hBD-1 & Thioredoxin - Epigenetics - Rtt109 Enzymes - Epidermis & Desmosomes - Breaking LPS & BAD - Pam3CSK4
randall
How your gut serves a curve BALL to the BAD Gut BUGs...
And it's not due to some BAD tamale you ATE...
Get some sunshine or eat some vitamin D3 and your body pumPs out LL-37
(cathelicidins). It's like your Body creates a natural condom for
you.... LOL
<or as kofi suggests get a D3 shot from your doc>
One FLU over the latitude next?
So?
Natural antibiotics LL-37 for crud like the flu virus that make us
sick?
But since i'm psoriatic i almost NEVER ever EVER GOT sick.
Unless i was a REALLY really BAD BOY... or found a bad girl and got
badder together.
Good think i avoid those kinda FOLKs now. :)
OK what are you ON about?
Oh nothing...
http://www.eurekalert.org/pub_releases/2011-01/tum-dma012111.php
Defense mechanism against bacteria and fungi deciphered
Mystery of 'inactive' defensin solved
Under standard laboratory conditions, the human beta-defensin 1
(hBD-1), a human antibiotic naturally produced in the body, had always
shown only little activity against microbes. Nevertheless the human
body produces it in remarkable quantities. The solution to the puzzle
was the investigation process itself, as the research group led by Dr.
Jan Wehkamp at the Dr. Margarete Fischer-Bosch Institute for Clinical
Pharmacology of the Stuttgart-based Robert Bosch Hospital found out.
Before the research group took a new approach to this research,
defensins were usually tested in the presence of oxygen, although
little oxygen is present, for example, in the human intestine.
Starting out from the discovery that a special antibiotic-activating
protein of the human body is diminished in patients with inflammatory
bowel diseases, Crohn's Disease and Ulcerative Colitis, the working
group investigated how defensins act under low-oxygen conditions.
During their investigations the scientists found out that under these
conditions hBD-1 unfolds a strong antibiotic activity against lactic
acid bacteria and yeast.
Furthermore the researchers discovered that another human protein,
thioredoxin, is able to activate beta-defensin 1 even in the presence
of oxygen. Moritz Marcinowski and Professor Johannes Buchner from the
Department of Chemistry at the Technical University of Munich, used
circular dichroism spectroscopy to elucidate the differences between
the folded inactive and the unfolded active form of the protein.
Surprisingly, while almost all proteins are active only in their
folded form, in the case of the small defensin the opposite is true.
To activate the beta-defensin 1 the thioredoxin opens the three
disulphide bridges that hold the molecule together. The molecule then
opens up into the active state. Using this mechanism the body has the
opportunity to selectively activate the defensin.
So far the cause of inflammatory bowel disease is unclear. Genetic as
well as environmental factors seem to play a role, finally leading to
a weakening of the antimicrobial barrier, which is mainly mediated by
defensins. Accordingly the identified mechanism might contribute to
the development of new therapies to treat affected patients.
###
Original publication:
„Reduction of disulfide bonds unmasks potent antimicrobial activity of
human β-defensin 1", B.O. Schroeder, Z. Wu, S. Nuding, S. Groscurth,
M. Marcinowski, J. Beisner, J. Buchner, M. Schaller, E.F. Stange, J.
Wehkamp, Nature, DOI: 10.1038/nature09674
<snip>
I've got a few crohn's hits for hbd-1. Over a dozen
http://groups.google.com/groups/search?hl=en&q=hbd-1+crohn%27s+randall&sitesearch=
Nearly 40 for me and psor:
http://groups.google.com/groups/search?hl=en&q=hbd-1+psoriasis+randall&sitesearch=
Only 222 for : hbd thioredoxin - ALL groups
http://groups.google.com/groups/search?hl=en&q=hbd++thioredoxin+&btnG=Search&sitesearch=
Selenocysteine and glutathione's should perk Kofi's interest.
How much intra or inter cellular craP are autoimmune folks FULL OF?
Anywhey... use your whey proteins and sweet whey to save the DAY> LOL
OK back to:
Their abstract:
http://www.ncbi.nlm.nih.gov/pubmed/21248850
Nature. 2011 Jan 20;469(7330):419-23.
Reduction of disulphide bonds unmasks potent antimicrobial activity of
human β-defensin 1.
Schroeder BO, Wu Z, Nuding S, Groscurth S, Marcinowski M, Beisner J,
Buchner J, Schaller M, Stange EF, Wehkamp J.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376
Stuttgart, Germany.
Comment in:
Nature. 2011 Jan 20;469(7330):309-10.
Abstract
Human epithelia are permanently challenged by bacteria and fungi,
including commensal and pathogenic microbiota. In the gut, the
fraction of strict anaerobes increases from proximal to distal,
reaching 99% of bacterial species in the colon. At colonic mucosa,
oxygen partial pressure is below 25% of airborne oxygen content,
moreover microbial metabolism causes reduction to a low redox
potential of -200 mV to -300 mV in the colon. Defensins, characterized
by three intramolecular disulphide-bridges, are key effector molecules
of innate immunity that protect the host from infectious microbes and
shape the composition of microbiota at mucosal surfaces. Human β-
defensin 1 (hBD-1) is one of the most prominent peptides of its class
but despite ubiquitous expression by all human epithelia, comparison
with other defensins suggested only minor antibiotic killing activity.
Whereas much is known about the activity of antimicrobial peptides in
aerobic environments, data about reducing environments are limited.
Herein we show that after reduction of disulphide-bridges hBD-1
becomes a potent antimicrobial peptide against the opportunistic
pathogenic fungus Candida albicans and against anaerobic, Gram-
positive commensals of Bifidobacterium and Lactobacillus species.
Reduced hBD-1 differs structurally from oxidized hBD-1 and free
cysteines in the carboxy terminus seem important for the bactericidal
effect. In vitro, the thioredoxin (TRX) system is able to reduce hBD-1
and TRX co-localizes with reduced hBD-1 in human epithelia. Hence our
study indicates that reduced hBD-1 shields the healthy epithelium
against colonisation by commensal bacteria and opportunistic fungi.
Accordingly, an intimate interplay between redox-regulation and innate
immune defence seems crucial for an effective barrier protecting human
epithelia.
PMID: 21248850
------
http://en.wikipedia.org/wiki/Beta_defensin
Beta defensins are a family of mammalian defensins. The beta defensins
are antimicrobial peptides implicated in the resistance of epithelial
surfaces to microbial colonization.
Defensins are 2-6 kDa, cationic, microbicidal peptides active against
many Gram-negative and Gram-positive bacteria, fungi, and enveloped
viruses[1], containing three pairs of intramolecular disulfide bonds.
On the basis of their size and pattern of disulfide bonding, mammalian
defensins are classified into alpha, beta and theta categories. Every
mammalian species explored thus far has beta-defensins. In cows, as
many as 13 beta-defensins exist in neutrophils. However, in other
species, beta-defensins are more often produced by epithelial cells
lining various organs (e.g. the epidermis, bronchial tree and
genitourinary tract).
<snip>
-----
http://en.wikipedia.org/wiki/Thioredoxin
Symbols TXN; DKFZp686B1993; MGC61975; TRX
Thioredoxin is a class of small redox proteins known to be present in
all organisms. It plays a role in many important biological processes.
In humans, it is encoded by the TXN gene.[1] Loss-of-function mutation
of either of the two human thioredoxin genes is lethal at the four-
cell stage of the developing embryo. Although not entirely understood,
thioredoxin plays a central role in humans and is increasingly linked
to medicine though their response to reactive oxygen species (ROS). In
plants, thioredoxins perform a spectrum of critical functions, ranging
from photosynthesis to growth, flowering and the development and
germination of seeds. It has also recently been found to play a role
in cell-to-cell communication.[2]
FunctionThioredoxins are proteins that act as antioxidants by
facilitating the reduction of other proteins by cysteine thiol-
disulfide exchange. Thioredoxins are found in nearly all known
organisms and are essential for life in mammals.[3][4]
Thioredoxin is a 12-kD oxidoreductase enzyme containing a dithiol-
disulfide active site. It is ubiquitous and found in many organisms
from plants and bacteria to mammals. Multiple in vitro substrates for
thioredoxin have been identified, including ribonuclease,
choriogonadotropins, coagulation factors, glucocorticoid receptor, and
insulin. Reduction of insulin is classically used as an activity test.
[5]
Thioredoxins are characterized at the level of their amino acid
sequence by the presence of two vicinal cysteines in a CXXC motif.
These two cysteines are the key to the ability of thioredoxin to
reduce other proteins. Thioredoxin proteins also have a characteristic
tertiary structure termed the thioredoxin fold.
The thioredoxins are kept in the reduced state by the flavoenzyme
thioredoxin reductase, in a NADPH-dependent reaction.[6] Thioredoxins
act as electron donors to peroxidases and ribonucleotide reductase.[7]
The related glutaredoxins share many of the functions of thioredoxins,
but are reduced by glutathione rather than a specific reductase.
Plants have an unusually complex complement of Trxs composed of six
well-defined types (Trxs f, m, x, y, h, and o) that reside in
different cell compartments and function in an array of processes.
Recently, it has been discovered for the first time that thioredoxin
proteins are able to move from cell to cell, representing a novel form
of cellular communication in plants.[8]
Interactions
Thioredoxin has been shown to interact with TXNIP,[9] ASK1,[10][11]
[12] Collagen, type I, alpha 1[13] and Glucocorticoid receptor.[14]
<snip>
Besides the obvious crohn's (IBD/colitis) ramifications, psoriasis
can't be FAR BEHIND.
http://www.ncbi.nlm.nih.gov/pubmed/21178014
J Immunol. 2011 Feb 1;186(3):1411-20. Epub 2010 Dec 22.
CCL20 and {beta}-Defensin-2 Induce Arrest of Human Th17 Cells on
Inflamed Endothelium In Vitro under Flow Conditions.
Ghannam S, Dejou C, Pedretti N, Giot JP, Dorgham K, Boukhaddaoui H,
Deleuze V, Bernard FX, Jorgensen C, Yssel H, Pène J.
INSERM Unité 844, Hôpital St. Eloi, Université Montpellier I, 34967
Montpellier, France;
Abstract
CCR6 is a chemokine receptor that is expressed at the cell surface of
Th17 cells, an IL-17- and IL-22-secreting population of CD4(+) T cells
with antipathogenic, as well as inflammatory, properties. In the
current study, we have determined the involvement of CCR6 in human
Th17 lymphocyte migration toward inflamed tissue by analyzing the
capacity of its ligands to induce arrest of these cells onto inflamed
endothelium in vitro under flow conditions. We show that polarized, in
situ-differentiated, skin-derived Th17 clones activated via the TCR-
CD3 complex produce CCL20 in addition to IL-17 and IL-22. The latter
cytokines induce, in a synergic fashion, the production of human β-
defensin (hBD)-2, but neither hBD-1 nor hBD-3, by epidermal
keratinocytes. Both CCL20 and hBD-2 are capable of inducing the arrest
of Th17 cells, but not Th1 or Th2 cells, on HUVEC in an CD54-dependent
manner that is CCR6 specific and independent from the expression of
CXCR4, reported to be an alternative receptor for hBD-2. In addition,
Ag-specific activation induces a transient loss of CCR6 expression,
both at the transcriptional and protein level, which occurs with slow
kinetics and is not due to endogenous CCL20-mediated internalization
of CCR6. Together, these results indicate that Ag-specific activation
will initially contribute to CCR6-mediated Th17 cell trafficking
toward and sequestration in inflamed tissue, but that it eventually
results in a transitory state of nonresponsiveness to further
stimulation of these cells with CCR6 ligands, thus permitting their
subsequent migration out of the inflamed site.
PMID: 21178014
This is GOOD? Unless it's part of Th1 pathogenesis for crohn's?
Did kofi mention M2 in his post the other day?
H'mm?
http://www.ncbi.nlm.nih.gov/pubmed/20100591
Int J Biochem Cell Biol. 2010 Jun;42(6):800-4. Epub 2010 Jan 25.
Human beta-defensin 1: a restless warrior against allergies,
infections and cancer.
Prado-Montes de Oca E.
Molecular Biology Laboratory, Southeast Unit, Research Center in
Technology and Design Assistance of Jalisco State (CIATEJ, AC),
National Council of Science and Technology (CONACYT), Calle 30
(Circuito Colonias) #151, García Ginerés, C.P. 97070, Mérida, Yucatán,
Mexico. ernest...@hotmail.com
Abstract
Human beta-defensin 1 (hBD-1) is probably the most important
antimicrobial peptide in epithelial tissues. Its alleles and/or
altered gene expression have been associated with at least 20 human
diseases. hBD-1 is a tumor suppressor and DEFB1 is the only innate
immunity gene that shows long-term balanced selection and heterozygote
advantage. It is unique in its constitutive expression, but is still
capable of upregulation upon inflammatory or microbial stimuli. The
present minireview focuses on hBD-1 properties, biological function,
its proposed pathogenic mechanisms and the potential uses of
elicitors, inhibitors or the peptide itself in the treatment of hBD-1-
related human diseases including allergies, infections and cancer.
PMID: 20100591
And since LL-37 is part of psoriasis going goofy on us.
28 hits for : HBD-1 AND LL-37
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=hbd-1+LL-37
And since i'm a nut for all things LPS.
12 hits for : HBD-1 AND LPS
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=hbd-1+lps
OK so hbd-2 is bigger for IBD then hbd-1?
Four hits for : hbd-2 and IBD - pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=hbd-2+ibd
-----------
#1 of these four:
http://www.ncbi.nlm.nih.gov/pubmed/19184352
Inflamm Res. 2009 Apr;58(4):192-7.
Concentrations of alpha- and beta-defensins in plasma of patients with
inflammatory bowel disease.
Yamaguchi N, Isomoto H, Mukae H, Ishimoto H, Ohnita K, Shikuwa S,
Mizuta Y, Nakazato M, Kohno S.
Second Department of Internal Medicine, Nagasaki University School of
Medicine, Nagasaki, Japan.
Abstract
BACKGROUND: Impaired production/release of defensins, representative
endogenous antimicrobial peptides, is associated with the pathogenesis
of inflammatory bowel disease (IBD).
MATERIAL AND METHODS: Employing in house radioimmunoassay, we examined
concentrations of the major forms alpha-defensins, human neutrophil
peptides (HNP) 1-3 and human beta-defensin (HBD)-2 in plasma of 55 IBD
patients consisting of 29 patients with ulcerative colitis (UC) and 26
with Crohn's disease (CD) and 57 controls.
RESULTS: The circulating HNP 1-3, but not HBD-2, levels in IBD
patients were significantly higher than those in controls. Plasma HNP
1-3 concentrations in CD patients significantly correlated with
Crohn's disease activity index, peripheral white blood cell counts,
serum CRP values and TNF-alpha levels.
CONCLUSIONS: Elevation of circulating alpha-defensins levels is
suggestive of their physiopathological roles in IBD. Plasma HNP 1-3
concentrations may be an indicator for CD activity and their
association with CRP and TNF-alpha supports a possible association
with the inflammatory process.
PMID: 19184352
The other 3 are quite good, kofi.
And just so we don't MISS anything.
HBD-2 AND Crohn's - pubmed: 10 hits--> (pick up another two hits
droPPing the 2 off hbd)
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=hbd-2+crohn's
I see a nod2, card15 microflora PMID: 18371140 .
And i'll do a few more after these psor hits.
============
OK for MY group some dumb psoriasis links. LOL
http://www.businesswire.com/news/home/20110121005779/en/Maven-Semantic-Psoriasis-Research-Database
January 21, 2011 12:11 PM Eastern Time
Maven Semantic: Psoriasis Research Database
DUBLIN--(BUSINESS WIRE)--Maven Semantic (http://www.mavensemantic.com)
announces updates to their Psoriasis research database.
Search Over 11,000 People and Over 1,000 Psoriasis Research
Organisations
Psoriasis is a chronic autoimmune disease that appears on the skin. It
occurs when the immune system sends out faulty signals that speed up
the growth cycle of skin cells. There are five types of psoriasis:
plaque, guttate, inverse, pustular and erythrodermic.
The new database is now available to marketing, business development,
competitor intelligence, KOL, medical affairs and related departments
in the life sciences sector.
The database currently tags 11,000 individuals working in Psoriasis.
http://bit.ly/h5u7xn.
same link as previous only clicked:
http://www.mavensemantic.com/Search.aspx#command=search&type=people&text=Psoriasis&ref=BW&refValue=267
Eugene Farber from StanFord Uni comes up 1st.
Top 10 Countries for Psoriasis Research (ranked by number of senior
researchers)
United States Of America (3,071)
Germany (836)
United Kingdom (772)
Japan (579)
Italy (541)
France (396)
The Netherlands (287)
Spain (237)
Canada (221)
China (196)
Leading organisations in Psoriasis research include:
Aarhus University Hospital
Anhui Medical University
Asahikawa Medical College
Baylor University Medical Center
Ben-Gurion University of the Negev
Bispebjerg Hospital
Brigham and Women's Hospital
Cairo University
Center for Dermatology Research
Columbia University
Emory University School of Medicine
Guy's Hospital
Harvard Medical School
Helsinki University Central Hospital
Hope Hospital
Johns Hopkins University School of Medicine
Karolinska Institutet
Leicester Royal Infirmary
Marselisborg Hospital
Massachusetts General Hospital
Mayo Clinic
Medical University of Vienna
Mount Sinai School of Medicine
National Cancer Institute
National Institutes of Health
National Skin Centre
New York University Medical Center
Ninewells Hospital and Medical School
Psoriasis Research Institute
Radboud University Nijmegen Medical Centre
Royal Victoria Infirmary
Sahlgrenska University Hospital
St John's Institute of Dermatology
Tel Aviv University
University Hospital Nijmegen
University of British Columbia
University of California
University of Kiel
University of Leeds
University of Leicester
University of Michigan Medical Center
University of Oulu
University of Pennsylvania
University of Szeged
University of Texas Southwestern Medical Center
University of Tokyo
University of Toronto
University of Ulm
University of Vienna
Veterans Administration Medical Center
Wake Forest University School of Medicine
Washington University School of Medicine
Yale University School of Medicine
The database also includes pharmaceutical companies, biotech
companies, CROs, hospitals, government labs and other organisations
active in the Psoriasis research field.
Sample companies in database include:
Abteilung Biochemie der Dr. Karl Thomae GmbH
ACO HUD AB
Advanced Biotherapy Inc
Advitech Inc
Allergan Inc
Altus Biologics Inc
Amgen Inc
Amygdala Ltd
AnaptysBio, Inc
Bayer Schering Pharma AG
Biogen Idec Inc
Boehringer Ingelheim Pharmaceuticals, Inc
Centocor, Inc
Chugai Pharmaceutical Co., Ltd
Connetics Corporation
Genentech Inc
Grünenthal GmbH
Immune Response Corporation
Isis Pharmaceuticals, Inc
Italfarmaco SpA
Klinikum Hanau GmbH
Leo Pharmaceutical Products Ltd
Lupin Ltd
NeoStrata Company, Inc
Novartis Pharma
Pfizer Inc
Protein Design Laboratories, Inc
Protein Design Labs, Inc
Signal Pharmaceuticals Inc
Synovo GmbH
Tanabe Seiyaku Co. Ltd
Texas Dermatology Associates
United BioSource Corporation
ZymoGenetics, Inc
What is Maven:
- Largest database of international medical professionals, with over
6,000,000 people and over 500,000 medical organisations;
- All records are downloadable to excel or in-house database, with
email, postal address and phone contacts;
- Profile and segment the entire database using over 47,000 diseases
and therapeutic areas
For more information visit http://www.mavensemantic.com/
<snip>
all this psor craP and they haven't a clue. LOL
But do you?
Of course i do... i can cure CRAP... and have and will again.
Or WILL you>?
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Don't snort coke... snort my psor flakes?
YeP... some idiot did it. LOL
http://www.music-news.com/shownews.asp?H=Liam-Gallaghers-dandruff-snorted-by-fan&nItemID=38838
Liam Gallagher's dandruff snorted by fan
added: 21 Jan 2011 // by: newsdesk
[...] Liam revealed that as he's got the skin condition psoriasis he's
prone to flaky bits.
"I've got bad skin. I've got psoriasis all over my f****** body.
Everywhere except for me face. And every now and again on me head".
<sniP>
Maybe LIAM doesn't have BAD SKIN just to much SFB in his Ileum and
small intestines?
Fine... have it your way.
I know... SWEEET... LOL
====================================
Whoops... forgot i had this HERE... just go on and don't bother with
it.
http://www.signaling-gateway.org/update/featured/index.html
Caspase control: IAPs as NEDD8 E3 ligases
A new role of inhibitor of apoptosis (IAP) proteins in caspase
regulation is revealed: they can promote conjugation of the ubiquitin-
like protein NEDD8 as well as ubiquitin. This adds to the complexity
of IAP-mediated signaling.
Inhibitor of apoptosis (IAP) proteins act as ubiquitin E3 ligases and
regulate caspase activity through ubiquitin-mediated proteasomal
degradation; deubiquitylating enzymes (DUBs) can reverse the activity
of ubiquitin and ubiquitin-like (UBL) proteins, such as NEDD8. In
transgenic Drosophila expressing IAP antagonists to induce apoptosis,
Broemer et al. have now systemically knocked down individual DUBs
using RNA interference and identified three NEDD8-specific proteases
that, when knocked down, suppress cell death in vivo.
Apoptosis was reduced in the null mutants of one of these genes,
Deneddylase 1 (DEN1), and the effector caspase drICE was found to be
neddylated in vivo, which suggested a role for NEDD8 in apoptosis.
Interestingly, UV mediated reduction in Drosophila IAP 1 (DIAP1)
protein levels reduced neddylation of drICE and induced apoptosis,
indicating that DIAP1 is a NEDD8 E3 ligase for drICE.
Further investigation showed that DIAP1 neddylates drICE in a RING-
and binding-dependent manner leading to reduced drICE proteolytic
activity, and further mass spectrometry analysis identified nine
lysine residues in drICE as sites for neddylation.
As XIAP, a mammalian IAP, also promoted neddylation of caspase 7 in a
RING-dependent manner, IAP-mediated neddylation seems to be
evolutionarily conserved.
This study demonstrates that IAPs can function as E3 ligases for NEDD8
as well as for ubiquitin and extends the complexity of IAP-mediated
signaling.
Iley Ozerlat
Signaling Gateway
Reference:
Broemer M. et al.
Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases.
Mol. Cell 40, 810-812 (2010)
full text
http://www.cell.com/molecular-cell/abstract/S1097-2765%2810%2900849-X
=================
Mercola best and worst bottled WATERs
http://articles.mercola.com/sites/articles/archive/2011/01/21/best-and-worst-bottled-water-brands.aspx
mercola: you need supplementa vitamin B12 for efficient energy
metabolization
http://products.mercola.com/vitamin-b12-spray/?source=nl
<randall note: either that or intrinsic factor in gut cells>
=============
speaking of gut cells and stuff down there:
I didn't post this one?
Am i nuts?
Maybe.. LOL
http://www.ncbi.nlm.nih.gov/pubmed/21178008
J Immunol. 2010 Dec 22.
Restricted Microbiota and Absence of Cognate TCR Antigen Leads to an
Unbalanced Generation of Th17 Cells.
Lochner M, Bérard M, Sawa S, Hauer S, Gaboriau-Routhiau V, Fernandez
TD, Snel J, Bousso P, Cerf-Bensussan N, Eberl G.
Lymphoid Tissue Development Unit, Department of Immunology, Institut
Pasteur, 75724 Paris, France;
Abstract
Retinoic acid-related orphan receptor (ROR)γt(+) TCRαβ(+) cells
expressing IL-17, termed Th17 cells, are most abundant in the
intestinal lamina propria. Symbiotic microbiota are required for the
generation of Th17 cells, but the requirement for microbiota-derived
Ag is not documented. In this study, we show that normal numbers of
Th17 cells develop in the intestine of mice that express a single TCR
in the absence of cognate Ag, whereas the microbiota remains essential
for their development. However, such mice, or mice monocolonized with
the Th17-inducing segmented filamentous bacteria, fail to induce
normal numbers of Foxp3(+) RORγt(+) T cells, the regulatory
counterpart of IL-17(+)RORγt(+) T cells. These results demonstrate
that a complex microbiota and cognate Ag are required to generate a
properly regulated set of RORγt(+) T cells and Th17 cells.
PMID: 21178008
LOL.... i guess at this point in time it fits the FRAME work best?
And my next trial should tell me a LITTLE more i would suspect?
===================================
http://www.ncbi.nlm.nih.gov/pubmed/21211658
J Allergy Clin Immunol. 2011 Jan;127(1):238-245.e3.
Bet v 1-specific T-cell receptor/forkhead box protein 3 transgenic T
cells suppress Bet v 1-specific T-cell effector function in an
activation-dependent manner.
Schmetterer KG, Haiderer D, Leb-Reichl VM, Neunkirchner A, Jahn-Schmid
B, Küng HJ, Schuch K, Steinberger P, Bohle B, Pickl WF.
Institute of Immunology, Center for Pathophysiology, Infectiology and
Immunology, Medical University of Vienna, Vienna, Austria.
Abstract
BACKGROUND: Regulatory T (Treg) cells establish and maintain tolerance
to self-antigens and many foreign antigens, such as allergens, by
suppressing effector T-cell proliferation and function. We have
previously shown that human T-cell receptor (TCR) αβ-chains specific
for allergen-derived epitopes confer allergen specificity on
peripheral blood T cells of individuals with and without allergy.
OBJECTIVE: To study the feasibility of generating allergen-specific
human Treg cells by retroviral transduction of a transcription unit
encoding forkhead box protein 3 (FOXP3) and allergen-specific TCR αβ-
chains.
METHODS: cDNAs encoding the α and β-chains of a Bet v 1(142-153)-
specific TCR (TCR alpha variable region 6/TCR beta variable region 20)
and human FOXP3 were linked via picornaviral 2A sequences and
expressed as single translational unit from an internal ribosomal
entry site-green fluorescence protein-containing retroviral vector.
Retrovirally transduced peripheral blood T cells were tested for
expression of transgenes, Treg phenotype, and regulatory capacity
toward allergen-specific effector T cells.
RESULTS: Transduced T cells displayed a Treg phenotype with clear-cut
upregulation of CD25, CD39, and cytotoxic T-lymphocyte antigen 4. The
transduced cells were hyporesponsive in cytokine production and
secretion and, like naturally occurring Treg cells, did not
proliferate after antigen-specific or antigen-mimetic stimulation.
However, proliferation was inducible upon exposure to exogenous IL-2.
In coculture experiments, TRAV6(+)TRBV20(+)FOXP3(+) transgenic T
cells, unlike FOXP3(+) single transgenic T cells or naturally
occurring Treg cells, highly significantly suppressed T cell cytokine
production and proliferation of corresponding allergen-specific
effector T cells in an allergen-specific, dose-dependent manner.
CONCLUSION: We demonstrate a transgenic approach to engineer human
allergen-specific Treg cells that exert their regulatory function in
an activation-dependent manner. Customized Treg cells might become
useful for tolerance induction therapies in individuals with allergic
and other immune-mediated diseases.
2010 American Academy of Allergy, Asthma & Immunology. Published by
Mosby, Inc.
PMID: 21211658
==================================
OK back to the toP shelf ::
40,000 hits -hbd thioredoxin glutathione intracellular - WEB google
search:
http://www.google.com/search?hl=en&q=hbd+thioredoxin+glutathione+intracellular&aq=f&aqi=&aql=&oq=
Wouldn't you JUST know that HIV research would correlate glutathione
with immunity somehow?
LOL
http://herzenberg.stanford.edu/Redox/sahaf.html
[...]
Bita Sahaf , Ph.D.
Research Associate
Sr. Research Associate;
Associate Director
Stanford Shared FACS Facility
Research:
Currently my research studies are divided in three distinct but
complementary approaches. First the patient oriented study of redox
regulation and lymphocytes subtypes, the complementary basic science
and in vitro method development and the relationship between the redox
parameters and B cell development. The unique 11 color- 13 parameter
(Hi-D) FACS gives us the unparalleled opportunity to study the
lymphocyte subtypes as well as the redox parameters that we are
interested in.
A) Study of thioredoxin and thioredoxin reductase in healthy
individuals and in HIV infected individuals with or without B cell
lymphomas. In HIV patients, there is an imbalance of T-cell function
favoring the presence of pro-inflammatory cytokines that exert
continuous oxidative stress on cells. The Herzenberg laboratory and
others have shown that reduced glutathione (GSH) levels decrease
progressively as HIV disease progresses. In fact, the advanced stages
of HIV infection may be considered a model dominated by excessive pro-
inflammatory cytokines and low intracellular GSH levels. Importantly,
for our interest here, elevated thioredoxin levels in HIV infected
individuals correlate with decreased GSH levels and decreased numbers
of CD4 T cells.
Placebo controlled trials in the Herzenberg laboratory have shown that
intracellular GSH levels are restored in HIV infected individuals a by
per oral administration with N-acetylcysteine (NAC), which supplies
the cysteine needed to restore GSH. Consistent with this finding, a
small substudy in the Herzenberg placebo-controlled trial showed that
NAC treatment resulted in significantly decreases thioredoxin levels.
These data are consistent with evidence showing that in vitro
treatment of a thioredoxin-producing neoplastic cell line decreases
thioredoxin release. Both findings thus implicate oxidative stress in
increased production/release of thioredoxin.
The oxidative stress in HIV infection recently suggested a new study
in which the Herzenberg and Nolan laboratories at Stanford
collaboratively showed that motexafin gadolinium (Gd-Tex) selectively
kills human T cells infected in vitro with HIV. GD-Tex, which induces
intracellular oxidative stress, is in Phase III trials as a drug to
increase sensitivity of neoplasms to irradiation. Our studies with Gd-
Tex showed that it selectively induces apoptosis in HIV-1-infected
CD4+ T cells in IL-2-stimulated cultures of peripheral blood
mononuclear cells infected in vitro with HIV-1.
Continuing with studies in which the Herzenberg laboratory detected
elevated thioredoxin levels in HIV infected people and showed that
these elevated levels were associated with impaired survival, the
studies proposed here will determine whether the frequency of
thioredoxin elevation is decreased in the protease inhibitor (triple
therapy) era. In addition, my studies will evaluate the potential
relationship between thioredoxin elevations and the occurrence or
progress of AIDS-related B cell neoplasms.
B) Investigation of redox status of the cell surface. Since the cell
surface microenvironment contributes to the redox status of the thiol
(-SH) groups on thiol-containing proteins on the cell surface, we are
including surface thiol measurements as an additional index of redox
changes that may influence T and B cell functions. In the studies I
will use measurements of intracellular glutathione, intracellular
thioredoxin and thioredoxin reductase, and surface thiols to determine
whether the general redox imbalance that occurs in HIV infection
predicts the neoplastic changes that lead to the development of B
lymphomas in HIV disease. We have recently demonstrated that increased
intracellular thioredoxin correlates with elevated surface thiols on T
cells in HIV-infected individuals. We now plan to extend our studies
to include these and the remaining markers to evaluate the
relationship between oxidative stress and neoplastic transformation of
B cells in HIV-infected and uninfected subjects. We also have
developed methods to measure the glutathionylation of proteins using
the HI-D FACS, which will also help us understand the redox changes on
the cell surface proteins and the consequences for the cell function.
C) Relationship between the redox regulation (intracellular GSH,
surface thiol and thioredoxin system) and B-1 cell development, clonal
expansion and survival in mice. In studies conducted in parallel with
the HIV studies, we will use mouse model systems to investigate the
expansion of normal and neoplastic B cells (principally B-1 cells).
Based on the characteristic cell surface features, anatomical location
and developmental history, B cells in adult mice are divided into two
major subsets/lineage, termed B-1 and B-2. B-2 constitutes the
majority of the B cells in mouse spleen and lymph nodes. Most of the
B-2 cells are small, long lived resting cells that reside in B cell
follicles and express low levels of surface IgM, high amounts of IgD,
a variety of other surface markers, including CD23. However, they do
not express the CD5 surface glycoprotein that is found on all T cells.
B-1 cells, in contrast, comprise less than 5% of splenic B cells, are
found at very low frequencies in lymph nodes but represent the
dominant population in the peritoneal cavity. These cells express high
levels of IgM, low levels of IgD and, for the most part, express low
level of CD5.
B-1 cells produce most or all of the innate antibodies in serum. They
undergo Ig class switching and represent roughly half of the IgA
producing plasma cells in lamina propria of the gut. They respond to
antigenic stimulation but are mainly (although not exclusively)
involved in T-cell independent antibody responses. Reconstitution and
other studies demonstrate that unlike B-2 cells, which develop de novo
from precursors in the bone marrow throughout life, B-1 cells develop
almost exclusively during the fetal/neonatal period and persist as a
self-replenishing population thereafter.
B-1 cell neoplasms in the mouse have often been considered a model for
human chronic lymphocytic leukemia (CLL) since CLL frequently express
the CD5 surface marker. However, AIDS-related B cell lymphomas also
often express CD5 and thus information derived from studies of B-1
normal and neoplastic cells may also shed light on the origins of the
AIDS-related tumors and the mechanisms that control their growth.
In particular, since thioredoxin has been implicated in the regulation
of B-1 neoplastic growth, and also redox (through hypoxia induced
factor HIF-1 ) seems to regulate the B-1 cell proliferation, there is
reason to suspect that the elevated thioredoxin levels in HIV disease
may play a role in inducing or expanding B-1 neoplasms. Therefore, we
have planned this dual-species project in which we will investigate
the relationship between the thioredoxin system and B-1 cell
development, clonal expansion and survival in mice and in HIV infected
individuals.
Basically, we plan to study the effect of this increased thioredoxin
levels on B-1 cell development, clonal expansion and survival in the
mouse model and in HIV infected individuals (particularly those with
AIDS-related B cell lymphomas), applying knowledge gained in each
sphere to the other as our work progresses.
Publications:
<snip>
I hope J is OK with this?
RAM< gluthathione down their you KNOW whatz it's.
=================
OK so i'd be remiss to not check
BDB and Glutathione - 12 hits - pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=hbd+glutathione
<be sure to look at these YOU... you mean me? Who else? LOL>
==================
Let's get all physical like olivia fig newton john?
OK... but let's try epigenetic instead.
Duh.. that's what i meant, dork brain.
So?
Oh yeah.
http://www.eurekalert.org/pub_releases/2011-01/twi-hth012011.php
How the hat fits: Structural biology study reveals shape of epigenetic
enzyme complex
Acetylation complex fits like a halo over a histone
-------------
IMAGE: Histone acetyltransferases (HATs) are enzymes that can
epigenetically modify gene regulation. Just how they modify their
targets depends on the shape they form. This ring structure is formed
by two...
http://www.eurekalert.org/multimedia/pub/28932.php?from=177105
-------
To understand the emerging science of epigenetics—a field that
describes how genes may be regulated without altering the underlying
DNA itself—scientists are deciphering the many ways in which enzymes
act on the proteins surrounding DNA within cells.
One type of these enzymes, proteins known as histone
acetyltransferases (HATs), act on DNA by modifying DNA-bound proteins
called histones. This act of modification, called acetlyation, can
dictate how histones interact with DNA and other proteins affecting
processes such as DNA replication, transcription (reading the gene),
and repair. In the February 9 issue of the journal Structure,
available online, researchers at The Wistar Institute are the first to
describe the complete atomic structure formed by a yeast HAT, known as
Rtt109, and one of its associated proteins. Their findings demonstrate
how a particular histone acetylation event works, a crucial step to
understanding epigenetics and the related processes that underlie both
health and disease.
According to the study's senior author, Ronen Marmorstein, Ph.D.,
professor and program leader of Wistar's Gene Expression and
Regulation Program, two copies of Rtt109 bind to two copies of a
"chaperone" protein to form a ring.
"The ring fits atop a histone much like a halo, and we find that the
type of chaperone dictates exactly how the enzyme affects the histone
by determining the exact position of acetylation," said Marmorstein.
"The structure represents a nice model system for the regulation of
protein acetylation, and teaches us something new about the biology of
this enzyme, Rtt109."
The act of acetylation adds an "acetyl group," a small chemical
structure, to a lysine—one of the amino acids that make up a given
protein. Altering one lysine could change the shape of a protein, such
as a histone, in a subtle way, perhaps redirecting how it functions.
Rtt109, the researchers say, acetylates any of three specific lysines
on histones, and exactly which of the histone lysines are modified is
determined by which chaperone escorts Rtt109 into place. Since
histones are such crucial DNA-associated proteins, altering a single
lysine in a single part of the structure can have profound effects on
the "behavior" of that histone, such as exposing a particular set of
genes to be read, for example.
In the paper, Marmorstein and his colleagues show how Rtt109
associates with a particular chaperone called Vps75. Rtt109 also
associates with another chaperone, Asf1, which has been shown to
enable the Rtt109 to modify lysines in a different spot on a given
histone, creating a different effect in how that histone interacts
with DNA and in turn changing the cell's biological properties.
Their study is the first to show that two Rtt109 enzymes pair up with
two Vps75 chaperones to form a ring. The laboratory created crystals
of the protein complex and used a technique called X-ray
crystallography to "see" the structure of the complex by analyzing the
patterns formed when X-rays bounce off the crystals. They used the
powerful X-ray source at the Argonne National Laboratory's Advanced
Photon Source, which enabled the team to determine the structure of
the protein complex at the atomic scale—at a resolution of 2.8
angstroms (2.8 billionths of a meter), which is smaller than the
distance between individual rungs on the DNA ladder.
Since the Marmorstein laboratory began its work on HATs over a decade
ago, several large-scale studies have shown that acetylation occurs to
over 2000 proteins, not just histones. According to Marmorstein, it
appears there is an entire web of communication going on within cells
directly attributable to protein acetylation, another level of
complexity in an already-complex field.
"We have seen many different proteins over several different pathways
become affected by acetylation, which can alter the processes of RNA
metabolism, cell cycle control, cancer, and a number of different
aspects of life. It looks like protein acetylation has much broader
biological implications than initially appreciated," said
Marmorstein.
"In many ways, it seems a lot like what we have seen in recent years
with protein kinases and cell signaling," said Marmorstein. "What
we're learning is that these HATs, and possibly other protein
acetyltransferases, are regulated in much the same way. They have
these profound effects within cells, but it is still very new to
science. How it works is a big black box that we intend to decipher."
###
This work from the Marmorstein laboratory was supported by a grant
from the National Institute of General Medical Sciences.
The lead author of the study is Yong Tang, Ph.D., a staff scientist in
the Marmorstein laboratory. Wistar co-authors also include Katrina
Meeth, a research associate and Hua Yuan, Ph.D., a postdoctoral fellow
in the Marmorstein laboratory. Collaborators include Philip A. Cole,
Ph.D., and his laboratory at the Johns Hopkins University School of
Medicine, including Marc A. Holbert, Ph.D.; and the laboratories of
Alain Verreault, Ph.D., and Pierre Thibault, Ph.D., at the Institute
for Research in Immunology and Cancer at the Université de Montréal;
and their colleagues, including research associates, Neda Delgoshaie,
Paul Drogaris, Chantal Durette, and Eun-Hye Lee, and postdoctoral
fellows Hugo Wurtele, Ph.D., and Benoit Guillemette, Ph.D.
<snip>
49 hits : Rtt109 enzymes- pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=Rtt109+enzymes
The latest abstract for
Author "Marmorstein R"[Author]- 108 hits is LAST year in JULY?
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Marmorstein%20R%22%5BAuthor%5D
He does have six hits with RTT109
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=Rtt109+Marmorstein
Maybe tomorrow the current one will be here?
=======================
Whoops almost forgot Nie and Garrod::
The TRUsTY one in the hinterlands is protecting my HEART and SKIN. LOL
Their latest abstract isn't available either.
http://www.eurekalert.org/pub_releases/2011-01/uom-cbd012011.php
Cell binding discovery brings hope to those with skin and heart
problems
A University of Manchester scientist has revealed the mechanism that
binds skin cells tightly together, which he believes will lead to new
treatments for painful and debilitating skin diseases and also lethal
heart defects.
Professor David Garrod, in the Faculty of Life Sciences, has found
that the glue molecules bind only to similar glue molecules on other
cells, making a very tough, resilient structure. Further investigation
on why the molecules bind so specifically could lead to the
development of clinical applications.
Professor Garrod, whose Medical Research Council-funded work is paper
of the week in the Journal of Biological Chemistry (JBC) tomorrow
(Friday), said: "Our skin is made up of three different layers, the
outermost of which is the epidermis. This layer is only about 1/10th
of a millimetre thick yet it is tough enough to protect us from the
outside environment and withstand the wear and tear of everyday life.
"One reason our epidermis can do this is because its cells are very
strongly bound together by tiny structures called desmosomes,
sometimes likened to rivets. We know that people who have defects in
their desmosomes have problems with their epidermis and get extremely
unpleasant skin diseases. Understanding how desmosomes function is
essential for developing better treatments for these and other types
of skin disease and for non-healing wounds.
"Desmosomes are also extremely important in locking together the
muscle cells of the heart, and hearts where desmosomes are defective
can fail catastrophically, causing sudden death in young people.
Hence our findings may also be relevant in the heart and in developing
new treatments for heart disease."
ProfessorGarrod and his team, Zhuxiang Nie, Anita Merritt, Mansour
Rouhi and Lydia Tabernero, used chemical cross-linking to study cells
of the epidermis and found what they believe to be the principal
mechanism by which the glue molecules of desmosomes of skin cells bind
to each other.
"For reasons that we do not fully understand there are several
different but closely-related glue molecules within each desmosome,"
he explained.
"Our results show that each glue molecule on one cell binds primarily
to another of the same type on the neighbouring cell, meaning the
binding is highly specific. This was very surprising because previous
studies using different techniques had not been able to give such a
clear answer on the specificity of binding."
He added: "Our result suggests that this type of specific binding is
of fundamental importance in locking together cells of the epidermis
into a tough, resilient structure. It is an important step forward in
our research, which aims to develop better treatments for non-healing
wounds, other skin diseases and heart problems. We could do this if we
understood how to make medicines that would lock or unlock the
desmosomes as required."
###
Note to editors:
The paper 'Membrane-impermeable crosslinking provides evidence for
homophilic, isoform-specific binding of desmosomal cadherins in
epithelial cells' (Journal of Biological Chemistry) is available.
<snip>
41 hits -Desmosomes psoria* -pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=Desmosomes+psoria*
"Garrod DR"[Author]- 127 hits:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Garrod%20DR%22%5BAuthor%5D
226 - "Nie Z"[Author] - pubmed:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Nie%20Z%22%5BAuthor%5D
==============
http://www.ncbi.nlm.nih.gov/pubmed/19907407
G Ital Dermatol Venereol. 2009 Dec;144(6):689-700.
The skin's barrier.
Jensen JM, Proksch E.
Department of Dermatology, University Hospitals of Schleswig-Holstein,
University of Kiel, Kiel, Germany. mje...@dermatology.uni-kiel.de
Abstract
The skin provides an effective barrier between the organism and the
environment, preventing the invasion of pathogens and fending off
chemical and physical assaults, as well as the unregulated loss of
water and solutes. In this review we provide an overview of several
components of the physical barrier, as well as how barrier function is
regulated and altered in association with dermatoses. The physical
barrier localized primarily in the stratum corneum (SC) and consists
of protein-enriched cells (corneocytes with cornified envelope and
cytoskeletal elements, as well as corneodesmosomes) and lipid-enriched
intercellular domains. The nucleated epidermis, with its tight, gap
and adherens junctions, additional desmosomes and cytoskeletal
elements, also contributes to the barrier. Lipids are synthesized in
the keratinocytes during epidermal differentiation and are then
extruded into the extracellular domains, where they form lipid-
enriched extracellular layers. The cornified cell envelope, a robust
protein/lipid polymer structure, is located below the cytoplasmic
membrane on the exterior of the corneocytes. Ceramides A and B,
forming the backbone for the subsequent addition of free ceramides,
free fatty acids and cholesterol in the SC, are covalently bound to
cornified envelope proteins. Filaggrin is cross-linked to the
cornified envelope and aggregates keratin filaments into macrofibrils.
Cytokines, cAMP and calcium influence the formation and maintenance of
barrier function. Changes in lipid composition and epidermal
differentiation lead to a disturbed skin barrier, which allows the
entry of environmental allergens, immunological reaction and
inflammation in atopic dermatitis. A disturbed skin barrier is an
important component in the pathogenesis of contact dermatitis,
ichthyosis, psoriasis, and atopic dermatitis.
PMID: 19907407
http://www.ncbi.nlm.nih.gov/pubmed/19703225
Exp Dermatol. 2010 Jun;19(6):501-10. Epub 2009 Aug 23.
Topical calcineurin inhibitors compromise stratum corneum integrity,
epidermal permeability and antimicrobial barrier function.
Kim M, Jung M, Hong SP, Jeon H, Kim MJ, Cho MY, Lee SH, Man MQ, Elias
PM, Choi EH.
Department of Dermatology, Yonsei University Wonju College of
Medicine, Wonju, Korea.
Abstract
BACKGROUND: Topical calcineurin inhibitors (TCIs) such as pimecrolimus
and tacrolimus have recently been used for dermatologic diseases
including atopic dermatitis instead of topical glucocorticoids,
because they display comparable efficacy, but less-frequent side
effects. Although even short-term topical glucocorticoid compromise
epidermal permeability barrier homeostasis, the effects of TCI on
barrier function have not yet been reported. However, viral infections
such as eczema herpeticum and molluscum contagiosum, which could
indicate an impaired skin barrier, continue to occur with TCI use in
atopic dermatitis.
OBJECTIVES: We determined here whether TCIs disrupt epidermal
permeability barrier and antimicrobial function, and whether these
effects can be prevented.
METHODS AND RESULTS: In normal humans, topical pimecrolimus and
tacrolimus applied twice-daily for 5 days, delay barrier recovery
without an increase in basal transepidermal water loss was observed.
Co-application of physiologic lipid mixture (PLM) containing an
equimolar ratio of ceramides, cholesterol and free fatty acids
normalized barrier homeostasis in the face of topical TCIs. In
hairless mice, 4 days of TCI treatment also disrupted barrier function
significantly. TCIs-treated epidermis showed the decrease of epidermal
lipid content, lamellar body number and secretion, and lipid synthesis-
related enzymes such as 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
reductase, serine-palmitoyl transferase and fatty acid synthase,
implying decreased lipid synthesis. TCIs also suppressed expression of
IL-1alpha and antimicrobial peptides, CRAMP and mouse beta-defensin 3.
However, these TCI-induced abnormalities can be overridden by topical
replacement with PLM.
CONCLUSIONS: Our results demonstrate that TCIs induce negative effects
on the skin barrier including permeability and antimicrobial
functions, which are mediated by decreasing epidermal lipid synthesis,
lamellar body secretion and antimicrobial peptides expression through
suppression of cytokine such as IL-1alpha, therefore co-treatment with
PLM would be helpful to overcome these negative effects.
PMID: 19703225
Maybe this Jeon H has Jays MaJic herb?
141 "Jeon H"[Author] - pubmed:
http://www.ncbi.nlm.nih.gov/pubmed?term=%22Jeon%20H%22%5BAuthor%5D
==================
I shall remind myself to check his herbs. LOL
I've got bigger fish to FRY now.
Shashimi isn't BAD either. I've only eaten a pound in the last few
days or so it seems. <W>
Hey... you get good tuna you EAT it before it goes BAD.
Breaking BAD... love that show..
http://www.ncbi.nlm.nih.gov/pubmed/20472611
Innate Immun. 2010 May 14.
Paracellular permeability is increased by basal lipopolysaccharide in
a primary culture of colonic epithelial cells; an effect prevented by
an activator of Toll-like receptor-2.
Hanson PJ, Moran AP, Butler K.
Life and Health Sciences, Aston University, Birmingham, UK.
Abstract
Lipopolysaccharide (LPS), which generally activates Toll-like receptor
4 (TLR4), is expressed on commensal colonic bacteria. In a number of
tissues, LPS can act directly on epithelial cells to increase
paracellular permeability. Such an effect in the colon would have an
important impact on the understanding of normal homeostasis and of
pathology. Our aim was to use a novel primary culture of colonic
epithelial cells grown on Transwells to investigate whether LPS, or
Pam3CSK4, an activator of TLR2, affected paracellular permeability.
Consequently, [(14)C]-mannitol transfer and transepithelial electrical
resistance (TEER) were measured. The preparation consisted primarily
of cytokeratin-18 positive epithelial cells that produced superoxide,
stained for mucus with periodic acid-Schiff reagent, exhibited
alkaline phosphatase activity and expressed TLR2 and TLR4. Tight
junctions and desmosomes were visible by transmission electron
microscopy. Basally, but not apically, applied LPS from Escherichia
coli increased the permeability to mannitol and to a 10-kDa dextran,
and reduced TEER. The LPS from Helicobacter pylori increased
paracellular permeability of gastric cells when applied either
apically or basally, in contrast to colon cells, where this LPS was
active only from the basal aspect. A pan-caspase inhibitor prevented
the increase in caspase activity caused by basal E. coli LPS, and
reduced the effects of LPS on paracellular permeability. Synthetic
Pam3CSK4 in the basal compartment prevented all effects of basal E.
coli LPS. In conclusion, LPS applied to the base of the colonic
epithelial cells increased paracellular permeability by a mechanism
involving caspase activation, suggesting a process by which
perturbation of the gut barrier could be exacerbated. Moreover,
activation of TLR2 ameliorated such effects.
PMID: 20472611
So?
Does Jay from mumbai need an herb that knocks down H. Pylori?
Or is crohn's REALLY really his concern? <w>
What was i doing just now? LOL
Pam3CSK4 - 92 hits - pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=Pam3CSK4
One hit for gut monkey business.
http://www.ncbi.nlm.nih.gov/pubmed/17805211
Pediatr Res. 2007 Nov;62(5):542-6.
Butyrate regulates the expression of pathogen-triggered IL-8 in
intestinal epithelia.
Weng M, Walker WA, Sanderson IR.
Department of Pediatrics, Division of Pediatric Gastroenterology and
Nutrition, Massachusetts General Hospital and Harvard Medical School,
Charlestown, Massachusetts 02129, USA.
Abstract
Inflammatory bowel disease (IBD) is characterized by an exaggerated
immune response that involves pro-inflammatory cytokines including
IL-8. Production of these pro-inflammatory cytokines is triggered by
pathogen-associated molecular patterns (PAMP). Butyrate, a product of
bacterial fermentation of carbohydrates, has been reported to modulate
inflammation in IBD, possibly by regulating production of pro-
inflammatory cytokines. However, this effect of butyrate is
controversial. In this study, we used Pam3CSK4 (Pam3CysSerLys4), the
acylated NH2-terminus of the bacterial lipoprotein (a PAMP), to mimic
in vivo infection of pathogens. Butyrate transiently down-regulated
expression of IL-8 stimulated by Pam3CSK4. Treatment of cells with
butyrate before Pam3CSK4, however, enhanced production of IL-8.
Furthermore, butyrate induced expression of A20, a negative regulator
of the nuclear factor-kappaB pathway. Over-expression of A20 inhibited
Pam3CSK4-triggered IL-8 expression. Our data suggest that the
inflammatory modulation of butyrate in IBD is mediated by A20 and a
short pulse rather than continuous administration of butyrate may
provide a protective effect on IBD.
PMID: 17805211
=================================
randall... i know kofi will be HOT tomorrow... or SO i suspect
anywhey.
Kofi
IBD. Gut inflammation impairs the ability to detoxify H2S in IBD,
rendering toxic this downstream messenger of cholinergic function and
possible thioredoxin trigger. H2S (hydrogen sulfide) can boost
thioredoxin and thioredoxin is downstream of Keap1-Nrf2. Also of
interest, Nrf2 (-/-) mice are prone to lupus.
Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H801-6. Epub 2008 Jun
20.
�
Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of
antioxidant and antiapoptotic signaling.
Jha S, Calvert JW, Duranski MR, Ramachandran A, Lefer DJ.
Department of Medicine, Division of Cardiology, Albert Einstein College
of Medicine, Bronx, NY, USA.
Hydrogen sulfide (H(2)S) is an endogenously produced gaseous signaling
molecule with diverse physiological activity. The potential protective
effects of H(2)S have not been evaluated in the liver. The purpose of
the current study was to investigate if H(2)S could afford
hepatoprotection in a murine model of hepatic ischemia-reperfusion (I/R)
injury. Hepatic injury was achieved by subjecting mice to 60 min of
ischemia followed by 5 h of reperfusion. H(2)S donor (IK1001) or vehicle
were administered 5 min before reperfusion. H(2)S attenuated the
elevation in serum alanine aminotransferase (ALT) by 68.6% and aspartate
aminotransferase (AST) by 70.8% compared with vehicle group.
H(2)S-mediated cytoprotection was associated with an improved balance
between reduced glutathione (GSH) vs. oxidized glutathione (GSSG), an
attenuated formation of lipid hydroperoxides, and an increased
expression of thioredoxin-1 (Trx-1). Furthermore, H(2)S inhibited the
progression of apoptosis after I/R injury by increasing the protein
expression of heat shock protein (HSP-90) and Bcl-2. These results
indicate that H(2)S protects the murine liver against I/R injury through
an upregulation of intracellular antioxidant and antiapoptotic signaling
pathways.
Publication Types:
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't
PMID: 18567706
lactate can stimulate sulphide formation by sulphate-reducing bacteria
(SRB) present in the colon, with possible consequences for conditions
such as colitis since H2S is toxic in high doses; SRB¹s are in
competition with butyrate-producing species for the lactate [PMID
19732152] and an imbalance would underproduce butyrate and overproduce
sulphides (by competing with other bacteria for lactate,
butyrate-producing species reduce the production of H2S thus the
butyrate pathway may be correlated with properly controlled H2S levels);
Clinical studies suggest that colonic luminal hydrogen sulfide (H(2)S),
produced by sulfate-reducing bacteria or through other pathways, might
be involved in the pathogenesis of inflammatory bowel disease (IBD).
Nonetheless, this hypothesis has been poorly investigated by basic
studies using laboratory animals. We thus focused on two enzymes,
cystathionine-gamma-lyase (CSE) that generates H(2)S from l-cysteine,
and rhodanese that directly or indirectly detoxifies H(2)S, particularly
in relation to the colitis induced by dextran sulfate sodium (DSS) in
mice. CSE was a major H(2)S-forming enzyme in colonic and renal
homogenates from mice and rats, and the rhodanese activity was also
detectable in both tissues. Colitis-related symptoms including decreased
body weight gain, diarrhea, hematochezia and shortening of colon length
were observed in the mice drinking DSS. Those symptoms were not or only
slightly attenuated by repeated administration of a CSE inhibitor. CSE
activity and protein levels in the colonic tissue did not notably change
in the mice with colitis. In contrast, the activity and protein/mRNA
levels of rhodanese in the colon, but not kidney, significantly
decreased nearly in parallel with the development of colitis, followed
by elevation of rhodanese activity in red blood cells (RBCs). These data
show that rhodanese, but not CSE, is associated with DSS-induced colitis
in mice, leading to a hypothesis that impaired detoxification of H2S due
to down-regulation or suppression of colonic rhodanese is involved in
IBD. The delayed enhancement of rhodanese activity in RBCs, a possible
compensative event, might be available as a disease marker for IBD [PMID
19647029]
Hydrogen sulfide (H(2)S), a metabolic end product of sulfate-reducing
bacteria, represents a genotoxic insult to the colonic epithelium, which
may also be linked with chronic disorders such as ulcerative colitis and
colorectal cancer. This study defined the early (30 min) and late (4 hr)
response of nontransformed human intestinal epithelial cells (FHs 74
Int) to H(2)S. The genotoxicity of H(2)S was measured using the
single-cell gel electrophoresis (comet) assay. Changes in gene
expression were analyzed after exposure to a genotoxic, but not
cytotoxic, concentration of H(2)S (500 muM H(2)S) using pathway-specific
quantitative RT-PCR gene arrays. H(2)S was genotoxic in a concentration
range from 250 to 2,000 muM, which is similar to concentrations found in
the large intestine. Significant changes in gene expression were
predominantly observed at 4 hr, with the greatest responses by PTGS2
(COX-2; 7.92-fold upregulated) and WNT2 (7.08-fold downregulated). COX-2
was the only gene upregulated at both 30 min and 4 hr. Overall, the
study demonstrates that H(2)S modulates the expression of genes involved
in cell-cycle progression and triggers both inflammatory and DNA repair
responses. This study confirms the genotoxic properties of H(2)S in
nontransformed human intestinal epithelial cells and identifies
functional pathways by which this bacterial metabolite may perturb
cellular homeostasis and contribute to the onset of chronic intestinal
disorders [PMID 20120018]
mice lacking the antioxidant/detoxification enzyme Nrf2 (Nrf2 -/- or
Nrf2 (-/-)) develop an autoimmune condition resembling lupus [PMID
15173550]
the absence of Nrf2 in mice also exacerbates allergy-driven asthma; this
increased migration of inflammatory cells into airways
<http://www.sciencedaily.com/releases/2005/07/050706004103.htm>
In article
<cb1090d7-3621-4391...@d1g2000pra.googlegroups.com>,
randall
> This may stem from the perturbations of hydrogen sulfide metabolism in
> IBD. Gut inflammation impairs the ability to detoxify H2S in IBD,
> rendering toxic this downstream messenger of cholinergic function and
> possible thioredoxin trigger. H2S (hydrogen sulfide) can boost
> thioredoxin and thioredoxin is downstream of Keap1-Nrf2. Also of
> interest, Nrf2 (-/-) mice are prone to lupus.
> [PMID: 19647029]
> snip [PMID 20120018]
>
> [PMID
> 15173550]
>
> the absence of Nrf2 in mice also exacerbates allergy-driven asthma; this
> increased migration of inflammatory cells into airways
> <http://www.sciencedaily.com/releases/2005/07/050706004103.htm>
>
> In article
>
><snip>> > PMID: 21248850- Hide quoted text -
>
> - Show quoted text -
Kofi
I just heard. We LOST Jack LaLanne. He passed this afternoon. :(
DARN it. I was hoping he'd go till 123 y/o.
And prove that exercise is radically HOT...
http://www.google.com
Fitness guru Jack LaLanne, 96, dies at Calif. home
(AP) – 14 minutes ago
MORRO BAY, Calif. (AP) — Fitness guru Jack LaLanne (lah-LAYN'), who
inspired television viewers to trim down and pump iron decades before
exercise became a national obsession, has died at age 96.
His agent, Rick Hersh, says LaLanne died of respiratory failure due to
pneumonia Sunday afternoon at his home in Morro Bay on California's
central coast.
Hersh says Lalanne ate healthy and exercised every day of his life up
until the end.
LaLanne credited fitness with transforming his life as a teen, and he
worked over the next eight decades to transform others' lives, too.
He said, "The only way you can hurt the body is not use it." LaLanne's
workout show was a television staple from the 1950s to '70s. He
maintained a youthful physique into his 80s.
<snip>
http://en.wikipedia.org/wiki/Pneumonia#Clinical
Maybe his glutathione levels droPPed or something jejune like that?
Or thiol lowerings and liver enzymes perhaPs?
146 hits: pneumonia glutathione - pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=pneumonia+glutathione
#1 of these 146:
http://www.ncbi.nlm.nih.gov/pubmed/21240372
Bull Exp Biol Med. 2010 Aug;150(2):198-202.
Role of Thiol-Disulfide System in Mechanisms of Functional Changes in
Neutrophils under Conditions of Oxidative Stress.
[Article in English, Russian]
Stepovaya EA, Petina GV, Zhavoronok TV, Ryazanceva NV, Ivanov VV,
Ageeva TS, Tetenev FF, Novitsky VV.
Department of Biochemistry and Molecular Biology, Department of
Pathophysiology, Department of Fundamental Bases of Clinical Medicine,
Department of Propedeutics of Internal Dieseases, Siberian State
Medical University, Federal Agency for Health Care and Social
Development, Tomsk; Department of Postgraduate Medical Education,
Tomsk Military Medical Institute, Ministry of Defense of the Russian
Federation, Russia. tav...@ngs.ru.
Abstract
We studied the state of the thiol-disulfide system (contents of
reduced and oxidized glutathione, their ratio, and concentrations of
protein SH-groups and protein-bound glutathione) and functional
properties of neutrophils (production of hydroxyl radicals, IL-8, and
TNF-α and myeloperoxidase activity) from healthy donors under
conditions of oxidative stress in vitro induced by H(2)O(2)in a final
concentration of 200 μM and from patients with community-acquired
pneumonia. We evaluated the role of reduced and protein-bound
glutathione in the regulation of functional state of blood neutrophils
from patients with community-acquired pneumonia and during oxidative
stress in vitro under conditions cell incubation with N-ethylmaleimide
or 1,4-dithioerythritolsulfhydryl, the blocker and protector of
sulfhydryl groups, respectively.
PMID: 21240372
WELL?
I could just tell you. LOL
Back to your liver and H2S or is it mine?
WE've had some HIGH AST ALH liver enzymes and sulfides in our group:
11 results for hydrogen sulfide
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=hydrogen+sulfide
Besides the current one, i like the one from jan 11, 2002.
46 hits --> For:: ast alt - p NG:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=alt+ast
In the crohn's-colitis group: 95 hits for : ast alt
http://groups.google.com/group/alt.support.crohns-colitis/search?hl=en&group=alt.support.crohns-colitis&q=alt+ast+&qt_g=Search+this+group
THE KEY word for BOTH groups (psoriasis/crohn's-colitis) is ELEVATED.
Sulfur can be a mercurial topic, whether sitting next to a rotten egg
or gaseous swamp.
Yet
What differentiates one from the udder?
http://en.wikipedia.org/wiki/Colitis#Autoimmune
Certainly so many overlaPPing pathways would indict some common
element, say SFB in the small intestines, as a common enemy IMHO for
IBD'ers
and psoriatics.
What is it with lesion-ary inside (IBD) versus outside skin
(psoriasis) in the autoimmune GAME?
Is the ratio of gut deniZENs like sFB and clostridium the it as in a
causal factor?
As far as smelly eggish sulferous FART GAS goes i doubt it lends any
HUGE clues.
Yet, will do some perfunctory googlings.
http://en.wikipedia.org/wiki/Hydrogen_sulfide#Function_in_the_body
Hydrogen sulfide is produced in small amounts by some cells of the
mammalian body and has a number of biological signaling functions.
(Only two other such gases are currently known: nitric oxide (NO) and
carbon monoxide (CO).)
The gas is produced from cysteine by the enzymes cystathionine beta-
synthase and cystathionine gamma-lyase. It acts as a relaxant of
smooth muscle and as a vasodilator[19] and is also active in the
brain, where it increases the response of the NMDA receptor and
facilitates long term potentiation,[20] which is involved in the
formation of memory.
Eventually the gas is converted to sulfite in the mitochondria by
thiosulfate reductase, and the sulfite is further oxidized to
thiosulfate and sulfate by sulfite oxidase. The sulfates are excreted
in the urine.[21]
Due to its effects similar to nitric oxide (without its potential to
form peroxides by interacting with superoxide), hydrogen sulfide is
now recognized as potentially protecting against cardiovascular
disease.[19] The cardioprotective role effect of garlic is caused by
catabolism of the polysulfide group in allicin to H2S, a reaction that
could depend on reduction mediated by glutathione.[22]
Though both nitric oxide and hydrogen sulfide have been shown to relax
blood vessels, their mechanisms of action are different: while NO
activates the enzyme guanylyl cyclase, H2S activates ATP-sensitive
potassium channel in smooth muscle cells. Researchers are not clear
how the vessel-relaxing responsibilities are shared between nitric
oxide and hydrogen sulfide. However there exists some evidence to
suggest that nitric oxide does most of the vessel-relaxing work in
large vessels and hydrogen sulfide is responsible for similar action
in smaller blood vessels.[23]
Like nitric oxide, hydrogen sulfide is involved in the relaxation of
smooth muscle that causes erection of the penis, presenting possible
new therapy opportunities for erectile dysfunction.[24][25]
In Alzheimer's disease the brain's hydrogen sulfide concentration is
severely decreased.[26] In trisomy 21 (the most common form of Down
syndrome) the body produces an excess of hydrogen sulfide.[21]
Hydrogen sulfide is also involved in the disease process of type 1
diabetes. The beta cells of the pancreas in type 1 diabetes produce an
excess of the gas, leading to the death of beta cells and to a reduced
production of insulin by those that remain.[23]
<snip>
Is it alimentary to recognize pioneering organisms (disaster taxa) vs
defensins as a evolutionary function?
OK , so i'm having fun now. LOL
http://en.wikipedia.org/wiki/Pioneer_organism
Even the earth farted off it's shield in quest of anoxic or hyPoxic
whatever that was 220 million years aglow.
Are we NOT that which precedes us and therefore have those links
methinks evolutionarilly within?
Good one.
I'm really having FUN now. LOL
I'm doing the jack la lanne brain triP.... all neurons are firing
without H2S, but without mct cooonut oil either. :(
Yet the Gi tract is more hypoxic then anoxic and LAB is still the best
way to handle sulfur from poPPing off.
What?
YOU don't like sniffing the odorous swamP gas of some well fed ....
you get it?
But without a slightly acidic colon milieu in side of you, this might
perpetuate autoimmunity and
TAX thiols and glutathiones to the breaking point?
Makes total sense to me... and think what that might do to iodine
levels?
You could end up a moron if this happens unchecked in early years....
no wonder i felt so sPaced out. LOL
I see DEAD pimpLES... and even worse.... the psor skin curse. LOL
And without MMR they still have indigenous heavy metals to look at?
http://www.ncbi.nlm.nih.gov/pubmed/20628440
J Gastroenterol. 2011 Jan 21.
Comparison of the fecal microbiota profiles between ulcerative colitis
and Crohn's disease using terminal restriction fragment length
polymorphism analysis.
Andoh A, Imaeda H, Aomatsu T, Inatomi O, Bamba S, Sasaki M, Saito Y,
Tsujikawa T, Fujiyama Y.
Division of Mucosal Immunology, Graduate School of Medicine, Shiga
University of Medical Science, Seta Tsukinowa, Otsu, 520-2192, Japan,
an...@belle.shiga-med.ac.jp.
Abstract
BACKGROUND: Terminal restriction fragment length polymorphism (T-RFLP)
analysis is a powerful tool to assess the diversity of a microbial
community. In this study, we performed T-RFLP analysis of the fecal
microbiota from patients with ulcerative colitis (UC) and those with
Crohn's disease (CD).
METHODS: Thirty-one patients with UC, 31 patients with CD, and 30
healthy individuals were enrolled. The polymerase chain reaction (PCR)
products obtained from the 16S rRNA genes of fecal samples were
digested with BslI, and T-RF lengths were determined.
RESULTS: The fecal microbial communities were classified into 5
clusters. Twenty-eight of the 30 healthy individuals and 17 of the 18
patients with inactive UC were classified into clusters I, II, and
III, but these clusters included a small number of patients with
active UC and inactive/active CD. In contrast, 8 of the 13 patients
with active UC and the majority of CD patients (12 of the 16 patients
with inactive CD, and 11 of the 15 patients with active CD) were
included in clusters IV and V. Based on the BslI-digested T-RFLP
database, the bacteria showed a significant decrease in the
Clostridium family in patients with active UC and inactive/active CD.
In contrast, Bacteroides were significantly increased in CD patients.
No significant differences were observed between patients with active
UC and those with active CD.
CONCLUSION: The fecal microbial communities of IBD patients were
different from those of healthy individuals. The gut microbiota of
patients with inactive UC tended to be closer to that of healthy
individuals, suggesting different roles for the fecal microbiota in
the pathophysiology of UC and CD.
PMID: 21253779
What if, what THEY tax is more then being a moron as gut flora becomes
indicted in this incestuous
game of merCATan and MOUSE?
You mean mercapton?
Right, but it didn't FIT. LOL
Like the plasticity of my immunities my thinking is without stinking
barriers. :)
http://en.wikipedia.org/wiki/Thiol
[...] Thiols are often referred to as mercaptans
I know by looking at LE this will keeP kofi hot. LOL
While that which dictates immunity is so sneaky and benign right under
our nostrils. <w>
496 hits: colon hypoxi*
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=colon+hypoxi*
496 hits : gastrointestinal hypoxi*
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=gastrointestinal+hypoxi*
795 hits: colon polyamines
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=colon+polyamines
http://www.ncbi.nlm.nih.gov/pubmed/21253788
Recent Results Cancer Res. 2011;188:49-64.
Targeting polyamines and inflammation for cancer prevention.
Babbar N, Gerner EW.
Research and Development, Osmetech Molecular Diagnostic, 757 S Raymond
Avenue, Pasadena, CA, 91105, USA, naveen...@osmetech.com.
Abstract
Increased polyamine synthesis and inflammation have long been
associated with intraepithelial neoplasia, which are risk factors for
cancer development in humans. Targeting polyamine metabolism (by use
of polyamine synthesis inhibitors or polyamine catabolism activators)
and inflammation (by use of nonsteroidal anti-inflammatory drugs) has
been studied for many cancers, including colon, prostate, and skin.
Genetic epidemiology results indicate that a genetic variant
associated with the expression of a polyamine biosynthetic gene is
associated with risk of colon and prostate cancers. A clinical trial
of difluoromethylornithine (DFMO), a selective inhibitor of polyamine
synthesis, showed that the 1 year treatment duration reduced prostate
volume and serum prostate-specific antigen doubling time in men with a
family history of prostate cancer. A second, clinical trial of DFMO in
combination with sulindac, a NSAID in patients with prior colon polyps
found that the 3-year treatment was associated with a 70% reduction of
all, and over a 90% reduction of advanced and/or multiple metachronous
colon adenomas. In this chapter, we discuss that similar combination
prevention strategies of targeting polyamines and inflammation can be
effective in reducing risk factors associated with the development of
human cancers.
PMID: 21253788
cronh's and psoriasis have high amounts of polyamines, spermines et
al?
http://www.ncbi.nlm.nih.gov/pubmed/20122516
===========
http://www.ncbi.nlm.nih.gov/pubmed/19572337
Inflamm Bowel Dis. 2010 Mar;16(3):518-24.
Potential for amino acids supplementation during inflammatory bowel
diseases.
Coëffier M, Marion-Letellier R, Déchelotte P.
Appareil Digestif Environnement Nutrition (ADEN EA4311), Institute for
Biomedical Research, European Institute for Peptide Research (IFRMP
23), Rouen University and Rouen University Hospital, Rouen, France.
moise.c...@univ-rouen.fr
Abstract
The pathophysiology of inflammatory bowel diseases (IBDs) is
multifactorial and involves interactions of gut luminal content with
mucosal barrier and especially immune cells. Malnutrition is a
frequent issue during IBD flares, especially in Crohn's disease (CD)
patients, and nutritional support is frequently used to treat
malnutrition but also in an attempt to modulate intestinal
inflammation. The use of oral or enteral nutrition intervention in
IBDs may be effective, alone or in combination with drugs, to achieve
and maintain remission. However, standard diets are less effective
than new-generation biotherapies and could be improved by
supplementation with specific immunomodulatory amino acids.
Experimental studies evaluating glutamine, the preferential substrate
for enterocytes, are promising. Some clinical studies with oral
glutamine in CD are until now disappointing, but new formulations and
targeting could enhance glutamine efficacy at the site of mucosal
lesions. The role of arginine, involved in nitric oxide and polyamines
synthesis, still remains debated. However, the effects of these amino
acids in IBD have been poorly documented in humans. Other candidates
like glycine, cysteine, histidine, or taurine should also be evaluated
in the future.
PMID: 19572337
===========
http://www.nature.com/nrgastro/journal/v7/n5/abs/nrgastro.2010.39.html
Hypoxia: an alarm signal during intestinal inflammation
Sean P. Colgan & Cormac T. Taylor About the authors
Top of pageAbstractIntestinal epithelial cells that line the mucosal
surface of the gastrointestinal tract are positioned between an
anaerobic lumen and a highly metabolic lamina propria. As a result of
this unique anatomy, intestinal epithelial cells function within a
steep physiologic oxygen gradient relative to other cell types.
Furthermore, during active inflammatory disease such as IBD, metabolic
shifts towards hypoxia are severe. Studies in vitro and in vivo have
shown that the activation of hypoxia-inducible factor (HIF) serves as
an alarm signal to promote the resolution of inflammation in various
mouse models of disease. Amelioration of disease occurs, at least in
part, through transcriptional upregulation of nonclassic epithelial
barrier genes. There is much interest in harnessing hypoxia-inducible
pathways, including stabilizing HIF directly or via inhibition of
prolyl hydroxylase enzymes, for therapy of IBD. In this Review, we
discuss the signaling pathways involved in the regulation of hypoxia
and discuss how hypoxia may serve as an endogenous alarm signal for
the presence of mucosal inflammatory disease. We also discuss the pros
and cons of targeting these pathways to treat patients with IBD
<snip>
Their whole taco: <this is xlnt btw- worth a look see>
http://www.ucdenver.edu/academics/colleges/medicalschool/departments/medicine/Gastroenterology/Faculty/Documents/Colgan_12.pdf
[...] Both the absorptive and barrier
functions of the intestinal epithelium are regulated
by the availability of oxygen.3
it is widely understood that the gastrointestinal tract
functions in a state of low-grade inflammation.
[...] loss of epithelial barrier function with the resultant
unrestricted flux of luminal antigens to the mucosal
immune system underlies the pathology of iBD, and
results in hypoxia within the chronically inflamed
mucosa, particularly within the epithelial cell layer.
ongoing studies suggest that hypoxia-regulated pathways
are highly associated with iBD and contribute to
the resolution of ongoing inflammation. in this review
we discuss the signaling pathways involved in these
processes and the possibility of developing therapies to
modify the hypoxic state for the treatment of iBD.
Hypoxia and the immune response
sites of mucosal inflammation are characterized by
profound changes in tissue metabolism, including local
depletion of nutrients, imbalances in tissue oxygen supply
<snip>
[...]
Conclusions
the gastrointestinal mucosa is an interesting tissue in
which to investigate tissue oxygenation and diseasebased
metabolism. as outlined, there is evidence for
hypoxia as an important alarm signal to promote the
resolution of inflammation within the intestinal mucosa.
Cultured cell systems, animal models and patient-derived
materials have all been used to show that hypoxia is a
significant component of the inflammatory microenvironment.
likewise, studies in animal models of
intestinal inflamma tion have demonstrated an almost
uniformly beneficial influence of HiF stabilization on
disease outcomes. it should be noted that the increased
susceptibility to colitis following the deletion of Hif1 in
intestinal epithelial cells may be somewhat model dependent
and will require additional validation with PHD
inhibitors before clinical studies can be implemented.
ongoing studies to define the differences and similarities
between innate and adaptive immune responses
will continue to teach us important lessons about the
complexity of the gastrointestinal tract. such information
will provide new insights into the pathogenesis of
iBD and, importantly, will provide new targets for the
development of therapies for iBD.
<snip>
http://en.wikipedia.org/wiki/Colon_(anatomy)#Function
[...] The pH in the colon varies between 5.5 and 7 (slightly acidic to
neutral). [7]
Why wouldn't the closer to 5.5 be the desired state of BEING?
Because those big pharma's want to sell us craP. LOL
Instead of there just being craP in us they want to block the excess
TNF crap
with their mAb crap and make BIG PIG bucks like uncle sam i am. <G>
Oh NO you don't..
What?
Indict the obama as uncle sam i am...
Why not?
He's at war with bussiness and making big pig sam the new how WELL i
am?
OK but get back on track jack..
K...
Certainly in the other direction is increased inflammations and cancer
both
in this case being uPstream of Th1 or Th2?
No way!
Yes and use sweet whey and protein whey to save the day. LOL
What about your coconut brain mct thing?
Haven't started it yet.
I'm flailing around like a ding bat without his cocoNUT groove on. LOL
http://www.ncbi.nlm.nih.gov/pubmed/20970751
Transl Res. 2010 Nov;156(5):282-91. Epub 2010 Aug 24.
Enteral diets enriched with medium-chain triglycerides and N-3 fatty
acids prevent chemically induced experimental colitis in rats.
Kono H, Fujii H, Ogiku M, Tsuchiya M, Ishii K, Hara M.
First Department of Surgery, Faculty of Medicine, University of
Yamanashi, Chuo, Yamanashi, Japan. hko...@yamanashi.ac.jp
Abstract
The specific purpose of this study was to evaluate the significant
effects of medium-chain triglycerides (MCTs) and N-3 fatty acids on
chemically induced experimental colitis induced by 2,4,6-
trinitrobenzene sulphonic acid (TNBS) in rats. Male Wistar rats were
fed liquid diets enriched with N-6 fatty acid (control diets), N-3
fatty acid (MCT- diets), and N-3 fatty acid and MCT (MCT+ diets) for 2
weeks and then were given an intracolonic injection of TNBS. Serum and
tissue samples were collected 5 days after ethanol or TNBS enema. The
severity of colitis was evaluated pathologically, and tissue
myeloperoxidase activity was measured in colonic tissues. Furthermore,
protein levels for inflammatory cytokines and a chemokine were
assessed by an enzyme-linked immunosorbent assay in colonic tissues.
Induction of proinflammatory cytokines tumor necrosis factor-α and
interleukin-1β in the colon by TNBS enema was markedly attenuated by
the MCT+ diet among the 3 diets studied. Furthermore, the induction of
chemokines macrophage inflammatory protein-2 and monocyte chemotactic
protein-1 also was blunted significantly in animals fed the MCT+
diets. As a result, MPO activities in the colonic tissue also were
blunted significantly in animals fed the MCT+ diets compared with
those fed the control diets or the MCT- diets. Furthermore, the MCT+
diet improved chemically induced colitis significantly among the 3
diets studied. Diets enriched with both MCTs and N-3 fatty acids may
be effective for the therapy of inflammatory bowel disease as
antiinflammatory immunomodulating nutrients.
PMID: 20970751
Is Jays maJic herb BERRY GOOD?
http://www.ncbi.nlm.nih.gov/pubmed/20955650
Br J Nutr. 2010 Oct;104 Suppl 3:S48-66.
Colonic metabolites of berry polyphenols: the missing link to
biological activity?
Williamson G, Clifford MN.
School of Food Science and Nutrition, University of Leeds, Leeds, UK.
g.will...@leeds.ac.uk
Abstract
The absorption of dietary phenols, polyphenols and tannins (PPT) is an
essential step for biological activity and effects on health. Although
a proportion of these dietary bioactive compounds are absorbed intact,
depending on their chemical structure and the nature of any attached
moiety (e.g. sugar, organic acid), substantial amounts of lower
molecular weight catabolites are absorbed after biotransformation by
the colon microflora. The main products in the colon are (a) benzoic
acids (C6-C1), especially benzoic acid and protocatechuic acid; (b)
phenylacetic acids (C6-C2), especially phenylacetic acid per se; (c)
phenylpropionic acids (C6-C3), where the latter are almost entirely in
the dihydro form, notably dihydrocaffeic acid, dihydroferulic acid,
phenylpropionic acid and 3-(3'-hydroxyphenyl)-propionic acid. As a
result of this biotransformation, some of these compounds can each
reach mm concentrations in faecal water. Many of these catabolites are
efficiently absorbed in the colon, appear in the blood and are
ultimately excreted in the urine. In the case of certain polyphenols,
such as anthocyanins, these catabolites are major products in vivo;
protocatechuic acid is reported to represent a substantial amount of
the ingested dose of cyanidin-3-O-glucoside. The major catabolites of
berries, and especially blackcurrants, are predicted based on
compositional data for polyphenols from berries and other sources.
Since microbial catabolites may be present at many sites of the body
in higher concentration than the parent compound, it is proposed that
at least a part of the biological activities ascribed to berry
polyphenols and other PPT are due to their colonic catabolites.
PMID: 20955650
-------------------
Br J Nutr. 2010 Oct;104 Suppl 3:S67-90.
Berry flavonoids and phenolics: bioavailability and evidence of
protective effects.
Del Rio D, Borges G, Crozier A.
Department of Public Health, University of Parma, Parma, Italy.
Abstract
Berries contain vitamin C and are also a rich source of
phytochemicals, especially anthocyanins which occur along with other
classes of phenolic compounds, including ellagitannins, flavan-3-ols,
procyanidins, flavonols and hydroxybenzoate derivatives. This review
examines studies with both human subjects and animals on the
absorption of these compounds, and their glucuronide, sulphate and
methylated metabolites, into the circulatory system from the
gastrointestinal tract and the evidence for their localisation within
the body in organs such as the brain and eyes. The involvement of the
colonic microflora in catabolising dietary flavonoids that pass from
the small to the large intestine is discussed along with the potential
fate and role of the resultant phenolic acids that can be produced in
substantial quantities. The in vitro and in vivo bioactivities of
these polyphenol metabolites and catabolites are assessed, and the
current evidence for their involvement in the protective effects of
dietary polyphenols, within the gastrointestinal tract and other parts
of the body to which they are transported by the circulatory system,
is reviewed.
PMID: 20955651
Jay the aPPleseed, konjac root and psyllium husk-er of mumbai?
Is that the maJic herb of blurb that JAY so deserves? LOL
http://www.ncbi.nlm.nih.gov/pubmed/20400476
Carcinogenesis. 2010 Oct;31(10):1822-32. Epub 2010 Apr 16.
An apple oligogalactan prevents against inflammation and
carcinogenesis by targeting LPS/TLR4/NF-κB pathway in a mouse model of
colitis-associated colon cancer.
Liu L, Li YH, Niu YB, Sun Y, Guo ZJ, Li Q, Li C, Feng J, Cao SS, Mei
QB.
Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia
Medica of the State Administration of Traditional Chinese Medicine,
Department of Pharmacology, School of Pharmacy, Fourth Military
Medical University, Xian 710032, Shaanxi, People's Republic of China.
Abstract
Evidence strongly supported a link between inflammation and cancer.
Patients with colitis have high risk for development of colon cancer.
Nuclear factor-kappa B (NF-κB), partially induced by
lipopolysaccharide (LPS) binding to Toll-like receptor (TLR) 4, is a
vital molecule in supervising the transformation of colitis to colon
cancer. It could be a good strategy to prevent colitis carcinogenesis
for targeting LPS/TLR4/NF-κB pathway. In the present study, we
obtained an oligogalactan composed of five galacturonic acids from
apple pectin and evaluated its protective efficacy on intestinal
toxicities and carcinogenesis in a mouse model of colitis-associated
colon cancer induced by 1,2-dimethylhydrazine and dextran sodium
sulfate (DSS). The apple oligogalactan (AOG) was highly effective
against intestinal toxicities and carcinogenesis and decreased the
elevated levels of TLR4 and tumor necrosis factor-α (TNF-α) induced by
inflammation in vivo in this model system. In vitro studies, AOG alone
only slightly increased the levels of protein expression and messenger
RNA of TLR4, phosphorylation of IκBα and production of TNF-α in HT-29
cells. However, AOG significantly decreased the elevation of all the
biomarkers induced by LPS when it was combined with LPS. The effect of
AOG may be related to membrane internalization and redistribution of
TLR4 from cell membrane to cytoplasm. AOG is active against
inflammation and carcinogenesis through targeting LPS/TLR4/NF-κB
pathway. Both AOG and LPS are agonists of TLR4 for sharing the same
ligand but AOG has a much lower intrinsic activity than that of LPS.
AOG may be useful for treatment of colitis and prevention of
carcinogenesis in the clinics.
PMID: 20400476
Maybe the high or low pH is due to the Th1 skew being protective of
cancer in general?
Maybe lipozene is it?
LOL...
Sorry this chick pushing lipozene ( i clicked over while watching
football) has me mesmerized. What's Amorphophallus konjac ?
Sounds phallic and i'm watching FOOTBALL to boot. <g>
H'mm, could be more then propitious this hot babe blathering about
being svelte?
Lose weight with glucomannan in a weight loss product:
http://en.wikipedia.org/wiki/Glucomannan#Dietary_supplements
http://en.wikipedia.org/wiki/Glucomannan#Natural_sources
Hey this is serious stuff pushed by a tv cutie pie for those desirous
of svelte or physical
demeaour. REALLY
LOL
http://www.ncbi.nlm.nih.gov/pubmed/20799709
J Agric Food Chem. 2010 Sep 22;58(18):10277-81.
Comparative effects of cellulose and soluble fibers (pectin, konjac
glucomannan, inulin) on fecal water toxicity toward Caco-2 cells,
fecal bacteria enzymes, bile acid, and short-chain fatty acids.
Chen HL, Lin YM, Wang YC.
School of Nutrition, Chung Shan Medical University, and Department of
Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan.
hlc...@csmu.edu.tw
Abstract
The aim of this study was to compare the effects of cellulose and
three soluble dietary fibers, pectin, konjac glucomannan (KGM), and
inulin, on the cytotoxicity and DNA damage of fecal water-treated
Caco-2 cells, a human colon adenocarcinoma cell line, and to
investigate the fecal components that potentially modulate the fecal
toxicity, that is, bacterial enzymes, bile acids, and short-chain
fatty acids. Six-week-old BALB/cJ mice were randomly allocated to
consume an AIN-93 diet that contained no dietary fiber (fiber-free) or
5% (w/w) cellulose, pectin, KGM, and inulin for 3 weeks. Feces were
collected during days 18-21. Fecal waters were co-incubated with
Caco-2 cells to determine the cytotoxicity and DNA damage. In
addition, the fecal bacterial enzymes, bile acids, and short-chain
fatty acids were determined. Results indicated that all fiber diets
similarly increased the survival rate (%) of fecal water-treated
Caco-2 cells as compared with the fiber-free diet. The inhibition of
fecal water-induced DNA damage in Caco-2 cells was greater for the
pectin and inulin diets than for the cellulose and KGM diets. In
contrast, cellulose exerted the greatest inhibitory effect on the
fecal β-glucuronidase activity. Cellulose and all soluble dietary
fibers reduced the secondary bile acid concentrations in the fecal
water, but only soluble fibers increased the fecal concentrations of
short-chain fatty acids, as compared with no fiber. Therefore, this
study suggests that all dietary fibers substantially reduced the fecal
water toxicity, which is associated with decreased secondary bile acid
levels by all fibers, reduced fecal β-glucuronidase activity by
cellulose, and increased short-chain fatty acid levels by soluble
dietary fibers.
PMID: 20799709
http://www.ncbi.nlm.nih.gov/pubmed/18460488
[...] CONCLUSION: The modest dose of KGM supplement promoted bowel
movement by 30% and improved colonic ecology in constipated adults.
PMID: 18460488
http://www.ncbi.nlm.nih.gov/pubmed/17027233
Konjac acts as a natural laxative by increasing stool bulk and
improving colonic ecology in healthy adults.
[...] CONCLUSION: Supplementation of KGM into a low-fiber diet
promoted the defecation frequency in healthy adults, possibly by
increasing the stool bulk, thus promoting the growth of lactic acid
bacteria and colonic fermentation.
PMID: 17027233
http://www.ncbi.nlm.nih.gov/pubmed/21208006
J Agric Food Chem. 2011 Jan 5.
Effects of Konjac Glucomannan on Putative Risk Factors for Colon
Carcinogenesis in Rats Fed a High-Fat Diet.
Wu WT, Chen HL.
School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
Abstract
The aim of this study was to determine effects of konjac glucomannan
(KGM) in a high fat corn oil diet on risk factors of colon
carcinogenesis, that is, fecal β-glucuronidase, mucinase, and bile
acids, and on preventive factors, that is, fecal microflora and cecal
short-chain fatty acids (SCFAs). Sprague-Dawley rats (n = 8 animals
per group) were fed a normal-fat fiber-free (5% corn oil, w/w) or high-
fat (25% corn oil, w/w) diet containing no fiber, KGM (5%, w/w), or
inulin (5%, w/w, as a prebiotic control) for 4 weeks. Results
indicated that the high-fat fiber-free diet significantly elevated the
fecal β-glucuronidase and mucinase activities and total bile acid
concentration and decreased cecal SCFA contents, as compared with its
normal-fat counterpart. The incorporation of KGM, as well as inulin,
into the high-fat fiber-free diet beneficially reduced the fecal β-
glucuronidase and mucinase activities and lithocholic acid (secondary
bile acid) concentration. Although KGM elevated the daily fecal total
bile acid excretion, the change was due to the primary, instead of the
secondary, bile acids. In addition, KGM beneficially promoted the
daily fecal excretion of bifidobacteria and lactobacilli and cecal
SCFA contents, as compared with the high-fat fiber-free diet.
Therefore, the present study suggests that KGM potentially attenuated
the high fat-induced risk in colon carcinogenesis.
PMID: 21208006
How about some apple pectin with konjac and psyllium husk? And toss
in those
berries? Or how about pomegranate juice, Concord grape juice,
blueberry juice, and or resveratrol rich red wine?
And since clostridium induce or induct (see Kenya Honda/PMID:
21205640)
TREGs then it's salient in so far as inflammation is curtailed
http://www.ncbi.nlm.nih.gov/pubmed/12111144
Appl Microbiol Biotechnol. 2002 Jul;59(2-3):182-9. Epub 2002 May 3.
Dietary-fiber-degrading enzymes from a human intestinal Clostridium
and their application to oligosaccharide production from nonstarchy
polysaccharides using immobilized cells.
Nakajima N, Ishihara K, Matsuura Y.
Department of Nutritional Science, Okayama Prefectural University,
Soja, Japan. naka...@fhw.oka-pu.ac.jp
Abstract
The secretion of nonstarchy polysaccharide-degrading enzymes from an
anaerobic human intestinal bacterium, Clostridium butyricum-
beijerinckii (isolated from human feces), was investigated. Growth of
the bacterium was found when laminarin, konjac glucomannan, and pectic
acid were added separately to the culture media as sole carbon source.
The corresponding degrading enzymes for these dietary fibers,
laminarinase (endo-1,3- beta-glucanase), endo-1,4-beta-mannanase,
endo- and exo-pectate lyases, and pectin methylesterase, were then
purified and characterized. These extracelluar enzymes, which were
secreted by the bacterium in the human large intestine, were
considered to contribute to digestion of the ingested dietary fibers
to their oligosaccharides, following by short-chain fatty acid
fermentation by the bacterium. We have developed cell immobilization
techniques of the bacterium on cellulose-foam carriers that are
effective for continuous production of the oligosaccharides from the
dietary fibers in a fed-batch reactor system. From 9 g of pectic acid,
a total of 3.96 g of 4,5-unsaturated digalacturonic acid was produced
over 40 h in four 500-ml batchcultures. In the same manner, the
corresponding oligosaccharides were obtained from konjac glucomannan
and laminarin with average conversion rates of around 30-40%.
PMID: 12111144
http://www.ncbi.nlm.nih.gov/pubmed/12570821
Curr Pharm Des. 2003;9(4):333-46.
Modification of intestinal flora in the treatment of inflammatory
bowel disease.
Kanauchi O, Mitsuyama K, Araki Y, Andoh A.
Nutrient Food & Feed Division, Kirin Brewery Co Ltd, 10-1-2 Shinkawa
Chuo-ku, Tokyo, 104-8288, Japan. kana...@kirin.co.jp
Abstract
Because the intestinal microflora play an important role in the
development of inflammatory bowel disease (IBD), there is currently
some interest in the manipulation of the composition of the microflora
towards a potentially more remedial community. This review summarizes
the clinical and experimental efficacy of the manipulation of
microflora by the use of prebiotics, probiotics, synbiotics, and
antibiotics in IBD. Prebiotics, defined as nondigestible food
ingredients that beneficially affect the host by selectively
stimulating the growth or activity of one or a limited number of
bacterial species already resident in the colon, can modulate the
colonic microbiota by increasing the number of specific bacteria and
thus changing the composition of the microbiota. Prebiotics for IBD
include lactosucrose, oligofructose, inulin, bran, psyllium, and
germinated barley foodstuff (GBF). GBF, which mainly consists of
dietary fiber and glutamine-rich protein, is a prebiotic foodstuff for
ulcerative colitis. GBF has shown to be converted into a preferential
nutrient for colonocytes through Eubacterium and Bifidobacterium and
also inactivate nuclear factor kappa B (NFkB). Moreover, it exhibits a
potent water-holding capacity and bile-acid binding capacity.
Probiotics, which are microbial food supplements that beneficially
affect the host by improving the intestinal microbial balance, have
been used to change the composition of colonic microbiota. The
approaches for IBD include VSL#3, Nissle1917, Clostridium butyricum
and Bifidobacterium-fermented milk. Use of Lactococci secreting IL-10
provides excellent results. The combination of prebiotics and
probiotics in a synbiotic has not been studied in IBD but is
promising. The use of antibiotics continues to be of interest.
Although these strategies hold great promise and appear to be useful
in some settings, more clinical study is needed to firmly establish
the relevance of these therapies.
PMID: 12570821
If they KNEW this (below abstract) clostridium & SFB stuff in 1999,
why didn't they make a cure for autoimmune folks by now?
How come Itoh didn't call kenya Honda and say hey, these sFB and
clostridium control immunity.
We should LOOK at this?
And eleven-ish years later they DO it?
Huh?
WELL look:
Itoh and honda January 21 2011 and Itoh as far back as 1986 working on
clostridium.
22 hits : "Itoh k"[Author] AND clostridium - pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=%22Itoh+k%22%5BAuthor%5D+AND+clostridium
Here's #11 of these from 1999 for BOTH SFB and clostridium in the same
abstract:
http://www.ncbi.nlm.nih.gov/pubmed/10377132
Infect Immun. 1999 Jul;67(7):3504-11.
Differential roles of segmented filamentous bacteria and clostridia in
development of the intestinal immune system.
Umesaki Y, Setoyama H, Matsumoto S, Imaoka A, Itoh K.
Yakult Central Institute for Microbiological Research, Yaho 1796,
Kunitachi-shi, Tokyo 186-8650, Japan.
Abstract
The presence of microflora in the digestive tract promotes the
development of the intestinal immune system. In this study, to
evaluate the roles of two types of indigenous microbe, segmented
filamentous bacteria (SFB) and clostridia, whose habitats are the
small and large intestines, respectively, in this immunological
development, we analyzed three kinds of gnotobiotic mice contaminated
with SFB, clostridia, and both SFB and clostridia, respectively, in
comparison with germfree (GF) or conventionalized (Cvd) mice
associated with specific-pathogen-free flora. In the small intestine,
the number of alpha beta T-cell receptor-bearing intraepithelial
lymphocytes (alpha betaIEL) increased in SFB-associated mice (SFB-
mice) but not in clostridium-associated mice (Clost-mice). There was
no great difference in Vbeta usage among GF mice, Cvd mice, and these
gnotobiotic mice, although the association with SFB decreased the
proportion of Vbeta6(+) cells in CD8beta- subsets to some extent,
compared to that in GF mice. The expression of major
histocompatibility complex class II molecules on the epithelial cells
was observed in SFB-mice but not in Clost-mice. On the other hand, in
the large intestine, the ratio of the number of CD4(-) CD8(+) cells to
that of CD4(+) CD8(-) cells in alpha betaIEL increased in Clost-mice
but not in SFB-mice. On association with both SFB and clostridia, the
numbers and phenotypes of IEL in the small and large intestines
changed to become similar to those in Cvd mice. In particular, the
ratio of the number of CD8alpha beta+ cells to that of CD8alpha alpha+
cells in alpha betaIEL, unusually elevated in the small intestines of
SFB-mice, decreased to the level in Cvd mice on contamination with
both SFB and clostridia. The number of immunoglobulin A (IgA)-
producing cells in the lamina propria was more elevated in SFB-mice
than in Clost-mice, not only in the ileum but also in the colon. The
number of IgA-producing cells in the colons of Clost-mice was a little
increased compared to that in GF mice. Taken together, SFB and
clostridia promoted the development of both IEL and IgA-producing
cells in the small intestine and that of only IEL in the large
intestine, respectively, suggesting the occurrence of
compartmentalization of the immunological responses to the indigenous
bacteria between the small and large intestines.
PMID: 10377132
H'mm and there are several others from others besides itoh before this
one.
11 hits: segmented filamentous clostridium - pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=segmented+filamentous+clostridium
why don't we blame big pharma or the prezident for that matter?
Obama is on target NOW?
LOOKs like FULL STEAM aHEAD?
http://www.nytimes.com/2011/01/23/health/policy/23drug.html
Federal Research Center Will Help Develop Medicines
By GARDINER HARRIS
Published: January 22, 2011
http://graphics8.nytimes.com/images/2011/01/23/us/SUB-DRUG/SUB-DRUG-popup.jpg
The Obama administration has become so concerned about the slowing
pace of new drugs coming out of the pharmaceutical industry that
officials have decided to start a billion-dollar government drug
development center to help create medicines.
The new effort comes as many large drug makers, unable to find enough
new drugs, are paring back research. Promising discoveries in
illnesses like depression and Parkinson’s that once would have led to
clinical trials are instead going unexplored because companies have
neither the will nor the resources to undertake the effort.
The initial financing of the government’s new drug center is
relatively small compared with the $45.8 billion that the industry
estimates it invested in research in 2009. The cost of bringing a
single drug to market can exceed $1 billion, according to some
estimates, and drug companies have typically spent twice as much on
marketing as on research, a business model that is increasingly
suspect.
The National Institutes of Health has traditionally focused on basic
research, such as describing the structure of proteins, leaving
industry to create drugs using those compounds. But the drug
industry’s research productivity has been declining for 15 years, “and
it certainly doesn’t show any signs of turning upward,” said Dr.
Francis S. Collins, director of the institutes.
The job of the new center, to be called the National Center for
Advancing Translational Sciences, is akin to that of a home seller who
spruces up properties to attract buyers in a down market. In this case
the center will do as much research as it needs to do so that it can
attract drug company investment.
That means that in some cases, the center will use one of the
institutes’ four new robotic screeners to find chemicals that affect
enzymes and might lead to the development of a drug or a cure. In
other cases, the center may need to not only discover the right
chemicals but also perform animal tests to ensure that they are safe
and even start human trials to see if they work. All of that has
traditionally been done by drug companies, not the government.
“None of this is intended to be competitive with the private sector,”
Dr. Collins said. “The hope would be that any project that reaches the
point of commercial appeal would be moved out of the academic support
line and into the private sector.”
Whether the government can succeed where private industry has failed
is uncertain, officials acknowledge, but they say doing nothing is not
an option. The health and human services secretary, Kathleen Sebelius,
sent a letter to Congress on Jan. 14 outlining the plan to open the
new drug center by October — an unusually rapid turnaround for an idea
first released with little fanfare in December.
Creating the center is a signature effort of Dr. Collins, who once
directed the agency’s Human Genome Project. Dr. Collins has been
predicting for years that gene sequencing will lead to a vast array of
new treatments, but years of effort and tens of billions of dollars in
financing by drug makers in gene-related research has largely been a
bust.
As a result, industry has become far less willing to follow the latest
genetic advances with expensive clinical trials. Rather than wait
longer, Dr. Collins has decided that the government can start the work
itself.
“I am a little frustrated to see how many of the discoveries that do
look as though they have therapeutic implications are waiting for the
pharmaceutical industry to follow through with them,” he said.
Dr. Collins’s ability to conceive and create such a center in a few
short months would have been impossible for most of his predecessors,
who had nice offices but little power. But Congress in recent years
has invested real budgetary and administrative authority in the
director’s office, and Dr. Collins is the first to fully use these new
powers.
Under the plan, more than $700 million in research projects already
under way at various institutes and centers would be brought together
at the new center. But officials hope that the prospect of finding new
drugs will lure Congress into increasing the center’s financing well
beyond $1 billion.
Hopes of new money may be optimistic. Republicans in the House have
promised to cut the kind of discretionary domestic spending that
supports the health institutes, and officials are already bracing for
significant cuts this year. But Dr. Collins has hinted that he is
willing to cannibalize other parts of the health institutes to bring
more resources to the new center.
“There are some people that would say this is not the time to do
something bold and ambitious because the budget is so tight,” he said.
“But we would be irresponsible not to take advantage of scientific
opportunity, even if it means tightening in other places.”
For the plan to go into effect by October, the administration must by
law get rid of one of the 27 centers and institutes already in
existence at the N.I.H. — something that has never been done before.
So the administration plans to downgrade the National Center for
Research Resources, in part by giving some of its functions to the new
drug center.
Researchers and staff members connected to the research resources
center have inundated a complaint blog about the coming change. Mark
O. Lively, a professor of biochemistry at Wake Forest University and a
member of an advisory council to the research resources center, said
that he could not understand why the administration was moving so
quickly with its plans.
“And the N.I.H. is not likely to be very good at drug discovery, so
why are they doing this?” Dr. Lively asked.
But Dr. Garret A. FitzGerald, a professor of medicine and pharmacology
at the University of Pennsylvania, said the new center could inspire
universities to train a new generation of investigators who could
straddle the divide between academia and industry.
“It could be a really good idea,” he said.
Both the need for and the risks of this strategy are clear in mental
health. There have been only two major drug discoveries in the field
in the past century; lithium for the treatment of bipolar disorder in
1949 and Thorazine for the treatment of psychosis in 1950.
Both discoveries were utter strokes of luck, and almost every major
psychiatric drug introduced since has resulted from small changes to
Thorazine. Scientists still do not know why any of these drugs
actually work, and hundreds of genes have been shown to play roles in
mental illness — far too many for focused efforts. So many drug makers
have dropped out of the field.
For Dr. Thomas R. Insel, director of the National Institute of Mental
Health, the drug industry’s departure from this vital research area
shows that the government must do something, although he acknowledges
the risk.
“Would we be foolish — we being an agency that has never developed
drugs and actually doesn’t know how to do therapeutics that well — to
get into this space?” Dr. Insel asked.
But Dr. William Potter, who was once a top researcher at the mental
health institute and retired last year as the vice president of
translational neuroscience at the giant drug maker Merck, said that
far more basic research needed to be done on the causes of mental
illness before anyone — industry or government — could successfully
create breakthrough drugs.
“We still don’t even understand how lithium works,” Dr. Potter said.
“So how do people think we can find drugs systematically for mental
illness?”
<snip>
Like i've said before.... i'd be the best czar of health in MY WHOLE
world... LOL
And why should i cotton to less then my constitutional rights without
due process...
Instead of a FART from aglove in your FACE?
---------------
http://www.hillsdale.edu/news/imprimis/archive/issue.asp?year=2010&month=11
November 2010
Larry P. Arnn
President, Hillsdale College
Outline of a Platform for Constitutional Government
-----------------
I think nOW, that this jack La Lanne thing got me ALL a twitter and
discombobulated.
randall... but i'm not a Jack La Lanne by a far shot.
More like mouse potato with lit neurons on steroids? LOL