The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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rT3 may be a cancer support hormone

Discussion in 'Other Health News and Research' started by pattismith, Mar 3, 2018.

  1. pattismith

    pattismith Senior Member

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    Nonthyroidal Illness Syndrome (Low T3 syndrome) and Thyroid Hormone Actions at Integrin αvβ3(review)
    Aleck Hercbergs Shaker A Mousa Paul J Davis
    The Journal of Clinical Endocrinology & Metabolism, jc.2017-01939, https://doi.org/10.1210/jc.2017-01939
    Published:
    01 February 2018

    Abstract
    Context
    The nonthyroidal illness syndrome (NTIS) is a constellation of changes in circulating thyroid hormone levels that occur in euthyroid patients with acute or chronic systemic diseases. The changes that occur include reduction in serum T3, increase in serum rT3 and variable changes in circulating T4 levels. No consensus yet exists on therapeutic intervention on NTIS.

    Methods
    We briefly review the published literature on the physiological actions of T4 and of rT3—hormones that until recently have been seen to have little or no bioactivity—and analyze specifically the apparent significance of changes in circulating T4 and T3 encountered in the setting of NTIS in cancer patients. In the case of T4, these actions may be initiated at a cancer or endothelial cell plasma membrane receptor on integrin αvβ3 or at the cytoskeleton.

    Results
    The possible utility emerges in this review of therapeutic intervention in NTIS in cancer patients in terms of T4 reduction and of T3 support. Evidence also exists that rT3 may be a cancer support hormone.

    Conclusions
    Prospective study is proposed of pharmacological reduction of normal or elevated T4 in cancer-associated NTIS and of support to normal of circulating levels of T3 in such patients.
     
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  2. Ema

    Ema Senior Member

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    Midwest USA

    So if this is saying that rT3 is also sodium channel blocker, modulating intracellular Ca, this is kind of a Big Deal.
     
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  3. pattismith

    pattismith Senior Member

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    Ema, could you tell me where does your quote come from, do you have an access to the full article, or is it from another one?

    "rT3 has recently been shown to have metabolic activity, in that it normalizes metabolism in the hypothyroid developing rodent brain (35). rT3 has been shown to be capable of blocking the actions of T3 on myocyte plasma membrane sodium current (36). Sodium current/channels are important to cancer cell invasiveness (37) and to intracellular Ca2+ oscillations that have been linked to metastatic activity of breast and prostate cancer cells (38)."
     
  4. Ema

    Ema Senior Member

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    Yes, it’s from the full article. PM me if you’d like to read it.
     
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  5. pattismith

    pattismith Senior Member

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    thank you Ema,

    I got to read the article I wish, I can't understand how it got so little interest in the scientific community, and I am glad that this american team resurected it!

    Acute effects of thyroid hormone analogs on sodium currents in neonatal rat myocytes. (1999)
    Huang CJ1, Geller HM, Green WL, Craelius W.
    Author information
    1
    Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
    Abstract
    We previously reported that T3(3,3',5-triiodo-L-thyronine) acutely increases sodium currents (INa) in neonatal rat myocytes.

    Here we compare the effects of several thyroid hormone analogs, including T4(3,3',5,5'-tetraiodo-L-thyronine), rT3(3,3',5'-triiodo-L-thyronine), D-T3(3,3',5-triiodo-D-thyronine), 3,5-T2(3,5-diiodo-L-thyronine), DIT (3,5-diiodo-L-tyrosine), MIT (3-monoiodo-L-tyrosine), tetrac (3,3',5,5'-tetraiodo-thyroacetic acid), triac (3, 3',5-triiodo-thyroacetic acid), and tyrosine, on INa in cultured neonatal rat myocytes (n ranged from 9 to 28 for each comparison).


    T4, T3, 3,5-T2, and DIT (10 n m) all increased current density relative to control to a similar degree: to 1.22+/-0.2, 1.21+/-0.03, 1.16+/-0.02 and 1.16+/-0.03, respectively, P<0.05.

    In contrast, thyroid hormone analogs with an altered side group of the inner iodophenyl ring, including tetrac, triac, and D-T3, had no effect on INa nor did rT3, MIT or tyrosine.

    Pretreatment with rT3 inhibited the effects of T4, T3, 3,5-T2, and DIT.

    Conversely, the dose-dependent inhibitory effect of amiodarone, an iodinated benzofuran derivative that antagonizes thyroid hormone actions, on INa was blocked when myocytes were pretreated with T3(100 n m, n=3), suggesting an interaction of T3 with amiodarone.

    The enhancement of INa by T3 and 3, 5-T2 could not be blocked by propranolol, suggesting that the effects are not mediated through beta -adrenergic signaling pathways.

    In conclusion, the present results suggest that the acute effects of thyroid hormone and analogs on cardiac INa are mediated by a non-genomic thyroid hormone receptor with a unique structure-activity relationship.


    Note: if these non-genomic thyroid hormon receptors were to exist in other cells than myocytes, rT3 could have this blocking activity of sodium current on them.
     
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  6. pattismith

    pattismith Senior Member

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    This is exactely the track I am on. I think I was rescued by T3 by non-genomic quick action on intracellular calcium in my muscles and brain, (action that was potentially blocked by my excess rT3).:thumbsup:
     
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  7. pattismith

    pattismith Senior Member

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    D3/rT3 pathway seems important to fight bacteria:

    "In neutrophils, the inactivating D3 is highly expressed.
    in these cells, the release of inorganic iodine was related to improve killing of bacteria.
    This is a very attractive concept because it might well explain the stimulating effects of TH on phagocytosis and killing independant of genomic effects.

    In conclusion, the hypothetical sequence of events during inflammation would be:
    rapid increase of TH at 4 hours
    then rapid downregulation of HP-thyroid axis (low T3 syndrome)
    Normal local T3 levels in metabolic organs which might serve the immune system by the breakdown of energy rich substrate (known for skeletal muscle)
    Activated neutrophils would be nourished by these circulating substrates and in parallel, increased D3 expression to provide inorganis iodine necessary to kill bacteria"


    https://books.google.fr/books?id=ka...Q6AEIQDAD#v=onepage&q=Rt3 NEUTROPHILS&f=false
     
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  8. pattismith

    pattismith Senior Member

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    Reverse T3 interacts with αvβ3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms.
    2017
    Abstract
    In the present study we provide evidence that 3,3',5'-triiodothyronine (reverse T3, rT3) restores neurochemical parameters induced by congenital hypothyroidism in rat hippocampus.

    Congenital hypothyroidism was induced by adding 0.05% propylthiouracil in the drinking water from gestation day 8 and continually up to lactation day 15. In the in vivo rT3 exposure, hypothyroid 12-day old pups were daily injected with rT3 (50 ng/kg body weight) or saline until day 14. In the ex vivo rT3 treatment, hippocampal slices from 15-day-old hypothyroid pups were incubated for 30 min with or without rT3 (1 nM).

    We found that ex vivo and/or in vivo exposure to rT3 failed in restoring the decreased 14C-glutamate uptake; however, restored the phosphorylation of glial fibrillary acidic protein (GFAP), 45Ca2+ influx, aspartate transaminase (AST), glutamine synthetase (GS) and gamma-glutamate transferase (GGT) activities, as well as glutathione (GSH) levels in hypothyroid hippocampus.
    In addition, rT3 improved 14C-2-deoxy-D-glucose uptake and lactate dehydrogenase (LDH) activity. Receptor agonists/antagonists (RGD peptide and AP-5), kinase inhibitors of p38MAPK, ERK1/2, CaMKII, PKA (SB239063, PD98059, KN93 and H89, respectively), L-type voltage-dependent calcium channel blocker (nifedipine) and intracellular calcium chelator (BAPTA-AM) were used to determine the mechanisms of the nongenomic rT3 action on GGT activity.

    Using molecular docking analysis, we found rT3 interaction with αvβ3 integrin receptors, nongenomically activating signaling pathways (PKA, CaMKII, p38MAPK) that restored GGT activity. We provide evidence that rT3 is an active TH metabolite and our results represent an important contribution to elucidate the nonclassical mechanism of action of this metabolite in hypothyroidism.

    It is worth noticing that on the other hand Tetrac is blocking the αvβ3 integrin receptors, and inhibit the T3 or T4 binding to these receptors.

    https://www.ncbi.nlm.nih.gov/pubmed/23021374

    This also means that the ability of rT3 in blocking Na currents from activation by T4, T3, T2 and DIT is not dependant on binding to αvβ3 integrin receptors...
     

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