Topic: Increase NADPH oxidase p47 pox OR simply lower NADPH
Marnie
Frequent Contributor (5K+ posts)
Member # 773
posted
Watch for the ***
I believe Bb has a PKC (DELTA) inhibitor.
``PKCD plays a pivotol role in
***stimulating monocyte NADPH oxidase
activity*** through
its regulation of the
phosphorylation and translocation of p47 pox.''
Thus monocyte
NADPH oxidase acitivity maybe being INHIBITED if Bb indeed has a PKCD inhibitor.
First NADPH oxidase:
"NADPH oxidase
It is made up of six subunits. These subunits are:
� a Rho guanosine triphosphatase (GTPase), usually Rac1 or Rac2 (Rac stands for Rho-related **C3 botulinum toxin** substrate)
� Five "phox" units. (Phox stands for phagocytic oxidase.)
� P91-PHOX (contains heme)
� p22phox
� p40phox
� ***p47phox **** (PKCD)
� p67phox
Mutations in the NADPH oxidase subunit genes cause several Chronic Granulomatous Diseases (CGD), such as
� X-linked chronic granulomatous disease (CGD),
� autosomal recessive cytochrome b-negative CGD,
� autosomal recessive cytochrome b-positive CGD type I and
� autosomal recessive cytochrome b-positive CGD type II.
In this disease cells have a low capacity for phagocytosis
and ***persistent bacterial infections occur.***
Areas of infected cells are common, granulomas. A similar disorder called neutrophil immunodeficiency syndrome is linked to a mutation in the RAC2, also a part of the complex."
"Identifying genes that regulate polygenic diseases influenced by the environment such as rheumatoid arthritis (RA), has so far proven to be difficult.
By using an alternative approach, i.e., linkage analysis using relevant animal models we succeeded in finding the
Ncf1 gene residing in the Pia4 quantitative trait locus to be responsible for the severity of pristane induced arthritis in rats.
The influence of another mutation in the mouse Ncf1 gene showed the same association between
***decreased oxidative burst and enhanced arthritis.*** (Note DECREASED oxidative burst)
In this case the mutation affected a splice site giving a non-detectable oxidative burst response and enhanced collagen induced arthritis as well as myelin oligodendrocyte protein induced experimental autoimmune encephalomyelitis.
These findings open up new possibilities for new treatments for autoimmune diseases, i.e., RA, targeting the NADPH oxidase pathway."
PMID: 15936744
Stick with me...
Phosphorylation (phosphate = PO4 transfer)...
"Phosphorylation of p47phox directs phox homology domain
from SH3 domain
toward phosphoinositides,
leading to phagocyte NADPH oxidase activation "
Which looks to be NOT HAPPENING.
Where can we "buy" some of the following?
"recombinant p47phox (rp47phox)
restores superoxide-generating activity to a cell-free assay containing cell membranes and cytosol
from p47phox-deficient CGD neutrophils. "
Some people (gene types) are in greater trouble:
"patients have an autosomal gene defect resulting in absence of p47phox protein"
Restating:
If PKCD is being inhibited, it appears NADPH oxidase is not stimulated and the oxidative burst (to clear some infections) does not happen.
If I've lost you already...perhaps I need to explain something...superoxide (powerful free oxygen radical), and H2O2, NO, etc. are made by our bodies to destroy pathogens.
Once they are destroyed, our antioxidants and antioxidant enzymes kick in to protect our healthy cells from excess free oxygen radicals which are very damaging to healthy cells too. This process happens incredibly fast...over and over...
Targeting infected cells is key...obviously.
Our body is trying to help:
"angiogenic factors ***TNF alpha*** and HIV1 Tat
activate an NAD(P)H oxidase in endothelial cells
which operates upstream of c-Jun amino terminal kinase (JNK), a MAPK involved in the determination of cell fate.
To further understand oxidant-related signaling pathways, we screened lung and endothelial cell libraries for
interaction partners of p47phox and recovered the orphan adapter
TNF-receptor associated factor 4 (TRAF4).
Domain analysis suggested a tail-to-tail interaction between the C-terminus of p47phox and the conserved TRAF domain of TRAF4.
In addition, TRAF4, like p47phox, was recovered largely in the cytoskeleton/membrane fraction.
***Coexpression of p47phox and TRAF4
increased oxidant production*** and JNK activation,
whereas ***each alone had minimal effect**.
(My note here...TNF alpha activated but p47phox kapoot because of Bb's PKCD inhibitor?)
In addition, a fusion between p47phox and the TRAF4 C-terminus constitutively activated JNK, and
***this activation was decreased by the antioxidant N-acetyl cysteine.***
In contrast, overexpression of the p47phox- binding domain of TRAF4
blocked endothelial cell JNK activation by TNF alpha and HIV1 Tat, suggesting an uncoupling of p47phox from upstream signaling events.
A secondary screen of endothelial cell proteins for TRAF4-interacting partners yielded a number of proteins known to control cell fate."
TNF alpha is triggered, but IL1 B looks to trigger TNF alpha and IL 1 B impacts beta insulin receptors...
I'm sure I'm losing a number of you...just hoping " research lurkers" are reading.
Onward...
During all fractionation procedures, the
H4 kinase
co-chromatographed with a trypsin-activated kinase
that catalyzed the phosphorylation of a peptide which corresponds to residues 297-331 of the
47 kDa subunit of the NADPH-oxidase complex (p47-phox)."
...histone H4 kinase
p47 phox (or p47 pox ??? hydrogen?)
The complex of enzymes that produces this superoxide radical include
The details of the complex are not known fully but p67PHOX binds cytochrome b558II directly (Dang et al, 2002),
and ***p47PHOX binds actin*** (Tamara et al, 2000).
***The significance of this later connection are presently unknown*** but possibly connected with the fact that actin depolymerization seems to be required for NADPH oxidase activation (Al-Mohanna et al, 1990), and that cofilin may be involved (Suzuki et al, 1995)."
"Thus the protein phosphorylation-driven conformational change of p47phox enables its PX domain to bind to phosphoinositides, the interaction of which
plays a crucial role in recruitment of p47phox
from the cytoplasm
to membranes and subsequent activation of the phagocyte oxidase."
What can do this i.e., transfer p47phox from the cytoplasm to membranes?
"2) PGE2 causes selective activation of PKC-delta, which likely mediates the action of PGE2 to reverse AVP inhibition of HCO-3 absorption; and
3) PGE2 activation of PKC-delta requires the presence of AVP, which may explain the fact that PGE2 influences HCO-3 transport
***only when AVP is present.*** arginine vasopressin (AVP).
***PGE2 10(6) M for 20 min) induced translocation of PKC-delta from the cytosolic fraction to the membrane fraction.***
This translocation was associated with an 85% increase in PKC-delta activity in the membrane fraction and a 70% decrease in PKC-delta activity in the cytosolic fraction."
Prostaglandin E2 + argine vasopressin.
...
"The protein expression of p47phox, another component of phagocyte NADPH oxidase, was also up-regulated by DHEA and ATRA (the all-trans-retinoic acid)."
This is odd...
p47phox is a key cytosolic subunit required for activation of phagocyte NADPH oxidase.
The X-ray structure of the p47phox PX domain revealed two distinct basic pockets on the membrane-binding surface,
each occupied by a sulfate."
Yet...
"Interestingly, DHEA sulfate (DHEAS), the sulfate ester of DHEA that exists in peripheral blood at a concentration approximately 3 orders of magnitude larger than that of DHEA,
did not stimulate the ATRA-induced differentiation of NB4 cells."
Remeber IL 1 Beta and insulin?
***Inhibition of PKCd***
or Src by PP2, a Src kinase family inhibitor,
***reduced insulin-induced glucose uptake***.
The results indicate that Src and PKCd play important roles in early IR (insulin receptor) signaling."
"Subsequent studies in PKCdelta-deficient macrophages demonstrated that, despite elevated levels of proinflammatory cytokines and NO production, increased escape of LM (a pathogen) from the phagosome into the cytoplasm and uncontrolled bacterial growth occurred.
Taken together these data identified PKCdelta as a critical factor for confinement of LM (pathogen) within macrophage phagosomes."
Bb is PFK (enzyme controls glycolysis) dependent. It appears to be LOWERING that enzyme. Insulin ACTIVATES it.
The supplemental form of DHEA that is supposedly the "safest" (does NOT raise testosterone or estrogen) is 7 Keto DHEA...a metabolite.
I don't know if it is AS effective.
***"DHEA is a potent uncompetitive inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH)
and as a consequence lowers NADPH levels*** !!!
and reduces NADPH-dependent oxygen-free radical production."
"NADPH is
produced by ***glucose-6-phosphate dehydrogenase*** (G-6-PDase)
and 6-phosphogluconate dehydrogenase (6-PGDase),
which are the first two steps of the hexose monophosphate shunt (HMS)."
"NADPH is also used for anabolic pathways, such as lipid synthesis, *cholesterol synthesis* and fatty acid chain elongation."
Get your cortisol/DHEA/S (ratio) levels checked and re-balance under a DOCTOR'S care!!!
By the way...
"Conclusion: The results of this study suggested that metamizol and ***magnesium sulfate*** have significant ***inhibition effect on the activity of glucose 6-phosphate dehydrogenase enzyme*** in both in vivo and in vitro."
Posts: 9424 | From Sunshine State | Registered: Mar 2001
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Marnie
Frequent Contributor (5K+ posts)
Member # 773
posted
Okay...I'll simplify...
ONE of MANY pathways Bb takes is the "cholesterol pathway".
Bb has lipoproteins in the cell walls which are oxidized via free radicals. Bb has LOTS of ways to protect itself from "oxidative damage" and can even repair that damage to its cell walls via its own cellular pumps! Rebuilds them.
So...
We can prevent the cell walls from forming in the first place via
Cholesterol lowering drugs (high doses)
OR...
via ***lowering glucose-6-phosphate dehydrogenase*** which is needed to make NADPH (which, in turn, is needed to make cholesterol)
Translated:
Glucose-6-phosphate dehydrogenase (plus other things) -> NADPH -> cholesterol.
2 things can lower glucose-6-phosphate dehydrogenase:
DHEA
OR
Mg sulfate (likely high doses needed IV (!) for several days).
Both of the above (DHEA and Mg sulfate) LOWER NADPH which is needed to make cholesterol.
Mg also is "anti-inflammatory" and INactivates HMG CoA reductase...effectively shutting off the cholesterol pathway which IS one of the pathway Bb takes.
NADPH is NOT being oxidized because Bb is preventing NADPH oxidase via its PKCD inhibitor.
Bb's PKC delta inhibitor damages a tiny portion of another enzyme - p47 of *NADPH oxidase*.
If we can PREVENT the cell walls from forming in the first place - they won't need to be "oxidized" and increase the potential DNA damage to our own cells from excessive "free radicals".
Penicillin is one of many drugs that inhibits cell wall synthesis.
If we inhibit cell wall synthesis, do we end up with cell wall deficient - stealth pathogens/mycoplasm instead?
"Mycoplasmas are unusual among bacteria in that most *require sterols* for the stability of their cytoplasmic *membrane*.
Sterols are acquired from the environment, usually as *cholesterol* from the animal host."
No cholesterol = no Bb pathogen in any form. Can't build its cell wall, can't survive as cell wall deficient...it appears.
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