New Atmosphere, New Vision: Gibson and Whittemore Kick Off Invest in ME Conference 2016
Mark Berry reports on Dr. Gibson's introduction and Dr. Whittemore's keynote speech, at the 11th Invest in ME International ME Conference in London.
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Hydroxylase inhibitors can trick the body into survival and repair responses

Discussion in 'Gastrointestinal and Urinary' started by kangaSue, Mar 14, 2017.

  1. kangaSue

    kangaSue Senior Member

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    This looks to be a line of research that could well have implications for those with ME/CFS too. I'll leave it to the links to do the explaining but this turned up looking into hypoxia in the GI tract and it's involvement of HIF (Hypoxia Inducible Factor) and inadequate tissue oxygenation, something which can be the result of reduced red blood cell mass (which is also a finding in some cases of Autonomic Neuropathy too) and is also a factor found in inflammation and other tissue ischemia.
    https://www.jci.org/articles/view/90055
    http://pubs.acs.org/doi/full/10.1021/jm400386j
    http://link.springer.com/article/10.1007/s00109-007-0277-z
     
    ScottTriGuy likes this.
  2. kangaSue

    kangaSue Senior Member

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    Given the recent flurry of interest in Metabolomics, I'm a bit surprised that this didn't draw further discussion seeing as the subject matter is related to processes that can lead to metabolic reprogramming.

    https://www.jci.org/articles/view/84433
    [It has recently become clear that, rather than simply being a consequence of inflammation, hypoxia can actively affect inflammatory processes through the regulation of oxygen-sensitive signaling pathways in multiple immune cell subtypes that are either resident within the inflamed tissue or have migrated from the oxygen-rich bloodstream to the hypoxic inflammatory milieu (6, 12).]

    [It has recently come to be appreciated that the metabolic status of an immune cell is intimately linked with its phenotype and function (2022). Therefore, in the context of immunity and inflammation, the sentinel role of HIF in the regulation of metabolic processes is of primary importance. HIF both regulates and is regulated by metabolism. For example, HIF is a strong driver of glycolytic gene expression and a repressor of oxidative phosphorylation (23), while metabolic intermediates including fumarate and succinate can modulate HIF-dependent signaling. Dysregulation of metabolic enzymes involved in the production of these intermediates in the tumor setting are associated with altered HIF-dependent signaling (24, 25). In the context of infection, LPS-dependent activation of macrophages leads to metabolic reprogramming, succinate release, and elevated IL-1β production downstream of HIF (26). Therefore, HIF sits in a prime position to link metabolic and immune/inflammatory processes.]

    [Hydroxylase inhibitors have recently been entered into clinical trials for the promotion of erythropoiesis in models of chronic kidney disease–associated anemia (116118). In these studies, the delivery of systemic doses of hydroxylase inhibitors was well tolerated by patients, paving the way for the possible use of these reagents for the treatment of inflammatory disorders and/or infectious disease. Notably, while systemic exposure of a patient to a hydroxylase inhibitor would be beneficial in anemia in order to promote erythropoiesis, the local delivery of these drugs would be desirable in the treatment of tissue-specific inflammation in order to avoid unwanted systemic effects such as erythropoiesis.]

    [Since the identification of HIF as a ubiquitous regulator of the cellular transcriptional response to hypoxia and the subsequent identification of hydroxylases as the key oxygen sensors in this pathway, our appreciation of the role of hypoxia as a driver of immunity and inflammation has expanded exponentially. The therapeutic payoff for a quarter of a century of basic research in this field is reflected by the recent entry to the clinic of hydroxylase inhibitors for the treatment of anemia. The potential for repurposing these drugs for inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and ischemia is a real possibility in the near future.]
     

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