FYI
randall
On Oct 23, 6:20 am, "Cruiser" <tg.cruis...@sympatico.ca> wrote:
> http://home.comcast.net/~john.kimball1/BiologyPages/I/Inflammation.htmlhttp://www.biology.neu.edu/faculty03/sitkovsky03.htmlhttp://www.rxpgnews.com/research/psychiatry/depression/article_4618.s...http://www.iantd.com/articles.html
>
> bye
Cruiser, where have you been and what have you done since your last
visit here?
Are these four links illustrative of your recent endeavors?
The first one is a good basic primer for inflammation but falls short
for P.
OK ok, as I see these... inflammation--> A2a(r)-->depression (increased
cortisol--blocked by Metryapone)
And, all fixed with scuba fitness. LOL
NO no, i'm laughing with you, honest. The usage of decompression on the
hyPoxia angle
could be fun.
More fun is the usage of red wine or pine needles for the
proanthocyanidin / Proanthocyanidine B2-3'-0-gallates.
Surely for those so primed with vitamin C, glutathione, (NAC) etc will
CLEARLY benefit with one or two
glasses of stressed red grape seeds each night. Could that bottle of
cab or merlot been
THE factor in your trials?
As to blocking A2a receptors, MTX (low dosage) is at play,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15972692&query_hl=7&itool=pubmed_docsum
With some yogic breathing aimed at the plaques we can disolve those
islands of psoriasis.
A veritable JXStern-ian P cocktail with lifestyle factors to boot.
Now if I could quantify my vitamin C and red wine usage against the IP6
and chondrotin/glucosamine.
Or do they all track equally in the clearing of P?
randall... time will tell and so will i! et tu?
Cruiser
Cruiser
GH3?
Cruiser
Ennnhhh!!! Wrong answer!
http://www.rxpgnews.com/research/psychiatry/depression/article_4618.shtml
Read it all!
Answer these questions.
What is a visceral?
What part of you detoxifies your body?
AHHA!
What is peripheral?
Do you have any peripheral parts inside?
(Hint: if it aint muscle.)
How well do these things perform with ongoing constricted blood flow?
Schoolboy stuff after all.
Cruiser
http://www.iantd.com/articles.html
Cruiser wrote:
> Ennnhhh!!! Wrong answer!
randall
On Oct 23, 11:42 am, "Cruiser" <tg.cruis...@sympatico.ca> wrote:
> GH3?
The cell line? Or the quackery?
The latter being much more fun!
http://www.quackwatch.org/01QuackeryRelatedTopics/PhonyAds/braswell.html
If you read this whole page, the clintons being slightly more insipid
then the Bush-ies
when it comes to credibility. Bill's recent touting of a sugar/ethanol
ad on tv being his latest blunder.
Paying Brazilian slave labor $9 a ton doesn't make cents! And huge fuel
guzzing machines
to harvest etc being an even bigger con game for energy BILLs.
http://members.shaw.ca/rolfwitzsche/canada/ethanol_slavery.html
Then again, when do we ever expect politics to make sense?
Back to raw science?
http://www.google.com/search?hl=en&lr=&q=gh3+cell+line&btnG=Search
(the rip off gerovital folks have their sponsored ads front and center.
LOL)
One can't even google for science without fraud sneaking in via paid
ads!
Or did you have some other gh3 in mind?
And have you taken some sort of posting silence vows? No typing, only
copy and pasting? LOL
randall... i'll have to tyPe that one some time! Like--- between now
and Mañana!
randall
On Oct 23, 4:17 pm, "Cruiser" <tg.cruis...@sympatico.ca> wrote:
> wrong reference use this instead:
>
> http://www.iantd.com/articles.html
Are you sure this is the right link? Keyword :: visceral isn't on this
page.
If your having a uwe-ian moment please share it with us.
randall... ePiPhany or not, i'm all ears...
Cruiser
Findings Show Cortisol's Major Role in AIDS and Other Diseases
PARIS, June 21, 1996 -- Researchers from Europe and the US gathered
here today to launch the International Association of Researchers in
Cortisol and Anti-Cortisols (IARCA) and present new findings showing
the negative causal effect of cortisol in diseases for which current
treatments still remain unsatisfactory. The founding of the new
association constitutes the group's first initiative and marks the
beginning of IARCA's contribution to improving the understanding of the
mechanisms of cortisol and its effect on human behavior and health.
Cortisol -- a powerful hormone produced by the adrenal gland -- is
found at a higher than normal level in many diseases and conditions
such as depression, alcoholism, substance abuse, anorexia nervosa,
heavy smoking, cancer, ulcers, myocardial infarction, diabetes, chronic
painful conditions (organic, i.e. arthritis and psychological),
strokes/cardiovascular accidents, Parkinson's, Multiple Sclerosis, skin
diseases (psoriasis, acne, eczema), stress, aging/Alzheimer's, AIDS and
even Space Adaptation Syndrome.
During the meeting, international researchers presented evidence in
support of high cortisol as a cause or major cause of such diseases.
"There has been a dramatic change in our understanding of how cortisol
affects the human body, and how 'high cortisol' precedes diseases
rather than being the result thereof. For example, the side effects
induced by cortisol when used in the treatment of certain diseases are
identical to symptoms and opportunistic infections encountered in
AIDS," said Dr. Alfred Sapse (Director of Research, Steroidogenesis
Inhibitors, Las Vegas USA). "This new concept opens the possibility to
view anti- cortisol drugs as a new and beneficial therapy for diseases
which are still poorly understood and thus inadequately treated."
Results presented during the meeting by French researchers confirm this
new approach to cortisol. In five retrospective and prospective
studies(1) (2)conducted by Prof. Emmanuel A. Nunez and Dr. Nevena
Christeff (Dept. of Endocrine Biochemistry, Bichat Hospital, Paris),
results indicated that serum cortisol is elevated at all stages of
HIV-infection (+20 to 60%) particularly in AIDS patients (stage IVC as
defined by the Center for Disease Control criteria). "These significant
cortisol differences from HIV-negative and AIDS patients could
represent not only a good index of diagnosis and prognosis, but also
indicate new therapeutic approaches to the disease," said Professor
Emmanuel Nunez.
In contrast, serum DHEA (dehydroepiandrosterone) is higher during the
early stages of the disease (asymptomatic, stages II and III) than
during advanced stages (IVC) or control groups, and below the normal
level during advanced stages of AIDS (IVC). The results presented
showing elevated cortisol during all stages of HIV-infection and high
serum DHEA only during the early asymptomatic stages, suggest that the
cortisol/DHEA ratio might be used as a possible early sign of
HIV-positive switch towards AIDS.
Researchers have already started to explore the therapeutic benefits of
such an approach through the use of anti-cortisol drugs, such as
RU-486, DHEA, Ketaconazole, Anticort and Tianeptine. In 'in vitro'
studies conducted recently (Weiner, 1995), results obtained showed that
by blocking cortisol, not only the infectivity of HIV was blunted, but
also the production of HIV by the already infected cells which dropped
by 70%. Anticort, a high dose form of stabilized procaine HCL, is being
successfully tested in pilot clinical studies in Brazil and the U.S.,
in HIV+ and AIDS populations.
To further the understanding of cortisol and potential benefits of
anti-cortisols, the members of IARCA intend to hold a second conference
on the topic which will tentatively take place in Las Vegas, Nevada in
September 1997.
---------------------------------------------------------
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9264141&dopt=Abstract
Cortisol, high cortisol diseases and anti-cortisol therapy.
Sapse AT.
Steroidogenesis Inhibitors, Inc, Las Vegas, NV 89119, USA.
Elevated cortisol is found in many diseases, including infectious,
aging-related, depression and depression-associated conditions; even in
some with no known origin, and no known therapy. While it was initially
thought that 'high cortisol' is the result of these diseases, there is
mounting evidence to the contrary, namely, that high cortisol actually
plays a major role in inducing them, opening the possibility that
anti-cortisol drugs might represent a new beneficial therapy. Evidence
is here presented, showing that the use of anti-cortisol drugs has
already induced beneficial results in conditions ranging from AIDS to
depression. A main reason for not realizing the major role played by
cortisol is due to a defective interpretation of cortisol results. If
cortisol is within normal range of 0800 h or 1700 h, it has been
considered normal, without realizing that swings, sometimes at
immunosuppressive levels, might occur during its 24 h circadian rhythm.
We suggest that a first step toward unveiling the role of cortisol in
diseases would be to develop a standardized cortisol circadian rhythm
chart that would show normal levels at any time during a 24 h period,
enabling a more accurate comparison with cortisol values obtained under
pathological conditions.
-------------------------------------------------------------
http://www.medscape.com/medline/abstract/15293872?queryText=anticortisol
Procaine oral stabilised--Samaritan pharmaceuticals: SP-01, SP001.
Medscape Newsletters
Drugs R D. 2004; 5(2):108-9 (ISSN: 1174-5886)
Samaritan Pharmaceuticals (formerly Steroidogenesis Inhibitors) is
developing a high-dose oral stabilised formulation of procaine
hydrochloride [AnticortSP 01, SP001, Virucort] as an anticortisol drug
for the treatment of HIV and AIDS. Preclinical investigations for its
potential in the treatment of patients with Alzheimer's disease are
also underway with Samaritan. The levels of cortisol, a hormone
produced by the adrenal gland, are increased in many diseases,
including AIDS. Serum cortisol levels are elevated during all stages of
HIV infection, particularly in AIDS patients, whereas
dehydroepiandrosterone (DHEA) levels are higher in the early stages of
disease rather than in the advanced stages. Anticortisol drugs have
been shown to reduce both the infectivity and the production of HIV in
vitro. Anticort is available for licensing. Altachem Pharma had an
exclusive licence to manufacture, use, distribute and sell oral
procaine in Canada with an option to purchase the same rights for other
Commonwealth countries. However, this agreement has been terminated.
Cato Research in the US has been enlisted to implement a long-range
clinical and business development plan to facilitate US FDA approval
and manufacturing of the procaine formulation worldwide. Altachem
Pharma received approval to begin a phase I trial of Anticort in Canada
in HIV-positive patients receiving anti-HIV treatment. In January 2004,
Cortisol Research International-Romania filed for orphan drug
designation with the US FDA for Virucort 50 for the treatment of
depression in children with HIV. A study examining the efficacy of
Anticort in children infected with HIV has been conducted in Romania.
One aspect of this study will investigate the possibility of reducing
the dosage of zidovudine required if it is used in combination with
Anticort. Following early indications that children treated with
placebo in this trial have deteriorated while some children under the
Anticort have shown improvements, especially in the 150-200mg group,
Romanian clinicians have asked the Romanian FDA Commissioner for
approval to switch children receiving placebo to receive Anticort.
??????????????????????
http://www.gh3.co.uk/aboutGH3_1.htm
??????????????????????
randall
On Oct 24, 6:43 am, "Cruiser" <tg.cruis...@sympatico.ca> wrote:
> http://www.pslgroup.com/dg/9ac6.htm
<sniP>
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...
>
<sniP>
>
> http://www.medscape.com/medline/abstract/15293872?queryText=anticortisol
>
<sniP>
>
> http://www.gh3.co.uk/aboutGH3_1.htm
>
I'm more then a bit leery with this line of rational. Yet, i'm sure
yMMV.
If it worked for P, wouldn't we know by now? Gh3 been around as long as
mtx and
cyclosporine. Even adjusting for placebo effect there must be an emPty
hole here,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20psoria*+procaine
Furthermore look at all the shams and con jobs with P on their pages.
I'm surprised the lies
aren't more prominent for gh3 and P and pages like this leave me rather
cold,
http://en.wikipedia.org/wiki/Gerovital
Most of the hyPed longevity supplements usually toss P in to the mix as
some sort of
imprimatur. Braswell and his goons in my opinion belong behind bars.
(as opposed to in them spending their ill gotten gains.)
http://en.wikipedia.org/wiki/Almon_Glenn_Braswell
If your willing to prove the old saying from PT Barnum,
"There's a sucker born every minute...and two to take 'em."
Be my guest, it's your money. I've wasted more of mine then I like to
recall.
And,
If I were you i'd stick with the breakdown products mentioned in the
above links.
"Some advocates acknowledge that despite the stabilizers, the procaine
in Gerovital H3 breaks down rapidly into DMAE and PABA, but ascribe the
beneficial effects to these breakdown products."
Once uPon a time in my studies dmae did do something positive for P
iirc. Durk and Sandy
pushed it in their longevity tome, life extension.
& an abstract to encourage you on,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15675889&query_hl=8&itool=pubmed_docsum
OTOH, I took the sweet whey and added in IP6 and
glucosamine/chondroitin with vitamin C!
I guess I found my own way. The road less travelled?
http://en.wikipedia.org/wiki/The_Road_Not_Taken
Two roads diverged in a yellow wood,
And sorry I could not travel both
And be one traveler, long I stood
And looked down one as far as I could
To where it bent in the undergrowth;
Then took the other, as just as fair,
And having perhaps the better claim,
Because it was grassy and wanted wear;
Though as for that the passing there
Had worn them really about the same,
And both that morning equally lay
In leaves no step had trodden black.
Oh, I kept the first for another day!
Yet knowing how way leads on to way,
I doubted if I should ever come back.
I shall be telling this with a sigh
Somewhere ages and ages hence:
Two roads diverged in a wood, and I-
I took the one less traveled by,
And that has made all the difference.
---------------------
randall... with my sweet whey i'm down to sub 2% Pasi levels!
manfred
Br J Dermatol. 1982 Apr;106(4):423-7. Related Articles, Links
Plasma aldosterone and cortisol levels in psoriasis and atopic
dermatitis.
van de Kerkhof PC.
The levels of plasma aldosterone were significantly raised in groups of
patients with psoriasis and atopic dermatitis compared with a control
group of patients with other skin diseases. Simultaneous assay of
plasma cortisol indicated that these changes were not the effects of
prior corticosteroid therapy. The reasons for the increased aldosterone
levels are not clear, but our findings are compatible with a
"permissive" role for this hormone in psoriasis and atopic dermatitis.
PMID: 7073966 [PubMed - indexed for MEDLINE]
Hey, Cruiser
Welcome back. I think you have made your point. So, have you found
the solution and are taunting us--making us learn it for ourselves?
Have you tried the GH3? Or are you still searching like the rest of
us. Come clean. You may just "cure" all of us!!
Cruiser
http://www.medscape.com/medline/abstract/7168211
[Measurement of arterial O 2 pressure with and without O 2 inhalation
after lung damage by smoke. Bioenergetic switch of the microcirculation
in the whole body with various effects on the lung and moreover in the
tissue. Decrease of venous mixed pO 2 as further basic effect of the O
2 multistep regeneration process]
Medscape Newsletters
Z Erkr Atmungsorgane. 1982; 159(2):166-82 (ISSN: 0303-657X)
von Ardenne M
During an (involuntary) self-test with pulmonary impairment by smoke
exposure the following physiological basic principles were disclosed in
the blood capillary system (and lung alveoli):
1. The normal arterial response of the lung to pO2 changes can be
paralysed by severe smoke exposure to such an extent that the Oxygen
Multistep Regeneration Process is not or hardly able to elevate the
arterial pO2 resting level above the age-matched expected value. As a
cause of this failure a very large volume of functionally shunted blood
of 15-20% was detected using a method according to Thews. Very
intensive and long-lasting exercise training acts as an antidote.
2. Severe stress influences lead to such changes in the tissue
capillary system that the oxygen utilization deteriorates markedly and,
hence, both the peripheral (pO2-ven) and mixed venous pO2-ven increase
noticeably, followed by a surprisingly diminished oxygen transport to
tissue (see eta nomogram).
3. Both the peripheral venous pO2-ven and the mixed venous pO2-ven are
permanently decreased by the Oxygen Multistep Regeneration Process. It
follows that by this process the utilization eta of oxygen-binding
capacity of blood is much more improved than hitherto supposed (see
measurement given in the text: decrease of pO2-ven from 40 mm Hg (5.3
kPa) to 27 mm Hg (3.6 kPa). This corresponds to an increase of eta from
20 to 44% [!] ).
Considering these recent findings, it is inadmissible to conclude only
from the lack of permanently increased arterial pO2 to the failure of
the Oxygen Multistep Regeneration Process. According to our suggestions
these three basic principles are jointly founded on an bioenergetic
switch (or trigger) mechanism of microcirculation exerting different
influences on the lung (change of arterial pO2) and on the peripheral
tissue (change of pO2-ven). The trigger mechanism mentioned above is
discussed in more detail in this paper. In case of pulmonary impairment
by smoke exposure appropriate therapeutic measures have to aim at
re-opening of the capillary network in the best possible way and at
restoring optimum gassing of alveoli, i.e., reducing micro-atelectases.
Cruiser
http://www.sciencedaily.com/releases/2005/10/051007094528.htm
DURHAM, N.C. A persistent scarcity of oxygen in bodytissues a
widespread problem in patients with heart or lung disease can create a
defect of red blood cells that further exacerbates thecondition by
constricting blood vessels in the lung, Howard HughesMedical Institute
researchers at Duke University Medical Center havefound. What's more,
the team demonstrated through studies in people andanimals that
inhalation of a 'souped up' form of nitric oxide, whichtargets red
blood cells, reverses the blood abnormality to restorenormal lung
pressure.
The team's findings will appear in theonline Early Edition of
Proceedings of the National Academy of Sciencesnext week (October 3-7,
2005). The work was supported by the NationalHeart, Lung, and Blood
Institute and the National Science Foundation.Stamler is a paid
consultant for Nitrox LLC, a biotechnology companydeveloping NO-based
drugs for disorders of the heart, lung and blood.
Thepotentially fatal lung condition, pulmonary hypertension,
ischaracterized by high blood pressure in the lungs. The disorder is
acommon complication of chronic diseases such as emphysema,
arthritis,sickle cell disease and heart failure. However, pulmonary
hypertensioncan also arise in otherwise healthy people for unknown
reasons.Symptoms include shortness of breath under minimal exertion,
fatigue,chest pain, dizzy spells and fainting.
"Many people sufferpulmonary hypertension as a complicating factor of
other chronicdisease," said study senior author Jonathan Stamler, M.D.
"In suchcases, the lung condition is often predictive of poorer
outcomes. Forothers, pulmonary hypertension is the primary disease."
"We havenow established a molecular defect of the red blood cells as
animportant contributing cause of hypertension in the lung,"
addedTimothy McMahon, lead author of the study. Physicians had
previouslyconsidered an abnormality within the lung itself as the
primary sourceof the condition, he explained. Physicians had not
considered red bloodcells as a cause of lung disease.
"We have found that when redblood cells are exposed to abnormally low
oxygen for long periods, theybecome depleted of an essential substance
that they normally release torelax blood vessels in the lung," McMahon
continued. "But not only doblood cells, which of course perfuse the
lung, cause lung problems,we've also found that inhalation of a new
drug designed to correct theblood defect can reverse this condition."
Stamler's groupreported in 1996 that hemoglobin in red blood cells acts
as a finelytuned biosensor, adjusting blood flow to provide exactly the
optimumamount of oxygen to tissues and organs. The blood cell adjusts
bloodflow by changing shape and releasing a nitric oxide-like
moleculecalled s-nitrosothiol (SNO), which the cell carries through
thebloodstream along with oxygen.
When oxygen levels are high,hemoglobin scavenges excess oxygen and NO,
constricting blood vesselsand reducing blood flow. When oxygen levels
drop, the NO is released torelax blood vessels and improve blood flow.
The Duke team now findsthat with prolonged oxygen shortage, or hypoxia,
blood cells becomedepleted of SNOs, therefore losing their ability to
relax blood vessels.
Morerecent evidence from the Duke group has indicated that other types
ofSNOs might offer new therapeutic approaches to diseases of the
heart,lung and blood. For example, the researchers found that SNOs
played acritical role in septic shock, a common cause of death in
intensivecare units. They later showed that the compounds are lacking
in theblood of patients with sickle cell disease and also play a part
inpreventing asthma. The latest findings extend the role of SNOs in
redblood cells to include pulmonary hypertension.
A new chemicaltherapy, which replenished SNO levels in the blood of
patients,restored the red blood cells' ability to dilate vessels,
loweredpressures, and improved the transfer of oxygen to tissues.
Similarly,in the lab, exposure of red blood cells to sustained hypoxia
led to adeficiency of the SNO vessel relaxant, according to the
researchers.The SNO-deficient blood cells failed to relax blood vessels
of thelungs in laboratory studies and constricted pulmonary blood
vessels inpigs, they reported. Restoration of SNO levels in the animals
likewiselowered pressures in the lungs.
The researchers demonstrated thatunder conditions of prolonged oxygen
deficiency, which is very commonin sick patients, red cells become
deficient for SNO, thereby losingtheir capacity to relax blood vessels
and boost blood flow, Stamlersaid. Pressure came down in the lungs of
animals given red blood cellsreplete in SNOs, whereas transfusion of
red blood cells deficient inSNO raised pressures, the team reported.
To examine the relevanceof the findings to human disease, the
researchers compared the level ofSNO in the blood of patients with
pulmonary hypertension to that ofhealthy people. Normal individuals had
five times more SNO in theirblood than did those with elevated lung
pressure. In fact, those withthe lung condition almost completely
lacked hemoglobin with bound SNO,a finding consistent with the effects
of hypoxia observed in the lab,Stamler said. That SNO-deficiency led to
impaired blood vessel dilationby the red cells, they showed.
The researchers reasoned that ifdeficiency of SNO in red blood cells
causes the lung condition, thenrestoring SNO levels should reverse the
disease. Ten patients treatedwith an inhaled SNO-generating gas
exhibited an increase in SNO in thebloodstream, found the researchers.
After therapy, patients' red bloodcells again relaxed blood vessels in
a manner comparable to that ofnormal red cells. In addition, the
pressures came down in the lungs ofthe patients.
"We have followed this process all the way fromcharacterizing the
molecular defect of red blood cells through thetranslation of this
basic scientific finding into a promising newtherapy," Stamler said. A
larger clinical trial effort now underwaywill further examine the
therapy's potential to relieve pulmonaryhypertension, he said.
Collaborators on the study include TimothyMcMahon, Gregory Ahearn,
Martin Moya, Andrew Gow, Yuh-Chin Huang,Raphael Nudelman, Yun Yan,
Abigail Krichman, Thomas Bashore, RobertCaliff, Claude Piantadosi and
Victor Tapson, all of Duke. BenjaminLuchsinger and David Singel of
Montana State University alsocontributed to the research.
manfred
candidates for psoriasis and other chronic inflammatory
skin diseases."
http://ajp.amjpathol.org/cgi/reprint/161/4/1409.pdf
American Journal of Pathology, Vol. 161, No. 4, October 2002
Copyright © American Society for Investigative Pathology
Nitric Oxide Donors Suppress Chemokine
Production by Keratinocytes in Vitro and in Vivo
<snip>
Chemicals
Glutathione (GS-H), S-nitrosoglutathione (GS-NO) and
( )-(E)-methyl-2-((E)-hydroxyimino)-5-nitro-6-methoxy-3-
hexenamide (NOR-1) were purchased from Calbiochem
(Darmstadt, Germany).
<snip>
Discussion
Psoriasis is a genetically determined skin disease characterized
by aberrant proliferation and differentiation of
keratinocytes as well as cutaneous inflammation. T cellmediated
immune mechanisms have a primary role in the
pathogenesis of psoriasis.29-32 In particular, activated
Th1 cells releasing IFN- and TNF- stimulate keratinocytes
to produce cytokines, chemokines, and adhesion
molecules, which further amplify the inflammatory response.
Keratinocyte production of chemokines contributes
relevantly to the establishment of the inflammatory
infiltrate. Specifically, IL-8 and related chemokines are
responsible for the intraepidermal collection of neutrophils.
5 MCP-1, RANTES, IP-10, and other CXCR3 ligands
attract predominantly monocytes and Th1 cells,6-8
whereas MIP-3 (CCL20) recruits Langerhans cells and
dendritic cells.33,34 Moreover, psoriatic keratinocytes
may have intrinsic defects leading to exaggerated synthesis
of certain chemokines such as IL-8, MCP-1, and
IP-10.5,8 Here we confirmed that keratinocytes cultured
from patients with psoriasis produce spontaneously
higher levels of IL-8, and on activation with IFN- and
TNF- higher amounts of IL-8, MCP-1, and IP-10. NO can
be made by several cell types residing in the skin including
both genuine immune-system cells as well as endothelial
cells, fibroblasts, and keratinocytes. NO actively
participates in the modulation of inflammatory reactions
and the trafficking of leukocytes.17,35 In particular, NO
and NO donors inhibit the expression of adhesion molecules
(eg, ICAM-1, VCAM-1, E-selectin) on endothelial
cells, and impede the rolling, firm adherence and/or
transmigration of monocytes and granulocytes.22,23
Moreover, NO can interfere with the activity of chemokines
by several mechanisms. NO as well as NO donors
can inhibit the production of IP-10, Mig, RANTES, and
MCP-1.19,20,21 Additionally, NO can reduce of activity of
chemokines (such as IL-8) through peroxynitrite-dependent
tyrosine nitration36 and it can function as an intracellular
messenger in chemokine signaling pathways.37
In this study, we have shown that NO donors reduce in
a dose-dependent manner the synthesis and release of
IP-10, RANTES, and MCP-1 from keratinocytes cultured
from healthy individuals and patients with psoriasis. In
contrast, IL-8 production was not affected by NO donors.
ICAM-1 provides a major adhesion mechanism by which
T cells and neutrophils bind to keratinocytes and are thus
retained in the epidermis. Psoriatic keratinocytes activated
with IFN- and TNF- showed a ICAM-1 induction
higher than normal keratinocytes. NO donors could efficiently
and dose dependently down-regulate membrane
and soluble ICAM-1 expression induced by IFN- and
TNF- in both normal and psoriatic keratinocytes. This
activity was specific because membrane HLA-DR expression
was not changed. In contrast to what observed
for chemokines, ICAM-1 mRNA was not affected by NO
donors, suggesting a posttranscriptional regulation. To
see whether NO donors could affect chemokine and
ICAM-1 expression also in vivo, a GS-NO-releasing ointment
was applied on psoriatic lesions for 14 days. The
results showed that GS-NO could markedly reduce IP-10,
RANTES, and MCP-1, but not IL-8 immunoreactivity in
keratinocytes, paralleling the in vitro results. In line with
the reduced production of chemokines by keratinocytes,
the skin treated with the GS-NO ointment showed diminished
keratinocyte ICAM-1 expression and lower numbers
of T cells and monocytes within and in proximity of
the epidermis as well as in the upper dermis. In contrast,
the number of T cells and monocytes in the deeper
dermis was not changed.
The signal transduction initiated by IFN- and TNF-
involves principally a cooperation between STAT-1 and
NF- B transcription factors.26,28 In contrast, AP-1 is
known to be less important in the signaling elicited by
these cytokines. We have shown that in transiently transfected
keratinocytes, IFN- and TNF- induced a strong
NF- B and STAT-1-binding activity, whereas the induction
of AP-1 function was less evident. Interestingly
enough, psoriatic keratinocytes exhibited a more prominent
NF- B and STAT-1, but not AP-1 activity compared
to control keratinocytes. Indeed, perturbation in signal
transduction pathways and in the activation of transcription
factors have been implicated in this dysregulated
functions of psoriatic keratinocytes.38,39 When keratinocyte
stimulation was performed in the presence of NO
donors an impaired NF- B and STAT-1, but not AP-1,
activation was observed. Inhibition of NF- B and STAT-1
activity may in part explain the capacity of NO donors to
reduce the synthesis of IP-10, RANTES, and MCP-1. The
inability of NO donors to influence IL-8 production may be
partially because of the lack of effects on AP-1, which is
critical for IFN- /TNF- -induced IL-8 gene expression.40
NO donors have been shown to inactivate keratinocyte
differentiation markers such as transglutaminase 1, loricrin,
and involucrin by interfering with AP-1 activity.41 In
this study, however, keratinocyte AP-1 transactivation
was induced by phorbol esters.
A variety of studies suggest that endogenous NO contributes
to the formation of psoriatic lesion. Nonetheless,
NO may have regulatory effects on diverse aspects of
inflammation. Our results indicate that NO donors efficiently
suppress IFN- /TNF- -induced keratinocyte activation
both in vitro and in vivo. In particular, NO donors
were potent inhibitors of the expression of chemokines
and adhesion molecules relevant to the generation of the
inflammatory infiltrate during psoriasis. Based on these
observations, NO donors seem interesting therapeutic
candidates for psoriasis and other chronic inflammatory
skin diseases.
manfred
It has been well established that all three NOS isoforms are
expressed in skin tissue. Expression of the constitutive neuronaltype
NOS isoform (nNOS) has been observed in keratinocytes
and melanocytes [23,44±47] ; expression of the endothelial-type
NOS (eNOS) could be detected in keratinocytes of the basal
epidermal cell layer and in dermal ®broblasts, endothelial capillaries
and eccrine gland cells [38,48,49]. The presence of constitutively
expressed nNOS and eNOS isoforms in the skin, that
are activated by elevated intracellular Ca#+ levels and generate
only small amounts of NO, suggests an involvement in maintaining
skin homoeostasis in regulating resting blood ¯ow and
responses to local warming and UV-B radiation [16]. These
constitutive, Ca#+}calmodulin-dependent NOS isoforms are
activated after UV irradiation in keratinocytes; theNOproduced
subsequently is responsible for the stimulation of melanogenesis
or the development of sunburn erythema [18,39,50]. In contrast,
the iNOS isoenzyme is not expressed in resident cells but is
strongly induced by in¯ammatory cytokines and endotoxins.
The induction of iNOS then results in the release of large
amounts of NO from the cells [4,5]. In general, the presence of
iNOS is associated with pathological conditions, which is also
true of skin tissue. The expression of iNOS has been described
for in¯ammatory diseases of the skin, including in¯ammatory
dermatoses and psoriasis [19±22]. Therefore a potential role for
NO as a novel mediator serving the communication between cells
by triggering cellular gene expression, as described previously
[9±13], became evident also for the skin. For these reasons our
interest focused on the identi®cation of novel NO-regulated
genes in keratinocytes to gain new insights into the origin of
these diseases.Weidenti®ed Cu}ZnSODas a novel NO-regulated
gene in keratinocytes, whose expression is strongly induced by
exogenously added and also endogenously produced NO in Šitro.
It is remarkable that the induction of Cu}Zn SOD is clearly
restricted to NO, because none of the many growth factors and
in¯ammatory cytokines tested were able to in¯uence Cu}Zn
SOD expression at all. The observed dependence on NO might
re¯ect a general mechanism of Cu}Zn SOD regulation by NO,
because we have also demonstrated NO-triggered Cu}Zn SOD
expression in rat mesangial cells in Šitro and during endotoxic
shock in rats in ŠiŠo [9].
The involvement of antioxidant enzyme systems in the regulation
of keratinocyte proliferation has been reported recently
[29±31]. Irradiation-stimulated keratinocyte proliferation was
inhibited by the addition of the antioxidative enzymes SOD
and catalase, thus demonstrating that the scavenging of O#
−d and
H#O# suppressed the enhanced proliferation of these cells [30].
This proposal is supported by the observation that proliferating
keratinocytes decreased their release of O#
−d when cells reached
con¯uence [29]. However, the situation turned out to be more
complex. The application of SIN-1, a donor releasing both NO
and O#
−d, resulted in the cytostasis of keratinocyte cultures. This
cytostatic effect of NO}O#
−d action could be reversed by
scavenging either the NO or the O#
−d released from SIN-1, thus
transforming SIN-1 to a O#
−d or NO donor respectively [31].
Furthermore, it has been shown that exogenously applied NO
stimulated keratinocyte proliferation in a biphasic manner. Low
concentrations of NO mediated keratinocyte proliferation,
whereas high doses of NO acted in an anti-proliferative manner
and subsequently initiated differentiation [25]. Moreover, we
have recently demonstrated the function of NO as a growth
factor in ŠiŠo for keratinocytes too. The inhibition of a functional
iNOS during the in¯ammatory phase of cutaneous wound repair
resulted in markedly decreased keratinocyte proliferation, atrophied
hyperproliferative epithelia at the wound edges and thus a
severely impaired re-epithelialization [24]. Therefore the dependence
of Cu}Zn SOD expression on NO (the present study)
clearly suggests a functional link between the actions of NO and
O#
−d. Remarkably, we observed a differential effect of NO on
Cu}ZnSODexpressional regulation, because low doses (100 lM)
of NO donors did not alter Cu}Zn SOD levels, whereas high
concentrations (500 lM) strongly induced Cu}Zn SOD mRNA
and protein levels. It is noteworthy that this expressional
regulation was exclusively under the control of NO, because
growth factors, cytokines and O#
−d did not alter Cu}Zn SOD
expression levels. Thus large amounts of NO are most likely to
decrease intracellular O#
−d levels by inducing the O#
−d dismutating
enzyme Cu}Zn SOD in keratinocytes. Because O#
−d levels have
been discussed as being involved in keratinocyte proliferation,
we speculated that NO-elevated Cu}Zn SOD levels in keratinocytes
might contribute to an anti-proliferative effect observed
at high concentrations of NO. This would be in line with the
observation that NO-triggered keratinocyte proliferation at low
concentrations [25] (see Figure 4) was associated with unaltered
manfred
Sorry--contiuned from above post:
Cu}Zn SOD expression levels. Indeed our results suggest that
the induction of Cu}Zn SOD levels was directly involved in the
proliferative behaviour of keratinocytes, because the cell line
psp1CZ1N revealed markedly decreased proliferation after the
ponasterone-induced overexpression of Cu}Zn SOD (Figure 6).
Moreover, we could mimic the anti-proliferative actions of high
doses of NO by the NO-independent induction of Cu}Zn SOD
within the cells. These results suggest that NO-regulated Cu}Zn
SOD might contribute to the cytostatic effects observed at high
concentrations of NO in keratinocytes.
To evaluate the possible relevance of our results in Šitro to a
situation in ŠiŠo, we chose to investigate iNOS and Cu}Zn SOD
expression in the in¯ammatory skin disease psoriasis. Histological
examination of psoriatic plaques reveals three major
pathogenic factors : abnormal keratinocyte differentiation,
hyperproliferation
of keratinocytes and in®ltration of in¯ammatory
cells into the skin [51], indicating that iNOS-inducing cytokines
are present in psoriatic skin. Several studies demonstrated the
involvement of different in¯ammatory cytokines, chemokines
and their receptors in psoriasis [52±57]. The presence of these
proin¯ammatory cytokines (especially IL-1, IL-6, IL-8 and TNFa)
explains the in®ltration of immune cells into psoriatic diseased
skin [58]. These cytokines trigger T-cell activation in lesional
psoriatic epidermis [59], further amplifying the in¯ammatory
process. These results suggest that in¯ammatory cytokines that
are potent inducers of iNOS might trigger a NO-dependent
Cu}Zn SOD overexpression in ŠiŠo. Recent studies independently
demonstrated an increased expression of iNOS in psoriatic skin
lesions [20±22]. Additionally, Cu}Zn SOD is expressed in normal
human skin and psoriatic plaques [27,28]. In line with our
observations in Šitro, we should have been able to detect, at
least, increased Cu}Zn SOD levels that were directly correlated
with overexpressed iNOS in psoriatic lesions in comparison with
uninvolved skin. This was indeed true (Figure 7), because a
strong induction of iNOS at the mRNA and protein levels
occurred in all examined biopsies of lesional skin, whereas no
iNOS expression was detected in control skin. We found a
marked increase in Cu}Zn SOD mRNA and protein levels in the
same psoriatic lesions that were strongly positive for iNOS
expression. It is worth emphasizing the strong increase in Cu}Zn
SOD levels in psoriatic plaques (Figure 7), although
immunohistochemical
studies indicated an expression of Cu}Zn SOD
that was almost exclusively restricted to the basal cells of the
lowest parts of the elongated rete ridges in psoriasis [27].
Interestingly, in situ hybridization against iNOS also revealed
that keratinocytes of the highly proliferative basal epidermal
layer at the tips of the rete ridges expressed the largest amounts
of iNOS mRNA [21]. This situation suggests that a correlation
between the presence of iNOS and Cu}Zn SOD expression in
keratinocytes might be of importance in in¯ammatory skin
diseases in ŠiŠo. Bruch-Gerharz et al. [60] discussed the role of
NOas a cytostatic mechanism to counteract excessive mitogenesis
in psoriasis. In line with this hypothesis, our results suggest an
anti-psoriatic role of NO in decreasing the epidermal proliferation
of the diseased skin: the overexpression of iNOS in psoriatic
lesions might contribute, at least partly, to the observed high
levels of Cu}Zn SOD. Furthermore, our results suggest that the
up-regulation of Cu}Zn SOD in keratinocytes might be involved
in mechanisms initiated to counteract the onset of keratinocyte
hyperproliferation in psoriatic skin.
From:
Biochem. J. (2000) 346, 719±728 (Printed in Great Britain) 719
Identification of copper/zinc superoxide dismutase as a nitric
oxideregulated
gene in human (HaCaT) keratinocytes : implications for
keratinocyte proliferation
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1220905&blobtype=pdf
The point of this being "results suggest an
anti-psoriatic role of NO in decreasing the epidermal proliferation
of the diseased skin"
manfred
http://www.liebertonline.com/doi/abs/10.1089/act.2006.12.59
Alternative & Complementary Therapies
Nitric Oxide, a Powerful Clinical Therapy
Apr 2006, Vol. 12, No. 2 : 59 -65
Associate Professor Chris D. Meletis, N.D.
National College of Naturopathic Medicine, Portland.
Nieske Zabriskie, N.D.
randall
On Oct 25, 1:37 pm, "manfred" <manfre...@lycos.com> wrote:
> I wish I could get to this one.
Why bother? While there are few hits for cu/zn,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20psoria*+cu/zn
It doesn't mean anything is out of order uP stream in regards to cu and
or zn per se.
Same for nitric oxide,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20psoria*+nitric
So? Why is that?
How about gut problems uP stream?
OH yes!
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17060119&query_hl=7&itool=pubmed_docsum
Malabsorption in psoriatic patients: Cause or consequence?
* Ojetti V,
* De Simone C,
* Aguilar Sanchez J,
* Capizzi R,
* Migneco A,
* Guerriero C,
* Cazzato A,
* Gasbarrini G,
* Amerio P,
* Gasbarrini A.
Departments of Internal Medicine, Catholic University, Rome, Italy.
Objective. The aetiopathogenesis of psoriasis is still unclear.
Associations between gut and skin diseases are well known, since
psoriatic patients show a high prevalence of coeliac disease.
Small-bowel abnormalities can cause clinical or, more frequently,
laboratory alterations that give rise to malabsorption. The aim of the
study was to evaluate the prevalence of malabsorption in psoriatic
patients. Material and methods. Fifty-five (29 M, 26 F, mean age 51+/-8
years) psoriatic patients in the Dermatology Centre of our hospital and
65 healthy controls (36 M, 29 F, mean age 47+/-9 years) were screened
for malabsorption using a D-xylose test. Psoriatic subjects who
resulted positive were further investigated in order to reach a better
characterization of the malabsorption using serum antigliadin,
antiendomysium and anti-transglutaminase antibodies, H2 lactulose
breath test, the parasitological faecal test and colonoscopy with
retrograde ileoscopy. Results. Altered D-xylose absorption was found in
60% (33/55) of psoriatic patients and in 3% (2/65) of controls. Of the
former, 6% had coeliac disease, 21% had bacterial overgrowth, 3% had
parasitic infections and 1 patient presented eosinophilic
gastroenteritis. Conclusions. Malabsorption was more prevalent among
psoriatic patients than among controls. Coeliac disease, bacterial
overgrowth, parasitic infestations and eosinophilic gastroenteritis
could be possible causes of malabsorption in these patients. Further
studies are needed to clarify the pathogenesis and possible causative
associations between gut and skin diseases.
PMID: 17060119
So, fixing anything uPstream including genetics may fix all the
downstream consequences.
Or at least one would hope.
But still, fingering the Gi tract isn't a bad idea for a natural
treatment.
randall... works for me!
randall
On Oct 25, 9:32 pm, "randall" <ranhu...@aol.com> wrote:
> On Oct 25, 1:37 pm, "manfred" <manfre...@lycos.com> wrote:
>
> > I wish I could get to this one.Why bother? While there are few hits for cu/zn,http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&t...
>
> It doesn't mean anything is out of order uP stream in regards to cu and
> or zn per se.
This reminds me of a test i've thought about previously.
Zn and carnosine from December to late spring as a test to determine
gut permeabilty.
How good is this for the gut (small intestines), zinc-carnosine,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20zinc+carnosine+mucosal
Will this test pan out? Or go the opposite direction, like the
L-glutamine tests?
While L-glutamine is touted as good for the Gi tract, it seemingly
increased p severity.
randall... can't win em all!
manfred
American Journal of Pathology, Vol. 162, No. 1, January 2003
Copyright © American Society for Investigative Pathology
Arginase 1 Overexpression in Psoriasis
Limitation of Inducible Nitric Oxide Synthase Activity as a
Molecular Mechanism for Keratinocyte Hyperproliferation
[...]
Our data, therefore, unequivocally demonstrate
that ARG1 activity will restrict the rate of iNOSderived
NO production in activated epidermal keratinocytes.
In psoriatic keratinocytes, low NO production
because of ARG1 overexpression could thus have important
implications for disease pathogenesis.
[...]
low NO levels
promote keratinocyte proliferation; high levels, however,
arrest cell proliferation and initiate differentiation.4
[...]
indeed endogenous iNOS-derived NO will
induce growth arrest in human keratinocytes in complete
accordance to our previous findings with exogenously
applied NO. Moreover, our data underscore the potent
growth-regulatory action of NO in human keratinocytes.
...it becomes evident
that NO is essential for reprogramming human keratinocytes
toward a proliferation stop.
[...]
Indeed, slightly increased NO levels
have been measured by chemiluminescence above psoriatic
plaques as compared to uninvolved skin.24 However,
two problems make such a result currently difficult
to interpret: first, as all three NO synthase isotypes are
expressed in the skin, the relative contribution of iNOS is
impossible to determine; and, second, there is currently
no information on NO levels generated by a fully active
iNOS in vivo. Moreover, a significant contribution could
potentially come from the numerous infiltrating immunocytes
in the dermis, if NO really permeates so far.
[...]
In conclusion, these findings together with our previous
analyses of psoriatic disease pathogenesis indicate that
ARG1 overexpression could be a molecular mechanism
for keratinocyte hyperproliferation in psoriasis by limitation
of iNOS activity. Moreover, our observations raise the
interesting possibility that inappropriately low iNOS activity
because of ARG1 co-expression would permit uncontrolled
and thus chronic inflammatory response, because
high-output NO synthesis has an important homeostatic
role in limiting immune-mediated inflammatory processes.
This contention is supported by previous findings
demonstrating that inhibition of NO synthesis exacer-
bates chronic inflammatory and immune-mediated processes.
22,23,30
Although the precise mechanism of keratinocyte hyperproliferation
in psoriasis is not clear, it is generally
believed that unbalanced immune responses play an
important role. Indeed, an altered activation status of
nuclear factor- B and differences in apoptosis resistance
have been observed in psoriatic keratinocytes, both factors
also being essential in immunoregulation.31,32 In this
context, an antagonistic interaction between iNOS and
ARG1 in psoriatic keratinocytes is mechanistically intriguing,
because the balance between both enzymes is normally
reciprocally regulated by Th1 and Th2 cells in
diverse settings of immunopathology, including cutaneous
wound healing processes.33 Thus, Th1 cytokines
induce iNOS and down-regulate ARG expression,
whereas Th2 cytokines induce ARG and suppress
iNOS.34,35 In psoriasis, the co-expression of iNOS and
ARG1 thus appears to represent a pathophysiological
state and an aberrant regulation of Th1- and Th2-type
responses.
In view of the assumed deleterious role of NO in a
number of pathological conditions, both inside and outside
the skin, a great deal of effort is being made to
develop therapeutic strategies aimed at suppressing the
action or production of NO. Our data suggest that attempts
to inhibit NO in chronic inflammatory diseases,
including psoriasis, should be re-evaluated, particularly
in view of a number of studies indicating that high NO
levels are of functional importance for the resolution of
chronic inflammatory processes.36 On this basis, a better
understanding of the mechanisms that restrict NO production
in pathophysiological situations may pave the
way for the design of therapeutic approaches to treat and
prevent psoriatic skin disease.
manfred
http://ajp.amjpathol.org/cgi/content/full/163/6/2642
American Journal of Pathology. 2003;163:2642-2643.)
© 2003 American Society for Investigative Pathology
--------------------------------------------------------------------------------
Correspondence
Explaining Decreased Nitric Oxide Production in Psoriatic Lesions:
Arginase 1 Overexpression versus Calcitonin Gene-Related Peptide
Mohammad Reza Namazi
Shiraz University of Medical Sciences, Shiraz, Iran
To the Editor-in-Chief:
I read with great interest the paper written by Bvuch-Gerharz et al,1
published in the January 2003 issue of The American Journal of
Pathology. In this paper, the authors have explained the reason for the
low NO concentration in the psoriatic plaques, in the face of high
expression of inducible NO synthase (iNOS) mRNA and protein, by showing
that arginase 1, which substantially regulates iNOS activity by
competing for the common substrate L-arginine, is highly overexpressed
in the psoriatic epidermis.
This is a feasible explanation, but not the only one. As a complement
to the explanation for the low NO concentrations in psoriatic plaques,
I would like to mention the effects of calcitonin gene-related peptide
(CGRP) on nitric oxide generation. The pathogenesis of psoriatic plaque
lesions is closely related to the overexpression of CGRP and it has
been shown that CGRP-containing nerve fibers are more dense in the
psoriatic epidermis.2 Taylor and co-workers3 have shown that CGRP
suppresses the production of NO most probably through inhibition of
iNOS enzymatic activity.
Therefore, it could be concluded that in addition to the overexpression
of arginase 1, overexpression of CGRP in the psoriatic lesions could
decrease the production of NO, thereby preventing the NO concentration
to reach the keratinocytostatic levels
manfred
I posted this from the eczema/psoriasis group a while ago:
I have been taking the supplement Proline (which is the amino acid,
L-Proline) for a month now and I am very quickly clearing up. It is
amazing. My derm.,
who has studied the skin for over 50 years, suggested it and his
patients
have been having amazing results !!
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3955053&dopt=Abstract
Biochim Biophys Acta. 1986 Mar 28;870(2):181-4. Related Articles,
Links
Kinetics of inhibition of rat liver and kidney arginases by proline and
branched-chain amino acids.
Carvajal N, Cederbaum SD.
The effects of proline, leucine, isoleucine and valine on kidney and
liver arginases were studied. At pH 7.5 and at nearly physiological
concentrations, the branched-chain amino acids caused a significant
inhibition of liver arginase A1 and only minor effects on kidney
arginase A4. Kidney arginase was, however, much more sensitive to
inhibition by proline than the liver enzyme. The inhibition of liver
and kidney arginases by branched-chain amino acids was partial,
indicating the existence of allosteric sites on both enzymes. The
function of kidney arginase in proline biosynthesis and a possible role
of branched-chain amino acids in the hydrolysis of arginine in liver is
discussed.
PMID: 3955053 [PubMed - indexed for MEDLINE]
randall
On Oct 28, 9:01 pm, "manfred" <manfre...@lycos.com> wrote:
> manfred wrote:
> >http://ajp.amjpathol.org/cgi/reprint/162/1/203.pdf
>
I've taken issue with MR Namazi before.
If he's really on to something or simply muddling thru it would surely
turn up in his recent work since this link.
If you find anything in the last three years on a positive note, let me
know.
randall...
manfred
Ok--if you don't like Namazi, forget him. He's not the author of the
original paper:
http://ajp.amjpathol.org/cgi/reprint/162/1/203.pdf
For increased vasodialation, how about trying this:
Am J Physiol Heart Circ Physiol. 2006 Aug 11; [Epub ahead of print]
Acute ascorbate supplementation alone or combined with arginase
inhibition augments reflex cutaneous vasodilation in aged human skin.
· Holowatz LA,
· Thompson CS,
· Kenney WL.
Kinesiology, Penn State, University Park, Pennsylvania, United States.
In summary, acute Asc supplementation incre(39)ased reflex cutaneous
vasodilation in aged skin. Asc supplementation combined with arginase
inhibition, to
increase L-arginine availability for NO synthesis through NOS, resulted
in a greater
increase in skin blood flow during hyperthermia. These treatments did
not alter reflex
cutaneous vasodilation in young subjects. Collectively, these data
indicate that agerelated
increases in oxidative stress and upregulated arginase activity may
contribute to
attenuated reflex cutaneous vasodilation.
randall
On Oct 29, 8:00 pm, "manfred" <manfre...@lycos.com> wrote:
> randall wrote:
> > On Oct 28, 9:01 pm, "manfred" <manfre...@lycos.com> wrote:
> > > manfred wrote:
> > > >http://ajp.amjpathol.org/cgi/reprint/162/1/203.pdf
>
> > I've taken issue with MR Namazi before.
>
> > If he's really on to something or simply muddling thru it would surely
> > turn up in his recent work since this link.
>
> >http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&it...
>
> > If you find anything in the last three years on a positive note, let me
> > know.
>
> > randall...Ok--if you don't like Namazi, forget him.
Never said I didn't like him. Just don't get him at times.
Not that there is anything there. LOL
> > He's not the author of the
> original paper:http://ajp.amjpathol.org/cgi/reprint/162/1/203.pdf
OK, lets see what Kolb-Bachofen V, has to say! Here's a few of her most
recent.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16291263&query_hl=4&itool=pubmed_docsum
(Does this one not point to the compensatory nature of psoriasis)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16281581&query_hl=4&itool=pubmed_docsum
(rats--no abstract, but doesn't the title say it all?)
This is getting redundant.
Try #22 (january/2003) to get back to Victoria Kolb-Bachofen study that
is your original cite.
Not like she hasn't solved our problem with the dozen or more studies
since this one. Oh wait
she hasn't.
At least I found her,
http://www.uni-duesseldorf.de/Immunbio/Englisch/staff.htm
She looks like a nice lady, maybe her next study will figure it all
out. Or the next ten?
>
> For increased vasodialation, how about trying this:
>
> Am J Physiol Heart Circ Physiol. 2006 Aug 11; [Epub ahead of print]
> Acute ascorbate supplementation alone or combined with arginase
> inhibition augments reflex cutaneous vasodilation in aged human skin.
> · Holowatz LA,
> · Thompson CS,
> · Kenney WL.
> Kinesiology, Penn State, University Park, Pennsylvania, United States.
>
> In summary, acute Asc supplementation incre(39)ased reflex cutaneous
> vasodilation in aged skin. Asc supplementation combined with arginase
> inhibition, to
> increase L-arginine availability for NO synthesis through NOS, resulted
> in a greater
> increase in skin blood flow during hyperthermia. These treatments did
> not alter reflex
> cutaneous vasodilation in young subjects. Collectively, these data
> indicate that agerelated
> increases in oxidative stress and upregulated arginase activity may
> contribute to
> attenuated reflex cutaneous vasodilation.
Well, i'm already taking around six grams a day of ascorbate. What? IV
the C next?
Or just don't eat high levels of L-arginine? Isn't that what cruiser
worked on for a few years?
randall...
manfred
>
> OK, lets see what Kolb-Bachofen V, has to say! Here's a few of her most
> recent.
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16987824&query_hl=4&itool=pubmed_docsum
>
Here she say "When we competed for L-arginine influx via the cationic
amino acid transporters by addition of L-lysine, we find a 60-70%
inhibition of arginase activity without significant loss of NOS-2
activity. Addition of L-valine, as an arginase inhibitor, leads to a
25% increase in NO formation and an 80-90% decrease in arginase
activity."
This sounds like what we need to do. Do we also need to increase
NOS-2?
From
http://rheumatology.oxfordjournals.org/cgi/content/full/45/suppl_3/iii17
The role of nitric oxide
V. Kolb-Bachofen1,, A. Kuhn2 and C. V. Suschek1,3
....More recently, our understanding of the role of NOS-2-derived NO
has shifted. We now know that NO has a direct impact on gene expression
by altering the expression levels of several hundred genes leading to a
protective 'stress response'. It also serves the important task of
down-regulating inflammation and suppressing leucocyte infiltration. In
summary, at present, NOS-2-derived NO synthesis is regarded as an
important regulatory and beneficial signal that is started by
pro-inflammatory events and--in the mode of a classical feed back
cycle--contributes to down-regulate inflammation [5].
Recently, several findings point to insufficient NO synthesis during
inflammation as a factor contributing to the chronicity of diseases.
Current evidence for this idea is found in three diseases, Psoriasis
[6], asthma and sickle cell anaemia. All three pathological entities
are characterized by NOS-2 expression and simultaneously by an
over-expression of arginase-1, an enzyme that competes effectively for
the common substrate L-arginine, thereby limiting NO synthesis. Indeed,
it has been shown that even under physiological, non-inflammatory
conditions, the L-arginine availability restricts the formation of NO,
and the L-arginine supplementation increases NO output significantly
[7]. In addition, there is also indirect evidence that the availability
of essential cofactors--especially of tetrahydro-biopterin-may be
limited in some diseases [8]. Several old and new data show
convincingly that under conditions of increased NO requirement,
increased or de novo expression of other NOS family members will occur
[9]. Thus, the observation of NOS-2 expression in the ET-1
[endothelin-1] over-expressing mice may represent exactly this
**** increased need for NO to counterbalance the ET-1 activity, or an
inadequately low NO output due to restricted substrate or cofactor
supply, or a combination of both.****
Indeed, the presence of infiltrating leucocytes argues in favour of
low NO formation, otherwise the anti-adhesive activity of NO would
protect from infiltration.
> This is getting redundant.
> Not like she hasn't solved our problem with the dozen or more studies
> since this one. Oh wait
Ø she hasn't.
OK, so she still believes in her (their) theory and is still validating
and improving upon it.
Nope-you don't want to avoid L-arginine. You want "Asc
supplementation combined with arginase inhibition, to increase
L-arginine availability"
I don't know if inhibiting arginase with L-lysine (Uwe did comment on
cold sores healing quickly) and/or L-Valine and/or L-Proline and
possibly throwing in some additional L-Arginine will help. Or how
about adding L-ornithine leading "to a highly significant increase
in hepatocytic NOS-2 activity with a concomitant and complete
abolishment of its dependence on extracellular L-arginine
concentrations."
Uwe did say the scientist were going in the wrong direction and I just
think this a new that theory deserves consideration and maybe some
experimentation. Wish I could. How about you?
randall
On Oct 30, 11:04 am, "manfred" <manfre...@lycos.com> wrote:
> randall wrote:
>
> > OK, lets see what Kolb-Bachofen V, has to say! Here's a few of her most
> > recent.
>
> >http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&...Ø http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&...
>
> Here she say "When we competed for L-arginine influx via the cationic
> amino acid transporters by addition of L-lysine, we find a 60-70%
> inhibition of arginase activity without significant loss of NOS-2
> activity. Addition of L-valine, as an arginase inhibitor, leads to a
> 25% increase in NO formation and an 80-90% decrease in arginase
> activity."
>
> This sounds like what we need to do. Do we also need to increase
> NOS-2?
I don't know. I just came off a rant! LOL
Hoping i"m not flaring now!
Look, i took the arginine/ornithine mixture pushed by Dirk and sandy
back in the 80's.
It wasn't good for Psoriasis iirc.
>
> Fromhttp://rheumatology.oxfordjournals.org/cgi/content/full/45/suppl_3/iii17
> > since this one. Oh waitØ she hasn't.
>
> OK, so she still believes in her (their) theory and is still validating
> and improving upon it.
Why not look closer at endothelins? There are three of them?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&dispmax=100&term=%20psoria*+endothelins
http://www.google.com/search?hl=en&lr=&q=endothelins&btnG=Search
ok and let's add in our keywords now,
http://www.google.com/search?hl=en&lr=&q=endothelins+arginine+lysine&btnG=Search
OKK you take the time and let me know.
And i'll share what i've done in regards to this.
I DID take lysine with the alcar supplements recently when I nearly
cleared 100%. I also
took several other things. Google me for alcar back last summer. I'm
sure i posted on it.
> > > For increased vasodialation, how about trying this:
>
> >http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&...
>
> > > Am J Physiol Heart Circ Physiol. 2006 Aug 11; [Epub ahead of print]
> > > Acute ascorbate supplementation alone or combined with arginase
> > > inhibition augments reflex cutaneous vasodilation in aged human skin.
> > > · Holowatz LA,
> > > · Thompson CS,
> > > · Kenney WL.
> > > Kinesiology, Penn State, University Park, Pennsylvania, United States.
>
> > > In summary, acute Asc supplementation incre(39)ased reflex cutaneous
> > > vasodilation in aged skin. Asc supplementation combined with arginase
> > > inhibition, to
> > > increase L-arginine availability for NO synthesis through NOS, resulted
> > > in a greater
> > > increase in skin blood flow during hyperthermia. These treatments did
> > > not alter reflex
> > > cutaneous vasodilation in young subjects. Collectively, these data
> > > indicate that agerelated
> > > increases in oxidative stress and upregulated arginase activity may
> > > contribute to
> > > attenuated reflex cutaneous vasodilation.
>
> > Well, i'm already taking around six grams a day of ascorbate. What? IV
> > the C next?
Don't laugh now. I'm serious on this one. LOL
>
> > Or just don't eat high levels of L-arginine? Isn't that what cruiser
> > worked on for a few years?Nope-you don't want to avoid L-arginine. You want "Asc
> supplementation combined with arginase inhibition, to increase
> L-arginine availability"
>
> I don't know if inhibiting arginase with L-lysine (Uwe did comment on
> cold sores healing quickly)
Do a dirk and sandy pearson google with lysine. OK i'll do it,
http://www.google.com/search?hl=en&lr=&q=dirk+pearson+arginine+lysine&btnG=Search
H'mmm looking at the first one, i'm gonna have to take the time to read
these. Sheesh!
> and/or L-Valine and/or L-Proline and
> possibly throwing in some additional L-Arginine will help. Or how
> about adding L-ornithine leading "to a highly significant increase
> in hepatocytic NOS-2 activity with a concomitant and complete
> abolishment of its dependence on extracellular L-arginine
> concentrations."
> Uwe did say the scientist were going in the wrong direction and I just
> think this a new that theory deserves consideration and maybe some
> experimentation. Wish I could. How about you?
Been there and continue to be there. Now i'm sucking down green onion
leaves, kale, garlic
and all the rest of my turbo chargers.
And starting some anti-inflammation ::
http://en.wikipedia.org/wiki/Prophylaxis
randall... and i'm off and running wild!
manfred
Randall,
Do you feel that the Sweet Whey--IP6--glucosamine/chondroitin--vitamin
C combination is giving you the clearing you are currently
experiencing? Would you mind sharing the name of the whey product you
are using now? You said you were using a Jay Robb product but were not
happy with it. Why? And what are you using now?
Thanks!
randall
manfred wrote:
> Randall,
> Do you feel that the Sweet Whey--IP6--glucosamine/chondroitin--vitamin
> C combination is giving you the clearing you are currently
> experiencing?
I think it certainly helped. But i've already taken NAC out of the mix
and many
other supplements I was taking as well. I've added in mainly foods to
my shakes
to see what the differences would be. As mentioned previously, i've
added in
onion leaves/green onions, crushed garlic, more ginger and fruits in
season.
It's been over two months off the NAC and I expected some flares and
quickly getting right back on it. Boy was I wrong.
The last two months till recently were sub 3% pasi levels.
And it's 80 degrees outside right now. I may partake!
>Would you mind sharing the name of the whey product you
> are using now? You said you were using a Jay Robb product but were not
> happy with it. Why?
I have one more day of Jay.
Then I go with Bob's Red Mill, Sweet dairy whey.
Somebody in the group put up a link for it.
Looks identical to Jays product. I paid about $11 for 96 oz.s in
four packages. Not a bad price but shipping/handling charges
were $9...
What I liked about the proflora product, which was produced
by Land O' Lakes, was a fluffed up texture via an aeration process
that the rest of them don't bother with. I'll keep looking for it.
> And what are you using now?
Have not stopped taking glucosamine/chondroitin 2X day =
1500mgs/1200mgs
Also taking the IP6 every morning at least a half hour before taking
two grams of vitamin C.. Hour or so later I make my protein/sweet whey
shake with frozen fruits et al added in.
Later in the day I take another two grams of C, between 2-4 pm. Then
eat
supper and take two more grams of vitamin C about 9-9:30 pm.
I do take supplements which include fish oil/borage/flax/cod liver, a
multi-vitamin,
folates, milk thistle, glucosamine/chondroitin, and and ...
(For the time being i'm off the magnesium, nac, alcar, CoQ10, and a few
other items)
This week was unusual as I'm on 500 mgs of amoxicillin/3X-day for ten
days.
http://en.wikipedia.org/wiki/Amoxicillin
My p increased about 50% in six days. Maybe it's a herx effect?
http://en.wikipedia.org/wiki/Herxheimer_reaction
If it gets worse i'll look in to it, i suppose.
I know i'm forgetting something. LOL
randall... must be the selenium/etc
> Thanks!
manfred
Amino Acid Profile Per Serving (Jay Robb's Whey Protein)
Isoleucine (Branch Chain Amino Acid) 1757 mg.
Leucine (Branch Chain Amino Acid) 3031 mg.
Valine (Branch Chain Amino Acid) 1273 mg.
Alanine 1085 mg.
Arginine 997 mg.
Aspartic Acid 2168 mg.
Cysteine 1416 mg.
Glutamic Acid 2953 mg.
Glycine 611 mg.
Histidine 299 mg.
Lysine 2483 mg.
Methionine 679 mg.
Phenylalanine 1456 mg.
Proline 236 mg.
Serine 1316 mg.
Tryptophan 563 mg.
Threonine 967 mg.
Tyrosine 981 mg.
I couldn't find a listing of the amino acids in the other whey
products you mention but in the Jay Robb product you are getting the
arginase inhibitors (Isoleucine, Lucine, Valine, Lysine, Proline)
mentioned in the abstracts!
> > And what are you using now?
>
> Have not stopped taking glucosamine/chondroitin 2X day =
> 1500mgs/1200mgs
>
> Also taking the IP6 every morning at least a half hour before taking
> two grams of vitamin C.. Hour or so later I make my protein/sweet whey
> shake with frozen fruits et al added in.
>
> Later in the day I take another two grams of C, between 2-4 pm. Then
> eat
> supper and take two more grams of vitamin C about 9-9:30 pm.
And by taking Vitamin C you are getting the "abscorbic acid combined
with arginase inhibition, to increase L-arginine availability"
So I guess you are doing exactly what is suggested in the above studies
and it works for you. Maybe increasing the amounts of the inhibitors
would work even better. I don't know if the amount in one shake a
day is enough.
> I do take supplements which include fish oil/borage/flax/cod liver, a
> multi-vitamin,
> folates, milk thistle, glucosamine/chondroitin, and and ...
>
> (For the time being i'm off the magnesium, nac, alcar, CoQ10, and a few
> other items)
All great for pretty much every body. Why did you stop the lysine and
alcar if you were near 100% clear? Testing?
> This week was unusual as I'm on 500 mgs of amoxicillin/3X-day for ten
> days.
>
> http://en.wikipedia.org/wiki/Amoxicillin
>
> My p increased about 50% in six days. Maybe it's a herx effect?
>
> http://en.wikipedia.org/wiki/Herxheimer_reaction
I always flare from infections--colds, ear infection, cold sores,
especially strep.
manfred
Here's a few more for your reading enjoyoment.
http://cgmp.blauplanet.com/tool/arginase.html
Most of the cells that synthesizes NO also contain arginase. Arginases
are a group of enzymes that catalyze the hydrolysis of L-arginine to
yield L-ornithine and urea. Arginase I is constitutively expressed and
arginase II is induced by endotoxin. The role of arginase in the
regulation of NO/cGMP system is probably understimated. This enzyme is
clearly crucial in the modulation of NO production under inflammatory
conditions (NO synthesis by NOS2), but it might also play an important
role in constitutive synthesis of NO. See references 1-8 for additional
information:
1Buga GM, Singh R, Pervin S, Rogers NE, Schmitz DA, Jenkinson CP,
Cederbaum SD, Ignarro LJ.
Arginase activity in endothelial cells: inhibition by
NG-hydroxy-L-arginine during high-output NO production. Am J Physiol
1996;271:H1988.
2Boucher JL, Moali C, Tenu JP. Nitric oxide biosynthesis, nitric oxide
synthase inhibitors and arginase competition for L-arginine
utilization. Cell Mol Life Sci 1999;55:1015 REVIEW .
3Tenu JP, Lepoivre M, Moali C, Brollo M, Mansuy D, Boucher JL.
Effects of the new arginase inhibitor N(omega)-hydroxy-nor-L-arginine
on NO synthase activity in murine macrophages. Nitric Oxide 1999;3:427.
4Colleluori DM, Ash DE.
Classical and slow-binding inhibitors of human type II arginase.
Biochemistry 2001;40:9356.
5Hein TW, Zhang C, Wang W, Chang CI, Thengchaisri N, Kuo L. I
schemia-reperfusion selectively impairs nitric oxide-mediated dilation
in coronary arterioles: counteracting role of arginase. FASEB J
2003;17:2328.
6Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S,
Shoukas AA, Nyhan D, Champion HC, Hare JM.
Arginase reciprocally regulates nitric oxide synthase activity and
contributes to endothelial dysfunction in aging blood vessels.
Circulation 2003;108:2000.
7Masuda H, Yano M, Sakai Y, Kihara K, Yamauchi Y, Azuma H.
Modulation of intrinsic cavernous tone and nitric oxide production by
arginase in rabbit corpus cavernosum. J Urol 2004;171:490.
8Zhang C, Hein TW, Wang W, Miller MW, Fossum TW, McDonald MM, Humphrey
JD, Kuo L. Upregulation of Vascular Arginase in Hypertension Decreases
Nitric Oxide-Mediated Dilation of Coronary Arterioles Hypertension
2004;44:935.
>From our group:
FYI:
A few months ago I had a cold sore on my lip. My brother-in-law
suggested
taking L-Lysine to help it heal. Not only did the cold sore heal, but
my
psoriasis appears to have improved. It hasn't cleared, but has become
noticeably better.
Steve
(The Duck)
http://www.blackwell-synergy.com/doi/full/10.1111/j.1346-8138.2006.00131.x
The Journal of DermatologyVolume 33 Page 557 - August
2006doi:10.1111/j.1346-8138.2006.00131.x
CASE REPORT
Necrolytic migratory erythema without glucagonoma in a patient with
short bowel syndrome
ABSTRACT
Necrolytic migratory erythema (NME) is an uncommon inflammatory
dermatosis with a distinctive clinical and histological appearance. It
shows irregular erythema, bullae, erosion, crusts and pigmentation.
While it is typically associated with glucagonoma, some cases of NME
without glucagonoma have been reported. Herein, we report a case of
necrolytic migratory erythema associated with malabsorption 30 years
after ileocolectomy. She presented erosive erythema with scale or
partly flaccid bullae on her intergluteal cleft, buttock and
extremities. Her laboratory data revealed essential amino acid
deficiency and a slightly decreased serum zinc level, while her plasma
glucagon level was low. With diagnosis of non-glucagonoma-associated
NME with malabsorption due to short-bowel syndrome, she was treated and
improved by i.v. *****amino acid supplement***** . Histological
findings of NME include necrotic changes of keratinocytes in the upper
epidermis, proliferation of those in the lower epidermis and
inflammatory cell infiltration of upper dermis. We also examined the
expression pattern of epidermal keratins (K6, K10) and Ki-67, one of
the markers of proliferative activity, to assess the proliferation and
differentiation of keratinocytes in a NME lesion by immunostaining. The
findings with these immunostainings support the characteristics of
HE-staining, and suggest ****hyponutrition may induce changing
differentiation/proliferation of keratinocytes****
>From the discussion:
...Most patients with NME, with or without glucagonoma, have amino acid
deficiency, and have improvement after administration of i.v. amino
acids. Some cases are successfully treated by zinc supplement alone.9
The relationship between amino acids and zinc has been revealed
recently; amino acids are needed for production of peptides that carry
zinc,19 and some proteinases require zinc as catalyst.20 It has not
been elucidated how amino acid and zinc deficiency affects the
pathogenesis of NME...
...In our patients, the upregulation of K6 and the suppression of K10
meet the hyperproliferative nature of the epidermis as seen in
psoriasis....Amino acid deficiency may cause altered
differentiation/proliferation of keratinocytes in the NME lesion.
manfred
Current Opinion in Clinical Nutrition & Metabolic Care. 1(6):531-538,
November 1998.
Efron, David T.; Barbul, Adrian
Abstract:
Arginine holds a key position in the cellular functions and
interactions that occur during inflammation and immune responses. The
competition for arginine as a substrate between nitric oxide synthase
and arginase appears to be at the core of the regulation of the
inflammatory process. This review examines some of the recently defined
effects of arginine on various inflammatory processes and immune cell
functions.
PMID: 10565406 [PubMed - indexed for MEDLINE]
Randall, you posted this study in 2005:
Received: 3 June 2005 Accepted: 4 June 2005 Published online: 8
August 2005
Summary. Citrulline (Cit, C6H13N3O3), which is a ubiquitous amino acid
in mammals, is strongly related to arginine. Citrulline metabolism in
mammals is divided into two fields: free citrulline and citrullinated
proteins. Free citrulline metabolism involves three key enzymes: NO
synthase (NOS) and ornithine carbamoyltransferase (OCT) which produce
citrulline, and argininosuccinate synthetase (ASS) that converts it
into argininosuccinate. The tissue distribution of these enzymes
distinguishes three "orthogonal" metabolic pathways for citrulline.
Firstly, in the liver, citrulline is locally synthesized by OCT and
metabolized by ASS for urea production. Secondly, in most of the
tissues producing NO, citrulline is recycled into arginine via ASS to
increase arginine availability for NO production. Thirdly, citrulline
is synthesized in the gut from glutamine (with OCT), released into the
blood and converted back into arginine in the kidneys (by ASS); in this
pathway, circulating citrulline is in fact a masked form of arginine to
avoid liver captation. Each of these pathways has related pathologies
and, even more interestingly, citrulline could potentially be used to
monitor or treat some of these pathologies. Citrulline has long been
administered in the treatment of inherited urea cycle disorders, and
recent studies suggest that citrulline may be used to control the
production of NO. Recently, citrulline was demonstrated as a
potentially useful marker of short bowel function in a wide range of
pathologies.
*****One of the most promising research directions deals with the
administration of citrulline as a more efficient alternative to
arginine, especially against underlying splanchnic* sequestration
of amino acids. Protein citrullination results from post-translational
modification of arginine; that occurs mainly in keratinization-related
proteins and myelins, and insufficiencies in this citrullination occur
in some auto-immune diseases such as rheumatoid arthritis,
psoriasis****
or multiple sclerosis.
*splanchnic--relating to or affecting the viscera
"splanchnic nerve"
sysnonyms-visceral
viscera--internal organs collectiveley, expecially those in the
abdominal cavity
synonyms--entrails, innards
What was Cruiser hinting at when he asked "what is a visceral"?
More about citruline:
The choice of citrulline as a potential tool to increase muscle protein
synthesis appears to be an elegant and very logical strategy. As a
matter of fact, among amino acids citrulline has a unique metabolism:
it is not used by the intestine, and it is not taken up by the liver
(11). Hence, administering citrulline is a tool to deliver nitrogen
(through endogenous metabolism into arginine) available for protein
synthesis in the peripheral tissues, including the muscle.
(good-for-uwe)
http://ajpendo.physiology.org/cgi/content/full/291/3/E582
arginase can downregulate NO production by decreasing intracellular
arginine concentrations. iNOS and arginase activities are regulated
reciprocally in macrophages by cytokines, and this may guarantee the
efficient production of NO. In contrast, iNOS and arginase isoforms
(type I and/or II) are coinduced in immunostimulated macrophages, but
not in PC12 cells and glial cells. These results indicate that NO
production is modulated by the recycling and degradation of arginine.
Arginase also plays an important role in regulation of polyamine and
proline synthesis.
Citrulline that is formed as a by-product of the NOS reaction can be
recycled to arginine by successive actions of argininosuccinate
synthetase (AS) and argininosuccinate lyase (AL), forming the
citrulline-NO cycle
NO production in ß-cells is regulated positively by the citrulline-NO
cycle (17) and negatively by arginase (18). Therefore, modulation of
either pathway may be effective in attenuating NO production.
http://jn.nutrition.org/cgi/content/full/134/10/2820S
Could the citrulline-NO cycle be what Uwe was refering to when he
talked said
"It works like recharging your battery of these
nutrients. Each day is worth 3-4 years of depletion."
Dr. Christ suggests that any patient who is seriously interested
in getting rid of Psoriasis, to drink absolutely no alcohol, at least
until the skin is clear. If the patient's skin does not recover
within
a few weeks, he suggests to give the patient liver tablets, especially
those metabolic products which are found in the fumaric acid cycle
(L-Arginine, L-Citrulline, L-Aspartate and L-Ornithine). He would
give these in the form of an injection intravenously every day for 2
to 3 weeks. Very frequently the patient will then experience a dramatic
improvement of the skin
http://ajpregu.physiology.org/cgi/reprint/291/3/R684.pdf
[Immune correction in the therapy of patients with prevalent psoriasis
with the help of amino acid complex]
[Article in Russian]
In patients with prevalent psoriasis a positive influence amino acid
addition (with the standart therapy) on the clinical status of patients
and their immune status induces. As a result of this addition use the
lesion area diminished, prolongation of remission periods, reduction of
the time spent in hospital.
PMID: 15154363 [PubMed - indexed for MEDLINE] Vopr Pitan.
2004;73(2):8-10
Guidelines for use: Amino acid supplements are more effective when they
don't have to compete with the amino acids in high-protein foods. Take
the supplements at least an hour and a half before or after meals
(first thing in the morning or at bedtime may be best). Individual
amino acid supplements should not be used for longer than three months,
unless you are under the supervision of a doctor familiar with their
use. Take mixed amino acid supplements on an empty stomach and also at
a different time of day than you take the individual supplement.
http://www.rd.com/content/openContent.do?contentId=1503
randall
So, around $20 for six pounds.
Then go vegetarian. Your taking the amino acids to a very friendly
level versus psoriasis.
But also beware of arachidonic acid from other foodstuffs. Soy bean
oils etc.
My mind is turning towards foxp3 and T-regs now.
As the article in sciam pointed out, the direction is for a cancer cure
due to
high levels of T-regs. While autoimmune conditions have lower levels of
T-regs.
I'm back to Th1/Th2 with a new twist.
Th1 = low T-reg's
Th2= HIGH T-regs
Obviously we can only do so much with diet.
Will it be enough? In my case yes!
Poping some NAC may even let me go hog wild!
(pork is bad= high in arachidonic acids)
Funny huh! I have to explain my stupid jokes...
And what about curcumin?
I've got that option open. As well as kalawalla, oregon grape etc.
We have loads of options. Or I do anyway.
>
> > > And what are you using now?
> >
> > Have not stopped taking glucosamine/chondroitin 2X day =
> > 1500mgs/1200mgs
> >
> > Also taking the IP6 every morning at least a half hour before taking
> > two grams of vitamin C.. Hour or so later I make my protein/sweet whey
> > shake with frozen fruits et al added in.
> >
> > Later in the day I take another two grams of C, between 2-4 pm. Then
> > eat
> > supper and take two more grams of vitamin C about 9-9:30 pm.
>
> And by taking Vitamin C you are getting the "abscorbic acid combined
> with arginase inhibition, to increase L-arginine availability"
>
> So I guess you are doing exactly what is suggested in the above studies
> and it works for you. Maybe increasing the amounts of the inhibitors
> would work even better. I don't know if the amount in one shake a
> day is enough.
If your right it's more then enough as i've gone crazy eating foods
loaded with arachidonic acids. Meats (pork, red meat etc), eggs, dairy
etc.
I still avoid the oils. Soy bean, egg yolks (regular types), will eat
the
high dha/epa eggs (thanks to J), and I wasn't drinking much milk
during the time period when I changed supplements.
So. Do I go back and redo the whole supplement trials and drink milk.
LOL
Got milk?
Got P!
>
> > I do take supplements which include fish oil/borage/flax/cod liver, a
> > multi-vitamin,
> > folates, milk thistle, glucosamine/chondroitin, and and ...
> >
> > (For the time being i'm off the magnesium, nac, alcar, CoQ10, and a few
> > other items)
>
>
> All great for pretty much every body. Why did you stop the lysine and
> alcar if you were near 100% clear? Testing?
Yes.... the alcar blew my mind. I'm looking at answers to gaining
reasonable levels of energy without strapping the body with turbo
chargers.
>
> > This week was unusual as I'm on 500 mgs of amoxicillin/3X-day for ten
> > days.
> >
> > http://en.wikipedia.org/wiki/Amoxicillin
> >
> > My p increased about 50% in six days. Maybe it's a herx effect?
> >
> > http://en.wikipedia.org/wiki/Herxheimer_reaction
>
> I always flare from infections--colds, ear infection, cold sores,
> especially strep.
But I didn't have anything. It was preventative due to minor surgery.
I suppose the doctor needs to cover his behind and i'm on antibiotics
for ten days.
A good test of my gut flora? May as well make the best of it.
>
> > If it gets worse i'll look in to it, i suppose.
It's very dry here the last few days, but changing tomorrow or so they
say.
My skin doesn't look bad enough to worry at this point.
> >
> > I know i'm forgetting something. LOL
> >
> > randall... must be the selenium/etc
> >
> >
> >
> > > Thanks!
I almost forgot the selenium. I also recalled something else that i've
subsequently forgotten.
I won't forget to vote today.
"Always vote for principle, though you may vote alone, and you may
cherish the sweetest reflection that your vote is never lost." - John
Quincy Adams
randall...
randall
I'm not meaning to side track you with my stuff.
OK, i'm starting the foray.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16635787&query_hl=14&itool=pubmed_docsum
Immune tolerance to self-major histocompatibility complex class II
antigens after bone marrow transplantation: role of regulatory T cells.
* Hess AD,
* Thoburn CJ.
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins
University, Baltimore, Maryland 21231, USA. adh...@jhmi.edu
The immune system undergoes rapid reconstitution after autologous or
syngeneic bone marrow transplantation with the re-establishment of
tolerance to self-antigens. Administration of drugs such as
cyclosporine that inhibit thymic-dependent clonal deletion disrupts the
reconstitution of the immune system. In the absence of a peripheral
regulatory T cells eliminated by the preparative regimen, systemic
autoimmunity with pathology similar to graft-versus-host disease often
develops. Moreover, the resolution of autoaggression is dependent on
the reconstitution of CD4+ regulatory T cells. This study examined the
specificity and function of this regulatory population assessed ex vivo
that plays a critical role in down-regulating the autoreactive T
lymphocyte response in cyclosporine-induced syngeneic graft-versus-host
disease. The results suggest that both the antigen-specific regulatory
and pathogenic effector T cells recognize a common peptide antigen
framework (CLIP, a peptide derived from the invariant chain) presented
by major histocompatibility complex class II molecules. Analysis of the
CD4+ T-cell compartment revealed two subsets of CLIP-reactive T cells
that differentially require the N- and C-terminal flanking domain of
this peptide. Regulatory function is associated with the cells that
require the C-terminal flanking domain. This population expresses the
Foxp3 nuclear transcription factor and plays a critical role in
re-establishing tolerance to self-major histocompatibility complex
class II antigens. In addition to suppressing the production of type 1
cytokines, these regulatory T cells can direct the apoptotic death of
the pathogenic autoreactive lymphocytes. This study also suggests that
the development of functional regulatory activity is an active response
initiated by the presence of autoreactive lymphocytes that can present
the target antigen (major histocompatibility complex class II CLIP) to
the regulatory T cells. Moreover, this process can be mimicked by
peptide antigen in the absence of the pathogenic effector lymphocytes
leading to the development of functional regulatory T-cell activity.
PMID: 16635787
http://www.biocarta.com/pathfiles/h_mhcPathway.asp
Clip and the invariant chain rears its head again. So, we go with it,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16984974&query_hl=14&itool=pubmed_docsum
&
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16725235&query_hl=14&itool=pubmed_docsum
We have vaccine possibilties once they figure out structure and
pathogenesis.
Time line: ten years? five if we're lucky?
-----------------
Till we have that vaccine and it could be a long long while, we can
hunker down with gut decisions.
Raising T-regs is that strategy,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16888164&query_hl=16&itool=pubmed_docsum
Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in
vivo: therapeutic applications in autoimmunity and transplantation.
* Chorny A,
* Gonzalez-Rey E,
* Ganea D,
* Delgado M.
Instituto de Parasitologia y Biomedicina, CSIC, Avd. Conocimiento, PT
Ciencias de la Salud, Granada 18100, Spain.
CD4+ CD25+ regulatory T cells (Treg) control the immune response to a
variety of antigens, including self-antigens, and several models
support the idea of the peripheral generation of CD4+ CD25+ Treg from
CD4+ CD25- T cells. However, little is known about the endogenous
factors and mechanisms controlling the peripheral expansion of CD4+
CD25+ Treg. We have found that the immunosuppressive neuropeptide
vasoactive intestinal peptide (VIP) induces functional Treg in vivo.
The administration of VIP together with specific antigen to
TCR-transgenic mice results in the expansion of the CD4+ CD25+,
Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell
proliferation through direct cellular contact. The VIP-generated CD4+
CD25+ Treg transfer suppression, inhibiting delayed-type
hypersensitivity in the hosts, prevent graft-versus-host disease in
irradiated host reconstituted with allogeneic bone marrow, and
significantly ameliorate the clinical score in the collagen-induced
arthritis model for rheumatoid arthritis and in the experimental
autoimmune encephalomyelitis model for multiple sclerosis.
PMID: 16888164
And since those Tregs are linked to your gut & P now, diet and
starvation cocktails will still be the leading edge.
It's taken me from a high moderate/semi-severe at times to a mild case.
randall... Good God-Whats not to like?
randall
Expanding the T-reg theme of this thread in to drugs in the PiPeline.
There was another GOOD article recently in sciam (scientific american),
mentioned in this thread already. Here's a page from Immune Response
corp,
Oct. 11, 2006,
http://www.imnr.com/news/2006/2006OCT11.htm
[...]
FOXP3+ Highlighted in latest issue of Scientific American (Oct/2006)
This large NeuroVax™ trial will also give us the opportunity to
further explore the FOXP3+ regulatory T-cell mechanism of action that
was demonstrated in our Phase IIa trial data presented this past April
at AAN. As evidenced by the article entitled “Peacekeepers of the
Immune System” in the latest issue of Scientific American, the role
of FOXP3+ regulatory T-cells in controlling autoimmune disease has
become a very important topic in immunology in the last 18 months. To
our knowledge, NeuroVax™ is the first therapeutic that has been shown
in clinical trials to boost FOXP3+ levels in patients with MS. Our new
trial will generate substantial additional data related to this
mechanism which we hope will help scientists better understand the
potential for NeuroVax™ to alter the course of MS by amplifying
FOXP3+ responses.
Beyond MS, we believe that our approach that impacts on the FOXP3+
immune regulatory mechanism could well prove to be a major breakthrough
for autoimmune disease in general including psoriasis and rheumatoid
arthritis (RA) for which we have TCR peptide-based therapeutic vaccines
(ZORCELL™ for psoriasis and RaVax™ for RA) with Investigational New
Drug Applications with the FDA. During the next year, we plan to
initiate new clinical work with at least one of these products aimed at
evaluating the effect on FOXP3+. This work will expand our autoimmune
product pipeline and position us to further exploit the potential of
our intellectual property position with respect to clinical
applications of vaccines and diagnostics that impact FOXP3+.
----------------------------------
First a refresher (posted Aug. 13/2006),
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16902287&query_hl=3&itool=pubmed_docsum
Depletion of CD4+ CD25+ Foxp3+ naturally occurring regulatory T cells
(T(reg)) induces autoimmune phenomena. These cells have not yet been
fully characterized in the skin of psoriatic patients. <sniP>
There are many Th1 I.M.I.D's requiring more Treg's. MS leading the
pack.
Does Michael Fox really need new stem cells to accomplish this?
The drugs will be coming. Here's more on the above.
http://www.drugnewswire.com/867
[...]
NeuroVax(TM), which is based on the Company's patented T-cell receptor
(TCR) peptide vaccine technology, has shown potential clinical value in
the treatment of relapsing forms of MS. NeuroVax(TM) has been shown to
stimulate strong, disease-specific cell-mediated immunity in nearly all
patients treated and appears to work by enhancing levels of FOXP3+ Treg
cells that are able to down regulate the activity of pathogenic T-cells
that cause MS. Increasing scientific findings have associated
diminished levels of FOXP3+ Treg cell responses with the pathogenesis
and progression of MS and other autoimmune diseases such as rheumatoid
arthritis (RA), psoriasis and Crohn's disease. In addition to MS, the
Company has open Investigational New Drug Applications (IND) with the
FDA for clinical evaluation of TCR peptide-based immune-based therapies
for RA and psoriasis.
------------------------------
Here's the next possiblity for P.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17091277&query_hl=1&itool=pubmed_docsum
In situ depletion of CD4(+) T cells in human skin by Zanolimumab.
* Villadsen LS,
* Skov L,
* Dam TN,
* Dagnaes-Hansen F,
* Rygaard J,
* Schuurman J,
* Parren PW,
* van de Winkel JG,
* Baadsgaard O.
Department of Dermatology, University of Copenhagen, Gentofte Hospital,
Hellerup, Denmark, lov...@gentoftehosp.kbhamt.dk.
CD4(+) T cells, in activated or malignant form, are involved in a
number of diseases including inflammatory skin diseases such as
psoriasis, and T cell lymphomas such as the majority of cutaneous T
cell lymphomas (CTCL). Targeting CD4 with an antibody that inhibits
and/or eliminates disease-driving T cells in situ may therefore be a
useful approach in the treatment of inflammatory and malignant skin
diseases. Depletion of CD4(+) T cells in intact inflamed human skin
tissue by Zanolimumab, a fully human therapeutic monoclonal antibody
(IgG1, kappa) against CD4, was studied in a human psoriasis xenograft
mouse model. Zanolimumab treatment was shown to induce a significant
reduction in the numbers of inflammatory mononuclear cells in upper
dermis. This reduction in inflammatory mononuclear cells in situ was
primarily due to a significant reduction in the numbers of
skin-infiltrating CD4(+), but not CD8(+) CD3(+) T cells. The capacity
of Zanolimumab to deplete the CD4(+) T cells in the skin may be of
importance in diseases where CD4(+) T cells play a central role.
Indeed, in a phase II clinical trial Zanolimumab has shown a
dose-dependent clinical response in patients with CTCL and the antibody
is currently in a phase III clinical trial for CTCL, a disease for
which there is no safe and effective treatment available today.
PMID: 17091277
------------------------
Some viral parts may be used to design these T-reg drugs.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17038643&query_hl=3&itool=pubmed_docsum
Coxsackievirus B3 Induces T Regulatory Cells, Which Inhibit
Cardiomyopathy in Tumor Necrosis Factor-{alpha} Transgenic Mice.
* Huber SA,
* Feldman AM,
* Sartini D.
Department of Pathology, University of Vermont, Colchester; and
Department of Medicine, Center for Translational Medicine, Thomas
Jefferson University, Philadelphia, Pa.
Innate immunity promotes both the generation of autoimmunity and
immunoregulation of adaptive immunity. Transgenic mice expressing the
tumor necrosis factor-alpha (TNFalpha) gene under the cardiac myosin
promoter (TNF1.6 mice) develop dilated cardiomyopathy. Transgenic mice
show extensive cardiac inflammation, suggesting that immunopathogenic
mechanisms may promote cardiomyopathy. Two coxsackievirus B3 (CVB3)
variants infect and replicate in the heart. H3 variant is highly
myocarditic, but H310A1 variant activates CD4(+) T regulatory cells,
which protect against viral myocarditis. T-cell depletion of TNF1.6
mice using monoclonal anti-CD3 or anti-CD4 antibody significantly
reduced heart size and plasma troponin I concentrations compared with
control TNF1.6 mice. Cardiomyopathy in TNF1.6 mice correlates to a
CD4(+)Th1 response and autoimmune IgG2a antibodies. TNF1.6 mice
infected with H310A1 virus reduced heart size and cardiac inflammation
corresponding to the activation of CD4(+)CD25(+)FoxP3(+) (T regulatory
cells). Immunosuppression is dependent on IL-10 but not TGFbeta.
Adoptive transfer of the CD4(+)CD25(+) cells from H310A1-infected mice
into uninfected TNF1.6 recipients abrogated cardiomyopathy. Exogenous
administration of recombinant TNFalpha to H310A1-infected mice for 4
days abrogated immunosuppression. Cardiac enlargement in TNF1.6 mice is
partly attributable to T-cell activation and humoral autoimmunity
caused by cytokine expression. T regulatory cells induced by H310A1
virus abrogate autoimmunity caused by TNFalpha overexpression. H3 virus
infection induces high levels of systemic TNFalpha, whereas H310A1
virus does not. The low TNFalpha response during H310A1 infections is
likely responsible for the T regulatory cell response in these animals.
PMID: 17038643
--------------------------------
And lastly the usage of the gut to generate IL-10 by increasing T-regs,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16204628&query_hl=10&itool=pubmed_docsum
Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in
vivo.
* Delgado M,
* Chorny A,
* Gonzalez-Rey E,
* Ganea D.
Department of Biological Sciences, Rutgers University, Newark, NJ
07102, USA.
CD4+CD25+ regulatory T (Treg) cells control the immune response to a
variety of antigens, including self-antigens, and several models
support the idea of the peripheral expansion of CD4+CD25+ Treg cells.
Although hormones such as estrogen and alpha-melanocyte-stimulating
hormone have been recently reported to expand the CD4+CD25+
Foxp3-expressing Treg cell compartment, little is known about the
endogenous factors and mechanisms controlling the peripheral expansion
of CD4+CD25+ Treg cells. In this study, we report on the capacity of
the vasoactive intestinal peptide (VIP), an immunosuppressive
neuropeptide, to induce functional Treg cells in vivo. The
administration of VIP together with specific antigen to T cell receptor
(TCR)-transgenic (Tg) mice results in the expansion of the CD4+CD25+,
Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell
proliferation through direct cellular contact. In addition to the
increase in the number of CD4+CD25+ Treg cells, VIP induces more
efficient suppressors on a per-cell basis. The VIP-generated CD4+CD25+
Treg cells transfer suppression, inhibit delayed-type hypersensitivity
in TCR-Tg hosts, and prevent graft-versus-host disease in irradiated
hosts reconstituted with allogeneic bone marrow.
PMID: 16204628
Randall.... The remains of the day! Tregs! More please!
On Nov 8, 4:55 pm, "randall" <ranhu...@aol.com> wrote:
> Hi Manfred,
>
> I'm not meaning to side track you with my stuff.
>
> OK, i'm starting the foray.
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&...
> Clip and the invariant chain rears its head again. So, we go with it,http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&...
> &http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&...
>
> We have vaccine possibilties once they figure out structure and
> pathogenesis.
>
> Time line: ten years? five if we're lucky?
>
> -----------------
>
> Till we have that vaccine and it could be a long long while, we can
> hunker down with gut decisions.
>
> Raising T-regs is that strategy,http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&...
> &http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=p...
Ed F
Ed F
record, when I first got P I was eating a lot of pork but also taking a
weight lifting suppliment called NO2, which is supposed to be a "nitric
oxide generator."
http://www.gnc.com/sm-medical-research-institute-no--pi-2133512.html
I have taken it for short periods afterward and not seen any effect on
my P.
Ed