Urine Metabolomics Exposes Anomalous Recovery Tom Qab Kev Tawm Tsam Tshaj Plaws hauv Poj Niam ME/CFS Cov Neeg Mob Part 2

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2.4. Txoj Kev Ntsuas Topology Highlights Hloov Carbohydrates thiab Amino Acid Metabolism raws li qhov tshwm sim ntawm kev tawm dag zog

Qhov sib txawv ntawm ME/CFS thiab kev tswj cov ntsiab lus ntawm qib metabolic txoj kev tau raug soj ntsuam siv txoj hauv kev tsom xam module hauv Metaboanalyst 5.0 webtool (www. metaboanalyst.ca, nkag mus rau 14 Lub Kaum Ob Hlis 2{{10 }}}22), uas sib txuas ua ke kom muaj nuj nqis ntxiv kev txheeb xyuas thiab kev txheeb xyuas txoj hauv kev topology. Nyob rau hauv tag nrho, 453 tawm ntawm 734 paub cov tebchaw ntawm 1154 lub tebchaw soj ntsuam tau suav nrog hauv qhov kev tshuaj ntsuam no, vim muaj kev txwv hauv Human Metabolome Database (HMDB) ID txuam. Qhov kev tshuaj xyuas no tau ua ob zaug rau txhua qhov kev sib piv, nrog Kyoto Encyclopedia of Genes thiab Genomes (KEGG) thiab tom qab ntawd cov ntaub ntawv me me ntawm txoj hauv kev database (SMPDB) tib neeg siv metabolomes los txhais txoj hauv kev. Kev txheeb xyuas ntau ntxiv siv qhov kev sim thoob ntiaj teb los sib piv ob pawg, uas siv cov txheej txheem logistic regression los ntsuas seb cov metabolites hauv txoj hauv kev pab txhim kho kev faib tawm ntawm cov qauv li ME / CFS lossis kev tswj hwm, nrog rau qhov kev xav tsis zoo uas tsis muaj metabolite. nyob rau hauv txoj kev muaj ib tug sib txawv concentration nyob rau hauv ob pawg [31,32]. Cov p-values ​​los ntawm qhov kev xeem no yog hloov kho rau ntau qhov kev sib piv uas siv cov txheej txheem BH, nrog q < 0.2 raws li qhov tseem ceeb. Qhov chaw pib no tau raug xaiv los tso cai rau kev tshuaj xyuas cov kev tshawb pom muaj txiaj ntsig zoo los txiav txim siab tus qauv me me thaum ua kom ntseeg tau tias txhua txoj hauv kev tseem ceeb tseem muaj p < 0.05. Qhov kev txheeb xyuas no txawv ntawm ChemRICH kev txheeb xyuas qhov zoo tshaj plaws hauv qhov uas nws tso cai sib tshooj, yog li ob peb txoj hauv kev yuav muaj tib lub ntsiab lus tseem ceeb. Thaum ntsuas cov ntsiab lus tseem ceeb, peb kuj qhia txog lawv qhov tseem ceeb raws li ib tus neeg sib txuas hauv LMM, uas peb tau ua haujlwm nruj dua (q <0.1). Cov txiaj ntsig ntawm kev tsom xam topology yog qhov cuam tshuam ntawm 0 txog 1. Qhov qhab nia no yog muab los ntawm cov txiaj ntsig ntawm metabolite ntawm qhov tseem ceeb suav nrog kev ntsuas kev txheeb ze nruab nrab ntawm qhov nruab nrab, uas yog tom qab ntawd normalized kom qhov siab tshaj plaws ntawm txhua txoj hauv kev yog 1. Qhov cuam tshuam. Cov qhab nia yog cov lej ntawm qhov tseem ceeb ntsuas rau txhua qhov sib txuam metabolite node hauv txoj hauv kev.

Cistanche tuaj yeem ua raws li kev tiv thaiv kev qaug zog thiab lub zog ua kom muaj zog, thiab cov kev tshawb fawb sim tau pom tias decoction ntawm Cistanche tubulosa tuaj yeem tiv thaiv daim siab hepatocytes thiab endothelial hlwb puas hauv cov nas ua luam dej hnyav, txhawb kev qhia ntawm NOS3, thiab txhawb cov kab mob siab glycogen. synthesis, yog li exerting los tiv thaiv qaug zog. Phenylethanoid glycoside-nplua nuj Cistanche tubulosa extract tuaj yeem txo cov ntshav creatine kinase, lactate dehydrogenase, thiab lactate qib, thiab nce qib hemoglobin (HB) thiab piam thaj hauv ICR nas, thiab qhov no tuaj yeem ua lub luag haujlwm tiv thaiv kev qaug zog los ntawm kev txo qis cov leeg nqaij. thiab ncua lub lactic acid enrichment rau lub zog cia hauv nas. Compound Cistanche Tubulosa ntsiav tshuaj ua rau lub sijhawm ua luam dej hnyav, nce siab glycogen cia, thiab txo qis qib urea tom qab kev tawm dag zog hauv cov nas, qhia nws cov nyhuv tiv thaiv kev qaug zog. Lub decoction ntawm Cistanchis tuaj yeem txhim kho kev ua siab ntev thiab ua kom lub cev qaug zog hauv kev tawm dag zog nas, thiab tuaj yeem txo qhov siab ntawm cov ntshav creatine kinase tom qab kev tawm dag zog thiab ua kom lub cev nqaij daim tawv nqaij ntawm cov nas ib txwm muaj tom qab kev tawm dag zog, uas qhia tau hais tias nws muaj cov teebmeem. ntawm kev txhim kho lub cev muaj zog thiab tiv thaiv qaug zog. Cistanchis kuj tseem ua rau lub sijhawm muaj sia nyob ntawm cov nas uas muaj nitrite-poisoned thiab txhim kho lub siab ntev tiv thaiv hypoxia thiab qaug zog.

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Ib zaug ntxiv, tsis muaj qhov sib txawv tseem ceeb ntawm cov zis metabolites ntawm lub hauv paus hauv ME / CFS thiab pawg tswj hwm. Txawm li cas los xij, muab piv rau ME / CFS cov neeg mob thiab kev tswj hwm ntawm lub sijhawm ua haujlwm tom qab lub sijhawm thiab kev hloov pauv raws sijhawm siv qhov kev hloov pauv hauv cov ntsiab lus tom qab kev tawm dag zog / lub hauv paus hloov pauv, ob qho tib si muaj ntau txoj hauv kev hloov pauv metabolic (Daim duab 4).

Thaum 24 teev tom qab kev tawm dag zog, xya txoj hauv kev hauv SMPDB thiab ib txoj hauv kev hauv KEGG tau hloov pauv ntau hauv cov neeg mob ME/CFS vs. tswj (Daim duab 4A, q < 0.2). Tsib ntawm yim txoj kev hloov pauv tseem ceeb tau koom nrog hauv cov piam thaj metabolism, uas cuam tshuam nrog kev tsim hluav taws xob. Fructose yog qhov tseem ceeb hauv txhua txoj hauv kev cuam tshuam nrog cov piam thaj hauv cov metabolism, nrog p < 0 01 hauv LMM thaum muab piv rau ME / CFS cov neeg mob thiab tswj kev tawm dag zog tom qab; Txawm li cas los xij, fructose tsis yog qhov tseem ceeb hauv kev tshuaj ntsuam univariate tom qab ntau qhov kev sib piv kho. Txoj hauv kev nrog cov qhab nias siab tshaj plaws yog catecholamine biosynthesis ua raws li tyrosine metabolism. Ob txoj hauv kev muaj dehydroascorbate (p < 0.01) raws li cov ntsiab lus tseem ceeb, tab sis dua, qhov sib xyaw no tsis tseem ceeb hauv LMM tom qab FDR kho. Rau tyrosine metabolism, ascorbate (vitamin C) (p <0.01) yog ib qho tseem ceeb ntxiv tab sis kuj tsis tseem ceeb tom qab FDR kho.

Kaum txoj hauv kev, tag nrho hauv KEGG database, muaj qhov sib txawv ntawm qhov kev tawm dag zog tom qab kev tawm dag zog / lub hauv paus sib piv hauv ME / CFS cov neeg mob thiab kev tswj hwm, qhia tias lawv hloov pauv txawv raws sijhawm (Daim duab 4B, q < 0.2). Plaub txoj hauv kev uas muaj kev cuam tshuam ntau tshaj yog tag nrho cov koom nrog hauv cov amino acid metabolism: arginine thiab proline metabolism, cysteine ​​thiab methionine metabolism, lysine degradation, thiab aminoacyl-tRNA biosynthesis. Tag nrho cov proteinogenic amino acids koom nrog hauv txoj hauv kev aminoacyl-tRNA biosynthesis, yog li nws ua rau kev nkag siab tias txoj hauv kev muaj kev cuam tshuam loj heev vim ntau yam ntawm cov amino acids no txawv heev hauv qhov kev sib piv no (saib Daim Duab Ntxiv S2). Rau KEGG arginine thiab proline metabolism txoj hauv kev, proline yog tib qho kev sib xyaw uas tseem ceeb hauv LMM (q < 0.1) thiab tseem muaj ib qho ntawm cov qhab nia tseem ceeb tshaj plaws.

Cysteine ​​hloov pauv txawv tom qab kev tawm dag zog hauv ME / CFS cov neeg mob vs. kev tswj hauv LMM qauv (q < {{0}}.1) thiab yog qhov tseem ceeb hauv KEGG txoj hauv kev cysteine ​​thiab methionine metabolism thiab pantothenate thiab Coenzyme. A (CoA) biosynthesis. CoA yog ib qho tseem ceeb ntawm cofactor uas yuav tsum tau rau fatty acid metabolism thiab lub voj voog tricarboxylic acid (TCA). Nws biosynthesis xav tau cysteine, uas yog ib qho tshwj xeeb amino acid vim nws tsuas yog ib qho uas muaj thiol pawg. Valine tseem koom nrog hauv kev hloov pauv pantothenate thiab Coenzyme A (CoA) biosynthesis txoj hauv kev thiab muaj q <0.1 hauv LMM.

Txoj hauv kev tseem ceeb tshaj plaws rau qhov kev sib piv no yog ether lipid metabolism, tab sis nws muaj qhov cuam tshuam tsawg. Txawm hais tias tsuas yog ob lub metabolites uas peb tshawb pom tau sib phim rau txoj hauv kev no, lawv ob qho tib si tseem ceeb hauv LMM nrog q < {{{0}}}.1: glycerophosphoethanolamine thiab glycerophosphorylcholine (GPC) (ob qho tib si categorized li phospholipid metabolism los ntawm Metabolon®. , saib Daim Duab Ntxiv S2). Purine metabolism kuj tseem ceeb heev, nrog adenosine 30, 50 -cyclic monophosphate (cAMP) ua cov ntsiab lus tseem ceeb (q <0.1 hauv LMM).

2.5. Acyl Glycines muaj qis qis hauv cov zis ntawm cov neeg mob ME / CFS piv rau Kev Tswj 24 teev tom qab kev tawm dag zog

Plaub qhov metabolites pom nyob rau ntawm qhov qis qis hauv ME / CFS vs. tswj cov ntsiab lus ntawm lub sijhawm tom qab qoj ib ce hauv kev ntsuas LMM univariate (q < 0.1) yog 3- hydroxyoctanoylglycine, hexanoylglycine (C6. ), 2-octenoylglycine, thiab tsis paub X–24334. Peb lub tebchaw paub yog tag nrho hauv Metabolon® subpathway ntawm acyl glycine fatty acid metabolism. Daim duab tshav kub hauv daim duab 5A qhia txog osmolality-normalized concentration tom qab qoj ib ce rau cov metabolites rau txhua qhov kev kawm. Siv agglomerative hierarchical clustering, cov ntsiab lus tau muab faib ua peb pawg: (1) rau 6 yam kev tswj hwm, (2) ob yam kev tswj hwm thiab ib qho ME / CFS cov ntsiab lus, thiab (3) seem cuaj ME / CFS cov ntsiab lus. Cov pawg tswj hwm feem ntau pom muaj ntau dua rau tag nrho plaub cov metabolites thaum pawg ntawm ME / CFS cov ntsiab lus qhia qis dua rau tag nrho plaub cov metabolites. Cov pawg me me nrog cov ncauj lus los ntawm ob pab pawg qhia cov txiaj ntsig nruab nrab. Cov thawv ntawv hauv daim duab 5B qhia qhov tsawg kawg nkaus ntawm kev sib tshooj ntawm ME / CFS thiab tswj pawg rau cov metabolites. Tawm ntawm plaub lub metabolites, tsuas yog X-24334 kuj tseem hloov pauv txawv txav ntawm lub sijhawm ntawm kev tswj hwm thiab ME / CFS cov neeg mob hauv LMM thiab nce ntxiv tom qab kev tawm dag zog hauv pawg tswj hwm.

2.6. Cov metabolites uas hloov pauv txawv thaum kev tawm dag zog rov qab hauv ME / CFS Cov Neeg Mob vs. Kev Tswj Xyuas Feem ntau yog Amino Acids thiab Lipids

Txoj hauv kev zoo tshaj plaws nrog cov tshuaj hloov pauv ntau tshaj plaws yog amino acid thiab lipid thaum xav txog 110 cov khoom sib txuas uas muaj kev cuam tshuam tseem ceeb (q <0.1) ntawm cov kab mob (ME / CFS vs. tswj) thiab lub sijhawm (piv txwv li vs. post-exercise) (Cov duab ntxiv S2). Daim duab 6 qhia cov ntaub ntawv rau txhua qhov kev kawm hauv ob pawg ntawm ob qho tib si hauv paus thiab tom qab kev tawm dag zog rau cov kev hloov pauv loj hauv ntau cov amino acid subpathways (Daim duab 6A-D). Daim duab 7 qhia cov ntaub ntawv rau txhua yam kev kawm ntawm ob qho tib si hauv paus thiab kev tawm dag zog tom qab rau cov kev hloov pauv loj hauv cov lipid subpathways xaiv (Daim duab 7A, B). Rau daim duab no, peb ua ke peb txoj hauv kev koom nrog hauv acylcarnitine fatty acid metabolism (dicarboxylate, hydroxy, thiab cov saw nruab nrab) thiab plaub steroid subpathways (androgenic, cortico-, pregnenolone, thiab progestin). Txhua qhov sib xyaw ua ke qhia hauv daim duab 6 thiab 7 kuj tseem nce ntxiv hauv cov zis tom qab qoj ib ce vs. lub hauv paus hauv kev tswj hwm sedentary.

Plaub lub tebchaw hauv lub voj voog urea; arginine thiab proline metabolism subpathway hloov pauv txawv tom qab kev tawm dag zog hauv ME / CFS cov neeg mob thiab kev tswj hwm: carboxy-methylarginine, proline, symmetric dimethylarginine (SDMA), thiab dimethylarginine (ADMA) (Daim duab 6A). Proline yog lub tsev thaiv ntawm collagen thiab yog li ntawd yog ib qho tseem ceeb ntawm cov ntaub so ntswg sib txuas. SDMA thiab ADMA yog ob qho tib si regulators thiab kev sib tw inhibitors ntawm nitric oxide (NO) ntau lawm. Tsis muaj kev pabcuam hauv kev kho cov hlab ntsha hauv cov tib neeg noj qab haus huv [33], thiab txo qis NO ntau lawm cuam tshuam nrog endothelial tsis ua haujlwm thiab kab mob plawv [34]. ADMA tuaj yeem raug tshem tawm los ntawm kev tso zis los yog nws tuaj yeem degraded hauv daim siab [35]. Qhov nce excretion ntawm SDMA thiab ADMA hauv kev tswj tab sis tsis nyob rau hauv cov neeg mob tom qab kev tawm dag zog txhais tau hais tias kev tswj hwm yuav tshem tawm ntau tshaj NO synthase inhibitors kom tswj hwm vascular homeostasis thiab tias qhov kev hloov pauv zoo rau kev tawm dag zog yuav tsis tshwm sim hauv cov neeg mob. Kev sib raug zoo ntawm TSIS MUAJ thiab ME / CFS tsis meej; plasma los ntawm ME / CFS cov ntsiab lus ntawm lub hauv paus tau pom tias yuav ua rau tsis muaj kev tsim tawm los ntawm cov hlwb endothelial hauv vitro [36], tab sis nws tsis paub tias yog vim muaj qib siab dua ntawm ADMA lossis SDMA hauv ME / CFS plasma, raws li lawv tau ua. tsis ntsuas nyob rau hauv txoj kev tshawb no thiab tsis muaj kev cai yog complex.

Peb lub tebchaw hauv methionine, cysteine, S-adenosylmethionine (SAM), thiab taurine subpathway tau hloov pauv ntau: methionine sulfone, cysteine, thiab s-methylcysteine ​​sulfoxide (Daim duab 6B). Cysteine ​​​​yog ib qho tshwj xeeb amino acid nyob rau hauv uas nws muaj ib pawg thiol thiab tuaj yeem koom nrog cov tshuaj tiv thaiv redox [37]. Cysteine ​​tuaj yeem hloov mus rau hauv pyruvate, qhov pib ntawm TCA lub voj voog.

Polyamine metabolism subpathway muaj tsib yam metabolites sib txawv: asicoga, (N(1) + N(8))-acetylspermidine, diacetylspermidine, N1, N12-diacetylspermine, thiab N-acetyl-isoputreanine (Daim duab 6C). Polyamines muaj ntau yam kev ua haujlwm lom neeg thiab koom nrog hauv cellular proliferation, sib txawv, thiab apoptosis [38]. Kev nce hauv polyamines yog ib feem ntawm cov lus teb ib txwm rau cov kev ntxhov siab, suav nrog kev tawm dag zog [39].

Lub leucine, isoleucine, thiab valine metabolism subpathway kuj muaj tsib yam hloov pauv metabolites: 3-methylglutarylcarnitine, tiglyl carnitine, valine, beta-hydroxyisovalerate, thiab beta-hydroxyisovaleroylcarnitine (Daim duab 6D). Leucine, isoleucine, thiab valine yog ceg saw amino acids (BCAAs). Cov amino acids tseem ceeb no txhawb cov protein anabolism hauv tib neeg cov leeg uas pab tsim cov leeg nqaij tom qab qoj ib ce [40]. Lub catabolism ntawm peb BCAAs ua rau lub zog metabolism txoj hauv kev thiab valine yog glucogenic, txhais tau tias nws hloov mus rau hauv qabzib precursors uas tuaj yeem nkag mus rau TCA lub voj voog. Thaum feem ntau cov amino acids yog catabolized nyob rau hauv daim siab, BCAAs feem ntau catabolized nyob rau hauv lwm cov ntaub so ntswg nrog rau lub cev nqaij daim tawv, hlwb, lub raum, thiab cov ntaub so ntswg adipose [41]. Isoleucine yog ob qho tib si glucogenic thiab ketogenic, thiab leucine yog ketogenic. Cov metabolites sib txawv no yog tsim thaum lub sij hawm catabolism ntawm tag nrho peb BCAAs. 3-methylglutarylcarnitine, nrog rau 3-hydroxyhexanoylcarnitine (uas yog categorized li acylcarnitine los ntawm Metabolon®, saib daim duab 7A), yog tsim tawm li leucine hloov mus rau acetyl-CoA thiab acetoacetate. Thaum lub sij hawm isoleucine degradation rau acetyl-CoA los yog propionyl-CoA, tiglylcarnitine yog tsim nyob rau hauv ob kauj ruam sib txawv. Beta-hydroxy isovalerate yog tsim los ntawm peb theem sib txawv ntawm txoj kev valine degradation.

Tsib ntawm cov kev hloov pauv loj ntawm ME / CFS cov neeg mob thiab kev tswj hwm tau koom nrog hauv acyl carnitine fatty acid metabolism: pimeloylcarnitine/3-methyladipoylcarnitine, 3- hydroxyhexanoylcarnitine, hexanoylcarnitine, suberoylcarnitine, thiab {{2}carnitine Daim duab 7A). Acyl carnitines ua lub luag haujlwm tseem ceeb hauv cov saw ntev fatty acid -oxidation, uas yog thawj hom ntawm lub zog metabolism thaum lub sij hawm aerobic ce [42].

Tsib ntawm cov kev hloov pauv tseem ceeb tau muab cais ua steroids (Daim duab 7B). 11- ketoetiocholanolone glucuronide yog ib qho androgenic steroid. 3alpha, 21-dihydroxy-5betapregnane-11, 20-dione 21-glucuronide thiab cortolone glucuronide yog corticosteroids. 17alphahydroxypregnanolone glucuronide yog pregnenolone steroid. pregnanediol-3-glucuronide yog progestin steroid. Glucuronides yog tsim nyob rau hauv daim siab pab nyob rau hauv excretion ntawm cov tshuaj los ntawm ua rau lawv ntau dej-soluble. Corticosteroids ua haujlwm raws li kev taw qhia cov molecules hauv ntau yam txheej txheem, suav nrog kev txhawb nqa cov protein catabolism thaum lub sijhawm ua haujlwm lossis lwm yam kev ntxhov siab [43], kho cov lus teb rau qhov mob [43], thiab tswj kev noj qab haus huv ntsev thiab kua dej ntau ntau [44]. Kev hloov pauv corticosteroid metabolism tuaj yeem ua rau muaj kev tsis haum rau orthostatic, lwm tus tsos mob ME / CFS. Progestin steroids, androgenic steroids, thiab corticosteroids kuj tseem pom muaj qis dua hauv cov poj niam ME / CFS cov neeg mob ntshav plasma piv rau lwm txoj kev tshawb fawb, txawm hais tias txoj kev tshawb fawb no tau tshawb xyuas cov theem pib nkaus xwb [11].

2.7. Tib yam metabolites nyob rau hauv cov zis thiab ntshav plasma muaj kev sib raug zoo heev

Peb pab pawg yav dhau los luam tawm cov ntaub ntawv plasma metabolomics los ntawm tib yam kev kawm [25]. Cov kev kawm no tau ua tiav ob hnub CPET raws tu qauv thiab nrog rau kev sau cov zis, ntshav tau los ntawm txhua qhov kev kawm ntawm plaub lub ntsiab lus: hauv paus (P1), 15–3{{40}} min tom qab CPET (P2), 24 teev tom qab CPET (P3), thiab 15–30 min tom qab CPET thib ob (P4) uas tau ua 24 teev tom qab thawj CPET (Daim duab 1A hauv [25]). Tawm ntawm 1403 urine metabolites thiab 1157 plasma metabolites kuaj pom los ntawm Metabolon®'s platforms, 727 cov tshuaj tau ntsuas hauv cov zis thiab ntshav. Kev sib raug zoo ntawm cov zis thiab ntshav plasma metabolomes nrog rau lub zog ntawm kev tawm dag zog ntawm qhov kev sib raug zoo no tau soj ntsuam los ntawm kev suav cov Pearson correlation coefficients®) ntawm cov zis thiab ntshav cov ntaub ntawv rau txhua qhov metabolite ntawm txhua lub sijhawm taw tes thiab lub sijhawm taw tes piv ua ke (Cov ntaub ntawv ntxiv S3). Rau lub sijhawm cov ntsiab lus, peb tau xaiv tsom mus rau kev sib xyaw ntawm cov zis thiab ntshav los ntawm tib hnub (cov zis hauv paus (U1) nrog P1 thiab P2, thiab cov zis tom qab qoj ib ce (U3) nrog P3 thiab P4). Peb kuj tau tshuaj xyuas kev sib raug zoo ntawm qhov kev sib tw tom qab kev tawm dag zog / lub hauv paus piv txwv hauv cov zis (U3 / U1) thiab peb qhov sib txawv tom qab kev tawm dag zog hauv cov ntshav (P4 / P1, P3 / P2, P3 / P1) los tshawb xyuas seb cov qib metabolite hloov pauv li cas thaum lub sijhawm ua haujlwm. 24 teev rov qab nyob rau hauv cov zis vs. plasma. Cov p-values ​​raug xam rau txhua qhov kev sib raug zoo siv t-test nrog rau qhov kev xav tsis zoo ntawm R=0 (BH FDR kho, q < 0.15). Tus naj npawb ntawm kev sib raug zoo, uas peb txhais tau tias R> 0.7 lossis R < −0.7, yog kwv yees li 40% ntawm 727 metabolites thaum saib lub sijhawm sib txheeb (Daim duab 8). Tshwj xeeb tshaj yog, rau txhua lub sij hawm taw tes ua khub, muaj tsawg heev tsis zoo correlations ntawm cov zis thiab ntshav plasma. Rau qhov sib piv kev sib raug zoo, tus naj npawb ntawm cov kev sib raug zoo tsis zoo yog nce hauv kev tswj kev noj qab haus huv. Rau txhua qhov kev sib raug zoo, tus naj npawb ntawm cov kev sib raug zoo muaj zog yog siab dua hauv cov neeg mob ME / CFS dua li hauv kev tswj hwm.

2.8. Kev soj ntsuam cov tshuaj nrog kev sib txheeb ntawm cov zis thiab ntshav uas txawv hauv ME / CFS Cov Neeg Mob thiab Tswj

Peb tau mus soj ntsuam cov tebchaw nrog qhov sib txawv tseem ceeb tshaj plaws ntawm kev tswj hwm thiab cov neeg mob, siv cov txheej txheem nruj hauv qab no: (1) |R| > 0.7, p < 0.05, thiab q < 0.15 hauv ME/CFS cov neeg mob lossis kev tswj hwm; (2) R < 0.3 nrog tib lub cim lossis R-tus nqi nrog rau qhov sib txawv (piv txwv li, tsis zoo yog tias qhov kev sib raug zoo tseem ceeb) hauv lwm pawg (tswj lossis cov neeg mob); (3) cov tebchaw uas muaj qhov tsis txaus ntseeg feem ntau cuam tshuam rau txoj kev sib raug zoo raug tshem tawm (hloov z-cov qhab nia ntawm kev tshawb pom qhov tsis txaus ntseeg, nrog rau qhov pib ntawm z> 6). Thaum lub outlier tsuas pom nyob rau hauv lub sij hawm taw tes cov ntaub ntawv, lub compound raug tshem tawm rau tag nrho cov tab sis tsuas yog lub sij hawm taw tes sib piv. Thaum cov outlier pom nyob rau hauv qhov piv cov ntaub ntawv, cov compound no raug tshem tawm rau tag nrho tiam sis tsuas yog tus piv piv. Cov ntsiab lus ntawm cov tebchaw uas ua tau raws li cov txheej txheem saum toj no tau tshwm sim raws li daim duab tshav kub ntawm R qhov tseem ceeb hauv daim duab 9.

Lub heatmap muaj cov metabolites hla 35 subpathways nrog ib tug overrepresentation ntawm subpathways nyob rau hauv lub amino acid superpathway, 11 tawm ntawm 15. Nyob rau hauv lub amino acid subpathways, tryptophan metabolism raws li zoo raws li leucine, isoleucine, thiab valine metabolism, muaj cov feem cuam tshuam cov tebchaw, nrog rau 9. /21 (43%) thiab 8/27 (30%), ntsig txog

Kynurenate yog ib feem ntawm txoj kev tryptophan thiab yog ib qho ntawm cov metabolites nrog qhov sib txawv loj tshaj plaws hauv kev sib raug zoo coefficients ntawm ME / CFS thiab cov tswj cohorts (Daim duab 9, P4 / P1 nrog U3 / U1). Cov kynurenate correlation graphs rau tag nrho cov kev sib piv los ntawm lub tshav kub ntawm daim duab 9 yog qhia nyob rau hauv daim duab 10A. Peb tuaj yeem pom qhov sib cuam tshuam ntawm qhov "P4/P1 nrog U3/U1" daim duab uas R=0.74 (ME/CFS) thiab R=−0.77 (tswj). Qhov kev sib raug zoo zoo nyob rau hauv cov neeg mob ME / CFS zoo ib yam thoob plaws qhov kev sib raug zoo, qhov kev sib raug zoo tsis zoo hauv kev tswj tsis zoo ib yam. Lub sij hawm taw tes kev sib raug zoo qhia tus qauv zoo sib xws, nrog rau kev sib raug zoo rau pawg ME / CFS. Thaum kynurenate tsuas yog tryptophan compound nrog kev sib raug zoo nyob rau hauv ob qho tib si lub sij hawm taw tes thiab qhov piv ntawm sab ntawm lub heatmap, qhov sib txawv pom nyob rau hauv plasma thiab tso zis correlations nyob rau hauv lwm yim lub tebchaw, uas tshwm sim nyob rau hauv ntau qhov chaw nyob rau hauv lub tryptophan txoj kev, ua pov thawj rau ib tug tob. dysregulation ntawm txoj kev no hauv ME / CFS cov neeg mob piv rau kev tswj hwm. Tsis tas li ntawd, lwm qhov sib xyaw ua ke ntawm daim duab tshav kub, quinolinate, yog cov metabolite uas txuas cov tryptophan metabolism rau nicotinate thiab nicotinamide metabolism, uas yog txoj hauv kev tseem ceeb rau kev tsim NAD + thiab NADP +. Ib qho dysregulation nyob rau hauv txoj kev kynurenate tau pom tias yog qhov tshwm sim ntawm ME / CFS pathophysiology vim nws lub luag haujlwm tseem ceeb hauv kev tsim hluav taws xob ntawm tes thiab kev koom tes hauv kev kho lub cev tiv thaiv kab mob raws li kev tshuaj xyuas los ntawm Kavyani li al. [45].

Yim lub tebchaw hauv leucine, isoleucine, thiab valine subpathway muaj qhov sib txawv ntawm kev sib raug zoo ntawm ME / CFS cov neeg mob thiab kev tswj hwm rau lub sijhawm xaiv thiab qhov sib piv piv (Daim duab 9). Rau tsib ntawm cov tebchaw no, qhov sib txawv yog nyob rau hauv kev sib piv tom qab, nrog plaub ntawm tsib lub tebchaw muaj qhov sib txawv thaum sib txheeb U3 / U1 (24 h tom qab qoj ib ce / lub hauv paus tso zis) nrog P3 / P2 (lub 24 h tom qab qoj ib ce. / 15 min postexercise plasma). Beta-hydroxy isovalerate yog ib qho zoo sib xws, nrog kev sib raug zoo thiab muaj txiaj ntsig zoo hauv ME / CFS cov neeg mob ntawm U3 / U1 thiab P3 / P2 thiab tsis muaj zog, tsis muaj qhov cuam tshuam tsis zoo hauv kev tswj hwm (Daim duab 10B). Beta-hydroxy isovalerate kuj hloov pauv ntau lub sijhawm hauv cov zis ntawm ME / CFS cov neeg mob piv rau cov tswj hauv LMM (Daim duab 6D). Cov yim lub tebchaw no hla tag nrho peb ceg ntawm BCAA catabolism txoj hauv kev. Isovalerylglycine thiab isovalerylcarntine yog tsim thaum lub sij hawm leucine catabolism (ketogenic). 2-methylbutrylcarnitine thiab 3-methyl-2-isovalerate yog tsim thaum lub sij hawm isoleucine catabolism (ketogenic thiab glucogenic). Betahydroxyisovalerate, raws li tau hais los saum no, yog downstream ntawm valine catabolism (glucogenic). Qhov no yog pov thawj ntxiv tias muaj kev ua haujlwm tsis zoo ntawm metabolic rov qab los ntawm kev tawm dag zog hauv ME / CFS cov neeg mob cuam tshuam nrog BCAA catabolism, uas cuam tshuam rau tag nrho peb BCAAs. Peb BCAAs muaj ib qho enzyme uas koom nrog hauv thawj kauj ruam ntawm txoj kev, BCAA aminotransferase. Txawm li cas los xij, txiav txim siab tias muaj kev tsis sib haum xeeb hauv ntau cov amino acid subpathways, nws zoo li qhov no yog pov thawj ntawm cov teeb meem metabolic thoob ntiaj teb.

Nyob rau hauv lipid superpathway, plaub subpathways txog steroids kuj ntes tau peb mloog. Tseeb, yim steroid tebchaw los ntawm plaub txoj kev subways muaj qhov sib txawv ntawm cov ntshav thiab cov zis hauv ME / CFS cov neeg mob thiab kev tswj hwm, suav nrog androgenic steroids, corticosteroids, pregnenolone steroids, thiab progestin steroids (Daim duab 9). Pregnanediol-3-glucuronide, uas yog progestin steroid thiab cov khoom ntawm progesterone catabolism, muaj kev sib raug zoo thiab tseem ceeb (R=0.78) ntawm U3/U1 thiab P3/P1 hauv ME/CFS cov neeg mob thiab muaj kev sib raug zoo thiab tseem ceeb tsis zoo hauv kev tswj hwm kev noj qab haus huv (R=−0.8) (Daim duab 10C). Hauv cov neeg mob ME/CFS, thaum pregnanediol{12}}glucuronide nce hauv plasma 24 teev tom qab kev tawm dag zog, nws kuj nce hauv cov zis thiab rov ua dua. Txawm li cas los xij, hauv kev tswj hwm kev noj qab haus huv, cov neeg kawm uas muaj qhov loj tshaj plaws hauv cov zis ntau ntxiv ntawm pregnanediol-3-glucuronide 24 h tom qab qoj ib ce muaj qhov txo qis hauv cov ntshav plasma. Qhov zoo sib xws no yog pom nyob rau hauv cov zis thiab ntshav correlation rau lwm qhov kev sib piv piv. Qhov kev sib xyaw no kuj tseem hloov pauv qhov sib txawv ntawm LMM ntawm ME / CFS cov neeg mob thiab kev tswj hwm, qhov twg cov kev tswj hwm muaj qhov sib npaug tom qab kev tawm dag zog hauv cov zis ntau ntxiv uas tsis pom hauv ME / CFS cov neeg mob (Daim duab 7B). Ntawm tag nrho plaub lub sij hawm sib piv, cov ntshav thiab zis theem ntawm pregnanediol-3-glucuronide muaj kev sib raug zoo nyob rau hauv ob pawg ntawm cov ntsiab lus, uas tau qhia ua ntej [46]. Nws tsuas yog thaum kuaj xyuas qhov hloov pauv raws sijhawm tom qab kev tawm dag zog uas qhov sib txawv ntawm ME / CFS cov neeg mob thiab kev tswj hwm kev noj qab haus huv tshwm sim. Txawm hais tias pregnanediol-3- qib glucuronide tsis tau tshaj tawm hauv kev tshawb fawb txog kev tawm dag zog, nws tau raug ntsuas thoob plaws hauv kev coj khaub ncaws hauv kev tawm dag zog thiab cov poj niam cev xeeb tub, thiab cov poj niam qoj ib ce feem ntau muaj qis qis tag nrho piv rau cov poj niam sedentary [46,47] . Raws li peb cov txiaj ntsig, nws muaj peev xwm hais tias qhov kev tawm dag zog hnyav pib ua rau muaj kev nce ntxiv hauv cov zis pregnanediol-3- qib glucuronide hauv cov poj niam noj qab haus huv sedentary vim lawv tau tso tawm thiab tsis hloov pauv. Cov lus teb zoo rau kev tawm dag zog no tsis tshwm sim hauv ME / CFS cov neeg mob, uas tseem muaj pov thawj ntxiv rau lawv qhov kev hloov pauv metabolic tag nrho rau kev tawm dag zog.

Peb tau tsim lwm daim ntawv qhia ua cua sov uas muaj cov tsis paub, ib feem ntawm cov qauv molecules, thiab cov khoom noj uas ua tau raws li cov qauv siv los tsim daim duab 9 (Cov duab ntxiv S5). Qhov no yog muab los ua cov ntaub ntawv ntxiv los qhia txog qhov muaj peev xwm ntawm qee qhov tseem-rau-tau-tau txheeb xyuas cov metabolites. Raws li qhov piv txwv, X-25524 tsis tu ncua qhia qhov muaj kev sib raug zoo zoo rau pawg ME / CFS tab sis tsis muaj kev sib raug zoo rau pawg tswj tsis hais txog kev tawm dag zog. Kev txheeb xyuas qhov sib xyaw ua ke no tuaj yeem pab txhim kho tus cim ntsuas rau ME / CFS los ntawm kev ntsuas ntshav thiab zis ntau ntxiv.

【 Hu rau】 Email: george.deng@wecistanche.com / WhatsApp: 008613632399501 / Wechat: 13632399501