tag:blogger.com,1999:blog-731209728901315912024-03-15T01:48:26.281-07:00Follow ME in DenmarkThoughts and guesses about research in Myalgic encephalomyelitis/(Chronic Fatigue Syndrome)Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.comBlogger257125tag:blogger.com,1999:blog-73120972890131591.post-34114549344266859022024-03-13T04:26:00.000-07:002024-03-15T01:47:46.131-07:00Vedvarende aktivitet i immunforsvaret menes at være den grundlæggende årsag til Myalgisk Encephalomyelitis<p><span style="font-size: medium;"><span>National Institute of Health i USA står bag artiklen,</span><br /><br /><span><b><a href="https://www.nature.com/articles/s41467-024-45107-3">Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome</a></b></span></span></p><p><span style="font-size: medium;">som er udgivet i det anerkendte tidsskrift Nature Communications (1).</span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;">National Institute of Health har skrevet om studiet her:</span></p><p><span style="font-size: medium;"></span></p><span style="font-size: medium;"><a href="https://www.nih.gov/news-events/nih-research-matters/insight-into-mechanisms-mecfs"><b>Insight into mechanisms of ME/CFS</b></a></span><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">De skriver bl.a.: "They found differences in B cells, which make antibodies to help fight pathogens. People with PI-ME/CFS had more naïve B cells, which can be activated by any foreign substance. But they had fewer switched memory B cells, which respond to a specific pathogen that the body has encountered before. B cell dysfunction was more prominent in women. These findings suggests that the immune system continues to be activated in the absence of infection."</span><p><span style="font-size: medium;"><b><br /></b></span></p><p><span style="font-size: medium;"><b>Deltagere i studiet</b></span></p><p><span style="font-size: medium;"><span>Der deltog 17 patienter med Post-Infectious M</span><span>yalgic Encephalomyelitis/Chronic Fatigue Syndrome (PI-ME/CFS, herefter kun kaldet ME). Til sammenligning deltog 21 raske kontrolpersoner (healthy volunteers, HV). I nogle undersøgelser deltog et færrre antal ME patienter og kontrolpersoner. Dette er angivet i artiklen ved hver undersøgelse.</span></span></p><p><span style="font-size: medium;"><span>ME patienterne opfyldte følgende diagnose-kriterier:</span></span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">14 opfyldte Fukuda Criteria</span></li><li><span style="font-size: medium;">9 opfyldte Canadien Consensus Criteria</span></li><li><span style="font-size: medium;">alle 17 opfyldte Institute of Medicine Diagnostic Criteria</span></li></ul><p></p><p><span style="font-size: medium;">ME diagnoserne blev bekræftet af et panel af ME eksperter. Infektionerne der gik forud for ME omfattede:</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">10 tilfælde af forskellige infektioner i øvre luftveje</span></li><li><span style="font-size: medium;">3 tilfælde af Epstein Barr Virus infektion</span></li><li><span style="font-size: medium;">1 tilfælde af maveinfektion</span></li><li><span style="font-size: medium;">1 tilfælde af atypisk hepatitis</span></li><li><span style="font-size: medium;">1 tilfælde af Ramsay Hunt syndrom pga herpes zoster (herpes zoster er reaktivering af varicella (=skoldkoppevirus))</span></li><li><span style="font-size: medium;">1 tilfælde af herpes zoster ophthalmicus</span></li></ul><p></p><p><span style="font-size: medium;">Da patienterne deltog i studiet havde de haft ME i gennemsnit 33 måneder. 13 måneder for den korteste tid med ME og 59 måneder for den længste tid med ME.</span></p><p><span style="font-size: medium;"><span>Rekruttering af patienter foregik mellem dec 2016 og feb 2020. </span><span>Efter afslutning af studiet blev ME patienterne kontaktet mellem nov 2021 og juli 2022. Her var 4 af de 17 ME patienter blevet helt raske. Der er efterfølgende fremsat kritik af studiets snævre udsnit af patienter, og den høje spontane helbredelsesprocent har vakt undren.</span></span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>Autonom dysfunktion påvist hos ME patienter</b></span></p><p><span style="font-size: medium;">Undersøgelser viste tegn på, at ME patienterne havde:</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">øget hjerteryme om dagen (tegn på øget sympatisk aktivitet)</span></li><li><span style="font-size: medium;">formindsket fald i hjerterytmen om natten (tegn på nedsat parasympatisk aktivitet)</span></li><li><span style="font-size: medium;">nedsat baroflex-cardiovagal funktion</span></li></ul><p></p><span style="font-size: medium;">Konklusionen fra artiklen var: "...these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change."</span><p><span style="font-size: medium;"><b><br /></b></span></p><p><span style="font-size: medium;"><b>Forringet kardio-pulmonær motionstest hos ME patienter</b></span></p><p><span style="font-size: medium;">Tidligere forsøg har vist, at to kardio-pulmonære motionstest (CPET) adskilt af 24 timer er en effektiv måde at påvise motions-intolerance og post exertional malaise (PEM) hos ME patienter. Desværre blev en sådan dobbelt test IKKE medtaget i det ellers så omfattende studie. Men en enkelt CPET viste, at ME patienter havde</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">lavere VO</span>2<span style="font-size: medium;"> peak</span></li><li><span style="font-size: medium;">lavere procent af forventet VO</span>2<span style="font-size: medium;"> peak</span></li><li><span style="font-size: medium;">lavere puls revovery</span></li><li><span style="font-size: medium;">lavere VO</span>2<span style="font-size: medium;"> ved anaerob tærskelværdi</span></li></ul><p></p><span style="font-size: medium;">Det var således muligt at skelne mellem ME patienter og raske kontrolpersoner ved en kardiopulmonær motionstest. Konklusionen fra artiklen var. "...despite successful CPET engagement, PI-ME/CFS participants were less likely to achieve their predicted maximal output, suggesting a differential cardiorespiratory performance related to autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life."</span><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>Immunaktivering og køns-specifikke forskelle i immunforsvaret hos ME patienter</b></span></p><p><span style="font-size: medium;">Blodprøver fra ME patienter viste:</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">øget niveau af naive B-celler</span></li><li><span style="font-size: medium;">formindsket niveau af switched memory B-celler</span></li><li><span style="font-size: medium;">formindsket niveau af CD8+ T-celler undertype CD226</span></li><li><span style="font-size: medium;">øget niveau af CD8+ naive T-celler (KUN kvinder)</span></li></ul><p></p><p><span style="font-size: medium;">Cerebrospinalvæske prøver fra ME patienter viste:</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">øget niveau af CD8+ T-celler undertype PD-1 (= markør for T-celle aktivering)</span></li><li><span style="font-size: medium;">øget niveau af CD8+ T-celler CXCR5 (KUN mænd)</span></li></ul><span style="font-size: medium;"><div><span style="font-size: medium;"><br /></span></div>Der blev også udført en analyse af gen ekspression i immun-celler (peripheral blood mononuclear cells, PBMC). Der blev påvist forskellig ekspression af flere gener (differentially expressed genes, DE genes) hos ME patienter:<br /><ul style="text-align: left;"><li><span style="font-size: medium;">gener relateret til et protein netværk omkring STAT4-TLR9 stivejen var opreguleret (KUN mænd)</span></li><li><span style="font-size: medium;">gener relateret til protein netværk omkring B-celler (KUN kvinder)</span></li></ul></span><div><span style="font-size: medium;"><br /></span><div><span style="font-size: medium;">Konklusionen fra artiklen: "Additionally, DE genes were also enriched in cytokine and lymphocyte proliferation processes. These data are consistent with expansion of naïve B-cells by the STAT4-TLR9 and other B-cell pathways observed in PI-ME/CFS by flow cytometry."</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Der blev endvidere udført en <a href="https://en.wikipedia.org/wiki/Aptamer">aptamer</a> analyse af serum og cerebrospinal væske. Det er en analyse, der kan påvise forekomst af forskellige proteiner. Der blev IKKE påvist nogen FDR-korrigeret statistisk signifikant forskel mellem ME patienter og kontrolpersoner. Men ved at analysere data kønsspecifikt kunne der påvises proteiner, der var specifikke for ME. Artiklen oplyser, at der er behov for at undersøge disse fund i nye studier og validere resultaterne. Figur S15 og S16 viser aptamer analyse resulaterne.</span></div><div><span style="font-size: medium;"><br /></span></div><span style="font-size: medium;">Topscore resultater af aptamer analyse af serum (KUN mænd):<br /><ul style="text-align: left;"><li><span style="font-size: medium;">nedsat niveau af alfa-1-antitrypsin</span></li><li><span style="font-size: medium;">øget niveau af ferritin</span></li><li><span style="font-size: medium;">øget niveau af protein S</span></li><li><span style="font-size: medium;">øget niveau af GPC5</span></li></ul><br />og cerebrospinalvæske (KUN mænd):<br /><ul style="text-align: left;"><li><span style="font-size: medium;">øget niveau af HB-EGF</span></li><li><span style="font-size: medium;">nedsat niveau af CLM6</span></li><li><span style="font-size: medium;">øget niveau af protein disulfid isomerase</span></li><li><span style="font-size: medium;">nedsat niveau af IMDH2</span></li></ul><br />Topscore resultater af aptamer analyse af serum (KUN kvinder):<br /><ul style="text-align: left;"><li><span style="font-size: medium;">øget niveau af plasminogen</span></li><li><span style="font-size: medium;">nedsat niveau af galectin-4</span></li><li><span style="font-size: medium;">øget niveau af lymfotoxin a2/b1</span></li><li><span style="font-size: medium;">nedsat niveau af iC3b</span></li></ul><br />og cerebrospinalvæske (KUN kvinder):<br /><ul style="text-align: left;"><li><span style="font-size: medium;">øget niveau af sFRP-3</span></li><li><span style="font-size: medium;">øget niveau af PTN</span></li><li><span style="font-size: medium;">øget niveau af IGFBP-2</span></li><li><span style="font-size: medium;">øget niveau af IGFBP5</span></li></ul><br />Artiklen oplyser: ".. in the female cohorts, gene expression profiling of PBMCs identified perturbations in B-cell and leukocyte proliferation processes with a corresponding identification of plasma lymphotoxin α1β2, which may act as a proliferative signal in secondary lymphoid tissues."</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">"The cause of immune dysregulation is not clear but may suggest the possibility of persistent antigenic stimulation."</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">I artiklens supplerende afsnit står der: "PI-ME/CFS individuals had immune activation and immune exhaustion."</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>Lidt basisviden:</b> Et antigen er et fremmed stof, som aktiverer kroppens immunforsvar. En vedvarende præsentation af det fremmede protein til immunforsvaret kan ses ved f. eks. infektion, autoimmunitet (hvor et af kroppens egne proteiner anses for fremmed) eller ved transplantationer (2): </span><span style="font-size: medium;"><br /><br /><a href="https://onlinelibrary.wiley.com/doi/full/10.1111/imr.12836">Regulation of T and B cell responses to chronic antigenic stimulation during Infection, autoimmunity and transplantation</a></span></div><div><span style="font-size: medium;"><br /></span><br /></div><div><div><span style="font-size: medium;"><b>Dysreguleret katekolamin niveau og tryptofan stivej hos ME patienter</b></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Dopamin, adrenalin og noradrenalin kaldes katekolaminer. De fungerer som neurotransmittere i centralnervesystemet (CNS) og i periferien. </span><span style="font-size: medium;">Jeg vil anbefale, at man lige kaster et blik på omsætningen af disse neurotransmittere: <a href="https://en.wikipedia.org/wiki/Catecholamine">Catecholamine</a></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Cerebrospinalvæske prøver fra ME patienterne viste:</span></div><span style="font-size: medium;"><div><ul style="text-align: left;"><li>formindsket niveau af 3,4-dihydroxyphenylalanine (DOPA)</li><li><span style="font-size: medium;">formindsket niveau af 3,4-dihydroxyphenylacetic acid (DOPAC)</span></li><li><span style="font-size: medium;">formindsket niveau af (S)-3,5-dihydroxyphenylglycine (DHPG)</span></li></ul></div><br /></span><div><span style="font-size: medium;">Niveauet af dopamin (= 3,4-dihydroxyphenethylamine, DA), cys-DOPA og noradrenalin var ikke forskelligt fra niveauet hos kontrolpersonerne.<br /></span><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Cerebrospinalvæske prøver fra ME patienterne viste endvidere:</span></div><div><ul style="text-align: left;"><li><span style="font-size: medium;"><span>ændret niveau af flere tryptofan metabolitter</span></span></li><li><span style="font-size: medium;"><span>nedsat niveau af glutamat</span></span></li><li><span style="font-size: medium;"><span>nedsat niveau af polyaminer</span></span></li><li><span style="font-size: medium;"><span>nedsat niveau af citronsyre cyklus metabolitter</span></span></li></ul></div><div><br /></div><div><span style="font-size: medium;">Af figur S13 fremgår topscorerne over metabolitter med nedsat niveau i cerebrospinal væske fra mænd (de første fem):</span></div><div><ul style="text-align: left;"><li><span style="font-size: medium;">orotidine</span></li><li><span style="font-size: medium;">dimetyl sulfone</span></li><li><span style="font-size: medium;">mannitol/sorbitol</span></li><li><span style="font-size: medium;">threonin</span></li><li><span style="font-size: medium;">N6, N6-dimetyllysine</span></li></ul></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">og topscore over metabolitter med nedsat niveau i cerebrospinal vsæske for kvinder (de første fem):</span></div><div><ul style="text-align: left;"><li><span style="font-size: medium;">5-hydroxyindolacetat</span></li><li><span style="font-size: medium;">picolinate</span></li><li><span style="font-size: medium;">4-guanidinobutanoate</span></li><li><span style="font-size: medium;">dimetyl sulfone</span></li><li><span style="font-size: medium;">4-acetamidobutanoate</span></li></ul></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>Udholdenhed i håbdgrebsstyrke var nedsat hos ME patienter</b></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Ved en enkelt test af håndgrebsstyrke var der ikke forskel mellem ME patienter og kontrolpersoner. Ved gentagne test havde ME patienter mindre udholdenhed og mistede hurtigt styrken i grebet (p-værdi = 0,0002).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Det område i hjernen, der sender besked til musklen om aktivitet, hedder <a href="https://en.wikipedia.org/wiki/Motor_cortex">motor cortex</a>. Styrken i signalet fra hjerne til muskel kan måles med <a href="https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP281885">Motor Evoked Potentials</a> (MEPs). Under vedvarende brug af musklerne til håndgrebsstyrke testen faldt MEP signalet hos kontrolpersonerne, men MEP signalet steg hos ME patienter. Så selv om motor cortex udsendte stigende signaler til musklen, blev håndgrebsstyrken forringet. </span></div><div><span style="font-size: medium;"><br /></span></div><span style="font-size: medium;">Konklusion fra artiklen var: "This indicates that the primary motor cortex remained excitable for PI-ME/CFS, suggesting reduced motor engagement from this group."<br /><br />En hjernscanning af 8 ME patienter og 10 krontrolpersoner viste, at under håndgrebsstyrke testen havde ME patienterne lavere aktivitet end kontrolpersonerne i følgende hjerneområder:<br /></span><div><ul style="text-align: left;"><li><span style="font-size: medium;">temporo-parietal junction (TPJ)</span></li><li><span style="font-size: medium;">superior parietal lobule</span></li><li><span style="font-size: medium;">right temporal gyrus</span></li></ul></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /><b>ME patienter havde ændret præference for valg af opgavers sværhedsgrad</b></span></div><div><span style="font-size: medium;"><br /></span></div><span style="font-size: medium;">Der blev gennemført en <a href="https://www.treadlab.org/tools">Effort-Expenditure for Rewards Task</a> (EEfRT). Den viste, at ME patienter var mere tilbøjelige til at vælge en let opgave (med lavere belønning) end en svær opgave (med højere belønning). Opgaverne var PC styrede og man skulle trykke på en knap få eller mange gange afhængig af opgavens sværhedsgrad.</span><div><span style="font-size: medium;"><br /></span><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>Artiklens diskussions afsnit - hvordan tolkes resultaterne?</b></span></div><div><span style="font-size: medium;"><br /></span></div><span style="font-size: medium;">Det store spørgsmål er hvordan resultatet af alle undersøgelser samlet skal tolkes. Jeg har nedenstående samlet citater fra artiklens diskussions afsnit: <br /><br />"Compared to HVs, PI-ME/CFS participants failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This difference in performance correlated with decreased activity of the right temporal-parietal junction, a part of the brain that is focused on determining mismatch between willed action and resultant movement."<br /><br />"...the fatigue of PI-ME/CFS participants is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored. "<br /><br />" Interviews with PI-ME/CFS participants revealed that sustained effort led to post-exertional malaise. Conscious and unconscious behavioral alterations to pace and avoid discomfort may underlie the differential performance observed."<br /><br />"We measured peripheral fatigue (high:low ratio) and central fatigue (post exercise depression). Both types of fatigue were seen in the HVs but not in the PI-ME/CFS participants. Moreover, testing of effort preference and the participants’ own words (Supplementary Information, p.10) are consistent with this finding. Together these findings suggest that effort preference, not fatigue, is the defining motor behavior of this illness."<br /><br />"Interestingly, PI-ME/CFS participants’ catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms. This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints. The pattern suggests decreased central catecholamine biosynthesis in PI-ME/CFS. Similarly, decreased serum catechols and their metabolites have recently been reported in Long COVID-19."<br /><br />"Metabolomics of cerebrospinal fluid identified downregulation of tryptophan metabolites in the PI-ME/CFS cohort, consistent with prior ME/CFS and Long COVID-19 studie."<br /><br />"The cause of immune dysregulation is not clear but may suggest the possibility of persistent antigenic stimulation."<br /><br />"Considering all the data together, PI-ME/CFS appears to be a centrally mediated disorder. We posit this hypothetical mechanism of how an infection can create a cascade of physiological alterations that lead to the PI-ME/CFS phenotype (Fig. <a href="https://www.nature.com/articles/s41467-024-45107-3#Fig10">10</a>). Exposure to an infection leads to concomitant immune dysfunction and changes in microbial composition. Immune dysfunction may be related to both innate and adaptive immune responses that are sex dependent. One possibility is that these changes are related to antigen persistence of the infectious pathogen"<br /><br />"Therapeutically targeting downstream mechanisms, with exercise, cognitive behavioral therapy, or autonomic directed therapies, may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS. However, combination therapy affecting multiple pathways could be considered."<br /><br />Som jeg læser diskussions afsnittet i artiklen, så sender forskerne blandede signaler om ME patienters fatigue. Der er de klare fakta om immun og katekolamin dysfunktion, og så er der de lidt mere uklare signaler, om hvordan effort preference skal tolkes. Den hypotese de ender op med kan ses på figur 10 i artiklen:</span><div><div><span style="background-color: white; color: #222222; font-family: Harding, Palatino, serif; font-size: medium;"><br /></span></div><div><span style="background-color: white; color: #222222; font-family: Harding, Palatino, serif; font-size: medium;"><a href="https://www.nature.com/articles/s41467-024-45107-3/figures/10"><span>https://www.nature.com/articles/s41467-024-45107-3/figures/10</span></a><br /></span></div><div><span style="color: #222222; font-family: Harding, Palatino, serif;"><span style="font-size: medium;"><br /></span></span></div><span style="font-size: medium;">Hypotesen har vedvarende antigen præsentation som grundlæggende årsag til ME. Det vedvarende aktive immunforsvar er årsag til det dysregulerede niveau af signalstoffer i central nerve systemet (CNS), som igen påvirker de områder i hjerne der styrer motor cortex. <br /><br />Forskerne henviser til en anden artikel, som tidligere har foreslået vedvarende antigen præsentation som årsag til ME:</span><br /><div><br /><span style="font-size: medium;"><a href="https://journals.sagepub.com/doi/10.1177/26331055221114817">At the Root of 3 “Long” Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome</a><br /></span></div><div><span style="font-size: medium;"><br /></span><div><span style="font-size: medium;"><span><b>Læs også bloggen Health Rising, der har skrevet om studiet:</b></span></span></div><div><span style="font-size: medium;"><span><br /></span></span></div><div><span style="font-size: medium;"><span><a href="https://www.healthrising.org/blog/2024/02/22/chronic-fatigue-syndrome-me-cfs-brain-disease/">The Nath ME/CFS Intramural Study Pt. I: “It’s a Brain Disease…”</a><br /></span><br /></span></div><div><span style="font-size: medium;"><a href="https://www.healthrising.org/blog/2024/02/27/nath-chronic-fatigue-syndrome-nih/">The Nath Intramural ME/CFS Study Pt. II: Missed Opportunities, Misreadings and… Success (?)</a><br /></span></div><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>Referencer:</b></span></p><p><span style="font-size: medium;"><span>1) </span><span face="-apple-system, BlinkMacSystemFont, "Segoe UI", Roboto, Oxygen-Sans, Ubuntu, Cantarell, "Helvetica Neue", sans-serif" style="background-color: white; color: #222222;">Walitt, B., Singh, K., LaMunion, S.R. </span><i style="background-color: white; box-sizing: inherit; color: #222222; font-family: -apple-system, BlinkMacSystemFont, "Segoe UI", Roboto, Oxygen-Sans, Ubuntu, Cantarell, "Helvetica Neue", sans-serif;">et al.</i><span face="-apple-system, BlinkMacSystemFont, "Segoe UI", Roboto, Oxygen-Sans, Ubuntu, Cantarell, "Helvetica Neue", sans-serif" style="background-color: white; color: #222222;"> Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. </span><i style="background-color: white; box-sizing: inherit; color: #222222; font-family: -apple-system, BlinkMacSystemFont, "Segoe UI", Roboto, Oxygen-Sans, Ubuntu, Cantarell, "Helvetica Neue", sans-serif;">Nat Commun</i><span face="-apple-system, BlinkMacSystemFont, "Segoe UI", Roboto, Oxygen-Sans, Ubuntu, Cantarell, "Helvetica Neue", sans-serif" style="background-color: white; color: #222222;"> </span><span face="-apple-system, BlinkMacSystemFont, "Segoe UI", Roboto, Oxygen-Sans, Ubuntu, Cantarell, "Helvetica Neue", sans-serif" style="background-color: white; box-sizing: inherit; color: #222222; font-weight: bolder;">15</span><span face="-apple-system, BlinkMacSystemFont, "Segoe UI", Roboto, Oxygen-Sans, Ubuntu, Cantarell, "Helvetica Neue", sans-serif" style="background-color: white; color: #222222;">, 907 (2024). <a href="https://doi.org/10.1038/s41467-024-45107-3">https://doi.org/10.1038/s41467-024-45107-3</a></span></span></p><span style="font-size: medium;"><br />2) Ahmed R, Ford ML, Sanz I. Regulation of T and B cell responses to chronic antigenic stimulation during Infection, autoimmunity and transplantation. Immunol Rev. 2019 Nov;292(1):5-8. doi: 10.1111/imr.12836. PMID: 31883175. </span></div><div><span style="font-size: medium;"><a href="https://onlinelibrary.wiley.com/doi/full/10.1111/imr.12836">https://onlinelibrary.wiley.com/doi/full/10.1111/imr.12836</a></span><p><br /></p></div></div></div></div></div></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-55935041038013656282023-10-12T03:41:00.000-07:002023-10-12T03:41:47.531-07:00NUP98 er involveret i ME sygdomsmekanismen.<span style="font-size: medium;">..fortsættelse af tidligere blogindlæg:</span><div><span style="font-size: medium;"><br /><a href="https://followmeindenmark.blogspot.com/2023/10/kirrel3-tnk2-prune1-tph2-og-slc6a4-er.html">KIRREL3, TNK2, PRUNE1, TPH2 og SLC6A4 er involveret i ME sygdomsmekanismen</a></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><a href="https://www.ncbi.nlm.nih.gov/gene/4928">NUP98</a> (nucleoporin 98) er også et ef de 11 gener, som er involveret i ME sygdomsmekanismen (tabel 4 i ref 1).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>Basisviden om NUP98</b></span></div><div><span style="font-size: medium;">Vores celler indeholder en cellekerne (nucleus) med DNA. DNA er koden ("bageopskriften") for de proteiner og enzymer, som cellerne skal producere. Beskeder i form af specielle proteiner føres ind og ud af cellekernen gennem kontrollerede åbninger. Åbningerne er opbygget som et nuklear pore compleks (NPC). I dette kompleks indgår forskellige nucleoporiner. Nogle nucleoporiner har også andre arbejdsopgaver. </span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Tidligere blogindlæg om NPC og NUP98: <br /><br /><a href="https://followmeindenmark.blogspot.com/2018/07/nucleoporins-in-me.html">Nucleoporins in ME</a></span></div><span style="font-size: medium;"><br /><a href="https://followmeindenmark.blogspot.com/2018/07/mrna-export-in-me.html">mRNA export in ME</a></span><div><span style="font-size: medium;"><br /></span><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>NUP98, DHX9, DDX5 og DDX17</b></span></div><div><span style="font-size: medium;"><span>NUP98 binder sig til </span><a href="https://www.ncbi.nlm.nih.gov/gene/1660">DHX9</a><span> og herved reguleres ekspression af en række gener. NUP98 protein-protein-interaktions-netværket fremgår af figur 4 i ref 2. I dette netværk indgår </span><a href="https://www.ncbi.nlm.nih.gov/gene/1655">DDX5</a><span> og </span><a href="https://www.ncbi.nlm.nih.gov/gene/10521">DDX17</a><span> (2). </span></span></div><div><span style="font-size: medium;"><br /></span></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi5Q_BH1yYEYeJB_HDkFu0QnQ72KfjbKDa-Pu540r32SqEYV5k6l3sIB9XlhNHxob90SpBtj-tcBFrkIDU5mS5Qk03u0cyi0ivLpgGp9d0fsHbQbw1JRK_WjlYfrkQu5_eeLj133iA9oS_LcZ7izoyzuppH9s_u4f5e_WVYg-BxjCQsCPf3oNdIoC-pt5J4/s1500/lax_18825_elife-18825-fig2-v2.tif.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1500" data-original-width="1058" height="534" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi5Q_BH1yYEYeJB_HDkFu0QnQ72KfjbKDa-Pu540r32SqEYV5k6l3sIB9XlhNHxob90SpBtj-tcBFrkIDU5mS5Qk03u0cyi0ivLpgGp9d0fsHbQbw1JRK_WjlYfrkQu5_eeLj133iA9oS_LcZ7izoyzuppH9s_u4f5e_WVYg-BxjCQsCPf3oNdIoC-pt5J4/w377-h534/lax_18825_elife-18825-fig2-v2.tif.jpg" width="377" /></a></div><br /><span style="font-size: x-small;">Figur 4 fra <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Capitanio JS, Montpetit B, Wozniak RW. Human Nup98 regulates the localization and activity of DExH/D-box helicase DHX9. Elife. 2017 Feb 21;6:e18825. doi: 10.7554/eLife.18825. PMID: 28221134; PMCID: PMC5338925.</span></span></div><div><span style="font-size: medium;"><br /></span></div><div><br /></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>DDX5 og DDX17 styrer celledifferentiering</b></span></div><div><span style="font-size: medium;">Under fosterets udvikling udføres omfattende celledifferentiering. Nogle celler skal blive til hjerneceller, andre skal bliver til immunceller og andre igen skal blive til muskelceller. I voksenlivet er celleudviklingen mere begrænset, men foregår stadigvæk. Celler fra knoglemarven udvikles og differentieres til forskellige immunceller og satellitceller fra musklerne udvikles til rigtige muskelceller. Forskning har vist, at DDX5 og DDX17 er involveret i udvikling af satellitceller til muskelceller (myoblast til myotuber) (3, 4).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /></span></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEih_2IgGtUCSsXGEnGmUmgOZfaCliEAKDz7mA-vpQZFUJVNZHvsk2Jwas06IoWkvVr6OHbI8e-vuMMankd1yedIN91qZBog28kCHR30Za7I8Y8sn3Q3C0pLnOY0f0l50mwSxTa8ymO-8EqEak4VYh1KtesPUTU3MUVrI2gvAVTDfzf_lpVNyekCrOpHFesF/s505/gr7.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="217" data-original-width="505" height="247" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEih_2IgGtUCSsXGEnGmUmgOZfaCliEAKDz7mA-vpQZFUJVNZHvsk2Jwas06IoWkvVr6OHbI8e-vuMMankd1yedIN91qZBog28kCHR30Za7I8Y8sn3Q3C0pLnOY0f0l50mwSxTa8ymO-8EqEak4VYh1KtesPUTU3MUVrI2gvAVTDfzf_lpVNyekCrOpHFesF/w573-h247/gr7.jpg" width="573" /></a></div><br /></div><div><span style="font-size: x-small;"><span><span class="label figure__label" data-fv-label="Fig. 7" face="helvetica, sans-serif" style="background-color: white; box-sizing: border-box; display: inline; float: none; font-weight: 700; margin-bottom: 0.8125rem; margin-right: 0.3125rem;">Figure 7 fra:</span><span class="figure__title__text" face="helvetica, sans-serif" style="background-color: white; box-sizing: border-box; color: #505050; font-weight: 700;">Orchestrated Regulation of Gene Expression by DDX5 and DDX17 during Cell Differentiation. </span></span><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Dardenne E, Polay Espinoza M, Fattet L, Germann S, Lambert MP, Neil H, Zonta E, Mortada H, Gratadou L, Deygas M, Chakrama FZ, Samaan S, Desmet FO, Tranchevent LC, Dutertre M, Rimokh R, Bourgeois CF, Auboeuf D. RNA helicases DDX5 and DDX17 dynamically orchestrate transcription, miRNA, and splicing programs in cell differentiation. Cell Rep. 2014 Jun 26;7(6):1900-13. doi: 10.1016/j.celrep.2014.05.010. Epub 2014 Jun 6. PMID: 24910439.</span></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b><br /></b></span></div><div><span style="font-size: medium;"><b>DDX5 og DDX17 i ME</b></span></div><div><span style="font-size: medium;">Nguyen er al har påvist dysreguleret immun gen netværk i en undergruppe af unge ME/CFS patienter. I dette netværk indgår DDX5 og DDX17 (se figur 1 i ref 5).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /><b>Virus og nucleoporiner</b></span></div><div><span style="font-size: medium;">En del virus er i stand til at "besætte" NPC for at fremme deres egen virus replikation. Forskellige nucleoporiner (herunder NUP98) bliver udnyttet til dette formål (6, 7, 8).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">NUP98 binder sig til et andet af vores proteiner <a href="https://www.ncbi.nlm.nih.gov/gene/8480">RAE1</a> og sørger for mRNA export gennem NPC. Gammaherpesvirus kan hæmme denne transport.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Proteinet dUTPase kodes af både mennesker og nogle virus, f. eks:</span></div><div><ul style="text-align: left;"><li><span style="font-size: medium;">Mennesket: <a href="https://www.ncbi.nlm.nih.gov/gene/1854">DUT</a></span></li><li><span style="font-size: medium;">Epstein Barr Virus (EBV = (HHV-4): <a href="https://www.ncbi.nlm.nih.gov/gene/3783715">BLLF3</a></span></li><li><span style="font-size: medium;">Human Herpes Virus 6 (HHV-6): <a href="https://www.ncbi.nlm.nih.gov/gene/1487924">U45</a></span></li><li><span style="font-size: medium;">Varicella Zoster Virus (VZV = HHV-3)): <a href="https://www.ncbi.nlm.nih.gov/gene/1487671">ORF8</a></span></li><li><span style="font-size: medium;">Murin gammaherpesvirus MHV68: ORF10</span></li></ul></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Feng et al har vist, at proteinet ORF10 binder sig til NUP98-RAE1-komplekset. Herved hæmmes mRNA export funktionen (9).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><span>SARS-CoV-2 er et betacoronavirus med et protein kodet af ORF6, som ligeledes kan interagere med </span><span>NUP98-RAE1-komplekset og blokere for mRNA export (8). </span></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Halpin et al har vist, at ca. 30-50% af en gruppe ME patienter havde antistoffer mod herpesvirus dUTPase og/eller human dUTPase i forhold til ca. 17% hos kontrolpersoner (10).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Spørgsmålet er hvilken betydning har disse fund? Hypoteser om at kronisk ekspression af dele af virusproteiner spiller en rolle i post-virale syndromer som long COVID og ME diskuteres (11, 12).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><span>Og hvad betyder det, at NUP98 er i Pihur's tabel? Er NUP98 op-eller nedreguleret i ME sygdomsmekanismen? Er NUP98, DDX5 og DDX17 involveret i immuncelle funktion? Eller i satellitcelle funktion? Eller begge dele? </span><span>Eller er der noget helt andet galt?</span></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Foreløbig må vi blot konstatere, at NUP98 er en potentiel ME puslespilsbrik.</span></div><div><div><br /><br /><span style="font-size: large;">Referencer</span></div><div><span style="font-size: medium;"><br /></span></div><div><span face="Arial, Tahoma, Helvetica, FreeSans, sans-serif" style="color: #222222;">1) </span><span face="Arial, Tahoma, Helvetica, FreeSans, sans-serif" style="color: #212121;">Pihur V, Datta S, Datta S. Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data. Bioinformation. 2011 Apr 22;6(3):120-4. doi: 10.6026/97320630006120. PMID: 21584188; PMCID: PMC3089886. </span><a href="https://pubmed.ncbi.nlm.nih.gov/21584188/" style="font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif;">https://pubmed.ncbi.nlm.nih.gov/21584188/</a></div><div><br /></div><div>2) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Capitanio JS, Montpetit B, Wozniak RW. Human Nup98 regulates the localization and activity of DExH/D-box helicase DHX9. Elife. 2017 Feb 21;6:e18825. doi: 10.7554/eLife.18825. PMID: 28221134; PMCID: PMC5338925. </span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;"><a href="https://pubmed.ncbi.nlm.nih.gov/28221134/">https://pubmed.ncbi.nlm.nih.gov/28221134/</a><br /></span></div><div><br /></div><div>3) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Dardenne E, Polay Espinoza M, Fattet L, Germann S, Lambert MP, Neil H, Zonta E, Mortada H, Gratadou L, Deygas M, Chakrama FZ, Samaan S, Desmet FO, Tranchevent LC, Dutertre M, Rimokh R, Bourgeois CF, Auboeuf D. RNA helicases DDX5 and DDX17 dynamically orchestrate transcription, miRNA, and splicing programs in cell differentiation. Cell Rep. 2014 Jun 26;7(6):1900-13. doi: 10.1016/j.celrep.2014.05.010. Epub 2014 Jun 6. PMID: 24910439. </span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/24910439/">https://pubmed.ncbi.nlm.nih.gov/24910439/</a><br /></span></div><div><br /></div><div>4) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Caretti G, Schiltz RL, Dilworth FJ, Di Padova M, Zhao P, Ogryzko V, Fuller-Pace FV, Hoffman EP, Tapscott SJ, Sartorelli V. The RNA helicases p68/p72 and the noncoding RNA SRA are coregulators of MyoD and skeletal muscle differentiation. Dev Cell. 2006 Oct;11(4):547-60. doi: 10.1016/j.devcel.2006.08.003. PMID: 17011493. </span><a href="https://pubmed.ncbi.nlm.nih.gov/17011493/" style="font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;">https://pubmed.ncbi.nlm.nih.gov/17011493/</a></div><div><br /></div><div>5) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Nguyen CB, Kumar S, Zucknick M, Kristensen VN, Gjerstad J, Nilsen H, Wyller VB. Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome. Brain Behav Immun. 2019 Feb;76:82-96. doi: 10.1016/j.bbi.2018.11.008. Epub 2018 Nov 9. PMID: 30419269. <a href="https://pubmed.ncbi.nlm.nih.gov/30419269/">https://pubmed.ncbi.nlm.nih.gov/30419269/</a></span></div><div><br /></div><div>6) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Le Sage V, Mouland AJ. Viral subversion of the nuclear pore complex. Viruses. 2013 Aug 16;5(8):2019-42. doi: 10.3390/v5082019. PMID: 23959328; PMCID: PMC3761240. </span><a href="https://pubmed.ncbi.nlm.nih.gov/23959328/" style="font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;">https://pubmed.ncbi.nlm.nih.gov/23959328/</a></div><div><br /></div><div>7) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Guo J, Zhu Y, Ma X, Shang G, Liu B, Zhang K. Virus Infection and mRNA Nuclear Export. Int J Mol Sci. 2023 Aug 9;24(16):12593. doi: 10.3390/ijms241612593. PMID: 37628773; PMCID: PMC10454920. </span><a href="https://pubmed.ncbi.nlm.nih.gov/37628773/" style="font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;">https://pubmed.ncbi.nlm.nih.gov/37628773/</a></div><div><br /></div><div>8) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Hall R, Guedán A, Yap MW, Young GR, Harvey R, Stoye JP, Bishop KN. SARS-CoV-2 ORF6 disrupts innate immune signalling by inhibiting cellular mRNA export. PLoS Pathog. 2022 Aug 25;18(8):e1010349. doi: 10.1371/journal.ppat.1010349. PMID: 36007063; PMCID: PMC9451085. </span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/36007063/">https://pubmed.ncbi.nlm.nih.gov/36007063/</a><br /></span></div><div><br /></div><div>9) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Feng H, Tian H, Wang Y, Zhang Q, Lin N, Liu S, Yu Y, Deng H, Gao P. Molecular mechanism underlying selective inhibition of mRNA nuclear export by herpesvirus protein ORF10. Proc Natl Acad Sci U S A. 2020 Oct 27;117(43):26719-26727. doi: 10.1073/pnas.2007774117. Epub 2020 Oct 8. PMID: 33033226; PMCID: PMC7604486. </span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/33033226/">https://pubmed.ncbi.nlm.nih.gov/33033226/</a><br /></span></div><div><br /></div><div>10) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Halpin P, Williams MV, Klimas NG, Fletcher MA, Barnes Z, Ariza ME. Myalgic encephalomyelitis/chronic fatigue syndrome and gulf war illness patients exhibit increased humoral responses to the herpesviruses-encoded dUTPase: Implications in disease pathophysiology. J Med Virol. 2017 Sep;89(9):1636-1645. doi: 10.1002/jmv.24810. Epub 2017 Apr 26. PMID: 28303641; PMCID: PMC5513753. </span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/28303641/">https://pubmed.ncbi.nlm.nih.gov/28303641/</a><br /></span></div><div><br /></div><div>11) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Lafon-Hughes L. Towards Understanding Long COVID: SARS-CoV-2 Strikes the Host Cell Nucleus. Pathogens. 2023 Jun 6;12(6):806. doi: 10.3390/pathogens12060806. PMID: 37375496; PMCID: PMC10301789. </span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/37375496/">https://pubmed.ncbi.nlm.nih.gov/37375496/</a><br /></span></div><div><br /></div><div>12) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Ariza ME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules. 2021 Jan 29;11(2):185. doi: 10.3390/biom11020185. PMID: 33572802; PMCID: PMC7912523. </span><a href="https://pubmed.ncbi.nlm.nih.gov/33572802/" style="font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;">https://pubmed.ncbi.nlm.nih.gov/33572802/</a></div></div></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-1692616357711248072023-10-08T21:40:00.002-07:002023-10-14T00:40:13.142-07:00KIRREL3, TNK2, PRUNE1, TPH2 og SLC6A4 er involveret i ME sygdomsmekanismen<p><span style="font-size: medium;">Pihur og kolleger har udpeget 11 gener, der har betydning for ME sygdomsmekanismen (tabel 4 i ref 1):</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;"><a href="https://www.ncbi.nlm.nih.gov/gene/10810">WASF3</a> = WAVE3</span></li><li><span style="font-size: medium;"><a href="https://www.ncbi.nlm.nih.gov/gene/4928">NUP98</a></span></li><li><span style="font-size: medium;">PRUNE = <a href="https://www.ncbi.nlm.nih.gov/gene/58497">PRUNE1</a></span></li><li><span style="font-size: medium;">KIRREL (Der findes flere KIRREL'er. <a href="https://www.ncbi.nlm.nih.gov/gene/84623">KIRREL3</a> er nævnt i tabel 1 og 2 i ref 1) </span></li><li><span style="font-size: medium;"><a href="https://www.ncbi.nlm.nih.gov/gene/10188">TNK2</a> = ACK1</span></li><li><span style="font-size: medium;">EIF3S8 = <a href="https://www.ncbi.nlm.nih.gov/gene/8663">EIF3C</a></span></li><li><span style="font-size: medium;"><a href="https://www.ncbi.nlm.nih.gov/gene/3198">HOXA1</a></span></li><li><span style="font-size: medium;">PMS2L5 = <a href="https://www.ncbi.nlm.nih.gov/gene/5383">PMS2P5</a></span></li><li><span style="font-size: medium;">HDAC7A = <a href="https://www.ncbi.nlm.nih.gov/gene/51564">HDAC7</a></span></li><li><span style="font-size: medium;">GRP41 = <a href="https://www.ncbi.nlm.nih.gov/gene/2865">FFAR3</a></span></li><li><span style="font-size: medium;"><a href="https://www.ncbi.nlm.nih.gov/gene/10746">MAP3K2</a></span></li></ul><p></p><p><span style="font-size: medium;">Disse gener er under Pihur's analyse sat i releation til <a href="https://www.ncbi.nlm.nih.gov/gene/121278">TPH2</a> og <a href="https://www.ncbi.nlm.nih.gov/gene/6532">SLC6A4</a>, fordi <a href="https://medlineplus.gov/genetics/understanding/genomicresearch/snp/">SNPs</a> i disse gener er relateret til ME (se tabel 1 og 2 i ref 1).</span></p><p><span style="font-size: medium;">Betydningen af WASF3 i ME sygdomsmekanismen er lige blevet afdækket. Øget niveau af WASF3 i muskelceller ødelægger mitokondrie superkomplekser. Dette er associeret med Endoplasmatisk Reticulum (ER) stress. Niveauet af ER stress sensoren PERK (=EIF2AK3) er forhøjet (2).</span></p><p><span style="font-size: medium;">Så mangler vi at forstå, hvilken rolle de ti andre gener (samt TPH2 og SLC6A4) spiller. I dette indlæg vil jeg gennemgå viden om KIRREL3, TNK2, PRUNE1, TPH2 og SLC6A4. Men først lidt basisviden.</span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>Basisviden</b></span></p><p><span style="font-size: medium;">ER sørger for foldning og kvalitetskontrol af proteiner. Ved motion ophobes misfoldede proteiner i muskelcellerne. Dette udløser ER stress, som cellerne imødekommer med en "oprydningsproces", der kaldes unfolded protein response (UPR). Den midlertidige tilstand af ER stress ved motion er normalt, men ved kronisk ER stress (som påvist i ME) vil der ske tab af muskelceller (3).</span></p><p><span style="font-size: medium;">Reparation af muskler efter beskadigelse (4, 5, 6):</span></p><span style="font-size: medium;"><ul style="text-align: left;"><li><span style="font-size: medium;">Muskler indeholder hvilende <a href="https://en.wikipedia.org/wiki/Myosatellite_cell">satellitceller</a>, som er et forstadie til rigtige muskelceller.</span></li><li><span style="font-size: medium;">Når muskler bliver beskadigede aktiveres satellitcellerne og modnes til myoblaster, der hver indeholder én cellekerne.</span></li><li><span style="font-size: medium;">Myoblaster udvikles videre til myocytter, der har en aflang form.</span></li><li><span style="font-size: medium;">Flere myocytter fusioneres til en myotube indeholdende mange cellekerner.</span></li><li><span style="font-size: medium;">Det er vigtigt, at cellekernerne bliver placeret korrekt i myotuberne.</span></li><li><span style="font-size: medium;">Placering af cellekerner er reguleret af CDC42.</span></li></ul></span><div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Den neuromuskulære junction (NMJ) forbinder motorneuroner med muskler, således at elektriske signaler fra nervesystemet kan inducere muskelsammentrækninger. Der er en stor samling af cellekerner i muskelfibrene under NMJ, hvilket har betydning for NMJ's funktion. NMJ og satellitcellerne arbejder sammen. Hvis der mangler satellitceller vil det påvirke vedligehold af NMJ. Satellitcelle dysfunktion er involveret i flere neuromuskulære sygdomme (7).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Satellitcellers regenerative evne vedligeholdes af mitokondriers påvirkning af metabolismen og af mitofagi (8).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">PERK og UPR regulerer satellitcelle medieret muskel regeneration (9).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>KIRREL3</b></span></div><div><span style="font-size: medium;">KIRREL3 hos bananfluer under udvikling er involveret i myoblast fusion. Og forskellige varianter af KIRREL3 findes i muskler hos mennesker (10).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">KIRREL3 proteinet hos mus regulerer de morfologiske ændringer af myoblaster, der er nødvendige for den senere fusion til myotuber med mange cellekerner. KIRREL3 kan betegnes som et myoblast adhesions molekyle. Det er rimeligt at antage, at KIRREL3 proteinet har samme funktion hos mennesker (11).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>TNK2</b></span></div><div><span style="font-size: medium;">TNK2 er en tyrosine kinase, der kan regulere en række proteiner. TNK2 regulerer <a href="https://www.ncbi.nlm.nih.gov/gene/998">CDC42</a> aktivitet. CDC42 har betydning for musklers evne til at regenerere, idet CDC42 er involveret i cellekernernes placering i både myoblaster og andre celletyper (5, 6, 7).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><span>I kræftceller kan TNK2 aktiverer ATP syntase F1 subunit alfa (= ATP5F1A = ATP5A). Herved øges stabiliteten af ATP syntase (= </span><span>mitokondrie kompleks V) (12).</span></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">ME forskning har vist, at kompleks V arbejder ineffektivt (13).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">I NK celler fra ME patienter blev ekspression af kinase gener undersøgt. TNK2 havde den mest nedregulerede ekspression (mindste p-værdi) (tabel 3 i ref 14).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>PRUNE1</b></span></div><div><span style="font-size: medium;">PRUNE1 stimulerer vækst af knoglemarvs kræftceller ved at stimulere purin metabolismen, purin syntese enzymer og mitokondrie funktion (15).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Dysreguleret purin metabolisme er flere gange blevet påvist i ME (f.eks. i ref 16 og 17).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">PRUNE1 mutation er forbundet med neuromuskulære symptomer og påvirkning af motorneuroner (18).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">PRUNE1 ekspression er opreguleret i aktiverede satellitceller fra mus (figur 3 i ref 7).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>TPH2 og SLC6A4</b></span></div><div><span style="font-size: medium;">Serotonin (=5-hydroxytryptamine, 5-HT) er bedst kendt som neurotransmitter, men har også andre funktioner.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">TPH2 (=tryptofan hydroxylase 2) katalyserer det første trin i syntese af serotonin.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">SLC6A4 (=5-HTT = SERT) transporterer serotonin og kaldes også for 5-HT transporter.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">HTR2A (= 5-HT2A) og HTR2B (= 5-HT2B) er serotonin receptorer.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Anthony Yasmann har i en doktorgrad afhandling gjort rede for serotonins rolle i reparation af muskler. SLC6A4, HTR2A og HTR2B blev påvist i myoblaster. Det blev også påvist, at serotonin er involveret i at øge antallet af myoblaster i en cellekultur (19).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><b>ME puslespilsbrikker</b></span></div><div><span style="font-size: medium;">Vi har mitokondrie/superkompleks dysfunktion og ER stress, som ME puslespilsbrikker. Jeg tror, at vi skal have dysregulerede muskel satellitceller med som endnu en brik.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Måske kan satellitceller være med til at forklare endothel dysfunktion hos i ME og ME komorbiditeten POTS? Når muskler bliver beskadigede, bliver de små blodkar også påvirkede. Endothelceller, muskelceller og satellitceller interagerer under regenerationen. Under denne proces er de små blodkar udvidede. Kontrollen med blodkarsammentrækning og blodkarudvidelse fungerer ikke optimalt. Forsøg har vist, at kontrollen først reetableres efter ca. 21 dage efter en skade på det kapillære netværk (20). </span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Pihur's artikel indeholder flere "puslespilsbrikker" end de her nævnte. Jeg håber, at ME forskerne er i gang med at nærstudere Pihur og kollegers artikel.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /></span></div><span style="font-size: medium;"><b>Tidligere blogindlæg om WASF3:</b><br /><br />Årsagen til ME patienters motionsintolerance er fundet</span><div><span style="font-size: medium;"><div><a href="https://followmeindenmark.blogspot.com/2023/08/arsagen-til-me-patienters.html">https://followmeindenmark.blogspot.com/2023/08/arsagen-til-me-patienters.html</a></div><div><br /></div><div><b>Tidligere blogindlæg om muskel skade:</b></div></span><span style="font-size: medium;"><br />Increased serum and urine 3-methylhistidine in ME patients<br /><a href="https://followmeindenmark.blogspot.com/2020/03/increased-serum-and-urine-3.html">https://followmeindenmark.blogspot.com/2020/03/increased-serum-and-urine-3.html</a><br /><br />ME - a failure of inducing exercise tolerance?</span></div><div><span style="font-size: medium;"><a href="https://followmeindenmark.blogspot.com/2020/03/me-failure-of-inducing-exercise.html">https://followmeindenmark.blogspot.com/2020/03/me-failure-of-inducing-exercise.html</a><br /><br />Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients</span><br /></div><div><span style="font-size: medium;"><a href="https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html">https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html</a><br /></span></div><div><br /></div><div><p><span style="font-size: medium;"><b>Referencer</b></span></p><p><span style="font-size: medium;">1) </span><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Pihur V, Datta S, Datta S. Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data. Bioinformation. 2011 Apr 22;6(3):120-4. doi: 10.6026/97320630006120. PMID: 21584188; PMCID: PMC3089886.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/21584188/">https://pubmed.ncbi.nlm.nih.gov/21584188/</a></span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">2) Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. PMID: 37579159; PMCID: PMC10450651.</span>2) </p><p><a href="https://pubmed.ncbi.nlm.nih.gov/37579159/">https://pubmed.ncbi.nlm.nih.gov/37579159/</a><br /></p><p>3) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Marafon BB, Pinto AP, Ropelle ER, de Moura LP, Cintra DE, Pauli JR, da Silva ASR. Muscle endoplasmic reticulum stress in exercise. Acta Physiol (Oxf). 2022 May;235(1):e13799. doi: 10.1111/apha.13799. Epub 2022 Feb 21. PMID: 35152547.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/35152547/">https://pubmed.ncbi.nlm.nih.gov/35152547/</a></span></p><p>4) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Rodríguez-Fdez S, Bustelo XR. Rho GTPases in Skeletal Muscle Development and Homeostasis. Cells. 2021 Nov 2;10(11):2984. doi: 10.3390/cells10112984. PMID: 34831205; PMCID: PMC8616218.</span></p><p><a href="https://pubmed.ncbi.nlm.nih.gov/34831205/">https://pubmed.ncbi.nlm.nih.gov/34831205/</a><br /></p><p>5) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">McNally EM, Demonbreun AR. Resealing and rebuilding injured muscle. Science. 2021 Oct 15;374(6565):262-263. doi: 10.1126/science.abm2240. Epub 2021 Oct 14. PMID: 34648349; PMCID: PMC9112225.</span></p><p><a href="https://pubmed.ncbi.nlm.nih.gov/34648349/">https://pubmed.ncbi.nlm.nih.gov/34648349/</a><br /></p><p>6) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Cadot B, Gache V, Gomes ER. Moving and positioning the nucleus in skeletal muscle - one step at a time. Nucleus. 2015;6(5):373-81. doi: 10.1080/19491034.2015.1090073. PMID: 26338260; PMCID: PMC4915500.</span></p><p><a href="https://pubmed.ncbi.nlm.nih.gov/26338260/">https://pubmed.ncbi.nlm.nih.gov/26338260/</a> </p><p><span style="font-size: medium;">7) </span><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Ganassi M, Zammit PS. Involvement of muscle satellite cell dysfunction in neuromuscular disorders: Expanding the portfolio of satellite cell-opathies. Eur J Transl Myol. 2022 Mar 18;32(1):10064. doi: 10.4081/ejtm.2022.10064. PMID: 35302338; PMCID: PMC8992676.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/35302338/">https://pubmed.ncbi.nlm.nih.gov/35302338/</a><br /></span></p><p>8) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Hong X, Isern J, Campanario S, Perdiguero E, Ramírez-Pardo I, Segalés J, Hernansanz-Agustín P, Curtabbi A, Deryagin O, Pollán A, González-Reyes JA, Villalba JM, Sandri M, Serrano AL, Enríquez JA, Muñoz-Cánoves P. Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy. Cell Stem Cell. 2022 Sep 1;29(9):1298-1314.e10. doi: 10.1016/j.stem.2022.07.009. Epub 2022 Aug 22. Erratum in: Cell Stem Cell. 2022 Oct 6;29(10):1506-1508. PMID: 35998641.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/35998641/">https://pubmed.ncbi.nlm.nih.gov/35998641/</a><br /></span></p><p>9) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Xiong G, Hindi SM, Mann AK, Gallot YS, Bohnert KR, Cavener DR, Whittemore SR, Kumar A. The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration. Elife. 2017 Mar 23;6:e22871. doi: 10.7554/eLife.22871. PMID: 28332979; PMCID: PMC5391206.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/28332979/">https://pubmed.ncbi.nlm.nih.gov/28332979/</a><br /></span></p><p><span style="font-size: medium;">10) </span><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Durcan PJ, Conradie JD, Van deVyver M, Myburgh KH. Identification of novel Kirrel3 gene splice variants in adult human skeletal muscle. BMC Physiol. 2014 Dec 9;14:11. doi: 10.1186/s12899-014-0011-3. PMID: 25488023; PMCID: PMC4269076.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/25488023/">https://pubmed.ncbi.nlm.nih.gov/25488023/</a></span></p><p>11) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Tamir-Livne Y, Mubariki R, Bengal E. Adhesion molecule Kirrel3/Neph2 is required for the elongated shape of myocytes during skeletal muscle differentiation. Int J Dev Biol. 2017;61(3-4-5):337-345. doi: 10.1387/ijdb.170005eb. PMID: 28621431.</span></p><p><a href="https://pubmed.ncbi.nlm.nih.gov/28621431/">https://pubmed.ncbi.nlm.nih.gov/28621431/</a><br /></p><p><span style="background-color: white;"><span face="BlinkMacSystemFont, -apple-system, Segoe UI, Roboto, Oxygen, Ubuntu, Cantarell, Fira Sans, Droid Sans, Helvetica Neue, sans-serif" style="color: #212121;">12) </span></span><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Chouhan S, Sawant M, Weimholt C, Luo J, Sprung RW, Terrado M, Mueller DM, Earp HS, Mahajan NP. TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability. Autophagy. 2023 Mar;19(3):1000-1025. doi: 10.1080/15548627.2022.2103961. Epub 2022 Jul 27. PMID: 35895804; PMCID: PMC9980697.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/35895804/">https://pubmed.ncbi.nlm.nih.gov/35895804/</a><br /></span></p><p>13) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Missailidis D, Annesley SJ, Allan CY, Sanislav O, Lidbury BA, Lewis DP, Fisher PR. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Int J Mol Sci. 2020 Feb 6;21(3):1074. doi: 10.3390/ijms21031074. PMID: 32041178; PMCID: PMC7036826.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/32041178/">https://pubmed.ncbi.nlm.nih.gov/32041178/</a><br /></span></p><p>14) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Chacko A, Staines DR, Johnston SC, Marshall-Gradisnik SM. Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. Gene Regul Syst Bio. 2016 Aug 28;10:85-93. doi: 10.4137/GRSB.S40036. PMID: 27594784; PMCID: PMC5003121.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/27594784/">https://pubmed.ncbi.nlm.nih.gov/27594784/</a><br /></span></p><p>15) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Xu J, Wang Y, Li P, Chen C, Jiang Z, Wang X, Liu P. PRUNE1 (located on chromosome 1q21.3) promotes multiple myeloma with 1q21 Gain by enhancing the links between purine and mitochondrion. Br J Haematol. 2023 Sep 4. doi: 10.1111/bjh.19088. Epub ahead of print. PMID: 37666675.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/37666675/">https://pubmed.ncbi.nlm.nih.gov/37666675/</a><br /></span></p><p>16) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">McGregor NR, Armstrong CW, Lewis DP, Gooley PR. Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases. Diagnostics (Basel). 2019 Jul 4;9(3):70. doi: 10.3390/diagnostics9030070. PMID: 31277442; PMCID: PMC6787670.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/31277442/">https://pubmed.ncbi.nlm.nih.gov/31277442/</a><br /></span></p><p>17) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Germain A, Giloteaux L, Moore GE, Levine SM, Chia JK, Keller BA, Stevens J, Franconi CJ, Mao X, Shungu DC, Grimson A, Hanson MR. Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2022 May 9;7(9):e157621. doi: 10.1172/jci.insight.157621. PMID: 35358096; PMCID: PMC9090259.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/35358096/">https://pubmed.ncbi.nlm.nih.gov/35358096/</a><br /></span></p><p>18) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Okur D, Daimagüler HS, Danyeli AE, Tekgül H, Wang H, Wunderlich G, Çırak S, Yiş U. Bi-allelic mutations in PRUNE lead to neurodegeneration with spinal motor neuron involvement and hyperCKaemia. Turk J Pediatr. 2019;61(6):931-936. doi: 10.24953/turkjped.2019.06.015. PMID: 32134588.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/32134588/">https://pubmed.ncbi.nlm.nih.gov/32134588/</a><br /></span></p><p>19) Anthony Yasmann: From receptor to organ: Serotonin's interaction with the 5-HT1B
receptor and its role in skeletal muscle repair. Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München. 2021. Arbejdet blev udført ved Pasteur Instituttet i Frankrig.</p><p><a href="https://edoc.ub.uni-muenchen.de/28019/1/Yasmann_Anthony.pdf">https://edoc.ub.uni-muenchen.de/28019/1/Yasmann_Anthony.pdf</a><br /></p><p>20) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Pepe GJ, Albrecht ED. Microvascular Skeletal-Muscle Crosstalk in Health and Disease. Int J Mol Sci. 2023 Jun 21;24(13):10425. doi: 10.3390/ijms241310425. PMID: 37445602; PMCID: PMC10341943.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/37445602/">https://pubmed.ncbi.nlm.nih.gov/37445602/</a></span></p></div></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-62179534061797049972023-08-30T04:33:00.001-07:002023-08-30T04:40:12.197-07:00Palmitinsyre giver Endoplasmatisk Retikulum Stress<p><span style="font-size: medium;"><a href="https://en.wikipedia.org/wiki/Palmitic_acid">Palmitinsyre</a> (PA) er en mættet fedtsyre med 16 kulstofatomer (C16:0).</span></p><span style="font-size: medium;">Palmitinsyre findes i animalsk fedt og fedtholdige mejeriprodukter. Palmitinsyre indholdet er meget højt (44%) i palmeolie, som anvendes i vid udstrækning i fødevareindustrien.<br /><br />Fra reference 1: <br />Palm Oil is generally found in: baked goods, candies, cakes, cheese analogs, chips, chocolate, confectionary fats, cookies, cooking oil, crackers, doughnuts, frozen meals (pancakes, pies, pizza, potatoes), ice cream, industrial frying fats, instant noodles and oatmeals, margarines, microwave popcorn, non-dairy creamers, peanut butter, salad dressings, snacks, soups, supplements/vitamins, vegetable ghee.<br /><br />Der er påvist Endoplasmatisk Retikulum (ER) Stress hos ME patienter pga forhøjet niveau af proteinet WASF3 og mitokondrie dysfunktion (2). </span><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Palmitinsyre inducerer ER stress.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Fra reference 1 og referencer i denne artikel:<br />Palmitic Acid overload induce apoptotic cell death by ER stress [<a href="https://www.mdpi.com/1420-3049/20/9/17339#B129-molecules-20-17339">129</a>,<a href="https://www.mdpi.com/1420-3049/20/9/17339#B130-molecules-20-17339">130</a>]; moreover elevated concentrations of Palmitic Acid determine apoptosis and autophagy through mitochondrial dysfunction and ER stress, mediated by oxidative stress increase, in hepatocytes [<a href="https://www.mdpi.com/1420-3049/20/9/17339#B131-molecules-20-17339">131</a>], pancreatic beta cells [<a href="https://www.mdpi.com/1420-3049/20/9/17339#B132-molecules-20-17339">132</a>] and muscle cells [<a href="https://www.mdpi.com/1420-3049/20/9/17339#B133-molecules-20-17339">133</a>,<a href="https://www.mdpi.com/1420-3049/20/9/17339#B134-molecules-20-17339">134</a>,<a href="https://www.mdpi.com/1420-3049/20/9/17339#B135-molecules-20-17339">135</a>]. FFAs are oxidized by the β-oxidation process in mitochondria, the most important source of reactive oxygen species (ROS) [<a href="https://www.mdpi.com/1420-3049/20/9/17339#B136-molecules-20-17339">136</a>].</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Når ME patienters ER stress respons allerede er belastet, er det næppe godt at belaste det yderligere ved højt indtag af palmitinsyre. <br /><br /></span><p><span style="font-size: medium;">Læs om WASF3 og ER stress hos ME patienter:</span></p><a href="https://followmeindenmark.blogspot.com/2023/08/arsagen-til-me-patienters.html"><span style="font-size: medium;">Årsagen til ME patienters motionsintolerance er fundet</span></a><p><br /></p><p><span style="font-size: medium;"><b>Referencer</b></span></p><p>1) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Mancini A, Imperlini E, Nigro E, Montagnese C, Daniele A, Orrù S, Buono P. Biological and Nutritional Properties of Palm Oil and Palmitic Acid: Effects on Health. Molecules. 2015 Sep 18;20(9):17339-61. doi: 10.3390/molecules200917339. PMID: 26393565; PMCID: PMC6331788.</span></p><p><a href="https://www.mdpi.com/1420-3049/20/9/17339">https://www.mdpi.com/1420-3049/20/9/17339</a><br /></p><p>2) <span face="Arial, Tahoma, Helvetica, FreeSans, sans-serif" style="color: #212121;">Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. PMID: 37579159. </span></p><p><span face="Arial, Tahoma, Helvetica, FreeSans, sans-serif" style="color: #212121;"><a href="https://www.pnas.org/doi/10.1073/pnas.2302738120">https://www.pnas.org/doi/10.1073/pnas.2302738120</a></span></p><p><br /></p></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-25034554891899220382023-08-27T00:51:00.002-07:002023-08-29T04:38:03.702-07:00Are ME and MCS disease mechanisms linked through TRP ion channel dysfunction and ER stress?<p><span style="font-size: medium;">Myalgic encephalomyelitis (ME) patients have increased level of WASF3, disrupted mitochondrial respiration, and this is related to Endoplasmic Reticulum (ER) stress (1).</span></p><p><span style="font-size: medium;">Griffith University suggest ME is a Transient Receptor Potential (TRP) ion channelopathy (2).</span></p><p><span style="font-size: medium;">TRP channels may be leading actors in ER stress modulation (3).</span></p><p><span style="font-size: medium;">Many ME patients have Multiple Chemical Sensitivity (MCS). MCS disease mechanism is related to TRPA1 and TRPV1 (4). </span></p><p><span style="font-size: medium;">MCS patients do not tolerate environmental irritants, including volatile/semivolatile chemicals, (eg wood smoke and perfume).</span></p><p><span style="font-size: medium;">Recent findings demonstrated that TRPA1 and TRPV3 channel's activity (using wood smoke particle exposure) is directly correlated to the ER stress process in an opposite manner (5).</span></p><p><span style="font-size: medium;">This result has been further investigated, and has resulted in a hypothesis for how TRPA1 activation may affect the expression/function of TRPs involved in calcium handling (TRPV1 and TRPV3) and cytotoxic Endoplasmic Reticulum stress, thus modulating responses to TRPA1 stimuli (6):</span></p><p><span style="font-size: medium;"><br /></span></p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi6NwOBbTTC1I-JKCrWpa6jhBaCs40g6McS5NexAPXj2CSANWeHTP7FIGNByHAXR-GOoG0lGlluRrlpKLX5Ew6xuSNkR4qR5ndTbm6chCnSMwL3m6Fkb0PxUdPsij7YeOJ44Fjx3pENfYkm5sdLhQOWBQWTeWauWSBIEGbPr4AxD83yKABSElsHAjD6XpXF/s771/foto.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="672" data-original-width="771" height="438" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi6NwOBbTTC1I-JKCrWpa6jhBaCs40g6McS5NexAPXj2CSANWeHTP7FIGNByHAXR-GOoG0lGlluRrlpKLX5Ew6xuSNkR4qR5ndTbm6chCnSMwL3m6Fkb0PxUdPsij7YeOJ44Fjx3pENfYkm5sdLhQOWBQWTeWauWSBIEGbPr4AxD83yKABSElsHAjD6XpXF/w503-h438/foto.jpg" width="503" /></a></div><br /><span style="font-size: medium;">Figure 12 from <a href="https://ehp.niehs.nih.gov/doi/10.1289/EHP11076">reference 6</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/36847817/#&gid=article-figures&pid=figure-12-uid-11">Link to figure.</a></span><p></p><p><span style="font-size: large;"><br /></span></p><p><span style="font-size: large;">Are ME and MCS disease mechanisms linked through TRP ion channel dysfunction and ER stress?</span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>References</b></span></p><p><span style="font-size: medium;">1) </span><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. PMID: 37579159; PMCID: PMC10450651.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://www.pnas.org/doi/10.1073/pnas.2302738120">https://www.pnas.org/doi/10.1073/pnas.2302738120</a></span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">2) Du Preez S, Eaton-Fitch N, Smith PK, Marshall-Gradisnik S. Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Biomolecules. 2023 Jun 26;13(7):1039. doi: 10.3390/biom13071039. PMID: 37509075; PMCID: PMC10377690.</span></p><p><a href="https://www.mdpi.com/2218-273X/13/7/1039">https://www.mdpi.com/2218-273X/13/7/1039</a></p><p>3) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Vestuto V, Di Sarno V, Musella S, Di Dona G, Moltedo O, Gomez-Monterrey IM, Bertamino A, Ostacolo C, Campiglia P, Ciaglia T. New Frontiers on ER Stress Modulation: Are TRP Channels the Leading Actors? Int J Mol Sci. 2022 Dec 22;24(1):185. doi: 10.3390/ijms24010185. PMID: 36613628; PMCID: PMC9820239.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://www.mdpi.com/1422-0067/24/1/185">https://www.mdpi.com/1422-0067/24/1/185</a><br /></span></p><p>4) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Molot J, Sears M, Anisman H. Multiple chemical sensitivity: It's time to catch up to the science. Neurosci Biobehav Rev. 2023 Aug;151:105227. doi: 10.1016/j.neubiorev.2023.105227. Epub 2023 May 10. PMID: 37172924.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://www.sciencedirect.com/science/article/pii/S0149763423001963">https://www.sciencedirect.com/science/article/pii/S0149763423001963</a></span></p><p>5) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Nguyen ND, Memon TA, Burrell KL, Almestica-Roberts M, Rapp E, Sun L, Scott AF, Rower JE, Deering-Rice CE, Reilly CA. Transient Receptor Potential Ankyrin-1 and Vanilloid-3 Differentially Regulate Endoplasmic Reticulum Stress and Cytotoxicity in Human Lung Epithelial Cells After Pneumotoxic Wood Smoke Particle Exposure. Mol Pharmacol. 2020 Nov;98(5):586-597. doi: 10.1124/molpharm.120.000047. Epub 2020 Sep 16. PMID: 32938721; PMCID: PMC7569310.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/32938721/">https://pubmed.ncbi.nlm.nih.gov/32938721/</a><br /></span></p><p>6) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Rapp E, Lu Z, Sun L, Serna SN, Almestica-Roberts M, Burrell KL, Nguyen ND, Deering-Rice CE, Reilly CA. Mechanisms and Consequences of Variable TRPA1 Expression by Airway Epithelial Cells: Effects of </span><i style="background-color: white; box-sizing: inherit; color: #212121; font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;">TRPV1</i><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"> Genotype and Environmental Agonists on Cellular Responses to Pollutants </span><i style="background-color: white; box-sizing: inherit; color: #212121; font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;">in Vitro</i><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"> and Asthma. Environ Health Perspect. 2023 Feb;131(2):27009. doi: 10.1289/EHP11076. Epub 2023 Feb 27. PMID: 36847817; PMCID: PMC9969990.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://ehp.niehs.nih.gov/doi/10.1289/EHP11076">https://ehp.niehs.nih.gov/doi/10.1289/EHP11076</a></span></p>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-24608028366004115332023-08-22T03:47:00.004-07:002023-09-20T07:02:57.533-07:00Årsagen til ME patienters motionsintolerance er fundet<p><span style="font-size: medium;">Forskere fra National Institute of Health (NIH) i USA har vist, at proteinet Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3) ødelægger mitokondriernes respiration, og dette medfører motionsintolerance hos ME patienter (1). Artiklen er her:</span></p><p><span style="font-size: medium;"><a href="https://www.pnas.org/doi/10.1073/pnas.2302738120">WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome</a><br /></span></p><p><span style="font-size: large;">I det følgende gennemgås afsnittene i artiklen, men først lidt basisviden.</span></p><p><span style="font-size: medium;"><b>Basisviden</b></span></p><p><span style="font-size: medium;"><a href="https://da.wikipedia.org/wiki/Mitokondrie">Mitokondrier</a> er cellernes kraftværker. De danner energi under forbrug af ilt (respiration). Mitokondrier består af 5 dele, kaldet mitokondriekompleks I-V. For at virke optimalt dannes superkomplekser af to enheder af kompleks III og en enhed af kompleks IV, de kaldes III</span><span style="font-size: x-small;">2</span><span style="font-size: medium;">+IV. Kompleks IV kaldes også for cytochrome c oxidase. Komplekset har to under-enheder kaldet mitocondrially encoded cytochrome oxidase 1 og 2 (<a href="https://www.ncbi.nlm.nih.gov/gene/4512">MTCO1</a> og <a href="https://www.ncbi.nlm.nih.gov/gene/4513">MTCO2</a> (COX1 og COX2) ). Mitokondriers forbrug af ilt og hermed deres evne til at danne energi kan måles med et <a href="https://www.agilent.com/en/products/cell-analysis/how-seahorse-xf-analyzers-work">SeaHorse apparat</a>. Resultatet angives som oxygen consumption rate (OCR).</span></p><p><span style="font-size: medium;"><a href="https://en.wikipedia.org/wiki/Protein_kinase">Protein kinaser</a> er enzymer, der kan sætte en fosfat-gruppe på et protein. Dette kaldes fosforylering, og er en metode celler anvender til at aktivere eller inaktivere proteinet. </span><span style="font-size: medium;">F. eks kan kinase <a href="https://www.ncbi.nlm.nih.gov/gene/1432">p38</a> (MAPK14) fosforylere proteinet <a href="https://www.ncbi.nlm.nih.gov/gene/7157">p53</a> (TP53) et sted på proteinet kaldet Ser46. Herved aktiveres p53.</span></p><p><span style="font-size: medium;"><a href="https://en.wikipedia.org/wiki/Protein_phosphatase">Protein fosfataser</a> er enzymer, der kan fjerne en fosfatgruppe fra et protein. Et eksempel på en fosfatase er <a href="https://en.wikipedia.org/wiki/Protein_phosphatase_1">Protein fosfatase 1</a> (PP1).</span></p><p><span style="font-size: medium;"><a href="https://da.wikipedia.org/wiki/Endoplasmatisk_reticulum">Endoplasmatisk Retikulum</a> (ER) er et organel i cellen, der bl.a. sørger for foldning og kvalitetskontrol af de proteiner, som cellen producerer. ER stress kan opstå af flere årsager, f.eks. viral infektion. Ved ER stress lukkes ned for protein translation. Vigtige ER proteiner: </span></p><p><span style="font-size: medium;"><a href="https://www.ncbi.nlm.nih.gov/gene/9451">PERK</a> (EIF2AK3) - en kinase, der fungerer som stress-sensor. Ved ER stress sætter PERK en fosfat-gruppe på proteinet <a href="https://www.ncbi.nlm.nih.gov/gene/1965">eIF2alfa</a> (EIF2S1), hvorved proteinet inaktiveres og translation standser. </span></p><p><span style="font-size: medium;"><a href="https://www.ncbi.nlm.nih.gov/gene/3309">GRP78</a> (BIP, HSPA5) er involveret i foldning og samling af proteiner i ER og er et nøgleprotein i regulering af ER homøostasen. Mitokondrie-proteinet <a href="https://www.ncbi.nlm.nih.gov/gene/55210">ATAD3A</a> stabiliserer GRP78 og reducerer ER stress.</span></p><p><span style="font-size: medium;">Dvs ved et normalt ER stress respons er niveauet af både PERK og GRP78 forhøjede.</span></p><p><br /></p><p><span style="font-size: large;">Afsnittene i artiklen:</span></p><p><span style="font-size: medium;"><b>Nedsat mitokondrie funktion i en patient med kronisk træthed</b></span></p><p><span style="font-size: medium;">Forskerne undersøgte en 38-årig kvinde med kronisk træthed og motionsintolerance. Kvinden var fra en familie med en kræft-forårsagende mutation i genet TP53. Kvindens motionsintolerance startede efter, at hun havde mononukleose som 16-årig. Mononukleose er kendt for at udløse ME, men kvinden havde ikke fået diagnosen. Hendes far og bror havde også TP53 mutationen, men de havde ikke kronisk træthed. Kvindens bror var rask. Kvinden (benævnt S1) og broren (benævnt S2) blev undersøgt i relation til kræftgenet. Broren fungerede som rask kontrolperson. Der blev udtaget fibroblast celler fra huden på dem begge til nærmere undersøgelse. Forskerne fandt, at kvinden (S1) i forhold til broren (S2) havde:</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">lavere OCR, dvs lavere iltforbrug</span></li><li><span style="font-size: medium;">formindsket niveau af proteinerne MTCO1 og MTCO2</span></li><li><span style="font-size: medium;">øget fosforylering af proteinet p53 ved Ser46</span></li><li><span style="font-size: medium;">øget aktivering af kinasen p38 (MAPK14)</span></li><li><span style="font-size: medium;">normal aktivering af kinaserne MKK3 og JNK</span></li><li><span style="font-size: medium;">øget niveau af WASF3</span></li></ul><p></p><p><span style="font-size: medium;"><span>Ø</span><span>get fosforylering af p53 betyder, at der var et celle stress respons. Det stemte overens med det øgede aktivitet af p38. Men hvad aktiverede p38? Normalt ville MKK3 og JNK være aktiverede, men noget andet påvirkede den biokemiske stivej. Og det var WASF3, som også kan aktivere p38 MAPK signalerings stivejen. </span></span></p><p><span style="font-size: medium;">WASF3 er i et studie fra 2011 udpeget, som det gen, der er mest associeret med ME (2). Manglende iltforbrug og mitokondrie dysfunktion er allerede påvist hos ME patienter. </span></p><p><span style="font-size: medium;">Niveauet af MTCO1 var formindsket med ca. 34%, og niveauet af WASF3 var øget med ca. 40%. Var der en sammenhæng mellem mitokondrie dysfunktion og WASF3? Og kunne det have relation til ME?</span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>WASF3 undertrykker mitokondriel respiration</b></span></p><p><span style="font-size: medium;">For at undersøge sammenhængen mellem niveauet af WASF3 og mitokondriernes funktion manipulerede forskerne celler fra kvinden S1. Cellernes niveau af WASF3 blev reduceret (=knock down), og cellernes funktion blev igen undersøgt i forhold til normale celler fra den raske bror S2. Kvindens celler uden WASF3 viste nu: </span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">forbedret mitokondriel funktion</span></li><li><span style="font-size: medium;">øget niveau af under-enheder til mitokondrie kompleks IV</span></li><li><span style="font-size: medium;">nedsat fosforylering af p53 og p38, men ikke JNK</span></li></ul><p></p><p><span style="font-size: medium;">Der blev foretaget en del yderligere kontrolforsøg med andre cellekulturer for at sikre, at reduktionen af WASF3 virkelig kunne forbedre mitokondriernes funktion. Og det blev eftervist, at kvindens mutation i TP53 genet ikke havde noget at gøre med den defekte regulering af WASF3.</span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>Overekspression af WASF3 formindsker motionskapaciteten og mitokondriernes metabolisme hos mus</b></span></p><p><span style="font-size: medium;">Forskerne frembragte mus med øget ekspression af WASF3. Musene havde:</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">øget niveau af WASF3 i muskler</span></li><li><span style="font-size: medium;">formindsket niveau af under-enheder i mitokondrie kompleks IV</span></li><li><span style="font-size: medium;">ikke øget WASF3 i hjerte, hjerne eller lever, men der var en mindre reduktion af kompleks IV under-enheder</span></li><li><span style="font-size: medium;">reprogrammering af metabolismen mod glykolyse (= glucose forbrænding)</span></li><li><span style="font-size: medium;">højere niveau af laktat i blodet</span></li><li><span style="font-size: medium;">lavere niveau af glykogen i muskler</span></li><li><span style="font-size: medium;">ca 50% reduktion af den maximale motionskapacitet</span></li><li><span style="font-size: medium;">normal gribestyrke</span></li><li><span style="font-size: medium;">normal levetid</span></li></ul><p></p><p><span style="font-size: medium;">Tidligere forskning har vist, at ME patienter har forhøjet niveau af laktat i blodet under hvile, og dette korrelerer med deres postexertional malaise (PEM). </span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>WASF3 er lokaliseret til mitokondrierne og regulerer samlingen af respiratoriske superkomplekser</b></span></p><p><span style="font-size: medium;"><span>Forsøg med muse myoblast celle kultur (C2C12) med øget niveau af WASF3 viste:</span></span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">WASF3 findes både i cellens cytoplasma og i association til mitokondrierne</span></li><li><span style="font-size: medium;">WASF3 er fosforyleret, når det er i kontakt med mitokondrier</span></li><li><span style="font-size: medium;">når WASF3 er lokaliseret til mitokondrierne, ødelægges dannelsen af mitkondrie superkomplekser III</span><span style="font-size: x-small;">2</span><span style="font-size: medium;">+IV</span></li></ul><span style="font-size: medium;"><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Forsøg både med C2C12 med øget WASF3 og med muskelceller fra mus med øget WASF3 viste:</span></div><div><ul style="text-align: left;"><li><span>ca. 50% reduktion af III</span><span style="font-size: x-small;">2</span><span>+IV aktivitet, mens kompleks I aktivitet var lidt højere</span></li></ul></div></span><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>Forhøjet ekspression af WASF3 i ME patienters muskler er associeret med ER stress</b></span></p><p><span style="font-size: medium;">Idet S1's symptomer var identiske med ME patienters, undersøgte forskerne muskel biopsier fra ME patienter og sammenlignede med biopsier fra raske kontrolpersoner. Her fandt man, at ME patienter havde: </span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">øget niveau af WASF3</span></li><li><span style="font-size: medium;">formindsket niveau af mitokondrie kompleks IV under-enheder</span></li><li><span style="font-size: medium;">øget niveau af ER stress sensoren PERK (EIF2AK3)</span></li><li><span style="font-size: medium;">lavere niveau af GRP78 (BIP, HSPA5)</span></li><li><span style="font-size: medium;">niveauet af kompleks IV under-enheder korrelerede omvendt både med niveauet af WASF3 og PERK</span></li></ul><p></p><p><span style="font-size: medium;">Dette resultat tyder på, at den biokemiske ER stress stivej er forrringet. Fænomenet "ER Stress Response Failure" menes at resultere i metaboliske forstyrrelser.</span></p><p><span style="font-size: medium;">For yderligere at teste sammenhængen mellem ER stress og WASF3, blev en menneske celle kultur (myoblasts) behandlet med kemikalier, således ER stress blev induceret. Herefter kunne måles:</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">øget niveau af WASF3</span></li><li><span style="font-size: medium;">nedsat niveau af kompleks IV under-enhed MTCO1</span></li><li><span style="font-size: medium;">øget niveau af PERK (EIF2AK3)</span></li><li><span style="font-size: medium;">øget niveau af BIP (GRP78, HSPA5)</span></li></ul><p></p><p><span style="font-size: medium;">Så blev mus udsat for lipopolysakkararid (LPS), som er et endotoxin, der er kendt for at inducere ER stress. Herefter blev der udtaget muskelprøver fra musene. De viste:</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">øget niveau af WASF3</span></li><li><span style="font-size: medium;">øget niveau af PERK (EIF2AK3)</span></li><li><span style="font-size: medium;">øget niveau af BIP (GRP78, HSPA5))</span></li><li><span style="font-size: medium;">formindsket niveau af kompleks IV under-enhed MTCO1</span></li></ul><span style="font-size: medium;"><div><span style="font-size: medium;"><br /></span></div>Det betyder, at den træthed, der følge efter LPS kan relateres til WASF3. </span><br /><p></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>Farmakologisk inhibering af ER stress mindsker WASF3 og hjælper dannelsen af superkomplekser og respiration</b></span></p><p><span style="font-size: medium;">ER stress vil normalt medføre nedlukning af protein <a href="https://en.wikipedia.org/wiki/Translation_(biology)">translation</a>. PERK kinase aktivitet vil medføre en fosforylering af protein translations faktor eIF2alfa (EIF2S1), som inaktiverer translations faktoren. Dette var ikke tilfældet med kvinden S1. Kvindens eIF2alfa var meget mindre fosforyleret end hendes brors, og hermed stadig aktivt. Det betyder, at der var ER Stress Response Failure hos kvinden, ligesom der også var det i ME patienternes muskel biopsier.</span></p><p><span style="font-size: medium;">Der findes forskellige kemiske stoffer, som kan inhibere ER stress. To af disse inhibitorer, tauroursodeoxycholic acid og <a href="https://en.wikipedia.org/wiki/Salubrinal">salubrinal</a>, blev afprøvet på fibroblast celler fra kvinden S1. Salubrinal havde en effekt, idet niveauet af både PERK og WASF3 blev reduceret.</span></p><p><span style="font-size: medium;">Salubrinal inhibere enzymet protein fosfatase 1 (PP1), og dette medfører, at fosfat-gruppen ikke fjernes fra proteinet eIF2alfa. Hermed bliver der lukket ned for protein translation, som en normal del af ER stress responset. Salubrinal behandlingen fik genskabt mitokondrie komplekserne og respirationen blev forbedret.</span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>Diskussion</b></span></p><p><span style="font-size: medium;">Under dette afsnit skriver forskerne bl.a.:</span></p><p><span style="font-size: medium;">I dette studie har vi vist, at WASF3 induceret af ER stress ødelægger dannelsen af respiratoriske superkomplekser og reducerer mitokondriernes forbrug af ilt. Dette giver en molekylær forklaring på energimangel symptomer ved motionsintolerance og postexertional malaise (PEM) i en patient med kronisk træthed.</span></p><p><span style="font-size: medium;">I overensstemmelse med dette blev der fundet forhøjet ER stress og WASF3 niveau i association med reduceret niveau af mitokondrie kompleks IV under-enheder i muskelbiopsier fra ME patienter. Vigtigt er det, at farmakologisk inhibering af ER stress i celler fra den 38-årige patient nedbragte niveauet af WASF3 og forbedrede superkompleks dannelsen og respiration, hvilket giver udsigt til terapeutiske muligheder for at lindre træthedssymptomer hos patienter med ME.</span></p><p><span style="font-size: medium;">Ydermere skriver forskerne i dette afsnit, at forekomst af WASF3 bør overvejes i andre relaterede træthedstilstande, som f.eks. long COVID.</span></p><p><br /></p><p><span style="font-size: medium;"><b>Referencer</b></span></p><p><span style="font-size: medium;">1) </span><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. PMID: 37579159. </span></p><a href="https://www.pnas.org/doi/10.1073/pnas.2302738120">https://www.pnas.org/doi/10.1073/pnas.2302738120</a><br /><p><br /></p><p>2) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Pihur V, Datta S, Datta S. Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data. Bioinformation. 2011 Apr 22;6(3):120-4. doi: 10.6026/97320630006120. PMID: 21584188; PMCID: PMC3089886.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/21584188/">https://pubmed.ncbi.nlm.nih.gov/21584188/</a><br /></span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><br /></span></p>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-70146594712984959362023-07-14T03:01:00.017-07:002023-07-29T05:33:15.876-07:00Er Myalgisk Encephalomyelitis en TRP ionkanalopati?<p><span style="font-size: medium;">Et stigende antal artikler peger på dysregulering af calcium ion signalering hos ME patienter. Dette involverer Transient Receptor Potential (TRP) ion kanal dysfunktion (Reference 1 og referencer i denne artikel).</span></p><p><span style="font-size: medium;">Senest har forskere fra Griffith Universitet påvist dysregulering af TRPM7 i NK celler fra ME patienter. Forskningsgruppen har tidligere påvist dysregulering af TRPM3 og skriver i deres nye artikel:<br /><br /><i>"<span style="font-family: times;"><span style="background-color: white; color: #222222; text-align: justify;">Findings from this investigation suggest that TRPM7-dependent Ca</span><span style="background-color: white; bottom: 0.33em; box-sizing: border-box; color: #222222; line-height: 0; max-height: 1e+06px; position: relative; text-align: justify; vertical-align: baseline;">2+</span><span style="background-color: white; color: #222222; text-align: justify;"> influx is reduced with agonism and increased with antagonism in ME/CFS patients relative to the age- and sex-matched HCs.</span></span></i></span><i><span style="font-family: times;"><span style="font-size: medium;"> The outcomes reported here potentially reflect TRPM3 dysfunction identified in this condition </span><span style="font-size: large;">suggesting that ME/CFS is a TRP ion channelopathy.</span></span><span style="font-size: medium;">"</span></i></p><p><span style="font-size: medium;">TRPM7 er en ionkanal, der er involveret i regulering af flere forskellige immun celler (2).</span></p><p><span style="font-size: medium;">F.eks. regulerer TRPM7 proliferation og polarisering af makrofager (3). Og TRPM7 kinase aktivitet regulerer degranulering af mastceller hos mus (4).</span></p><p><span style="font-size: medium;">TRP ion kanaler er også dysregulerede i ME komorbiditeten Multiple Chemical Sensitivity (MCS):</span></p><p><span style="font-size: medium;"></span></p><span style="font-size: medium;">Biokemisk forklaring på Multiple Chemical Sensitivity</span><div><a href="http://followmeindenmark.blogspot.com/2023/07/biokemisk-forklaring-pa-multiple.html"><span style="font-size: medium;">http://followmeindenmark.blogspot.com/2023/07/biokemisk-forklaring-pa-multiple.html</span></a><p><br /></p><p><span style="font-size: medium;"><b>Referencer</b></span></p><p><span face="Arial, Arial, Helvetica, sans-serif" style="background-color: white; color: #222222;">1) Du Preez, S.; Eaton-Fitch, N.; Smith, P.K.; Marshall-Gradisnik, S. Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. </span><em style="background-color: white; box-sizing: border-box; color: #222222; font-family: Arial, Arial, Helvetica, sans-serif; line-height: inherit; max-height: 1e+06px;">Biomolecules</em><span face="Arial, Arial, Helvetica, sans-serif" style="background-color: white; color: #222222;"> </span><span face="Arial, Arial, Helvetica, sans-serif" style="background-color: white; box-sizing: border-box; color: #222222; font-weight: 700; line-height: inherit; max-height: 1e+06px;">2023</span><span face="Arial, Arial, Helvetica, sans-serif" style="background-color: white; color: #222222;">, </span><em style="background-color: white; box-sizing: border-box; color: #222222; font-family: Arial, Arial, Helvetica, sans-serif; line-height: inherit; max-height: 1e+06px;">13</em><span face="Arial, Arial, Helvetica, sans-serif" style="background-color: white; color: #222222;">, 1039. https://doi.org/10.3390/biom13071039</span></p><p><a href="https://www.mdpi.com/2218-273X/13/7/1039">https://www.mdpi.com/2218-273X/13/7/1039</a></p><p>2) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Liang HY, Chen Y, Wei X, Ma GG, Ding J, Lu C, Zhou RP, Hu W. Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases. Immunology. 2022 Jan;165(1):3-21. doi: 10.1111/imm.13420. Epub 2021 Oct 5. PMID: 34558663.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;"><a href="https://onlinelibrary.wiley.com/doi/full/10.1111/imm.13420">https://onlinelibrary.wiley.com/doi/full/10.1111/imm.13420</a></span></p><p>3) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Schilling T, Miralles F, Eder C. TRPM7 regulates proliferation and polarisation of macrophages. J Cell Sci. 2014 Nov 1;127(Pt 21):4561-6. doi: 10.1242/jcs.151068. Epub 2014 Sep 9. PMID: 25205764; PMCID: PMC4215710.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;"><a href="https://pubmed.ncbi.nlm.nih.gov/25205764/">https://pubmed.ncbi.nlm.nih.gov/25205764/</a></span></p><p>4) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Zierler S, Sumoza-Toledo A, Suzuki S, Dúill FÓ, Ryazanova LV, Penner R, Ryazanov AG, Fleig A. TRPM7 kinase activity regulates murine mast cell degranulation. J Physiol. 2016 Jun 1;594(11):2957-70. doi: 10.1113/JP271564. Epub 2016 Jan 27. PMID: 26660477; PMCID: PMC4887679.</span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;"><a href="https://pubmed.ncbi.nlm.nih.gov/26660477/">https://pubmed.ncbi.nlm.nih.gov/26660477/</a><br /></span></p></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-58198797264043424432023-07-13T01:37:00.000-07:002023-07-13T01:37:23.942-07:00Biokemisk forklaring på Multiple Chemical Sensitivity <p><span style="font-size: medium;">Med over 600 referencer er artiklen "Multiple Chemical Sensitivity: It's time to catch up to the science" en meget grundig gennemgang af den mulige biokemi bag Multiple Chemical Sensitivity (MCS). </span><br /><br /><span style="font-size: medium;">Highlights fra artiklen: <br /></span></p><ul style="text-align: left;"><li><span style="font-size: medium;"><span style="font-size: medium;">Functional imaging studies demonstrated multiple brain changes in MCS.</span></span></li><li><span style="font-size: medium;"><span style="font-size: medium;">These brain regions express TRPV1 and TRPA1 receptors.</span></span></li><li><span style="font-size: medium;"><span style="font-size: medium;">TRPV1 and TRPA1 receptors are sensitized in MCS.</span></span></li><li><span style="font-size: medium;"><span style="font-size: medium;">Similar brain regions are involved in comorbid physical and psychological conditions.</span></span></li><li><span style="font-size: medium;"><span style="font-size: medium;">TRP receptor hypersensitivity may contribute to comorbidity in MCS.</span></span></li></ul><p></p><span style="font-size: medium;"><br /><br /><b>Reference: </b>Molot J, Sears M, Anisman H. Multiple chemical sensitivity: It's time to catch up to the science. Neurosci Biobehav Rev. 2023 Aug;151:105227. doi: 10.1016/j.neubiorev.2023.105227. Epub 2023 May 10. PMID: 37172924.</span><div><span style="font-size: medium;"><a href="https://www.sciencedirect.com/science/article/pii/S0149763423001963">https://www.sciencedirect.com/science/article/pii/S0149763423001963</a><br /><br /></span><p><span style="font-size: medium;"><b>Tidligere blogindlæg om MCS og TRPA1: </b><br /><br />Transient Receptor Potential in Multiple Chemical Sensitivity</span></p><p><a href="http://followmeindenmark.blogspot.com/2013/02/transient-receptor-potential-in.html"><span style="font-size: medium;">http://followmeindenmark.blogspot.com/2013/02/transient-receptor-potential-in.html</span></a></p><span style="font-size: medium;"><br />Multiple Chemical Sensitivity, TRPA1 og aktivering af det autonome nervesystem og immunforsvaret</span><div><a href="http://followmeindenmark.blogspot.com/2014/08/multiple-chemical-sensitivity-trpa1-og.html"><span style="font-size: medium;">http://followmeindenmark.blogspot.com/2014/08/multiple-chemical-sensitivity-trpa1-og.html</span></a><div><span style="font-size: medium;"><br /><br />A role for TRPs in ME/CFS/POTS/MCS/pain/endothelial dysfunction...?<br /></span></div><div><a href="http://followmeindenmark.blogspot.com/2014/02/a-role-for-trps-in-mecfspotsmcspainendo.html"><span style="font-size: medium;">http://followmeindenmark.blogspot.com/2014/02/a-role-for-trps-in-mecfspotsmcspainendo.html</span></a></div><div><div class="post-header" style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 10.8px; line-height: 1.6; margin: 0px 0px 1.5em;"><div class="post-header-line-1"></div></div></div></div></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-63280745826594247192023-02-18T05:49:00.000-08:002023-02-18T05:49:54.908-08:00ME patienter har endotel dysfunktion<p>Som en del af det norske rituximab behandlings-studie af ME patienter, blev endotel (engelsk: endothelial) funktion undersøgt (1).</p><p>Endothelium er betegnelsen for det tynde lag af celler, der dækker det indre af vores blodkar. Endotel funktion undersøges ved at undersøge blodgennemstrømningen. Det blev gjort på to måder:</p><p></p><ul style="text-align: left;"><li>Flow-mediated dilation (FMD). Dilation betyder udvidelse.</li><li>Post-occlusive reactive hyperemia (PORH). Post-occlusive betyder efter tillukning. Hyperemia betyder øget blodtilstrømning.</li></ul><p></p><p>Ved FMD måles diameter på en arterie ved hvile og efter 5 minutters tillukning, når blodet igen strømmer. Resultatet er øgningen af diameteren angivet i %.</p><p>Ved PORH måles mikrovaskulær blodgennemstrømning i huden 2 minutter efter, der har været lukket af for blodtilførsel. Resultatet angives i Perfusion Units (PU).</p><p>Undersøgelserne viste:</p><p></p><ul style="text-align: left;"><li>FMD hos ME patienter 5,1%</li><li><span>FMD hos kontrolpersoner<span> </span><span> <span> </span> 8,2%</span></span></li></ul><p></p><p><span><span>Det betyder, at ME patienter var ringere til at sende blod gennem blodkarret efter det havde været tillukket (p < 0,0001).</span></span></p><p></p><ul style="text-align: left;"><li><span><span>PORH hos ME patienter <span> </span><span> <span> </span>1354 PU</span></span></span></li><li>PORH hos kontrolpersoner 2208 PU</li></ul><p></p><p>Det betyder, at ME patienter var ringere til at sende blod gennem hudens små blodkar efter de havde været tillukket (p = 0,002).</p><p>Konklusionen var, at ME patienter har reduceret makro- og mikrovaskulær endotel funktion. </p><p><br /></p><p><b>Reference:</b></p>1) Sandvik MK, Sørland K, Leirgul E, Rekeland IG, Stavland CS, Mella O, Fluge Ø. Endothelial dysfunction in ME/CFS patients. PLoS One. 2023 Feb 2;18(2):e0280942. doi: 10.1371/journal.pone.0280942. PMID: 36730360; PMCID: PMC9894436.<p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/36730360/">https://pubmed.ncbi.nlm.nih.gov/36730360/</a><br /></span></p><p><br /></p><p><br /><b>Mere viden: </b></p><p>Post occlusive reactive hyperemia<br /><br /><a href="https://www.perimed-instruments.com/content/post-occlusive-reactive-hyperemia/">https://www.perimed-instruments.com/content/post-occlusive-reactive-hyperemia/</a></p><p><br /></p><p><br /></p><p><br /></p><p><br /></p>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-2286056508308526892023-02-18T00:41:00.023-08:002023-02-18T00:48:19.294-08:00Neurovaskulær dysregulering påvist hos ME patienterUnder motion skal venerne trække sig sammen, således veneblodet returneres til hjertet i tilstrækkeligt omfang. Hvis dette ikke sker, er der ikke blod nok til et fyldetryk i hjertekammeret. Det dysregulerede blodkredsløb medfører manglende iltforsyning til cellerne og hermed motionsintolerance. (engelsk: depressed cardiac output from impaired venous return - preload failure). <div><br /></div><div>Systrom's forskerteam har undersøgt om lægemidlet pyridostigmine kunne forbedre motionskapaciteten hos en gruppe ME patienter med lavt fyldetryk i højre hjertekammer (right artrial pressure (RAP) under 6,5 mm Hg. (1) </div><div><br /></div><div>45 ME patienter blev delt i to grupper. Begge grupper gennemgik invasiv kardiopulmonær motionstest (iCPET). Herefter fik den ene gruppe 60 mg pyridostigmine og den anden gruppe fik placebo. 50 minutter senere gennemgik alle en iCPET igen.
Den maksimale iltoptagelse (peak Vo2 mL/min) blev målet under begge test. </div><div><br /></div><div>ME patientgruppen der fik pyridostigmine forbedrede den maksimale iltoptaglese ved test 2 med 13,3 mL/min i forhold til første test. ME placebogruppen havde en forrringet maksimal iltoptagelse ved test 2 på minus 40,2 mL/min i forhold til deres første test. Det vil sige behandlingsresponset af pyridostigmine var 53,6 mL/min. Forsøget viste også, at faldet i peak Vo2 hos placebogruppen var forårsaget af et fald i cardiac output og preload failure. </div><div><br /></div><div>De fysiologiske ændringer i iltoptagelsen er små og ikke klinisk relevante, men de fortæller os noget om ME sygdomsmekanismen (1): </div><div><br /></div><div> "Interpretation: Pyridostigmine improves peak Vo2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise Vo2, cardiac output, and right atrial pressure following placebo may signal the onset of postexertional malaise. We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS." </div><div><br /></div><div><br /></div><div><b>Reference:</b></div><div>1) Joseph P, Pari R, Miller S, Warren A, Stovall MC, Squires J, Chang CJ, Xiao W, Waxman AB, Systrom DM. Neurovascular Dysregulation and Acute Exercise Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest. 2022 Nov;162(5):1116-1126. doi: 10.1016/j.chest.2022.04.146. Epub 2022 May 6. </div><div><a href="https://pubmed.ncbi.nlm.nih.gov/35526605/">https://pubmed.ncbi.nlm.nih.gov/35526605/</a><br /></div><div><br /></div><div><br /></div><div><b>Læs også:</b></div><div><span style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif;">Lav arteriel-venøs iltindhold difference hos ME patien</span><span style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif;">ter</span></div><div><div><a href="http://followmeindenmark.blogspot.com/2021/11/lav-arteriel-vens-iltindhold-difference.html">http://followmeindenmark.blogspot.com/2021/11/lav-arteriel-vens-iltindhold-difference.html</a><br /></div><div class="post-header" style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 10.8px; line-height: 1.6; margin: 0px 0px 1.5em;"><div class="post-header-line-1"></div></div><div class="post-body entry-content" id="post-body-8075709372659475532" itemprop="description articleBody" style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px; line-height: 1.4; position: relative; width: 570px;"></div></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-11487501091948770222022-05-02T01:41:00.054-07:002022-05-06T02:32:45.950-07:00Efter motion har ME patienter forhøjet niveau af pyrroline-5-carboxylate<span style="font-size: medium;">...fortsættelse. Læs først:<br />Metaboliske ændringer hos ME patienter før og efter to dages motion</span><div><div><span style="font-size: medium;"><a href="http://followmeindenmark.blogspot.com/2022/04/metaboliske-ndringer-hos-me-patienter.html">http://followmeindenmark.blogspot.com/2022/04/metaboliske-ndringer-hos-me-patienter.html</a><br /></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Efter motion var niveauet af pyrroline-5-carboxylate (P5C) signifikant øget hos kvinder med ME i forhold til raske kontrolpersoner (1).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">FC og p-værdier for P5C:</span></div><div><ul style="text-align: left;"><li><span style="font-size: medium;">D1PRE: FC = 1,18, p = 0,10</span></li><li><span style="font-size: medium;">D1POST: FC = 1,36, p = 0,009</span></li><li><span style="font-size: medium;">D2PRE: FC = 1,20, p = 0,13</span></li><li><span style="font-size: medium;">D2POST: FC = 1,72, p = 0,0000122</span></li></ul></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">P5C blev også fundet forhøjet hos ME patienter i Naviaux et al's studie (2).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">P5C er et mellemprodukt i omsætning af aminosyrerne prolin, glutamat og ornitin.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Ved iltmangel (hypoxia) fungerer P5C og prolin som et redoxpar, der påvirker NADP+/NADPH ratioen (3):</span></div><div><span style="font-size: large;"><br /></span></div><div><span style="font-size: large;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEhuV9-zB_D61j0yue34SO2F71SitFthCfG_UTXadO_WbIvFXbCbH16ul79yuwYeFsc3GOTu3_1Ho1Of78CTRPdPeEwTe6jdl4qASUsCM7176K4GuuppSpr5DJeBOPvwWWMTGcayiMT9XSM_wYCkjxSWvmEAFCQAKvwyOctXfgx-BuwXrGAFiDyNf7IVnA" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="526" data-original-width="744" height="354" src="https://blogger.googleusercontent.com/img/a/AVvXsEhuV9-zB_D61j0yue34SO2F71SitFthCfG_UTXadO_WbIvFXbCbH16ul79yuwYeFsc3GOTu3_1Ho1Of78CTRPdPeEwTe6jdl4qASUsCM7176K4GuuppSpr5DJeBOPvwWWMTGcayiMT9XSM_wYCkjxSWvmEAFCQAKvwyOctXfgx-BuwXrGAFiDyNf7IVnA=w500-h354" width="500" /></a></div><br /></span>Figure 1. The metabolic pathways of P5C—physiological intracellular intermediate of the interconversion of proline,
ornithine, and glutamate. Acetyl-CoA—acetyl coenzyme A, ATP—adenosine triphosphate, α-KG—α-ketoglutarate, Glu—glutamate, GSAL—L-glutamate-γ-semialdehyde, METC—mitochondrial electron transport chain, NAD+—oxidized form
of nicotinamide adenine dinucleotide, NADH—reduced form of nicotinamide adenine dinucleotide, NADP+ –oxidized
form of nicotinamide adenine dinucleotide phosphate, NADPH—reduced form of nicotinamide adenine dinucleotide
phosphate, ORN—ornithine, P5C—∆
1
-pyrroline-5-carboxylate, P5CDH—P5C dehydrogenase, P5CS—P5C synthase,
PAT1—proton-coupled amino acid transporter 1, PRODH/POX—proline dehydrogenase/oxidase, PROT—L-proline transporter PROT, PYCR1/2/L—P5C reductase 1/2/L, ROS—reactive oxygen species, SIT1—sodium/imino-acid transporter 1,
SNAT1/2—sodium-coupled neutral amino acid transporter 1/2, TCA cycle—tricarboxylic acid cycle, δOAT—ornithine
δ-aminotransferase. Reference: <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Chalecka M, Kazberuk A, Palka J, Surazynski A. P5C as an Interface of Proline Interconvertible Amino Acids and Its Role in Regulation of Cell Survival and Apoptosis. Int J Mol Sci. 2021 Oct 29;22(21):11763. doi: 10.3390/ijms222111763. PMID: 34769188; PMCID: PMC8584052. <a href="https://www.mdpi.com/1422-0067/22/21/11763">https://www.mdpi.com/1422-0067/22/21/11763</a></span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"></span></div><div><span style="font-size: large;"><br /></span></div><div><span style="font-size: large;"><br /></span></div><div><span style="font-size: medium;">Efter motion på 2. dagen var niveauet af proline signifikant øget hos kvinder med ME i forhold til raske kontrolpersoner (1): </span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">FC og p-værdier for proline: </span></div><div><ul><li><span style="font-size: medium;">D1PRE: FC = 1,03, p = 0,76</span></li><li><span style="font-size: medium;">D1POST: FC = 1,04, p = 0,88</span></li><li><span style="font-size: medium;">D2PRE: FC = 1,15, p = 0,13</span></li><li><span style="font-size: medium;">D2POST: FC = 1,18, p = 0,03</span></li></ul></div><span style="font-size: medium;"><div><span style="font-size: medium;"><br /></span></div></span></div><div><span style="font-size: medium;">Pyrroline-5-carboxylate synthase (P5CS) katalyserer syntesen af P5C. P5CS mærker cellestress og tilpasser metabolismen ved at regulere mitokondriel respiration. P5CS er nødvendig for den oxidative respiration i mitokondrierne (4).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Hvad betyder det øgede niveau af P5C og proline hos ME patienter? Har det forbindelse til hypoxia? Stiger niveauet af P5C, fordi den oxidative respiration i mitokondrierne er udfordret af ME sygdom-mekanismen?<br /><br /><br /><b>Læs også: </b><br />Lav arteriel-venøs iltindhold difference hos ME patienter</span><div><span style="font-size: medium;"><a href="http://followmeindenmark.blogspot.com/2021/11/lav-arteriel-vens-iltindhold-difference.html">http://followmeindenmark.blogspot.com/2021/11/lav-arteriel-vens-iltindhold-difference.html</a><br /></span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><br /></span></div><span style="font-size: medium;"><b>Andre gode artikler om P5C:</b><br />Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions</span><div><span style="font-size: medium;"><a href="https://pubmed.ncbi.nlm.nih.gov/35108535/">https://pubmed.ncbi.nlm.nih.gov/35108535/</a><br /></span></div><div><span style="font-size: medium;"><br />Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis</span></div><div><span style="font-size: medium;"><a href="https://pubmed.ncbi.nlm.nih.gov/34825974/">https://pubmed.ncbi.nlm.nih.gov/34825974/</a></span></div><div><span style="font-size: medium;"><br /></span><div><span style="font-size: large;"><br /></span></div><div><span style="font-size: large;"><b>Referencer</b></span></div><div><span style="font-size: large;"><br /></span></div><div><span style="font-size: medium;"><span>1) </span><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Germain A, Giloteaux L, Moore GE, Levine SM, Chia JK, Keller BA, Stevens J, Franconi CJ, Mao X, Shungu DC, Grimson A, Hanson MR. Plasma metabolomics reveals disrupted response and recovery following maximal exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. JCI Insight. 2022 Mar 31:e157621. doi: 10.1172/jci.insight.157621. Epub ahead of print. PMID: 35358096.</span></span></div><div><span style="font-size: medium;"><a href="https://insight.jci.org/articles/view/157621" style="background-color: white; color: #2288bb; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; text-decoration-line: none;">https://insight.jci.org/articles/view/157621</a> </span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">2) </span><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, Gordon E. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5472-80. doi: 10.1073/pnas.1607571113. Epub 2016 Aug 29. Erratum in: Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3749. PMID: 27573827; PMCID: PMC5027464.</span></span></div><div><span style="background-color: white;"><span face="BlinkMacSystemFont, -apple-system, Segoe UI, Roboto, Oxygen, Ubuntu, Cantarell, Fira Sans, Droid Sans, Helvetica Neue, sans-serif" style="color: #212121; font-size: medium;"><a href="https://pubmed.ncbi.nlm.nih.gov/27573827/">https://pubmed.ncbi.nlm.nih.gov/27573827/</a></span></span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: medium;"><br /></span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: medium;">3) Chalecka M, Kazberuk A, Palka J, Surazynski A. P5C as an Interface of Proline Interconvertible Amino Acids and Its Role in Regulation of Cell Survival and Apoptosis. Int J Mol Sci. 2021 Oct 29;22(21):11763. doi: 10.3390/ijms222111763. PMID: 34769188; PMCID: PMC8584052.</span></div><div><a href="https://www.mdpi.com/1422-0067/22/21/11763"><span style="font-size: medium;">https://www.mdpi.com/1422-0067/22/21/11763</span></a></div></div></div><div><br /></div><div>4) <span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Yang Z, Zhao X, Shang W, Liu Y, Ji JF, Liu JP, Tong C. Pyrroline-5-carboxylate synthase senses cellular stress and modulates metabolism by regulating mitochondrial respiration. Cell Death Differ. 2021 Jan;28(1):303-319. doi: 10.1038/s41418-020-0601-5. Epub 2020 Aug 7. PMID: 32770108; PMCID: PMC7853148.</span></div><div><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;"><a href="https://www.nature.com/articles/s41418-020-0601-5">https://www.nature.com/articles/s41418-020-0601-5</a><br /></span></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-62637894103274832942022-04-30T00:39:00.013-07:002022-05-02T01:08:20.281-07:00ME patienter har lavt niveau af tridecenedioate<p><span style="font-size: medium;"> ...fortsættelse. Læs først:</span></p><h3 class="post-title entry-title" itemprop="name" style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-stretch: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-weight: normal; line-height: normal; margin: 0.75em 0px 0px; position: relative;"><span style="font-size: small;">Metaboliske ændringer hos ME patienter før og efter to dages motion</span></h3><div><a href="http://followmeindenmark.blogspot.com/2022/04/metaboliske-ndringer-hos-me-patienter.html">http://followmeindenmark.blogspot.com/2022/04/metaboliske-ndringer-hos-me-patienter.html</a><br /></div><div><br /></div><div><span style="font-size: medium;">En af metabolitterne fra figur 4 er tridecenedioate (C13:1-DC). Figuren viser metabolitter, hvor niveauet er signifikant forskelligt hos kvinder med ME i forhold til raske kontrolpersoner (1). </span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Data for tridecenedioate fremgår af supplerende tabel 4:</span></div><div><span style="font-size: medium;">D1PRE (dag 1 før motion)</span></div><div><ul style="text-align: left;"><li><span style="font-size: medium;">p = 0,0000244</span></li><li><span style="font-size: medium;">q = 0,000685</span></li><li><span style="font-size: medium;">FC = 0,540</span></li></ul></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">D2POST (dag 2 efter motion)</span></div><div><ul style="text-align: left;"><li><span style="font-size: medium;">p = 0,000000516</span></li><li><span style="font-size: medium;">q = 0,000580</span></li><li><span style="font-size: medium;">FC = 0,453</span></li></ul></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Det betyder, at vi er meget sikre på, at kvinder med ME kun har halvt så meget af denne metabolit i forhold til raske kontrolpersoner.</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Tridecenedioate er en monoumættet dicarboxylic fedtsyre, som menes at have neuroproktektive egenskaber (2).</span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;">Et studie har vist, at fodboldatleter med gentagne hovedskader havde et lavere niveau af denne fedtsyre. Det lave niveau var associeret med en stigning i det inflammatoriske mir-505. Ydermere kunne data relateres til skanninger af hovedet. Se figur fra artiklen (2): </span></div><div><span style="font-size: medium;"><br /></span></div><div><span style="font-size: medium;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjjZst341W3gnnKYLtvAlN1OAwmvuhxyyaYopeF5nqXuMp1Q_L6FnkjImroH_o39p-ZE7nNrq0O3sCX9XDOpvP1uoRjgrFllOJ97hNekPXj032VpjgD_q5yVjKVRKUVcoRBUK8HOeo5kl6OZzKNnDi3BPbaO2N7vW8CdKTdM7QDmPf9lyPbpCtC0q-UpA" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="270" data-original-width="622" height="226" src="https://blogger.googleusercontent.com/img/a/AVvXsEjjZst341W3gnnKYLtvAlN1OAwmvuhxyyaYopeF5nqXuMp1Q_L6FnkjImroH_o39p-ZE7nNrq0O3sCX9XDOpvP1uoRjgrFllOJ97hNekPXj032VpjgD_q5yVjKVRKUVcoRBUK8HOeo5kl6OZzKNnDi3BPbaO2N7vW8CdKTdM7QDmPf9lyPbpCtC0q-UpA=w519-h226" width="519" /></a></div><div class="separator" style="clear: both; text-align: center;"><br /></div></span></div><div><span style="box-sizing: border-box; color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 16px; margin: 0px; padding: 0px;">Synopsis figure summarizing the interplay between moderation variables. Repetitive head acceleration events (HAE) in football athletes have been related to changes in brain homeostasis, as evidenced by neuroimaging studies. In the present study, significant moderation effects were observed with <a class="topic-link" href="https://www.sciencedirect.com/topics/neuroscience/default-mode-network" style="box-sizing: border-box; color: #2e2e2e; margin: 0px; padding: 0px; text-decoration-color: rgb(46, 46, 46); text-decoration-thickness: 1px; text-underline-offset: 1px; word-break: break-word;" title="Learn more about default mode network from ScienceDirect's AI-generated Topic Pages">default mode network</a> (DMN) </span><em style="box-sizing: border-box; color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 16px; margin: 0px; padding: 0px;">fingerprint similarity</em><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 16px;">, miR-505, VR balance task performance, and tridecenedioate. Tridecenedioate, a dicarboxylic fatty acid with one double bond, significantly decreased from </span><em style="box-sizing: border-box; color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 16px; margin: 0px; padding: 0px;">Pre</em><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 16px;"> to </span><em style="box-sizing: border-box; color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 16px; margin: 0px; padding: 0px;">Post-</em><span style="box-sizing: border-box; color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 16px; margin: 0px; padding: 0px;">season. The double bond in this metabolite is hypothesized to act as a <a class="topic-link" href="https://www.sciencedirect.com/topics/neuroscience/reactive-oxygen-species" style="box-sizing: border-box; color: #2e2e2e; margin: 0px; padding: 0px; text-decoration-color: rgb(46, 46, 46); text-decoration-thickness: 1px; text-underline-offset: 1px; word-break: break-word;" title="Learn more about reactive oxygen species from ScienceDirect's AI-generated Topic Pages">reactive oxygen species</a> (ROS) scavenger. Indeed, previous research supports an increase in reactive oxygen species (ROS) following repetitive exposure to head impacts; therefore, a depletion of tridecenedioate would support its role as an ROS scavenger. Even with scavenging, ROS can still remain elevated and cause damage to neurophysiological systems. This may ultimately result in damage to neuronal connectivity as observed by decreased similarity in DMN and interactions with VR balance task performance. Together, these complex relationships may explain why behavioral changes in subconcussed athletes are not consistently observed, but how repetitive, long-term exposure to HAE, chronic increases of inflammatory-miRNAs, and acute changes to resting state networks could result in behavioral disturbances later in life.</span></div><div><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;">Reference: </span><span face=""Courier New", Courier, monospace, arial, sans-serif" style="background-color: white; font-size: 14px; white-space: pre-wrap;">Sumra Bari, Nicole L. Vike, Khrystyna Stetsiv, Alexa Walter, Sharlene Newman, Keisuke Kawata, Jeffrey J. Bazarian, Linda Papa, Eric A. Nauman, Thomas M. Talavage, Semyon Slobounov, Hans C. Breiter,</span><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; font-size: 14px; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;">Integrating multi-omics with neuroimaging and behavior: A preliminary model of dysfunction in football athletes,
Neuroimage: Reports,Volume 1, Issue 3,2021,100032,ISSN 2666-9560,
https://doi.org/10.1016/j.ynirp.2021.100032.
(https://www.sciencedirect.com/science/article/pii/S2666956021000301)</pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; font-size: 14px; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><br /></pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;">Hvad betyder det lave niveau af tridecenedioate for ME patienter?</span></pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;"><br /></span></pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;"><br /></span></pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;"><b>Læs også:</b></span></pre><span style="font-size: medium;">A metabolomic measure of energy metabolism moderates how an inflammatory miRNA relates to rs-fMRI network and motor control in football athletes</span></div><div><span style="font-size: medium;"><a href="https://arxiv.org/abs/2006.14930">https://arxiv.org/abs/2006.14930</a><br /></span><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;"><br /></span></pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;"><br /></span></pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;"><b>Referencer</b></span></pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;"><br /></span></pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;">1)</span>Germain A, Giloteaux L, Moore GE, Levine SM, Chia JK, Keller BA, Stevens J, Franconi CJ, Mao X, Shungu DC, Grimson A, Hanson MR. Plasma metabolomics reveals disrupted response and recovery following maximal exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. JCI Insight. 2022 Mar 31:e157621. doi: 10.1172/jci.insight.157621. Epub ahead of print. PMID: 35358096. </pre><p style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px;"><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="color: #212121; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/35358096/" style="color: #2288bb; text-decoration-line: none;">https://pubmed.ncbi.nlm.nih.gov/35358096/</a><br /></span></p><p style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: 13.2px;"><span style="font-size: medium;"><a href="https://insight.jci.org/articles/view/157621" style="color: #2288bb; text-decoration-line: none;">https://insight.jci.org/articles/view/157621</a></span></p><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;"><br /></span></pre><pre class="aLF-aPX-K0-aPE" style="background-color: white; font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><pre class="aLF-aPX-K0-aPE" style="font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;">2) Sumra Bari, Nicole L. Vike, Khrystyna Stetsiv, Alexa Walter, Sharlene Newman, Keisuke Kawata, Jeffrey J. Bazarian, Linda Papa, Eric A. Nauman, Thomas M. Talavage, Semyon Slobounov, Hans C. Breiter,
Integrating multi-omics with neuroimaging and behavior: A preliminary model of dysfunction in football athletes,
Neuroimage: Reports,
Volume 1, Issue 3,2021,100032,ISSN 2666-9560,
https://doi.org/10.1016/j.ynirp.2021.100032.</span></pre><pre class="aLF-aPX-K0-aPE" style="font-family: "Courier New", Courier, monospace, arial, sans-serif; margin-bottom: 0px; margin-top: 0px; overflow-wrap: break-word; user-select: text; white-space: pre-wrap;"><span style="font-size: medium;"><a href="https://www.sciencedirect.com/science/article/pii/S2666956021000301">https://www.sciencedirect.com/science/article/pii/S2666956021000301</a>
</span></pre></pre><br /></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-2792504318464896512022-04-29T06:08:00.000-07:002022-04-29T06:08:16.178-07:00Metaboliske ændringer hos ME patienter før og efter to dages motion<p><span style="font-size: medium;">Der er blevet udført et studie, hvor ME patienter og kontrolpersoner motionerede to dage i træk. Der blev udtaget blodprøver lige før og lige efter motion begge dage. De fire tidspunkter blev benævnt</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">D1PRE</span></li><li><span style="font-size: medium;">D1POST</span></li><li><span style="font-size: medium;">D2PRE</span></li><li><span style="font-size: medium;">D2POST</span></li></ul><p></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;">Blodprøverne blev undersøgt for indhold af metabolitter (metabolomics). </span></p><p><span style="font-size: medium;">Mængden af en metabolit hos ME patienter i forhold til kontrolpersoner er angivet som FoldChange (FC):</span></p><p></p><ul style="text-align: left;"><li><span style="font-size: medium;">FC mellem 0,9 og 1,1 - niveauet anses for uændret</span></li><li><span style="font-size: medium;">FC over 1,1 - niveauet af metabolitten er højere hos ME patienter</span></li><li><span style="font-size: medium;">FC under 0,9 - </span><span style="font-size: large;">niveauet af metabolitten er lavere hos ME patienter</span></li></ul><p></p><p><span style="font-size: large;"><br /></span></p><p><span style="font-size: large;">FC er signifikant ændret, når p-værdien er under 0,05. Der kan dog forekomme falsk positive værdier, der er derfor udført en Wilcoxon ranksum test. Denne angives ved en q-værdi, som skal være under 0,05. Denne grænse er meget konservativt sat og kan udelukke data, som er værd at kigge nærmere på. Derfor er q-værdier under 0,15 også angivet i artiklen. </span></p><p><span style="font-size: medium;">Den første blodprøve før motion på dag 1 (D1PRE) viste, at kvinder med ME havde 7 metabolitter, der var signifikant forskellige fra kontrolpersoner. Se figur 4 i artiklen <a href="https://insight.jci.org/articles/view/157621/pdf">https://insight.jci.org/articles/view/157621/pdf</a></span></p><p><span style="font-size: medium;">Efter 2 dage med motion (D2POST) var 56 metabolitter hos kvinder med ME ændrede. Se figur 3 i artiklen <a href="https://insight.jci.org/articles/view/157621/pdf">https://insight.jci.org/articles/view/157621/pdf</a></span></p><p><span style="font-size: medium;">Mange biokemiske stiveje var påvirkede hos kvinder med ME. Se figur 2 i det supplerende materiale <a href="https://insight.jci.org/articles/view/157621/sd/5">https://insight.jci.org/articles/view/157621/sd/5</a></span></p><p><span style="font-size: medium;">Det her studie er meget værdifuldt, og jeg er sikker på, at vi kommer til at høre meget mere om det. </span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;"><b>Reference</b></span></p><p><span style="background-color: white; color: #212121; font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;">Germain A, Giloteaux L, Moore GE, Levine SM, Chia JK, Keller BA, Stevens J, Franconi CJ, Mao X, Shungu DC, Grimson A, Hanson MR. Plasma metabolomics reveals disrupted response and recovery following maximal exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. JCI Insight. 2022 Mar 31:e157621. doi: 10.1172/jci.insight.157621. Epub ahead of print. PMID: 35358096. </span></p><p><span style="background-color: white; color: #212121; font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/35358096/">https://pubmed.ncbi.nlm.nih.gov/35358096/</a><br /></span></p><p><span style="font-size: medium;"><a href="https://insight.jci.org/articles/view/157621">https://insight.jci.org/articles/view/157621</a><br /></span></p><p><br /></p>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-80757093726594755322021-11-01T02:58:00.009-07:002021-11-01T03:08:47.332-07:00Lav arteriel-venøs iltindhold difference hos ME patienter<p><span style="font-size: medium;">Hjertet pumper iltet blod fra lungerne rundt i kroppen. Det iltrige blod føres ud i kroppen gennem arterier og kaldes for <b>arterielt blod</b>. Det iltfattige blod føres tilbage til hjertet gennem vener, for igen af blive pumpet ud i lungerne til iltning. Det iltfattige blod i venerne kaldes <b>venøst blod</b>.</span></p><p><span style="font-size: large;">Forskellen i iltindhold mellem arterielt blod og venøst blod kaldes på engelsk: </span></p><p><span style="font-size: medium;">"arterial-venous oxygen content difference".</span></p><p><span style="font-size: medium;">Det er hæmoglobin, der bærer ilt og iltindhold differencen skal vurderes i forhold til hæmoglobin koncentrationen. Der for ser formlen for iltindhold difference således ud: </span></p><p><span style="font-size: medium;">"(C</span><span style="font-size: x-small;">a-v</span><span style="font-size: medium;">O</span><span style="font-size: x-small;">2</span><span style="font-size: medium;">) / koncentrationen af Hb".</span></p><p><span style="font-size: medium;">Hvis den arteriel-venøse iltindhold difference er stor, så har kroppen optaget en masse ilt fra blodet. Og omvendt, hvis differencen er lav, betyder det, at det venøse blod vender tilbage til hjertet uden, at der er optaget så meget ilt.</span></p><p><span style="font-size: large;">Forskere fra Havard Medical School er eksperter i at måle iltindhold differencen under motion hos mennesker med motionsintolerance. Dette gøres ved en invasiv kardiopulmonær motionstest. Iltindhold differencen er under motionstest målt hos ME patienter:</span></p><p><span style="font-size: medium;">Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome</span></p><p><a href="https://journal.chestnet.org/article/S0012-3692(21)00256-7/fulltext" style="font-size: large;">https://journal.chestnet.org/article/S0012-3692(21)00256-7/fulltext</a></p><p><span style="font-size: medium;">Forskerne udvalgte data fra en patientgruppe, der både havde lavt fyldetryk i højre hjertekammer ("right arterial pressure" under 6,5 mm Hg) og som opfyldte ME diagnosekriterierne. Analyse af data viste, at ME patienterne under motion havde en lav arteriel-venøs iltindhold difference. Det betyder, at ME patienterne ikke optog/udnyttede ilten i blodet i tilstrækkelig grad. Dette medfører motionsintolerance. Forskerne udelukker dekonditionering som årsag til motionsintolerancen hos ME patienterne. I stedet peger de på mulige årsager, der kan bidrage til motionsintolerancen: </span></p><p><span style="font-size: medium;"> - Under motion bliver veneblodet ikke returneret til hjertet i tilstrækkeligt omfang, og der er herved ikke nok blod til et fyldetryk i hjertekammeret (engelsk: depressed cardiac output from impaired venous return - preload failure).</span></p><p><span style="font-size: medium;">- Manglende ilt udnyttelse fordi blodet passerer fra arterier til vener uden at komme ud i de helt små blodkar (kapillærer), hvor en stor del af ilten udnyttes. Fænomenet kaldes arteriel-venøs shunting (AV-shunting). AV-shunting kan forekomme ved småfiber neuropati, som blev påvist hos en del ME patienter i artiklen.</span></p><p><span style="font-size: medium;"><br /></span></p><p><span style="font-size: medium;">Reference: </span></p><p><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121; font-size: 16px;">Joseph P, Arevalo C, Oliveira RKF, Faria-Urbina M, Felsenstein D, Oaklander AL, Systrom DM. Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Chest. 2021 Aug;160(2):642-651. doi: 10.1016/j.chest.2021.01.082. Epub 2021 Feb 10. PMID: 33577778.</span></p>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-87528648385502514912020-09-01T01:03:00.007-07:002020-09-01T01:18:47.538-07:00ZFR suppresses the antiviral response, but not in ME? Is macroH2A1/H2AFY involved?<p><span style="font-size: large;">ME peripheral blood mononuclear cell (PBMC) proteomes reveal decreased level of zinc finger RNA-binding protein (ZFR), foldchange = 0,52, p-value = 0,00047 (1).</span></p><p><span style="font-size: large;"><span>ZFR suppresses interferon-beta induction and the antiviral response. </span>ZFR controls interferon signaling by preventing aberrant splicing and nonsense-mediated decay (NMD) of histone variant <a href="https://www.ncbi.nlm.nih.gov/gene/9555">macroH2A1/H2AFY</a> mRNAs (2).</span></p><span style="font-size: large;">Serum from ME patients contains an activity which induces a powerful antiviral state, but it seems like the interferon response has been ruled out in the ME pathomechanism (3, 4).<br /><br />However, macroH2A1 has also been shown to bind and repress interferon-stimulated genes (ISG) promoters, raising the possibility that the constitutive ISG induction in ZFR-depleted cells could be partially due to loss of direct action of macroH2A1 on these genes. Taking the available data together, macroH2A1 appears to both suppress the initiation of type I interferon signaling by inhibiting IFNB1 transcription <u>and</u> by modulating the consequences of IFNB1 transcription by directly repressing ISG promoters (2).<br /><br />The gene macroH2A1/H2AFY is differentially methylated in PBMC from ME patients. Read the blogpost:<br /><br />H2AFY and ME</span><div><span style="font-size: large;"><a href="https://followmeindenmark.blogspot.com/2018/10/h2afy-and-me.html">https://followmeindenmark.blogspot.com/2018/10/h2afy-and-me.html</a><br /></span><div><span style="font-size: large;"><br />Is dysregulated macroH2A1/H2AFY involved in the ME pathomechanism?<br /><br /></span><h4 style="text-align: left;"><span style="font-size: large;">MacroH2A1 can buffer transcriptional noise associated with the antiviral response</span></h4><span style="font-size: large;">Knockdown of macroH2A causes a dramatic change in the antiviral gene expression program. Genes that normally do not respond to virus infection get activated or repressed (5).<br /><br /><br /><br /></span><div><div><p><span style="font-size: large;"><b>References</b></span></p><span style="font-size: large;">preprint 1) Eiren Sweetman, Torsten Kleffmann, Christina Edgar, Michel de Lange, Rosamund Vallings Howick Warren Tate: A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction<br /><a href="https://assets.researchsquare.com/files/rs-52172/v1/6b319d19-80fb-46e3-b56e-3687ae1c7203.pdf">https://assets.researchsquare.com/files/rs-52172/v1/6b319d19-80fb-46e3-b56e-3687ae1c7203.pdf</a></span></div><div><span style="font-size: large;"><br /></span></div><div><span style="font-size: large;">2) Haque N, Ouda R, Chen C, Ozato K, Hogg JR. ZFR coordinates crosstalk between RNA decay and transcription in innate immunity. Nat Commun. 2018;9(1):1145. Published 2018 Mar 20. doi:10.1038/s41467-018-03326-5<br /></span><span style="font-size: large;"><a href="https://www.nature.com/articles/s41467-018-03326-5">https://www.nature.com/articles/s41467-018-03326-5</a><br /></span><span style="font-size: large;"><br />3) Schreiner P, Harrer T, Scheibenbogen C, et al. Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Immunohorizons. 2020;4(4):201-215. Published 2020 Apr 23. doi:10.4049/immunohorizons.2000006<br />https://pubmed.ncbi.nlm.nih.gov/32327453/<br /><br /></span><span style="font-size: large;">4) Corbitt M, Eaton-Fitch N, Staines D, Cabanas H, Marshall-Gradisnik S. A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID). BMC Neurol. 2019;19(1):207. Published 2019 Aug 24. doi:10.1186/s12883-019-1433-0<br /><br />5) Lavigne MD, Vatsellas G, Polyzos A, et al. Composite macroH2A/NRF-1 Nucleosomes Suppress Noise and Generate Robustness in Gene Expression. Cell Rep. 2015;11(7):1090-1101. doi:10.1016/j.celrep.2015.04.022</span><br /></div></div><div><span class="citation-doi" face="" style="background-color: white; box-sizing: inherit; color: #5b616b; display: inline-block; font-size: 16px; line-height: 1.5;"></span></div></div></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-35490225739620795422020-08-28T05:27:00.014-07:002020-08-30T10:50:07.471-07:00Atrogin 1 mRNA is elevated in muscle biopsies of ME patients<p><span style="font-size: large;"><span> Quote reference 1):<br />"Levels of Atrogin 1 mRNA were significantly elevated in muscle biopsies of patients with ME/CFS compared with HCs </span><span>(Healthy Controls)</span><span> suggesting an increase in protein </span><span>degradation processes in muscles of patients with ME/CFS compared with HCs. Atrogin-1 binds to polyubiquitinated proteins to direct them for subsequent degradation by the 26S proteasome and as such is an important regulator of ubiquitin-mediated protein degradation in skeletal muscle (69). Increased levels of Atrogin-1 mRNA are associated with reduced muscle mass (69) and in this study Atrogin-1 was associated with a significant reduction in muscle fibre size, although a detailed examination of muscle protein degradation was not undertaken."</span></span></p><p><span style="font-size: large;"><br />Atrogin 1, also known as muscle atrophy F-box (MAFbx), is encoded by <a href="https://www.ncbi.nlm.nih.gov/gene/114907">FBXO32</a>. Atrogin 1 degrades various muscle proteins, such as titin, nebulin, troponin, myosin-binding protein C, myosin light chains 1 and 2 and myosin heavy chains (2).</span></p><span style="font-size: large;">Increased degradation of myosin light chain proteins may lead to increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine (TMAP) (3). <br /><br /><br />Read the blogpost: <br /><a href="http://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html">Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients</a><br /><a href="https://www.blogger.com/#">http://followmeindenmark.blogspot.com/2020/02/</a><br /><br /><br /></span><div><p><span style="font-size: large;"><b>References:</b><br />preprint: 1) Arief Gusnanto, Kate Elizabeth Earl, George K Sakellariou, Daniel J Owens, Adam Lightfoot, Sandra A Fawcett, Euan Owen, Caroline A Staunton, Tu Shu, Fiona C Croden, Manuel Fenech, Melanie A Sinclair, Libuse Ratcliffe, Kasia A Whysall, Rebecca I Haynes, Nicola M Wells, Malcolm J Jackson, Graeme L Close, Clare L Lawton, Michael BJ Beadsworth, Louise Dye, Anne MCARDLE:<br />Discriminatory cytokine profiles predict muscle function, fatigue and cognitive function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<br />doi: https://doi.org/10.1101/2020.08.17.20164715<br /><a href="https://www.medrxiv.org/content/10.1101/2020.08.17.20164715v1">https://www.medrxiv.org/content/10.1101/2020.08.17.20164715v1</a><br /><br />2) Steinbacher and Eckl: Impact of oxidative stress on exercising skeletal muscle. Biomolecules 2015 Apr 10;5(2):356-77.<br />doi: 10.3390/biom5020356.<br /><a href="https://pubmed.ncbi.nlm.nih.gov/25866921/">https://pubmed.ncbi.nlm.nih.gov/25866921/</a><br /><br />3) Velenosi, T.J., Thomson, B.K.A., Tonial, N.C. et al. Untargeted metabolomics reveals N, N, N-trimethyl-L-alanyl-L-proline betaine (TMAP) as a novel biomarker of kidney function. Sci Rep 9, 6831 (2019). <a href="https://www.nature.com/articles/s41598-019-42992-3">https://www.nature.com/articles/s41598-019-42992-3</a><br />https://doi.org/10.1038/s41598-019-42992-3 PMID: 31048706 PMCID: <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6497643/">PMC6497643</a><br /></span><br /></p></div>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-72905064447636780272020-07-31T11:41:00.001-07:002020-07-31T11:41:39.794-07:00Mutationer i muciner kan måske forklare øget immun aktivering og kemikalie intolerance hos ME patienter<span style="font-size: large;">Muciner er en gruppe glykoproteiner, som findes i slimhinderne i luftveje, tarm, skede urinrør og øjne.</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Muciner sørger for at slimhinde-laget bliver tykt og højviskøst, så slimhinden bliver svær gennemtrængelig for virus, bakterier, skimmel og toxiner. Samtidig virker mucinerne som lokkemad for mikroorganismerne, der klistrer sig fast til sukkermolekylerne på mucinerne. Herved kan mikroorganismerne udstødes fra kroppen sammen med den slim, som kontinuerlig udskilles fra slimhinderne.</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Under slimhindelaget findes et lag epitel med immunceller, som aktiveres hvis mikroorganismer eller toxiner alligevel slipper igennem slimhindelaget. Mutationer i muciner kan påvirke slimhindernes beskaffenhed, således at der sker en større indtrængning af mikroorganismer og toxiner til epitelet. Herved vil immunforsvaret hyppigt aktiveres (1).</span><br />
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<span style="font-size: large;"><b>Muciner og ME</b></span><br />
<span style="font-size: large;">Der er fundet mutationer i muciner hos ME patienter, og det danner baggrund for en ny hypotese: </span><br />
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<span style="font-size: large;">Mutations in ME/CFS nasal mucins result in compromised protective barriere</span><br />
<br />
<ul>
<li><span style="font-size: large;">an altered nasal microbiome</span></li>
<li><span style="font-size: large;">a highly sensitive and irritated epithelial layer</span></li>
<li><span style="font-size: large;">chronic low grade non-allergic inflammatory response</span></li>
<li><span style="font-size: large;">exacerbation of ME/CFS symptomatology</span></li>
</ul>
<br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Hypotesen er fremlagt i et webinar. Indslaget begynder til tiden cirka 1 time og 55 minutter:<br />INIM Webinar - Understanding ME/CFS Today: A Clinical & Research Approach</span><br />
<a href="https://www.youtube.com/watch?v=QfrCF2atQxI&feature=youtu.be&t=8591"><span style="font-size: large;">https://www.youtube.com/watch?v=QfrCF2atQxI&feature=youtu.be&t=8591</span></a><br />
<span style="font-size: large;"><br />Forskerne bag studiet oplyser, at en mutation i mucin19 (MUC19) har særlig betydning for en beskadiget slimhinden i næse/øvre luftveje. Dette kan medføre øget følsomhed over for de kemikalier, som vi indånder. Det betyder at mutiple chemical sensitivity (MCS) kan forklares med hypotesen. MUC19 mutationen er nævnt i reference 2. </span><br />
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<span style="font-size: large;">Den nye mucin hypotese er forenelig med anden ME forskning: </span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Der er tidligere fundet mutationer i IDO2 genet hos meget syge ME patienter, og det danner baggrund for IDO ME hypotesen (3). IDO har betydning for nasal tolerance (4).</span><br />
<span style="font-size: large;">Læs blog: </span><span style="font-size: large;">IDO-ME hypotesen er forenelig med AHR-MCS hypotesen</span><br />
<span style="font-size: large;"><a href="http://followmeindenmark.blogspot.com/2019/06/ido-me-hypotesen-er-forenelig-med-ahr.html">http://followmeindenmark.blogspot.com/2019/06/ido-me-hypotesen-er-forenelig-med-ahr.html</a><br /><br /></span>
<span style="font-size: large;">Det er tidligere vist, at ME patienter har nedsat sygdomtolerance, og nasal stimulation kan afhjælpe ME symptomer (5).</span><br />
<span style="font-size: large;">Læs blog: </span><span style="font-size: large;">Det inflammatoriske respons og induktion af sygdomstolerance er dysreguleret hos ME patienter</span><br />
<span style="font-size: large;"><a href="http://followmeindenmark.blogspot.com/2020/03/det-inflammatoriske-respons-og.html">http://followmeindenmark.blogspot.com/2020/03/det-inflammatoriske-respons-og.html</a></span><br />
<div>
<span style="font-size: large;"><br /></span></div>
<div>
<span style="font-size: large;">Proteinet cathelicidin antimicrobial peptide (CAMP) kan påvises ved inflammatorisk respons. Det er f.eks. påvist i tarmens slimhinde hos patienter med inflammatory bowel disease (IBD). Plasma niveauet af CAMP er for forhøjet hos ME patienter (6).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Mere viden om CAMP:</span><br />
<span style="font-size: large;">Topical cathelicidin (LL-37) an innate immune peptide induces acute olfactory epithelium inflammation in a mouse model <a href="https://pubmed.ncbi.nlm.nih.gov/28837619/">https://pubmed.ncbi.nlm.nih.gov/28837619/</a></span></div>
<div>
<br />
<br />
<span style="font-size: large;">Læs også om mucin studiet på Health Rising bloggen:<br />Surprise Gene Finding Could Give Pathogens and Toxins a Leg Up in ME/CFS</span><br />
<span style="font-size: large;"><a href="https://www.healthrising.org/blog/2020/07/11/mucosal-genes-chronic-fatigue-syndrome/">https://www.healthrising.org/blog/2020/07/11/mucosal-genes-chronic-fatigue-syndrome/</a></span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;"><br /></span>
<span style="font-size: large;"><b>Referencer:</b></span><br />
<span style="font-size: large;">1) </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Linden+SK&cauthor_id=19079178" style="font-size: x-large;">S K Linden</a><span style="font-size: large;">, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Sutton+P&cauthor_id=19079178" style="font-size: x-large;">P Sutton</a><span style="font-size: large;">, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Karlsson+NG&cauthor_id=19079178" style="font-size: x-large;">N G Karlsson</a><span style="font-size: large;">, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Korolik+V&cauthor_id=19079178" style="font-size: x-large;">V Korolik</a><span style="font-size: large;">, </span><a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=McGuckin+MA&cauthor_id=19079178" style="font-size: x-large;">M A McGuckin</a><span style="font-size: large;">: Mucins in the mucosal barrier to infection. Mucosal Immunol 2008 May;1(3):183-97. doi: 10.1038/mi.2008.5. Epub 2008 Mar 5. </span><a href="https://pubmed.ncbi.nlm.nih.gov/19079178/" style="font-size: x-large;">https://pubmed.ncbi.nlm.nih.gov/19079178/</a><br />
<span style="font-size: large;"><br />2) <a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Perez+M&cauthor_id=31179255">Melanie Perez</a> et al: Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study Front Pediatr. 2019 May 24;7:206. doi: 10.3389/fped.2019.00206. eCollection 2019. <a href="https://pubmed.ncbi.nlm.nih.gov/31179255/">https://pubmed.ncbi.nlm.nih.gov/31179255/</a></span><br /><br /><span style="font-size: large;">3) <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kashi%20AA%5BAuthor%5D&cauthor=true&cauthor_uid=31357483">Kashi AA</a> <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Davis%20RW%5BAuthor%5D&cauthor=true&cauthor_uid=31357483">Davis RW</a> and, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Phair%20RD%5BAuthor%5D&cauthor=true&cauthor_uid=31357483">Phair RD</a>: The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS. <a href="https://www.ncbi.nlm.nih.gov/pubmed/31357483#">Diagnostics (Basel).</a> 2019 Jul 26;9(3). pii: E82. doi: 10.3390/diagnostics9030082. <a href="https://www.mdpi.com/2075-4418/9/3/82">https://www.mdpi.com/2075-4418/9/3/82</a><br /><br />4) <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=van%20der%20Marel%20AP%5BAuthor%5D&cauthor=true&cauthor_uid=17617580">van der Marel AP</a>1, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Samsom%20JN%5BAuthor%5D&cauthor=true&cauthor_uid=17617580">Samsom JN</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Greuter%20M%5BAuthor%5D&cauthor=true&cauthor_uid=17617580">Greuter M</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=van%20Berkel%20LA%5BAuthor%5D&cauthor=true&cauthor_uid=17617580">van Berkel LA</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=O%27Toole%20T%5BAuthor%5D&cauthor=true&cauthor_uid=17617580">O'Toole T</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kraal%20G%5BAuthor%5D&cauthor=true&cauthor_uid=17617580">Kraal G</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Mebius%20RE%5BAuthor%5D&cauthor=true&cauthor_uid=17617580">Mebius RE</a>. Blockade of IDO inhibits nasal tolerance induction. <a href="https://www.ncbi.nlm.nih.gov/pubmed/17617580#">J Immunol.</a> 2007 Jul 15;179(2):894-900.<br /><a href="https://www.ncbi.nlm.nih.gov/pubmed/17617580">https://www.ncbi.nlm.nih.gov/pubmed/17617580</a><br /><br />5) Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin: Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance<br />doi: https://doi.org/10.1101/2020.02.20.958249<br /><a href="https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract">https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract</a></span><br />
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<span style="font-size: large;">6) <a href="https://pubmed.ncbi.nlm.nih.gov/?sort=date&term=Milivojevic+M&cauthor_id=32692761">Milica Milivojevic</a> et al: Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS. PLoS One . 2020 Jul 21;15(7):e0236148. doi: 10.1371/journal.pone.0236148. eCollection 2020. <a href="https://pubmed.ncbi.nlm.nih.gov/32692761/">https://pubmed.ncbi.nlm.nih.gov/32692761/</a></span></div>
Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-7340544513227910422020-05-29T00:39:00.001-07:002020-07-31T11:02:06.034-07:00Kynurenine skal afprøves til behandling af ME patienter<span style="font-size: large;"><a href="https://www.omf.ngo/">Open Medicine Foundation</a> finansierer et nyt placebo-kontrolleret studie, hvor ME patienter skal behandles med kynurenine:</span><br />
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Kynurenine Clinical Trial for ME/CFS<br /><a href="https://omfcanada.ngo/kynurenine-clinical-trial-for-me-cfs/">https://omfcanada.ngo/kynurenine-clinical-trial-for-me-cfs/</a></span><br />
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<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Jonas Bergquist, MD, PhD, direktør for det svenske ME/CFS forskningscenter i Uppsala, skal stå for studiet.</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">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:<br /><br />ME hypotese: The Metabolic Trap - den metaboliske fælde<br /><a href="https://followmeindenmark.blogspot.com/2019/06/me-hypotese-metabolic-trap-den.html">https://followmeindenmark.blogspot.com/2019/06/me-hypotese-metabolic-trap-den.html</a><br /><br />Kynurenine metabolitter opstår ved omsætning af tryptofan, og disse metabolitter er vigtige for normal funktion af bl.a. hjerne og immunforsvar. Dette er vist i dette blogindlæg: </span><br />
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<span style="font-size: large;">Tryptofan metabolitten kynureninsyre har immunmodulerende egenskaber<br /><a href="https://followmeindenmark.blogspot.com/2019/06/tryptofan-metabolitten-kynureninsyre.html">https://followmeindenmark.blogspot.com/2019/06/tryptofan-metabolitten-kynureninsyre.html</a><br /><br /><br />Yderligere blogindlæg om kynurenine og den metaboliske fælde:<br /><br />Is the ME hypothesis "the metabolic trap" able to explain endothelial dysfunction?<br /><a href="https://followmeindenmark.blogspot.com/2019/06/is-me-hypothesis-metabolic-trap-able-to.html">https://followmeindenmark.blogspot.com/2019/06/is-me-hypothesis-metabolic-trap-able-to.html</a><br /><br />Kynurenine metabolisme påvirkes af motion<br /><a href="https://followmeindenmark.blogspot.com/2019/06/kynurenine-metabolisme-pavirkes-af.html">https://followmeindenmark.blogspot.com/2019/06/kynurenine-metabolisme-pavirkes-af.html</a><br /><br />Omsætning af tryptofan og forgrenede aminosyrer hos ME patienter under motion<br /><a href="https://followmeindenmark.blogspot.com/2019/06/omstning-af-tryptofan-og-forgrenede.html">https://followmeindenmark.blogspot.com/2019/06/omstning-af-tryptofan-og-forgrenede.html</a><br /><br />Is the kynurenic acid responsive Gpr35 involved in the ME pathomechanism?<br /><a href="https://followmeindenmark.blogspot.com/2019/06/is-kynurenic-acid-responsive-gpr35.html">https://followmeindenmark.blogspot.com/2019/06/is-kynurenic-acid-responsive-gpr35.html</a><br /><br />IDO-ME hypotesen er forenelig med AHR-MCS hypotesen<br /><a href="https://followmeindenmark.blogspot.com/2019/06/ido-me-hypotesen-er-forenelig-med-ahr.html">https://followmeindenmark.blogspot.com/2019/06/ido-me-hypotesen-er-forenelig-med-ahr.html</a><br /><br />Mutations in the IDO2 gene and DNA methylations in genes in the NAD/NADP synthesis pathway in ME<br /><a href="https://followmeindenmark.blogspot.com/2019/07/mutations-in-ido2-gene-and-dna.html">https://followmeindenmark.blogspot.com/2019/07/mutations-in-ido2-gene-and-dna.html</a></span><br />
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<span style="font-size: large;">Reference: </span><br />
<span style="font-size: large;">1) <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Kashi%20AA%5BAuthor%5D&cauthor=true&cauthor_uid=31357483">Kashi AA</a> <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Davis%20RW%5BAuthor%5D&cauthor=true&cauthor_uid=31357483">Davis RW</a> and, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Phair%20RD%5BAuthor%5D&cauthor=true&cauthor_uid=31357483">Phair RD</a>: The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS. <a href="https://www.ncbi.nlm.nih.gov/pubmed/31357483#">Diagnostics (Basel).</a> 2019 Jul 26;9(3). pii: E82. doi: 10.3390/diagnostics9030082. <a href="https://www.mdpi.com/2075-4418/9/3/82">https://www.mdpi.com/2075-4418/9/3/82</a></span><span style="font-size: large;"><br /></span>
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Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-52510308172930335192020-05-04T06:23:00.002-07:002020-05-04T06:23:29.298-07:00Serum fra ME patienter udviser antiviral aktivitet<span style="font-size: large;">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).</span><br />
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<span style="font-size: large;">Citat fra artiklen (1), side 213: </span><br />
<span style="font-size: large;">"...<i> 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.</i>"</span><div>
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<span style="font-size: large;">Det er ukendt, hvad det er i serum, som udløser og udøver den antivirale aktivitet. Schreiner et al har en hypotese om, at en delvis aktivering af herpesvirus (HHV-6) kan være årsag til den kroniske immunaktivering hos ME patienter. Forskerne understøtter hypotesen med et forsøg, hvor en cellekultur udsat for delvis aktivering af HHV-6 udskilder et stof som har samme effekt som serum fra ME patienter (1). </span></div>
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<span style="font-size: large;">Citat fra artiklen (1), side 206:<br /><i>"...These results showed that cells containing latent HHV-6A DNA that had been transactivated by TSA (trichostatin-A) secreted a potent activity that could be adoptively transferred and induce mitochondrial fragmentation and a proinflammatory CDR (cell danger response) in naive responder cells, conferring strong protection from both DNA and RNA virus infections." </i></span><div>
<span style="background-color: white; font-family: "Open Sans";"><span style="font-size: large;"><i><br /></i></span></span>
<span style="font-size: large;">ME er tidligere sat i forbindelse med kronisk herpes infektion (2).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Schreiner et al foreslår, at nye forsøg skal vise om ME patienter har en produktion af HHV-6 proteiner (<u>ikke</u> hele, levende HHV-6).</span><br />
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<span style="font-size: large;">Citat fra artiklen (1), side 213:<br /><i>"Larger multicohort studies involving ME/CFS patients from different age groups should be carried out in the future and should include methods for detecting and quantifying both productive and nonproductive (incomplete) viral reactivation events. Furthermore, potential factors affecting mitochondrial dynamics in ME/CFS patients should be systematically evaluated for their ability to induce a powerful antiviral state."</i></span><span style="font-size: large;"><span style="background-color: white; font-family: "Open Sans";"><br /></span></span>
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<span style="font-size: large;"><b>Læs også:</b></span><br />
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<span style="font-size: large;">For ME/CFS Patients, Viral Immunities Come at a Devastating, Lifelong Cost<br /><a href="https://health.ucsd.edu/news/releases/Pages/2020-04-27-for-me-cfs-patients-viral-immunities-come-at-lifelong-cost.aspx">https://health.ucsd.edu/news/releases/Pages/2020-04-27-for-me-cfs-patients-viral-immunities-come-at-lifelong-cost.aspx</a></span><div>
<span style="font-size: large;"><br />Explaining ME/CFS? Prusty / Naviaux Study Ties Infections to Energy Breakdowns<br /><a href="https://www.healthrising.org/blog/2020/04/26/explaining-chronic-fatigue-syndrome-naviaux-prusty/">https://www.healthrising.org/blog/2020/04/26/explaining-chronic-fatigue-syndrome-naviaux-prusty/</a></span></div>
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<span style="font-size: large;"><br /></span></div>
<span style="font-size: large;">Viden om fragmenteret mitokondriel netværk:<br />Mitochondria in Innate Immune Responses<br /><a href="https://pubmed.ncbi.nlm.nih.gov/21597473/">https://pubmed.ncbi.nlm.nih.gov/21597473/</a></span><div>
<span style="font-size: large;">Figur: <a href="https://pubmed.ncbi.nlm.nih.gov/21597473/#&gid=article-figures&pid=figure-2-uid-1">https://pubmed.ncbi.nlm.nih.gov/21597473/#&gid=article-figures&pid=figure-2-uid-1</a></span><div>
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<span style="font-size: large;"><br /><b>Referencer:</b><br /><br />1) Philipp Schreiner, Thomas Harrer, Carmen Scheibenbogen, Stephanie Lamer, Andreas Schlosser, Robert K. Naviaux and Bhupesh K. Prusty<br />Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome<br />Immunohorizons. 2020 Apr 23;4(4):201-215. <br />DOI: <a href="https://doi.org/10.4049/immunohorizons.2000006">10.4049/immunohorizons.2000006</a></span><div>
<span style="font-size: large;">PMID: 32327453 </span></div>
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<span style="font-size: large;">2) <span style="color: black;">Nuno Sepúlveda, Jorge Carneiro, Eliana Lacerda, Luis Nacul </span>Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections<br />Front Immunol 2019 Nov 21;10:2684. doi: 10.3389/fimmu.2019.02684. eCollection 2019.<br /><a href="https://www.frontiersin.org/articles/10.3389/fimmu.2019.02684/full">https://www.frontiersin.org/articles/10.3389/fimmu.2019.02684/full</a></span></div>
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Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-61400787658742804162020-04-20T06:21:00.001-07:002020-05-31T01:37:51.080-07:00Kan POTS patienter være mindre sårbare over for COVID-19 pga mindre ACE2 aktivitet?<span style="font-size: large;">Coronavirus anvender et af menneskets enzymer til at komme ind i cellerne. Enzymet hedder angiotensin converting enzyme 2 (ACE2).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">ACE-hæmmere er lægemidler, der anvendes til behandling af for højt blodtryk. </span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Der er fremsat en hypotese om at ACE-hæmmere kan øge ACE2 og hermed fremme indtrængning af coronavirus i cellerne. Læs om emnet her: </span><br />
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<span style="font-size: large;">ACE-hæmmere øger muligvis risikoen for at dø af COVID-19</span><br />
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<span style="font-size: large;"><a href="https://dagensmedicin.dk/ace-haemmere-oeger-muligvis-risikoen-for-at-doe-af-covid-19/">https://dagensmedicin.dk/ace-haemmere-oeger-muligvis-risikoen-for-at-doe-af-covid-19/</a> </span><br />
<span style="font-size: large;"><br /></span></div>
<span style="font-size: large;">Danske forskere vil undersøge årsag til visse patienters coronadød<br /><a href="https://sundhedspolitisktidsskrift.dk/nyheder/3250-er-patienter-i-bestemt-behandling-i-storre-risiko-for-at-blive-alvorligt-syge-af-coronavirus.html">https://sundhedspolitisktidsskrift.dk/nyheder/3250-er-patienter-i-bestemt-behandling-i-storre-risiko-for-at-blive-alvorligt-syge-af-coronavirus.html</a> </span><br />
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<span style="font-size: large;">COVID-19, ACE2, and the Cardiovascular Consequences<br /><a href="https://pubmed.ncbi.nlm.nih.gov/32228252/">https://pubmed.ncbi.nlm.nih.gov/32228252/</a><br /><br />Renin-Angiotensin-Aldosterone System: Double-Edged Sword in COVID-19 Infection<br /><a href="https://www.preprints.org/manuscript/202003.0365/v1">https://www.preprints.org/manuscript/202003.0365/v1</a><br /><br />Der er også fremsat en hypotese om, at lupus patienter måske har øget sårbarhed over for COVID-19 på grund af mulig øget ekspression af ACE2: </span><span style="font-size: large;"><i>"...we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2..." </i></span><br />
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<span style="font-size: large;">Citat fra: </span><span style="font-size: large;">Epigenetic Dysregulation of ACE2 and Interferon-Regulated Genes Might Suggest Increased COVID-19 Susceptibility and Severity in Lupus Patients<br /><a href="https://pubmed.ncbi.nlm.nih.gov/32276140/">https://pubmed.ncbi.nlm.nih.gov/32276140/</a></span><br />
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<span style="font-size: large;"><br /></span></div>
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<span style="font-size: large;">Der er så vidt jeg ved IKKE fremsat hypotese om COVID-19 og patienter med Postural Ortostatisk Takykardi Syndrom (POTS). Men jeg vil henlede opmærksomheden på viden fra to artikler, der omhandler POTS og ACE2:</span></div>
<span style="font-size: large;"><br />Defects in Cutaneous Angiotensin-Converting Enzyme 2 and angiotensin-(1-7) Production in Postural Tachycardia Syndrome<br /><a href="https://pubmed.ncbi.nlm.nih.gov/19289653/">https://pubmed.ncbi.nlm.nih.gov/19289653/</a><br /><br />Abnormalities of Angiotensin Regulation in Postural Tachycardia Syndrome<br /><a href="https://pubmed.ncbi.nlm.nih.gov/21266211/">https://pubmed.ncbi.nlm.nih.gov/21266211/</a><br /><br />Citat fra sidstnævnte artikel:<br /><i>"Estimated angiotensin-converting enzyme-2 (ACE2) activity was significantly lower in POTS patients than in controls (0.25 ± 0.02 vs 0.33 ± 0.03, P = .038)."</i></span></div>
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<span style="font-size: large;"><br /></span></div>
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<span style="font-size: large;">Kan POTS patienter være mindre sårbare over for COVID-19 pga mindre ACE2 aktivitet? Eller vejer ulempen ved at have en kronisk sygdom tungere på vægtskålen?</span></div>
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Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-45318834575295781282020-03-05T00:29:00.001-08:002020-03-05T00:29:51.731-08:00ME - a failure of inducing exercise tolerance?<span style="font-size: large;">ME hypothesis from Karolinska Institutet and Karolinska University Hospital in Sweden (1):<br /><br />"ME - a failure of inducing disease tolerance upon chronic immune activation"<br /><br />My question: <br />Is ME also a failure of inducing exercise tolerance?<br /><br />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. <br /><br />Quote from a review "Impact of oxidative stress on exercising skeletal muscle" (2): <br />"It is well established that muscle contractions during exercise lead to elevated levels of reactive oxygen species (ROS) in skeletal muscle. These highly reactive molecules have many deleterious effects, such as a reduction of force generation and increased muscle atrophy. Since the discovery of exercise-induced oxidative stress several decades ago, evidence has accumulated that ROS produced during exercise also have positive effects by influencing cellular processes that lead to increased expression of antioxidants. These molecules are particularly elevated in regularly exercising muscle to prevent the negative effects of ROS by neutralizing the free radicals. In addition, ROS also seem to be involved in the exercise-induced adaptation of the muscle phenotype.<br /><br />Chronic oxidative stress is associated with an increase in protein loss and muscle atrophy. High ROS levels cause a sustained activation of NF-κB and of FoxO which then activate two muscle-specific E3 ubiquitin ligases, atrogin-1 or muscle atrophy F-box (MAFbx) and muscle RING (Really Interesting New Gene)-finger protein 1 (MuRF-1) [<a href="https://www.mdpi.com/2218-273X/5/2/356/htm#B52-biomolecules-05-00356">52</a>]. MAFbx and MuRF-1 then degrade various proteins, such as titin, nebulin, troponin, myosin-binding protein C, myosin light chains 1 and 2 and myosin heavy chain [<a href="https://www.mdpi.com/2218-273X/5/2/356/htm#B53-biomolecules-05-00356">53</a>,<a href="https://www.mdpi.com/2218-273X/5/2/356/htm#B54-biomolecules-05-00356">54</a>]. Recently, it was demonstrated that excessive oxidative stress also enhances the transcription factor C/EBP homology protein (CHOP). This transcription factor also enhances expression of MuRF1, which again results in increased protein degradation [<a href="https://www.mdpi.com/2218-273X/5/2/356/htm#B35-biomolecules-05-00356">35</a>]."<br /><br />It seems like ME patients have increased muscle protein degradation: <br /><br />Increased serum and urine 3-methylhistidine in ME patients<br /><a href="http://followmeindenmark.blogspot.com/2020/03/increased-serum-and-urine-3.html">http://followmeindenmark.blogspot.com/2020/03/increased-serum-and-urine-3.html</a><br /><br />Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients<br /><a href="https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html">https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html</a><br /><br />Proline, P5C and 4-hydroxyglutamate in ME<br /><a href="http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html">http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html</a><br /><br />And do remember the transcription profile analysis of skeletal muscle from ME patients (3), quote: <br />"In an effort to establish which pathways might be involved in the onset and development of muscle symptoms, we used global transcriptome analysis to identify genes that were differentially expressed in the vastus lateralis muscle of female and male CFS patients. We found that the expression of genes that play key roles in mitochondrial function and oxidative balance, including superoxide dismutase 2, were altered, as were genes involved in energy production, muscular trophism and fiber phenotype determination. Importantly, the expression of a gene encoding a component of the nicotinic cholinergic receptor binding site was reduced, suggesting impaired neuromuscular transmission. We argue that these major biological processes could be involved in and/or responsible for the muscle symptoms of CFS."</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Are the inflammatory reponse to disease <u>and</u> the adaptive response to exercise dysregulated in ME through the same pathways?</span><br />
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<h3>
<span style="font-size: large;">Reference</span></h3>
<span style="font-size: large;">1) Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin: Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance<br />doi: https://doi.org/10.1101/2020.02.20.958249<br /><a href="https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract">https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract</a><br /><br />2) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Steinbacher+P&cauthor_id=25866921">Peter Steinbacher</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Eckl+P&cauthor_id=25866921">Peter Eckl</a>: <br />Impact of Oxidative Stress on Exercising Skeletal Muscle</span><br />
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<span style="font-size: large;">DOI: <a href="https://doi.org/10.3390/biom5020356">10.3390/biom5020356</a><br /><a href="https://pubmed.ncbi.nlm.nih.gov/25866921-impact-of-oxidative-stress-on-exercising-skeletal-muscle/">https://pubmed.ncbi.nlm.nih.gov/25866921-impact-of-oxidative-stress-on-exercising-skeletal-muscle/</a><br /><a href="https://www.mdpi.com/2218-273X/5/2/356">https://www.mdpi.com/2218-273X/5/2/356</a><br /><br />3) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Pietrangelo+T&cauthor_id=19822097">T Pietrangelo</a> <a href="https://pubmed.ncbi.nlm.nih.gov/19822097-transcription-profile-analysis-of-vastus-lateralis-muscle-from-patients-with-chronic-fatigue-syndrome/#affiliation-1">1</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Mancinelli+R&cauthor_id=19822097">R Mancinelli</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Toniolo+L&cauthor_id=19822097">L Toniolo</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Montanari+G&cauthor_id=19822097">G Montanari</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Vecchiet+J&cauthor_id=19822097">J Vecchiet</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Fan%C3%B2+G&cauthor_id=19822097">G Fanò</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Fulle+S&cauthor_id=19822097">S Fulle</a><br />Transcription Profile Analysis of Vastus Lateralis Muscle From Patients With Chronic Fatigue Syndrome. Int J Immunopathol Pharmacol, Vol 22 (3), 795-807, 2009<br /><a href="https://pubmed.ncbi.nlm.nih.gov/19822097-transcription-profile-analysis-of-vastus-lateralis-muscle-from-patients-with-chronic-fatigue-syndrome/">https://pubmed.ncbi.nlm.nih.gov/19822097-transcription-profile-analysis-of-vastus-lateralis-muscle-from-patients-with-chronic-fatigue-syndrome/</a><br /><a href="https://journals.sagepub.com/doi/abs/10.1177/039463200902200326">https://journals.sagepub.com/doi/abs/10.1177/039463200902200326</a></span></div>
Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-58380723851615885262020-03-03T02:05:00.001-08:002020-03-04T04:34:51.279-08:00Det inflammatoriske respons og induktion af sygdomstolerance er dysreguleret hos ME patienter<span style="font-size: large;">Forskere fra Karolinska Instituttet og Karolinska Universitetshospital har beskrevet en ME hypotese (1):</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">"ME - a failure of inducing disease tolerance upon chronic immune activation"</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">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.</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Vagusnerve og hjernestamme regulerer systemisk inflammation ved at skrue op eller ned for den inflammatoriske refleks. Nerver der fører fra kroppen (afferent vagus nerve endings) til hjernestamme sender besked om immunstatus i kroppen. Nerverne kan f.eks. sende besked om aktivitet fra patogene mikroorganismer i tarmen. Nerver der fører fra hjernestamme (efferente) til kroppen sender signaler via acetylcholin om at dæmpe inflammationen. </span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Det er kendt viden, at påvirkning af vagusnerven kan dæmpe inflammatoriske tilstande.</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Forskerne fra Karolinska afprøvede Intranasal Mekanisk Stimulation (INMEST) på en gruppe ME patienter. INMEST udstyret består af et tyndt plasticrør, som placeres i næsen. Udstyret vibrerer og danner en turbulent luftstrøm. Dette inducerer en nervereflex, som påvirker vagusnerven. Behandlingen dæmpede nogle ME symptomer (men ikke fatigue), og blodprøver fra patienterne viste normalisering af inflammatoriske tilstande (1).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">En analyse af sygdomstoleranceprogrammer viste, at INMEST behandling opregulerede disse programmer.</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Forskerene påpegede, at årsagen til den manglende induktion af tolerance hos ME patienter skal klarlægges. Samtidig henviser de til forskningen i IDO2 enzymet, som netop er involveret i regulering af sygdomstolerance.</span><br />
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<br />
<br />
<span style="font-size: large;"><b>Mere viden om emnet kan findes her:</b><br /><br />Neural Reflexes in Inflammation and Immunity<br /><a href="https://pubmed.ncbi.nlm.nih.gov/22665702-neural-reflexes-in-inflammation-and-immunity/">https://pubmed.ncbi.nlm.nih.gov/22665702-neural-reflexes-in-inflammation-and-immunity/</a><br /><br />The Vagus Nerve and the Inflammatory Reflex--Linking Immunity and Metabolism<br /><a href="https://pubmed.ncbi.nlm.nih.gov/23169440-the-vagus-nerve-and-the-inflammatory-reflex-linking-immunity-and-metabolism/">https://pubmed.ncbi.nlm.nih.gov/23169440-the-vagus-nerve-and-the-inflammatory-reflex-linking-immunity-and-metabolism/</a><br /><br />Er der behandlingsmuligheder i lægemidler, der øger aktivitet i acetylcholin-stiveje?:</span><br />
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<span style="font-size: large;">Central and peripheral anti-inflammatory effects of acetylcholinesterase inhibitors<br /><a href="https://www.sciencedirect.com/science/article/abs/pii/S0028390820300861">https://www.sciencedirect.com/science/article/abs/pii/S0028390820300861</a><br /><br />Aryl Hydrocarbon Receptor Control of a Disease Tolerance Defence Pathway<br /><a href="https://pubmed.ncbi.nlm.nih.gov/24930766-aryl-hydrocarbon-receptor-control-of-a-disease-tolerance-defence-pathway/">https://pubmed.ncbi.nlm.nih.gov/24930766-aryl-hydrocarbon-receptor-control-of-a-disease-tolerance-defence-pathway/</a></span><br />
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<span style="font-size: large;"><b>Relevante blogindlæg:</b></span><br />
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<span style="background-color: white; color: #222222; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;"><span style="font-size: large;">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 (AHR = Arylhydrocarbon receptor, MCS = multiple chemical sensitivity): </span></span></div>
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<span style="background-color: white; color: #222222; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;"><span style="font-size: large;"><br /></span></span></div>
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<span style="background-color: white; color: #222222; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;"><span style="font-size: large;">IDO-ME hypotesen er forenelig med AHR-MCS hypotesen</span></span></div>
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<a href="http://followmeindenmark.blogspot.com/2019/06/ido-me-hypotesen-er-forenelig-med-ahr.html"><span style="font-size: large;">http://followmeindenmark.blogspot.com/2019/06/ido-me-hypotesen-er-forenelig-med-ahr.html</span></a></div>
<h3 class="post-title entry-title" itemprop="name" style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-stretch: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-weight: normal; line-height: normal; margin: 0.75em 0px 0px; position: relative;">
<span style="font-size: large;">Tryptofan metabolitten kynureninsyre har immunmodulerende egenskaber</span></h3>
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<a href="http://followmeindenmark.blogspot.com/2019/06/tryptofan-metabolitten-kynureninsyre.html"><span style="font-size: large;">http://followmeindenmark.blogspot.com/2019/06/tryptofan-metabolitten-kynureninsyre.html</span></a></div>
<span style="font-size: large;"><br /><br /><b>Reference</b><br /><br />1) Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin: Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance<br />doi: https://doi.org/10.1101/2020.02.20.958249<br /><a href="https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract">https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract</a></span></div>
Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-60787460619874859742020-03-02T01:42:00.001-08:002020-03-02T01:42:28.396-08:00Increased serum and urine 3-methylhistidine in ME patients<span style="font-size: large;">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).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Fluge et al found increased serum 3-metylhistidine in male ME patients (2).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">McGregor et al found increased urine 3-metylhistidine in post-exertional malaise (PEM) ME patients (1).</span><br />
<br />
<span style="font-size: large;">Quote from McGregor et al (1):<br />"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 treatments such as graded exercise may be more detrimental than beneficial as claimed in some studies [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787670/#B39-diagnostics-09-00070">39</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787670/#B40-diagnostics-09-00070">40</a>]. Until such time as these biological changes can be further investigated, the use of graded exercise as a therapy for those with severe forms of ME/CFS should be considered potentially harmful. In support of this, the use of graded exercise therapy has caused significant protest by ME/CFS sufferers as they see it as harmful [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787670/#B41-diagnostics-09-00070">41</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787670/#B42-diagnostics-09-00070">42</a>]."<br /><br /><br /><b>Further reading about possible breakdown of skeletal muscles in ME patients :</b><br /><br />Proline, P5C and 4-hydroxyglutamate in ME<br /><a href="http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html">http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html</a><br /><br />Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients<br /><a href="https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html">https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html</a></span><br /><span style="font-size: large;"><br /><br /><br /><b>Referencer</b><br />1) McGregor et al: Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases <a href="https://www.ncbi.nlm.nih.gov/pubmed/31277442#">Diagnostics (Basel).</a> 2019 Jul 4;9(3). pii: E70. doi: 10.3390/diagnostics9030070. <a href="https://www.ncbi.nlm.nih.gov/pubmed/31277442">https://www.ncbi.nlm.nih.gov/pubmed/31277442</a><br /><br />2) 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</span>Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-55366893946793368322020-02-19T23:50:00.004-08:002020-02-19T23:54:36.121-08:00Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients<span style="font-size: large;">N,N,N-trimethyl-L-alanyl-L-proline betaine (TMAP) is a plasma biomarker of reduced kidney function (1).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Quote from ref 1:</span><br />
<span style="font-size: large;">"<span style="background-color: white; font-family: "times new roman" , "stixgeneral" , serif;">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 bond with proline (</span></span>26<span style="font-size: large;">)<span style="background-color: white; font-family: "times new roman" , "stixgeneral" , serif;">. Therefore, MYL protein degradation may be responsible for the release of TMAP. Further study is necessary to determine the biological origin and potential physiological effects of TMAP."</span></span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Myosin light chains are components of macromcular myosin complexes. Fx. myosin II is the myosin type responsible for producing muscle contractions in muscle cells. Myosin II contains two heavy chains and four ligtht chains. ( <a href="https://en.wikipedia.org/wiki/Myosin">Wikipedia. Myosin</a> )</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Plasma TMAP was increased in ME patients in Germain et al's metabolomic study (2020) (2).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">As far as I know, ME patients have normal kidney function, so why is TMAP increased? Is the turnover of myosin light chains increased? And/or do the increased TMAP level reflect the breakdown of skeletal muscles?</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;"><br /></span>
<b><span style="font-size: large;">Further reading about possible </span><span style="font-size: large;">breakdown of skeletal muscles in ME patients</span><span style="font-size: large;"> :</span></b><br />
<h3 class="post-title entry-title" itemprop="name" style="background-color: white; color: #222222; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-stretch: normal; font-variant-east-asian: normal; font-variant-numeric: normal; font-weight: normal; line-height: normal; margin: 0.75em 0px 0px; position: relative;">
<span style="font-size: large;">Proline, P5C and 4-hydroxyglutamate in ME</span></h3>
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<a href="http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html"><span style="font-size: large;">http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html</span></a></div>
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<span style="font-size: large;"><br /></span>
<span style="font-size: large;"><b>References:</b></span><br />
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<span style="font-size: large;">1) Velenosi, T.J., Thomson, B.K.A., Tonial, N.C. et al. Untargeted metabolomics reveals N, N, N-trimethyl-L-alanyl-L-proline betaine (TMAP) as a novel biomarker of kidney function. Sci Rep 9, 6831 (2019). <a href="https://www.nature.com/articles/s41598-019-42992-3">https://www.nature.com/articles/s41598-019-42992-3</a></span><br />
<span style="font-size: large;">https://doi.org/10.1038/s41598-019-42992-3 PMID: 31048706 PMCID: <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6497643/">PMC6497643</a></span><br />
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<span style="font-size: large;">2<span style="background-color: white; color: #222222; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;">) </span><a href="https://pubmed.ncbi.nlm.nih.gov/?term=Germain+A&cauthor_id=31947545" style="background-color: white; color: #888888; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; text-decoration-line: none;">Arnaud Germain</a><span style="background-color: white; color: #222222; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;"> , </span><a href="https://pubmed.ncbi.nlm.nih.gov/?term=Barupal+DK&cauthor_id=31947545" style="background-color: white; color: #888888; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; text-decoration-line: none;">Dinesh K Barupal</a><span style="background-color: white; color: #222222; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;"> , </span><a href="https://pubmed.ncbi.nlm.nih.gov/?term=Levine+SM&cauthor_id=31947545" style="background-color: white; color: #888888; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; text-decoration-line: none;">Susan M Levine</a><span style="background-color: white; color: #222222; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;"> , </span><a href="https://pubmed.ncbi.nlm.nih.gov/?term=Hanson+MR&cauthor_id=31947545" style="background-color: white; color: #888888; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; text-decoration-line: none;">Maureen R Hanson</a><span style="background-color: white; color: #222222; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;">: </span></span><span style="background-color: white; color: #222222; font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif; font-size: large;">Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites 2020, 10(1), 4; </span><a href="https://doi.org/10.3390/metabo10010034" style="background-color: white; color: #888888; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; font-size: x-large; text-decoration-line: none;">https://doi.org/10.3390/metabo10010034</a><br />
<span style="font-size: large;"><a href="https://www.mdpi.com/2218-1989/10/1/34" style="background-color: white; color: #888888; font-family: Arial, Tahoma, Helvetica, FreeSans, sans-serif; text-decoration-line: none;">https://www.mdpi.com/2218-1989/10/1/34</a></span><span style="font-size: large;"><br /></span>
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Helle Nielsenhttp://www.blogger.com/profile/13779967748632121875noreply@blogger.com0tag:blogger.com,1999:blog-73120972890131591.post-79837601187422320182020-02-05T04:12:00.000-08:002020-02-05T04:12:03.225-08:00Proline, P5C and 4-hydroxyglutamate in ME<span style="font-size: large;">What do</span><br />
<br />
<ul>
<li><span style="font-size: large;">Pre-eclampsia</span></li>
<li><span style="font-size: large;">The inborn error of metabolism: Primary Hyperoxaluria Type 3</span></li>
<li><span style="font-size: large;">Myalgic encephalomyelitis (ME)</span></li>
</ul>
<br />
<span style="font-size: large;">have in common?</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Increased levels of 4-hydroxyglutamate (1, 2, 3).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Germain et al's (2020) new metabolomic study found increased level of plasma 4-hydroxyglutamate in ME patients compared to controls (3).</span><br />
<span style="font-size: large;"><br /></span>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjkuGMcjU1PJd1hUUQKaTA4szyQIQp8hRGaP2Q33OqTP6lgslvsMLFXxq8KEMD3xZbgrBGm6oZl6RiA1vvLiEdRflsoKdNGDpSUbi4F8URDVS1X22Y2V5RQ3dBLDF7MEvBUiXtJBf2WGCC9/s1600/image.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="400" data-original-width="300" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjkuGMcjU1PJd1hUUQKaTA4szyQIQp8hRGaP2Q33OqTP6lgslvsMLFXxq8KEMD3xZbgrBGm6oZl6RiA1vvLiEdRflsoKdNGDpSUbi4F8URDVS1X22Y2V5RQ3dBLDF7MEvBUiXtJBf2WGCC9/s320/image.png" width="240" /></a></div>
<b>From figure S1 in reference 3. 4-hydroxyglutamate.</b> 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. <a href="https://www.mdpi.com/2218-1989/10/1/34">https://www.mdpi.com/2218-1989/10/1/34</a><span style="font-size: large;"><br /></span>
<span style="font-size: large;"><br /></span><br />
<span style="font-size: large;">Proline and its metabolite hydroxyproline (OH-proline) are amino acids. They constitute one-third of the amino acids in collagen proteins.</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">High levels of 4-hydroxyglutamate could result from increased collagen turnover and the release of proline and 4-hydroxyproline. The latter is metabolized to </span><span style="font-size: large;">4-hydroxyglutamate. Proline is re-used and </span><span style="font-size: large;">4-hydroxyproline is broken down and excreted in this pathway (4):</span><br />
<span style="font-size: large;"><br /></span>
<img src="https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3188589/bin/pone.0026021.g001.jpg" /><br />
<br />
<b>Figure 1 from Riedel et al, reference 4: Metabolism of 4-hydroxyproline and glyoxylate.</b><br />
<div>
Four mitochondrial enzymes are responsible for 4-hydroxproline (4-Hyp) breakdown: hydroxyproline oxidase (HPOX), Δ1-pyrroline-5-carboxylate dehydrogenase (1P5CDH), aspartate aminotransferase (AspAT), and 4-hydroxy-2-oxoglutarate aldolase (HOGA). The terminal HOGA reaction cleaves 4-hydroxy-2-oxoglutarate (HOG) into pyruvate and glyoxylate. Glyoxylate is metabolized either to glycolate by glyoxylate reductase (GR) in the mitochondria and cytoplasm or to glycine by peroxisomal alanine-glyoxylate aminotransferase (AGT). AGT and GR are mutated within primary hyperoxaluria (type 1 and 2, respectively) patients resulting in the buildup of glyoxylate and its conversion by lactate dehydrogenase (LDH) to oxalate, a key component of kidney stones.</div>
<div>
<a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026021">https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026021</a><br />
<br />
<span style="font-size: large;">Naviaux et al showed increased plasma level of hydroxyproline in female ME patients (5).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Primary hyperoxaluria type 3 with increased urine 4-hydroxyglutamate is caused by mutations in the HOGA1 gene (4, 6).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Increasd levels of 4-hydroxyglutamate could also result from decreased activity of glutamic-oxaloacetic transaminase 2 (GOT2 = AspAT in figure 1 from ref 4) (1).</span><br />
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Schutzer et al showed decreased level of GOT2 precursor in cerebrospinal fluid from ME patients. Number of unique peptides in cerebrospinal fluid (table S1 in ref. 7): </span><br />
<span style="font-size: large;">1) Controls: 6<br />2) ME patients: 1<br />3) Post treatment Lyme patients: 8</span></div>
<div>
<span style="font-size: large;"><br /></span>
<span style="font-size: large;">Why is 4-hydroxyglutamate increased in ME?</span><br />
<span style="font-size: large;"><br /></span>
<br />
<h2>
<span style="font-size: large;">Is the proline-P5C cycle dysregulated in ME?</span></h2>
<span style="font-size: large;">Naviaux et al showed increased plasma level of 1-pyrroline-5-carboxylic acid (P5C) in ME patients (5).</span><br />
<span style="font-size: large;"><br />A unique aspect of proline metabolism is the cycling of proline and P5C to maintain redox homeostasis between the cytosol and mitochondria. Proline biosynthesis, catabolism, and cycling, known as "the proline-P5C cycle" have been implicated as metabolic pathways selectively altered in cancer cells providing ATP, macromolecules, and redox cofactors (8).</span></div>
<span style="font-size: large;"><br />The proline metabolism plays an important role in metabolic reprogramming, not only in cancer but also in related fields such as aging, senescence, and development (9).</span><br />
<div>
<span style="font-size: large;"><br /></span></div>
<div>
<span style="font-size: large;">The proline-P5C cycle: </span></div>
<div>
<div>
<br />
<img height="273" src="https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6338564/bin/fig-3.jpg" width="400" /><br />
<b>Figure 3 from reference 9. Hypothesis for proline cycle revised.</b></div>
<div>
The cycle has been revised according to locations of the enzymes. The colored areas are for emphasis and do not represent specific locations. The dotted arrows represent putative shuttle systems, for example, malate/aspartate shuttle. PYCR1/2/L, pyrroline-5-carboxylate reductase 1/2/L.</div>
<div>
<a href="https://www.liebertpub.com/doi/10.1089/ars.2017.7350">https://www.liebertpub.com/doi/10.1089/ars.2017.7350</a></div>
<div>
<br /></div>
<div>
<span style="font-size: large;">Quote from reference 9: </span></div>
<span style="font-size: large;">"The enzyme that oxidizes proline to P5C is tightly bound to mitochondrial inner membranes (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/#B30">30</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/#B37">37</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/#B38">38</a>) and is linked to site II of the mitochondrial electron transport chain (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/#B30">30</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/#B61">61</a>) with a flavine adenine dinucleotide at the active site, which transfers electrons from proline to coenzyme Q (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/#B30">30</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/#B95">95</a>); at site III, proline-derived electrons have two dispositions. They can be transferred to cytochrome c, which is oxidized at complex IV with electrons transferred to O2 to form H2O. On the contrary, proline-derived electrons can directly reduce dissolved oxygen at complex III to form superoxide (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/#B23">23</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/#B30">30</a>). Since complex III has access to both the matrix space and the intermembrane space, ROS can evolve in the mitochondrial matrix or in the intermembrane space to be transferred into the cytosol as a putative redox signal. "</span></div>
<div>
<span style="font-size: large;"><br /></span></div>
<div>
<span style="font-size: large;">Is the collagen being broken down in ME patients to provide electrons for ATP synthesis?</span></div>
<div>
<span style="font-size: large;"><br /></span></div>
<div>
<span style="font-size: large;">If so, is AMPK involved in the process? And when/if AMPK "gives up", do ME cells go into senescence?</span></div>
<div>
<span style="font-size: large;"><br /></span>
<div>
<br /></div>
<div>
<img alt="An external file that holds a picture, illustration, etc.
Object name is fig-2.jpg" height="169" src="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/bin/fig-2.jpg" width="400" /><br />
<span style="font-size: large;"><br /></span>
<b>Figure 2 from reference 9. PRODH/POX-mediated signaling. </b></div>
<div>
AMPK, AMP-activated protein kinase; ETC, electron transport chain; MYC, myelocytomatosis oncogene cellular homologue; PPARγ, peroxisome proliferator-activated receptor gamma. PRODH/POX, proline dehydrogenase/proline oxidase; ROS, reactive oxygen species.</div>
<div>
<a href="https://www.liebertpub.com/doi/10.1089/ars.2017.7350">https://www.liebertpub.com/doi/10.1089/ars.2017.7350</a><br />
<span style="font-size: large;"><br /></span>
<br />
<span style="font-size: large;">A concern for a dysregulated proline-P5C cycle is the potential for cells to accumulate P5C, which was recently listed among the top 30 damage-prone endogenous metabolites. (8, 10).</span><br />
<br />
<br />
<br />
<span style="font-size: large;"><b>References: </b></span><br />
<br />
1) Sovio et al: 4-Hydroxyglutamate Is a Novel Predictor of Pre-Eclampsia. <br />
PMID: 31098639 DOI: <a href="https://doi.org/10.1093/ije/dyz098">10.1093/ije/dyz098</a><br />
<br />
2) Pitt et al: 4-hydroxyglutamate Is a Biomarker for Primary Hyperoxaluria Type 3<br />
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270872/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270872/</a><br />
PMID: 24563386 PMCID: <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4270872/">PMC4270872</a> DOI: <a href="https://doi.org/10.1007/8904_2013_291">10.1007/8904_2013_291</a><br />
<br />
3) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Germain+A&cauthor_id=31947545">Arnaud Germain</a> , <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Barupal+DK&cauthor_id=31947545">Dinesh K Barupal</a> , <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Levine+SM&cauthor_id=31947545">Susan M Levine</a> , <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Hanson+MR&cauthor_id=31947545">Maureen R Hanson</a>: <br />Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites 2020, 10(1), 4; <a href="https://doi.org/10.3390/metabo10010034">https://doi.org/10.3390/metabo10010034</a><br /><a href="https://www.mdpi.com/2218-1989/10/1/34">https://www.mdpi.com/2218-1989/10/1/34</a><br /><br />4) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Riedel+TJ&cauthor_id=21998747">Travis J Riedel</a> , <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Johnson+LC&cauthor_id=21998747">Lynnette C Johnson</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Knight+J&cauthor_id=21998747">John Knight</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Hantgan+RR&cauthor_id=21998747">Roy R Hantgan</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Holmes+RP&cauthor_id=21998747">Ross P Holmes</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Lowther+WT&cauthor_id=21998747">W Todd Lowther</a>: Structural and Biochemical Studies of Human 4-hydroxy-2-oxoglutarate Aldolase: Implications for Hydroxyproline Metabolism in Primary Hyperoxaluria.<br />
Plos One <a href="https://doi.org/10.1371/journal.pone.0026021">https://doi.org/10.1371/journal.pone.0026021</a><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026021">https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026021</a><br />
<br />
5) 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. <a href="https://doi.org/10.1073/pnas.1607571113">https://doi.org/10.1073/pnas.1607571113</a> <br />
<br />
6) Greed, L., Willis, F., Johnstone, L. et al. Metabolite diagnosis of primary hyperoxaluria type 3. Pediatr Nephrol 33, 1443–1446 (2018). https://doi.org/10.1007/s00467-018-3967-6<br />
<a href="https://link.springer.com/article/10.1007/s00467-018-3967-6">https://link.springer.com/article/10.1007/s00467-018-3967-6</a><br />
<br />
7) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue<a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287">https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287</a><br />
<br />
8) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Tanner+JJ&cauthor_id=29648801">John J Tanner</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Fendt+SM&cauthor_id=29648801">Sarah-Maria Fendt</a> , <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Becker+DF&cauthor_id=29648801">Donald F Becker</a> , <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Tanner+JJ&cauthor_id=29648801">John J Tanner</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Fendt+SM&cauthor_id=29648801">Sarah-Maria Fendt</a> , <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Becker+DF&cauthor_id=29648801">Donald F Becker</a>: The Proline Cycle As a Potential Cancer Therapy Target<br />
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026536/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026536/</a><br />
<a href="https://pubs.acs.org/doi/10.1021/acs.biochem.8b00215">https://pubs.acs.org/doi/10.1021/acs.biochem.8b00215</a><br />
<br />
9) Phang: Proline Metabolism in Cell Regulation and Cancer Biology: Recent Advances and Hypotheses. Antioxid Redox Signal, 30 (4), 635-649 2019 Feb 1<br />
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/</a><br />
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10) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=Lerma-Ortiz+C&cauthor_id=27284066">Claudia Lerma-Ortiz</a> et al: Nothing of Chemistry Disappears in Biology': The Top 30 Damage-Prone Endogenous Metabolites. <br />
PMID: 27284066 DOI: <a href="https://doi.org/10.1042/bst20160073">10.1042/BST20160073</a> Biochem Soc Trans (2016) 44 (3): 961–971.<br />
<a href="https://doi.org/10.1042/BST20160073" style="background-color: white; border: 0px; color: #cf4520; cursor: pointer; font-family: Roboto, Helvetica, Arial, sans-serif; font-size: inherit; margin: 0px; outline: 0px; padding: 0px; text-decoration-line: none; vertical-align: baseline; word-break: normal;" target="_blank">https://doi.org/10.1042/BST20160073</a></div>
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