Review: 'Through the Shadowlands’ describes Julie Rehmeyer's ME/CFS Odyssey
I should note at the outset that this review is based on an audio version of the galleys and the epilogue from the finished work. Julie Rehmeyer sent me the final version as a PDF, but for some reason my text to voice software (Kurzweil) had issues with it. I understand that it is...
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mTor Inhibitor Rapamune Helps 5 ME/CFS Patients in Dallas

Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by Jesse2233, Apr 6, 2017.

  1. JaimeS

    JaimeS Senior Member

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    It could! Rapamycin increased appetite in one rat study, though more in rats of the lady persuasion.

    From here:
    Halloran, J., Hussong, S., Burbank, R., Podlutskaya, N., Fischer, K., Sloane, L., … Galvan, V. (2012). Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience, 223, 102–113. http://doi.org/10.1016/j.neuroscience.2012.06.054
     
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  2. XenForo

    XenForo

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    I was just thinking today that it seems like I'm more tolerant of the cold; I was diagnosed with Raynaud's.

    I'm curious if I'd also respond to the macrolide azthromycin; I wonder if other macrolides also help some of us - the ones who respond to sirolimus / rapamycin.
     
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  3. JaimeS

    JaimeS Senior Member

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    Some of these guys may interact with / boost (other?) mTOR inhibitors.
     
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  4. nanonug

    nanonug Senior Member

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    Suppressing the immune system leads to reduced creation of reactive oxygen/nitrogen species, such as superoxide and peroxynitrite. This, in turn, leads to a reduction in the expression of pyruvate dehydrogenase kinase, leading to the reactivation of the pyruvate dehydrogenase complex that feeds the electron transport chain responsible for the creation of the majority of ATP by the mitochondria.

    Makes sense to me. At least until one gets a serious infection or cancer due to a suppressed immune system.
     
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  5. ScottTriGuy

    ScottTriGuy Stop the harm. Start the research and treatment.

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    Me too, I only wear 2 layers of gloves this winter, not 4 (and would still have painfully cold hands). Although it may be due to switching from synthroid to dessicated thyroid in the spring.
     
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  6. JaimeS

    JaimeS Senior Member

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    Heard mTOR inhibition may interfere with TSH? Be cautious.
     
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  7. nanonug

    nanonug Senior Member

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    Myself and a few others here on PR use dichloroacetate (because of Naviaux et al.)

    Today I decided to do a Pubmed search on DCA (dichloroacetate) and mTOR. I found the following which qualifies as very interesting from my perspective.

    Overexpression of pyruvate dehydrogenase kinase supports dichloroacetate as a candidate for cutaneous melanoma therapy.

    Abstract
    OBJECTIVE:
    We aimed to verify if there is evidence to consider dichloroacetate (DCA), which inhibits the pyruvate dehydrogenase kinase (PDK) and reverts the metabolic shift of cancer cells from glycolysis to oxidative phosphorylation, as a promising drug for therapy of cutaneous melanoma (CM) patients.
    RESEARCH DESIGN AND METHODS:
    We assessed the expression profile of PDK 1, 2 and 3 in a series of melanoma samples, to verify if melanoma tumors express the DCA targets, if this expression correlates with the activation of important signaling cascades for melanomagenesis and also with the prognosis of melanoma patients. We also established the sensitivity of melanoma cell lines to DCA treatment, by assessing their metabolic alterations, proliferation and survival.
    RESULTS:
    We observed that both PDK 1 and 2 isoforms are overexpressed in CM compared to nevi, this expression being associated with the expression of the mTOR pathway effectors and independent of the BRAF mutational status. Melanoma cell lines treated with DCA showed a shift in metabolism, that is, a decrease in glucose consumption and lactate production, downregulation of proliferation, an increase of apoptosis and a decrease in mTOR pathway activation.
    CONCLUSION:
    Our results suggest that PDK expression may play a role in melanoma development and that DCA can be useful for CM therapy, alone or in combination with mTOR inhibitors.


    Dichloroacetate induces protective autophagy in esophageal squamous carcinoma cells

    Abstract
    Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase, which promotes the flux of carbohydrates into mitochondria and enhances the aerobic oxidation of glucose. DCA has previously been demonstrated to exhibit antitumor properties. The present study revealed that treatment with DCA induced increased levels of autophagy-associated proteins in esophageal squamous carcinoma cells while minimally affecting apoptosis. The present study examined the localization of light chain (LC)-3 by adenovirus infection with a green fluorescent protein (FP)-red FP-LC3 reporter construction and confirmed that DCA treatment induced significant autophagy. Furthermore, the inhibition of DCA-induced autophagy facilitated cell apoptosis and improved the drug sensitivity of esophageal squamous carcinoma cells to DCA and 5-FU (5-fluorouracil). The proliferation of TE-1 cells was markedly inhibited at low concentrations of DCA and 5-FU treatment when subjected to Atg5 mRNA interference, indicating that autophagy performed a protective role in cell survival upon DCA treatment. To determine the underlying mechanism of DCA-induced autophagy, the present study measured alterations in autophagy-associated signaling pathways. Notably, the protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) signaling pathway, an important negative regulator of autophagy, was demonstrated to be suppressed by DCA treatment. These results may direct the development of novel strategies for the treatment of esophageal squamous carcinoma based on the combined use of DCA and autophagy inhibitors.


    Dichloroacetate induces autophagy in colorectal cancer cells and tumours

    Abstract
    BACKGROUND:
    Dichloroacetate (DCA) has been found to have antitumour properties.
    METHODS:
    We investigated the cellular and metabolic responses to DCA treatment and recovery in human colorectal (HT29, HCT116 WT and HCT116 Bax-ko), prostate carcinoma cells (PC3) and HT29 xenografts by flow cytometry, western blotting, electron microscopy, (1)H and hyperpolarised (13)C-magnetic resonance spectroscopy.
    RESULTS:
    Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo. We observed increased production of reactive oxygen species (ROS) and mTOR inhibition (decreased pS6 ribosomal protein and p4E-BP1 expression) as well as increased expression of MCT1 following DCA treatment. Steady-state lactate excretion and the apparent hyperpolarised [1-(13)C] pyruvate-to-lactate exchange rate (k(PL)) were decreased in DCA-treated cells, along with increased NAD(+)/NADH ratios and NAD(+). Steady-state lactate excretion and k(PL) returned to, or exceeded, control levels in cells recovered from DCA treatment, accompanied by increased NAD(+) and NADH. Reduced k(PL) with DCA treatment was found in HT29 tumour xenografts in vivo.
    CONCLUSIONS:
    DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced k(PL) and increased NAD(+)/NADH ratio. The observed cellular and metabolic changes recover on cessation of treatment.


    Dichloroacetate induces protective autophagy in LoVo cells: involvement of cathepsin D/thioredoxin-like protein 1 and Akt-mTOR-mediated signaling

    Abstract
    Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase (PDK), and recently it has been shown as a promising nontoxic antineoplastic agent. In this study, we demonstrated that DCA could induce autophagy in LoVo cells, which were confirmed by the formation of autophagosomes, appearance of punctate patterns of LC3 immunoreactivity and activation of autophagy associated proteins. Moreover, autophagy inhibition by 3-methyladenine (3-MA) or Atg7 siRNA treatment can significantly enhance DCA-induced apoptosis. To determine the underlying mechanism of DCA-induced autophagy, target identification using drug affinity responsive target stability (DARTS) coupled with ESI-Q-TOF MS/MS analysis were utilized to profile differentially expressed proteins between control and DCA-treated LoVo cells. As a result, Cathepsin D (CTSD) and thioredoxin-like protein 1 (TXNL1) were identified with significant alterations compared with control. Further study indicated that DCA treatment significantly promoted abnormal reactive oxygen species (ROS) production. On the other hand, DCA-triggered autophagy could be attenuated by N-acetyl cysteine (NAC), a ROS inhibitor. Finally, we demonstrated that the Akt-mTOR signaling pathway, a major negative regulator of autophagy, was suppressed by DCA treatment. To our knowledge, it was the first study to show that DCA induced protective autophagy in LoVo cells, and the potential mechanisms were involved in ROS imbalance and Akt-mTOR signaling pathway suppression.


    My observations:
    • dichloroacetate is a good candidate drug to deal with Naviaux's hypometabolic state
    • it appears that dichloroacetate also inhibits mTOR
    • if mTOR inhibition is desirable as a treatment for SEID, then dichloroacetate would be truly a magic drug!
     
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  8. perrier

    perrier Senior Member

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    Are any of the ME doctors trying this?
     
  9. nanonug

    nanonug Senior Member

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  10. perrier

    perrier Senior Member

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  11. nanonug

    nanonug Senior Member

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    Not that I know of.
     
  12. perrier

    perrier Senior Member

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    Is there any way someone could show this to Dr. Davis? To see what he thinks. He's the most curious of all the doctors, willing to look at every lead.
     
  13. XenForo

    XenForo

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    The Center for Complex Diseases in Mountain View, CA diagnosed me with MCAS (Mast Cell Activation Syndrome) and my doc there thinks the Rapamune might have been helping to alleviate my MCAS. I've been doing much better on the MCAS drugs and have gone off Rapamune for now.
     
    Last edited: Apr 16, 2018
  14. XenForo

    XenForo

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    Wow, I'm doing MUCH, MUCH better on lots of meds for MCAS. I do wonder if Rapamune helps with MCAS symptoms. Any other Rapamune responders find out you have MCAS?
     
    Last edited: Apr 16, 2018
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  15. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Grats!! What kind of drugs is that?
     
  16. ScottTriGuy

    ScottTriGuy Stop the harm. Start the research and treatment.

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    I've been taking Rapamune since Nov.

    What MCAS testing was done and, if you don't mind, what tests were you positive? My doc is very open so would pursue this line of inquiry.
     
  17. XenForo

    XenForo

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    It is so nice to have a skilled doctor I trust to help direct my care. It is so much better than desperately ordering drugs online without a doctor's direction. Anyway, here's what my doc is prescribing for my MCAS:
    Zantac 1 tab 2x day
    Zyrtec 1 tab pm
    Claritan 1 tab in am
    Hydroxizyne tabs, titrated up to 50 mg 2 or 3 times a day
    Xanax .25mg 2x day
    Chromolyn Sodium 15 to 30 minutes before eating, titrating up to maybe 3 or 4 ampules. I'm still at 2 ampules
    Phosphatidyl choline 1 gelcap 3x day
    Low dose naltrexone 6mg at night
    Ketotifen titrating up to 3mg 2 times a day
    and a bunch of supplements like vit. D, B12, methylfolate, magnesium threonate (sp?) etc.
    I'm still doing really really well. Scheduled to go back to work Wednesday next week. I'm going to start at 4 hours and see how it goes. I'm not sure I'm ready for that, but I'm going to try and see how it goes. I'm really looking forward to it.
     
    Last edited: Apr 19, 2018
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  18. XenForo

    XenForo

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    I'll mention a couple things that I'm guessing are big clues to MCAS: I had allergy testing in the past (before going to Mountain View CCD) and I reacted to everything (or almost everything, I can't remember) except the control. I had lots and lots of vomiting between the ages of 1 and 2 or whenever that is when you first start walking to about age 2, 2 1/2 or so. And I've had lots of diarrhea and digestion issues throughout my life. No doctor has ever been able to address the root causes except CCD. One other clue is I've always had seasonal asthma (sp?). And of course, the PEM, but I guess that one is not specific. Specific tests and results pm'd.
     
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  19. XenForo

    XenForo

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    If no one else in this thread has MCAS maybe the MCAS stuff should be split into it's own thread? Any other Rapamune responders have an opinion about a possible relationship between MCAS and Sirolimus or other mTOR inhibitors?
     

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