Marnie
Frequent Contributor (5K+ posts)
Member # 773
posted
This is very complex and linked to many 2013 = "cutting edge" legitimate medical research abstracts and pdf(s).
I see a HUGE potential for berberine's (chloride) use possibly in conjunction with Minocycline.
Printed out, this will be at least 11 pages long.
MOST of you will not understand this. It is my hope that those of you who have been deeply into the study of borrelia burdorferi and how our body responds to this pathogen MIGHT catch on.
Scott...I hope you will read this and pass it along...to you know who. Despite our differences, our goal has been and is one in the same...
find a CURE.
Here goes:
In addition, berberine increased adenosine monophosphate-activated protein kinase (AMPK)
and acetyl-coenzyme A carboxylase *phosphorylation.*
Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce
malonyl-CoA
through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT).
ACC is a multi-subunit enzyme in most prokaryotes and in the chloroplasts of most plants and algae, whereas it is a large, multi-domain enzyme in the endoplasmic reticulum of most eukaryotes.
The most important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids.
The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. The human genome contains the genes for two different ACCs— ACACA and ACACB.
AMPK is the main kinase regulator of ACC, able to phosphorylate a number of serine residues on both isoforms of ACC.
On ACC1, AMPK phosphorylates Ser79, Ser1200, and Ser1215.
On ACC2, AMPK phosphorylates Ser218.
Protein kinase A also has the ability to phosphorylate ACC, with a much greater ability to phosphorylate ACC2 than ACC1.
However, the physiological significance of protein kinase A in the regulation of ACC is currently unknown.
Researchers hypothesize there are other ACC kinases important to its regulation as there are many other possible phosphorylation sites on ACC.
When insulin binds to its receptors on the cellular membrane, it activates a phosphatase enzyme called protein phosphatase 2A (PP2A) to dephosphorylate the enzyme; thereby removing the inhibitory effect.
This protein may use the morpheein model of allosteric regulation
At the juncture of lipid synthesis and oxidation pathways, ACC presents many clinical possibilities for the production of novel antibiotics and the development of new therapies for diabetes, obesity, and other manifestations of metabolic syndrome.
Researchers aim to take advantage of structural differences between ***bacterial *** and human ACCs
to create antibiotics specific to the
bacterial ACC,
in efforts to minimize side effects to patients.
Promising results for the usefulness of an ACC inhibitor include the finding that ACC2 -/- mice (mice with no expression of ACC2) have continuous fatty acid oxidation, reduced body fat mass, and reduced body weight despite an increase in food consumption.
ACC2 -/- mice are also protected from diabetes.It should be noted that mutant mice lacking ACC1 are embryonically lethal.
However, it is unknown whether drugs targeting ACCs in humans must be specific for ACC2
I can’t help but wonder about Bb’s OspA and OspB = (OspAB) and OspC (which it expresses on its way out of the tick).
During investigations into mechanisms by which the Lyme disease spirochete controls synthesis of its
***Erp surface proteins,***
it was discovered that the borrelial PUR domain protein, Bpur, binds with high affinity to double-stranded DNA adjacent to the erp transcriptional promoter.
It looks like Bb’s OspC (outer surface protein C) contains ACC.
What happens if berberine phosphorylates ACC1 and ACC2?
Is Bb’s OspC upregulated or downregulated?
If it is UPregulated, will our body then recognize it and make antibodies to it?
OspC negative spirochetes
can replicate but cannot infect (mice).
If we have an antibody/antibiotic to OspC…
This looks to make berberine (Glycox) – to upregulate OspC AND/together with an antibiotic perhaps an ideal situation.
“Rapid Decline of OspC Borreliacidal Antibodies ***following Treatment*** of Patients with Early Lyme Disease
The results confirmed that the ELISA was an effective alternative for detection of OspC borreliacidal antibodies produced during early Lyme disease in humans and also provided strong evidence that
*a significant decline in the response* coincides with successful treatment of the illness.”
So we DO initially make antibodies to OspC EARLY during lyme disease, but with early treatment (antibiotics) OspC then declines.
So, it would appear beneficial to try to UPREGULATE Bb’s OspC (via berberine) and then hit Bb with antibiotics. ?
We know berberine has antibiotic capabilities too, but alone it might not be enough.
Just like giving huge doses of Mg (anti-inflammatory, anti-histamine) PLUS an antibiotic. Minocycline AND Glycox (chloride…doseage, timing)…both pulsed or not?
In other words, we have to get OspC excpression back up and then down (with abx.).
Read slowly..
“Interleukin-6 Enhances Production of Anti-OspC Immunoglobulin G2b Borreliacidal Antibody”
So we rapidly clear that antibody (immunoglobulin G2b) to Bb’s OspC.
Remember without OspC, Bb can’t infect, but CAN replicate,
but
our antibodies to OspC (immunoglobulin G2b) are rapidly cleared.
‘This report demonstrates that transforming growth factor (TGF)B1, previously shown to induce IgA dass switching, selectively stimulates IgG2b secretion by BALB/c resting B cells activated with LPS”
Backing up...TGF-B1 is induced by high glucose and TGF-B1 stimulates IgG2b secretion.
What we initially did was to make antibodies to Bb’s OspC - Anti-OspC (Anti-OspC Immunoglobulin G2b Borreliacidal Antibody)
So by lowering glucose (berberine) TGF-B1 would not be induced to stimulate IgG2b secretion = less immunoglobulin G2b.
TGFB1 encodes an RGD-containing protein that binds to type I, II and IV collagens.
(Cannot post link because of parenthesis in link.)
***Inflammatory stimuli that activate macrophages enhance the
release of active TGF-beta ***
by promoting the activation of plasmin.
Cancerous cells increase their production of TGF-β, which also acts on surrounding cells.
(Me…this gets really complex because…)
TGF-β1 plays an important role in controlling the immune system, and shows
different activities
on different types of cell,
or cells at different developmental stages.
(Confusing…)
The effects of TGF-β1 on macrophages and monocytes is predominantly suppressive;
this cytokine can inhibit the proliferation of these cells and prevent their production of reactive oxygen (e.g. superoxide (O2−)) and nitrogen (e.g. nitric oxide (NO)) intermediates
(And yet…)
phagocytic killing by macrophages can be increased by the action of TGF-β1
*Inhibition of* TGF-β1 signaling promotes central memory T cell differentiation. (2013)
This study affirmed that isolated CD8(+) T cells express mRNA and *produce TGF-β* following cognate peptide recognition.
Blockage of endogenous TGF-β with either a TGF-β-blocking Ab or a small molecule inhibitor of TGF-βRI enhances the generation of CD62L(high)/CD44(high)
central memory CD8(+) T cells accompanied with a robust recall response.
Interestingly, the augmentation within the central memory T cell pool occurs in lieu of cellular proliferation or activation, but with the expected increase in the ratio of the Eomesoderm/T-bet transcriptional factors.
Yet, the signal transduction pathway(s) seems to be noncanonical, independent of SMAD or mammalian target of rapamycin signaling.
***Enhancement of central memory generation by TGF-β blockade*** is also confirmed in human PBMCs.
The findings underscore the role(s) that autocrine TGF-β plays in T cell homeostasis and, in particular, the balance of effector/memory and central/memory T cells.
These results may provide a rationale to
targeting TGF-β signaling to enhance Ag-specific CD8(+) T cell memory
Interesting link about our CD8 T cell memory as it relates to viral infections too (proteins).
Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch
Here we show that rapid interferon-γ (IFN-γ) production of effector memory (EM) CD8+ T cells, activated through stimulation mediated by the T cell antigen receptor (TCR) and the costimulatory receptor CD28 or through cognate interactions, was linked to
increased glycolytic flux.
Thus, CD8+ memory T cells have an Akt-dependent 'imprinted'
glycolytic potential
that is required for efficient immediate-early IFN-γ recall responses.
Effector-like CD8+ T Cells in the Memory Population Mediate Potent Protective Immunity
Here we investigate the protective capacities of CD8+ T cell subsets present at the memory stage of the immune response.
Together, these data suggest that long-lived effector CD8+ T cells are optimal for protective immunity against certain pathogens.
Cannot post link because of parenthesis in the link.
Virtual memory CD8 T cells display unique functional properties
Previous studies revealed the existence of foreign antigen-specific memory phenotype CD8 T cells in unimmunized mice.
Considerable evidence suggests this population, termed “virtual memory” (VM) CD8 T cells, arise via physiological homeostatic mechanisms.
However, the antigen-specific function of VM cells is poorly characterized, and hence their potential contribution to immune responses against pathogens is unclear.
Here we show that naturally occurring, polyclonal VM cells have unique functional properties, distinct from either naïve or antigen-primed memory CD8 T cells.
In striking contrast to conventional memory cells, VM cells showed poor T cell receptor-induced IFN-γ synthesis and
preferentially differentiated into central memory phenotype cells after priming.
Importantly, VM cells showed efficient control of Listeria monocytogenes infection, indicating memory-like capacity to eliminate certain pathogens.
These data suggest naturally arising VM cells display unique functional traits, allowing them to form
a bridge
between the innate and adaptive phase of a response to pathogens.
Oddly…when researching berberine, I often read about a berberine “bridge”.
Getting deeper…
Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy.
After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function.
It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells.
We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells.
We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool
compared with cells taking up high amounts of glucose.
Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8+ T cells to form long-term memory.
Conversely, activation of CD8+ T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality.
Our data indicate that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state,
while its inhibition preserves the formation of long-lived memory CD8+ T cells.
These results have important implications for improving the efficacy of T cell–based therapies against chronic infectious diseases and cancer.
Consistent with this view, we found that
inhibition of glycolysis using 2DG was a
ssociated with increased activity of AMPK,
an evolutionarily conserved protein kinase that enforces quiescence to limit energy demands in response to energy stress (9).
Recently, AMPK has emerged as a key regulator of memory CD8+ T cell formation.
***For example, AMPKα1-deficient T cells were found to have profound defects in their ability to generate memory CD8+ T cell responses during Listeria monocytogenes infection (39),
whereas pharmacologic activation of AMPK with metformin resulted in
Berberine phosphorylates both forms of ACC (acetyl-CoA carboxylase) which is a substrate (think ingredient of) AMPK thus berberine upregulates AMPK (which is stated in numerous web links)
Results and Innovation: In inflammatory macrophages, BBR attenuated LPS-induced expression of inflammatory genes (inducible nitric oxide synthase [iNOS], cyclooxygenase-2 [COX2], interleukin [IL]-6), and the generation of nitric oxide and reactive oxygen species,
but increased the transcription of Nrf2-targeted antioxidative genes (NADPH quinone oxidoreductase-1 [NQO-1], heme oxygenase-1 [HO-1]), as well as the nuclear localization and
phosphorylation of Nrf2 protein.
Importantly, we found BBR-induced activation of Nrf2 is AMPK-dependent, as either pharmacologically or genetically inactivating AMPK blocked the activation of Nrf2.
Consistent with in vitro experiments,
BBR down-regulated the expression of proinflammatory genes but
upregulated those of Nrf2-targeted genes in lungs of LPS-injected mice,
and these effects were attenuated in Nrf2-deficient mice.
Moreover, the effect of BBR on survival time extension and plasma redox regulation in endotoxin-shocked mice was largely weakened
when Nrf2-depleted.
Conclusions: Our results demonstrate convergence between AMPK and Nrf2 pathways and this intersection is essential for anti-inflammatory effect of BBR in LPS-stimulated macrophages and endotoxin-shocked mice.
(nuclear factor erythroid-2-related factor-2 (Nrf2), a critical transcriptional activator for antioxidative responses)
Nrf2 is a powerful protein that is latent within each cell in the body, unable to move or operate
until it is released by an Nrf2 activator.
Once released it migrates into the cell nucleus and bonds to the DNA at the location of the Antioxidant Response Element (ARE) or also called hARE (Human Antioxidant Response Element) which is the master regulator of the total antioxidant system that is available in ALL human cells.
“High levels of free radicals turn on a specific protein
in the cell’s nucleus called Nrf2.
Activation of Nrf2 essentially opens the door for the production a vast array our body’s most important antioxidants.
It is clear that excessive free radicals induce better antioxidant production through this pathway, but the obvious question is, what else activates Nrf2?
It turns out that a variety of foods are powerful activators of the Nrf2 pathway.
While not necessarily rich in antioxidants, they directly and dramatically amplify our innate ability to produce vast antioxidant protection by signaling our DNA.
In this way, specific molecules from Nrf2 activating foods can trigger the production of thousands of antioxidant molecules, providing far better protection against the brain-damaging effects of free radicals compared to standard antioxidant supplements.
(I think the p8 protein that Bb picks up in the tick's saliva may be a lysine acetyltransferase. That protein prevents the mannose binding lectin initial response of our immune system.)
SIRT1…
Furthermore, we observe that the ***prevention of mitochondrial dysfunction*** by BBR, the increase in mitochondrial biogenesis, as well as BBR-induced AMPK activation, are blocked in cells
in which SIRT1 has been knocked-down.
Taken together, these data reveal an important role for SIRT1 and mitochondrial biogenesis in the preventive effects of BBR on diet-induced insulin resistance.
A significant change in the expression levels of sirtuin 1 (SIRT1) and apoptosis-related proteins was also observed in the BBR-pretreated hepatocytes under exposure to H2 O2 .
Furthermore, BBR exhibited a time-dependent effect on
upregulation of SIRT1 in L02 cells.
This study demonstrated that the protective effect of BBR against H2 O2 -induced apoptosis was associated with regulation of SIRT1 in hepatic cell line L02,
which provided a possible explanation for its antioxidant activity, and implied an application of BBR for the therapeutic relevance in oxidative-stress-related liver diseases.
Here’s another nutrient in food – a flavonoid – that also helps reduce H2O2 cell damage levels.
Interesting alternative:
Calorie restriction also promotes central
neuroprotection by
increasing brain expression of neural growth factors, ***Sirt1**, and heat shock proteins.
The benefits evoked by calorie restriction are not crucially dependent on calorie deficit per se, since
alternate day fasting has likewise been shown to increase maximal lifespan and promote neuroprotection – even if animals maintain their previous calorie intakes by eating ravenously on the fed days.
Hence, repeated prolonged episodes of diminished insulin, free IGF- I, and glucose appear sufficient to achieve the aging retardant and health benefits associated with calorie restriction.
Modified alternate-day fasting – allowing modest calorie intake during the “fasting” days – has shown clinical utility for
ameliorating inflammatory disorders
and promoting weight loss, but is probably too rigorous to achieve widespread popularity.
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