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The Marshall Protocol Study Site > PROF. MARSHALL'S PERSPECTIVE > Prof. Marshall's Perspective > Chlorogenic Acid in Coffee is powerful Immune modulator


Chlorogenic Acid in Coffee is powerful Immune modulator
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Dmitry
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 Posted: Fri Oct 18th, 2019 08:37

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So caffeine messes up with adenosine receptors in a good or bad way?

...

Interestingly, Staphylococcus aureus, Bacillus antracis, and some other bacterial pathogens express adenosine synthase, a cell wall-anchored enzyme with 5′-nucleotidase signature sequences, and via generation of adenosine promote their escape from phagocytic clearance during host infection and subsequent survival and replication in organ tissues (27).

Last edited on Fri Oct 18th, 2019 08:48 by Dmitry



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 Posted: Fri Oct 18th, 2019 08:49

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Caffeine interferes with adenosine system, blocks 4 type of adenosine receptors. But this paper suggests that mice can elliminate borrelia on its own, in 2-4 weeks or at least dampen inflammation. So i am confused.



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 Posted: Fri Oct 18th, 2019 09:25

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A2B Adenosine Receptor Blockade Enhances Macrophage-Mediated Bacterial Phagocytosis and Improves Polymicrobial Sepsis Survival in Mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708265/

Regulation of Macrophage Function by Adenosine
https://www.ahajournals.org/doi/10.1161/ATVBAHA.111.226852

Staphylococcus aureus synthesizes adenosine to escape host immune responses.
https://www.ncbi.nlm.nih.gov/pubmed/19808256?dopt=Abstract
Collectively, these results suggest that staphylococci and other bacterial pathogens exploit the immunomodulatory attributes of adenosine to escape host immune responses.
...
Although extracellular adenosine is essential for the suppression of inflammation, build-up of excess adenosine is also detrimental. This is exemplified in patients with a deficiency in adenosine deaminase, an enzyme that converts adenosine to inosine (Giblett et al., 1972). Adenosine deaminase deficiency causes severe compromised immunodeficiency syndrome, with impaired cellular immunity and severely decreased production of immunoglobulins (Buckley et al., 1997). As the regulation of extracellular adenosine is critical in maintaining immune homeostasis, perturbation of adenosine levels is likely to affect host immune responses during infection.
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In addition to neutrophils, tissue macrophages are essential for the clearance of bacterial infections. Adenosine directly impairs the ability of macrophages to combat infection by decreasing the phagocytic activity of these cells (Eppell et al., 1989). Further, adenosine attenuates macrophage antibacterial activity by suppressing the production of superoxide (Edwards et al., 1994) and nitric oxide (Haskó et al., 1996; Xaus et al., 1999), both of which are integral to the killing of phagocytosed bacteria. Macrophage deactivation by adenosine also suppresses antibacterial defense mechanisms by decreasing the production of proinflammatory cytokines that both orchestrate inflammatory/immune functions of other cell types and act as regulators of macrophage function (Haskó and Szabó, 1998). For example, TNF is a regulator of neutrophil, endothelial cell, and lymphocyte function, and the production of TNF has been shown to be under negative control of adenosine. Finally, an important consideration is that adenosine, through the activation of macrophages, may decrease T cell antibacterial effector mechanisms. In support of this conjecture, adenosine decreases the expression of MHC II on macrophages (Edwards et al., 1994) and dendritic cells (Panther et al., 2001), and it decreases macrophage production of IL-12, a pivotal stimulus for Th1-type immune responses (Haskó et al., 2000).


https://www.jimmunol.org/content/165/11/6364
MHC II molecules are heterodimers that are expressed on the surface of a limited number of cells and are required to present Ags[antigens] to T cells. A lack of class II expression leads to severe immunodeficiency (14), whereas an abnormal expression may cause autoimmune diseases (15). Thus, regulation of the expression of MHC II molecules is a critical point in the control and maintenance of the immune response. The expression of MHC class II molecules in macrophages is induced by IFN-γ (16).

What if caffeine facilitates the adenosine build-up?

Caffeine alters plasma adenosine levels
http://wurtmanlab.mit.edu/static/pdf/921.pdf
We now report that caffeine increases plasma adenosine concentration in a manner that is dose-related, saturable, and mimicked by peripheral adenosine receptor blockade. Opposite effects are seen after caffeine withdrawal, indicative of a receptor-mediated effect.
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Rats were allowed ad libitum access to 0.1% caffeine in drinking water for two weeks (consumption averaged 65±10 mg per kg per day). A control group consumed tap water3,4. On the morning after the twoweek period we anaesthetized and cannulated the animals and took samples. Plasma adenosine increased from a control concentration of 0.32±0.5 mM to 3.17±0.30 mM in those rats that continued to drink caffeine (Fig. 1; P*0.0001). When the caffeinated solution was withdrawn and replaced with tap water on the evening before the measurement3,4, the plasma adenosine concentration declined to 0.10±0.03 mM compared to a second control group level of 0.26±0.04 mM (Fig. 1; P*0.05).
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Our data show that adenosine antagonists such as caffeine and 8SPT influence plasma adenosine concentrations, by an unknown mechanism, at caffeine doses approximating those provided to humans by 3–6 cups of coffee per day6. Heavy users may easily double this level of caffeine intake (6–12 cups is equivalent to 15 mg per kg per day7). This finding may have implications for individuals who cavalierly increase or withdraw from consumption of caffeine, a compound generally considered to be a useful but innocuous stimulant. Sudden changes in methylxanthine consumption — and thus in plasma adenosine concentrations — could dramatically alter the physiology of many organ systems, and provoke bronchospasm, alter blood pressure, change cardiac rhythms, or influence seizure thresholds.



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Chlorogenic acid attenuates lipopolysaccharide-induced mice mastitis by suppressing TLR4-mediated NF-κB signaling pathway.
https://www.ncbi.nlm.nih.gov/pubmed/24457123
The results showed that CGA significantly reduced TNF-α, IL-1β, and IL-6 production compared with LPS group. Besides, western blot analysis showed that CGA could inhibit the expression of TLR4 and the phosphorylation of NF-κB and IκB induced by LPS.

Involvement of TLR2 and TLR9 in the anti-inflammatory effects of chlorogenic acid[CGA] in Herpes Simplex Virus-1-infected microglia.
https://www.ncbi.nlm.nih.gov/pubmed/25744394
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CGA could attenuate HSV(Herpes Simplex Virus)-induced TNF-α and IL-6 release into the supernatant. The mRNA levels of TNF-α and IL-6 were also significantly inhibited by CGA. The expression of NF-κB p65 increased significantly in the nucleus in HSV-1-stimulated microglia but could be reduced by CGA.
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CGA inhibits the inflammatory reaction in HSE(Herpes Simplex Virus Encephalitis) via the suppression of TLR2/TLR9-Myd88 signaling pathways.

Last edited on Fri Oct 18th, 2019 13:43 by Dmitry



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 Posted: Sat Oct 19th, 2019 05:08

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Purinergic system is very complex and it affects other systems... https://en.m.wikipedia.org/wiki/Purinergic_signalling



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 Posted: Sat Oct 19th, 2019 11:54

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Question is: does adenosine decreases MHC II through its corresponding receptors (A1, A2A, A2B and A3) or through diff pathway[s]. If later then oops: coffee could indeed suppress at least blood monocytes through adenosine build-up(if there is enough concentration to have an effect, of course).



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 Posted: Sat Oct 19th, 2019 14:20

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Whats mhc2? Cells express different receptors to adenosine depending on conditions



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 Posted: Sat Oct 19th, 2019 14:20

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Last edited on Sat Oct 19th, 2019 14:21 by wrotek



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 Posted: Sat Oct 19th, 2019 14:23

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adenosine downregulates MHC class II:
https://en.wikipedia.org/wiki/MHC_class_II

here is the corresponding paper: https://www.ncbi.nlm.nih.gov/pubmed/8071590
MDL 201,112 and adenosine were also effective in decreasing m phi opsonized zymosan-stimulated O2- levels and MHC class II Ia+ antigen expression in vivo.
...
In summary, our data provide compelling evidence that immunoregulatory carbocyclic nucleoside analogues such as MDL 201,112 or adenosine appear to regulate LEW/N rat m phi activation through novel molecular mechanisms and may have important therapeutic implications for acute and chronic inflammatory diseases.


P.S. even if adenosine downregulates МHC2 through one of the A-receptors, coffeine, by shutting down others could indirectly increase binding of adenosine with МHC2 associated one effectively acting as an indirect МHC2 inhibitor.

Last edited on Sat Oct 19th, 2019 15:30 by Dmitry



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 Posted: Sat Oct 19th, 2019 22:16

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I used to follow watercure therapy, which involves avoidance of caffeine as a diuretic. The results were incredible one lady in 2 weeks got better in 75% from RSD, the inflammations subsided. The more i read the more i realize and wonder why is caffeine legal i dont know.



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 Posted: Sat Oct 19th, 2019 23:07

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> i realize and wonder why is caffeine legal i dont know.

Caffeine masks mild CFS for a majority of human population - it can be legal partly due to the pure economic reasons. :)



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 Posted: Mon Oct 21st, 2019 12:50

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Mikheila Peterson was using adderal to google research her disease ;) i was running on coffee



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 Posted: Mon Nov 4th, 2019 12:19

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Association of coffee consumption with serum adiponectin, leptin, inflammation and metabolic markers in Japanese workers: a cross-sectional study

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347755/

https://en.wikipedia.org/wiki/Leptin

Leptin (from Greek λεπτός leptos, "thin") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger

so that is why i want to eat so much after coffee

https://en.wikipedia.org/wiki/Adiponectin

Conclusion:

Coffee consumption was associated with high adiponectin and low leptin levels. We speculated that adipocytokines mainly explain the associations of coffee consumption with lipids and hs-CRP. Factors other than adipocytokines may explain the association between coffee consumption and liver function.



fascinating coffee effects are on human body, the complexity is...

Last edited on Mon Nov 4th, 2019 12:48 by wrotek



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 Posted: Wed Nov 6th, 2019 10:23

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https://www.amazon.com/Welcome-Dance-Caffeine-Cerebral-Progressive/dp/1412050006/ref=sr_1_3?keywords=caffeine+allergy&qid=1573035780&sr=8-3



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 Posted: Sat Nov 9th, 2019 11:55

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https://www.ncbi.nlm.nih.gov/pubmed/25744394
CGA[chlorogenic acid] inhibits the inflammatory reaction in HSE(Herpes Simplex Virus Encephalitis) via the suppression of TLR2/TLR9-Myd88 signaling pathways.

Macrophage mediated recognition and clearance of Borrelia burgdorferi elicits MyD88-dependent and -independent phagosomal signals that contribute to phagocytosis and inflammation
https://www.biorxiv.org/content/10.1101/593566v1
Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi (Bb). It is believed that the robust inflammatory response induced by the host’s innate immune system is responsible for the clinical manifestations associated with Bb infection. The macrophage plays a central role in the immune response to many bacterial infections and is thought to play a central role in activation of the innate immune response to Bb. Previous studies have shown that following phagocytosis of spirochetes by macrophages, phagosome maturation results in degradation of Bb and liberation of bacterial lipoproteins and nucleic acids, which are recognized by TLR2 and TLR8, respectively, and elicit MyD88-mediated phagosome signaling cascades. Bone marrow-derived macrophages (BMDMs) from MyD88−/− mice show significantly reduced spirochete uptake and inflammatory cytokine production when incubated with Bb ex vivo. Paradoxically, additional studies revealed that Bb-infected MyD88−/− mice exhibit inflammation in joint and heart tissues. To determine the contribution of MyD88 to macrophage-mediated spirochete clearance, we compared wildtype (WT) and MyD88−/− mice using a murine model of Lyme disease. MyD88−/− mice showed increased Bb burdens in hearts 28 days post infection, while H&E staining and immunohistochemistry showed significantly increased inflammation and greater macrophage infiltrate in the hearts of MyD88−/− mice. This suggests that Bb triggers MyD88-independent inflammatory pathways in macrophages to facilitate cell recruitment to tissues. Upon stimulation with Bb ex vivo, WT and MyD88−/− BMDMs exhibit significant differences in bacteria uptake, suggesting that MyD88 signaling mediates cytoskeleton remodeling and the formation of membrane protrusions to enhance bacteria phagocytosis. A comprehensive transcriptome comparison in Bb-infected WT and MyD88−/− BMDMs identified a large cohort of MyD88-dependent genes that are differentially expressed in response to Bb, including genes involved in actin and cytoskeleton organization (Daam1, Fmnl1). We also identified a cohort of differentially-expressed MyD88-independent chemokines (Cxcl2, Ccl9) known to recruit macrophages. We identified master regulators and generated networks which model potential signaling pathways that mediate both phagocytosis and the inflammatory response. These data provide strong evidence that MyD88-dependent and -independent phagosomal signaling cascades in macrophages play significant roles in the ability of these cells to phagocytose Bb and mediate infection.

Last edited on Sun Nov 10th, 2019 12:03 by Dmitry



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