 Re: Possible new cure for Psoriasis article
colinkin89@yahoo.com wrote in message news:<f9484ddf.0408161620.7b90ff75@posting.google.com>
..
> Oh MY GOSH! If anything, we are getting closer to cure!!!!
>
> http://www.scienceblog.com/community/article3637.html
Hi colinkin89,
Lets look at what their talking about from a Pubmed look see,
UPregulation of MMP in diseased P skin,
http://www.ncbi.nlm.nih.gov/entrez/..t_uids=14708597
Matrix metalloproteinase-19 expression in normal and diseased skin:
dysregulation by epidermal proliferation.
Sadowski T, Dietrich S, Muller M, Havlickova B, Schunck M, Proksch E,
Muller MS, Sedlacek R.
Institute of Biochemistry, university of Kiel, Kiel, Germany.
Most of the matrix metalloproteinases (MMP) are not expressed in
normal intact skin but they are upregulated in inflamed or diseased
skin. The recently cloned MMP-19 is one of the few MMP members that
are also expressed in healthy epidermis. In this study, we found that
MMP-19 is generally coexpressed with cytokeratin 14 that is confined
to keratinocytes of the stratum basale. MMP-19 was also detected in
hair follicles, sebaceous glands, and eccrine sweat glands. Its
expression, however, changed in cutaneous diseases exhibiting
increased alternations of epidermal proliferation, such as psoriasis,
eczema, and tinea. In the affected area, MMP-19 was also found in
suprabasal and spinous epidermal layers. We also studied the
regulation of MMP-19 expression at the protein level, as well as by
using a promoter assay. The constitutive expression of MMP-19 was
upregulated with phorbol myristate acetate and downregulated with
retinoic acid and dexamethasone. Tumor necrosis factor-alpha,
interleukin (IL)-6, TGF-beta, IL-15, IL-8, and RANTES as well as the
bacterial compounds lipopolysaccharide and lipoteichoic acid did not
show any profound effect in HaCaT cells. In contrast, type IV and type
I collagens upregulated MMP-19 significantly. The dysregulation of
MMP-19 expression in epidermis suggests its possible involvement in
the perpetuation of cutaneous infections and proliferative disorders
such as psoriasis.
PMID: 14708597
In other words if your gonna make P you need MMP-19 in the reciPe.
OK NOW, we got that much. Lets see if we can find more on that theme.
More of the same from a different source,
http://www.ncbi.nlm.nih.gov/entrez/..t_uids=12735638
[snip] MMP-19 and MMP-28, was investigated in psoriatic lesional and
non-lesional skin. MMP-19 protein was detected by immunohistochemistry
in 28/29 samples in keratinocytes in the same regions as Ki67 (marker
of proliferating keratinocytes) and p63 (marker of keratinocyte stem
cells).
And looky here, HA (hyaluronan, hyaluronic acid is an inhibitor of
MMPs!!!
No wonder my HA supplements are doing so much! I'm more Jazzed
then ever now,
http://www.ncbi.nlm.nih.gov/entrez/..t_uids=14872494
Inhibition of interleukin-1beta-stimulated production of matrix
metalloproteinases by hyaluronan via CD44 in human articular
cartilage.
OBJECTIVE: To investigate the mechanism of the inhibitory action of
hyaluronan (HA) on interleukin-1beta (IL-1beta)-stimulated production
of matrix metalloproteinases (MMPs) in human articular cartilage.
METHODS: IL-1beta was added to normal and osteoarthritic (OA) human
articular cartilage in explant culture to stimulate MMP production.
Articular cartilage was incubated or preincubated with a clinically
used form of 800-kd HA to assess its effect on IL-1beta-induced MMPs.
Levels of secreted MMPs 1, 3, and 13 in conditioned media were
detected by immunoblotting; intracellular MMP synthesis in
chondrocytes was evaluated by immunofluorescence microscopy.
Penetration of HA into cartilage tissue and its binding to CD44 were
analyzed by fluorescence microscopy using fluoresceinated HA. Blocking
experiments with anti-CD44 antibody were performed to investigate the
mechanism of action of HA. RESULTS: Treatment and pretreatment with
800-kd HA at 1 mg/ml resulted in significant suppression of
IL-1beta-stimulated production of MMPs 1, 3, and 13 in normal and OA
cartilage explant culture. Fluorescence histocytochemistry revealed
that HA penetrated cartilage tissue and localized in the pericellular
matrix around chondrocytes. HA-binding blocking experiments using
anti-CD44 antibody demonstrated that the association of HA with
chondrocytes was mediated by CD44. Preincubation with anti-CD44
antibody, which suppressed IL-1beta-stimulated MMPs, reversed the
inhibitory effect of HA on MMP production that was induced by IL-1beta
in normal and OA cartilage. CONCLUSION: This study demonstrates that
HA effectively inhibits IL-1beta-stimulated production of MMP-1,
MMP-3, and MMP-13, which supports the clinical use of HA in the
treatment of OA. The action of HA on IL-1beta may involve direct
interaction between HA and CD44 on chondrocytes.
PMID: 14872494
And more proof for using HA, (Activation of DCs)
http://www.ncbi.nlm.nih.gov/entrez/..t_uids=14657275
Hyaluronan-oligosaccharide-induced transcription of metalloproteases.
Activated dendritic epidermal Langerhans cells and metastatic tumour
cells share many properties. Both cell types can invade the
surrounding tissue, enter the lymphatic system and travel to regional
lymph nodes. We have recently shown that fragments of the
extracellular matrix component hyaluronan, which are typically
produced at sites of inflammation, can activate dendritic cells. Upon
activation, dendritic cells upregulate expression of matrix
metalloproteases (MMPs). These observations prompted us to investigate
whether exposure to hyaluronan fragments also induces MMP expression
in tumour cells. Here, we report that MMP-9, MMP-13 and urokinase
plasminogen activator are upregulated in murine 3LL tumour cells after
exposure to mixed-size hyaluronan. Similarly upregulated MMP-9 and
MMP-13 expression was observed in primary fibroblasts. By using
size-fractionated hyaluronan preparations, we show that the enhanced
expression of MMP-9 and MMP-13 is only induced by small hyaluronan
(HA) fragments. Although our data suggest that HA-fragment-induced
MMP-9 and MMP-13 expression is receptor mediated, they rule out an
involvement of the hyaluronan receptors CD44, RHAMM/IHAP and TLR-4.
Finally, we show that HA fragment-induced MMP-9 transcription is
mediated via NF-kappa B. Our results suggest that the
metastasis-associated HA degradation in tumours might promote invasion
by inducing MMP expression.
PMID: 14657275
And we need to look at CD44 more closely for P when working with
HA (remember i'm taking it now via an oral supplement. How much is
ending
uP in my psoriatic plaques is highly questionable. What isn't a
question
is how fast i'm clearing. Even in the face of eating those very things
that flare the craP outa me!!)
Look at this,
Requirement for _CD44_ in activated T cell extravasation into an
inflammatory site. Science 278(5338):672-675 (Oct 24 1997).
Laboratory of Molecular Pathology, Department of Pathology,
University of Texas Southwestern Medical Center, 5323 Harry Hines
Boulevard, Dallas, TX 75235, USA.
Abstract: Leukocytes extravasate from the blood into inflammatory
sites through complementary ligand interactions between leukocytes and
endothelial cells. Activation of T cells increases their binding to
hyaluronate (HA) and enables CD44-mediated primary adhesion (rolling).
This rolling could be induced in vivo in murine Vbeta8+ T cells in
response to specific superantigen stimulation; it was initially found
in lymph nodes, then in peripheral blood, and finally within the
peritoneum, the original inflamed site. The migration of Vbeta8+ cells
into the peritoneal cavity was dependent on CD44 and HA, as shown by
inhibition studies. Thus, CD44-HA interactions can target lymphocytes
to specific extralymphoid effector sites.
Taken from here,
http://groups.google.com/groups?q=c..br />
s&rnum=1
So how do we activate CD44 to decongest inflammation at the site
of P plaques?
Answer: TNF-a ???
http://groups.google.com/groups?q=c..br />
s&rnum=2
I don't know about you, but i thought we had to much TNF-a. Do we
have to much of it systemic wide and not enough locally in the p
sites?
I have to doubt that when i look at raptiva charts of the mechanism of
action in the psoriatic plaques. They show RAPTIVA taking out the
TNF right in or close to the site of psoriasis plaques.
So, what is it with HA slowing down psoriasis inflammation?
Back to pubmed,
http://www.ncbi.nlm.nih.gov/entrez/..st_uids=7511363
Hyaluronan and CD44 in psoriatic skin. Intense staining for hyaluronan
on dermal capillary loops and reduced expression of CD44 and
hyaluronan in keratinocyte-leukocyte interfaces.
The distributions of hyaluronan (HA) and its presumptive receptor,
CD44, were studied in skin samples from 13 psoriasis vulgaris
patients, using an HA-specific probe (HABC), and monoclonal
antibodies, respectively. The general distribution of HA and CD44 in
psoriatic lesional epidermis resembled that in normal epidermis.
However, areas of epidermis invaded by leukocytes showed a local
depletion of HA and CD44, particularly at the contact areas of
keratinocytes to lymphocytes and neutrophils. Removal by cellular
uptake or extracellular degradation of CD44 and HA may be required for
tight adherence between a keratinocyte and a leukocyte. On the dermal
side, the tips of the prolonged dermal papillae in psoriatic lesions
were intensively stained with HABC. The dilated capillaries and the
space below the tip basal lamina, in particular, were heavily covered
with HA. Occasionally, a similar intense staining was seen around an
enlarged capillary in uninvolved psoriatic skin. CD44-positive
leukocytes were found around the affected capillaries. The
accumulation of HA in the dermal papillae may support the growth of
psoriatic lesions, since HA stimulates the growth of capillaries as
well as attracting inflammatory cells.
PMID: 7511363
Now this is clearing up my clearing dilemma!! The MOA of HA is coming
to light, without having to take my P to the light at the same time!!
Wahooo!!
This is great, lets go back and search out the MOA of MMPs and P,
http://www.ncbi.nlm.nih.gov/entrez/..t_uids=15308656
Delineating the molecular basis of the inactivity of tissue inhibitor
of metalloproteinase (TIMP)-2 against TNF-a converting enzyme (TACE).
Lee MH, Rapti M, Murphy G.
Cambridge Institute for Medical Research, Cambridge University,
Cambridge CB2 2XY.
TNF-a converting enzyme (TACE, ADAM-17) is a zinc-dependent ADAM (a
disintegrin and metalloproteinase) metalloproteinase (MP) of the
metzincin superfamily. The enzyme regulates the shedding of a variety
of cell surface-anchored molecules such as cytokines, growth factors
and receptors. The activities of the MPs are modulated by the
endogenous inhibitors, the tissue inhibitor of metalloproteinases
(TIMPs). Among the four mammalian TIMPs (TIMP-1 to -4), TACE is
selectively inhibited by TIMP-3. The rationale for such selectivity is
not fully understood. Here, we examine the molecular basis of
TIMP-TACE selectivity using TIMP-2 as the scaffold. By systematically
replacing the surface epitopes of TIMP-2 with those of TIMP-3 and a
TIMP-1 variant V4S/TIMP-3 AB-loop/V69L/T98L, we created a novel TIMP-2
mutant that exhibits inhibitory potency almost equal to that of the
TIMP-3. The affinity of the mutant with TACE is 1.49 nM, a marked
improvement in comparison to that of the wild-type protein (Ki 893
nM). The inhibitory pattern of the mutant is typical of that of a
slow, tight-binding inhibitor. We identify phenylalanine-34, a residue
unique to the TIMP-3 AB-loop, as a vital element in TACE association.
Mutagenesis carried out on leucine-100 also upholds our previous
findings that a leucine on the EF-loop is critical for TACE
recognition. Replacement of the residue by other amino acids resulted
in dramatic decrease in binding affinity, although isolecine (L100I)
and methionine (L100M) are still capable of producing the slow,
tight-binding effect. Our findings here represent a significant
advance towards designing tailor-made TIMPs for specific MP targeting.
PMID: 15308656
http://www.ncbi.nlm.nih.gov/entrez/..t_uids=15306218
Conclusion: Cyclic strain stimulates MMP-2 expression, in part, by
stimulating both p38- and ERK-dependent pathways through activation of
Gbetagamma and tyrosine kinase in BAECs.
PMID: 15306218
MMP inhibitors for PsA,
http://www.ncbi.nlm.nih.gov/entrez/..t_uids=15144129
http://www.ncbi.nlm.nih.gov/entrez/..t_uids=15055993
Azasugar-based MMP/ADAM inhibitors as antipsoriatic agents.
As a part of synthetic studies on MMP (matrix metalloproteinase)/ADAM
(a disintegrin and metalloproteinase) inhibitors, we have
preliminarily communicated that azasugar-based compound 1a exhibited a
potential inhibitory activity on some metalloprotease-catalyzed
proteolytic reactions. To find promising candidates for the topical
treatment of psoriasis, we investigated stability in aqueous solution
of compound 1a and its derivative 1b and then optimized the P1'
substuent (2-5). In the present study, we synthesized novel
derivatives of compound 1a and evaluated their inhibitory activity
toward MMP-1, -3, and -9, TACE, and HB-EGF shedding, from a viewpoint
of versatility of azasugars as a functional scaffold. As a result, it
was found that compound 1b demonstrated desirable inhibitory activity
as an antipsoriatic agent, and some of the derivatives showed
selective inhibitory activity. In addition, it was found that compound
1b exhibited a significant therapeutic effect on a mouse TPA-induced
epidermal hyperplasia model. Therefore, compound 1b could become a
promising candidate as a practical antipsoriatic agent.
PMID: 15055993
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So, did i stumbe into the HA cure for P?
Don't know yet! I've slowed down on my loading dose this week as i'm
waiting for my next two week supply to show up.
After this mornings dosage i'm on hiatus till the mailman shows!!!
HA-PP-Y trails,
randall
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08-17-04 03:10 AM
I think i screwed up (the order) as i figured it would be here
already.
So, in essence i've taken a two week loading dose and now a little
respite. Hey thats a test in it self.
>Doesn't mean they're right, but certainly does obscure the
> MOA.
What it means to me is the HA is breaking down faster in the
plaques for whatever reason. As long as taking it works to block
MMP19,
then it may have a correlation to a safe effective P treatment.
And those abstracts in that last post blew my mind as they unfolded.
IMO one of my best posts ever as far as a crucial P fighter.
Last night i was somewhat bummed out i didn't get my order in
the mail. But i did get my wheatgrass supply and they always
toss in some of the cream as a freebee to the sprays.
So i moisturized with it and i'm looking better then ever.
And i've never gone in much for that type of thing.
I ended up with moist sore looking scales and nothing more.
But i figured it had wheatgrass in it so it has to be healing.
Now i can't wait to see how long that HA loading dose protects me.
I'm doing the HA/pause/WG test now, due to the postal screw uP!
Or mine!
I better get on the phone and re-order that HA right now!!!
I may not want to test being without for long. lol
>
> J.
