier - https://diabetes.diabetesjournals.org/content/53/5/1253

    Curcuminoids https://www.nature.com/articles/emm200646.pdf?origin=ppub demethoxycurcumin (DMC) and bis-de -methoxycurcumin (BDMC)

    Suramin & parasites - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412339/ A study using essential oils of cloves (Syzygium aromaticum), basil (Ocimum basilicum), and a yarrow (Achillea millefolium) and the main constituents, eugenol and linalool showed activity on T. cruzi bloodstream trypomastigotes and epimastigotes forms.

    Dietary Docosahexaenoic Acid (22:6) Incorporates into Cardiolipin at the Expense of Linoleic Acid (18:2) Analysis and Potential Implications - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509651/ Fish oil displaces linoleic in mitochondria via cardiolipin. However, The increased presence of 22:6 in the cardiac and skeletal muscle membrane has been linked with improved oxygen efficiency of muscular contractions and fatigue resistance. Yet these changes are likely underpinned by interactions occurring between phospholipids and proteins at the molecular level within the membrane. This is where the acyl composition of phospholipids can influence membrane proteins by changing factors such as; membrane fluidity, intramembrane pressure gradients and dipole potentials

    There are two questions a clinician needs to ask: Do these symptoms indicate an acute or chronic decease state?

    According to the doctors at bodybio, the decease state is acute requiring immediate intervention for which we can agree. This may mean a prescription of interventions specific for the diagnose which may not transcend to the public in general. Specially, the displacement of lipid 18:2 from the cardiolipin.

    Ether Lipids - https://www.lipidmaps.org/resources/lipidweb/index.php?page=lipids/complex/ethers/index.htm Lysoplasmalogen may also have a signalling function as it is known to activate cAMP-dependent protein kinase. The plasmalogen form of phosphatidylethanolamine is a major precursor of the endocannabinoid anandamide in brain. Similarly, it has been established that plasmenylcholine, which is abundant in linoleoyl species in heart mitochondria, is a substrate for the transacylase tafazzin and may be important for the remodelling of cardiolipin. Peroxisomal synthesis of plasmenyl-phospholipids in brown adipose tissue is believed to regulate thermogenesis by mediating mitochondrial fission.

    Tauroursodeoxycholic Acid /Sodium Phenylbutyrate Decreased Rate of Decline in ALS - https://practicalneurology.com/news...enylbutyrate-decreased-rate-of-decline-in-als

    Acetyl-CoA carboxylase is a biotin dependent enzyme -

    upload_2020-9-29_16-42-39.png

    Acetyl-CoA carboxylase (ACCase) catalysis of malonyl-CoA formation from acetyl-CoA. Catalysis is a multistep process, taking place at different catalytic sites of a single multifunctional protein. The reaction proceeds via the ATP-dependent carboxylation of a biotin group at the biotin carboxylase domain of ACCase, with the transfer of this (by a biotin carboxyl carrier peptide – BCCP) to the carboxyl transferase domain of ACCase.

    Lipsomal Biotin - https://www.quicksilverscientific.com/all-products/methyl-b-complex/

    Lipsomal Glutathione - https://www.quicksilverscientific.com/all-products/liposomal-glutathione/

    Why liposomal a better delivery - https://www.quicksilverscientific.com/quicksilver-delivery-systems/
     
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  10. Water instructs us best in understanding why Nature designed molecular collaboration. It shows us that water is preoccupited with extensive self-association. Water clathrates pull its positive electrons in and stratifies out its negative electrons. Nature reveals both a push toward surface tension and a cohesive pull, creating a beautiful spherical form. This gives water properties for hydration and solubility, yet it can repell “almost hold at bay” molecules like lipid hydrocarbons, fatty acids, without losing its innate characteristics.

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  11. JanSz

    JanSz Gold

  12. Nice !
    I find it eloquent that in water's design is a "desire" to loosely and tightly form 3D five sided shapes.
    When the molecules are "excited" by IR-A light, they tighten their hexagonal molecular structured.
    The question is why do hydrophilic surfaces encourage both the pull of a tighter hexagonal molecular structure and a push of looser structured water molecules away?
    Once we "think" we've figured that one out, then the next question is how does this behavior play out in plasma and cytoplasm of human cells?

    http://www.snowcrystals.com/science/Animation2.gif

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    https://ecee.colorado.edu/~ecen5555/SourceMaterial/Pollack13.pdf

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  13. JanSz

    JanSz Gold

    Last edited: Oct 30, 2020
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  14. Last edited: Dec 2, 2020
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