Dietary PPAR gamma agonists?
jay
herbs in the mint family trigger alpha, gamma and delta. (Still
looking for the majic herb :)
One pubmed abstract indicates that suppressing CPT1 reduced psoriasis
in some cases. So maybe CPT2 is not working well. I think CPT1
transfers fatty acids from cytoplasm to between mito's inner and outer
membrane and CPT2 transfers fatty acids from there to within mito.
jay
Kofi
<e7a5fa32-8f95-43fa...@i18g2000yqn.googlegroups.com>,
jay <jaym...@hotmail.com> wrote:
> Anyone know of common dietary sources of PPAR delta agonists?
PPARdelta/PPARbeta agonists cause cancer. That's why nobody markets a
PPARdelta agonist. Don't try to stimulate it.
> I think
> herbs in the mint family trigger alpha, gamma and delta. (Still
> looking for the majic herb :)
>
> One pubmed abstract indicates that suppressing CPT1 reduced psoriasis
> in some cases. So maybe CPT2 is not working well. I think CPT1
> transfers fatty acids from cytoplasm to between mito's inner and outer
> membrane and CPT2 transfers fatty acids from there to within mito
Try intermittent fasting.
As to PPARgamma, I refer you to the recent article on abscisic acid
refering to the safe and unsafe ways to hit that particular target.
Niacin can stimulate PPARgamma via PGJ2. Whether that's as unsafe as
Avandia is unknown. Curcumin stimulates PPARgamma - but you may have
side effects targetting this pathway. It blocks a number of other forms
of inflammation, some of which you need to fight infection. You also
have to inhibit a metabolizing enzyme to get a pharmacological dose of
curcumin and that causes a whole host of problems (similar to that
caused by mixing grapefruit juice and certain medications).
The problem with PPARalpha is that it may be part of a chain of events.
Simply upregulating or activating PPARalpha won't do anything if you
can't adequately absorb carnitine (via OCTN2) and then use it to
metabolize butyrate. In Crohn's, OCTN2 is down as is butyrate
production. This alters the entire epigenetics of the GI tract,
including Tregs. Intermittent fasting with a highly absorbable form of
carnitine plus butyrate (via lactobacillus) might do it.
jay
>
> PPARdelta/PPARbeta agonists cause cancer.
>That's why nobody markets a
> PPARdelta agonist. Don't try to stimulate it.
It seems dietary fats, exercise, green tea, retionids, nicotine, etc
activate PPARd. Like most things, too little and too much are a
problem. For most people, esp with Syndrome X, they may have too much
PPARb/d activation due to high levels of fats and minimal fresh
produce. In general, PPARd activation reduces fat reserves, increases
fat metabolism, increase detoxification enzymes. It also suppresses
inflammation, immune system and apoptosis. PPARd activation can -liver
disease, +physical endurance, -AGE-induced apoptosis, -dyslipidemia, -
autoimmune immune demyelinating disease, switches muscle fuel
preference from glucose to fats, -atherosclerosis, +lipolysis, -TG, -
weight, -IR, -western diet-induced NAFL in rats, even -proliferative
activity in some human cancer cells (PMID: 19633434).
PPARd (not a) promotes CPT2. Thus a deficient PPARd might explain why
blocking CPT1 reduced psoriasis in PMID 16225603. This might also
explain why many recommend a low-fat diet to treat psoriasis. This
might also explain the excess skin growth in psoriasis. If FA
oxidation in mitos is blocked, higher levels of FA in cytoplasm may
promote cell proliferation. esp in skin, intestine, etc.
> Try intermittent fasting.
A BMI under 18.5 is considered underweight.
Mine is 16.7. Not much room to fast :(
> As to PPARgamma, I refer you to the recent article on abscisic acid
> refering to the safe and unsafe ways to hit that particular target.
Thanks.
> Niacin can stimulate PPARgamma via PGJ2. Whether that's as unsafe as
> Avandia is unknown. Curcumin stimulates PPARgamma - but you may have
> side effects targetting this pathway. It blocks a number of other forms
> of inflammation, some of which you need to fight infection. You also
> have to inhibit a metabolizing enzyme to get a pharmacological dose of
> curcumin and that causes a whole host of problems (similar to that
> caused by mixing grapefruit juice and certain medications).
I frequently add a tsp of tumeric to my cooking. The most dangerous
part of this is getting on a white shirt :) Mostly like, PPARg is
stimulated by things that are anti-bacterial an thus the immune system
instead focuses of detoxifying the agent causing PPARg activation.
> The problem with PPARalpha is that it may be part of a chain of events.
Probably best to activate PPARs via natural foods vs pharmaceuticals.
I believe plant foods are loaded with them.
> Simply upregulating or activating PPARalpha won't do anything if you
> can't adequately absorb carnitine (via OCTN2) and then use it to
> metabolize butyrate. In Crohn's, OCTN2 is down as is butyrate
> production. This alters the entire epigenetics of the GI tract,
> including Tregs. Intermittent fasting with a highly absorbable form of
> carnitine plus butyrate (via lactobacillus) might do it.
Taking soluble fiber, ALCAR and L-Carnitine. Have seen some positive
effects but reducing/increase fat has a much bigger effect.
jay
> blocking CPT1 reduced psoriasis in PMID 16225603. This might also
> explain why many recommend a low-fat diet to treat psoriasis. This
> might also explain the excess skin growth in psoriasis. If FA
> oxidation in mitos is blocked, higher levels of FA in cytoplasm may
> promote cell proliferation. esp in skin, intestine, etc.
Or more generally, if fat oxidation is obstructed (ie CPT2 variant)
then the backlog of fat could hyper-activate PPARs (ie b/d) and thus
abnormal growth, possibly similar to that seen in psoriasis and breast
cancer (in my family tree). When I eat fats (ie almonds, EVOO, EVCO,
macadamia, clarified butter, FO, sardines, salmon), it accelerates the
growth of cuticles around finger nails to point of becoming sore and
swollen.
randall
Jay,
I posted PMID 16225603 in 2005
And ou posted it oct 9th
http://groups.google.com/groups/search?hl=en&qt_s=1&q=PMID+16225603
Br J Dermatol. 2005 Nov;153(5):937-44.
A new therapeutic approach to treat psoriasis by inhibition of fatty
acid oxidation by Etomoxir.
Caspary F, Elliott G, Navé BT, Verzaal P, Rohrbach M, Das PK,
Nagelkerken L, Nieland JD.
Medigene AG, Lochhamerstrasse 11, 82152 Martinsried, Germany.
Abstract
BACKGROUND: The dogma in psoriasis is that due to pathogen-induced
inflammatory responses, an autoreactive immune response is induced
that leads to tissue destruction. However, this model might be too
simplistic. Literature data suggest that the expression of enzymes
crucial for fatty acid oxidation is upregulated in the skin of
patients with psoriasis compared with healthy individuals.
OBJECTIVES: To examine the influence of fatty acid oxidation on
psoriasis with regard to expression and activity of the key enzyme in
fatty acid oxidation, carnitine palmitoyltransferase-1 (CPT-1) and the
effect of the CPT-1 inhibitor, Etomoxir.
METHODS: Experiments were performed with homogenates of lesional and
healthy skin, fibroblast cultures and a model of human psoriatic skin
transplanted on immune-deficient BNX mice.
RESULTS: CPT-1 was highly active in lesional skin. Etomoxir was able
to block CPT-1 activity in skin, implying that this antagonist may
have the potential to suppress psoriasis when administered topically.
In the mouse model, Etomoxir had an antipsoriatic effect that was at
least as good as that of betamethasone, as evidenced by reduction of
epidermal thickness, keratinocyte proliferation and differentiation.
CONCLUSIONS: We conclude that fatty acid metabolism and in particular
CPT-1 may be an excellent target for treatment of psoriasis.
PMID: 16225603
8 hits - p ng for etomoxir
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=Etomoxir&qt_g=Search+this+group
4,480 hits in ALL groups - etomoxir
http://groups.google.com/groups/search?hl=en&qt_s=1&q=Etomoxir
$110 in Germany
http://www.google.com/search?hl=en&q=Etomoxir&um=1&ie=UTF-8&tbo=u&tbs=shop:1&source=og&sa=N&tab=wf
Go fish?
OR
Eat a FISH.
Your magic herb is akin to the magic christian. LOL
Not really THE answer:
http://en.wikipedia.org/wiki/The_Magic_Christian_(film)
Can't you simply run kofi and cpt1?
http://groups.google.com/groups/search?hl=en&q=kofi+carnitine+palmitoyltransferase+1&sitesearch=
Plenty to ruminate over in that one.
I consumed flax seed oil and fish oil for YEARs to balance omega-6/w3
ratio.
Big deal i can eat ham and soy bean oil with nary a flare now.
Not that i'm gonna go HOG wild. <g>
And simply avoided as much w6 in my diet as possible.
That helped but wasn't the answer.
Fasting helps but not the answer.
Many things help but why do them if your not curing anything?
WELL to keep it homeostatic or whatever ain't BAD. <w>
Yet why eat an herb that doesn't CURE YOU?
You gonna do that the rest of your life?
The magic is knocking down SFB in your Gi tract IMO.
My last two posts today dealth with SFB in some context.
And I did just THAT, ate L. Plantarum, this time last year and now i'm
nearly CLEAR.
So clear it's odd.
But still have RA and PsA,.
And herbs do help those.
See:
holistic horizons, yerba prima
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&q=yerba++prima+holistic+&start=0&scoring=d&hl=en&
I took herbs from three different companies for awhile.
Knocked my psa and RA to kingdumb COME for 30 years. LOL
Keeping n3 and n6 in balance helped with clear skin but was never a
CURE.
Till i ate kimchi (L. plantarum) last year for three weeks, three
times a day and i was fairly
mild to start with and then very very mild. :)
Now i feel naked without nary a plaque to be found. Well i've got a
few
little ones.
But i keep at it regardless.
Doing coconut mct and fish oils next with a few other things might be
better
for those gray cells, which can use a tune up.
http://www.ncbi.nlm.nih.gov/pubmed/21111596
J Nutr Biochem. 2010 Nov 25.
Omega-3 fatty acids attenuate dendritic cell function via NF-κB
independent of PPARγ
Draper E, Reynolds CM, Canavan M, Mills KH, Loscher CE, Roche HM.
Immunomodulation Research Group, School of Biotechnology, Dublin City
University, Dublin 9, Ireland.
Abstract
Long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) have been shown
to modulate the immune response and have therapeutic effects in
inflammatory disorders. PUFA are also peroxisome proliferators-
activator receptor-gamma (PPARγ) ligands; a family of ligand-activated
transcription factors, which when activated antagonise the pro-
inflammatory capability of nuclear factor κB (NF-κB). PPARγ plays a
role in dendritic cell (DC) maturation and n-3 PUFA have been shown to
affect DC maturation by decreasing activation of NF-κB. While n-3 PUFA
can function as PPAR ligands, it is not known whether the NF-κB-
mediated immunomodulatory properties of n-3 PUFA are PPARγ-dependent.
In this study we examined whether the immunomodulatory effects of n-3
PUFA on DC activation were mediated through activation of PPARγ.
Treatment of murine bone marrow derived DCs with docosahexaenoic acid
(DHA; 25 μM) and eicosapentaenoic acid (EPA; 25 μM) attenuated LPS-
induced DC maturation. This was characterised by suppression of IL-12
production and expression of CD40, CD80, CD86 and MHC II and enhanced
production of IL-10 and expression of IL-10R. This was coincident with
enhanced PPARγ expression, suppressed NF-κB activity and increased the
physical interaction and cellular colocalization between NF-κB with
PPARγ. To understand the functional implication of the physical
association of PPARγ with NF-κB, we determined whether the specific
PPARγ inhibitor, GW9662 could abolish the anti-inflammatory effect of
n-3 PUFA Inhibiting PPARγ did not impede the NF-κB-mediated anti-
inflammatory cytokine profile induced by EPA and DHA alone. Thus n-3
PUFA activate PPARγ and interact with NF-κB in DC. However, the anti-
inflammatory effects of EPA and DHA on DCs are independent of PPARγ.
2010 Elsevier Inc. All rights reserved.
PMID: 21111596
48 hits ppar+gamma+omega-3 - pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=ppar+gamma+omega-3
56 hits ppar+gamma+carnitine+palmitoyltransferase+1 - pubmed
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=ppar+gamma+carnitine+palmitoyltransferase+1
#2 in this search
http://www.ncbi.nlm.nih.gov/pubmed/20656057
Biochim Biophys Acta. 2010 Nov;1801(11):1214-20. Epub 2010 Jul 23.
Citral, a component of lemongrass oil, activates PPARα and γ and
suppresses COX-2 expression.
Katsukawa M, Nakata R, Takizawa Y, Hori K, Takahashi S, Inoue H.
Department of Food Science and Nutrition, Nara Women's University,
Kitauoyanishi-machi, Nara-City, Nara 630-8506, Japan.
Abstract
Lemongrass is a widely used herb as a food flavoring, as a perfume,
and for its analgesic and anti-inflammatory purposes; however, the
molecular mechanisms of these effects have not been elucidated.
Previously, we identified carvacrol from the essential oil of thyme as
a suppressor of cyclooxygenase (COX)-2, a key enzyme for prostaglandin
synthesis, and also an activator of peroxisome proliferator-activated
receptor (PPAR), a molecular target for "lifestyle-related" diseases.
In this study, we evaluated the essential oil of lemongrass using our
established assays for COX-2 and PPARs. We found that COX-2 promoter
activity was suppressed by lemongrass oil in cell-based transfection
assays, and we identified citral as a major component in the
suppression of COX-2 expression and as an activator of PPARα and γ.
PPARγ-dependent suppression of COX-2 promoter activity was observed in
response to citral treatment. In human macrophage-like U937 cells,
citral suppressed both LPS-induced COX-2 mRNA and protein expression,
dose-dependently. Moreover, citral induced the mRNA expression of the
PPARα-responsive carnitine palmitoyltransferase 1 gene and the PPARγ-
responsive fatty acid binding protein 4 gene, suggesting that citral
activates PPARα and γ, and regulates COX-2 expression. These results
are important for understanding the anti-inflammatory and anti-
lifestyle-related disease properties of lemongrass.
2010 Elsevier B.V. All rights reserved.
PMID: 20656057
349 hits carnitine+palmitoyltransferase+inhibitor
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=carnitine+palmitoyltransferase+inhibitor
#2 mentions ALC Acetyl-L-carnitine to attenuate a stiffy. LOL
I find that using ALA and ALC gives me a stiffy.
Not a BAD thing but can get tiresome.
Maybe not to YOU. But...well...you'll figure it out.
randall...will the fickle finger of FATE intervene?
ps- you could do what kofi said? He sounds like me now. LOL
Which was and is
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/msg/e1551fa02d4fa51b
Try intermittent fasting.
As to PPARgamma, I refer you to the recent article on abscisic acid
refering to the safe and unsafe ways to hit that particular target.
Niacin can stimulate PPARgamma via PGJ2. Whether that's as unsafe as
Avandia is unknown. Curcumin stimulates PPARgamma - but you may have
side effects targetting this pathway. It blocks a number of other
forms
of inflammation, some of which you need to fight infection. You also
have to inhibit a metabolizing enzyme to get a pharmacological dose
of
curcumin and that causes a whole host of problems (similar to that
caused by mixing grapefruit juice and certain medications).
The problem with PPARalpha is that it may be part of a chain of
events.
randall
> On Dec 17, 8:32 pm, jay <jaym1...@hotmail.com> wrote:
Jay
OK i re-read the last one.
OK i've got it
Do you have any Asian genes?
http://en.wikipedia.org/wiki/CD36#CD36_deficiency_and_alloimmune_thrombocytopenia
IF NOt...
Buy this book:
http://www.masteringleptin.com/
Then do the leptin diet.
But first buy seaweed with iodine pills.
They cost around $5 for a few hundred.
Load heavy for a week and see what haPPens?
Back to your eto link.
Etomoxir 241 hits
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=etomoxir
Only 3 of these 241 have CD36:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=etomoxir+cd36
#1 in that search:
Cd36 protein
http://www.ncbi.nlm.nih.gov/pubmed/21147770
J Biol Chem. 2010 Dec 8.
Fatty acid (FFA) transport in cardiomyocytes revealed by imaging
unbound FFA is mediated by an FFA pump modulated by the CD36 protein.
Carley AN, Kleinfeld AM.
Torrey Pines Institute for Molecular Studies, United States.
Abstract
Free fatty acid (FFA) transport across the cardiomyocyte plasma
membrane is essential to proper cardiac function but the role of
membrane proteins and FFA metabolism in FFA transport remain unclear.
Metabolism is thought to maintain intracellular FFA at low levels,
providing the driving force for FFA transport, but intracellular FFA
levels have not been measured directly. We report the first
measurements of the intracellular unbound FFA concentrations
([FFA(i)]) in cardiomyocytes. The fluorescent indicator of FFA, ADIFAB
(acrylodan labeled rat intestinal fatty acid binding protein), was
microinjected into isolated cardiomyocytes from wild type (WT) and FAT/
CD36 null C57B1/6 mice. Quantitative imaging of ADIFAB fluorescence
revealed the time courses of FFA influx and efflux. For WT mice, rate
constants for efflux (~ 0.02 s(-1)) were twice influx and steady state
[FFA(i)] were more than 3-fold larger than extracellular unbound FFA
([FFA(o)]). The concentration gradient and the initial rate of FFA
influx saturated with increasing [FFA( o)]. Similar characteristics
were observed for oleate, palmitate and arachidonate. FAT/CD36 null
cells revealed similar characteristics except that efflux was 2-3 fold
slower than WT cells. Rate constants determined with intracellular
ADIFAB were confirmed by measurements of intracellular pH. FFA uptake
by suspensions of cardiomyocytes determined by monitoring [FFA(o)]
using extracellular ADIFAB confirmed the influx rate constants
determined from [FFA(i)] measurements and demonstrated that rates of
FFA transport and etomoxir sensitive metabolism are regulated
independently. We conclude that FFA influx in cardiac myocytes is
mediated by a membrane pump whose transport rate constants may be
modulated by FAT/CD36.
PMID: 21147770
These guys are at torrey pines so Bruce Beutler is not FAR away. LOL
http://en.wikipedia.org/wiki/Bruce_Beutler
Don't let him go hang gliding...
#2 in that search:
http://www.ncbi.nlm.nih.gov/pubmed/19429947
J Lipid Res. 2009 Sep;50(9):1789-99. Epub 2009 May 9.
Novel role of FATP1 in mitochondrial fatty acid oxidation in skeletal
muscle cells.
Sebastián D, Guitart M, García-Martínez C, Mauvezin C, Orellana-
Gavaldà JM, Serra D, Gómez-Foix AM, Hegardt FG, Asins G.
Departments of Biochemistry and Molecular Biology, School of Pharmacy,
University of Barcelona, Barcelona, Spain.
Abstract
Carnitine palmitoyltransferase 1 (CPT1) catalyzes the first step in
long-chain fatty acid import into mitochondria, and it is believed to
be rate limiting for beta-oxidation of fatty acids. However, in
muscle, other proteins may collaborate with CPT1. Fatty acid
translocase/CD36 (FAT/CD36) may interact with CPT1 and contribute to
fatty acid import into mitochondria in muscle. Here, we demonstrate
that another membrane-bound fatty acid binding protein, fatty acid
transport protein 1 (FATP1), collaborates with CPT1 for fatty acid
import into mitochondria. Overexpression of FATP1 using adenovirus in
L6E9 myotubes increased both fatty acid oxidation and palmitate
esterification into triacylglycerides. Moreover, immunocytochemistry
assays in transfected L6E9 myotubes showed that FATP1 was present in
mitochondria and coimmunoprecipitated with CPT1 in L6E9 myotubes and
rat skeletal muscle in vivo. The cooverexpression of FATP1 and CPT1
also enhanced mitochondrial fatty acid oxidation, similar to the
cooverexpression of FAT/CD36 and CPT1. However, etomoxir, an
irreversible inhibitor of CPT1, blocked all these effects. These data
reveal that FATP1, like FAT/CD36, is associated with mitochondria and
has a role in mitochondrial oxidation of fatty acids.
PMID: 19429947 PMCID: PMC2724792Free PMC Article
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19429947/?tool=pubmed
What's haPPening in the ER i wonder now. <w>
12hits cpt1+cd36 - pubmed
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=cpt1+cd36
So buy the book on mastering leptin by byron richards.
16 hits for mastering leptin in p ng:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=mastering+leptin
http://www.masteringleptin.com/
If you forgot already. <g>
-----------------------
http://en.wikipedia.org/wiki/CD36
CD36 (Cluster of Differentiation 36) is an integral membrane protein
found on the surface of many cell types in vertebrate animals and is
also known as FAT, SCARB3, GP88, glycoprotein IV (gpIV) and
glycoprotein IIIb (gpIIIb). CD36 is a member of the class B scavenger
receptor family of cell surface proteins. CD36 binds many ligands
including collagen,[1] thrombospondin,[2] erythrocytes parasitized
with Plasmodium falciparum,[3] oxidized low density lipoprotein,[4]
native lipoproteins,[5] oxidized phospholipids,[6] and long-chain
fatty acids.[7]
Recent work using genetically modified rodents have identified a clear
role for CD36 in fatty acid and glucose metabolism,[8][9] heart
disease,[10] taste,[11] and dietary fat processing in the intestine.
[12] It may be involved in glucose intolerance, atherosclerosis,
arterial hypertension, diabetes, cardiomyopathy and Alzheimer's
disease.[13]
http://en.wikipedia.org/wiki/CD36#Tertiary
What if your ____hairpin like___ CD36 gizmo is haywire?
That might be a problem. LOL
The gene (7q11.2) might tell us what's what?
http://groups.google.com/groups/search?hl=en&qt_s=1&q=7q11.2
www.scripps.edu/newsandviews/e_20050207/cd36.html
Molecular Component of Innate Immunity Discovered
By Jason Socrates Bardi
“There is no need to be a doctor or a scientist to wonder why the
human body is capable of resisting so many harmful agents in the
course of everyday life,” the great Russian immunologist Ilya
Mechnikov stated in his 1908 Nobel prize acceptance speech. And indeed
he was right—how in the world do we survive?
Humans, like all higher organisms, are constantly challenged in a
world filled with microbial pathogens. We are bathed in bacteria,
confronted with fungi, pilloried with parasites, and invaded by
viruses. And yet, most of the time, we survive.
One reason we do, as Mechnikov was one of the first to discover, is
that we possess an ancient and crucial physiology known as innate
immunity that is active in eukaryotic organisms as diverse as humans
and fruit flies. In fact, Mechnikov discovered innate immunity in
starfish, when he observed “phagocytic” starfish cells such as
macrophages, which could engulf and destroy foreign pathogens.
In the century that followed Mechnikov’s work, much of the broad
picture of innate immunity has become clear. Broadly speaking, the
recognition of foreign antigen triggers the immune system, which
responds with a multi-stage biochemical defense starting with the
unleashing of an army of white blood cells, like macrophages, which
engulf and destroy pathogens. The macrophages also fight the pathogens
by producing large amounts of chemicals that induce inflammation and
help the body clear the infection.
But many of the details of the molecules and signaling pathways that
allow this vigorous immune defense are still being elucidated.
Now, in a paper appearing in this week’s issue of the journal Nature,
Professor Bruce Beutler, Research Associate Kasper Hoebe, and their
colleagues at The Scripps Research Institute in La Jolla, CA have
identified one of the molecules that mediates innate immune recognition
—CD36.
Uncovering CD36’s Role
Normally, when human or mouse cells encounter bacteria or viruses,
they recognize proteins, lipids, or other molecular components of
these foreign invaders through a family of receptor proteins called
the toll-like receptors (TLRs). Humans have at least 10 different
TLRs, and one of Beutler’s goals is to identify how these receptors
and associated immune molecules such as CD36 mediate innate immunity.
One way he has approached this is through a technique known as
positional cloning, which combines classical genetic mapping methods
with high-powered computer-aided searches to identify relevant genes.
"We're attempting to create mutations that destroy innate immunity and
in this way, to identify all of the genes involved in innate immunity
or at least as many as we can,” Beutler says. “[When] we find a model
that is immunocompromised we can go back and positionally clone the
critical gene that we have hit."
About two years ago, they detected a genetic mutation termed oblivious
that renders its carriers’ macrophages unable to detect a molecule
called MALP-2, which is produced by the bacterium
Mycoplasmapneumoniae, and unable to detect a crude preparation of
commercial peptidoglycan derived from the bacterium Staphylococcus
aureus.
This mutation weakened the innate immune systems of the mice, which
are immunodeficient and highly susceptible to bacterial infections.
Using positional cloning, Beutler, Hoebe, and their colleagues mapped
the oblivious mutation to an obscure gene CD36, which has an
equivalent gene in humans
CD36 is produced by various types of cells associated with the blood
and the immune system. It can be found expressed in mammals both on
the surface of blood platelets and on endothelial cells lining the
blood vessels, where it is used for platelet adhesion. Previously,
CD36 had been identified on the surface of innate immune cells as a
class II scavenger—it scavenges or removes potentially dangerous
endogenous molecules from the body, such as human proteins that have
become oxidized or cross-linked.
Given CD36’s role in recognizing both endogenous human molecules and
exogenous bacterial molecules, Beutler, Hoebe, and their colleagues
suggest that it may be a mediator of what is known as a sterile
inflammation, in which immune cells release inflammatory chemicals in
the absence of any infection. Sterile inflammation is a condition
common to many different diseases, including autoimmune diseases.
It is still not clear whether TLRs are involved in sterile
inflammation, but CD36’s involvement strongly suggests that they may
be. If that is the case, then scientists will have a potentially
valuable target for the design of drugs aimed at treating diseases
involving sterile inflammation. By designing a way to block some part
of the TLR signaling pathway, they might succeed at reducing sterile
inflammation and ameliorating some of the diseases it causes.
The article, “CD36 is a sensor of diacylglycerides” is authored by
Kasper Hoebe, Philippe Georgel, Sophie Rutschmann, Xin Du, Suzanne
Mudd, Karine Crozat, Sosathya Sovath, Louis Shamel, Thomas Hartung,
Ulrich Zähringer, and Bruce Beutler and appears in the February 3,
2005 issue of the journal Nature. See:
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v433/n7025/full/nature03253_fs.html.
This work was supported by the National Institutes of Health.
jpg
http://www.scripps.edu/newsandviews/e_20050207/enlarge.html
Signaling Pathway in the Innate Immune System Revealed
The toll-like receptors TLR2 and TLR6 mediate innate immunity by
recognizing bacterial molecules like lipoteichoic acid (LTA) or
lipopeptide (LP). This recognition triggers a complicated signaling
cascade that leads to the expression of tumor necrosis factor (TNF)
and an immune response. However, the toll-like receptors do not act
alone, as revealed in the latest work by Scripps Research Professor
Bruce Beutler and Research Associate Kasper Hoebe. Animals with the
oblivious mutation, which Beutler and Hoebe mapped to the gene CD36,
show no immune response to LTA or LP—thus demonstrating that the
protein CD36 is one of the mediators of this arm of innate immunity.
<snip>
I like Bruce B. So i put this in here and when i re-read it i'll get
it. LOL
OTOH maybe you have h. pylori making your Gut (M1)Th1 skewed?
If so then knock that gut bug down
http://en.wikipedia.org/wiki/H._pylori#Treatment
Further information: Helicobacter pylori eradication protocols
Once H. pylori is detected in patients with a peptic ulcer, the normal
procedure is to eradicate it and allow the ulcer to heal. The standard
first-line therapy is a one week "triple therapy" consisting of proton
pump inhibitors such as omeprazole, lansoprazole and the antibiotics
clarithromycin and amoxicillin.[43] Variations of the triple therapy
have been developed over the years, such as using a different proton
pump inhibitor, as with pantoprazole or rabeprazole, or replacing
amoxicillin with metronidazole for people who are allergic to
penicillin.[44] Such a therapy has revolutionized the treatment of
peptic ulcers, and has made a cure to the disease possible;
previously, the only option was symptom control using antacids, H2-
antagonists or proton pump inhibitors alone.[45][46]
An increasing number of infected individuals are found to harbour
antibiotic-resistant bacteria. This results in initial treatment
failure and requires additional rounds of antibiotic therapy or
alternative strategies, such as a quadruple therapy, which adds a
bismuth colloid, such as bismuth subsalicylate.[33][47][48] For the
treatment of clarithromycin-resistant strains of H. pylori, the use of
levofloxacin as part of the therapy has been suggested.[49][50]
An article in the American Journal of Clinical Nutrition found
evidence that "ingesting lactic acid bacteria exerts a suppressive
effect on Helicobacter pylori infection in both animals and humans,"
noting that "supplementing with Lactobacillus- and Bifidobacterium-
containing yogurt (AB-yogurt) was shown to improve the rates of
eradication of H. pylori in humans."[51]
or see
http://en.wikipedia.org/wiki/Helicobacter_pylori_eradication_protocols
I've only mentioned Barry Marshall doing this a million times.
er' 17 times
randall..
> 8 hits - p ng for etomoxirhttp://groups.google.com/group/alt.support.skin-diseases.psoriasis/se...
>
> 4,480 hits in ALL groups - etomoxirhttp://groups.google.com/groups/search?hl=en&qt_s=1&q=Etomoxir
>
> $110 in Germanyhttp://www.google.com/search?hl=en&q=Etomoxir&um=1&ie=UTF-8&tbo=u&tbs...
>
> Go fish?
>
> OR
>
> Eat a FISH.
>
> Your magic herb is akin to the magic christian. LOL
>
> Not really THE answer:http://en.wikipedia.org/wiki/The_Magic_Christian_(film)
>
> Can't you simply run kofi and cpt1?
>
> http://groups.google.com/groups/search?hl=en&q=kofi+carnitine+palmito...
>
> Plenty to ruminate over in that one.
>
> I consumed flax seed oil and fish oil for YEARs to balance omega-6/w3
> ratio.
>
> Big deal i can eat ham and soy bean oil with nary a flare now.
>
> Not that i'm gonna go HOG wild. <g>
>
> And simply avoided as much w6 in my diet as possible.
>
> That helped but wasn't the answer.
>
> Fasting helps but not the answer.
>
> Many things help but why do them if your not curing anything?
>
> WELL to keep it homeostatic or whatever ain't BAD. <w>
>
> Yet why eat an herb that doesn't CURE YOU?
>
> You gonna do that the rest of your life?
>
> The magic is knocking down SFB in your Gi tract IMO.
>
> My last two posts today dealth with SFB in some context.
>
> And I did just THAT, ate L. Plantarum, this time last year and now i'm
> nearly CLEAR.
>
> So clear it's odd.
>
> But still have RA and PsA,.
>
> And herbs do help those.
>
> See:
> holistic horizons, yerba primahttp://groups.google.com/group/alt.support.skin-diseases.psoriasis/se...
> 48 hits ppar+gamma+omega-3 - pubmed:http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&...
>
> 56 hits ppar+gamma+carnitine+palmitoyltransferase+1 - pubmedhttp://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&...
> 349 hits carnitine+palmitoyltransferase+inhibitorhttp://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&...
>
> #2 mentions ALC Acetyl-L-carnitine to attenuate a stiffy. LOL
>
> I find that using ALA and ALC gives me a stiffy.
>
> Not a BAD thing but can get tiresome.
>
> Maybe not to YOU. But...well...you'll figure it out.
>
> randall...will the fickle finger of FATE intervene?
>
> ps- you could do what kofi said? He sounds like me now. LOL
>
> Which was and is
>
> http://groups.google.com/group/alt.support.skin-diseases.psoriasis/ms...
Kofi
> > Try intermittent fasting.
>
> A BMI under 18.5 is considered underweight.
> Mine is 16.7. Not much room to fast :(
It's isocaloric.
James Austin
> Do you have any Asian genes?
Yes!
> http://en.wikipedia.org/wiki/CD36...
Says 5 to 11% of Asian have a CD36 variant.
Something new to read up on. Thanks.
> We conclude that FFA influx in cardiac myocytes is
> mediated by a membrane pump whose transport rate constants
> may be modulated by FAT/CD36. PMID: 21147770
>
> These data reveal that FATP1, like FAT/CD36, is associated
> with mitochondria and has a role in mitochondrial oxidation
> of fatty acids. PMID: 19429947
>
> http://en.wikipedia.org/wiki/CD36
> CD36 is an integral membrane protein
> found on the surface of many cell types ...
> CD36 is a member of the class B scavenger
> CD36 binds many ligands
> including collagen, thrombospondin, erythrocytes parasitized
> with Plasmodium falciparum, oxidized low density lipoprotein,
> native lipoproteins, oxidized phospholipids, and long-chain
> fatty acids. ... a clear
> role for CD36 in fatty acid and glucose metabolism, heart
> disease, taste, and dietary fat processing in the intestine.
> It may be involved in glucose intolerance, atherosclerosis,
> arterial hypertension, diabetes, cardiomyopathy and Alzheimer's
> disease.
Hmm, I some symptoms related to heart, tongue & LCFA.
> http://en.wikipedia.org/wiki/CD36#Tertiary
> What if your ____hairpin like___ CD36 gizmo is haywire?
> That might be a problem. LOL
So in addition to Carnitine, PPARs and CPT1&2,
CD36 is a major factor related to fatty acid metabolism.
Another variable to investigate.
> Molecular Component of Innate Immunity Discovered
> ...Given CD36’s role in recognizing both endogenous human molecules and
> exogenous bacterial molecules, Beutler, Hoebe, and their colleagues
> suggest that it may be a mediator of what is known as a sterile
> inflammation, in which immune cells release inflammatory chemicals in
> the absence of any infection. Sterile inflammation is a condition
> common to many different diseases, including autoimmune diseases.
> ...By designing a way to block some part
> of the TLR signaling pathway, they might succeed at reducing sterile
> inflammation and ameliorating some of the diseases it causes.
>
> http://www.scripps.edu/newsandviews/e_20050207/enlarge.html
> ...Animals with the
> oblivious mutation, which Beutler and Hoebe mapped to the gene CD36,
> show no immune response to LTA or LP—thus demonstrating that the
> protein CD36 is one of the mediators of this arm of innate immunity.
> OTOH maybe you have h. pylori making your Gut (M1)Th1 skewed?
Took the 2 week, triple treatment some years ago, just in case.
Didn't seem to do anything.
> I consumed flax seed oil and fish oil for YEARs
> to balance omega-6/w3 ratio.
Recently tried freshly ground flaxseed again.
Caused soreness in finger cuticles and stab-like pain in foot joints.
I am cautious of too much n3s as they are very fragile and oxidation
prone.
> Big deal i can eat ham and soy bean oil with nary a flare now.
> Not that i'm gonna go HOG wild. <g>
Many year ago I ate a fatty piece of pork.
Within a few hours it felt as if a heat lamp was pointed at my knees.
More recently I had a lot of sausage patties at one breakfast.
Caused rhoids :(
> And simply avoided as much w6 in my diet as possible.
> That helped but wasn't the answer.
> Fasting helps but not the answer.
> Many things help but why do them if your not curing anything?
> WELL to keep it homeostatic or whatever ain't BAD. <w>
> Yet why eat an herb that doesn't CURE YOU?
> You gonna do that the rest of your life?
> The magic is knocking down SFB in your Gi tract IMO.
Eating substantial raw veggies (including cabbage)
seems to be among the most effective in
lowering inflammation, allergies but leaves me hungry.
Maybe the positive results are mainly due to increased levels
of friendly bacteria (including Plantarum) in intestines.
> ... ate L. Plantarum, this time last year
> and now i'm nearly CLEAR.
> So clear it's odd.
> But still have RA and PsA,.
> And herbs do help those.
> Till i ate kimchi (L. plantarum) last year for three weeks,
> three times a day and i was fairly
> mild to start with and then very very mild. :)
>
> Doing coconut mct and fish oils next with a few other things
> might be better for those gray cells, which can use a tune up.
I'll be interested to know your results.
They regular CO and FO make things worse for me.
> Omega-3 fatty acids attenuate dendritic cell function via NF-κB
> independent of PPARγ
> PMID: 21111596
N3s may also lower immune/inflammation response
by destabilizing "lipid rafts" in T-cell's membrane.
> Biochim Biophys Acta. 2010 Nov;1801(11):1214-20. Epub 2010 Jul 23.
> Citral, a component of lemongrass oil, activates PPARα and γ and
> suppresses COX-2 expression.
I bought some lemongrass last week after reading the posts here about
PPARg.
Apparently it is used frequently in Thai Cuisine.
jay
Randall, what is your current fat intake? Any problems with saturated
(ie butter) or mono-unsaturated (olive) fats?
It seems there are 2 major issues in psoriasis and similar. First a
dysregulated immune system that you are addressing successfully with
pre & probiotics. Second is some type of dysregulation within
epithelial-type cells. You have posted the below abstract twice
before. It says PPARd is already hyperactivated thus I would want to
reduce it, preferrably by addressing the underlying reason. Is PPARd
mostly activated by LCFAs? Maybe CPT1, 2 or CD36 variants increase
intercellular levels of LCFAs.
PPARdelta enhances keratinocyte proliferation in psoriasis and induces
heparin-binding EGF-like growth factor.
Psoriasis is a common skin disease involving keratinocyte
proliferation and altered differentiation, as well as T-cell
activation. Here, we show that altered gene transcription in psoriatic
skin lesions is highly reproducible between independent data sets.
Analysis of gene expression confirmed dysregulation in all expected
functional categories, such as IFN signaling and keratinocyte
differentiation, and allowed molecular fingerprinting of a previously
characterized dendritic cell subset associated with psoriasis tumor
necrosis factor alpha (TNF-alpha)- and inducible nitric oxide synthase
(iNOS)-producing CD11b(INT) DC (Tip-DC). Unexpectedly, a large group
of dysregulated transcripts was related to fatty acid signaling and
adipocyte differentiation, exhibiting a pattern consistent with the
activation of peroxisome proliferator-activated receptor delta
(PPARdelta). PPARdelta itself was strongly induced in psoriasis in
vivo. In primary keratinocytes, PPARdelta was induced by the
transcription factor activator protein 1, in particular by junB, but
not by canonical WNT signaling, in contrast to its regulation in colon
carcinoma cells. Activation of PPARdelta enhanced proliferation of
keratinocytes, while this was inhibited by knockdown of PPARdelta.
Finally, heparin-binding EGF-like growth factor (HB-EGF), known to
induce epidermal hyperplasia and itself overexpressed in psoriasis,
was identified as a direct target gene of PPARdelta. The present data
suggest that activation of PPARdelta is a major event in psoriasis,
contributing to the hyperproliferative phenotype by induction of HB-
EGF. PMID: 17637826
randall
> > Doing coconut mct and fish oils next with a few other things
>
> Randall, what is your current fat intake? Any problems with saturated
> (ie butter) or mono-unsaturated (olive) fats?
NOPE.
I can eat anything (lipids et al) with only minor problems
And that is in comparison of where i've BEEN btw. LOL
What is your exact situation JAY?
Do you have a GOOD Dx from a REAL doctor?
I really aPPreciate your psor and crohn's examinations as
you and Kofi help me to see more CLEARLY. :)
But i've cured me of the psoriasis for the most part.
Which i didn't expect as my last trial was in preparation for
a SERIOUS trial. And that would have DONE what the prepatory trial
did. LOL
Now i've got to find a way to do another trial with 20-100
autoimmune folks in a controlled environ.
Yet, think about it, i've come a long long ways since 1999
and my trial that year.
And immunological science HAS COME much FURTHER then i. :)
And now i'm in contact with some of the leaders IMO in
this field.
I'm as happy as a clam.
How can i help you?
Didn't hot kofi try with isocaloric? LOL <w>
>
> It seems there are 2 major issues in psoriasis and similar. First a
> dysregulated immune system that you are addressing successfully with
> pre & probiotics. Second is some type of dysregulation within
> epithelial-type cells. You have posted the below abstract twice
> before.
I said iirc that i posted it and you posted it?
OK,
So say i don't know what exactly you want and i'm merely looking
in to the looking glass.
Sorta down the rabbit hole if you get my drift?
You have to some lipids.
Right?
Even if your isocalorical or not?
Not getting any wiki hits worth a dime for it.
And this comes up #1.
http://www.trulyhuge.com/isocaloric_diet.htm
So your a skinny binny or ?
But..
What if you ONLY ate the GOOD FATS?
Would you be in heaven and have perfect health and live to 122 1/2 y/
o?
The ones that Jeanne Calment ate are OK with me btw. LOL
I wouldn't mind living as long as Jeanne, would you?
Jeanne also smoked a cig and drank alcoholic cocktail now and then.
Will mercola push Calment the way he pushed the 109 y/o Bernando
LaPallo vegetarian recently?
Bernando LaPallo - and THE OLDER Walter Breuning (114 y/o) eat low on
the totem pole:
http://articles.mercola.com/sites/articles/archive/2010/10/14/walter-breuning-the-oldest-living-man-in-the-world.aspx
Walter Breunig's case, proper food choices, abstinence from alcohol,
daily outdoor exercise, a spiritual and optimistic outlook on life,
and "taking things in stride," has made him the oldest man in America.
His daily diet consists of: Vegetables, Fruit (especially blueberries
and cantaloupe)
Beans (his primary source of protein) Nuts Soup Clean water Cinnamon
tea
Leafy green vegetables make up two-thirds of his daily diet, and foods
that need cooking are either lightly sautéed or lightly cooked
<snip>
Any MEAT in that SOUP? Will WALTER make it to 122 and a HALF like
Jeanne did?
I'm fairly sure Jeanne Calment didn't ____swill___ down n6 vegetable
oils.
With a ratio of 7 times more w6 then w3's soy bean oil is a POOR
choice IMO:
http://en.wikipedia.org/wiki/Soybean#Omega-3_fatty_acids
HAD ALL other things been equal and Jeanne been born in the USofA
would the
n6 vegetable oils like soy, corn, safflower et al, done her IN and
shorten her
LIFE SPAN?
IMO, YES. And IMO it's more of a pge2 then pgd2 event?
But like Th1 (M1) and Th2 (M2) it's semantics and still a glimmer of
reality
to making the hard choices in a soft genetical, epistatic,
epigenetical hierarchical
paradigm that even in the most uncertain of times is murky to say the
least or most. LOL
EATing soy bean oil (w6) at one time, even a very small amount, like
in a pill or ???, would trigger
a flare in ME. Even vitamin E pills or any pills with a soy oil base
were OUT. O U T. of me.
So i avoided n6 like the PLAQUE it caused. LOL
The PSOR Plaque of the plague was not bubonic for me but genetical and
autoimmunological to the
extreme and portended a short life. :(
But reason and hope was lite from inside the same place i felt the
psor came from.
The GUT Hunch:
And in a few months i lowered my psoriasis 30-35% and figured i was on
the gravy train.
Low and behold i plateaued. Mid 90's..
Took another five/six years to find the wit kit and that was by
accident.
I had tried to control LAB in the Gi tract twenty years prior
(1980's), unsuccessfully.
But being the infernal optimist i am i took another ride on the EEE
ticket.
<h'mm.. for your info.. a triple e ticket is a disneyland GOOD ride
lol)
And here i am, still thinking, if i can control my Th1 previously
skewed situation we may be able to
cure HIV and cancer being typical Th2 skewed conditions.
It that a big enough ______SFB__________ BUG to put under your bonnet?
As to FAT and FATe...?
And NOT having to HATE your BODY for the genetic MESS caused by SFB's?
--------------------?
Or you could die at 44-45 ish like St FRANCIS (Bernardone) did?
Didn't he follow the or A biblical diet? Is there ONE in there? <G>
IOWs.. we follow the path or the END of the ROAD catches uP to US.
and btw, i'm flying to get my idea's down... as i'm watching the
Pittsburgh steelers and Jets game and it's 92 yd's in the last two
seconds. LOL
And i've got be ready for the parade of lights on the BAY in less then
45 minutes.
So this is tight.
I might have to scramble faster then big BEN.
http://www.ncbi.nlm.nih.gov/pubmed/21160131
J Epidemiol. 2010 Dec 11.
Low Cholesterol is Associated With Mortality From Stroke, Heart
Disease, and Cancer: The Jichi Medical School Cohort Study.
Nago N, Ishikawa S, Goto T, Kayaba K.
Tokyo-kita Social Health Insurance Hospital, Clinical Education
Center.
Abstract
Background: We investigated the relationship between low cholesterol
and mortality and examined whether that relationship differs with
respect to cause of death.Methods: A community-based prospective
cohort study was conducted in 12 rural areas in Japan. The study
subjects were 12 334 healthy adults aged 40 to 69 years who underwent
a mass screening examination. Serum total cholesterol was measured by
an enzymatic method. The outcome was total mortality, by sex and cause
of death. Information regarding cause of death was obtained from death
certificates, and the average follow-up period was 11.9 years.
Results: As compared with a moderate cholesterol level (4.14-5.17 mmol/
L), the age-adjusted hazard ratio (HR) of low cholesterol (<4.14 mmol/
L) for mortality was 1.49 (95% confidence interval [CI]: 1.23-1.79) in
men and 1.50 (1.10-2.04) in women. High cholesterol (≥6.21 mmol/L) was
not a risk factor. This association was unchanged in analyses that
excluded deaths due to liver disease, which yielded age-adjusted HRs
of 1.38 (95% CI, 1.13-1.67) in men and 1.49 (1.09-2.04) in women. The
multivariate-adjusted HRs and 95% CIs of the lowest cholesterol group
for hemorrhagic stroke, heart failure (excluding myocardial
infarction), and cancer mortality significantly higher than those of
the moderate cholesterol group, for each cause of death.
Conclusions: Low cholesterol was related to high mortality even after
excluding deaths due to liver disease from the analysis. High
cholesterol was not a risk factor for mortality.
PMID: 21160131
STAT----> Activation of PPARbeta/delta in the epidermis and not in the
ER. (<w> <G>)
Crap Big BEN missed his man in the end zone. Pittsburgh lost to the
JETs...
Oh man...
Ben is the MAN.
But the JETs came to life and had their defense UP and win 22-17.
OK move on dork randall...
Sorry.. my id is wigging on my ego or super duPer egotestical nature.
LOL
BACK to JAY from mumbai?
I'm guessing. But if your Dx is h. pylori i wouldn't be surPrised.
This is the pmid for your ABSTRACT:
http://www.ncbi.nlm.nih.gov/pubmed/17637826 **
Shall we look at the MAIN author?
Why YES, why NOT?
62 hits with seven new ones since pmid: __17637826__ for "Foerster
J"[Author]
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Foerster%20J%22%5BAuthor%5D
"Foerster J"[Author] most recent:
<and didn't kofi mention activation of these would cause cancer in
this thread? But in this case autoimmunity?>
<makes one wonder if the SKeW is WHAT rules here?>
If i get extra up or down stream inflammation it means more Th1
autoimmunity.
But if your skewed Towards Th2 (IL-10 etc or M2) then you get CANCER.
Weird HUH? ;~?
http://www.ncbi.nlm.nih.gov/pubmed/20300524
PLoS One. 2010 Mar 16;5(3):e9701.
Activation of PPARbeta/delta causes a psoriasis-like skin disease in
vivo.
Romanowska M, Reilly L, Palmer CN, Gustafsson MC, __Foerster J.___
Division of Experimental Medicine, University of Dundee, Dundee,
United Kingdom.
Abstract
BACKGROUND: Psoriasis is one of the most frequent skin diseases world-
wide. The disease impacts enormously on affected patients and poses a
huge financial burden on health care providers. Several lines of
evidence suggest that the nuclear hormone receptor peroxisome
proliferator activator (PPAR) beta/delta, known to regulate epithelial
differentiation and wound healing, contributes to psoriasis
pathogenesis. It is unclear, however, whether activation of PPARbeta/
delta is sufficient to trigger psoriasis-like changes in vivo.
METHODOLOGY/PRINCIPAL FINDINGS: Using immunohistochemistry, we define
the distribution of PPARbeta/delta in the skin lesions of psoriasis.
By expression profiling, we confirm that PPARbeta/delta is
overexpressed in the vast majority of psoriasis patients. We further
establish a transgenic model allowing inducible activation of PPARbeta/
delta in murine epidermis mimicking its distribution in psoriasis
lesions. Upon activation of PPARbeta/delta, transgenic mice sustain an
inflammatory skin disease strikingly similar to psoriasis, featuring
hyperproliferation of keratinocytes, dendritic cell accumulation, and
endothelial activation. Development of this phenotype requires the
activation of the Th17 subset of T cells, shown previously to be
central to psoriasis. Moreover, gene dysregulation in the transgenic
mice is highly similar to that in psoriasis. Key transcriptional
programs activated in psoriasis, including IL1-related signalling and
cholesterol biosynthesis, are replicated in the mouse model,
suggesting that PPARbeta/delta regulates these transcriptional changes
in psoriasis. Finally, we identify phosphorylation of STAT3 as a novel
pathway activated by PPARbeta/delta and show that inhibition of STAT3
phosphorylation blocks disease development.
CONCLUSIONS: Activation of PPARbeta/delta in the epidermis is
sufficient to trigger inflammatory changes, immune activation, and
signalling, and gene dysregulation characteristic of psoriasis.
PMID: 20300524
==========================
So i go with WHAT i don't kNOW usually. LOL
You KNOW what i MeAN?
From HOT kofi to cool randall?
And in the same thread if you missed it
http://groups.google.com/group/alt.support.crohns-colitis/msg/b503d55cfceffecd?hl=en&&q=ppar+pge2
Let's see? Of 4571 hits in pubmed for Pgd2, this is the most recent.
http://www.ncbi.nlm.nih.gov/pubmed/21163901
Am J Physiol Gastrointest Liver Physiol. 2010 Dec 16.
Increased expression of lipocalin-type-prostaglandin D synthase in
ulcerative colitis and exacerbating role in murine colitis.
Hokari R, Kurihara C, Nagata N, Aritake K, Okada Y, Watanabe C, Komoto
S, Nakamura M, Kawaguchi A, Nagao S, Urade Y, Miura S.
1National Defense Medical College.
Abstract
Background The pathogenesis of ulcerative colitis (UC) is unclear, but
enhancement of disease activity by usage of NSAIDs suggests
involvement of prostanoid in its pathophysiology. However, biological
effect of of prostaglandin (PG)D(2) on intestinal inflammation remains
unknown. We investigated the expression of enzymes for PGD2 synthesis,
prostaglandin D synthase (PGDS), and its relation to the activity of
colitis in UC patients. The role of lipocalin-type-PGDS (L-PGDS) using
a murine colitis model was also assessed. Methods Tissue samples were
obtained by colonic biopsies from patients with UC. Expression levels
of mRNAs for L-PGDS and hematopoietic type PGDS were investigated by
quantitative RT-PCR. COX-2 and L-PGDS expression were investigated by
immunohistochemistry. Localization of L-PGDS expression was also
determined by in situ hybridization. In experimental study mice were
treated with dextran sodium sulfate in the drinking water to induce
colitis. Degree of colonic inflammation was compared with L-PGDS -/-
mice and control mice. Result The level of L-PGDS mRNA expression was
increased in UC patients in parallel with disease activity. Co-
localization of L-PGDS and COX 2 were observed in lamina proprial
infiltrating cells and muscularis mucosa in UC patients. Level of H-
PGDS mRNA expression did not differ from control mucosa. DSS treatment
to L-PGDS -/- mice showed lower disease activity than control mice.
Conclusion: We reported for the first time the presence of L-PGDS in
the COX-2 expressing cells in the mucosa of active UC patients and
that only L-PGDS increased with disease activity. Animal model study
suggests that PGD2 derived from L-PGDS expressing cells play
proinflammatory roles in colitis.
PMID: 21163901
JAY, so i don't need to look it back up, your exact Dx is what again?
Or are you JUST an interested IBD'ER? LoL
How do you expect me to nail this with that looming in the background.
I'm FAST doing these things but without sufficient info you see my
dilemma?
I hoPe you do.
I can tell you the whole jets / steelers game i saw IT just now.
But i'm not seeing you other then your words and something isn't
adding uP?
backto gpe2? OOP's pge2.
1476 of those 4571 have pge2 in them:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=pgd2+pge2
only two have the kicker: autoimmune
http://www.ncbi.nlm.nih.gov/pubmed/20929574
J Neuroinflammation. 2010 Oct 7;7:60.
Chronic immobilisation stress ameliorates clinical score and
neuroinflammation in a MOG-induced EAE in Dark Agouti rats: mechanisms
implicated.
Pérez-Nievas BG, García-Bueno B, Madrigal JL, Leza JC.
Department of Pharmacology, Faculty Medicine, University Complutense,
Centro de Investigación Biomédica en red de Salud Mental (CIBERSA),
Granada, Spain. bgom...@gmail.com
Abstract
BACKGROUND: Multiple sclerosis (MS) is the endpoint of a complex and
still poorly understood process which results in inflammation,
demyelination and axonal and neuronal degeneration. Since the first
description of MS, psychological stress has been suggested to be one
of the trigger factors in the onset and/or relapse of symptoms.
However, data from animal models of MS, such as experimental
autoimmune encephalomyelitis (EAE) are inconsistent and the effect of
stress on EAE onset and severity depends on duration and time of
application of the stress protocol and the underlying mechanisms.
METHODS: Dark Agouti rats were inoculated with MOG/CFA to induce EAE,
and an immobilisation stress protocol with two different durations (12
and 21 days, starting at the moment of MOG-inoculation) was applied in
order to analyse the effect of stress on disease onset and
neuroinflammation.
RESULTS: Twelve days of stress exposure increased EAE clinical score
in Dark Agouti rats. In addition, these animals presented higher
levels of MMP-9 and proinflammatory PGE2 in spinal cord. In contrast,
animals chronically exposed to stress (21 days) showed a significantly
lower incidence of EAE clinical signs and reduced myelin loss,
leukocyte infiltration and accumulation of inflammatory/oxidative
mediators in spinal cord. Interestingly, chronically stressed animals
showed a parallel increase in levels of the anti-inflammatory
prostaglandin 15d-PGJ₂, the main endogenous agonist of PPARγ.
CONCLUSIONS: Our results demonstrate that, depending on duration,
stress exposure elicits opposite effects on PGE₂/15d-PGJ₂ ratios in
spinal cord of EAE-induced Dark Agouti rats. Further studies are
needed to elucidate if these changes in prostaglandin balance are
sufficient to mediate the differences in clinical score and
inflammation here reported, and to establish the potential utility of
pharmacological intervention in MS directed toward anti-inflammatory
pathways.
PMID: 20929574
Free PMC article
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20929574/?tool=pubmed
OK i don't have time now, i'm flying to get my idea's OUT .. so i'm
outa here.
I've got less then 20 minutes or so and that's IT.
Or i post this on monday. <g?
===============
http://www.ncbi.nlm.nih.gov/pubmed/20036014
Vet Immunol Immunopathol. 2010 May 15;135(1-2):118-27. Epub 2009 Nov
24.
Characterization and modulation of canine mast cell derived
eicosanoids.
Lin TY, London CA.
Department of Veterinary Biosciences, College of Veterinary Medicine,
The Ohio State University, 454 VMAB, 1925 Coffey Road, Columbus, OH
43210, USA.
Abstract
Mast cells play an important role in both innate and acquired immunity
as well as several pathological conditions including allergy,
arthritis and neoplasia. They influence these processes by producing a
variety of mediators including cytokines, chemokines and eicosanoids.
Very little is currently known about the spectrum of inflammatory
mediators, particularly eicosanoids (prostaglandins and leukotrienes),
produced by canine mast cells. This is important since modulating mast
cell derived eicosanoids may help in the treatment of autoimmune and
inflammatory disorders. The purpose of this study was to investigate
the spectrum of eicosanoids produced by normal canine mast cells and
to evaluate the effects of cytokines and non-steroidal anti-
inflammatory mediators (NSAIDS) on eicosanoid production and release.
Canine bone marrow derived cultured mast cells (cBMCMCs) expressed
COX-1, COX-2, and 5-LOX and synthesized and released PGD2, PGE2, LTB4,
and LTC4 following activation by a variety of stimuli. The selective
COX-2 NSAIDs carprofen (Rimadyl) and deracoxib (Deramaxx) inhibited
PGD2 and PGE2 production but only slightly inhibited LTB4 and LTC4.
The mixed COX-1/COX-2 inhibitor piroxicam blocked PGD2 and PGE2
production, but upregulated LTC4 following treatment while tepoxilan
(Zubrin), a pan COX/LOX inhibitor, markedly reduced the production of
all eicosanoids. The LOX inhibitor nordihydroguaiaretic acid (NDGA)
prevented LTB4/LTC4 release and BMBMC degranulation. Pre-incubation of
cBMCMCs with IL-4 and SCF sensitized these cells to degranulation in
response to substance P. In conclusion, canine BMCMCs produce an array
of eicosanoids similar to those produced by mast cells from other
species. Tepoxilan appeared to be the most effective NSAID for
blocking eicosanoid production and thus may be useful for modulating
mast cell mediated responses in dogs.
2009 Elsevier B.V. All rights reserved.
PMID: 20036014
=====================
For pge2 AND autoimmun* - 155 hits pubmed
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=pge2+autoimmun*
Only 26 hits for pgd2 and autoimmun* pubmed
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=pgd2+autoimmun*
I'm not seeing anything to hooP RAH over.
Whatz hoop rah? LOL
When... never mind.
I've taken nAC and do like it.
But CAN'T take it while doing any TRIALs which i do ALL the time.
Cept for between trials like now and i can't take it either.
So my diet does the heavy lifting to make me healthy.
Which is OK as i'm HEALTHY.
But i don't get each and everything.
So what's 15dPGJ2 got to do with it?
Takes us back to YOUR post:
Kofi POSTED:
http://groups.google.com/group/alt.support.crohns-colitis/msg/348d82177b4f33d1
Stimulating PPARgamma can be a problem viz. adiposity and heart
function. It's unclear if abscisic acid dodges this. Celiacs might
want to be careful fooling around with PPARgamma since this might
stir
up transglutaminase.
From my previous postings here, you should know the IDO/niacin
pathway
well by now. PGD2, synthesized by niacin, predicts better recovery
from
IBD. 15d-PGJ2 is a PPARgamma agonist.
AA -> COX2 -> PGD2 -> 15d-PGJ2 -> PPARgamma, macrophages, mu opioid,
NGF
-> NO/cGMP/PKG/KATP+ (see hyperbaric O2, eNOS/SIRT1/NGF info)
PGD2 -> 15d-PGJ2 -> PPARgamma, macrophages -> NO/cGMP/PKG/KATP+
!
! AKR1C3 (Aldo-keto reductase (AKR) 1C3)
v
9alpha11beta-PGF(2alpha) / PGF2alpha
<hot kofi spells it out> <yet whatz missing? You tell me.. or do you
want me to tell you. LOL>
kofi said:
The fact that low-dose naltrexone helps to upregulate the mu opioid
receptor might indicate that mu opioid receptor levels are naturally
deficient in certain diseases like Crohn's, M.S. and cancer. Loss of
15d-PGJ2 or some other PPARgamma deficiency could plausibly explain
why
LDN is beneficial in these diseases.
<snip>
http://www.ncbi.nlm.nih.gov/pubmed/20489149
Am J Pathol. 2010 Jul;177(1):219-28. Epub 2010 May 20.
N-acetylcysteine and 15 deoxy-{delta}12,14-prostaglandin J2 exert a
protective effect against autoimmune thyroid destruction in vivo but
not against interleukin-1{alpha}/interferon {gamma}-induced inhibitory
effects in thyrocytes in vitro.
Poncin S, Colin IM, Decallonne B, Clinckspooor I, Many MC, Denef JF,
Gérard AC.
Unité de Morphologie Expérimentale (MOEX), Université catholique de
Louvain, UCL-5251, 52 Av. E.Mounier, B-1200, Brussels, Belgium.
Abstract
Reactive oxygen species (ROS) are crucial for thyroid hormonogenesis,
and their production is kept under tight control. Oxidative stress
(OS) is toxic for thyrocytes in an inflammatory context. In vitro, Th1
pro-inflammatory cytokines have already been shown to decrease thyroid-
specific protein expression. In the present study, OS level and its
impact on thyroid function were analyzed in vitro in Th1 cytokine
(interleukin [IL]-1alpha/interferon [IFN] gamma)-incubated thyrocytes
(rat and human), as well as in vivo in thyroids from nonobese diabetic
mice, a model of spontaneous autoimmune thyroiditis. N-acetylcysteine
(NAC) and prostaglandin, 15 deoxy-(Delta12,14)-prostaglandinJ2
(15dPGJ2), were used for their antioxidant and anti-inflammatory
properties, respectively. ROS production and OS were increased in
IL-1alpha/IFNgamma-incubated thyrocytes and in destructive
thyroiditis. In vitro, NAC not only reduced ROS production below
control levels, but further decreased the expression of thyroid-
specific proteins in addition to IL-1alpha/IFNgamma-inhibitory
effects. Thus, besides ROS, other intracellular intermediaries likely
mediate Th1 cytokine effects. In vivo, NAC and 15dPGJ2 reduced OS and
the immune infiltration, thereby leading to a restoration of thyroid
morphology. It is therefore likely that NAC and 15dPGJ2 mainly exert
their protective effects by acting on infiltrating inflammatory cells
rather than directly on thyrocytes.
PMID: 20489149
But why do we need it?
If it's due to h. pylori priming the M1 (Th1 skew) pump then it's the
target.
SEE: <the last quarter of this post: M1 and H. pylori)
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/browse_thread/thread/4d986485e24fabe2?hl=en#
Or if it's also in conjunction due to SFB then we have a TAG team
doing the Th1, Th17
induction skewyness.
http://www.ncbi.nlm.nih.gov/pubmed/20478974
J Physiol. 2010 Jul 15;588(Pt 14):2533-44. Epub 2010 May 17.
Enteric glia modulate epithelial cell proliferation and
differentiation through 15-deoxy-12,14-prostaglandin J2.
Bach-Ngohou K, Mahé MM, Aubert P, Abdo H, Boni S, Bourreille A, Denis
MG, Lardeux B, Neunlist M, Masson D.
INSERM U913 and Institut des Maladies de l'Appareil Digestif, 1, place
Alexis Ricordeau, 44093 Nantes Cedex 01, France. kb...@chu-nantes.fr
Abstract
The enteric nervous system (ENS) and its major component, enteric
glial cells (EGCs), have recently been identified as a major regulator
of intestinal epithelial barrier functions. Indeed, EGCs inhibit
intestinal epithelial cell (IEC) proliferation and increase barrier
resistance and IEC adhesion via the release of EGC-derived soluble
factors. Interestingly, EGC regulation of intestinal epithelial
barrier functions is reminiscent of previously reported peroxisome
proliferator-activated receptor gamma (PPARgamma)-dependent functional
effects. In this context, the present study aimed at identifying
whether EGC could synthesize and release the main PPARgamma ligand, 15-
deoxy-(12,14)-prostaglandin J2 (15dPGJ2), and regulate IEC functions
such as proliferation and differentiation via a PPARgamma dependent
pathway. First, we demonstrated that the lipocalin but not the
haematopoetic form for prostaglandin D synthase (PGDS), the enzyme
responsible of 15dPGJ2 synthesis, was expressed in EGCs of the human
submucosal plexus and of the subepithelium, as well as in rat primary
culture of ENS and EGC lines. Next, 15dPGJ2 was identified in EGC
supernatants of various EGC lines. 15dPGJ2 reproduced EGC inhibitory
effects upon IEC proliferation, and inhibition of lipocalin PGDS
expression by shRNA abrogated these effects. Furthermore, EGCs induced
nuclear translocation of PPARgamma in IEC, and both EGC and 15dPGJ2
effects upon IEC proliferation were prevented by the PPARgamma
antagonist GW9662. Finally, EGC induced differentiation-related gene
expression in IEC through a PPARgamma-dependent pathway. Our results
identified 15dPGJ2 as a novel glial-derived mediator involved in the
control of IEC proliferation/differentiation through activation of
PPARgamma. They also suggest that alterations of glial PGDS expression
may modify intestinal epithelial barrier functions and be involved in
the development of pathologies such as cancer or inflammatory bowel
diseases.
PMID: 20478974
427 hits 15-deoxy-(12,14)-prostaglandin J2
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=15-deoxy-+AND+(12,14)+AND+-prostaglandin+J2
ONLY ONE of these has h. pylori
http://www.ncbi.nlm.nih.gov/pubmed/19723089
Ann N Y Acad Sci. 2009 Aug;1171:457-63.
15-Deoxy-delta 12, 14,-prostaglandin J2 suppresses nuclear factor-
kappaB-mediated apoptosis of Helicobacter pylori-infected gastric
epithelial cells.
Cha B, Kim KH, Kim H.
Department of Pharmacology and Institute of Gastroenterology, Brain
Korea 21 Project, Yonsei University College of Human Ecology, Seoul,
Korea.
Abstract
Helicobacter pylori deregulates the genes that control homeostasis
between apoptosis and cell proliferation of gastric epithelial cells.
Nuclear factor-kappaB (NF-kappaB) has an important role in H. pylori-
induced apoptosis in gastric epithelial cells. The peroxisome
proliferator-activated receptor-gamma ligand 15-deoxy-Delta(12,14)-
prostaglandin J(2) (15d-PGJ(2)) regulates growth and the signaling
cascade in H. pylori-infected gastric epithelial cells. In the present
study, we determined whether 15d-PGJ(2) inhibits apoptosis by
regulating apoptotic gene expression and NF-kappaB activation in
gastric epithelial cells infected with CagA+, VacA+H. pylori in a
Korean isolate (HP99). 15d-PGJ(2) was found to inhibit H. pylori-
induced DNA fragmentation and cell death. 15d-PGJ(2) induced
downregulation of proapoptotic Bax and upregulation of antiapoptotic
Bcl-2 as well as suppression of NF-kappaB activation caused by H.
pylori in gastric epithelial cells. The results suggest that 15d-
PGJ(2) inhibits apoptotic cell death by inhibiting NF-kappaB
activation and apoptotic gene expression in gastric epithelial cells.
PMID: 19723089
I would venture to say it's in your genes or a BUG or a virus or all
three or a combo.
If you work SFB like i do, who knows?
You might get CLEAR?
OTOH what have you LOST if you don't?
I tried for half a century.
What if i blew the wit kit off in 1999?
Then i'd be bitter & PSOR CANDIDE with the Baron's BUTT UGLY daughter,
Lady Cunégonde.
Instead of clear SKIN RANDALL with butt ugly... well you know... <w>
And the MCT oil sharPen those brain cells btw.
If i flare, then I'LL say it feeds SFB. <G>
Ok i just got a phone call.. and my friend is awaiting me on the BOAT.
LOL...
I said .. hey we're not leaving till five and it's not even 4:30 pm..
So I better GO now.
randall.. but if i re-read this, which i will Mañana, will i find
coherency?
Kofi
<f434ff86-85c8-4a97...@35g2000prt.googlegroups.com>,
randall <ranh...@aol.com> wrote:
This is extremely misleading. The abstract doesn't indicate if the
model is acute colitis (one high dose of DSS) or chronic colitis
(several low doses of DSS). Many things that stop acute colitis in mice
(like sympathectomy) make chronic colitis worse. We know from plenty of
studies that higher PGD2 levels are associated with better recovery in
human colitis. We also know that COX-2 inhibitor use is associated with
the induction of colitis. The literature indicates that PGD2 is part of
the innate (esp. TLR4/CD14) response to bacterial LPS. Blocking PGD2,
then, would block something in the middle of the sympathetic/TLR
response both to bacteria and self-tolerance (IL-10 comes out of this
same response pathway). Without PGD2, you don't get the PPARgamma
agonist 15d-PGJ2. Then you recapitulate my recent postings on the
AKR1C3 pathway (without considering the conundrum in the above colitis
example).
The papers you cite on the enteric nervous system [PMID 20478974] and on
MS and MMP-9 (which impairs NGF) [PMID 20929574] indicates that one of
the ways PGD2 may work is by stimulating some form of sympathetic neuron
development. Thus in conditions where PGD2 is low or MMP9 is high,
you're seeing an erosion of antiinflammatory nerve control of the target
organ. (Too much innervation might explain why you see PGD2 associated
with atherosclerosis - where lowering it might actually make it worse.)
Although mainly expressed in neuronal cells, lipocalin-type PGD synthase
(L-PGDS) is detected in the macrophages infiltrated to atherosclerotic
plaques. However, the regulation and significance of L-PGDS expression
in macrophages are unknown. Here, we found that treatment of macrophages
with bacterial endotoxin (LPS) or Pseudomonas induced L-PGDS expression.
Epigenetic suppression of L-PGDS expression in macrophages blunted a
majority of PGD(2) produced after LPS treatment. Chromatin
immunoprecipitation assays show that L-PGDS induction was regulated
positively by AP-1, but negatively by p53. L-PGDS expression was
detected in whole lung and alveolar macrophages treated with LPS or
Pseudomonas. L-PGDS overexpressing transgenic mice improved clearance of
Pseudomonas from the lung compared with nontransgenic mice. Similarly,
intratracheal instillation of PGD2 enhanced removal of Pseudomonas from
the lung in mice. In contrast, L-PGDS knockout mice were impaired in
their ability to remove Pseudomonas from the lung. Together, our results
identify induction of L-PGDS expression by inflammatory stimuli or
bacterial infection, the regulatory mechanism of L-PGDS induction, and
the protective role of L-PGDS expression in host immune response. Our
study suggests a potential therapeutic usage of L-PGDS or PGD(2) against
Pseudomonas pneumonia [PMID 17675519]
>I would venture to say it's in your genes or a BUG or a virus or all
>three or a combo.
It could be a failure of the body to strike a balance in the immune
system that allows these parasites to recede in the background as
symbionts. That's true of latent viruses that aren't staying latent.
randall
> In article
> <f434ff86-85c8-4a97-a869-aa821b22f...@35g2000prt.googlegroups.com>,
>
> - Show quoted text -
I'm still wondering if JAY is asymptomatic for H. pylori?
Where did he go?
Do you suppose he's mal nourished? And needs brain sugars?
How about coconut mcts?
Why do i think these things?
See what you do to me?
Did brenda LEE really say i'm sorry or simply write the song?
Don't care now.
If it's subclinical (backgrounded?), then epistatic for Th1 (M1)
genetics and hypostatic for Th2 (M2) genetics?
And why would a maJic herb be so critical?
Is it only in the context of the thing and not critiCOW?
OMG where did LARRY Kudlow go? Michelle Caruso-Cabrera is doing his
show
today....and just said that obama is taking credit for the UP markets.
So they are going uP?
What does dougie kass think?
http://www.google.com/search?hl=en&q=doug%20kass%20seabreeze&um=1&ie=UTF-8&tbo=u&tbs=nws:1&source=og&sa=N&tab=wn
-----------
Back to fat backs and pork driPPings?
Right..
Without a cure why bother to stick your finger in the dike?
http://www.cartoonstock.com/lowres/vsh1064l.jpg
http://goldtent.net/wp_gold/wp-content/uploads/2009/02/finger-in-dike.jpg
Hey... i feel like that guy with his finger in the dike...<w>
------------
Which is Th- 1 and 2 in this polygenetical hyPotetical quandary?
http://upload.wikimedia.org/wikipedia/commons/c/c3/MHC_I_vs_MHC_II.png
http://en.wikipedia.org/wiki/Major_histocompatibility_complex#MHC_Class-II
http://en.wikipedia.org/wiki/KIR2DL1
http://www.ncbi.nlm.nih.gov/gene/3802
Agrawal is on it:
PMID: 16283405
http://www.ncbi.nlm.nih.gov/pubmed/16283405
[...] recurrent spontaneous abortion (RSA) and psoriasis vulgaris
(PV).
And KIRs and recurrent miscarriages HLA-C
http://www.ncbi.nlm.nih.gov/pubmed/21159685
pmid: 21159685
KIRs derailing in to autoimmunity
http://www.ncbi.nlm.nih.gov/pubmed/20722764
pmid: 20722764
56 hits - Killer immunoglobulin-like receptors autoimmun* - pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=Killer+immunoglobulin-like+receptors+autoimmun*
http://www.ncbi.nlm.nih.gov/pubmed/18635379
The Yin and Yang of HLA and KIR in human disease.
Kulkarni S, Martin MP, Carrington M.
Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Abstract
Killer cell immunoglobulin-like receptors (KIR) are expressed on
natural killer (NK) cells and subsets of T cells. The KIR genes are
polymorphic and the KIR gene complex is polygenic with varying numbers
of inhibitory and activating receptors. HLA class I molecules serve as
ligands for the KIR. Interactions of the independently segregating KIR
and HLA loci are important for recognition of targets by NK cells as
well as NK cell 'licensing'. Several disease association studies
indicate a role for interactions between these loci in infectious
diseases, autoimmune/inflammatory disorders, cancer and reproduction.
Emerging functional data supports a mechanism based on a continuum of
inhibition to activation through various compound KIR-HLA genotypes in
diseases.
PMID: 18635379
Wasn't there kirs in the eraP1 gwas?
IIRC yes? Or i guess:
http://www.ncbi.nlm.nih.gov/pubmed/20953190
pmid: 20953190
Where is it? LoL
Best read the FULL text on that one? If it's available nit wit.
==================
Do fatty things do things?
Bind or something.
I thought my IL-10 was LOW so it made sense?
http://en.wikipedia.org/wiki/Fatty_acid-binding_protein
The fatty-acid-binding proteins (FABPs) are a family of carrier
proteins for fatty acids and other lipophilic substances such as
eicosanoids and retinoids.[1] These proteins are thought to facilitate
the transfer of fatty acids between extra- and intracellular membranes.
[2] Some family members are also believed to transport lipophilic
molecules from outer cell membrane to certain intracellular receptors
such as PPAR.[3]
http://en.wikipedia.org/wiki/Adipocyte_protein_2
aP2 (adipocyte Protein 2)[1] is a carrier protein for fatty acids that
is primarily expressed in adipocytes and macrophages. aP2 is also
called fatty acid binding protein 4 (FABP4). Blocking this protein
either through genetic engineering or drugs[2][3] has the possibility
of treating heart disease,[4] diabetes,[5] asthma,[6] obesity,[7] and
fatty liver disease.
====================
Block the craP of psor not a good idea for IBD?
Is it a raPtiva thing?
PML.. yikes..
http://www.ncbi.nlm.nih.gov/pubmed/21170755
Dig Dis Sci. 2010 Dec 19.
Efalizumab, a Human Monoclonal Anti-CD11a Antibody, in the Treatment
of Moderate to Severe Crohn's Disease: An Open-Label Pilot Study.
James DG, Seo DH, Chen J, Vemulapalli C, Stone CD.
Division of Gastroenterology, Washington University School of
Medicine, Saint Louis, MO, USA.
Abstract
BACKGROUND AND AIMS: Efalizumab is a monoclonal antibody targeting
CD11a, an adhesion molecule involved in the activation and trafficking
of T-lymphocytes. This agent has proven efficacy in the treatment of
psoriasis. We performed an open-label study to evaluate the efficacy
and safety of efalizumab in Crohn's disease (CD).
METHODS: Fifteen subjects with moderate to severe CD (Crohn's Disease
Activity Index [CDAI] score 220-450) and who were refractory or
intolerant to standard therapy, received a weekly 1 mg/kg subcutaneous
injection of efalizumab for 8 weeks. The primary endpoint was clinical
response (decrease in the CDAI score of at least 70 points) at week 8.
Secondary endpoints included change in mean CDAI scores, the
proportion of subjects who achieved clinical remission (CDAI score ≤
150), change in the Inflammatory Bowel Disease Questionnaire (IBDQ)
scores, and report of adverse events.
RESULTS: At 8 weeks, ten (67%) subjects had clinical response and six
(40%) were in remission. The mean baseline and week 8 CDAI scores were
300 and 167 respectively (P < 0.001). Mean IBDQ scores at baseline and
week 8 were 124 and 168 respectively (P < 0.001). One subject with
Crohn's colitis had pre- and post-treatment colonoscopy that
demonstrated mucosal healing. No serious adverse events occurred.
CONCLUSIONS: Efalizumab induced a clinical response in the majority of
subjects with moderate to severe CD in this small, open-label pilot
study. There were no serious adverse events reported during this short-
term trial.
PMID: 21170755
If simPly blocking TNF was the IDEAL deal then we'd all have a
wonderful christmas.
Block me:
http://en.wikipedia.org/wiki/File:TNF_signaling.jpg
But even CANCER isn't giving up it's secrets.
Must be NO thing. See last post. <w>
Check dorkOHknowledge purview?
============================
What is the state of knowing GENEs?
http://www.technologyreview.com/article/26943/?mod=chthumb
A Decade of Genomics
On the 10th anniversary of the Human Genome Project, we ask: where are
the therapies?
January/February 2011 By Jason Pontin
The Human Genome Project, whose results were announced in June of 2000
and published in full 10 years ago, took 13 years and $3 billion to
complete. For biology, it was unprecedented in scale: it determined
the sequence of three billion units, or base pairs, of human DNA. What
life scientists wanted from the project was equally ambitious: they
hoped sequencing our DNA would reveal the genetic causes of disease
and lead to diagnoses, treatments, and cures for intractable illnesses
like many forms of cancer.
In this issue of Technology Review, we explore what happened to those
hopes.
Over the last 10 years, many advances in genomics have been made. As
Jon Cohen explains in the introduction to our package of stories on
the topic, "The price of sequencing DNA has dropped ... to mere
thousands [of dollars per person]. The number of single-gene
aberrations known to cause disease ... has jumped from 100 to nearly
3,000. The growing list of common diseases that have been traced to
multiple genetic variants includes everything from types of blindness
to autoimmune diseases and metabolic disorders like diabetes. Studies
have linked more than 200 genes to cancer."
But taken as a whole, it was a long, hard decade for genomics.
Researchers and clinicians will disagree about how quickly they
imagined the Human Genome Project would bear fruit, but no one will
contest that the genome has turned out to be bafflingly complex and
that genomic information has yielded few new cures. Cohen describes
some of the difficulties in his introduction, and Stephen Hall
provides more detail in "The Genome's Dark Matter": "Large-scale
genomic studies ... have mainly failed to turn up common genes that
play a major role in complex human maladies. More than three dozen
specific genetic variants have been associated with type 2
diabetes ... but together they have been found to explain about 10
percent of the disease's heritability ... Results have been similar
for heart disease, schizophrenia, high blood pressure, and other
common maladies."
In short, we have expended enormous energy on searching for disease
genes, but it has become clearer that a variety of other factors, once
thought minor, are in fact as important to our health as genes
themselves. These include how much or how little of a protein is
produced (gene expression); the degree to which gene expression can be
influenced by mechanisms other than changes in the underlying DNA
sequence (dubbed "epigenetics," because the field studies mechanisms
above—"epi"—the genome); and whether we have extra or missing copies
of genes (copy-number variation).
This "missing heritability" problem—the fact that individual genes
cannot account for much of a disease's heritability—has significant
implications for medicine. It turns out (as Hall explains) that "a
person's susceptibility to disease may depend more on the combined
effect of all the genes in the background than on the disease genes in
the foreground." Therefore, mapping this complex nest of genetic
relationships offers the best hope for turning genomics into therapies
or cures.
Consider cancer. In "Cancer's Genome" Emily Singer, Technology
Review's biomedicine editor, describes how research has proved that
cancer genomics are "even more complicated than scientists had
supposed." We now understand that five to as many as 20 mutations are
needed to trigger cancer's cellular proliferation. But cheaper, faster
sequencing technologies may, in the not-too-distant future, make
personalized cancer medicine a real possibility. Singer reports on
Foundation Medicine in Cambridge, Massachusetts, which wants to create
clinical tests that reveal which mutations have caused a patient's
particular cancer, how severe that cancer is, and what drugs will
affect it. According to Singer, early results from Foundation "suggest
that about half the patient tissue samples analyzed would yield
plausibly 'usable' information, meaning that the analysis might
suggest a particular class of drugs or better define the type of
cancer." If readers are looking for hope that genomics can lead to
cures for intractable diseases, companies like this are appropriate
inspiration.
In Cohen's introduction, Eric Lander, who was one of the leaders of
the Human Genome Project and now directs the Broad Institute (and who
is also a founder of Foundation Medicine), says we should not be
surprised that the genome is so complicated. He counsels a
historically informed patience as we work on new genomic medicines:
after all, 60 years passed between the development of germ theory and
the creation of antibiotics. Genomics is harder. Lander asks, "How
simple did you think it would be?"
<snip>
His mother should have named him osteo... then he'd be osteo pontin?
Or given him that as his middle name. James osteo pontin?
Spend another $30 billion?
Merry XMAS... santa US tax payer.
But SANTA... there is a magic DNA and magic HERB.
Is it real MAjIC
Here. SMOKE this BUD.
Why? i cry or do and die and i'd rather have a CAB. LOL
Did JaY want to cure his condition with a glass of CAB?
Or a curcumin side dish?
==========================
Turn off the spigot you bigot?
Duh... ok.. where is it?
Don't BE such a cARD, dork WAD.
Oh K...
http://www.sify.com/news/scientists-identify-new-infection-fighting-officer-news-international-kmknElehdgd.html
Scientists identify new 'infection fighting officer'
[...]Faced with infection, the body's white blood cells are commanded
by a protein - CARD11 - to either make more antibodies and white blood
cells that attack the invader or to stand down and abort the mission.
The new research shows that CARD11 is under the control of GAKIN,
another protein that supervises the directives given to each white
blood cell.
Because of CARD11's importance in the decision-making process, it
needs a regulator to make sure it turns off when it's no longer needed
to avoid the risk of hyperactivity.
If too many T or B cells, particular types of white blood cells, are
made or sent to battle infection, the consequences can be cancer or
autoimmune disease, said Pomerantz.
The discovery of GAKIN's role in immune cell activation began when
researchers attached the gene that codes for luciferase - a natural
protein that makes fireflies glow - to a gene that CARD11 turns on in
response to an infection.
This allowed them to see when a CARD11-responsive gene was turned on
by measuring the amount of light released from the cells. Pomerantz's
group discovered that the more GAKIN protein they added to the cells,
the less the cells glowed, meaning that GAKIN represses these genes'
activation.
<sniP>
http://www.ncbi.nlm.nih.gov/pubmed/21145487
Mol Cell. 2010 Dec 10;40(5):798-809.
The Dynamic Distribution of CARD11 at the Immunological Synapse Is
Regulated by the Inhibitory Kinesin GAKIN.
Lamason RL, Kupfer A, Pomerantz JL.
Department of Biological Chemistry, The Johns Hopkins University
School of Medicine, Baltimore, MD 21205, USA; Institute for Cell
Engineering, The Johns Hopkins University School of Medicine,
Baltimore, MD 21205, USA.
Abstract
T cell receptor (TCR) signaling to NF-κB is required for antigen-
induced T cell activation. We conducted an expression-cloning screen
for modifiers of CARD11, a critical adaptor in antigen receptor
signaling, and identified the kinesin-3 family member GAKIN as a
CARD11 inhibitor. GAKIN negatively regulates TCR signaling to NF-κB,
associates with CARD11 in a signal-dependent manner and can compete
with the required signaling protein, Bcl10, for association. In
addition, GAKIN dynamically localizes to the immunological synapse and
regulates the redistribution of CARD11 from the central region of the
synapse to a distal region. We propose that CARD11 scaffold function
and occupancy at the center of the synapse are negatively regulated by
GAKIN to tune the output of antigen-receptor signaling.
2010 Elsevier Inc. All rights reserved.
PMID: 21145487
I tried raking the gakin but will card it instead:
http://en.wikipedia.org/wiki/CARD11
Symbols CARD11; BIMP3; CARMA1; MGC133069
Caspase recruitment domain-containing protein 11 also known as CARD-
containing MAGUK protein 1 (Carma 1) is a protein that in humans is
encoded by the CARD11 gene.
Function
The protein encoded by this gene belongs to the membrane-associated
guanylate kinase (MAGUK) family, a class of proteins that functions as
molecular scaffolds for the assembly of multiprotein complexes at
specialized regions of the plasma membrane. This protein is also a
member of the CARD protein family, which is defined by carrying a
characteristic caspase-associated recruitment domain (CARD). This
protein has a domain structure similar to that of CARD14 protein. The
CARD domains of both proteins have been shown to specifically interact
with BCL10, a protein known to function as a positive regulator of
cell apoptosis and NF-κB activation. When expressed in cells, this
protein activated NF-kappaB and induced the phosphorylation of BCL10.
<snip>
BCL10
http://en.wikipedia.org/wiki/BCL10
Symbols BCL10; CARMEN; CIPER; CLAP; c-E10; mE10
B-cell lymphoma/leukemia 10 is a protein that in humans is encoded by
the BCL10 gene.[1][2]
This gene was identified by its translocation in a case of mucosa-
associated lymphoid tissue (MALT) lymphoma. The protein encoded by
this gene contains a caspase recruitment domain (CARD), and has been
shown to induce apoptosis and to activate NF-kappaB. This protein is
reported to interact with other CARD domain containing proteins
including CARD9, 10, 11 and 14, which are thought to function as
upstream regulators in NF-kappaB signaling. This protein is found to
form a complex with MALT1, a protein encoded by another gene known to
be translocated in MALT lymphoma. MALT1 and this protein are thought
to synergize in the activation of NF-kappaB, and the deregulation of
either of them may contribute to the same pathogenetic process that
leads to the malignancy
Interactions
BCL10 has been shown to interact with CARD10,[3] CARD11,[4] MALT1,[5]
TRAF2,[6] IKBKG[7] and CARD9.[
<snip>
Don't mAbs nail TRAF's?
Yes... we run traf2 we surely DO.
http://en.wikipedia.org/wiki/TRAF2
Symbols TRAF2; TRAP; MGC:45012; TRAP3
TNF receptor-associated factor 2 is a protein that in humans is
encoded by the TRAF2 gene.[1]
The protein encoded by this gene is a member of the TNF receptor
associated factor (TRAF) protein family. TRAF proteins associate with,
and mediate the signal transduction from members of the TNF receptor
superfamily. This protein directly interacts with TNF receptors, and
forms complexes with other TRAF proteins. TRAF2 is required for TNF-
alpha-mediated activation of MAPK8/JNK and NF-kappaB. The protein
complex formed by TRAF2 and TRAF1 interacts with the IAP family
members cIAP1 and cIAP2, and functions as a mediator of the anti-
apoptotic signals from TNF receptors. The interaction of this protein
with TRADD, a TNF receptor associated apoptotic signal transducer,
ensures the recruitment of IAPs for the direct inhibition of caspase
activation. cIAP1 can unbiquitinate and induce the degradation of this
protein, and thus potentiate TNF-induced apoptosis. Multiple
alternatively spliced transcript variants have been found for this
gene, but the biological validity of only one transcript has been
determined.[2]
TRAF2 has been shown to interact with BCL10,[3] CD30,[4][5] CFLAR,[6]
[7] IKK2,[8][9] MAP3K7IP2,[10][9] CD137,[11][12] Caveolin 1,[13][14]
CD27,[15][16] TNFRSF13B,[17] TANK-binding kinase 1,[18][19] TRAF1,[18]
[20] CD40,[21][22][23] UBE2N,[24] MAP3K14,[25][23] MAP4K2,[26]
CASP8AP2,[27] HIVEP3,[28] TNFAIP3,[29] TNFRSF1B,[18][1][20][30][31][32]
[33] TNFRSF1A,[34][35][36] SPHK1,[37] Low affinity nerve growth factor
receptor,[38] TNFRSF14,[39][32] CHUK,[40][8][9] CD134,[12] EDARADD,
[41] RIPK1,[20][42][34][23] RANK,[43][44][45][46] TNFSF14,[47] TANK,
[18][31][48][49] Baculoviral IAP repeat-containing protein 3,[50][51]
[3][52] BIRC2,[53][50][51][36][3][52] MAP4K5,[54] ASK1,[55][56][57]
TRADD,[18][20][58][59][42][35][23] MAP3K1[60] and TRAF interacting
protein.[61]
<sniP>
And surely this ALL begins in the Malt, galt and it's YOUR fault?
http://en.wikipedia.org/wiki/Mucosa-associated_lymphoid_tissue
The mucosa-associated lymphoid tissue (MALT) (also called mucosa-
associated lymphatic tissue) is the diffuse system of small
concentrations of lymphoid tissue found in various sites of the body
such as the gastrointestinal tract, thyroid, breast, lung, salivary
glands, eye, and skin.
MALT is populated by lymphocytes such as T cells and B cells, as well
as plasma cells and macrophages, each of which is well situated to
encounter antigens passing through the mucosal epithelium. In the case
of intestinal MALT, M cells are also present, which sample antigen
from the lumen and deliver it to the lymphoid tissue.
Components
The components of MALT are sometimes subdivided into the following:
GALT (gut-associated lymphoid tissue. Peyer's patches are a component
of GALT found in the lining of the small intestines.)
BALT (bronchus-associated lymphoid tissue)
NALT (nose-associated lymphoid tissue)
LALT (larynx-associated lymphoid tissue)
SALT (skin-associated lymphoid tissue)
VALT (vascular-associated lymphoid tissue. A newly recognized entity
that exists inside arteries; its role in the immune response is
unknown.)
CALT (conjunctiva-associated lymphoid tissue in the human eye)
Role in disease
MALT plays a role in regulating mucosal immunity. It may be the site
of lymphoma, usually non-Hodgkin lymphoma. A specific entity is the
MALT lymphoma linked to Helicobacter pylori in the stomach.
-------------------
http://www.ncbi.nlm.nih.gov/pubmed/21166663
Br J Dermatol. 2010 Dec 16. doi: 10.1111/j.1365-2133.2010.10192.x.
Abnormality of RUNX1 signal transduction in psoriatic CD34(+) bone
marrow cells.
Yin G, Li J, Wan Y, Hou R, Li X, Zhang J, Cheng T, Zhang K.
Department of Dermatology Internal Medicine, Taiyuan Center Hospital,
Affiliated to Shanxi Medical University, 1 Dong San Dao Xiang, Taiyuan
030009, Shanxi Province, China.
Abstract
Background: Although it has been shown that T cell dysfunction in
psoriasis correlates with various endogenous and exogeneous stimuli,
there are also intensive and complicated genetic background effects
indicating that intrinsic abnormalities may play a more predominant
role such as hematopoietic cells, hemopoietic microenvironment,
development of hematopoietic cells into T cells. Objective: To reveal
the activity of hematopoietic stem cells from psoriasis patients.
Methods: Bone marrow CD34(+) cells were isolated, then the
expressions were tested by RT-PCR and western-bolt. The binding site
for RUNX1 located between SLC9A3R1 and NAT9 as well as the apoptotic
index of CD34(+) cells were tested. Results: We found that expression
of RUNX1, SLC9A3R1, HLA-C, PKC-β I mRNA and RUNX1 protein in psoriasis
was significantly higher than controls, and SLC9A3R1 expression showed
a significant positive correlation with the PASI score. There was no
statistical significance for PDCD1 mRNA and PKC-β I protein expression
levels between the psoriasis and controls. Mutation of RUNX1 binding
sites between SLC9A3R1 and NAT9 was not detected, and the apoptotic
index of psoriasis showed no statistical significance compared with
controls. Conclusion: Expression of the critical transcription factor
RUNX1, which regulates CD34(+) cell development and differentiation,
was abnormal, and augmentation of these expression levels might induce
dysfunction of marrow hematopoietic stem cells and the hematopoietic
microenvironment and be involved in the progression of psoriasis.
2010 British Association of Dermatologists.
PMID: 21166663
The BRiTs rule.
Duh, why?
Down boy, down.... get that psor DOWN.
How kemo sabe?
RNA epigenetic wizZarlness?
http://www.ncbi.nlm.nih.gov/pubmed/21166662
Br J Dermatol. 2010 Dec 16. doi: 10.1111/j.1365-2133.2010.10191.x.
SiRNAs targeted at anti apoptotic mRNAs increase keratinocytes
sensitivity to apoptosis.
Lerman G, Volmana E, Sidi Y, Avni D.
Laboratory of Molecular Cell Biology, Center for Cancer Research. and
Department of Medicine C, Sheba Medical Center, Tel Hashomer, Israel
52621. Sackler School of Medicine, Tel Aviv University, Israel.
Abstract
Gene silencing RNAi technology concentrates on down regulation of gene
expression using specific double-stranded RNA molecules (siRNA), which
induce the degradation of complementary mRNA. SiRNAs therapeutics is
currently being tested in several clinical trials. The primary
essential step in the development of such therapeutics is the proof of
the validity of specific genes as useful targets. Another major
obstacle is the efficiency of selective delivery of siRNAs to cells.
Skin disorders are an attractive target for the application of siRNA
based technology due to the ability to apply effective agents by
topical application. In several inflammatory skin disorders the
barrier function of the skin is markedly impaired, thus it may
increase the delivery efficiency. Psoriasis is a very common skin
disorder. The characteristics of this disorder are abnormal
keratinocytes (KC) proliferation along with inflammation. KC from
psoriatic epidermis express much higher levels of the anti apoptotic
protein, Bcl-xL, as compared to normal KC. IGF-IR play a major role in
cell growth, differentiation and apoptosis in many cell types,
including KC. IGF-IR activation plays an important role in the
pathogenesis of psoriasis. KC from psoriatic patients are more
susceptible to IGF-1 stimulated proliferation as compared to normal
KC. IGF-1R is expressed by the proliferating basal and suprabasal KC
and is more abundant in psoriatic lesions. In the present manuscript
we were able to deliver efficiently siRNA targeting Bcl-xL or IGF-1R
to primary human KC cultures. We also showed that siRNAs targeting Bcl-
xL and IGF-1R induce growth inhibition, apoptosis and increased
sensitivity to UVB in KC. The present findings demonstrate that Bcl-xL
and IGF-1R are valid important targets to siRNA based technology
directed at the suppression of KC hyper proliferation.
2010 British Association of Dermatologists.
PMID: 21166662
=========================
What if you LIvE in Dorkville?
So? What?
Beingness is simple regardless unless there is NO THERE there.
And then your NOT being anyway. LOL
Just wait beingness will return and you won't notice 65 billion years
you've slePt.?
OK so what about iceland? LOL
Bummer. Late onset and the winter of your discontent?
-----
http://www.eurekalert.org/pub_releases/2010-12/jaaj-fot121610.php
Features of the metabolic syndrome common in persons with psoriasis
Individuals with psoriasis have a high prevalence of the metabolic
syndrome, according to a report posted online today that will appear
in the April 2011 print issue of Archives of Dermatology, one of the
JAMA/Archives journals.
According to background information in the article, individual
features of the metabolic syndrome include obesity, high blood
pressure, diabetes and high total cholesterol and triglycerides.
Additional background information notes that while past studies have
suggested a link between psoriasis and individual components of the
metabolic syndrome, there is little data available regarding the
association between psoriasis and the metabolic syndrome as a whole.
Using data from the National Health and Nutrition Examination Survey,
Thorvardur Jon Love, M.D., of Landspitali University Hospital,
Reykjavik, Iceland, and colleagues, examined the association between
psoriasis and the metabolic syndrome. The study included 6,549
individuals, and the mean (average) age of participants was 39, half
were men and the mean body mass index (BMI) was 28.
Overall, 40 percent of individuals with psoriasis also had features of
the metabolic syndrome, compared with 23 percent among controls. The
most common feature of the metabolic syndrome among individuals with
psoriasis was abdominal obesity (63 percent), followed by high
triglyceride levels (44 percent) and low levels of high-density
lipoprotein (HDL) or "good" cholesterol (34 percent). High
triglyceride levels are defined as at or above 150 milligrams per
deciliter, and low HDL levels are defined as less than 40 milligrams
per deciliter in men and less than 50 milligrams per deciliter in
women. No elements of the metabolic syndrome were found in 28 percent
of individuals without psoriasis compared with 13 percent of those
with psoriasis.
"In conclusion, these findings from a nationally representative sample
of U.S. adults show a doubling in the prevalence of the metabolic
syndrome among patients with psoriasis independent of age, sex, race/
ethnicity and C-reactive protein levels," the authors write.
"Given its associated serious complications, this comorbidity needs to
be recognized and taken into account when treating individuals with
psoriasis," they conclude.
###
(Arch Dermatol. Published online December 20, 2010. doi:10.1001/
archdermatol.2010.370. Available pre-embargo to the media at www.jamamedia.org.)
Editor's Note: This study was supported in part by grants from the
National Institute of Health, the Psoriasis Foundation and the
National Heart, Lung, and Blood Institute. Please see the article for
additional information, including other authors, author contributions
and affiliations, financial disclosures, funding and support, etc.
========================================
http://www.vrp.com/immune-system/immune-support-for-when-your-defenses-are-down?utm_content=article3104&utm_source=hn20101221
Immune Support for When Your Defenses Are Down
by VRP Staff
If you’re like most people, your restful nights, nutritious diet and
daily relaxation time have been replaced with holiday mayhem—and all
its cocktail parties, eggnog and crowded malls—for weeks now. Your
immune system is likely to suffer with all the added stress. So unless
you want to ring in the New Year with a bottle of cough syrup, your
immune system may need temporary support to get you through the season
with health on your side.
Fortunately, immune support isn’t so hard to find—in fact, research
shows that the right blend of botanicals can help to fight off a
stuffy nose or a scratchy throat by harnessing your body’s own natural
defenses.
For example, research shows that Forsythia suspense can balance the
numbers of inflammatory cells during aggressive immune responses,
thereby helping to maintain healthy, clear sinuses.1 Similarly,
studies indicate that constituents of Lonicera japonicas can promote
healthy inflammatory responses by inhibiting pro-inflammatory enzymes,
which can become overly active as the immune system upregulates its
response to various challenges and stressors.2-3
Glycyrrhizae uralensis, on the other hand, has been shown to increase
your body’s population of splenocytes, white blood cells that bolster
immune health and increase production of beneficial immune compounds.4
Meanwhile, Phragmites communis supports the health of your spleen and
thymus, both of which play critical roles in your immune system, and
Platycodon grandiflorum activates B-lymphocytes and macrophages, a
class of immune cells that are involved in the normal immune process
called phagocytosis, which facilitates the healthy deactivation and
removal of immune stressors.5-7
Several other botanicals also promote respiratory health, including
components of Arctium lappa, which animal studies show can strengthen
the lungs.8 The mint-derived extract Mentha arvensis has similar
benefits, with research indicating that it balances the histamine
response—a substance that triggers difficult breathing and congestion—
from mast cells.9-10
Vitamins and minerals play an equally essential role in the fight
against phlegm—in particular, the essential mineral zinc, which helps
to increase your body’s number of natural killer (NK) cells.11 Low
zinc levels, however, may increase your susceptibility to year-round
health challenges—as do deficiencies of vitamin A, which can impede
the regeneration of damaged mucosal barriers and diminish the immune
functions of a number of white blood cells, including macrophages,
neutrophils and NK cells.12
That’s why ample intake of both zinc and vitamin A is crucial—along
with an abundant supply of vitamin C. Concentrations of this
antioxidant vitamin dip during times of illness or stress, but
supplementation can support all facets of your immune system, from
production of beneficial immune factors to increased NK cell activity.
Research shows that vitamin C in combination with zinc supports
respiratory health and is able to support increased immune resistance
and well being.13
Ultimately, even if you keep your body primed and your immune system
in tip-top shape, sometimes additional, short-term immune support is
needed. Time-tested, multi-pronged nutritional support can be used at
the first sign you need to build up your natural defenses—and it’s
with this strategy in mind that Vitamin Research Products created Fast
Response®, a formula that synergistically combines all of the
nutrients and botanicals described above to produce unparalleled, all-
natural, short-term immune support. Ultimately, it’s like sending in
more troops even when you’re winning the battle, helping your immune
system work at its optimal best.
References:
<snip>
-----------
Resveratrol - cardio effects- et al:
http://www.vrp.com/heart-health/slow-your-bodys-clock-with-a-single-natural-compound?utm_content=article3103&utm_source=hn20101221
-----------
The "Calcium Lie" Every Woman Should Know About Posted By Dr. Mercola
| December 21 2010 | 85,064 views
http://articles.mercola.com/sites/articles/archive/2010/12/21/osteoporosis-prevention-and-treatments-exposed.aspx
[...] The Truth about Osteoporosis and Calcium Deficiency
I'm sure you've heard that the cause of osteoporosis and the key to
its prevention revolve around calcium, right?
Unfortunately, nothing could be further from the truth.
Dr. Robert Thompson, M.D., wrote an entire book on this subject
called, The Calcium Lie, which explains that bone is comprised of at
least a dozen minerals and the exclusive focus on calcium
supplementation is likely to worsen bone density and increase your
risk of developing osteoporosis!
< calcium lie: http://www.amazon.com/exec/obidos/ASIN/0981581854/optimalwellnessc
>
As mentioned in this previous article, Dr. Thompson recommends the use
of unprocessed salt as a far healthier alternative to calcium
supplementation.
I recommend using Himalayan salt as it is an excellent way to feed
your body the trace minerals it needs to function optimally.
Why Sally Field Could be Setting Herself Up for Osteoporosis with
Boniva
<snip>
[...] Steer Clear of Steroids
According to a study done at Washington University School of Medicine
in St. Louis, there is a strong link between osteoporosis and the use
of steroids:
http://news.wustl.edu/news/Pages/7424.aspx
"High-dose cortisone is the second most common cause of osteoporosis,
and we currently have no real treatment for this serious side effect,"
says senior author Steven L. Teitelbaum, M.D., Messing Professor of
Pathology and Immunology.
"Given how frequently these drugs are used to treat many different
conditions, that's a major clinical problem."
The conclusion of the study revealed that although the steroid
cortisone appears to inhibit the ability of osteoclasts to dismantle
old bones in genetically normal mice, the inability of the skeletal
structure to renew itself may cause bones to weaken dramatically from
aging and stress.
If you suffer from an autoimmune disease such as rheumatoid arthritis,
asthma, multiple sclerosis or chronic obstructive pulmonary disease,
click on the links above for natural alternatives for healing.
On the other hand there is one steroid hormone that will likely help
build bone and that is progesterone. Many pre and post menopausal
women are deficient in this important hormone.
<snip>
[...] Other Foods that Lead to Bone Loss
Processed and fast foods are the worst stuff you can put into your
body. In order for your body to function optimally, it needs the type
of balanced diet that I suggest in the next section.
Processed foods such as potato chips, french fries, microwaveable
"meals", soda and candy contain very little nutrients and are chock
full of undigestible fats and dangerous additives such as high
fructose corn syrup, aspartame and preservatives.
If you think switching from a mainly processed food diet to a healthy,
nutritious one will be next to impossible, I'm here to tell you it's
easier than you think. In my previous article, I explain how to wean
yourself off processed foods in 7 easy steps and how to give your body
what it's really craving.
When cooking, I advise you to avoid most all omega-6 based oils such
as corn, safflower or soy oil. These oils are loaded with highly
processed, damaged omega 6 fats, which contribute to inflammation in
your body.
Instead, I recommend using healthful olive- and coconut oils. For more
information, see my video on the health benefits of these oils.
http://articles.mercola.com/sites/articles/archive/2003/10/15/cooking-oil.aspx
http://products.mercola.com/coconut-oil/
<sniP>
--------------
Your INDEX finger ratio and health?
http://articles.mercola.com/sites/articles/archive/2010/12/21/what-the-length-of-your-index-finger-says-about-you.aspx
http://www.amazon.com/exec/obidos/ASIN/081353030X/optimalwellnessc
http://articles.mercola.com/sites/articles/archive/2010/01/23/Why-Your-DNA-Isnt-Your-Destiny-.aspx
http://articles.mercola.com/sites/articles/archive/2010/05/20/epigenetics-offers-new-approaches-to-degenerative-disease.aspx
[...] The new field of epigenetics has shown that the choice of which
of your genes are "expressed," or activated, is strongly affected by
environmental influences.
It is actually the cell's membrane -- operating in response to
environmental signals picked up by the membrane's receptors -- that
control the "reading" of the genes inside. And your actions, lifestyle
and even your thoughts make up these "environmental signals."
In other words, no matter what hand (or finger length) you were dealt
at birth, you can take steps to "activate" the disease-busting, health-
boosting genes and suppress those that will cause you harm. This is
evidenced perhaps most clearly by identical twins, who start out with
the exact same genetic code … but end up very different.
Epigenetic "malleability" helps to explain why identical twins become
distinct as they age. As you age, your genome does not change but your
epigenome changes dramatically, especially during critical periods of
life, such as adolescence. It is influenced by physical and emotional
stresses -- how you respond to everything that happens in your
environment, from climate change to childhood abuse.
You do not manifest disease merely by a defective gene, but by your
epigenome. Epigenetic therapy, which is essentially the curing of
disease by epigenetic manipulation, involves changing the instructions
to your cells -- reactivating desirable genes and deactivating
undesirable ones. This emerging field, now in its infancy, may
represent the future of medicine.
You can begin to do this on your own, long before you manifest a
disease, by encouraging your genes to express positive, disease-
fighting behaviors in the first place by leading a healthy lifestyle.
To get started, please read through my comprehensive nutrition plan,
which will give you tips and tools for eating healthy, dealing with
stress and living a lifestyle that will support your epigenetic
health, regardless of whether you were born with a high or low 2D-4D
ratio.
http://www.mercola.com/nutritionplan/index.htm
http://articles.mercola.com/sites/articles/archive/2010/01/23/Why-Your-DNA-Isnt-Your-Destiny-.aspx
<snip>
======================
http://www.wellnessresources.com/weight/articles/quercetin_helps_correct_fatty_liver_and_poor_metabolism/
Quercetin Helps Correct Fatty Liver and Poor Metabolism
Saturday, December 18, 2010 - Byron Richards, CCN
A new animal study with quercetin shows that the nutrient can help
undo damage caused by a high fat, high cholesterol, and high sugar
diet. Not only was fatty liver accumulation reversed, but many factors
involved with metabolism were improved including inflammation status,
insulin resistance, and problems with lipids (cholesterol and
triglycerides).
The accumulation of fat in your liver is a major health turning point
in the wrong direction. It correlates directly with your waistline
expanding. It means your liver, which is the brain of your body, has
become clogged with fatty sludge. This sets the stage for fat to
accumulate in all the wrong places all around your body, which is
never a good thing.
In the experiment, mice were fed the standard junk food Western diet
for 20 weeks at which point they were well on their way to serious
metabolic disease, including fatty liver build up. After 8 weeks on
quercetin their livers began to clear out and after 20 weeks they were
much better. Improvement included a boosting of the vital adiponectin
the prevents insulin resistance, turning off of the gene signals that
were laying down excess fat in the liver, and a restoration of the
antioxidant/anti-inflammatory defense system that is so often
compromised in situations of poor metabolic health.
<snip>
=====================
I love melatonin, Even MORE SO in COMBO with 5HTP (5-HTP):
http://www.wellnessresources.com/health/articles/anti-aging_effect_of_melatonin/
Anti-Aging Effect of Melatonin
Friday, December 17, 2010 - Byron Richards, CCN
The ability to tolerate inflammation, in whatever form, is a key to
healthy aging. A new study shows that melatonin can restore the
ability of important cell components to withstand the effects of
inflammatory stress. This is a distinct anti-aging effect on cells.
Since natural melatonin production declines with age, and is lower in
many people in the winter, it is an important nutrient to keep in mind
as part of your natural anti-aging team.
Endoplasmic reticulum is a functional sac-like network within your
cells that is responsible for assembling proteins and fats into
structures your cells can use as well as providing structural parts
for receptors on the surface of your cells. It does all of this
construction/ remodeling work in response to the demands placed on the
cell. If it can’t keep up then your cells die. During aging,
endoplasmic reticulum are not as efficient as when you were younger
and are thus more sensitive to stress of any type, meaning that once
they are overwhelmed and can’t make enough structural components for
your cells to keep on going then the cells die.
A new study shows that melatonin is able to correct many of the age-
associated malfunctions that stress induces in immune cells from older
people. In fact, whether cells are from a person who is young or old,
melatonin is highly protective against stress inducing cell death due
to overwhelm of the cellular repair and rejuvenation machinery known
as the endoplasmic reticulum.
Many studies support melatonin’s role in fostering a more rhythmic and
healthier immune response. Of course, melatonin is best known for its
role in helping prevent winter mood issues, which are aggravated as
the days become shorter and the temperature drops. Melatonin
production tends to decline about 0.5 mg per day every decade after
the age of 30. Thus, a dose of 0.5 – 2.0 mg may be relevant for many
as an anti-stress and anti-aging approach. Others may wish to use
higher doses of melatonin, especially if it helps them sleep better.
<snip>
===============
Olive Leaf Extract May Help Gout
http://www.wellnessresources.com/health/articles/olive_leaf_extract_may_help_gout/
------------
Is Excessive Sugar Intake Leading to Society-Wide Mental Illness? -
http://www.wellnessresources.com/health/articles/is_excessive_sugar_intake_leading_to_society-wide_mental_illness/
-------------
And i love iodine and NAC and 5htp and me me meism.
Why not?
Love you and others might as well also? LOL
================
http://www.ncbi.nlm.nih.gov/pubmed/21165208
Ann Dermatol. 2010 Nov;22(4):397-403. Epub 2010 Nov 5.
Role of CD4CD25FOXP3 Regulatory T Cells in Psoriasis.
Yun WJ, Lee DW, Chang SE, Yoon GS, Huh JR, Won CH, Lee MW, Kim SE, Kim
BJ, Moon KC, Choi JH.
Cleanup Dermatology Clinic, Seoul, Korea.
Abstract
BACKGROUND: CD4(+)CD25(high+)regulatory T cells (Tregs) are considered
to be of vital importance for maintaining immunologic self-tolerance
and preventing autoimmune diseases. These cells have been found to be
deficient in skin lesions and in the peripheral blood of patients with
psoriasis.
OBJECTIVE: To investigate the role of Tregs in the pathogenesis of
psoriasis and to evaluate the changes in Tregs in relation to the
severity and the clinical course of psoriasis.
METHODS: Immunohistochemistry (CD3, 4, 8, 79 and FOXP3) was performed
in 22 psoriatic patients compared to 5 normal controls. Flow cytometry
(CD3, 4, 8, 25 and FOXP3) was performed in 18 psoriatic patients and 8
normal volunteers and reverse transcriptase polymerase chain reaction
(foxp3 mRNA) was performed in 8 psoriasis patients.
RESULTS: An increase in the FOXP3(+) cell fraction was detected in the
lesional psoriatic skin irrespective of the severity of psoriasis as
compared with the normal skin. However, a decrease in FOXP3(+) cells
was observed in the samples obtained from psoriasis of 'acute course'.
FOXP3(+) Treg populations in the blood of the 'acute course' psoriasis
was not different compared to that of 'chronic course' psoriasis and
normal controls.
CONCLUSION: The deficiency of FOXP3(+) Tregs in the lesional psoriatic
skin might be responsible for the exacerbation of psoriasis.
PMID: 21165208
free pmc http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21165208/?tool=pubmed
============
Just toss some compound A at it?
http://www.ncbi.nlm.nih.gov/pubmed/19675162
J Immunol. 2009 Sep 1;183(5):3081-91. Epub 2009 Aug 12.
Compound A, a plant origin ligand of glucocorticoid receptors,
increases regulatory T cells and M2 macrophages to attenuate
experimental autoimmune neuritis with reduced side effects.
Zhang Z, Zhang ZY, Schluesener HJ.
Institute of Brain Research, University of Tuebingen, Tuebingen,
Germany. zhang...@yahoo.com
Abstract
Experimental autoimmune neuritis (EAN) is a helper T cell-mediated
autoimmune demyelinating inflammatory disease of the peripheral
nervous system and serves as the animal model for human inflammatory
demyelinating polyneuropathies. Compound A, a plant-derived phenyl
aziridine precursor, was reported to activate glucocorticoid receptors
to exert transrepression but not transactivation properties. In this
study, we investigated the effects of Compound A in EAN rats. Compound
A greatly suppressed paraparesis in EAN, even when administrated after
the appearance of the first neurological signs. Accumulation of
macrophages and lymphocytes, demyelination, and mRNA levels of
inflammatory molecules in sciatic nerves of EAN were greatly
attenuated by Compound A. In addition, Compound A inhibited
progression of neuropathic pain and repressed microglia but not
astrocyte activation and IL-1beta and TNF-alpha up-regulation in EAN
spinal cords. In EAN sciatic nerves, Compound A treatment increased
numbers of anti-inflammatory M2 macrophages. Furthermore, Compound A
induced the switch of macrophages from inflammatory M1 type to anti-
inflammatory M2 type in vitro. In lymph nodes of EAN rats, Compound A
depressed Th1 and Th17 cytokines, but increased Th2 cytokine and Foxp3
expression. An increase of Foxp3(+)/CD4(+) regulatory T cells was seen
in peripheral blood of EAN rats following Compound A treatment. In
addition, Compound A did not cause a hyperglycemia effect in EAN rats
as compared with the immunosuppressive steroid prednisolone.
Therefore, our data demonstrated that Compound A could effectively
suppress EAN with reduced side effects by attenuating inflammation,
suggesting that Compound A could be a potent candidate for treatment
of autoimmune neuropathies.
PMID: 19675162
Free Article
http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=19675162
============
http://www.ncbi.nlm.nih.gov/pubmed/21162653
Expert Rev Clin Immunol. 2011 Jan;7(1):93-109.
Osteopontin and allergic disease: pathophysiology and implications for
diagnostics and therapy.
Frenzel DF, Weiss JM.
University of Ulm, Department of Dermatology and Allergy, Maienweg 12,
D-89081 Ulm, Germany.
Abstract
Osteopontin (OPN) is a phosphoglycoprotein that is expressed by
various immune cells in a secreted and intracellular form. It has
cytokine, chemotactic and cell signaling functions enhancing Th1 and
Th17 immunity and protects against apoptosis. Recent studies found OPN
to be modulatory in cell-mediated and immediate-type allergic
diseases. In allergic asthma, OPN enhances sensitization but
downmodulates Th2-driven IL-4-dominated inflammation. The finding that
OPN expression is augmented during specific immunotherapy supports a
Th2 suppressive effect of OPN. In Th1-driven delayed-type allergy,
such as allergic contact dermatitis, OPN supports dendritic cell
migration and IL-12 expression and is secreted by T effector cells and
keratinocytes, augmenting Th1-mediated allergy and supporting disease
chronification. There are numerous missing links as to how OPN
variants modulate allergic inflammation through different OPN
receptors. OPN research in allergy is an interesting, rapidly
expanding field that has high potential for translational research.
PMID: 21162653
11 hits : osteopontin - P NG:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=osteopontin
=============
http://www.ncbi.nlm.nih.gov/pubmed/21151942
PLoS One. 2010 Dec 3;5(12):e15099.
Anti-inflammatory effects of resveratrol, curcumin and simvastatin in
acute small intestinal inflammation.
Bereswill S, Muñoz M, Fischer A, Plickert R, Haag LM, Otto B, Kühl AA,
Loddenkemper C, Göbel UB, Heimesaat MM.
Institut für Mikrobiologie und Hygiene, Charité - Universitätsmedizin
Berlin, Berlin, Germany.
Abstract
BACKGROUND: The health beneficial effects of Resveratrol, Curcumin and
Simvastatin have been demonstrated in various experimental models of
inflammation. We investigated the potential anti-inflammatory and
immunomodulatory mechanisms of the above mentioned compounds in a
murine model of hyper-acute Th1-type ileitis following peroral
infection with Toxoplasma gondii.
METHODOLOGY/PRINCIPAL FINDINGS: Here we show that after peroral
administration of Resveratrol, Curcumin or Simvastatin, mice were
protected from ileitis development and survived the acute phase of
inflammation whereas all Placebo treated controls died. In particular,
Resveratrol treatment resulted in longer-term survival. Resveratrol,
Curcumin or Simvastatin treated animals displayed significantly
increased numbers of regulatory T cells and augmented intestinal
epithelial cell proliferation/regeneration in the ileum mucosa
compared to placebo control animals. In contrast, mucosal T lymphocyte
and neutrophilic granulocyte numbers in treated mice were reduced. In
addition, levels of the anti-inflammatory cytokine IL-10 in ileum,
mesenteric lymph nodes and spleen were increased whereas pro-
inflammatory cytokine expression (IL-23p19, IFN-γ, TNF-α, IL-6, MCP-1)
was found to be significantly lower in the ileum of treated animals as
compared to Placebo controls. Furthermore, treated animals displayed
not only fewer pro-inflammatory enterobacteria and enterococci but
also higher anti-inflammatory lactobacilli and bifidobacteria loads.
Most importantly, treatment with all three compounds preserved
intestinal barrier functions as indicated by reduced bacterial
translocation rates into spleen, liver, kidney and blood.
CONCLUSION/SIGNIFICANCE: Oral treatment with Resveratrol, Curcumin or
Simvastatin ameliorates acute small intestinal inflammation by down-
regulating Th1-type immune responses and prevents bacterial
translocation by maintaining gut barrier function. These findings
provide novel and potential prophylaxis and treatment options of
patients with inflammatory bowel diseases.
PMID: 21151942
full text
http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21151942/?tool=pubmed
===========
http://www.ncbi.nlm.nih.gov/pubmed/19462506
Gastroenterology. 2009 May;136(6):1965-78.
The gastrointestinal tract and AIDS pathogenesis.
Lackner AA, Mohan M, Veazey RS.
Division of Comparative Pathology, Tulane National Primate Research
Center, Covington, Louisiana 70433, USA.
Abstract
Gastrointestinal disease has been recognized as a major manifestation
of human immunodeficiency virus infection since the earliest
recognition of acquired immunodeficiency syndrome (AIDS). Originally,
these disease manifestations were considered to be sequelae of the
immune destruction that characterizes AIDS rather than being central
to the pathogenesis of AIDS. Over time, it has become clear that the
mucosal immune system in general and the intestinal immune system in
particular are central to the pathogenesis of AIDS, with most of the
critical events (eg, transmission, viral amplification, CD4+ T-cell
destruction) occurring in the gastrointestinal tract. Compared with
peripheral blood, these tissues are not easily accessible for analysis
and have only begun to be examined in detail recently. In addition,
although the resulting disease can progress over years, many critical
events happen within the first few weeks of infection, when most
patients are unaware that they are infected. Moreover, breakdown of
the mucosal barrier and resulting microbial translocation are believed
to be major drivers of AIDS progression. In this review, we focus on
the interaction between primate lentiviruses and the gastrointestinal
tract and discuss how this interaction promotes the pathogenesis of
AIDS and drives immune dysfunction and progression to AIDS. This
article draws extensively on work done in the nonhuman primate model
of AIDS to fill gaps in our understanding of AIDS in humans.
PMID: 19462506
==============
http://www.ncbi.nlm.nih.gov/pubmed/21172868
J Immunol. 2010 Dec 20.
IL-23-Mediated Psoriasis-Like Epidermal Hyperplasia Is Dependent on
IL-17A.
Rizzo HL, Kagami S, Phillips KG, Kurtz SE, Jacques SL, Blauvelt A.
Department of Dermatology, Oregon Health & Science University,
Portland, OR 97239;
Abstract
IL-23 and Th17 cells producing IL-17A and IL-22 are found in excess in
skin affected by psoriasis. Previous studies showed that IL-22, but
not IL-17A, mediates psoriasis-like epidermal hyperplasia following
recombinant murine (rm)IL-23 injections into skin. To further
investigate the role of IL-17A, ears of mice were injected with
rmIL-23. Investigators blinded to treatment conditions and mouse
genotypes measured ear swelling, epidermal thickness, and cytokine
expression. In wild-type (WT) mice, rmIL-23 induced ear swelling (p <
0.001, all p values versus saline), epidermal hyperplasia by histology
(p < 0.001) and confocal microscopy (p < 0.004), and expression of
both IL-17A and IL-22. As expected, rmIL-23 injections into IL-22(-/-)
mice resulted in relatively little ear swelling (p < 0.09) and
epidermal hyperplasia (p < 0.51 by histology and p < 0.75 by confocal
microscopy). Notably, rmIL-23 injections into IL-17A(-/-) mice
produced little ear swelling (p < 0.001, versus IL-23-injected WT
mice) and epidermal hyperplasia (p < 0.001 by histology and p < 0.005
by confocal microscopy), even though IL-22 was readily induced in
these mice. Furthermore, systemic delivery of blocking Abs directed
against either IL-22 or IL-17A completely inhibited IL-23-induced
epidermal hyperplasia in WT mice. These results demonstrate that
IL-17A, like IL-22, is a downstream mediator for IL-23-induced changes
in murine skin and that both of these Th17 cytokines are necessary to
produce IL-23-mediated skin pathology. IL-17A may represent an
attractive therapeutic target in individuals with psoriasis by
blocking downstream effects of IL-23.
PMID: 21172868
I should have sPent my time with this and ditched the rest. LOL
Why?
http://en.wikipedia.org/wiki/Causality
Actions sPeak louder then wORDs...
And we agree as to whats what.
So what?
1984 and double speak it to death?
http://en.wikipedia.org/wiki/Doublespeak
randall.... Cause it's causal?