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Mechanisms of Action and Clinical Application of Macrolides...effect on intracel Calcium

Discussion in 'Other Health News and Research' started by pattismith, Sep 22, 2018.

  1. pattismith

    pattismith Senior Member

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    still looking for some explanations as why macrolids make me weak and heavy, like if I had a sudden paresis...
    in this article's extract, they talk about effect on intracellular calcium...

    "Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications



    Effects on Cell Signaling
    There have been so many different reported effects of macrolides on cell signaling pathways that attempts to put these actions together as one mechanism is difficult. In fact, all macrolides seem not to have similar ranges or degrees of activity. Proposed mechanisms and their influence on cell signaling are discussed below.

    Intracellular calcium.
    Intracellular Ca2+ plays a fundamental role in signal transduction and regulates many enzymes, such as proteases, phospholipases, and endonucleases (44).
    Moreover, alteration of intracellular Ca2+ homeostasis is an early event in the development of irreversible cell injury (209).

    In airway epithelium, intracellular Ca2+ mobilization induced by proinflammatory mediators influences various cell functions, including ion transport and mucus secretion (43, 141). Experiments on epithelial cell lines suggest that Ca2+ signaling is involved in activation of the ERK1/2-NF-κB pathway and in ATP release as well as TLR-mediated responses by P. aeruginosa or flagellin (70, 184, 231, 277). Furthermore, intracellular Ca2+ agonists such as bradykinin and ATP can also increase cytokine expression and secretion in airway epithelia (199, 234, 235).

    We and others (126, 127, 151, 289) have shown that macrolides inhibit purinoceptor-mediated intracellular Ca2+ oscillations and Ca2+ influx in primary cultured airway epithelial cells, thereby reducing Cl secretion, perhaps through suppression of Ca2+-activated Cl channels.

    Similarly, Zhao et al. (346) have shown that erythromycin inhibits the ATP-mediated Ca2+ increase by suppressing Ca2+ influx from the extracellular space in A549 cells.

    Although molecular mechanisms of macrolide action on Ca2+ dynamics remain unclear, erythromycin does not affect verapamil-sensitive, voltage-dependent Ca2+ channels (151, 346).

    The effect of macrolides on the calcium response has been observed in other cells.

    Ca2+ influx into neutrophils and the oxidative burst were inhibited by erythromycin but not clarithromycin, suggesting that effects of macrolides on calcium mobilization are not completely homogenous (189).

    Recently, roxithromycin was shown to suppress histamine release and prostaglandin D2 production from human β-defensin-2-stimulated mast cells, and this was accompanied by inhibition of the intracellular Ca2+ increase (130).

    Calcium signaling after activation of apical G-protein-coupled receptors by proinflammatory mediators is amplified in Chronic Fibrosis airway epithelia (234, 235). Data suggest that the increased Ca2+ signal in CF cells may be due to the endoplasmic reticulum Ca2+ store increase or to inositol 1,4,5-triphosphate receptor (IP3R) dysfunction (9, 234). Macrolides may normalize Ca2+ responses and stabilize intracellular Ca2+ levels."
     
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  2. Shoshana

    Shoshana Northern USA

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    Northern USA
    Are we talking , here, about ongoing, long-term by oral route, or other, of meds in the macrolides family, … such as.erythromycin…. ?
    Not that I know much or have the answers to your questions... just wanting to know if I am understanding the question and the issues correctly or not.
     
  3. Murph

    Murph :)

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    Interesting.

    I've personally nver noticed an effect of antiobiotics, but then again I've only ever taken them when I was already sick so it would be hard to get a baseline.

    worth saying that this terminology "purinoceptor-mediated intracellular Ca2+ oscillations " suggests calcium depends on those exact purines (ATP, adenosine, etc) that are theorised to be a problem by Naviaux and/or observed to be low by him.
     
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  4. Murph

    Murph :)

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    Perhaps by the by but I found a paper that says a failure of purines to get calcium in and out of brain cells properly might explain why I am terrible these days at forming new memories.

    "These findings suggest that ATP should have an excitatory role for the neuronal transmission in the hippo- campus. Long term potentiation (LTP), a phenomenon which may underlie the process of memory and learning (see Bliss & Lynch, 1988; Malenka et al., 1989) has been extensively studied in relation to glutamate, the major excitatory neurotransmitter in the hippocampus. A rise in [Ca2+]i mediated by glutamate receptors is an event considered to be essential for the induc- tion of LTP,"
     
  5. pattismith

    pattismith Senior Member

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    @Shoshana

    yes the question is about Macrolid antibiotics like erithro, clarithro azithromicin.

    All of them impaired my neuro-muscular transmission with a dose dependant effect, and I believe that understanding how I got negative and positive effect from different drugs on my neuro-muscular transmission will give me the key of the underlying pathophysiologic mechanisms at play.:)

    I had not much time to investigate it, but I read that memory is linked to Proteine Kinase:

    https://www.ncbi.nlm.nih.gov/pubmed/24042850

    ion channels are also involved!
    I had started to investigate this but my muscles issue is the first one I want to fix before fixing my brain. I noticed it is easier to be my own guinea pig for muscle experimentations than for brain. I just hope my muscle findings will help my brain as well...It seems there is a good correlation between the two parts for now...
     
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  6. pattismith

    pattismith Senior Member

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    yes this caught my eye, but they doesn't explain which purinoreceptor.
    If Macrolids were P2X7 inhibitors, they would cure CFS/ME according to Naviaux!

    (In my case, Macrolids cured my vertebral pains+associated hypnic jerks, but did my muscles and brain worse)

    My supposition is that Macrolids inhibit some others than P2X7.

    Here some details about how some purinergic receptors work and the links to calcium signaling:

    "Macrophages (Mφ) possess both P2X7 (formerly P2Z) and P2Y2 as major P2 receptors (15, 16).

    Ligation of P2X7 receptors with low concentrations of ATP (∼100 μM) causes the influx of extracellular Ca2+ across the cell membrane (17, 18), whereas prolonged activation with high concentrations of ATP (3 mM) results in the formation of large nonselective membrane pores permeable to hydrophilic molecules of up to 900 Da (19).
    These events are thought to cause subsequent changes in intracellular signaling and metabolic pathways leading to the activation of NF-κB and stress-activated protein kinase (SAPK)/JNK, caspases, and cell apoptosis (16, 20, 21, 22). P2Y2 receptors act via G proteins (Gq) to stimulate the phospholipase Cβ (PLCβ) signaling cascade, releasing Ca2+ from internal stores (16, 23)."
     
  7. pattismith

    pattismith Senior Member

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    interleukine IL8 was pointed as a biomarker by KDM;
    IL8 can be released by activation of some purinergic receptors which may be a link between Naviaux theory and KDM finding concerning IL8. Interestingly, some Macrolides have an impact on IL8, maybe a part of their positive effect for some patients.


    Erythromycin Modulates IL-8 Expression in Normal and Inflamed Human Bronchial Epithelial Cells

    [​IMG]
    Erythromycin (EM) and its 14-member macrolide analogues have attracted attention for its effectiveness in a variety of airway diseases, including diffuse panbronchiolitis (DPB), sinobronchial syndrome, and chronic sinusitis.

    However, its mechanisms of action remain unelucidated. We evaluated the effects of several antibiotics on IL-8 expression by normal and transformed human bronchial epithelial cells, an important source of this potent chemokine involved in cell recruitment into the airways.

    EM and clarithromycin (CAM) uniquely suppressed mRNA levels as well as the release of IL-8 at the therapeutic and noncytotoxic concentrations

    (% inhibition of IL-8 protein release: 25.0 ± 5.67% and 37.5 ± 8.99%, respectively, at 10− 6 M).

    The other antimicrobes, including a 16-member macrolide josamycin, showed no effect. Bronchial epithelial cells from very peripheral airways as well as from main bronchi were obtained from patients with chronic airway inflammatory diseases, and EM and CAM inhibited IL-8 release from these cells. Among five patients who underwent bronchoscopy before and after macrolide treatment, four showed decreased levels of IL-8 expression in airway epithelium as assessed by reverse transcription and polymerase chain reaction. Our findings showed these 14-member macrolides had inhibitory effect on IL-8 expression in human bronchial epithelial cells, and this new mode of action may have relevance to their clinical effectiveness in airway diseases.
    Erythromycin (EM) is a macrolide antibiotic widely used for the treatment of upper and lower respiratory tract infections. Recent reports showed that EM is effective for the treatment of chronic airway diseases such as diffuse panbronchiolitis (DPB), bronchial asthma, and chronic sinusitis (1-3). Its precise mechanisms, however, remain unclear. Several cytokines, including IL-8, have been reported to be elevated in bronchoalveolar lavage fluids from patients with such airway inflammatory diseases and to be decreased after appropriate therapy, suggesting roles in airway inflammatory processes (2, 4, 5). IL-8, a potent neutrophil chemoattractant and activating factor (6), is known to be released by monocytes (6), macrophages (7), and fibroblasts (8), and recent data showed that airway epithelial cells are an important source of this CXC-type chemokine (9, 10). Here, we evaluated the effect of several antimicrobes, including EM, on IL-8 expression by normal airway epithelial cells and by those from patients with chronic airway inflammatory disease. We further studied the changes in IL-8 mRNA in airway epithelial cells before and after macrolide therapy by quantitative reverse transcription and polymerase chain reaction (RT-PCR) technique.
     

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