torsdag den 11. juli 2019

ME/SEID hypotese: Formindsket regeneration af dihydrolipinsyre

Der er kommet en ny ME/SEID hypotese (1):

Hypotesen 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 mitochondrial redox regulation (2).

Jeg benytter de engelske ord for de kemiske forbindelser, så de er lettere at genfinde i wikipedia og i artiklen.

Lipoic acid (LA) og 2-keto-acid dehydrogenase komplekserne

Lipoic acid (LA) bliver dannet ud fra caprylic acid (= octanoic acid). Octa betyder otte. Dvs. LA dannes af en fedtsyre, der har en kulstof kæde-længde på otte kulstof atomer (C). Fedtsyrekæden har fået sat et svovl atom på kulstof atom nr. 6 og 8. De to svovl atomer er bundet sammen i en disulfid-binding (-S-S-).


Lipoic acid.svg

Figur er fra Wikipedia: Lipoic acid

Disulfid-bindingen i lipoic acid leverer reduktionspotentiale til de tre 2-keto-acid dehydrogenase komplekser:

  • PDC, pyruvate dehydrogenase complex
  • OGDC, 2-oxo-glutarate dehydrogenase comples (2-oxo-glutarate = alpha-ketoglutarate)
  • BCKDC, branched-chain alpha-keto dehydrogenase complex

Disse enzym komplekser er ens opbygget af tre subunits:

  • E1: decarboxylase
  • E2: lipoyltransferase
  • E3: dihydrolipoamide dehydrogense

PDC subunits:
E1: PDHA1,  pyruvate dehydrogenase E1 alpha 1 subunit
E2: DLATdihydrolipoamide acetyltransferase
E3. DLD,  dihydrolipoamide dehydrogenase
Herudover findes der et E3 bindings-protein (E3BP), som binder E2 og E3 sammen. E3BP kaldes også for PDC component X og kodes af genet PDHX

OGDC subunits:
E1: OGDH,  oxoglutarate dehydrogenase
E2: DLST, dihydrolipoamide S-succinyltransferase
E3. DLD,  dihydrolipoamide dehydrogenase

BCKDC subunits:
E1: BCKDHA,  branched chain keto acid dehydrogenase E1 subunit alpha og
BCKDHB branched chain keto acid dehydrogenase E1 subunit beta
E2: DBT,  dihydrolipoamide branched chain transacylase E2
E3. DLD,  dihydrolipoamide dehydrogenase

Som man kan se, benytter de tre enzym komplekser sammen E3 subunit: DLD. Herudover findes der et glycine cleavage system (GCS), som også benytter DLD.

GCS består af:
AMT, aminomethyltransferase
GLDC, glycine decarboxylase
DLD,  dihydrolipoamide dehydrogenase
GCSH, glycine cleavage system protein H

Der findes endvidere et enzym 2-oxoadipate dehydrogenase (2-OADH), som også kaldes dehydrogenase E1 and transketolase domain containing 1 ((DHTKD1). DHTKD1 decarboxylerer 2-oxoadipate til glutaryl-CoA, som sidste trin i nedbrydning af lysine. Enzymet indgår også i omsætning af  tryptophan.

Mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein består af:
DHTKD1, dehydrogenase E1 and transketolase domain containing 1
og så mener man, at enzymkomplekset deler E2 og E3 subunit med OGDC (3).

2-ketoacid dehydrogenaserne og deres betydning for TCA cyklus er vist i figur 3 i reference 2:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961061/figure/F3/

Nu standser vi op et øjeblik og tænker! Hypotesen siger: "Impairment of the E3 subunit...". Hvis hypotesen er sand på dette punkt, kan der forventes en påvirkning af alle enzym komplekser, der anvender E3 subunit DLD.  Det vil jeg vende tilbage til. Vi skal først forstå lipoic acid's rolle til bunds. 

Dannelse af lipoylated E2 subunit

Når lipoic acid bygges sammen med et protein, f.eks. enzymet subunit E2, kaldes det en lipoylation. Proteinet er blevet lipoylated. Den biokemiske stivej, der sørger for dette er ikke 100% klarlagt, så man møder en del uafklarede spørgsmål i litteraturen.

Figur 1B i reference 2 viser bedste bud på lipoylation af E2 subunit, som man mener, at det foregår hos mennesker.

Først dannes en octanoyl-ACP. ACP kaldes også for NDUFAB1 (ikke vist på figuren). Og så følger de tre trin beskrevet i figuren, hvor tre enzymer benyttes:

LIPT2lipoyl (octanoyl) transferase 2
LIAS,  lipoic acid synthetase
LIPT1,  lipoyltransferase 1

Structures, enzymes, and reaction mechanisms of lipoic acid metabolism (figur 1 fra reference 2).   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961061/figure/F1/

Jeg vil i det følgende gennemgå figuren, men først forklarer jeg dannelsen af octanoyl-ACP.

Dannelse af octanoyl-ACP

Octanoic acid er en organisk syre. En organisk syre er kendetegnet ved at have en -COOH gruppe. Når -OH gruppen fjernes fra en organisk syre, så opstår en acyl, som er et mellemprodukt til en videre biokemisk reaktion. Man benytter bogstaverne -oyl i nanvnet på den opståede acyl-gruppe.Enkelte af de kemiske forbindelser kaldes dog for -yl, som f.eks. formyl og acetyl.

Når octanoic acid får fjernet sin OH gruppe bliver den til en octanoyl. Dette octanoyl mellemprodukt bæres rundt i cellen af et acyl carrier protein (ACP). Det hedder en octanoyl-ACP. Octanoyl og ACP er bundet sammen via et svovl atom (-S-). 

LIPT2 - første trin i dannelse af lipoylated E2 subunit: Octanoyl-H-protein dannes

LIPT2 er genet for enzymet lipoyl (octanoyl) transferase 2. Transfer bedtyder overfører. LIPT2 overfører octanoyl fra octanoyl-ACP til et protein H under fraspaltning af ACP. Hermed dannes octanoyl-H protein. (Protein H anvendes også i GCS komplekset). Octanoyl og H protein er bundet sammen med en amid binding (-NH-). Dette er illustreret i første trin i figur 1B i reference 2.

LIAS - andet trin i dannelse af lipoylated E2 subunit: Lipoylated H-protein dannes

LIAS er genet for enzymet lipoic acid synthetase. LIAS sætter to svovl atomer (S) på octanoyl-H proteinet. Hermed dannes lipoylated H protein. Dvs et protein koblet sammen med lipoic acid. LIAS anvender svovl-atom donation fra et (4Fe-4S) cluster og reduktiv spaltning af S-adenosylmethionine (SAM) for at danne 5'deoxyadenosyl-5'radikaler, der kan fjerne hydrogenatomer (H) fra kulstof atom (C) nr 6 og nr 8 og i stedet indsætte svovatomer (S). Dette er illustreret i andet trin i figur 1B fra reference 2.

LIPT1 - tredie trin i dannelse af lipoylated E2 subunit: Lipoylated E2 subunit  dannes

LIPT1 er genet for enzymet lipoyltransferase 1. LIPT1 fjerner H protein fra octanoyl og sætter i stedet E2 subunit på. Hermed dannes lipoylated E2 subunit. Dette er illustreret i tredie trin i figur 1B fra reference 2.

Af reference 4 figur 1 fremgår det, at lipoylated E2 subunit kan dannes UDEN først at anvende et H-protein:


Fig 1. Lipoic acid biosynthesis.
mtFAS generates octanoyl-ACP, that enters the lipoic acid biosynthesis pathway. The octanoyl moiety is then transferred from ACP to H or E2 proteins. Subsequently, insertion of two sulfur atoms occurs on the octanoyl moiety to generate lipoylated H or E2 proteins. 2-KGDH, α-ketoglutarate dehydrogenase; 2-OADH, 2-oxoadipate dehydrogenase; ACP, acyl carrier protein; BCKDH, branched-chain ketoacid dehydrogenase; GCS, glycine cleavage system; LA, lipoic acid; LIAS, lipoic acid synthetase; LIPT1, lipoyl(octanoyl) transferase 1; LIPT2, lipoyl(octanoyl) transferase 2; mtFAS, mitochondrial fatty acidynthesis; PDH, pyruvate dehydrogenase.

Dihydrolipoamide

E3 subunit hedder "dihydrolipoamide dehydrogenase. Dihdro betyder to hydrogen (H). Det betyder, at svovlbindingen i lipoic acid er brudt, og der er sat en H på hver S. Amid er en -NH2, der er sat på C=O, dvs en amid er det neutrale derivat af en carboxylsyre. Hvis det ene H fjernes, så har vi en amid-bindingsgruppe -NH-, som kan kobles på en E2 subunit. E3 subunit fjerner to H, dvs den dehydrogenerer dihydrolipoamide. Heraf navnet dihyrolipoamide dehydrogense.



Dihydrolipoamide.svg

Figur fra Wikipedia: Dihydrolipoamide


Den subunit-bundne lipoic acid og dihydrolipoic acid og deres skifte mellem (-S-S-) og (-SH) gør, at cellen kan flytte rundt på elektroner og protoner (H+). 

Flere figurer kan findes her "Redox reactions involving thiols and disulfides":
https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Book%3A_Organic_Chemistry_with_a_Biological_Emphasis_(Soderberg)/16%3A_Oxidation_and_reduction_reactions/16.12%3A_Redox_reactions_involving_thiols_and_disulfides


Det skal fremhæves, at artiklen  påpeger, at kosttilskud af lipoic acid (LA) ikke hjælper: "The lack of an independent salvage pathway in humans abrogates the use of LA supplementation as a therapeutic option" (2).



2-keto-acid dehydrogenase komplekser i funktion

Figur 2 i reference 2 viser hvordan de tre subunits fungerer i samspil:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961061/figure/F2/

E1 benytter cofaktoren thiamine pyrophosphate  (TPP) til at decarboxylere alpha-keto acid. Herved dannes en acyl-TPP.
E2 overfører acyl-gruppen til Coenzym A (CoA). Herved dannes en acyl-CoA og den E2 bundne lipoic acid (LA) bliver til dihydrolipoamide (DHLA).
E3: Lipoic acid har under processen i E2 modtaget to hydrogen og er blevet til dihydrolipoamide (DHLA). Der er en sving-arm mellem E2 og E3, der flytter DHLA molekylet fra E2 til E3, I E3 fjernes de to hydrogen atomer og DHLA bliver herved regeneret til LA. Svingarmen kommer tilbage til E2 med LA. E3 benytter FAD og NAD til regenerering af DHLA til LA.

E3 subunit's kapacitet til at regenerere oxideret lipoic acid kontrolleres af NAD+/NADH ratio i mitokondrierne. Når der mangler NAD+, oxideres FADH2 i E3 subunit, og der dannes frie radikaler, som inaktiverer alpha-keto acid komplekserne.

PDC og OGDC kan beskyttes mod oxidativt stress ved glutathionylation. Gluathionylation inaktiverer enzymkomplekset. Glutathione-modifikationen kan igen fjernes med glutathione reductase 2, som kodes af genet GLRX2. OGDC bliver også beskyttet af thioredoxin reductase 2, som kodes af genet TXNRD2.

Figur 4 i reference to viser "Regulation of OGDH by reversible glutathionylation":
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961061/figure/F4/


ME/SEID hypotese sammenholdt med ME forskningen

ME forskning der viser påvirkning af PDC

Nedsat PDC funktion hos ME patienter er allerede sandsynliggjort i Fluge, Mella et al's studie (5).

Det øgede lactat niveau er foreneligt med nedsat PDC funktion. Øget lactat niveau hos ME patienter i forbindelse med motion er for nylig dokumenteret af Lien et al (6).

ME forskning der viser påvirkning af PDHX

PDHX gene promoter var hypomethyleret i peripheral blood mononuclear blood cells (PBMC) fra ME patienter (7).

PDHX genekspression i PBMC ændres ved motion (8). McGregor et al (9) henviser til reference 8 i deres tabel S1, hvor opmærksomheden henledes på, at PDHX er reguleret af histone deacetylaserne HDAC1 og HDAC2. Histone regulering er påvirket hos ME patienter i forbindelse med post exertional malaise (PEM) (9).


ME forskning der viser påvirkning af DLAT (E2 subnit i PDC)

Sirtuin 4 (SIRT4) er et enzym med flere funktioner. SIRT4 kan fungere som E2 subunit lipomidase og klippe lipoamiden af E2 subuniten, og hermed nedregulere PDC aktivitet. Citat fra reference 10: "We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity. We demonstrate SIRT4-mediated regulation of DLAT lipoyl levels and PDH activity in cells and in vivo, in mouse liver."

Figur 1 fra reference 10: SIRT4 interacts with the pyruvate dehydrogenase complex
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344121/figure/F1/

Der blev fundet øget mRNA ekspression af SIRT4 i PBMC fra ME patienter (p = 0,013) (5).

Der er blevet påvist spor af DLAT i spinalvæske fra ME patienter, men man ikke fandt DLAT spor hos kontrol personer eller hos Lyme patienter (patienter behandlet for borrelia infektion):
DLAT precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 11):
1) Controls: ingen værdi
2) ME patients: 1
3) Post treatment Lyme patients: ingen værdi


ME forskning der viser/ikke viser(?) påvirkning af DLD (den fælles E3 subnit)

Hvis DLD ikke fungerer kan man forvente, at alle DLD afhængige enzym komplekser er påvirkede. En genetisk mutation kan være dødelig (12): "E3-deficiency is a rare autosomal recessive genetic disorder frequently presenting with a neonatal onset and premature death."

Man må formode, at en mindre påvirkning af DLD vil give en mindre grad af alvorlighed. Spørgsmålet er således. Er alle DLD afhængige enzymer påvirkede hos ME patienter? Vi kender ikke svaret, men vi må holde øje med, hvad forskningen viser os.

En hæmning af OGDH vil give forhøjet niveau af alpha-ketoglutarate og 2-hydroxyglutarate, jvf figur 3 i reference 2. Et studie har vist forhøjet plasma niveau af alpha-ketoglutarate hos ME patienter (p = 0,003) (13). Gen ekspression af enzymet D-2-hydroxyglutarate dehydrogenase (D2HGDH) var opreguleret i fuldblod fra teen-age CFS patienter (p = 0,0555) (14). Genet D2HGDH var hypomethyleret (body) i PBMC fra ME patienter (15).

ME patienter anvender forgrenede aminosyrer som brændstof (5), så det må formodes at BCKDC fungerer.

Subunit E2 fra BCKDC hedder dihydrolipoamide branched chain transacylase E2 (DBT), og kaldes også for dihydrolipoyllysine-residue (2-methylpropanoyl) transferase. Plasma niveauet af S-(2-methylpropanoyl)-dihydrolipoamide var formindsket i plasma fra ME patienter (16). Hvad betyder dette fund?

Hvis glycine cleavage system (GCS) ikke fungerer, kommer der en ophobning af glycine. Glycine niveauet er normalt hos ME patienter. I reference 5 har ME pateinter et lidt højere serum niveau af glycine, men det er ikke statistisk signifikant (p = 0,082).

Gen promotor for AMT (som er den del af GCS) var hypomethyleret i PBMC fra ME patienter (7). Hvorfor?


ME forskning der viser påvirkning af mitokondrie fedtsyrer syntese - octanoic acid

Som det fremgår af reference 2, så starter produktionen af E2 subunit helt fra bunden af med en fedtsyre med 8 kulstofatmer, octanoic acid, (C8:0).

To uafhængig studier har påvist formindsket plasma niveau af 2-octenoylcarnitine (C8:1) hos ME patienter. Dvs carnitninen er sat sammen med en otte-kædet fedtsyre med en dobbeltbinding (17, 18).  Naviaux et al (17) kommenterer resultatet således: "Octenoic acid is produced as an intermediate of mitochondrial fatty acid and lipoic acid synthesis. It is the substrate for mitochondrial enoyl thioester reductase (ETR), a family of enzymes that requires NADPH to reduce the double bond to octanoic acid, which is then used for lipoic acid synthesis. Decreased levels of this C8:1 acylcarnitine are consistent with decreased mitochondrial fatty acid synthesis, increased oxidation, increased renal secretion, or a combination of the three."


ME forskning der viser påvirkning af mitokondrie fedtsyrer syntese - ACSM1

Der er diskussion om acyl-CoA synthetase medium chain family member 1, ACSM1, påvirker lipoic acid syntesen (2). I reference 2 står der: "There has been a report identifying a mammalian lipoic acid-activating enzyme that could activate exogenous lipoic acid (36); however, this function was ultimately attributed to the mitochondrial medium-chain acyl-CoA synthetase (ACSM1) (37, 38). This enzyme can utilize both the (R)- and (S)-enantiomers of LA and primarily uses GTP to activate the natural (R)-lipoic acid, but so far there has been no substantial evidence to support that this enzyme functions in LA metabolism in vivo (36). "

Om det er relevant eller ej skal det nævnes, at genet ACSM1 (TSS200) er påvist hypomethyleret i PBMC fra ME patienter i to uafhængige studier (7, 15). Ydermere er forskellig methylering af ACSM1 relateret til ME patient subtypes (19).


ME forskning der viser påvirkning af mitokondrie fedtsyrer syntese - ACACA og ACSF3

Malonyl-CoA er nødvendig for fedtsyre syntese i mitokondrierne og hermed også nødvendig for dannelse af lipoic acid. Acetyl-CoA carboxylase alpha (ACACA) katalyserer omdannelse af acetyl-CoA til malonyl-CoA. Acyl-CoA synthetase family member 3 (ACSF3) kan også danne malonyl-CoA. En mitokondriel isoform af ACACA og ACSF3 sørger i fællesskab for, at der er nok malonyl-CoA til at danne lipoic acid (20).

DNA methylering af ACACA og ACSF3 i PBMC fra ME patienter:

ACACA hypermethylering: 5'UTR;body og body (15), og body (21)

ACACA hypomethylering: to steder i 5'UTR, og to steder i en genic location, der ikke er angivet (7)

ACSF3 hypermethylering: tre steder body (15)

ACSF3 hypomethylering: tre steder 5'UTR og TSS100 (7), og body;5'UTR (15)

Forskellig methylering af ACSF3 (body) var relateret til ME patient subtypes (19).


ME forskning der viser påvirkning af LIPT1

Nogle mutationer i LIPT1 forårsager manglende aktivitet af PDC og OGDC, mens GCS stadig fungerer (22, 23). Der er rapporteret om dødelig lactis acidose i forbindelse med LIPT1 mutationer (24).

LIPT1 var hypermethyleret med en foldchange = 5,9 og p = 0,03 i CD4+ T celler fra ME patienter (25).


ME forskning der viser påvirkning af thioredoxin reductase og glutaredoxin 

TXNDR1 var hypomethyleret med en negativ foldchange = -3,6 og p = 0,000165 i CD4+ T celler fra ME patietner (25).

GLRX2 var hypermetyleret (TSS1500) i PBMC fra ME patienter i to studier (15, 21).

Gen ekspression af GLRX var opreguleret i fuldblod fra teen-age CFS patienter (p = 0,0005), hvilket var den laveste p-værdi i studiet (14).

Hvad sker der med redox i cellerne hos ME patienter? Og hvad betyder det for 2-keto-acid dehydrogenaser? Er de blevet glutathionylated?

Figur med Glutaredoxin (a) and thioredoxin (b) systems:
https://www.nature.com/articles/4401818/figures/1


Videre inspiration

Tak til Victoria Bohne, Oeyvind Bohne og de personer, der donerede til illustration af deres artikel om ME/SEID hypotesen. 

Vi skal helt sikkert et spadestik dybere ned i hvad der foregår i pyruvat dehydrogenase komplekset. Videre læsning må være:

Structural and Functional Analyses of the Human PDH Complex Suggest a “Division-of-Labor” Mechanism by Local E1 and E3 Clusters


Highlights herfra:

Binding of CoA to E2 primes PDHc lipoyl arms for subsequent E2 and E3 reactions


Referencer: 

1) Victoria J. Berdikova Bohne og Oeyvind BohneSuggested 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 Subunit 
https://www.sciencedirect.com/science/article/abs/pii/S0306987718312994

2) Solomonson og DeBerardinis: Lipoic acid metabolism and mitochondrila redox regulation. J Biol Chem. 2018 May 18;293(20):7522-7530. doi: 10.1074/jbc.TM117.000259. Epub 2017 Nov 30.
https://www.ncbi.nlm.nih.gov/pubmed/29191830

3) Nimeria et al: The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species Free Radic Biol Med. 2018 Feb 1;115:136-145. doi: 10.1016/j.freeradbiomed.2017.11.018. Epub 2017 Dec 1.
https://www.ncbi.nlm.nih.gov/pubmed/29191460

4) Bernadinelle et al: Mis-targeting of the mitochondrial protein LIPT2 leads to apoptotic cell death Plos One, june 9, 2017. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179591

5) Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276

6) Lien et al: Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome Physiol Rep. 2019 Jun;7(11):e14138. doi: 10.14814/phy2.14138.  https://www.ncbi.nlm.nih.gov/pubmed/31161646

7) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns. Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

8) Whistler et al: Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects BMC Physiol. 2005 Mar 24;5(1):5.

9) Mcgregor et al: Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases Diagnostics (Basel). 2019 Jul 4;9(3). pii: E70. doi: 10.3390/diagnostics9030070. https://www.ncbi.nlm.nih.gov/pubmed/31277442

10) Mathias et al: Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell. 2014 Dec 18;159(7):1615-25. doi: 10.1016/j.cell.2014.11.046. https://www.ncbi.nlm.nih.gov/pubmed/25525879

11) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287

12) Ambrus og Adam-Vizi: Human dihydrolipoamide dehydrogenase (E3) deficiency: Novel insights into the structural basis and molecular pathomechanism Neurochem Int. 2018 Jul;117:5-14. doi: 10.1016/j.neuint.2017.05.018. Epub 2017 Jun 2. https://www.ncbi.nlm.nih.gov/pubmed/28579060

13) Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.
https://www.ncbi.nlm.nih.gov/pubmed/30563204

14) Nguyen et al: Whole blood gene expression in adolescent CFS: an exploratory crosssectional study suggesting altered B cell differentiation and survival. J Transl Med. 2017,15,102. https://www.ncbi.nlm.nih.gov/pubmed/28494812

15) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

16) Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371 https://pubs.rsc.org/en/Content/ArticleLanding/2017/MB/C6MB00600K#!divAbstract

17) Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. https://doi.org/10.1073/pnas.1607571113

18) Reuter and Evans: Long-chain acylcarnitine deficiency in patients with CFS. Potential involvement of altered carnitine palmitoyltransferase-I-activity. J. Int. Med. 2011, 270.

19) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

20) Monteuuis et al. A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3. Biochem J. 2017 Nov 6;474(22):3783-3797. doi: 10.1042/BCJ20170416. https://www.ncbi.nlm.nih.gov/pubmed/28986507

21) de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104757

22) Soreze et al. Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase Orphanet J Rare Dis. 2013 Dec 17;8:192. doi: 10.1186/1750-1172-8-192. https://www.ncbi.nlm.nih.gov/pubmed/24341803

23) Tort et al. Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated with a specific lipoylation defect of the 2-ketoacid dehydrogenase complexes. Hum Mol Genet. 2014 Apr 1;23(7):1907-15. doi: 10.1093/hmg/ddt585. Epub 2013 Nov 20.https://www.ncbi.nlm.nih.gov/pubmed/24256811

24) Tache et al: Lipoyltransferase 1 Gene Defect Resulting in Fatal Lactic Acidosis in Two Siblings. Case Rep Obstet Gynecol. 2016;2016:6520148. doi: 10.1155/2016/6520148. Epub 2016 May 10. https://www.ncbi.nlm.nih.gov/pubmed/27247813


25) Brenu et al: Methylation profile of CD4+ T cells in CFS/ME. J. Clin Cell Immunol 5, 228https://www.omicsonline.org/open-access/methylation-profile-of-cd-t-cells-in-chronic-fatigue-syndromemyalgic-encephalomyelitis-2155-9899.1000228.php?aid=27598

mandag den 1. juli 2019

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 pathway
  • the Preiss–Handler pathway
  • the salvage pathway 


All of the enzymes in these three pathways are thoroughly described in reference 3. Some of these enzymes show up in ME research:

NAMPT = nicotinamide phosphoribosyltransferase. NAMPT is an enzyme in the salvage pathway.
NADSYN1 = NAD synthetase 1. NADSYN1 is an enzyme in the Preiss–Handler pathway.
QPRT = quinolinate phosphoribosyltransferase. QPRT is an enzyme the de novo pathway.
NADK = NAD kinase. NADK catalyzes the transfer of a phosphate group from ATP to NAD to generate NADP.

NAMPT gene expression was increased in whole blood from adolescent ME/CFS patients (adjusted p-value = 0,0621) (4).

NAMPT gene expression was increased in peripheral blood mononuclear cells (PBMC) from ME patients (5).


DNA methylations of genes in PBMC from ME patients:
  • NADSYN1 hypermethylated (gene probe cg 03146219) (6)
  • NADSYN1 hypomethylated (5'UTR) (7)
  • QPRT differentially methylated (1stExon) in ME patient subtypes (8)
  • NADK hypermethylated (gen probe cg00343906) (6)
  • NADK hypermethyltated (body) (9)
  • NADK differentially methylated (body) in ME patient subtypes (8)
  • NADK hypometylated (TSS1500) (7)


Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections

The tryptophan-kynurenine-nicotinamide adenine dinucleotide (oxidized; NAD+) pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in central nervous system (CNS) infections would improve our understanding of pathophysiology and end-organ damage, and, furthermore, open doors to its evaluation as a source of diagnostic and/or prognostic biomarkers (10).

The Trp-Kyn-NAD+ pathway is activated in CNS infections and provides highly accurate CSF biomarkers, particularly when combined with standard CSF indices of neuroinflammation (10).

The ME metabolic trap hypothesis predicts dysregulated Trp-Kyn- pathway in immune cells from ME patients (11).


Is the Trp-Kyn-NAD+ pathway dysregulated in the cerebrospinal fluid from ME patients?


References

1) National Institute of Health ME/CFS konference april 2019,
del 1: https://videocast.nih.gov/summary.asp?live=31636&bhcp=1
del 2: https://videocast.nih.gov/summary.asp?Live=31640&bhcp=1

2)  Health Rising,   NIH ME/CFS Conferencen, april 2019:
https://www.healthrising.org/blog/2019/04/10/nih-accelerating-chronic-fatigue-exhaustion-inflammation/

3) Xiao et al: NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism Antioxid Redox Signal. 2018 Jan 20;28(3):251-272. doi: 10.1089/ars.2017.7216. Epub 2017 Jul 28.
https://www.ncbi.nlm.nih.gov/pubmed/28648096

4) Nguyen et al: Whole blood gene expression in adolescent CFS: an exploratory crosssectional study suggesting altered B cell differentiation and survival. J Transl Med. 2017,15,102.  https://www.ncbi.nlm.nih.gov/pubmed/28494812

5) 12) Sweetman et al: Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Sweetman et al: Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.
https://www.ncbi.nlm.nih.gov/pubmed/30791746

6) 4) de Vega et al: DNA methylation Modifications associated with CFS. PlosOne, 2014, 9, 8. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104757

7) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns. Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

8) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

9) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230

10) Sühs et al: Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections J Infect Dis. 2019 Jun 5;220(1):127-138. doi: 10.1093/infdis/jiz048.
https://www.ncbi.nlm.nih.gov/pubmed/30721966

11) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phairhttps://www.youtube.com/watch?v=Quh-77gvw4Q


lørdag den 29. juni 2019

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):

  • kosten
  • metabolitter fra kynurenine stivejen
  • mikroorganismer på vores slimhinder
  • forurening


Anvend link til at se figur med AHR ligander (3): 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777317/figure/F2/

Se også tabel 1 over AHR ligander i artiklen (3).

AHR og IDO1/2 har et tæt samarbejde. AHR inducerer ekspression af IDO1/2, og kynurenine-metabolitterne dannes down-stream IDO1/2.

Den aktiverede AHR inducerer dannelsen af forskellige CYPs. CYPs nedbryder AHR liganderne, så AHR kan deaktiveres igen.

Anvend link til at se figur med AHR/CYP samarbejde (3):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777317/figure/F1/

IDO/KYN-metabolitterne/AHR - aksen er med til at holde immunforsvaret i balance. Det gælder i særdeleshed for  næsens slimhinder og tarmens slimhinder (3).

Indånding af skimmel er noget, der kan gøre en ME/MCS patient ganske syg. IDO er med til at inducere tolerance i næsens slimhinder, og mutationer i IDO-generne har betydning for kroppens reaktion på skimmel infektion (4, 5, 6).



Referencer

1) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phair
https://www.youtube.com/watch?v=Quh-77gvw4Q

ME hypotese: The Metabolic Trap - den metaboliske fælde
http://followmeindenmark.blogspot.com/2019/06/me-hypotese-metabolic-trap-den.html

2) de Luca et al: Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes. Toxicol Appl Pharmacol. 2010 Nov 1;248(3):285-92. doi: 10.1016/j.taap.2010.04.017. Epub 2010 Apr 27. https://www.ncbi.nlm.nih.gov/pubmed/20430047

3) Gutiérrez-Vázquez C Quintana FJ : Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity. 2018 Jan 16;48(1):19-33. doi: 10.1016/j.immuni.2017.12.012. https://www.ncbi.nlm.nih.gov/pubmed/29343438

4) van der Marel AP1, Samsom JN, Greuter M, van Berkel LA, O'Toole T, Kraal G, Mebius RE.
Blockade of IDO inhibits nasal tolerance induction. J Immunol. 2007 Jul 15;179(2):894-900.
https://www.ncbi.nlm.nih.gov/pubmed/17617580

5) Paveglio et al: Airway epithelial indoleamine 2,3-dioxygenase inhibits CD4+ T cells during Aspergillus fumigatus antigen exposure Am J Respir Cell Mol Biol. 2011 Jan;44(1):11-23. doi: 10.1165/rcmb.2009-0167OC. Epub 2010 Jan 29 https://www.ncbi.nlm.nih.gov/pubmed/20118221

6) Napolioni et al: Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans Front Immunol. 2019 May 7;10:890. doi: 10.3389/fimmu.2019.00890. eCollection 2019. https://www.ncbi.nlm.nih.gov/pubmed/31134053

mandag den 24. juni 2019

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 protein-coupled receptor Gpr35, which stimulates lipid metabolism, thermogenic, and anti-inflammatory gene expression in adipose tissue.  Kynurenic acid and Gpr35 enhance Pgc-1α1 expression and cellular respiration, and increase the levels of Rgs14 in adipocytes, which leads to enhanced beta-adrenergic receptor signaling (3).

Furthermore, KYNA has been reported to have anti-inflammatory properties and to modulate cytokine release from invariant natural killer T (iNKT) cells through Gpr35 activation (4).

ME patients show alterations in expression of iNKT phenotypes (5, 6).

The gene GPR35 is hypomethylated in peripheral blood mononuclear cells (PBMC) from ME patients (p-value = 6,44E-08, FDR = 0,0029) (7).

Gpr35 is an interesting receptor, it also interacts with the sodium potassium pump. The sodium potassium pump (Na/K-ATPase) ensures the electrochemical gradient of a cell through an energy-dependent process that consumes about one-third of regenerated ATP. Schneditz et al. report that Gpr35 interacts with the α chain of Na/K-ATPase and promotes its ion transport and Src signaling activity in a ligand-independent manner (8).

Is the kynurenic acid responsive Gpr35 involved in the ME pathomechanism?



References:


1) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phair 
https://www.youtube.com/watch?v=Quh-77gvw4Q

2) Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371 https://pubs.rsc.org/en/Content/ArticleLanding/2017/MB/C6MB00600K#!divAbstract

3) Agudelo et al: Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation. Cell Metab. 2018 Feb 6;27(2):378-392.e5. doi: 10.1016/j.cmet.2018.01.004.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30053-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413118300536%3Fshowall%3Dtrue

4) Fallarin et al: Expression of functional GPR35 in human iNKT cells. Biochem Biophys Res Commun. 2010 Jul 30;398(3):420-5. doi: 10.1016/j.bbrc.2010.06.091. Epub 2010 Jun 25.
https://www.ncbi.nlm.nih.gov/pubmed/20651116

5) Ramos er al: Regulatory T, natural killer T and γδ T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison. Asian Pac J Allergy Immunol. 2016 Dec;34(4):300-305. doi: 10.12932/AP0733. https://www.ncbi.nlm.nih.gov/pubmed/27001659

6) Hardcastle et al: J Transl Med. 2015 Sep 14;13:299. doi: 10.1186/s12967-015-0653-3.
Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. https://www.ncbi.nlm.nih.gov/pubmed/26370228
7) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

7) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

8) Schneditz et al. GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump. Sci Signal. 2019 Jan 1;12(562). pii: eaau9048. doi: 10.1126/scisignal.aau9048. https://www.ncbi.nlm.nih.gov/pubmed/30600262

tirsdag den 18. juni 2019

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 kynurenine stivejen påvirkes ved motion (2):

  • Enzymet AMPK er vigtig for regulering af glukose ligevægten og kroppens tilpasning til motion. AMPK styrer disse funktioner gennem proteinerne PGC-1alfa1, PPAR-alfa og PPAR-delta.
  • Ved motion danner musklerne  PGC-1alfa1. Proteinet inducerer dannelsen af mitokondrier og øger fedtsyrer oxidationen.
  • Sammen med proteinerne PPAR-alfa og PPAR-delta inducerer PGC-1alfa1 også dannelsen af enzymerne kynurenine aminotransferaser (KATs) i musklerne.
  • KATs omdanner kynurenine (KYN) til kynurenic acid (KYNA). Det betyder, at plasma niveauet af  KYN bliver lavere og plasma niveauet af KYNA bliver højere.
  • KYN er en neuro-toksisk metabolit. KYN kan krydse blod-hjerne-barrieren (BBB). Det kan KYNA ikke. Dvs. motion sænker plasma niveauet af KYN, så mindre KYN kan krydse BBB.
  • Man mener, at motion afhjælper depression, fordi der sker en øget omsætning af KYN til KYNA.
Figur 7 fra reference 2 viser ovenstående forløb

En let forståelig oversigtsartikel, Muscle over Mind, beskriver ligeledes ovenstående studie. Og viser denne figur over forsøget med mus:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016023/figure/F1/

Det kunne være interessant at få målt niveauet af kynurenine metabolitter i muskelceller, i plasma og i cerebrospinalvæske fra ME patienter før, under og efter motion.

Referencer

1) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phair
https://www.youtube.com/watch?v=Quh-77gvw4Q

2) Agudelo et al: Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell. 2014 Sep 25;159(1):33-45. doi: 10.1016/j.cell.2014.07.051.  https://www.ncbi.nlm.nih.gov/pubmed/25259918

mandag den 17. juni 2019

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 with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases (3).

Antibodies to thyreoperoxidase, to beta-adrenergic and muscarinic cholinergic receptors have been found in some ME patients (4).

Rheumatic heart disease is mediated by autoimmune reactions. Rheumatic fever and rheumatic heart disease lesions result from a complex network of several genes that control both the innate and adaptive immune responses after a S. pyogenes throat infection. An inflammatory process permeates the development of heart lesions with high production of inflammatory cytokines (IFNγ, TNFα, IL-17 and IL-23) and low numbers of cells producing IL-4, a regulatory cytokine of inflammation. Autoreactive CD4+ T cells infiltrate the heart tissue and trigger autoimmune reactions through molecular mimicry. A mutation in CTLA4 that affect the inhibitory function is found in some patients with rheumatic heart disease (5).

Autoimmunoreactive IgGs against cardic membrane proteins have been found in patients with POTS (6).

I wonder if some ME/POTS patients may have mutations in both IDO2 and CTLA4?

SOCS3 drives degradation of IDO

SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis (7, 8).

Use link to figure (7): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634889/figure/F7/

The transcription of SOCS3 has been found up-regulated in immune cells from ME patients (9).


References:


1) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phair
https://www.youtube.com/watch?v=Quh-77gvw4Q

2) Bourque JHawiger D: Immunomodulatory Bonds of the Partnership between Dendritic Cells and T Cells.  Crit Rev Immunol. 2018;38(5):379-401. doi: 10.1615/CritRevImmunol.2018026790.

3)  CTLA4 cytotoxic T-lymphocyte associated protein 4  https://www.ncbi.nlm.nih.gov/gene/1493

4) Loebel et al: Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. 2016 Feb;52:32-39. doi: 10.1016/j.bbi.2015.09.013. Epub 2015 Sep 21. https://www.ncbi.nlm.nih.gov/pubmed/26399744

5) Guilherme et al: Rheumatic Heart Disease: Genes, Inflammation and Autoimmunity. Rheumatol Curr Res 2012, S4 DOI: 10.4172/2161-1149.S4-001
https://www.longdom.org/abstract/rheumatic-heart-disease-genes-inflammation-and-autoimmunity-6499.html

6) Wang et al: Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome. Transl Res. 2013 Jul;162(1):34-44. doi: 10.1016/j.trsl.2013.03.002. Epub 2013 Apr 3. https://www.ncbi.nlm.nih.gov/pubmed/23562385

7) Orabona et al. SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20828-33. doi: 10.1073/pnas.0810278105. Epub 2008 Dec 16. https://www.ncbi.nlm.nih.gov/pubmed/19088199

8) Palotta et al: Proteasomal Degradation of Indoleamine 2,3-Dioxygenase in CD8 Dendritic Cells is Mediated by Suppressor of Cytokine Signaling 3 (SOCS3). Int J Tryptophan Res. 2010;3:91-7. Epub 2010 Jun 10. https://www.ncbi.nlm.nih.gov/pubmed/22084591

9) Sweetman et al: Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Sweetman et al: Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.https://www.ncbi.nlm.nih.gov/pubmed/30791746

fredag den 14. juni 2019

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-methyl tryptophan (1-MT) enhances vascular inflammation with upregulation of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1/CCL2), and increasing CD68+ macrophage infiltration in vascular area. Moreover, IDO inhibition-induced acceleration of atherosclerosis and vascular inflammation can be reversed by exogenous administration of the Trp catabolite 3-hydroxyanthranilic acid (3-HAA ) (3).


References:


1) Mewton et al: Large and small artery endothelial dysfunction in chronic fatigue syndrome International Journal of Cardiology, 2012 Feb 9; 154(3):335–6
ME Research UK has described the study here: Large and small artery endothelial dysfunction in chronic fatigue syndrome

2) Metabolic Traps in ME/CFS - Research Update by Dr. Robert Phair https://www.youtube.com/watch?v=Quh-77gvw4Q

3) Song et al: Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases Cell Mol Life Sci. 2017 Aug;74(16):2899-2916. doi: 10.1007/s00018-017-2504-2. Epub 2017 Mar 17.  https://www.ncbi.nlm.nih.gov/pubmed/28314892