3-metylhistidine is a breakdown product of muscle contractile proteins. Serum or urine 3-methylhistidine is used as a biomarker of muscle protein degradation (1).
Fluge et al found increased serum 3-metylhistidine in male ME patients (2).
McGregor et al found increased urine 3-metylhistidine in post-exertional malaise (PEM) ME patients (1).
Quote from McGregor et al (1):
"The findings that the PEM is associated with a loss of metabolites, reduction in acetylation, deregulation of purine metabolism, increased contractile protein breakdown and bacteremia associated with exercise suggest that treatments such as graded exercise may be more detrimental than beneficial as claimed in some studies [39,40]. 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 [41,42]."
Further reading about possible breakdown of skeletal muscles in ME patients :
Proline, P5C and 4-hydroxyglutamate in ME
http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html
Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients
https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html
Referencer
1) McGregor et al: Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases Diagnostics (Basel). 2019 Jul 4;9(3). pii: E70. doi: 10.3390/diagnostics9030070. https://www.ncbi.nlm.nih.gov/pubmed/31277442
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
mandag den 2. marts 2020
onsdag den 19. februar 2020
Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients
N,N,N-trimethyl-L-alanyl-L-proline betaine (TMAP) is a plasma biomarker of reduced kidney function (1).
Quote from ref 1:
"TMAP was the most consistently cleared metabolite by all hemodialysis modalities in our untargeted metabolomics analysis. Although the biological origin of TMAP has not been identified, we suggest that TMAP may be produced from degradation of myosin light chain (MYL) proteins. N,N,N-trimethylalanine is mainly found in myosin light chain (MYL) proteins and in each of the four MYL isoforms (MYL1, MYL2, MYL3, and MYL4), the c-terminus of N,N,N-trimethylalanine forms a peptide bond with proline (26). 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."
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. ( Wikipedia. Myosin )
Plasma TMAP was increased in ME patients in Germain et al's metabolomic study (2020) (2).
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?
Further reading about possible breakdown of skeletal muscles in ME patients :
References:
Quote from ref 1:
"TMAP was the most consistently cleared metabolite by all hemodialysis modalities in our untargeted metabolomics analysis. Although the biological origin of TMAP has not been identified, we suggest that TMAP may be produced from degradation of myosin light chain (MYL) proteins. N,N,N-trimethylalanine is mainly found in myosin light chain (MYL) proteins and in each of the four MYL isoforms (MYL1, MYL2, MYL3, and MYL4), the c-terminus of N,N,N-trimethylalanine forms a peptide bond with proline (26). 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."
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. ( Wikipedia. Myosin )
Plasma TMAP was increased in ME patients in Germain et al's metabolomic study (2020) (2).
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?
Further reading about possible breakdown of skeletal muscles in ME patients :
Proline, P5C and 4-hydroxyglutamate in ME
References:
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). https://www.nature.com/articles/s41598-019-42992-3
https://doi.org/10.1038/s41598-019-42992-3 PMID: 31048706 PMCID: PMC6497643
2) Arnaud Germain , Dinesh K Barupal , Susan M Levine , Maureen R Hanson: Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites 2020, 10(1), 4; https://doi.org/10.3390/metabo10010034
https://www.mdpi.com/2218-1989/10/1/34
https://doi.org/10.1038/s41598-019-42992-3 PMID: 31048706 PMCID: PMC6497643
2) Arnaud Germain , Dinesh K Barupal , Susan M Levine , Maureen R Hanson: Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites 2020, 10(1), 4; https://doi.org/10.3390/metabo10010034
https://www.mdpi.com/2218-1989/10/1/34
onsdag den 5. februar 2020
Proline, P5C and 4-hydroxyglutamate in ME
What do
have in common?
Increased levels of 4-hydroxyglutamate (1, 2, 3).
Germain et al's (2020) new metabolomic study found increased level of plasma 4-hydroxyglutamate in ME patients compared to controls (3).
From figure S1 in reference 3. 4-hydroxyglutamate. Box plot distribution of logged values from table 2 in reference 3. Controls are shown in red and ME patients in blue. The yellow diamond represents the mean. https://www.mdpi.com/2218-1989/10/1/34
Proline and its metabolite hydroxyproline (OH-proline) are amino acids. They constitute one-third of the amino acids in collagen proteins.
High levels of 4-hydroxyglutamate could result from increased collagen turnover and the release of proline and 4-hydroxyproline. The latter is metabolized to 4-hydroxyglutamate. Proline is re-used and 4-hydroxyproline is broken down and excreted in this pathway (4):
Figure 1 from Riedel et al, reference 4: Metabolism of 4-hydroxyproline and glyoxylate.
Why is 4-hydroxyglutamate increased in ME?
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).
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).
Figure 3 from reference 9. Hypothesis for proline cycle revised.
Figure 2 from reference 9. PRODH/POX-mediated signaling.
- Pre-eclampsia
- The inborn error of metabolism: Primary Hyperoxaluria Type 3
- Myalgic encephalomyelitis (ME)
have in common?
Increased levels of 4-hydroxyglutamate (1, 2, 3).
Germain et al's (2020) new metabolomic study found increased level of plasma 4-hydroxyglutamate in ME patients compared to controls (3).
Proline and its metabolite hydroxyproline (OH-proline) are amino acids. They constitute one-third of the amino acids in collagen proteins.
High levels of 4-hydroxyglutamate could result from increased collagen turnover and the release of proline and 4-hydroxyproline. The latter is metabolized to 4-hydroxyglutamate. Proline is re-used and 4-hydroxyproline is broken down and excreted in this pathway (4):
Figure 1 from Riedel et al, reference 4: Metabolism of 4-hydroxyproline and glyoxylate.
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.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026021
Naviaux et al showed increased plasma level of hydroxyproline in female ME patients (5).
Primary hyperoxaluria type 3 with increased urine 4-hydroxyglutamate is caused by mutations in the HOGA1 gene (4, 6).
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).
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):
1) Controls: 6
2) ME patients: 1
3) Post treatment Lyme patients: 8
Naviaux et al showed increased plasma level of hydroxyproline in female ME patients (5).
Primary hyperoxaluria type 3 with increased urine 4-hydroxyglutamate is caused by mutations in the HOGA1 gene (4, 6).
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).
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):
1) Controls: 6
2) ME patients: 1
3) Post treatment Lyme patients: 8
Why is 4-hydroxyglutamate increased in ME?
Is the proline-P5C cycle dysregulated in ME?
Naviaux et al showed increased plasma level of 1-pyrroline-5-carboxylic acid (P5C) in ME patients (5).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).
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).
The proline-P5C cycle:
Figure 3 from reference 9. Hypothesis for proline cycle revised.
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.
Quote from reference 9:
"The enzyme that oxidizes proline to P5C is tightly bound to mitochondrial inner membranes (30, 37, 38) and is linked to site II of the mitochondrial electron transport chain (30, 61) with a flavine adenine dinucleotide at the active site, which transfers electrons from proline to coenzyme Q (30, 95); 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 (23, 30). 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. "
Is the collagen being broken down in ME patients to provide electrons for ATP synthesis?
If so, is AMPK involved in the process? And when/if AMPK "gives up", do ME cells go into senescence?
Figure 2 from reference 9. PRODH/POX-mediated signaling.
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.
https://www.liebertpub.com/doi/10.1089/ars.2017.7350
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).
References:
1) Sovio et al: 4-Hydroxyglutamate Is a Novel Predictor of Pre-Eclampsia.
PMID: 31098639 DOI: 10.1093/ije/dyz098
2) Pitt et al: 4-hydroxyglutamate Is a Biomarker for Primary Hyperoxaluria Type 3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270872/
PMID: 24563386 PMCID: PMC4270872 DOI: 10.1007/8904_2013_291
3) Arnaud Germain , Dinesh K Barupal , Susan M Levine , Maureen R Hanson:
Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites 2020, 10(1), 4; https://doi.org/10.3390/metabo10010034
https://www.mdpi.com/2218-1989/10/1/34
4) Travis J Riedel , Lynnette C Johnson, John Knight, Roy R Hantgan, Ross P Holmes, W Todd Lowther: Structural and Biochemical Studies of Human 4-hydroxy-2-oxoglutarate Aldolase: Implications for Hydroxyproline Metabolism in Primary Hyperoxaluria.
Plos One https://doi.org/10.1371/journal.pone.0026021https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026021
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. https://doi.org/10.1073/pnas.1607571113
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
https://link.springer.com/article/10.1007/s00467-018-3967-6
7) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issuehttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287
8) John J Tanner, Sarah-Maria Fendt , Donald F Becker , John J Tanner, Sarah-Maria Fendt , Donald F Becker: The Proline Cycle As a Potential Cancer Therapy Target
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026536/
https://pubs.acs.org/doi/10.1021/acs.biochem.8b00215
9) Phang: Proline Metabolism in Cell Regulation and Cancer Biology: Recent Advances and Hypotheses. Antioxid Redox Signal, 30 (4), 635-649 2019 Feb 1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/
10) Claudia Lerma-Ortiz et al: Nothing of Chemistry Disappears in Biology': The Top 30 Damage-Prone Endogenous Metabolites.
PMID: 27284066 DOI: 10.1042/BST20160073 Biochem Soc Trans (2016) 44 (3): 961–971.
https://doi.org/10.1042/BST20160073
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).
References:
1) Sovio et al: 4-Hydroxyglutamate Is a Novel Predictor of Pre-Eclampsia.
PMID: 31098639 DOI: 10.1093/ije/dyz098
2) Pitt et al: 4-hydroxyglutamate Is a Biomarker for Primary Hyperoxaluria Type 3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270872/
PMID: 24563386 PMCID: PMC4270872 DOI: 10.1007/8904_2013_291
3) Arnaud Germain , Dinesh K Barupal , Susan M Levine , Maureen R Hanson:
Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites 2020, 10(1), 4; https://doi.org/10.3390/metabo10010034
https://www.mdpi.com/2218-1989/10/1/34
4) Travis J Riedel , Lynnette C Johnson, John Knight, Roy R Hantgan, Ross P Holmes, W Todd Lowther: Structural and Biochemical Studies of Human 4-hydroxy-2-oxoglutarate Aldolase: Implications for Hydroxyproline Metabolism in Primary Hyperoxaluria.
Plos One https://doi.org/10.1371/journal.pone.0026021https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026021
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. https://doi.org/10.1073/pnas.1607571113
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
https://link.springer.com/article/10.1007/s00467-018-3967-6
7) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issuehttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287
8) John J Tanner, Sarah-Maria Fendt , Donald F Becker , John J Tanner, Sarah-Maria Fendt , Donald F Becker: The Proline Cycle As a Potential Cancer Therapy Target
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026536/
https://pubs.acs.org/doi/10.1021/acs.biochem.8b00215
9) Phang: Proline Metabolism in Cell Regulation and Cancer Biology: Recent Advances and Hypotheses. Antioxid Redox Signal, 30 (4), 635-649 2019 Feb 1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338564/
10) Claudia Lerma-Ortiz et al: Nothing of Chemistry Disappears in Biology': The Top 30 Damage-Prone Endogenous Metabolites.
PMID: 27284066 DOI: 10.1042/BST20160073 Biochem Soc Trans (2016) 44 (3): 961–971.
https://doi.org/10.1042/BST20160073
fredag den 17. januar 2020
Naltrexone til behandling af ME
NK (Natural Killer) celler er en del af immunforsvaret. Det er gentagne gange påvist, at NK celler ikke fungerer optimalt hos ME patienter (1).
NK celler reguleres af en lang række celle signaler, - herunder calcium ion signalering. Ionkanalen TRPM3 bidrager væstentligt til calcium ion signalering i NK celler.
Der er påvist signifikant reduktion af TRPM3 ekspression på overfladen af NK celler fra ME patienter (1).
Den G-protein-koblede receptor mu-opoid receptor (μOR) interagerer med TRPM3. Når μOR stimuleres inhiberes TRPM3 (1).
μOR kan hæmmes af lægemidlet Naltrexone, som er et lægemiddel målrettet til opioid-afhængige mennesker (2). Naltrexone i lav dosis anvendes også off-label til at modulere immunforsvaret i en række forskellige sygdomme.
Et forsøg med NK celler isoleret fra ME patienter viste at ved tilsætning af Naltrexone til NK cellerne, blev TRPM3 aktiviteten normaliseret (1).
Spørgsmålet er om Naltrexone kan være en behandlingsmulighed til ME?
Læs også:
Low-dose naltrexone as a treatment for chronic fatigue syndrome
https://casereports.bmj.com/content/13/1/e232502.long
NK celler reguleres af en lang række celle signaler, - herunder calcium ion signalering. Ionkanalen TRPM3 bidrager væstentligt til calcium ion signalering i NK celler.
Der er påvist signifikant reduktion af TRPM3 ekspression på overfladen af NK celler fra ME patienter (1).
Den G-protein-koblede receptor mu-opoid receptor (μOR) interagerer med TRPM3. Når μOR stimuleres inhiberes TRPM3 (1).
μOR kan hæmmes af lægemidlet Naltrexone, som er et lægemiddel målrettet til opioid-afhængige mennesker (2). Naltrexone i lav dosis anvendes også off-label til at modulere immunforsvaret i en række forskellige sygdomme.
Et forsøg med NK celler isoleret fra ME patienter viste at ved tilsætning af Naltrexone til NK cellerne, blev TRPM3 aktiviteten normaliseret (1).
Spørgsmålet er om Naltrexone kan være en behandlingsmulighed til ME?
Læs også:
Low-dose naltrexone as a treatment for chronic fatigue syndrome
https://casereports.bmj.com/content/13/1/e232502.long
Finally Found – A Natural Killer Cell Enhancer for ME/CFS?
https://www.healthrising.org/blog/2019/12/19/50190/
1) Helene Cabanas, Katsuhiko Muraki, Donald Staines1 and Sonya Marshall-Gradisnik: Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Front. Immunol., 31 October 2019 | https://doi.org/10.3389/fimmu.2019.02545
https://www.frontiersin.org/articles/10.3389/fimmu.2019.02545/full
2) Naltrexone
http://pro.medicin.dk/Medicin/Praeparater/7045
Referencer:
https://www.frontiersin.org/articles/10.3389/fimmu.2019.02545/full
2) Naltrexone
http://pro.medicin.dk/Medicin/Praeparater/7045
torsdag den 2. januar 2020
Trådløs teknologi påvirker mitokondrierne, når cellerne er stressede
Forskere fra et universitet i Schweiz har undersøgt, hvordan nerveceller påvirkes af radiofrekvente elektromagnetiske felter (RF-EMF). Forskerne udsatte en cellekultur af nerveceller for 935 MHz, 4 W/kg i 24 timer. Forsøget viste ikke påvirkning af cellerne, når næring og metabolisme var under normale forhold. Men når glucosen blev fjernet og cellerne blev stressede, registrerede man forringet mitokondrie funktion ved den følgende maximale respiration (1):
"These findings indicate that RF-EMF might lead to an impairment of mitochondrial function that is only manifest at maximal respiration and additional stressors such as glucose deprivation."
I et andet studie af RF-EMF udsætter man immunceller for 1,8 GHz og 200 V/m i 20 timer. Forsøget viste øget mitokondriel respiration, som var relateret til mitokondrie complex V aktivitet (2). Complex V danner energi-molekylerne ATP og kaldes derfor også for ATP syntase.
En del patienter med Myalgisk Encephalomyelitis (ME) udvikler elektromagnetisk hypersensitivitet (EHS). Man kan således formode, at ME sygdomsmekanismen er relateret til en RF-EMF følsom celleproces.
En undersøgelse af en lymfoblast cellekultur fra ME patienter viste (3):
Cellestress, øget mitokondriel respiration og complex V påvirkning er således fællesnævnere for RF-EMF påvirkning og for ME.
Læs også:
Are rises in Electro-Magnetic Field in the human environment, interacting with multiple environmental pollutions, the tripping point for increases in neurological deaths in the Western World? https://www.ncbi.nlm.nih.gov/pubmed/31088653
Referencer
1) Niederhäusern et al: Effects of radiofrequency electromagnetic field exposure on neuronal differentiation and mitochondrial function in SH-SY5Y cells Toxicol In Vitro. 2019 Dec;61:104609. doi: 10.1016/j.tiv.2019.104609. Epub 2019 Jul 24.
https://www.ncbi.nlm.nih.gov/pubmed/31351122
2) Lassaivia et al: Exposure to 1.8 GHz electromagnetic fields affects morphology, DNA-related Raman spectra and mitochondrial functions in human lympho-monocytes. PLOS ONE. February 20, 2018.https://doi.org/10.1371/journal.pone.0192894
3) Missailidis, D.; Annesley, S.; Allan, C.; Sanislav, O.; Lidbury, B.; Lewis, D.; Fisher, P. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Preprints 2019, 2019090043 (doi: 10.20944/preprints201909.0043.v1). https://www.preprints.org/manuscript/201909.0043/v1
"These findings indicate that RF-EMF might lead to an impairment of mitochondrial function that is only manifest at maximal respiration and additional stressors such as glucose deprivation."
I et andet studie af RF-EMF udsætter man immunceller for 1,8 GHz og 200 V/m i 20 timer. Forsøget viste øget mitokondriel respiration, som var relateret til mitokondrie complex V aktivitet (2). Complex V danner energi-molekylerne ATP og kaldes derfor også for ATP syntase.
En del patienter med Myalgisk Encephalomyelitis (ME) udvikler elektromagnetisk hypersensitivitet (EHS). Man kan således formode, at ME sygdomsmekanismen er relateret til en RF-EMF følsom celleproces.
En undersøgelse af en lymfoblast cellekultur fra ME patienter viste (3):
- det stress-registrerende protein TORC1 var opreguleret
- mitokondrie complex V fungerede ineffektivt
- den mitokondrielle respiratoriske kapacitet var opreguleret (sandsynligvis for at kompensere for complex V ineffektivitet)
Cellestress, øget mitokondriel respiration og complex V påvirkning er således fællesnævnere for RF-EMF påvirkning og for ME.
Læs også:
Mitokondrie Complex V er dysreguleret hos ME patienter https://followmeindenmark.blogspot.com/2019/07/mitokondrie-complex-v-er-dysreguleret.html
Complex V is down in ME - does it also explain Electromagnetic Hypersensitivity? https://followmeindenmark.blogspot.com/2019/07/complex-v-is-down-in-me-does-it-also.html
Referencer
1) Niederhäusern et al: Effects of radiofrequency electromagnetic field exposure on neuronal differentiation and mitochondrial function in SH-SY5Y cells Toxicol In Vitro. 2019 Dec;61:104609. doi: 10.1016/j.tiv.2019.104609. Epub 2019 Jul 24.
https://www.ncbi.nlm.nih.gov/pubmed/31351122
2) Lassaivia et al: Exposure to 1.8 GHz electromagnetic fields affects morphology, DNA-related Raman spectra and mitochondrial functions in human lympho-monocytes. PLOS ONE. February 20, 2018.https://doi.org/10.1371/journal.pone.0192894
3) Missailidis, D.; Annesley, S.; Allan, C.; Sanislav, O.; Lidbury, B.; Lewis, D.; Fisher, P. An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients. Preprints 2019, 2019090043 (doi: 10.20944/preprints201909.0043.v1). https://www.preprints.org/manuscript/201909.0043/v1
torsdag den 21. november 2019
Kan viden om hajer hjælpe med at forklare ME- og EHS-sygdomsmekanismen?
Der må findes en biologisk forklaring på, hvorfor nogle ME patienter udvikler elektromagnetisk hypersensitivitet (EHS) mod selv ekstremt lave felter. Måske kan viden om hajer hjælpe os på sporet.
Hajer er de mest "el-følsomme" dyr i verden. De kan mærke felter med så lav en værdi som 5 nV/cm. Det elektriske felt bliver opfanget af sensorer, der kaldes ampullae of Lorenzini. Hajerne anvender deres sensorer til at mærke de svage elektriske felter fra deres byttedyr. Det er observeret, at hajer kan gå til angreb på telegraf-kabler på havets bund, fordi de fejlagtigt opfattes som byttedyr (1, 2).
Ampullae of Lorenzini indeholder keratansulfat, som er en proton (H+) conductor (en elektrisk leder). Det betyder, at protonerne (H+) kan blive transporteret langs med keratansulfat molekylekæder, som er omgivet af vand (H2O). H+ vandrer langs rækken af hydrogenbindinger mellem (H2O og hydrofile enheder (se figur 1 i reference 3). Hver ampul indeholder et lag af celler, der kan opfange de elektriske signaler. Mellem cellerne er der tætte samlinger, således at der ikke kan forekomme lækstrøm mellem cellerne (2, 3).
Fig 1 from reference 3. The keratan sulfate.
Protonerne (H+) i vandige opløsninger bindes til H2O og eksisterer således som H3O+. Protonerne (H+) eksisterer kun under 1% af tiden, hvor de overføres fra et vandmolekyle til et andet. En grundig beskrivelse af fænomenet findes i DeCourseys review, reference 4.
Bemærk at artiklen om keratansultat i hajer hedder (3):
Proton conductivity of glycosaminoglycans
Glycosaminglycaner (GAGs) er lange kæder af polysakkarider. Der findes fem typer GAGs (5):
Dette lag har stor betydning for udveksling af ilt, kuldioxid og protoner (figur 24 i reference 4, 5). Og det har betydning for immunforsvar, lungesygdomme og astma (5).
How Do Sharks and Rays Use Electricity to Find Hidden Prey?
Referencer:
1) Electroreception https://en.wikipedia.org/wiki/Electroreception
2) Ampullae of Lorenzini
https://en.wikipedia.org/wiki/Ampullae_of_Lorenzini
3) Selberg, Manping, Rolandi (2019): Proton conductivity of glycosaminoglycans. Plos One Published: March 8, 2019
https://doi.org/10.1371/journal.pone.0202713
4) DeCoursey TE. Voltage-gated proton channels and other proton transfer pathways (vol 83, pg 475, 2003). Physiological Reviews. 2003 Jul;83(3):1067–.
https://www.physiology.org/doi/full/10.1152/physrev.00028.2002
5) Souza-Fernandes AB1, Pelosi P, Rocco PR
Bench-to-bedside review: the role of glycosaminoglycans in respiratory disease. Crit Care. 2006;10(6):237.
https://www.ncbi.nlm.nih.gov/pubmed/17118216
Hajer er de mest "el-følsomme" dyr i verden. De kan mærke felter med så lav en værdi som 5 nV/cm. Det elektriske felt bliver opfanget af sensorer, der kaldes ampullae of Lorenzini. Hajerne anvender deres sensorer til at mærke de svage elektriske felter fra deres byttedyr. Det er observeret, at hajer kan gå til angreb på telegraf-kabler på havets bund, fordi de fejlagtigt opfattes som byttedyr (1, 2).
Ampullae of Lorenzini indeholder keratansulfat, som er en proton (H+) conductor (en elektrisk leder). Det betyder, at protonerne (H+) kan blive transporteret langs med keratansulfat molekylekæder, som er omgivet af vand (H2O). H+ vandrer langs rækken af hydrogenbindinger mellem (H2O og hydrofile enheder (se figur 1 i reference 3). Hver ampul indeholder et lag af celler, der kan opfange de elektriske signaler. Mellem cellerne er der tætte samlinger, således at der ikke kan forekomme lækstrøm mellem cellerne (2, 3).
(A) Chemical structure of KS. (B) An illustration of a three-monomer segment of KS. Possible intra- and inter-molecular hydrogen bonds as well as the hydrogen bonds between the water of hydration and the polar parts of the molecule form a continuous network comprised by hydrogen-bond chains. The sulfate group interacts with the hydrogen-bond network and forms an H3O+ (hydronium) ion. https://doi.org/10.1371/journal.pone.0202713.g001
Protonerne (H+) i vandige opløsninger bindes til H2O og eksisterer således som H3O+. Protonerne (H+) eksisterer kun under 1% af tiden, hvor de overføres fra et vandmolekyle til et andet. En grundig beskrivelse af fænomenet findes i DeCourseys review, reference 4.
Bemærk at artiklen om keratansultat i hajer hedder (3):
Proton conductivity of glycosaminoglycans
Glycosaminglycaner (GAGs) er lange kæder af polysakkarider. Der findes fem typer GAGs (5):
- heparan sulfate
- chondroitin sulphate
- dermatan sulphate
- keratan sulphate
- hyaluronic acid
Dvs der er flere typer GAGs med proton conductivity (kan lede protoner). Herudover kan også kollagen være leder for protoner (3).
Vores extracellulære matrix (ECM) er fyldt med GAGs.
Mellem alveolar epithelium og kapillær endothelium findes et tyndt lag ECM med GAGs og kollagen (5). På jævnt dansk: I et tyndt lag mellem det fine lungevæv og de små fine blodkar findes ECM (figur 2 i reference 5).
Dette lag har stor betydning for udveksling af ilt, kuldioxid og protoner (figur 24 i reference 4, 5). Og det har betydning for immunforsvar, lungesygdomme og astma (5).
Et nærliggende spørgsmål er om det også kan have betydning for iltoptagelse ved motion? Eller betydning for multiple chemical sensitivity (MCS)?
Og kan en dysregulering af GAGs og/eller lækstrøm i utætheder forårsage EHS?
YOU TUBE:
YOU TUBE:
INTERVIEW EXTRA: Ampullae of Lorenzini
1) Electroreception https://en.wikipedia.org/wiki/Electroreception
2) Ampullae of Lorenzini
https://en.wikipedia.org/wiki/Ampullae_of_Lorenzini
3) Selberg, Manping, Rolandi (2019): Proton conductivity of glycosaminoglycans. Plos One Published: March 8, 2019
https://doi.org/10.1371/journal.pone.0202713
4) DeCoursey TE. Voltage-gated proton channels and other proton transfer pathways (vol 83, pg 475, 2003). Physiological Reviews. 2003 Jul;83(3):1067–.
https://www.physiology.org/doi/full/10.1152/physrev.00028.2002
5) Souza-Fernandes AB1, Pelosi P, Rocco PR
Bench-to-bedside review: the role of glycosaminoglycans in respiratory disease. Crit Care. 2006;10(6):237.
https://www.ncbi.nlm.nih.gov/pubmed/17118216
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tirsdag den 12. november 2019
Photoimmunology and the ME IDO metabolic trap
The sun emits ultraviolet radiation (UVR) with different wavelengths:
UVR can cause sunburn and increase the risk of skin cancer. UVR is also immunomodulatory and can be beneficial in the case of inflammatory and autoimmune diseases, but UVR can also exacerbate some autoimmune diseases (1, 2).
Chromophores are the parts of a photorecpetor that absorb photons in light (1).
UVB radiation can be absorped by cytosolic tryptophan, which thus function as a chromophore. This results in the formation of tryptophan photoproducts in particular 6-formylindolo[3,2-b]carbazole (FICZ). FICZ binds to aryl hydrocarbon receptor (AhR) and activates downstream signalling pathways, which contribute to UVR-induced immunosupression (1).
Figur 1 from reference 3. Light dependent synthesis of FICZ. 6-Formylindolo[3,2-b]carbazole (FICZ) is formed by the action of light on tryptophan. FICZ activation of AhR regulates important biological pathways and increases expression of CYP1A1 as a feedback mechanism to induce its own metabolism (3).
AhR activation by FICZ reduces receptor for IgE (FcεRI) and upregulates IDO expression in Langerhans cells (4).
- UVA (320 - 400 nm)
- UVB (280 - 320 nm)
- UVC (< 280 nm)
UVR can cause sunburn and increase the risk of skin cancer. UVR is also immunomodulatory and can be beneficial in the case of inflammatory and autoimmune diseases, but UVR can also exacerbate some autoimmune diseases (1, 2).
Chromophores are the parts of a photorecpetor that absorb photons in light (1).
UVB radiation can be absorped by cytosolic tryptophan, which thus function as a chromophore. This results in the formation of tryptophan photoproducts in particular 6-formylindolo[3,2-b]carbazole (FICZ). FICZ binds to aryl hydrocarbon receptor (AhR) and activates downstream signalling pathways, which contribute to UVR-induced immunosupression (1).
Figur 1 from reference 3. Light dependent synthesis of FICZ. 6-Formylindolo[3,2-b]carbazole (FICZ) is formed by the action of light on tryptophan. FICZ activation of AhR regulates important biological pathways and increases expression of CYP1A1 as a feedback mechanism to induce its own metabolism (3).
AhR activation by FICZ reduces receptor for IgE (FcεRI) and upregulates IDO expression in Langerhans cells (4).
The IDO metabolic trap hypothesis for ME suggests that antigen-presenting cells are driven into a pathological state with increased cytosolic tryptophan. The following decrease in kynurenine products (including FICZ) may disturb the immune system homeostasis (5).
Several ME patients get better in the sun. Is it because sun-induced FICZ moderate the immune system?
References:
1) Bernard, J.J., Gallo, R.L. & Krutmann, J. Photoimmunology: how ultraviolet radiation affects the immune system. Nat Rev Immunol 19, 688–701 (2019) doi:10.1038/s41577-019-0185-9
https://www.nature.com/
2) Fritsche et al: Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8851-6. Epub 2007 May 14. https://www.ncbi.nlm.nih.gov/pubmed/17502624
3) Zhang, C., Creech, K.L., Zuercher, W.J. et al. Gram-scale synthesis of FICZ, a photoreactive endogenous ligand of the aryl hydrocarbon receptor. Sci Rep 9, 9982 (2019) doi:10.1038/s41598-019-46374-7
https://www.nature.com/articles/s41598-019-46374-7
4) Koch et al: AhR mediates an anti-inflammatory feedback mechanism in human Langerhans cells involving FcεRI and IDO. Allergy. 2017 Nov;72(11):1686-1693. doi: 10.1111/all.13170. Epub 2017 May 10. https://www.ncbi.nlm.nih.gov/pubmed/28376268
5) Efimov et el. The mechanism of substrate inhibition in human indoleamine 2,3 dioxygenase. J Am Chem Soc. 2012 Feb 15;134(6):3034-41. doi: 10.1021/ja208694g. Epub 2012 Feb 2. https://www.ncbi.nlm.nih.gov/pubmed/22299628
Several ME patients get better in the sun. Is it because sun-induced FICZ moderate the immune system?
1) Bernard, J.J., Gallo, R.L. & Krutmann, J. Photoimmunology: how ultraviolet radiation affects the immune system. Nat Rev Immunol 19, 688–701 (2019) doi:10.1038/s41577-019-0185-9
https://www.nature.com/
2) Fritsche et al: Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8851-6. Epub 2007 May 14. https://www.ncbi.nlm.nih.gov/pubmed/175026243) Zhang, C., Creech, K.L., Zuercher, W.J. et al. Gram-scale synthesis of FICZ, a photoreactive endogenous ligand of the aryl hydrocarbon receptor. Sci Rep 9, 9982 (2019) doi:10.1038/s41598-019-46374-7
https://www.nature.com/articles/s41598-019-46374-7
4) Koch et al: AhR mediates an anti-inflammatory feedback mechanism in human Langerhans cells involving FcεRI and IDO. Allergy. 2017 Nov;72(11):1686-1693. doi: 10.1111/all.13170. Epub 2017 May 10. https://www.ncbi.nlm.nih.gov/pubmed/28376268
5) Efimov et el. The mechanism of substrate inhibition in human indoleamine 2,3 dioxygenase. J Am Chem Soc. 2012 Feb 15;134(6):3034-41. doi: 10.1021/ja208694g. Epub 2012 Feb 2. https://www.ncbi.nlm.nih.gov/pubmed/22299628
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