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From: Kofi on 7 Mar 2007 21:32
Zinc L-carnosine appears to block the initiation of leaky gut syndrome.
I suspect this effect centers around betaine/carnitine/histidine
metabolic pathways. Ergothioneine is the betaine of a sulfur-containing
derivative of histidine (aka thiolhistidylbetaine or
2-thiol-L-histidine-betaine or thioneine/thionein). Ergothioneine is
the apoprotein of metallothionein (an apoprotein is a polypeptide chain
that has not yet formed a complex with the prosthetic group - a
non-amino acid compound attached to a protein required to form the
active holoprotein). So, ergothioneine depends on adequate amounts of
histidine (which is contained in carnosine) and betaine. Mercury and
lead poisoning induce leaky gut syndrome. Mercury can deplete the
natural chelator metallothionein, thus depleting carnitine, histidine,
betaine, ergothioneine and related compounds - in addition to
molybdenum, which is also found in metallothionein. (Mercury and an
opioid ligand in wheat both stimulate prolactin which then stimulates
B-cell production and can lead to autoimmunity.)

Why is this important?

Carnitine is built on a betaine. Inflammatory bowel injuries knock out
carnitine transport in the gut. Carnitine appears to play a role in
preventing PKC activation, which is required for zonulin signaling in
leaky gut. With inadequate carnitine levels, leaky gut may be easier to
induce. Curiously, zinc L-carnosine also seems to inhibit a leaky gut
pathway - PLC - at least in some other tissue types. PKC is important
to the function of mu opioid and thus cannabinoid receptors in the gut,
which seem adversely affected by inflammatory bowel injuries. Low-dose
naltrexone, which upregulates mu opioid receptors, is effective for such
conditions. In previous postings I've sketched these arguments out,
including how the loss of local cannabinoid receptor expression might
lead to B-cell overproduction and autoimmunity. There are also
important connections with local gut flora, which stimulate mu opioid
and cannabinoid receptors.

I'm as yet unclear how zinc L-carnosine figures into this network. I
suspect a direct effect on zonulin but I don't know if anyone's ever
looked at this. It contains histidine and that is necessary for
ergothioneine formation and vital to an important metabolic
detoxification pathway.


: Gut. 2007 Feb;56(2):168-75. Epub 2006 Jun 15. Related Articles, Links
�
Zinc carnosine, a health food supplement that stabilises small bowel
integrity and stimulates gut repair processes.

Mahmood A, FitzGerald AJ, Marchbank T, Ntatsaki E, Murray D, Ghosh S,
Playford RJ.

Department of Gastroenterology, Imperial College London, UK.

BACKGROUND: Zinc carnosine (ZnC) is a health food product claimed to
possess health-promoting and gastrointestinal supportive activity.
Scientific evidence underlying these claims is, however, limited. AIM:
To examine the effect of ZnC on various models of gut injury and repair,
and in a clinical trial. METHODS: In vitro studies used pro-migratory
(wounded monolayer) and proliferation ([(3)H]-thymidine incorporation)
assays of human colonic (HT29), rat intestinal epithelial (RIE) and
canine kidney (MDCK) epithelial cells. In vivo studies used a rat model
of gastric damage (indomethacin/restraint) and a mouse model of
small-intestinal (indomethacin) damage. Healthy volunteers (n = 10)
undertook a randomised crossover trial comparing changes in gut
permeability (lactulose:rhamnose ratios) before and after 5 days of
indomethacin treatment (50 mg three times a day) with ZnC (37.5 mg twice
daily) or placebo coadministration. RESULTS: ZnC stimulated migration
and proliferation of cells in a dose-dependent manner (maximum effects
in both assays at 100 micromol/l using HT29 cells), causing an
approximate threefold increase in migration and proliferation (both
p<0.01). Oral ZnC decreased gastric (75% reduction at 5 mg/ml) and
small-intestinal injury (50% reduction in villus shortening at 40 mg/ml;
both p<0.01). In volunteers, indomethacin caused a threefold increase in
gut permeability in the control arm; lactulose:rhamnose ratios were
(mean (standard error of mean)) 0.35 (0.035) before indomethacin
treatment and 0.88 (0.11) after 5 days of indomethacin treatment
(p<0.01), whereas no significant increase in permeability was seen when
ZnC was coadministered. CONCLUSION: ZnC, at concentrations likely to be
found in the gut lumen, stabilises gut mucosa. Further studies are
warranted.

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

PMID: 16777920 [PubMed - in process]

OCTN1 is associated with Crohn�s and rheumatoid arthritis; OCTN1 is
expressed in synovial tissues of people with rheumatoid arthritis; octn1
in mice is expressed in inflamed joints with collagen-induced arthritis,
but not in the joints of normal mice; RUNX1, an essential hematopoietic
transcription factor associated with acute myeloid leukemia and related
to RA and Sp1, is involved in the regulation of OCTN1 promoter activity;
IL-1beta and TNFalpha increased the expression of OCTN1 mRNA;
over-expression of NFkappaB activates promoter activity of OCTN1 [PMID
17142562]

genetic susceptibility to inflammatory bowel disease (IBD) is associated
with CARD15 (NOD2), DLG5, OCTN1, OCTN2, and CARD4 (NOD1); NOD2/CARD15
explains about 20% of genetic predisposition to Crohn�s [PMID 16961737]

Prostaglandin F2alpha (PGF2alpha) induces phosphoinositide hydrolysis by
phospholipase C (PLC) and phosphatidylcholine hydrolysis by
phospholipase D (PLD) through heterotrimeric GTP-binding protein,
resulting in the activation of protein kinase C (PKC) in osteoblast-like
MC3T3-E1 cells; PGF2alpha also stimulates the synthesis of interleukin-6
(IL-6) via PKC-dependent p44/p42 mitogen-activated protein (MAP) kinase
activation; zinc complex of l-carnosine (l-CAZ; zinc L-carnosine)
dose-dependently suppressed the PGF2alpha-stimulated IL-6 synthesis;
zinc alone reduced IL-6 synthesis; L-CAZ suppressed the
PGF2alpha-induced p44/p42 MAP kinase phosphorylation; the p44/p42 MAP
kinase phosphorylation induced by 12-O-tetradecanoylphorbol-13-acetate
(TPA), a direct activator of PKC, or NaF, a direct activator of
GTP-binding protein, was not affected by l-CAZ; l-CAZ reduced the
PGF2alpha-stimulated formation of inositol phosphates and choline; l-CAZ
did not affect the formation of inositol phosphates or choline induced
by NaF; this strongly suggests zinc reduces PGF2alpha-induced IL-6
synthesis via suppression of phosphoinositide-hydrolyzing phospholipase
C (PLC) and phosphatidylcholine-hydrolyzing phospholipase D in
osteoblasts [PMID 11968002]

SLC22A4 codes for an integral membrane protein OCTN1 - organic
cation/carnitine transporter 1 - which is responsible for carnitine
transport into cells; the key substrate for this transporter is
ergothioneine (the betaine of a sulfur-containing derivative of
histidine; also known as thiolhistidylbetaine
(2-thiol-L-histidine-betaine) and thioneine/thionein; thionein is the
apoprotein of metallothionein; an apoprotein is a polypeptide chain that
has not yet formed a complex with the prosthetic group (non-amino acid
compound attached to a protein) required to form the active holoprotein)

the anti-noceceptive (analgesic) effect of acetyl-l-carnitine is
dependent upon PKC and PLC; a phospholipase C inhibitor blocked the
ability of carnitine to raise the pain threshold whereas inducing PKC
blocked the effect but inhibiting PKC enhanced the analgesic effect of
acetyl-l-carnitine (wonder if it�s mediated via PPARalpha like with
green tea�s effects on analgesia?); inhibiting phosphatidylinositol
synthesis or Ca2+ release also blocked the effect; heparin, an IP(3)
receptor antagonist, also blocked the effect which was then restored by
D-myo-inositol [PMID 15223307]

activation of protein kinase C (PKC) by zonula occludens toxin (Zot) or
phorbol esters increases paracellular permeability in intestinal cells;
zonulin might also play a role in other tight junctions of endothelial
cells like the blood-brain barrier [PMID 11193578]

zonulin and Zot modulate intercellular tight junctions by binding to a
specific surface receptor and activating a signaling pathway which
involves phospholipase C and protein kinase C activation and actin
polymerization; human brain plasma membranes contain two Zot binding
proteins, tubulin and the zonulin/Zot receptor itself with multiple
sialic acid residues [PMID 10617135]

in colonocytes in a rat model of IBD induced by trinitrobenzene sulfonic
acid (TNBS), expression of carnitine transporters Octn2 and Atb0+
(required for beta-oxidation of butyrate; ATB0+ is also the glutamine
transporter which might explain the benefits of glutamine for bowel
disorders) decreased in inflammatory samples at translational and
functional level; butyrate oxidation, evaluated based on CO2 production
and acetyl-coenzyme A synthesis, was deranged in colonocytes from
TNBS-treated rats; treatment with carnitine-loaded liposomes corrected
the butyrate metabolic alterations in vitro and reduced the severity of
colitis in vivo; suggesting that carnitine depletion in colonocytes is
associated with the inability of mitochondria to maintain normal
butyrate beta-oxidation; carnitine is a rate-limiting factor for the
maintenance of physiological butyrate oxidation in colonic cells,
perhaps explaining the contradictory therapeutic efficacy of butyrate
supplementation observed in clinical trials of IBD [PMID 17065219]
From: Jack Campin - bogus address on 9 Mar 2007 12:36
Kofi <kofi(a)anon.un> wrote:
> Zinc L-carnosine appears to block the initiation of leaky gut syndrome.
> I suspect this effect centers around betaine/carnitine/histidine
> metabolic pathways. Ergothioneine is the betaine of a sulfur-containing
> derivative of histidine (aka thiolhistidylbetaine or
> 2-thiol-L-histidine-betaine or thioneine/thionein). [...]

Undigested verbiage fried in pure speculation gives me itchy pimples
on the bum. What do you suggest for it?

============== j-c ====== @ ====== purr . demon . co . uk ==============
Jack Campin: 11 Third St, Newtongrange EH22 4PU, Scotland | tel 0131 660 4760
<http://www.purr.demon.co.uk/jack/> for CD-ROMs and free | fax 0870 0554 975
stuff: Scottish music, food intolerance, & Mac logic fonts | mob 07800 739 557
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