On Jun 11, 10:58 am, Kofi <k...[at]anon.un> wrote:
- quote -

Saturated fatty acids are also known to stimulate AA release likely
via PLA2 activity. AFAIK sugar does the same and additionally
inhibits AA synthesis. What we need would be a nutrient/supplement
which downregulates 5-LOX while upregulating COX and leaves PLA2
alone. I can think of only AKBA which comes close to this at the
moment.

Taka

Kofi wrote:

- quote -

EGCG has different effects on the pancreas than it has on the liver.
EGCG can reduce some natural endogenous antioxidant enzymes at high
enough doses. "The effect of NAC and SOD on PEPCK and G6Pase gene
expression was also examined. As expected, NAC and SOD completely
reversed EGCG-mediated PEPCK and G6Pase gene repression. NAC partially
inhibited the effect on insulin-mediated repression of the PEPCK gene,
but not the G6Pase gene (Fig. 6, panels B and C). These results show
that EGCG regulates tyrosine phosphorylation and gene expression by a
redox-dependent mechanism and provides additional evidence that the
PEPCK and G6Pase genes are regulated by multiple signaling pathways.
[...] The effects of EGCG are reversed by NAC and SOD, whereas those of
insulin are mostly unaffected, suggesting that the former acts by a
different mechanism. In most cell types, EGCG is an antioxidant.
However, in hepatoma cells, EGCG is a pro-oxidant. This is not
completely unexpected because other compounds, such as ascorbate, can
act either as an antioxidant or pro-oxidant, depending on the cellular
environment (47). Curcumin, a phytochemical responsible for the color of
turmeric, has antioxidant activity in many different cell types but
displays pro-oxidant qualities in the presence of transition metals,
such as copper, which exist in the kidney and liver at relatively high
concentrations (48).
The data presented here suggest that EGCG regulates protein-tyrosine
phosphorylation by modulating the redox state of the cell. One possible
mechanism for the observed actions of EGCG in hepatoma cells is the
inhibition of PTPs, which contain an oxidizable cysteine in their active
site (39, 49). It is possible that EGCG causes oxidation of this
cysteine residue in redox-sensitive phosphatases, and NAC and SOD
reverse this effect. Several PTPs, including PTP-1B and leukocyte
antigen-related phosphatase, dephosphorylate the insulin receptor and
IRS-1, making these phosphatases candidates for modification by ROS
produced in response to EGCG (50-52)." Source: Epigallocatechin
Gallate, a Constituent of Green Tea, Represses Hepatic Glucose
Production - http://www.jbc.org/cgi/content/full/277/38/34933

Frank

In article <nospam-9BE4F2.06453308062008[at]newsclstr03.news.prodigy.net> ,
Bob Arnold <nospam[at]aol.com> wrote:

- quote -

Yeah. They *can* cause unexpected long-term problems in people with odd
forms of autoimmunity because of their actions on PGE2. It depends on
what else they're doing to balance it out. These substances are all
quite complicated and they may inhibit one type of enzyme in one cell
and do something completely different in another.

Most people taking curcumin or green tea aren't really getting
pharmacological levels of the substances for sustained periods of time.
EGCG requires citric acid or lemon juice to protect it through the
stomach and curcumin requires CYP inhibition. I've actually tried the
later and it severely exacerbated my autoimmune problems and difficulty
fighting infections. TGF-B1 inhibition/PPARgamma agonism might have
played a significant role. In particular, PPARgamma increases
transglutaminases which Celiacs target with autoantibodies. TGF-B1
activates Tregs.

- quote -

Interesting you bring this up. Omega-3s are competing substrates for
ALOX5/leukotrienes as well.


- quote -

Don't know, but butyrate has an interesting connection, as do
viagra-type compounds:

portal venous blood transfusions in organ transplantation is
immunosuppressive and may be mediated by increased Kupffer cell
production of the immunosuppressive arachidonic acid metabolite
prostaglandin E2 (PGE2); butyrate is known to enhance gene transcription
and enhances Kupffer cell PGE2 production by altering cyclooxygenase and
phospholipase A2 (PLA2) activity and augmenting the immunosuppressive
effect of portal venous transfusion in Lewis rats; Kupffer cells from
portally transfused animals produced significantly more PGE2 than
saline-transfused controls; adding butyrate to the culture medium
further increased PGE2 production as much as sevenfold in Kupffer cells
of portally transfused animals; short-chain fatty acids propionate and
hexanoate did not increase PGE2 production; butyrate added to Kupffer
cells from transfused animals slightly upregulated inducible
cyclooxygenase (COX-2) mRNA levels and increased PLA2 activity fivefold;
Kupffer cell immune function was affected by in vitro butyrate treatment
causing a significant drop in production of TNFalpha; butyrate may be a
useful immunoregulatory agent in organ transplantation protocols which
seek to enhance transcription of immunosuppressive molecules [PMID
9733608] (if butyrate more generally increases PGE2 in other cell types,
this would indicate that the anticancer effects of butyrate could be
boosted with specific COX-2 inhibition - which is exactly what an
earlier paper concluded [PMID 15378772])

phospholipids like arachidonic acid and phosphatidic acid are potent
activators of PLCepsilon, increasing the rate of PI hydrolysis by 8- and
50-fold; the mechanism appears to be a reduction of K(m); adding cPLA2
or PLD with PLCepsilon leads to activation of PDE activity
(phosphodiesterase) [PMID 16953585] (AT1R is coupled to PLC, activates
it and increases cytosolic Ca2+; other AT1 receptor effects include
vasoconstriction, aldosterone synthesis and secretion, increased
vasopressin secretion, cardiac hypertrophy, augmentation of peripheral
noradrenergic activity, vascular smooth muscle cells proliferation,
decreased renal blood flow, renal renin inhibition, renal tubular sodium
reuptake, modulation of central sympathetic nervous system activity,
cardiac contractility, central osmocontrol and extracellular matrix
formation; angiotensin II also increases thirst and the need for salt
and the secretion of ACTH in the anterior pituitary)

In article <kofi-837123.12350806062008[at]news.east.earthlink.net> ,
Kofi <kofi[at]anon.un> wrote:

- quote -

Really? So you tell people not to take curcumin or turmeric, green
tea, resveratrol, fish oil, Rosemary, or low-dose aspirin?

Kofi wrote:
- quote -

I need an education. Any idea where I can get one free?

--
Marshall Price of Miami
Known to Yahoo as d021317c

Kofi wrote:
- quote -

I have a suspicion the flush does me good somehow.

--
Marshall Price of Miami
Known to Yahoo as d021317c

Bob Arnold wrote:
- quote -

In a nutshell, what's pyrodoxamine all about?

(I take it it's a form of B-6 which has anti-glycation properties and
is of interest as a possible nootropic ("smart drug") and anti-aging
supplement.)

--
Marshall Price of Miami
Known to Yahoo as d021317c

Kofi wrote:
- quote -

I haven't had any such symptoms since my fast.

--
Marshall Price of Miami
Known to Yahoo as d021317c

On Jun 7, 2:35 am, Kofi <k...[at]anon.un> wrote:
- quote -

That was very educational, thanks much Kofi. Seems the prostaglandins
are deeply involved in almost everything. Because we can influence
their levels via diet (reducing or increasing arachidonic acid - AA -
from which they are made) there should be more studies focused on
returning the Omega-6 amounts consumed to what we had been evolving on
rather than trying to overcome the "soy and corn oils" by further
increasing the consumption of Omega-3 which basically act like the
NSAIDs. Also I think the "destructive" 5-LOX cascade may predominate
at higher AA levels compared to the sometimes useful COX-1/2
cascades. And high carbohydrate/sugar diet may be doing the same. Do
we need PLA-2 for making AA available to the COXs (this may be the
key)??

BTW it's known fact that aspirin induces asthma in susceptible
subjects ...

Taka

(LOX = lipoxygenase; PLA-2 phospholipase A2)

In article
<a25fb8a8-6eb4-4bc0-baa8-daf40acf58c1[at]s50g2000hsb.googlegroups.com> ,
Taka <taka0038[at]gmail.com> wrote:

- quote -

If it's got a "2" in its name, it's straight out of COX-2.

I keep trying to tell people *not* to inhibit the COX enzymes unless
they've got a life-threatening condition like cancer.

Here's a small list of what PGD2 and PGJ2 do:

sleep disturbances in depressed patients correlate with serum fatty acid
concentrations (myristic, palmitic, palmitoleic, oleic, linoleic,
eicosadienoic and docosahexaenoic acid/DHA), especially palmitoleic and
eicosadienoic acids; palmitoleic and oleic acids seem to be particularly
important given their role as precursors to the sleep-inducing oleamide;
linoleic and eicosadienoic acid could be important as precursors the the
sleep mediator PGD2 [PMID 17123808]

PGD2 can be harmful or helpful to neuron survival depending on which
receptor it docks to; high levels are protective against stroke damage
and its beneficial effects generally outweight its negative effects;
it¹s particularly good at protecting against glutamate excitotoxicity;
other products of COX-2 like PGE2 are also protective
<http://www.sciencedaily.com/releases/2005/02/050217224933.htm>

atherosclerotic plaques rupture when they contain more prostaglandin E2
than PGD2 (which would associate more with NFKB and MMP-9
downregulation); COX-2 inhibition is only protective when the pathway
tilts more toward PGD2 [PMID 15155382]

niacin interferes with the cAMP/PKA pathway and massively stimulates
PGD2 formation (perhaps accounting for its benefit in atherosclerosis);
the major metabolite of PGD2, 15d-PGJ2, is the body¹s most potent
PPARgamma activator [PMID 15037193]

topical application of methylnicotinate can greatly increase PGD2 levels
without going through the mast cells [PMID 1373750]

PPARgamma is expressed in vascular cells and has antiinflammatory
actions on them; atherosclerotic lesion development is promoted by the
presence of inflammatory cells like monocytes and T-cells which release
IL-6, TNF-a and the activation of vascular smooth muscle cells (VSMCs);
in monocyte/macrophages, PPARgamma turns down the inflammatory regulator
CCAAT/enhancer-binding protein-delta (C/EBP-delta) which controls TNF-a,
IL-1b, IL-6; PPARgamma has been found to inhibit NFKB, AP-1 and STAT
too; 15d-PGJ2 is a natural PPARgamma ligand and also inhibits
C/EBP-delta in VSMCs; oxidized linoleic acid, a component of oxidized
LDL, is also a natural PPARgamma ligand but may be proatherogenic by
promoting foam cells from monocytes
<http://circres.ahajournals.org/cgi/content/full/91/5/373>

PGE2 is essential to male sexual identity as pregnant female rats given
NSAIDs which inhibit PGE2 had male pups who were less interested in sex
whereas female pups exposed to PGE2 were masculinized; PGE2 increased
connections of the preoptic area to other neurons in the brain; this
indicates some deep connection between testosterone and inflammation
<http://www.newscientist.com/news/news.jsp?id=ns99995026>

PGE2 via EP2/EP4 receptor signaling has antiinflammatory effects on the
expression of inducible genes; in synovial fibroblasts, PGE2 inhibits
MCP-1 (monocyte chemoattractant protein-1) production by IL-1beta;
NSAIDs may intercept a natural regulatory circuit that limits the
magnitude of inflammation [PMID 15361371]

in lung cancer, COX-2 and PGE2 underlie an immunosuppressive network
that is important in the formation of non-small cell lung cancer; CD4+
CD25+ regulatory T-cells (Tregs) block antitumor immune responses when
tumors secrete PGE2 and activate Foxp3 in the Tregs which increases Treg
activity; this effect was significantly reduced without an EP4
(E-prostanoid) receptor and totally absent without an EP2 receptor;
COX-2 inhibitors (Vioxx, Celebrex) reduced Treg activity, blocked FoxP3
and decreased tumor growth (this provides a pathway whereby COX-2
inhibitors can exaggerate allergies) [PMID 15958566]

It is nice to know that the niacin flushing is mediated by the
arachidonic acid metabolites PGD2 and PGJ2 and that some antioxidants
naturally inhibit it. Do you know which particular cyclooxygenase
(COX) enzyme makes the PGD2 eicosanoid? Perhaps luteolin targets it
specifically.

Taka

Kofi wrote:
- quote -

On Wed, 4 Jun 2008 11:18:04 -0700 (PDT), jay <jaym1212[at]hotmail.com>
wrote:

- quote -

Circulation?

- quote -

Mine doesn't start unless I go over 140 - 150 (this number seems to be
the common point of onset for several of us) the bugger is a single
brief spike seems to have effects that last several hours even after
the BG has dropped back to normal, I take extra care what I eat when
I'm out for that very reason.

- quote -

Yes that'd work.

In article <kofi-7F3861.00004005062008[at]news.east.earthlink.net> ,
Kofi <kofi[at]anon.un> wrote:

- quote -

I take benfotiamine too. And, everything is divided into 4 doses
spread throughout the day, and taken with meals when possible. But, I
wasn't aware that uptake was an issue with any B vitamins.

- quote -

I take pyrodoxamine. Last I've seen, it's questionable whether it can
cause neuropathy like pyridoxine.

In article <7o-dnaTvdI6VKdnVnZ2dnUVZ_sTinZ2d[at]earthlink.com> ,
Marshall Price <d021317c[at]yahoo.com> wrote:

- quote -

Yes, I take fairly high doses of the rest of the b-complex.

- quote -

- quote -

Hair and nerves share some contradictory signals. I think this may have
to do with the fact that keratinocytes actually play a role at the very
edge of the nervous system, relaying temperature sensations through
various vannilloid receptors. In any event, ALCAR regenerates nerves by
slowly upregulating p75NGFR. Signaling through this receptor also sends
follicles into catagen. Carnitines in general also raise tolerance to
pain via PKC inhibition and carnitines are important in the
metabolization of butyrate, an HDAC inhibitor - and this activates FOXP3
and switches on regulatory T-cells (Tregs), which then guard against
autoimmunity. Since testosterone is a carnitine transporter, men have
greater natural levels of carnitine and this may be why we have a higher
pain threshold and are at less risk for upper body pain and autoimmune
disorders (except in redheads who have an MC-1 receptor mutation; they
have a higher tolerance of pain - esp. redheaded women - because opiates
stay around in their bloodstream longer; they also have greater skin
cancer risk and, perhaps not so coincidentally, they report enjoying sex
more). Hitting p75 also alters your cancer risk; some go up (like CNS
cancer); some go down.

These differential effects on hair and nerves also occur with other
neurogenic signals like BDNF, NGF, NT-3 and various other tyrosine
kinase ligands (which soy components like genistein also effect, by the
way). They're great for growing new neurons and preventing nerve cell
death but they're hell on hair follicles. Probably not so great if
you've got a brain tumor either. I explained the effects on hair at
alt.baldspot years ago.

Forgot one other approach to pain - fry the receptors.

resiniferatoxin is a tolerable analogue of capsaicin appropriate for in
vivo use; it is a vanilloid receptor agonist (TRPV1) which desensitizes
C-fibers that transmit pain; sensory nerve inactivation by
resiniferatoxin improves insulin sensitivity; desensitization improves
oral glucose tolerance, insulin secretion and whole body insulin
sensitivity in diabetic fatty Zucker rats; insulin secretion was lowered
and glucose uptake improved [PMID 15883192]

P.S. Did I mention mixing opiates with low-dose naltrexone to prevent
dependence and tolerance?

- quote -

It can stay in bones and fat a long time. Since diabetics also have low
molybdenum levels, this affects metallothionein synthesis and this could
lead you to move mercury out more slowly. In fact, mercury tends to
accumulate in diabetic cardiomyopathy because of loss of HDAC
inhibition. I posted on this in sci.life-extension if you're interested.

- quote -

Only if you have adequate gut bacteria levels. If you have a history of
antibiotic use, this could be a problem. Gut flora also decline with
age.

- quote -

GTE is also raises the pain threshold via PPARalpha agonism.

- quote -

No. But it would probably induce other heat shock protective factors.

- quote -

It's the rest phase for hair follicles. They fall out and go dormant.

- quote -

....

- quote -

I didn't suggest niacinamide for any of these reasons. It directly
produces NAD+ and thus raises the NAD+/NADH ratio. This has a
beneficial effect on local blood flow, reducing pressure on nerves.

The authors below seem oblivious to the beneficial role that PGD2 plays
in the effects of niacin [PMID 15037193]. FYI, niacin raises PGD2,
raises 15d-PGJ2 which activates PPARgamma. PPARgamma agonists raise
trans-glutaminase levels - and Celiacs make antibodies to
trans-glutaminase.


: Br J Pharmacol. 2008 Apr;153(7):1382-7. Epub 2008 Jan 28.

The flavonoid luteolin inhibits niacin-induced flush.

Papaliodis D, Boucher W, Kempuraj D, Theoharides TC.
Laboratory for Molecular Immunopharmacology and Drug Discovery,
Department of Pharmacology and Experimental Therapeutics, Tufts
University School of Medicine, Tufts-New England Medical Center, Boston,
MA, USA.

BACKGROUND AND PURPOSE: Sustained release niacin effectively lowers
serum cholesterol, LDL and triglycerides, while raising HDL. However,
75% of patients experience cutaneous warmth and itching known as flush,
leading to discontinuation. Acetylsalicylic acid (aspirin) reduces this
flush only by about 30%, presumably through decreasing prostaglandin D2
(PGD2). We investigated whether niacin-induced flush in a rat model
involves PGD2 and 5-HT, and the effect of certain flavonoids.
EXPERIMENTAL APPROACH: Three skin temperature measurements from each ear
were recorded with an infrared pyrometer for each time point immediately
before i.p. injection with either niacin or a flavonoid. The temperature
was then measured every 10 min for 60 min. KEY RESULTS: Niacin (7.5 mg
per rat, equivalent to a human dose of 1750 mg per 80 kg) maximally
increased ear temperature to 1.9+/-0.2 degrees C at 45 min. Quercetin
and luteolin (4.3 mg per rat; 1000 mg per human), administered i.p. 45
min prior to niacin, inhibited the niacin effect by 96 and 88%,
respectively. Aspirin (1.22 mg per rat; 325 mg per human) inhibited the
niacin effect by only 30%. Niacin almost doubled plasma PGD2 and 5-HT,
but aspirin reduced only PGD2 by 86%. In contrast, luteolin inhibited
both plasma PGD2 and 5-HT levels by 100 and 67%, respectively.
CONCLUSIONS AND IMPLICATIONS. Niacin-induced skin temperature increase
is associated with PGD2 and 5-HT elevations in rats; luteolin may be a
better inhibitor of niacin-induced flush because it blocks the rise in
both mediators.

Publication Types:
* Research Support, Non-U.S. Gov't

PMID: 18223672

- quote -

Taking this much won't actually enhance uptake. There's only so much
you can push into your system at once. You might want to consider
benfotiamine as a substitute.

- quote -

Keep in mind that too much B6 can cause symptoms resembling neuropathy.