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2020-05-29 08:39 Kynurenine skal afprøves til behandling af ME patienter

Open Medicine Foundation finansierer et nyt placebo-kontrolleret studie, hvor ME patienter skal behandles med kynurenine:Kynurenine Clinical Trial for ME/CFShttps://omfcanada.ngo/kynurenine-clinical-trial-for-me-cfs/Jonas Bergquist, MD, PhD, direktør for det svenske ME/CFS forskningscenter i Uppsala, skal stå for studiet.Baggrunden for studiet er Dr. Robert Phair's ME- hypotese "den metaboliske fælde", der beskriver, at ME patienter ikke omsætter aminosyren tryptofan i tilstrækkelig omfang i nogle af vores celletyper (1). Blogindlæg om den metaboliske fælde:ME hypotese: The Metabolic Trap - de ...

2020-05-04 14:23 Serum fra ME patienter udviser antiviral aktivitet

Et nyt studie af Schreiner et al har vist, at serum fra ME patienter udviser antiviral aktivitet mod både DNA- og RNA-virus i en cellekultur. Samtidig blev det observeret, at serummet inducerer et fragmenteret mitokondriel netværk og nedsat cellulær ATP produktion (1).Citat fra artiklen (1), side 213: "... we showed that serum from ME/CFS patients contained an activity that produced mitochondrial fragmentation, decreased mitochondrial ATP production, and induced a powerful antiviral state."Det er ukendt, hvad det er i serum, som udløser og udøver den antivirale aktivitet. Schreiner et al har e ...

2020-04-20 14:21 Kan POTS patienter være mindre sårbare over for COVID-19 pga mindre ACE2 aktivitet?

Coronavirus anvender et af menneskets enzymer til at komme ind i cellerne. Enzymet hedder angiotensin converting enzyme 2 (ACE2).ACE-hæmmere er lægemidler, der anvendes til behandling af for højt blodtryk. Der er fremsat en hypotese om at ACE-hæmmere kan øge ACE2 og hermed fremme indtrængning af coronavirus i cellerne. Læs om emnet her: ACE-hæmmere øger muligvis risikoen for at dø af COVID-19https://dagensmedicin.dk/ace-haemmere-oeger-muligvis-risikoen-for-at-doe-af-covid-19/ Danske forskere vil undersøge årsag til visse patienters coronadødhttps://sundhedspolitisktidsskrift.dk/nyheder/3250-er ...

2020-03-05 08:29 ME - a failure of inducing exercise tolerance?

ME hypothesis from Karolinska Institutet and Karolinska University Hospital in Sweden (1):"ME - a failure of inducing disease tolerance upon chronic immune activation"My question: Is ME also a failure of inducing exercise tolerance?At cellular level disease and inflammation result in increased reactive oxygen species (ROS) production. Stress-response pathways are countermeasures to ROS. Exercise also leads to increased ROS levels. The antioxidant enzyme superoxide dismutase 2 (SOD2) is one the primary mechanisms against ROS generated during exercise. Quote from a review "Impact of oxidative st ...

2020-03-03 10:05 Det inflammatoriske respons og induktion af sygdomstolerance er dysreguleret hos ME patienter

Forskere fra Karolinska Instituttet og Karolinska Universitetshospital har beskrevet en ME hypotese (1):"ME - a failure of inducing disease tolerance upon chronic immune activation"Sygdomstolerance er en overordnet betegnelse for en række stress-respons stiveje. Disse skal sørge for at begrænse skade fra patogene mikroorganismer og fra kroppens inflammationsproces.Vagusnerve og hjernestamme regulerer systemisk inflammation ved at skrue op eller ned for den inflammatorise refleks. Nerver der fører fra kroppen (afferent vagus nerve endings) til hjernestamme sender besked om immunstatus i kroppen ...

2020-03-02 09:42 Increased serum and urine 3-methylhistidine in ME patients

3-metylhistidine is a breakdown product of muscle contractile proteins. Serum or urine 3-methylhistidine is used as a biomarker of muscle protein degradation (1).Fluge et al found increased serum 3-metylhistidine in male ME patients (2).McGregor et al found increased urine 3-metylhistidine in post-exertional malaise (PEM) ME patients (1).Quote from McGregor et al (1):"The findings that the PEM is associated with a loss of metabolites, reduction in acetylation, deregulation of purine metabolism, increased contractile protein breakdown and bacteremia associated with exercise suggest that treatme ...

2020-02-20 07:50 Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients

N,N,N-trimethyl-L-alanyl-L-proline betaine (TMAP) is a plasma biomarker of reduced kidney function (1).Quote from ref 1:"TMAP was the most consistently cleared metabolite by all hemodialysis modalities in our untargeted metabolomics analysis. Although the biological origin of TMAP has not been identified, we suggest that TMAP may be produced from degradation of myosin light chain (MYL) proteins. N,N,N-trimethylalanine is mainly found in myosin light chain (MYL) proteins and in each of the four MYL isoforms (MYL1, MYL2, MYL3, and MYL4), the c-terminus of N,N,N-trimethylalanine forms a peptide b ...

2020-02-05 12:12 Proline, P5C and 4-hydroxyglutamate in ME

What doPre-eclampsiaThe inborn error of metabolism: Primary Hyperoxaluria Type 3Myalgic encephalomyelitis (ME)have in common?Increased levels of 4-hydroxyglutamate (1, 2, 3).Germain et al's (2020) new metabolomic study found increased level of plasma 4-hydroxyglutamate  in ME patients compared to controls (3).From figure S1 in reference 3. 4-hydroxyglutamate. Box plot distribution of logged values from table 2 in reference 3. Controls are shown in red and ME patients in blue. The yellow diamond represents the mean. https://www.mdpi.com/2218-1989/10/1/34Proline and its metabolite hydroxyproline ...

2020-01-17 09:03 Naltrexone til behandling af ME

NK (Natural Killer) celler er en del af immunforsvaret. Det er gentagne gange påvist, at NK celler ikke fungerer optimalt hos ME patienter (1).NK celler reguleres af en lang række celle signaler, - herunder calcium ion signalering. Ionkanalen TRPM3 bidrager væstentligt til calcium ion signalering i NK celler. Der er påvist signifikant reduktion af TRPM3 ekspression på overfladen af NK celler fra ME patienter (1).Den G-protein-koblede receptor mu-opoid receptor (μOR) interagerer med TRPM3. Når μOR stimuleres inhiberes TRPM3 (1).μOR kan hæmmes af lægemidlet Naltrexone, som er et lægemiddel målre ...

2020-01-02 10:12 Trådløs teknologi påvirker mitokondrierne, når cellerne er stressede

Forskere fra et universitet i Schweiz har undersøgt, hvordan nerveceller påvirkes af radiofrekvente elektromagnetiske felter (RF-EMF). Forskerne udsatte en cellekultur af nerveceller for 935 MHz, 4 W/kg i 24 timer. Forsøget viste ikke påvirkning af cellerne, når næring og metabolisme var under normale forhold. Men når glucosen blev fjernet og cellerne blev stressede, registrerede man forringet mitokondrie funktion ved den følgende maximale respiration (1):"These findings indicate that RF-EMF might lead to an impairment of mitochondrial function that is only manifest at maximal respiration and ...

2019-11-21 08:52 Kan viden om hajer hjælpe med at forklare ME- og EHS-sygdomsmekanismen?

Der må findes en biologisk forklaring på, hvorfor nogle ME patienter udvikler elektromagnetisk hypersensitivitet (EHS) mod selv ekstremt lave felter. Måske kan viden om hajer hjælpe os på sporet.Hajer er de mest "el-følsomme" dyr i verden. De kan mærke felter med så lav en værdi som 5 nV/cm. Det elektriske felt bliver opfanget af sensorer, der kaldes ampullae of Lorenzini. Hajerne anvender deres sensorer til at mærke de svage elektriske felter fra deres byttedyr. Det er observeret, at hajer kan gå til angreb på telegraf-kabler på havets bund, fordi de fejlagtigt opfattes som byttedyr (1, 2).Am ...

2019-11-12 08:44 Photoimmunology and the ME IDO metabolic trap

The sun emits ultraviolet radiation (UVR) with different wavelengths:UVA (320 - 400 nm)UVB (280 - 320 nm)UVC (< 280 nm)UVR can cause sunburn and increase the risk of skin cancer. UVR is also immunomodulatory and can be beneficial in the case of inflammatory and autoimmune diseases, but UVR can also exacerbate some autoimmune diseases (1, 2).Chromophores are the parts of a photorecpetor that absorb photons in light (1).UVB radiation can be absorped by cytosolic tryptophan, which thus function as a chromophore. This results in the formation of tryptophan photoproducts in particular 6-formylindol ...

2019-10-30 10:13 2-OGDO enzymer og jern redox status hos ME patienter

I de foregående tre blogindlæg har jeg redegjort for, at cellers jern redox status er vigtig for aktiviteten af en række enzymer.Enzymgruppen 2-oxoglutarate dependent dioxygenaser (2-OGDO) anvender også jern i ferro form (Fe2+) som cofactor.Jeg vil nu stille spørgsmålet: Er 2-OGDO enzym aktiviteterne i ME celler påvirket af en forstyrret jern redox ligevægt?2-OGDO enzymerne katalyserer en lang række biologiske processer, herunder (1):hydroxylering af kollagen demethylering af histoner første og sidste trin i dannelsen af carnitin nedbrydning af fytinsyre (eng: phytanic acid) Aktivering af 2-OG ...

2019-10-17 10:20 REDOX og NO-sGC-cGMP-stivejen

Der findes en gammel hypotese om, at NO-sGC-cGMP-stivejen og hermed blodgennemstrømningen er påvirket hos ME patienter (1).Nitrogenoxid (NO) er et gasformigt signalmolekyle, der har flere forskellige funktioner i kroppen. Soluble guanylate (eller guanylyl) cyclase (sGC) er receptor for NO. At den er soluble (opløselig) betyder, at den er intracellulær. På sGC molekylet findes et hæm-bindende område, der kan binde det gasformige molekyle NO. Hermed kan sGC producere guanosine 3’,5’-monophosphate (cGMP) fra guanosine triphosphate (GTP). Dette kaldes for NO-sGC-cGMP stivejen, som er relevant for ...

2019-10-16 09:45 REDOX status påvirker IDO enzym aktivitet

I forrige blogindlæg Forhøjet methæmoglobin og "rod i redox" hos ME patienter lærte vi, at hæmoglobin skal være i ferro (Fe2+) tilstand for at kunne binde ilt.Enzymet indolamine-2,3-dioxygenase (IDO) binder ligeledes ilt via jern i ferro (Fe2+) form. IDO omsætter aminosyren tryptofan til N-formylkynurenine. IDO sætter to iltatomer (to ilt = di oxygen) ind i indolringen på plads nr. 2 og 3 i tryptofan (1):Link til figur af den kemiske reaktion (1):https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280726/figure/sch1/Ligesom hæmoglobin kan auto-oxideres til methæmoglobin i ferri (Fe3+) form, kan IDO ...

2019-10-15 11:25 Forhøjet methæmoglobin og "rod i redox" hos ME patienter

Konklusionen på Germain et al (2018) metabolisme studiet var, at det er "rod i redox" (1):"Our hypothesis is that a disturbance in the redox status influences the status of chemical reaction donors and acceptors as well as their coenzymes such as NAD+/NADH, FAD+/FADH for dehydrogenases. Oxidases would obviously also be affected as catalyzers of redox reactions."Ordet redox er en sammentrækning af reduktion og oxidation. Det handler om at flytte elektroner mellem kemiske forbindelser.NAD+/NADH er et eksempel på et redox-par:NAD+ kan modtage en elektronNADH kan donere en elektronJern (latin: Fer ...

2019-10-04 09:38 En ny biosensor viser, at SS-31 er et potentielt lægemiddel til ME

Dr. Ron Davis fra Standford Universitet og hans team har udviklet en nano-elektrisk biosensor (på engelsk populært kaldet "the nanoneedle"). Den kan vise om immunceller fra en blodprøve kommer fra ME pateinter eller fra raske kontrolpersoner.Immunceller fra både ME patienter og raske kontrolpersoner udsættes for salt-stress (også kaldet osmotisk stress) i biosensoren ved, at der tilsættes en natriumklorid-opløsning. Biosensoren måler et elektrisk signal (impedansen), som er et resultat af celleprocesser udløst af salt-stress.Forskningen er beskrevet i denne artikel:A nanoelectronics-blood-base ...

2019-10-04 08:41 OMICS and iron metabolism in ME

Genomics in MEGene variants of TF, TFRC, and HPX have been identified as risk loci in ME patients (1):Slide from: Whole Genome Sequencing and Analysis of ME/CFShttps://www.youtube.com/watch?v=nIJX-Q7w_Z4Serotransferrin (usually just called transferrin), TF: iron-binding proteinTransferrin receptor, TFRC: plasma membrane protein that allows cellular uptake of iron-loaded transferrinHemopexin, HPX: a protein that binds free heme (or met-heme) and transport it to the liver for break-down and iron recovery.Haptoglobin, HP: a protein that binds free hemoglobin and transport it to the liver for brea ...

2019-09-09 16:38 Genomics and the cytokine network in ME

Genomics in MEGene variants of IL12B, IL1B and IL4R have been identified as a risk loci in ME (1):Slide from: Whole Genome Sequencing and Analysis of ME/CFShttps://www.youtube.com/watch?v=nIJX-Q7w_Z4 Cytokines in MEPlasma cytokine levels have been measured in ME patients with short-duration illness (≤3 years) and ME patients with long-duration illness (>3 years) (2).IL-12B (IL-12p40) was increased in short-duration and decreased in long-duration compared to normal controls.IL-1β was decreased in long-duration compared to short-duration and normal controls (2).IL4 was increased in short-duratio ...

2019-09-01 10:39 Genomics, proteomics and transcriptomics show the iNOS pathway is upregulated in ME

Activated macrophages produce an inducible NO synthase (iNOS or NOS2).  Although iNOS was originally identified and characterized in macrophages, it is present in numerous cell types including endothelial cells, fibroblasts, vascular smooth muscle cells and cardiac myocytes (1).Genomics in MEA gene variant of iNOS has been identified as a risk locus in ME (2):Slide from. Whole Genome Sequencing and Analysis of ME/CFShttps://www.youtube.com/watch?v=nIJX-Q7w_Z4 Proteomics in METhe pathway "Production of NO and ROS in macrophages" was upregulated in the cerebrospinal fluid from ME patients (table ...

2019-08-25 11:31 Does OXA1L, MRM2 and MRRF protein activity compensate for complex V inefficiency in ME patient cells?

ATP synthesis by Complex V is less efficient in ME/CFS cells. The other mitochondrial complexes work harder to compensate (1).Is this problem reflected in previous ME research?OXA1LOxidase (cytochrome c) assembly 1-like (OXA1L) is a mitochondrial inner membrane protein. It is required for the insertion of integral membrane proteins into the mitochondrial inner membrane. Essential for the activity and assembly of cytochrome oxidase. Required for the correct biogenesis of complex V and complex I in mitochondria (2).Knockdown of human Oxa1L impairs the biogenesis of complex V and NADH:ubiquinone ...

2019-08-22 10:45 AMPD3 in ME

Adenosine monophosphate deaminase (AMPD) converts AMP to inosine monophosphate (IMP).The AMP deaminase gene family:AMPD1, muscle (m) isoformAMPD2, liver (l) cells isoformAMPD3, erothrocyte (e) isoformThe isoforms are named after their predominant location, but are also expressed in other tissue. Fx. AMPD3 is also expressed in muscles.The purine nucleotide cycle of muscles consist of the conversion of AMP→IMP→AMP and requires AMP deaminase. Flux through this cycle increases during exercise.Genomics in MEA gene variant of AMPD3 has been identified as a risk locus in ME (1):Slide from. Whole Geno ...

2019-08-11 18:20 GPR35, ATPase inhibitor IF1 and ATP synthase subunits

The ME hypothesis "the metabolic trap" tell us that IDO function in immune cells may be compromised (1).IDO1 and IDO2 catalyze the first step in the kynurenine pathway: The conversion of tryptophan to N-formyl-kynurenine. N-formyl-kynurenine can be converted to kynurenine (KYN). KYN can be further processed to kynurenic acid (KYNA).ATP synthesis by Complex V is less efficient in ME/CFS cells (2).ATP synthase (also known as Complex V or F(1)F(o)-ATPase ) consists of several subunits (3). These subunits interact with the ATPase Inhibitory Factor.The ATPase Inhibitory Factor (ATPIF1) is a master ...

2019-07-26 11:49 Complex V is down in ME - does it also explain Electromagnetic Hypersensitivity?

Complex VComplex V (also known as ATP synthase or F0F1ATPase) is working less efficiently in cells from ME patients (1).Chemical Intolerance and Electromagnetic Hypersensitivity in MEME patients have chemical intolerance (CI), also knowns as multiple chemical sensitivity (MCS). I have asked the question:Complex V is down in ME - does it explain Chemical Intolerance?http://followmeindenmark.blogspot.com/2019/07/complex-v-is-down-in-me-does-it-explain.htmlSeveral ME patients also have electromagnetic hypersensitivity (EHS). It has been hypothesized that EHS and CI are two etiopathogenic aspects ...

2019-07-23 08:10 Complex V is down in ME - does it explain Chemical Intolerance?

Complex VComplex V (also known as ATP synthase or F0F1ATPase) is working less efficiently in cells from ME patients (1).The ATPase Inhibitory Factor 1 (IF1) is the physiological inhibitor of the mitochondrial ATP synthase (complex V). IF1 is a mitochondrial protein with very short half-life. It is tissue-specifically expressed and primarily controlled at posttranscriptional levels. Overexpressing of IF1 leads to inhibition of the ATP synthase and the reprograming of energy metabolism to an enhanced glycolysis. This reprogramming may protect cells from cytotoxic insults (2).Figur 1B from refere ...

2019-07-21 14:10 Mitokondrie Complex V er dysreguleret hos ME patienter

I mitokondrierne bliver vores mad omsat til energi i form af ATP. Dette sker via citronsyre cyklus og de fem mitokondrie komplekser. Basis viden om dette kan læses i wikipedia. Her ses citronsyre cyklus og de fem komplekser:Figur fra Wikipedia: Oxidative phosphorylationhttps://en.wikipedia.org/wiki/Oxidative_phosphorylationI øverste venstre hjørne ses ATP synthase også kaldet complex V. Complex V sætter en fosfat-gruppe på ADP, så der dannes ATP. Complex V er yderligere beskrevet i Wikipedia: ATP synthase:  https://en.wikipedia.org/wiki/ATP_synthaseProfessor Paul Fisher fra La Trobe Universite ...

2019-07-18 09:32 Betydning af acetyl-grupper for ME sygdomsmekanismen

ME patienter har dysreguleret glykolyse. McGregor et al (1) mener, at denne dysregulering medfører:nedsat dannelse af acetyl-grupperhistone deacetyleringnedsat acetylering af enzymerMcGregor et al artikel:Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Caseshttps://www.ncbi.nlm.nih.gov/pubmed/31277442McGregor holder foredrag om forskningen: An Omic Analysis of ME/CFS – an Assessment of Potential Mechanisms:https://www.youtube.com/watch?v=UvGMbbyGtvgBloggen Health Rising har gennemgået forskningen:Emerging Insights #1: McG ...

2019-07-11 09:58 ME/SEID hypotese: Formindsket regeneration af dihydrolipinsyre

Der er kommet en ny ME/SEID hypotese (1):Suggested Pathology of Systemic Exertion Intolerance Disease: Impairment of the E3 Subunit or Crossover of Swinging Arms of the E2 Subunit of the Pyruvate Dehydrogenase Complex Decreases Regeneration of Cofactor Dihydrolipoic Acid of the E2 SubunitHypotesen går ud på, at der er formindsket regeneration af dihydrolipinsyre (dihydrolipoic acid) til lipinsyre (lipoic acid).For at forstå hypotesen til bunds er det nødvendigt med basisviden om lipoic acid. Jeg vil derfor gennemgå basisviden fra wikipedia og fra artiklen:Lipoic acid metabolism and mitochondri ...

2019-07-01 10:24 Mutations in the IDO2 gene and DNA methylations in genes in the NAD/NADP synthesis pathway in ME

Results shown at the NIH ME/CFS conference indicate that all of the 20 of the severely ill ME patients had damaging mutations in their indolamine 2,3-dioxygenase 2 (IDO2) gene (1,2).The enzymes IDO1 and IDO2 catalyze the conversion of tryptophan to N-formyl-kynurenine. This is the first step in the kynurenine pathway and in the de novo pathway of biosynthesis of  NAD+  and  NADP+  (3).Use link below to see "Biosynthesis of NAD(P)+ in mammalian cells" (3):https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737637/figure/f2/NAD+ is synthesized by three pathways: the de novo pathwaythe Preiss–Handler p ...

2019-06-30 06:47 IDO-ME hypotesen er forenelig med AHR-MCS hypotesen

ME hypotesen "the metabolic trap" beskriver dysregulering af første trin i  kynurenine stivejen i immun celler fra ME patienter, idet tryptofan ikke omsættes til N-formyl-kynurenine i tilstrækkelig omfang  af enzymerne IDO1 og IDO2 (1).ME patienter har kemikalie intolerance - også kaldet Multiple Chemical Sensitivity (MCS).de Luca et al skrev i 2010, at en mulig forklaring af MCS kunne være undertrykkelse af Aryl Hydrocarbon Receptor (AHR) og/eller cytochrome P450 enzymerne (CYPs) (2).AHR er en ligand-aktiveret transkriptionsfaktor, der bliver aktiveret af små molekyler fra (3):kostenmetabolit ...

2019-06-24 12:16 Is the kynurenic acid responsive Gpr35 involved in the ME pathomechanism?

The ME hypothesis "the metabolic trap" tell us that IDO function in immune cells may be compromised (1).IDO1 and IDO2 catalyze the first step in the kynurenine pathway: The conversion of tryptophan to N-formyl-kynurenine.  N-formyl-kynurenine can be converted to kynurenine (KYN). KYN can be further processed to kynurenic acid (KYNA).Germain et al showed decreased levels of L-kynurenine / Formyl-5-hydroxykynurenamine in plasma from ME patients (2). Is the KYNA plasma level changed in ME patients?Agudelo et al have shown (in mice) that kynurenic acid increases energy utilization by activating G ...

2019-06-18 10:50 Kynurenine metabolisme påvirkes af motion

ME hypotesen "the metabolic trap" beskriver dysregulering af første trin i  kynurenine stivejen i immun celler fra ME patienter, idet tryptofan ikke omsættes til N-formyl-kynurenine i tilstrækkelig omfang (1).Fra forskning i depression ved man, at kynurenine stivejen påvirkes af motion, og man ved, at depression er forbundet med forhøjede niveauer af kynurenine. Det er således ikke det samme, der er galt med ME patienter (ifølge hypotesen), men vi kan lære noget om kynurenine stivejen ved at se på forskning i depression.Forskere fra Karolinska Institutet i Sverige har i forsøg med mus vist, at ...

2019-06-17 09:10 CTLA-4 induces IDO and SOCS3 drives degradation of IDO

The ME hypothesis "the metabolic trap" tell us that IDO function in immune cells may be compromised (1).Dendritic cells (DCs) and T cells work together to maintain immune tolerance.Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) downregulates the immune response. CTLA-4 binds to CD80 or CD86 on the surface of DCs. As a result DCs produce the tolerogenic tryptophan - catabolizing enzyme IDO (2):Use links to figures:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380512/figure/F1/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380512/figure/F2/Mutations in the gene CTLA4 have been associated wi ...

2019-06-14 13:46 Is the ME hypothesis "the metabolic trap" able to explain endothelial dysfunction?

Vascular endothelial dysfunction has been measured in ME patients (1).The ME hypothesis "the metabolic trap" tell us, that the first step in the kynurenine pathway is dysregulated (2).Dysregulated kynurenine pathway is highly associated with endothelial dysfunction and has been correlated with several cardiovascular diseases (3).Research indicates, that IDO can be nitrated and inactivated by peroxynitrite, and that nitration of IDO-Tyr15 is the most important factor for IDO inactivation (3).Research in apolipoprotein E knock-out mice on a high fat diet has shown: Systemic IDO inhibition by 1-m ...

2019-06-13 10:36 Tryptofan metabolitten kynureninsyre har immunmodulerende egenskaber

ME hypotesen "the metabolic trap" forudsiger højt niveau af tryptofan og lavt niveau af kynurenine inde i immuncellers cytoplasma (1).Germain et al påviste lavt niveau af L-kynurenine / Formyl-5-hydroxykynurenamine i plasma fra ME patienter (2).Kynurenine (KYN) kan omdannes til kynurenic acid (KYNA), på dansk kynureninsyre. Vi kan formode, at flere kynurenine metabolitter er påvirkede hos ME patienter - både i inde i cellerne, i plasma og i cerebrospinalvæsken. Så forhåbentlig er der forskere i gang med at bestemme niveauet af disse metabolitter, og hvad det kan betyde for ME sygdomsmekanismen ...

2019-06-11 15:11 Omsætning af tryptofan og forgrenede aminosyrer hos ME patienter under motion

Hypotesen om dysreguleret tryptofan metabolisme hos ME patienter (1) har skabt fornyet interesse for et studie fra 2003 (2).12 ME patienter og 11 kontrol personer motionerede til udmattelse. Der blev udtaget blodprøver under hvile, motion (udmattelse) og restitution. Der blev målt maximal ilt-optagelse (peak oxygen uptake) under motionen. Blodprøverne blev anvendt til at udmåle plasma niveauer af:fri tryptofan (free Trp)forgrenede aminosyrer (BCAA = branched-chain amino acids = leucin, isoleucin og valin)store neutrale aminosyrer (LNAA = large neutral amino acids)tyrosinListe over neutrale ami ...

2019-06-07 11:15 ME hypotese: The Metabolic Trap - den metaboliske fælde

Genetisk analyse har afsløret mutationer i genet IDO2 hos alvorligt syge ME patienter. Videre forskning i IDO2 har resulteret i, at Dr. Robert Phair har fremsat en ME hypotese "the metabolic trap", - den metaboliske fælde (1).Dr. Robert Phair fra Integrative Bioinformatics Inc samarbejder med Ron Davis og Open Medicine Foundation (2).Basisviden om tryptofan-omsætning via enzymerne TDO, IDO1 og IDO2Aminosyren tryptofan omsættes via to stiveje:I hjernen/hjernestamme omsættes tryptofan til neurotransmitteren serotonin.I immunceller omsættes tryptofan til kynurenine metabolitter, der bidrager til ...

2019-06-03 13:54 Påvirkning af hjernestammen hos ME/POTS patienter

Jennifer Brea, som har været diagnosticeret med ME/POTS, er blevet rask efter operation for craniocervical instabilitet og tethered cord syndrome (1). Vi kan formode, at lidelserne har forårsaget kompression af hjernestammen, og at dette har udløst dysregulering af hjernestammmens funktioner og ME/POTS symptomer. Lad os derfor se nærmere på basisviden om hjernestammen og scanninger af hjernestammen hos ME patienter.Hjernestammen - basisvidenHjernestammen består afmidthjernen (mesencephalon)hjernebroen (pons)den forlængede rygmarv (medulla oblongata)Hjernestammen indeholder de nerver, der forbi ...

2019-04-26 09:02 Mestinon til behandling af ME

Lægemidlet Mestinon (indholdsstof: pyridostigmine) er en potentiel behandlingsmulighed til ME.Mestinon hæmmer nedbrydning af acetylcholin og er udviklet til behandling af Myasthenia gravis (1)Mestinon er allerede på listen over den række lægemidler, som kan anvendes til behandling af ME-komorbiditeten POTS ( se tabel 4 i review fra Neurologisk afdeling, Mayo Clinic, ref 2).Det har i mange år været kendt viden, at nogle ME patienter opnår bedring af Mestinon. Et pilotstudie fra 2003 viste, at tre ME patienter havde gavn af en dosis på 10 eller 30 mg pyridostigmine (3).Associate professor of Med ...

2019-04-19 09:49 ME patienter har neuroinflammation

Forskere fra to amerikanske universiteter har undersøgt hjernen med Magnetisk Resonans Spektroskopi (MRS) hos 15 kvinder med ME. Det mest markante fund i dette studie var øget niveau af choline i det område i hjernen, der hedder venstre anterior cingulate cortex (ACC) (1).MRS kan påvise fri choline og vandopløselige nedbrydningsprodukter af celle-komponent-materialer, som phosphocholine og glycerophosphocholine. Påvisning af choline i hjernescanninger anvendes derfor som indikation på neuroinflammation (1),Andre undersøgelser har vist, at inflammation i ACC udløser cytokininduceret fatigue og ...

2019-04-17 09:38 ME versus Sepsis

Research in myalgic encephalomyelitis (ME) has shown:ME patients have impaired pyruvate dehydrogenase (PDH) function (1).Dichloroacetate (DCA) increases PDH activity. A pilot study has shown, that DCA may be a treatment of ME (2, 3).Some ME patients may also have decreased fatty acid oxidation (4, 5, 6).ME patients have:* abnormalities in the conversion of citrate to isocitrate in the TCA-cycle (7)* a possible flow of metabolites to replenish succinate in the TCA-cycle (7)* decreased succinylcarnitine (5)* decreased FAD (4)ME is a hypometabolic syndrome, which resembles hibernation (4).ME pati ...

2019-04-04 10:19 AMPK is a regulator of TRPA1

AMPK is a widely expressed intracellular energy sensor that monitors and modulates energy expenditure (1).AMPK activation is impaired in muscle cell cultures derived from ME patients (2).Transient receptor potential ankyrin 1 (TRPA1) channel is a widely recognized chemical and thermal sensor that plays vital roles in pain transduction (1).Some ME patients have single nucleotide polymorphism in TRPA1 (3).Wang et al discovered a functional link between AMPK and TRPA1 in dorsal root ganglion (DRG) neurons, in which AMPK activation rapidly resulted in downregulation of membrane-associated TRPA1 an ...

2019-04-02 08:40 Bivirkninger ved el-stimulering af muskler

Der er registreret bivirkninger - herunder 9 tilfælde af rabdomyolyse - ved anvendelse af udstyr til el-stimulering af muskler (1).Rabdomyolyse er en tilstand, hvor beskadigede muskler nedbrydes. Nedbrydningsprodukter strømmer ud i blodet og forårsager videre skade på kroppen (2).Personer med den medfødte metaboliske sygdom carnitine palmitoyltransferase 2 (CPT2) mangel er særligt udsatte for at udvikle rabdomyolyse (3).Ophobning af langkædede fedtsyrer og acyl-carnitiner (som set ved CPT2 mangel) kan have en detergent-lignende virkning på membraner og herved påvirke ion-kanaler og elektriske ...

2019-03-25 12:30 One-Carbon metabolism in ME

ME patients have dysregulated one-carbon metabolism (1).One-carbon metabolism has thoroughly been described in ref 2.An easy to read description of one-carbon metabolism is found in ref 3.Figure from ref 3:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518849/figure/fig1/The plasma level of serine was increased in male ME patients, and purine synthesis was decreased in both male and female ME patients. (1). We may hypothesize that serine was not turned into methylene-THF, methyl-THF and formyl-THF in adequate amounts.Bao et al have shown that mitochondrial dysfunction is able to remodel the one ...

2019-03-22 12:18 Chitotriosidase in ME

The enzyme chitotriosidase is involved in immune response to chitin-containing pathogens.Chitin is a polymer of N-acetylglucosamine. Chitin is the main component of the cell wall of fungi.Chitotriosidase is encoded by the gene CHIT1 (1).The CHIT1 gene promotor was hypomethylated in peripheral blood mononuclear cells (PBMC) from ME patients (2).The CHIT1 gene (genic region: body) was differentially methylated in PBMC from ME patient subtypes (3).Chitotriosidase is mainly expressed by blood and tissue macrophages. It is an important nonspecific marker of macrophage activation. Elevated chitotrio ...

2019-03-15 12:43 What does 1-pyrroline-5-carboxylate do to ME?

ME patients had increased plasma levels of 1-pyrroline-5-carboxylic acid (P5C) and arginine. Females had increased OH-proline (1).P5C is found at a crossroad, which exchanges metabolites from:proline degradation from collagenproline synthesisurea cycleTCA cycleResearch in tumor growth has shown(quote from ref 2):"The metabolism of the nonessential amino acid proline contributes to tumor metabolic reprogramming. Previously we showed that MYC increases proline biosynthesis (PB) from glutamine. Here we show MYC increases the expression of the enzymes in PB at both protein and mRNA levels. Blockad ...

2019-03-14 10:33 Fatty acid oxidation, CPS1 and urea cycle in ME

When beta-oxidation of fatty acids is blocked, there is an increase in omega-oxidatio, which produces dicarboxylic acids (adipic, suberic and sebacic acid). Elevated levels in plasma or urine of dicarboxylic acids are indicative of dysregulated fatty acid oxidation. Inadequate level of carnitine can lead to elevated levels of dicarboxylic acids. This is fx. observed in enteric dysfunction (1),Some ME patients have changed plasma levels in different studies compared to normal controls of the following metabolites:increased sebacic acid and pristanic acid (2)increased adipoylcarnitine (3, 4), an ...

2019-03-11 15:20 Polyamines, 5'-methylthioadenosine and symmetrical dimethylarginine in ME

The polyamines (putrescine, spermidine and spermine) are involved in replication, transcription, translation, and stabilization of macro-molecular complexes. They may also play a role in autoimmunity (1).Decarboxylated S-adenosylmethionine (dcSAM) and ornithine generates putrescine and subsequently spermine and spermidine. In these reactions, dcSAM is converted to 5′-methylthioadenosine (MTA). Accumulation of MTA inhibits the enzyme protein arginine N-methyltrasferase 5 (PRMT5), which uses SAM as a methyl donor to synthesize symmetrical dimethylarginine (sDMA) from arginine. In the methionine ...

2019-02-26 11:40 ME minder om medfødt metabolisk defekt

Vores mad indeholder kulhydrater, protein og fedt, som vi ved fordøjelse nedbryder til henholdsvis glukose, aminosyrer og fedtsyrer. Disse bestanddele anvender kroppen som byggesten og brændstof. Dette kaldes stofskifte eller metabolisme. Der findes forskellige former for stofskiftesygdomme og dysreguleret metabolisme.Hver sygdom har sin forklaring. Manglende evne til at omsætte glukose, som det ses ved diabetes type 1, skyldes autoimmunitet. Manglende evne til at nedbryde fedtsyrer kan skyldes medfødt defekt i enzymer, cofaktorer eller andre proteiner, der er involveret i fedtsyreforbrændinge ...

2019-01-21 13:55 En forklaring hentet fra rectum

Forleden dag havde jeg sat mig til rette for at skrive et kort resumé af Diane O'Leary´s meget kritiske artikel om begrebet bodyly distress syndrome (BDS). En gruppe forskere har valgt at konstruere begrebet BDS, som kun er en nuance-forskel fra hypokonderi. BDS skal bl.a. anvendes til at sættes i stedet for den neurologiske diagnose Myalgisk encephalomyelitis G93.3. Hermed bortforklares og tilsidesættes den biologiske forskning i sygdomsmekanismen. Uden denne forskning er ME patienter dømt til livslang invaliditet uden håb om, at der udvikles forståelse for sygdomsmekanismen og en helbredende ...

2018-12-28 18:52 Flippase, floppase and scramblase

The cell membrane is composed of cholesterol and phospholipids arranged in a lipid bilayer (outer and inner monolayer).There is a asymmetric phospholipid distribution in the bilayer. Three families of proteins are responsible for the translocation of phospholipids between the two monolayers (1):Flippases move phospholipids from the outer to the inner monolayer.Floppases do the opposite operation.Scramblases move phospholipids in both directions.ATP10A and ATP11AFlippase ATP10A flips phosphatidylcholine at the plasmamembrane. This activity drives membrane curvature (2).Flippase ATP11A has flipp ...

2018-11-30 12:56 Bile acid transporter SLCO3A1 and ME

Bile acid transporters maintain bile acid homeostasis.Solute Carrier Organic Anion Transporter Family Member 3A1 (SLCO3A1) Is a Bile Acid Efflux Transporter in Cholestasis (1).SLCO3A1 is up-regulated as an adaptive response to cholestasis (1).Genome-wide association analysis identified a single nucleotide polymorphism (SNP) in SLCO3A1 in ME patients (2).Epigentic analysis identified that the gene SLCO3A1 (5'UTR) was hypomethylated in peripheral blood mononuclear cells (PBMC) from ME patients. (3).Metabolomic analysis on plasma from ME patients identified lower levels of (4):glycocholateglycoch ...

2018-11-28 12:02 Lipid Transfer Proteins in ME

Lipid metabolism is dysregulated in ME patients (1, 2, 3).Genes encoding lipid transfer proteins (LTPs) are epigentic changed in peripheral blood mononuclear cells (PBMC) from ME patients (4, 5, 6, 7).Protein levels of LTPs are changed in the spinal fluid from ME patients (8).Lipid Transfer ProteinsWithin the eukaryotic cell, more than 1000 species of lipids define a series of membranes essential for cell function. Tightly controlled systems of lipid transport underlie the proper spatiotemporal distribution of membrane lipids, the coordination of spatially separated lipidmetabolic pathways, an ...

2018-11-23 13:18 Red blood cell deformability, metabolism and extracellular vesicles in ME/CFS

Red blood cell deformabilityRed blood cells (RBCs; erythrocytes) are typically biconcave in shape, transport hemoglobin-bound oxygen and are reversibly deformable facilitating trafficking through capillaries. Decreased deformability of RBCs adversely affects tissue oxygenation (1).RBC deformability is reduced in some ME/CFS patients (2).Metabolism and red blood cell membraneThe cell membranes in red blood cells are made up of proteins, fats, and carbohydrates. This means that abnormalities in the cell membrane can be a good way to spot disordered metabolism of these nutrients. Issues with prod ...

2018-11-06 14:55 NPY, AgRP, POMC and NUCB2 in ME

Hypothalamic Pro-opiomelanocortin (POMC) and Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP) neurons are critical nodes of a circuit within the brain that sense key metabolic cues as well as regulate metabolism. Importantly, these neurons retain an innate ability to rapidly reorganize synaptic inputs and electrophysiological properties in response to metabolic state (1).Exercise (single bout and/or chronic training) increases insulin sensitivity leading to improved insulin stimulated glucose uptake in muscle and reduced basal hepatic glucose production . Within the arcuate nucleus, the melano ...

2018-10-31 15:29 TECR (trans-2-enoyl-CoA reductase), VLCFAs and sphingolipids in ME

Very long-chain fatty acids (VLCFAs) are fatty acids (FAs) with a chain-length of ≥22 carbons. Mammals have a variety of VLCFAs differing in chain-length and the number of double bonds. Each VLCFA exhibits certain functions, for example in skin barrier formation, liver homeostasis, myelin maintenance, spermatogenesis, retinal function and anti-inflammation. These functions are elicited not by free VLCFAsthemselves, but through their influences as components of membrane lipids (sphingolipids and glycerophospholipids) or precursors of inflammation-resolving lipid mediators. VLCFAs are synthesize ...

2018-10-29 10:36 The role of endoplasmic reticulum-mitochondria contact sites

The contact sites that the endoplasmic reticulum (ER) forms with mitochondria, called mitochondria-associated membranes (MAMs), are a hot topic in biological research, and both their molecular determinants and their numerous roles in several signaling pathways are is continuously evolving (1).MAMs are now considered as structural platform for an optimal bioenergetics response allowing cellular adaptations to environmental changes. Indeed, the transfer of Ca2+from ER to mitochondria is crucial for the control of mitochondria energy metabolism, since mitochondrial Ca2+ levels control the activit ...

2018-10-28 16:38 PACS2 and ME

Endoplasmic reticulum (ER) and mitochondria are tubular organelles with a characteristic “network structure” that facilitates the formation of inter-organellar connections. As a result, mitochondria-associated ER membranes (MAMs), a subdomain of the ER that is tightly linked to and communicates with mitochondria, serve multiple physiological functions including lipid synthesis and exchange, calcium signaling, bioenergetics, and apoptosis. Importantly, emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzh ...

2018-10-24 11:23 MGRN1 and ME

Mahogunin ring finger 1 (MGRN1) is a cytosolic ubiquitin ligase.MGRN1 expression increases when cells are exposed to a variety of stressors.Mice lacking MGRN1 have reduced level of many mitochondrial proteins. They have mitochondrial dysfunction and develop neurodegeneration.MGRN1 is involved in:mitochondrial fusionmitochondrial trafficking via regulation of microtubulesregulation af ER-associated protein degradation and ER-mitochondria junctions via interaction with the ligase GP78(Ref1-5)Four studies have shown the gene MGRN1 is differentially methylated in PBMC from ME patients compared to ...

2018-10-18 10:50 H2AFY and ME

H2AFY (also known as macroH2A1) is a histone H2A variant. It replaces conventional H2A histones in a subset of nucleosomes.This gene encodes two splice isoforms, H2AFY1.1 and H2AFY1.2 (also known as mH2A1.1 and mH2A1.2). mH2A1.1 and mH2A1.2 are produced by mutually exclusive use of exons 6b and 6a.  The isoforms have distinct regulatory properties.H2AFY, ZFR and interferon signalingZFR (zinc finger RNA binding protein)  coordinates crosstalk between RNA decay and transcription in innate immunity.ZFR protein is required for H2AFY expression. ZFR regulates alternative splicing and decay of H2AFY ...

2018-10-12 09:41 CLYBL, itaconate and B12 - involved in ME?

The gene citrate lyase subunit beta-like (CLYBL) is a mitochondrial enzyme (1).Figure 1. A Novel Pathway Linked to Vitamin B12 Metabolism. The metabolic role of CLYBL is linked to B12 metabolism and the immunomodulatory metabolite, itaconate (1).CLYBL in METhe gene CLYBL (body) is hypermethylated in peripheral blood mononuclear cells (PBMC) from ME patients (table S1 in ref 2).Some ME patients have single nucleotide polymorphism  (SNP) in the gene CLYBL (3). CLYBL, itaconate and B12CLYBL participates in a relatively unexplored human C5 metabolic pathway.CLYBL is required for maintaining mitoch ...

2018-10-03 11:33 Is STING involved in ME?

NEW RESEARCHNitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signalingAbstract:The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in ...

2018-09-30 11:00 RPS6KB1, EIF4G1 and CD79A in ME/CFS

RPS6KB1 (5'UTR) is the most hypermethylated gene in peripheral blood mononuclear cells (PBMC) from ME patients with a mean beta-difference: 0,353 compared to controls (table S4 in ref 1).EIF4G1 (body) is the second most hypermethylated gene in PBMC from ME patients (table 2, page 5 in ref 2). EIF4G1 mRNA expression is upregulated in PBMC from ME patients (figure 1 in ref 3).CD79A is the gene with lowest expression in whole blood from adolescent CFS patients (table S3 in ref 4).These three gene products interact (5):Gene Cards STRING Interaction network RPS6KB1 (5)RPS6KB1: Ribosomal protein S6 ...

2018-09-01 09:10 HOX-genes and MIR10A in ME

The genes HOXB3, HOXB4, HOXB5, HOXB-AS3 (LOC404266) and MIR10A are located together on chromosome 17.MIR10A is hypermethylated, HOXB5 and LOC404266 are hypomethylated in CD4+ T-cells from ME patients (1).The HOXB4 gene promoter is hypomethylated in peripheral blood mononuclear cells (PBMC) from ME patients (table S7 in ref 2).HOXB3 (5'UTR), HOXB4 (1stExon, 5'UTR), LOC404266, HOXB5 (5'UTR), LOC404266 (TSS200, TSS1500) and MIR10A (1stExon, TSS1500) are hypomethylated in PBMC from ME patients (table S4 in ref 2).HOXB3 (5'UTR), HOXB4 (body), HOXB5 (3'UTR), LOC404266 (TSS200, TSS1500, body) and MIR ...

2018-08-25 07:50 FAM13A, fatty acid oxidation and ME

Lipid metabolism is dysregulated in ME patients (1, 2, 3, 4).Family with sequence similarity 13 number A (FAM13A) regulates fatty acid oxidation (FAO) (5).The gene FAM13A is hypomethylated (TSS200 and TSS1500) in peripheral blood mononuclear cells (PBMC) from ME patients (table S4 in ref 6).The gene FAM13A is hypermethylated (1stExon/5'UTR), CPT1A is hypermethylated (5'UTR) and CPT1B is hypermethylated (TSS200/5'UTR) in PBMC from ME patients. This DNA methylation pattern is related to quality of life in the ME patients (table S7 in ref 7).In whole blood from adolescent CFS patients FAM13A gene ...

2018-08-19 18:25 ACSL3, GPD2 og PDHX i ME

Forskere har anvendt en ny forbedret teknologi til at undersøge epigenetiske ændringer i blodceller fra ME patienter. Resultatet blev valideret på ME patienter fra både USA og Spanien (1).De supplerende tabeller i artiklen rummer værdifulde informationer. Jeg vil nævne tre eksempler (ACSL3, GPD2 og PDHX) fra Tabel 7.Tabel S7 er en liste over 144 hypomethylerede gen promotorer. Promotoren er det område på DNA'et, hvorfra transkriptionen af et gen starter. Ændret DNA methylering af promotoren har stor betydning for genekspressionen. Man kan formode, at de 144 hypomethylerede gener er "på overarb ...

2018-08-13 13:02 Functions of DNA methylation

Functions of DNA methylationAbstract (ref 1):DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription i ...

2018-08-12 13:51 Mitokondrieproteiner i ME

Vi forstår endnu ikke mitokondriernes rolle i ME sygdoms-mekanismen. Mitokondrieproteiner dukker sporadisk op i ME forskningen. Lad os se om disse mitokondrie påvirkninger danner et samlet billede, som kan lede os på sporet af hvad der foregår i ME sygdomsmekanismen.I studiet af DNA methyleringer på CD4+ - T celler fra ME patienter, er to gener, OXA1L og FTSJ2, henholdsvis hypo- og hypermethyleret. Generne koder proteiner, der anvendes af mitokondrierne (1).En tommelfingerregel er, at hypomethylering af et gen er forbundet med øget transkription, og hypermethylering er en nedregulering af gene ...

2018-08-11 15:28 SPI1 and ME

SPI1 (=PU.1) is a transcription factor involved in hematopoiesis. SPI1 regulates B-cell development, but is also important for maturation of macrophages, T cell progenitors and T helper 9 cells.SPI1 can either activate or repress the transcription of genes. This is mediated by the ability of SPI1 to build different complexes with a number of different protein partners (1).In leukemia SPI1 can be either an oncogene or a tumor suppressor. SPI1 overexpression can trigger cellular senescence, and may be a safeguard against leukemia (12).EP300 is a transcriptional co-activator, which interacts with ...

2018-07-31 06:37 HOXA9 and ME

Histones act as spools around which DNA winds.H3 and H4 histones have long tails. The tail can be modified in different ways, that lead to activation or repression of transcription of genes. Fx, trimethylation of H3 lysine 4 (H3K4me3) will acrivate transcription, and trimethylation of H3 lysine 27 (H3K27me3) will repress genes.COMPASS (complex of proteins associated with Set1) - like complexes activate transcription. They perform the histone modification H3K4me3.Polycomb complexes repress genes. The polycomb repressive complex 2 perform the histone modification H3K27me3.Several subunits of COM ...

2018-07-26 18:10 Nucleoporins in ME

The nuclear pore complex (NPC) mediates nuclear transport of RNA. Nucleoporins are the main components of the NPC. Certain nucleoporins have additional function in chromatin organization and transcription regulation.NUP98 and NUP96The gene NUP98 encodes nucleoporin Nup98 and Nup96. They are expressed from one mRNA. Following translation, autoprotelytic cleavage separates the two proteins. Alternatively, Nup98 can be spliced as a short mRNA that does not encode Nup96 (1).Interferon-induced gene promoters containing Nup98 accumulate poised RNA Pol II along with dimethylated histone H3K4 (1).NUP9 ...

2018-07-24 19:08 mRNA export in ME

DNA is transcribed into pre-mRNAs.mRNAs are packaged into pre-messenger ribonucleoproteins (pre-mRNPs).Pre-mRNPs are spliced into mature mRNPs.mRNPs are exported out of the nucleus through the nuclear pore complex (NPC).SUN1 (=UNC84) is a nuclear envelope protein.SYNE proteins (nesprins) are part of a network that connects the nuclear envelope to the cytoskeleton.NXF1 is an export factor.NUP153 is one of several nucleoporins.SUN1 recruits NFX1-containing mRNPs onto the nuclear envelope and hands them over to NUP153 (1).Figure from: Li and Noegel: Inner nuclear envelope protein SUN1 plays a pro ...

2018-03-04 13:50 GRAMD1A - a tether, which transfers sterols.

de Vega et al showed that the most hypermethylated gene associated with quality of life in ME patients was GRAMD1A. A hypermethylated gene is often associated with supressed transcription (1).GRAMD1A is a tether protein between the plasma membrane and endoplasmic reticulum (2).Figure 8 from Marina Besprozvannaya, et al. eLife. 2018;7:e31019 (2)GRAMD1A transfer sterols (3)Is GRAMD1A involved in the dysregulated sterol and sphingolipid homeostasis in ME patients?References:Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11GRAM domain ...

2018-01-20 15:44 KDM2B, PHYH, P3H2, PLOD3 and ME

Alpha-ketoglutarate dependent dioxygenases are also called 2-oxoglutarate oxygenases. They are a large family of enzymes with most diverse functions (1).The following examples are relevant for ME research.KDM2BKDM2B (lysine demethylase 2B) is one of the 2OG-oxygenases described in ref 1. The gene KDM2B is hypermethylated in ME patients (2). And KDM2B is hypomethylated in CD4+  T cells from ME patients (3). KDM2B is able to regulate histone 3 methylation. KDM2B expression is also known to regulate ribosome biogenesis, and is a positive regulator of glycolysis. KDM2B is an important mediator of ...

2018-01-19 05:51 D2HGDH, PHYKPL and ME

The gene D2HGDH is hypomethylated in ME patients, and this is associated with quality of life (1). Hypomethylation can result in upregulation of gene transcription. In agreement with this, gene expression of D2HGDH was upregulated in whole blood from adolescent ME/CFS patients (2).D2HGDH encodes D-2-hydroxy-glutarate dehydrogenase, which converts D-2-hydroxyglutarate to alpha-ketoglutarate (alpha - KG). Mutations in D2HGDH are present in D-2-hydroxyglutaric aciduria, a rare neurometabolic disorder.It is possible that 2-hydroxy glutarate is generated in relation to lysine breakdown. PHYKPL, 5-p ...

2018-01-07 20:12 DGKZ and ME

ME patients have two hypermeyhylated sites in the gene DGKZ. They are associated with quality of life (1). Hypermethylation can result in suppressed transcription of the gene.The enzyme diacylglycerol kinase zeta (DGKZ) catalyzes diacylglycerol (DAG) to phosphatidic acid (PA).DGKZ controls DAG metabolism at the immonological synapse between the T cell and a target cell.Disruption of DAG metabolism impairs the induction of T cell anergy, which is a process important to maintain peripheral T cell totelance.DGKZ deficiency is associated with enhanced T cell response (2).References:Vega et al: Epi ...

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