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Lipopolysaccharide-Induced Mitochondrial DNA Depletion

Discussion in 'Other Health News and Research' started by Waverunner, Sep 11, 2011.

  1. Waverunner

    Waverunner Senior Member

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    Very interesting since KDM tests and finds LPS in most of his patients.

    http://www.ncbi.nlm.nih.gov/pubmed/21767162

    Antioxid Redox Signal. 2011 Jul 18. [Epub ahead of print]

    Lipopolysaccharide-Induced Mitochondrial DNA Depletion.
    Choumar A, Tarhuni A, Lettron P, Reyl-Desmars F, Dauhoo N, Damasse J,
    Vadrot N, Nahon P, Moreau R, Pessayre D, Mansouri A. INSERM, U773,
    Centre de Recherche Biomdicale Bichat Beaujon CRB3 , Paris, France .

    Abstract Hepatic energy depletion has been described in severe sepsis,
    and lipopolysaccharide (LPS) has been shown to cause mitochondrial DNA
    (mtDNA) damage
    . To clarify the mechanisms of LPS-induced mtDNA damage
    and mitochondrial alterations, we treated wild-type (WT) or transgenic
    manganese superoxide dismutase-overerexpressing (MnSOD(+++)) mice with
    a single dose of LPS (5?mg/kg). In WT mice, LPS increased
    mitochondrial reactive oxygen species formation, hepatic inducible
    nitric oxide synthase (NOS) mRNA and protein, tumor necrosis factor-
    alpha, interleukin-1 beta, and high-mobility group protein B1
    concentrations. Six to 48?h after LPS administration (5?mg/kg), liver
    mtDNA levels, respiratory complex I activity, and adenosine
    triphosphate (ATP) contents were decreased. In addition, LPS increased
    interferon-? concentration and decreased mitochondrial transcription
    factor A (Tfam) mRNA, Tfam protein, and mtDNA-encoded mRNAs.
    Morphological studies showed mild hepatic inflammation. The LPS (5?mg/
    kg)-induced mtDNA depletion, complex I inactivation, ATP depletion,
    and alanine aminotransferase increase were prevented in MnSOD(+++)
    mice or in WT mice cotreated with 1400W (a NOS inhibitor), (2-(2,2,6,6-
    tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium
    chloride, monohydrate (a superoxide scavenger) or uric acid (a
    peroxynitrite scavenger). The MnSOD overexpression delayed death in
    mice challenged by a higher, lethal dose of LPS (25?mg/kg). In
    conclusion, LPS administration damages mtDNA and alters mitochondrial
    function. The protective effects of MnSOD, NOS inhibitors, and
    superoxide or peroxynitrite scavengers point out a role of the
    superoxide anion reacting with NO to form mtDNA- and protein-damaging
    peroxynitrite. In addition to the acute damage caused by reactive
    species, decreased levels of mitochondrial transcripts contribute to
    mitochondrial dysfunction.
    PMID:21767162
     
    rosie26 likes this.
  2. alex3619

    alex3619 Senior Member

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    Hi, KDM does not just find LPS in patients, he finds it proportional to severity of symptoms. Also, this is potentially the driving force behind the NO/ONOO issues and much of our oxidative stress. I wonder if it can also explain our mitochondrial dysfunction - and why it differs a little patient by patient, it may depend on which mitochondrial genes are damaged. Bye, Alex
     
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  3. Waverunner

    Waverunner Senior Member

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    Yes, the genes probably have an influence on how much our mitochondria get compromised. The most important question however seems to be what causes the LPS in our blood. Bacteria probably but why do we have these bacteria and why do they or a our immune system malfunction? Antibiotics are no solution, they can make things a lot better but the bacteria return sooner or later so what makes them grow so good?
     
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  4. alex3619

    alex3619 Senior Member

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    Hi waverunner, everyone has masses of LPS in the gut. The gut is supposed to detox it, and the liver picks up the rest. Therefore both the gut and liver detox have failed in us. So the question is, why have they failed? I don't know much/enough about specific LPS detox, but it would not surprise me if it is glutathione dependent. This could be feeback loops (eg methylation), cytokines or a virus infection as I see it, although other specific toxins may play a role. Bye, Alex
     
  5. Waverunner

    Waverunner Senior Member

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    Yes, one can probably break down the cause to a virus, methylation or a genetic defect. It's still sad however, that we have no answer also we probably could have, if more scientists would look into this field and if it would receive more attention.
     
  6. fla

    fla Senior Member

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    Montreal, Canada
    Can mitochondrial DNA depletion be reversed? Really hope so otherwise how can we find a cure for M.E.?
     
  7. rwac

    rwac Senior Member

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    The answer is yes.

    http://www.ncbi.nlm.nih.gov/pubmed/14640394
     
  8. rwac

    rwac Senior Member

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    And the best source of uridine is probably from an RNA supplement.
     
  9. Marco

    Marco Old blackguard

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    There is a French immunologist called Gregoire Cozon based in Lyon who reports detecting antigens to Candida albicans or Staphylococcus aureus in 50 to 60% of patients and hypothesises that we develop a abnormal immune reaction to these common microbes following vaccination or viral infection.

    Unfortunately I can't find the source document but if you Google it is described on a French blog that can be google translated.

    http://sfc-fibro.over-blog.com/pages/III_LES_EXAMENS_DE_SECONDES_INTENTIONS-1464549.html#

    Staphylococcus aureus has also been shown to disrupt the mitochondria.

    Guptal et al use LPS to induce fatigue in mice as an animal model of ME/CFS and have shown that various polyphenols (e.g. curcumin) reduce fatigue; and attenuate oxidative stress and TNF alpha :

    http://www.ncbi.nlm.nih.gov/pubmed/19159825

    Getting back to Staphylococcus aureus, SA sepsis causes oxidative stress and mitochondrial damage but this is reversed by mitochondrial biogenesis activated partly by coactivator peroxisome proliferator-activated receptor ? coactivator-1? (a PPAR) :

    http://respiratory.publishingtechnology.com/content/article/10.1164/rccm.200701-161OC

    PPAR activity can be stimulated by a range of compounds e.g. Quercetin :

    http://www.ncbi.nlm.nih.gov/pubmed/19211721

    So perhaps there may be an opportunity to repair acquired mito dysfunction?
     
  10. alex3619

    alex3619 Senior Member

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    Hi fla, I have a different answer to that given here, a better solution. I don't think it will be possible to reverse the DNA damage as suggested, not in our lifetimes. The solution is simpler than that. If all our mitochondria were damaged, we would be dead. We have many many healthy mitochondria still. What we need is a way to force those mitochondria to multiply, With more healthy mitochondria, the damaged mitochondrial DNA wont mean as much. DHEA is one substance that does this, but I am sure there are others. So the situation is not irreversible, nor as tricky as trying to repair damaged DNA.

    Bye
    Alex
     
  11. rwac

    rwac Senior Member

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    Yes, PQQ should help with generating new mitochondria. Helps me quite a bit.
     
  12. mellster

    mellster Marco

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    Hey rwac, something like brewers yeast for example? cheers
     
  13. rwac

    rwac Senior Member

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    Absolutely, brewer's yeast would work. Unfortunately it triggers asthma attacks for me, so I switched to the lef RNA supplement.
     
  14. Waverunner

    Waverunner Senior Member

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    I wanna throw in a comment: http://www.longecity.org/forum/topic/9534-anyone-have-experiences-with-rna-supplements/

    "I seriously doubt ingesting RNA would lead to the protein it initially coded for being expressed in any tissues. My reasoning is that RNA is generally speaking fairly unstable. If you wanted to extract RNA from cells in the lab (for use in a micro-array analysis for example) it is done on wet ice and with a cocktail of inhibitors. Even without RNase's it can break down. DNA is more stable because it has one less hydroxy group on the (deoxy)ribose sugar."

    "Be careful when using RNA/DNA supplements. The breakdown of these product causes excessive Uric acid which causes gout. I took the LEF RNA capsules for a year and my Uric acid level went above 7 or 8 causing severe joint pain. Stopped taking the RNA and after 12 months I was back to normal. I don't normally test for Uric Acid on my blood test, it was only after my joints became a pain that I found the culprit. "
     
  15. alex3619

    alex3619 Senior Member

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    This comment is technically correct, but not really so important if you have ME. The purine breakdown product is indeed uric acid, but its a highly protective antioxidant. For us this would be a good thing unless, as in gout, the acid crystallizes. Bye, Alex
     
  16. Waverunner

    Waverunner Senior Member

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    K, thanks, Alex.
     
  17. Marco

    Marco Old blackguard

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  18. aprilk1869

    aprilk1869 Senior Member

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    I just came across this, you can download the full pdf here: http://www.spandidos-publications.c...ype=article&article_id=ijmm_22_6_731&item=PDF

    Essential nutrients suppress inflammation by modulating key inflammatory gene expression

    We investigated the effects of a nutrient mixture (NM) consisting of ascorbic acid, quercetin, naringenin, hesperetin, tea catechins, lysine, proline, arginine and N-acetylcysteine on experimental in vivo and in vitro inflammation triggered by bacterial lipopolysaccharide (LPS). BALB/c mice (n=36) were administered NM (200 mg/kg BW) or ibuprofen (20 mg/kg BW) for two weeks. Blood plasma, collected three hours after a single intraperitoneal injection with LPS (1 mg/kg BW), was analyzed with 14 cytokine microarray. LPS inflammatory effects were analyzed in human U937 macrophages by cytokine release, cyclooxygenase (COX) enzymatic activity, COX protein expression (Western blot analysis), specific mRNA levels (RT-PCR), and nuclear factor ?? (NF??) activation (phosphorylated p65 immunoassay). Nutrient supplementation in mice altered the LPS-induced cytokine response in a manner similar to ibuprofen (r=0.4157, p=0.139). Cytokine response to LPS in cultured macrophages was similar to the in vivo study (r=0.718, p=0.023). NM inhibited COX-2 enzymatic activity, and COX-2 and pro-inflammatory cytokine protein expression levels were downregulated by NM at the transcription level complementing a blockade in NF?? activation. NM demonstrated strong beneficial effects on the experimental inflammation by targeting multiple responsible mechanisms in the complex process involved in the inflammatory reaction to pathogens.

    http://www.spandidos-publications.com/ijmm/22/6/731
     
  19. alex3619

    alex3619 Senior Member

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    Dr Andriya Martinovic

    Hi aprilk1869, the nutrient mixture abstract is interesting. Something similar was being used in the early to mid 90s to treat CFS but the researcher (my doctor at the time) could not get funding and had trouble publishing papers. In the end he was forced to stop treating his patients due to this being experimental medicine and not common practice. His success rate was ignored.

    Just to be clear, his treatment was similar but also different in that he used titration of key substrates to block COX2 hyperutilization.

    Bye
    Alex
     
  20. Marco

    Marco Old blackguard

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    A little initial digression with this anecdote if I may.

    When we first moved to France, one of the first things we noticed was that supermarkets were not the same 'one stop shops' that they are in the UK. For example, you can't buy cigarettes - you have to go to a tobacconist and you can't buy any health products over and above simple vitamin supplements or natural remedies. Any painkillers/cold flu remedies etc require a trip to the pharmacy. While this can be a little bit of a pain, I suppose it does help ensure that local town centres retain some commerce.

    Anyway, the first time one of came down with a seasonal cold or bug we went to the pharmacy and they gave us a product called Mucomyst - for drying up mucus. We have found this so useful we call it 'magic potion'. It seems to work on most things whether a cold, flu, bug or just generally feeling a little off colour (my wife doesn't have ME by the way).

    For me it has additional benefits. I'm very intolerant of high temperature and heat can frequently cause PEM. A sachet of Mucomyst can prevent this or get me back on my feet. I've also found that a sachet taken in advance can prevent PEM if I have any prolonged physical chores to do.

    Its only lately that I thought of trying to find out what was in our 'magic potions'. Its acetylcysteine.

    Apparently acetylcysteine is both a powerful antioxidant plus a glutathione precursor (for this reason its used as a treatment for paracetamol overdose).

    Maes also reports success in using acetylcysteine plus glutamine and zinc to treat ME/CFS leaky gut :

    http://www.ncbi.nlm.nih.gov/pubmed/19112401


    All anecdotal of course (my bits) but it works for me and its cheap as chips.
     
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