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Methylene Blue Is A Potent Anti-inflammatory, With Possibly The Broadest Spectrum

Discussion in 'Scientific Studies' started by haidut, Jan 30, 2018.

  1. haidut

    haidut Member

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    Some bold statements in this study, which combined both in vitro and in vivo models. The HED for methylene blue (MB) was just 0.15mg/kg, which is in the range of 10mg-15mg doses that showed great effectiveness in treating mental disorders like depression and psychosis. As you can see from the study below, the anti-inflamamtory mechanism of action was not so much opposition of NO and its synthesis (which MB does do quite well) but improvement of mitochondrial function. Finally, MB improved survival in a sepsis model, which probably makes it a great addition to thiamine for treating septic patients.
    @Travis @Koveras @aguilaroja

    Methylene blue inhibits NLRP3, NLRC4, AIM2, and non-canonical inflammasome activation
    "...In this study, we assessed the effect of methylene blue (MB) on canonical (NLRP3, NLRC4, and AIM2) and non-canonical inflammasome activation. We demonstrated that MB acts as an anti-inflammasome agent. Specifically, MB attenuated specific inflammasome trigger-mediated IL-1β/18 and caspase-1 secretion as well as Asc pyroptosome formation. MB also blocked mitochondrial ROS production, which triggers NLRP3 inflammasome activation, as well as NLRP3 and pro-IL-1β expression, which are essential components for inflammasome activation. In addition, MB attenuated activity of casaspe-1, which directly induces maturation of IL-1β/18. The anti-inflammasome properties of MB were further confirmed in an animal model. MB treatment reduced LPS-induced lethality and Listeria-mediated IL-1β secretion. Taken together, we suggest that MB can inhibit both the beginning and end of canonical and non-canonical inflammasome activation."

    "...In the present study, MB treatment increased the survival rates of LPS-treated mice (Fig. 4A). Although we demonstrated the inhibitory effect of MB on NLRP3 and/or non-canonical inflammasome activation for reduction of LPS lethality, blockage of NO production by MB might support increased survival rates in septic mice. On the other hand, we hypothesized that NO increases IL-1β secretion via inflammasome activation. For this, we treated L-arginine, an endogenous NO precursor, to LPS-primed BMDMs and assessed IL-1β secretion. As the result, L-arginine did not induce any IL-1β secretion in LPS-primed BMDMs (Supplementary Fig. 3). Thus, we conclude that MB attenuates inflammasome activation independent of NO production."

    "...MB is an oxidation-reduction (redox) agent previously used safely in humans as an antidote for certain metabolic poisons1 . In addition, MB prevents the formation of superoxide and nitric oxide in mitochondria and is able to improve brain oxidative metabolism by enhancing mitochondrial oxygen consumption1 . In animal studies, MB counteracts the damaging effect of rotenone, an inhibitor of the mitochondrial electron transfer complex I, on retinal neurons24. Thus, MB is suggested as a potential therapeutic target for mitochondrial dysfunction. Mitochondrial dysfunction plays a determinant role in a number of acute and chronic inflammatory diseases25. Mitochondrial dysfunction acts upstream of NLRP3 activation by providing ROS to trigger NLRP3 oligomerization or by inducing α-tubulin acetylation to relocate mitochondria in proximity to NLRP314,26. Based on our results and previous reports, we conclude that MB attenuates inflammasome activation by improving mitochondrial function."

    "...Inflammasome dysregulation has been implicated in neurologic disorders and metabolic diseases, neither of which are traditionally considered to be inflammatory diseases but which are increasingly recognized as having an inflammatory component that significantly contributes to the disease process and drives many forms of cancer in humans5 . Therefore, researchers have become interested in the regulation of inflammasome activation. So far, several reagents such as recombinant IL-1 receptor antagonist (anakinra), neutralizing IL-1β antibody (canakinumab), soluble decoy IL-1 receptor (rilonacept), IL-18–binding protein, soluble IL-18 receptors, and anti–IL-18 receptor monoclonal antibodies have been developed and applied to control inflammasome-mediated diseases5 . These reagents only control events downstream of inflammasome activation such as blockage of IL-1β/-18 signaling. However, we have attempted to screen natural compounds that selectively control events upstream of inflammasome activation32–38. Based on our finding, MB has the most wide range of anti-inflammasome agents and controls several events upstream of inflammasome activation. Specifically, MB blocks the NLRP3, NLRC4, and AIM2 inflammasomes as well as non-canonical inflammasome. In addition, MB attenuates crystal phagocytosis, the priming step of inflammasome activation, Asc speck formation, and caspse-1 activation."
     
  2. sladerunner69

    sladerunner69 Member

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    Any cause for concern if one were to combine MB with caffiene and aspirin and niacinimide? Because all of these substances are potent NO inhibitors I am worried that my blood pressure will drop too low or that my blood may thin out too much. I have heard others warn of taking MB with caffiene, and I ahve been using upwards of 500mg caffiene daily for a long time.
     
  3. Koveras

    Koveras Member

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    On the sepsis front (sort of)

    Can J Anaesth. 2013 Nov;60(11):1085-8. doi: 10.1007/s12630-013-0026-4. Epub 2013 Sep 14.
    A case of acute respiratory distress syndrome responsive to methylene blue during a carcinoid crisis.
    van Diepen S1, Sobey A, Lewanczuk R, Singh G, Sidhu S, Zibdawi M, Mullen JC.

    PURPOSE:
    In a carcinoid crisis, numerous vasoactive agents, such as bradykinin precursors, serotonin, and histamine, are secreted by tumour cells. Bradykinin has been shown to increase pulmonary vascular permeability and hypotension in animal models; however, little is known about its in vivo effects or targeted pharmacotherapy in a carcinoid crisis. We describe a case of acute respiratory distress syndrome (ARDS) in a carcinoid crisis refractory to conventional antiserotonin and antihistamine therapies.

    CLINICAL FEATURES:
    A 56-yr-old male with known liver metastases and previous resection of a small intestinal carcinoid tumour in 1991 underwent successful tricuspid and pulmonary valve replacements. On postoperative day 10, he developed hypotension, a fever, leukocytosis, and flushing. His hypotension was treated with a 200 μg octreotide iv bolus followed by a 150 μg·hr(-1) infusion, vasopressin, norepinephrine, and hydrocortisone. He also required tracheal intubation for ARDS (Pa02:FI02 ratio 96). After 72 hr of broad spectrum antibiotics and no clinical improvement, antiserotonin and antihistamine therapies were augmented with cyproheptadine, ranitidine, and serial octreotide boluses with an infusion of 1,500 μg·hr(-1). These interventions improved his oxygenation (Pa02:F i 02 ratio 162) and reduced his norepinephrine requirements. Following a methylene blue bolus (1 mg·kg(-1)) and 12-hr infusion (0.5 mg·kg(-1)·hr(-1)), all vasopressors were discontinued and his oxygenation improved (Pa02:F i 02 ratio 297).

    CONCLUSION:
    In a patient with a carcinoid crisis and ARDS refractory to conventional therapies, substantial hemodynamic and oxygenation improvements were observed following methylene blue administration. This case highlights the potential pathophysiologic role of bradykinin and methylene blue as an adjunct therapeutic option in carcinoid crises.
     
  4. OP
    haidut

    haidut Member

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    Things that lower NO tend to raise blood pressure.
     
  5. OP
    haidut

    haidut Member

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    Great find, thanks. It is especially relevant given that MB is known to raise serotonin when used in high doses. So, the fact that it was helpful in a person with already very high serotonin is very encouraging.
     
  6. Koveras

    Koveras Member

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    Also found recently that glycolysis is involved in pushing anti-inflammatory 'M2' macrophages towards inflammatory 'M1' macrophages ... makes sense then if methylene blue was promoting oxidative metabolism that it would be pushing the system to an anti-inflammatory tone through this mechanism as well.

    Abdel-Haleem, A. M., Lewis, N. E., Jamshidi, N., Mineta, K., Gao, X., & Gojobori, T. (2017). The Emerging Facets of Non-Cancerous Warburg Effect. Front Endocrinol (Lausanne), 8, 279. doi:10.3389/fendo.2017.00279

    Screen Shot 2018-01-27 at 7.12.43 PM.png
     
  7. Waynish

    Waynish Member

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    Would be helpful to determine why it sometimes raises serotonin. I've taken more of it at times and gotten high-serotonin symptoms - and when I was sick I took more (at least 1000micrograms) and did not get any of those symptoms.
     
  8. sladerunner69

    sladerunner69 Member

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    Oh interesting. I was under the wrong impression then. Likewise, is raising blood pressure too much a problem? The last few times Ive had a check up at the doctor, they did mention that my blood pressure was a bit high.
     
  9. Luckytype

    Luckytype Member

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    If you are otherwise heathy slade, it could be white coat syndrome. Many people experience it.

    Measure it a few times at your leisure at a store that has a free cuff chair. It wont be bang on but should be close.

    Chronic high bp puts a lot of extra work upon the heart to push past higher pressures and with excessive remaining pressure when the heart isnt pumping
     
  10. OP
    haidut

    haidut Member

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    So, a corollary of this would be that in cancer (excessive glycolysis) the body will be in extreme inflammatory state, right?
     
  11. Marcos galvão

    Marcos galvão Member

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  12. aguilaroja

    aguilaroja Member

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    I am still thinking on the usefulness of the various inflammasome schemas. MB clearly has supportive effects in many situations

    Another recent article further detailed neuroprotective effects of MB, specifically in relation to inflammasomes:

    Methylene Blue Mitigates Acute Neuroinflammation after Spinal Cord Injury through Inhibiting NLRP3 Inflammasome Activation in Microglia. - PubMed - NCBI
    “...we tested the effects of methylene blue on microglia both in vitro and in a rat SCI model. We found that methylene blue inhibited the protein levels of IL-1β and IL-18 rather than their mRNA levels in activated microglia. Further investigation indicated that methylene blue deceased the activation of NLRP3 inflammasome and NLRC4 inflammasome in microglia in vitro. Moreover, in the rat SCI model, the similar effect of methylene blue on post-SCI microglia was also observed, except that the activation of NLRC4 inflammasome was not seen. The inhibition of microglia NLRP3 inflammasome was associated with down-regulation of intracellular reactive oxygen species (ROS). The administration of methylene blue mitigated the overall post-SCI neuroinflammation, demonstrated by decreased pro-inflammatory cytokine production and leukocyte infiltrates.”

    Methylene blue attenuates traumatic brain injury-associated neuroinflammation and acute depressive-like behavior in mice. - PubMed - NCBI
     
  13. OP
    haidut

    haidut Member

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    Why would it stop muscle growth?
     
  14. TreasureVibe

    TreasureVibe Member

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    Following this topic, interested since methylene blue has similar effects to Anakinra, which is effective in treatment of patients that suffer from Still's disease, which I suffer from too.
     
  15. Yggr

    Yggr Member

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    Does methylene blue increase AMPK? Then possibly it would attenuate to some degree muscle protein synthesis.
     
  16. OP
    haidut

    haidut Member

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    Testosterone also increases AMPK, yet also increases muscle synthesis. It is a multitude of factors that determine the effects of MB. Since it has anti-cortisol mechanism (which T also does) I would expect it to actually improve muscle protein synthesis, at least in lower doses (<15mg daily).
    http://www.jbc.org/content/285/21/15714.long
    "...The Hsp90/Hsp70-based chaperone machinery regulates the activity and degradation of many signaling proteins. Cycling with Hsp90 stabilizes client proteins, whereas Hsp70 interacts with chaperone-dependent E3 ubiquitin ligases to promote protein degradation. To probe these actions, small molecule inhibitors of Hsp70 would be extremely useful; however, few have been identified. Here we test the effects of methylene blue, a recently described inhibitor of Hsp70 ATPase activity, in three well established systems of increasing complexity. First, we demonstrate that methylene blue inhibits the ability of the purified Hsp90/Hsp70-based chaperone machinery to enable ligand binding by the glucocorticoid receptor and show that this effect is due to specific inhibition of Hsp70. Next, we establish that ubiquitination of neuronal nitric-oxide synthase by the native ubiquitinating system of reticulocyte lysate is dependent upon both Hsp70 and the E3 ubiquitin ligase CHIP and is blocked by methylene blue. Finally, we demonstrate that methylene blue impairs degradation of the polyglutamine expanded androgen receptor, an Hsp90 client mutated in spinal and bulbar muscular atrophy. In contrast, degradation of an amino-terminal fragment of the receptor, which lacks the ligand binding domain and, therefore, is not a client of the Hsp90/Hsp70-based chaperone machinery, is enhanced through homeostatic induction of autophagy that occurs when Hsp70-dependent proteasomal degradation is inhibited by methylene blue. Our data demonstrate the utility of methylene blue in defining Hsp70-dependent functions and reveal divergent effects on polyglutamine protein degradation depending on whether the substrate is an Hsp90 client."
     
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