OCTN2 is upregulated by intermittent fasting, exercise, PPARalpha
agonists and, I think, testosterone.  It's vital for carnitine uptake
(which is antiinflammatory in the gut) and butyrate metabolism (crucial
for HDAC inhibition).

Drug Metab Dispos. 2009 Jun 1;
 
Changes in mRNA expression levels of solute carrier transporters in
inflammatory bowel disease patients.
Wojtal KA, Eloranta JJ, Hruz P, Gutmann H, Drewe J, Beglinger C, Fried
M, Kullak-Ublick GA, Vavricka SR.
University Hospital Zurich.

Inflammatory bowel disease (IBD) is an inflammatory condition that
affects gastrointestinal tract. Solute carrier superfamilly of
transporters (SLC) comprise proteins involved in the uptake of drugs,
hormones, and other biologically active compounds. The purpose of this
study was to determine the mRNA expression levels of 15 solute carrier
transporters in two regions of the intestine in IBD patients. Endoscopic
biopsies were taken from two locations (terminal ileum and colon) for
histological examination and RNA extraction. We quantitatively measured
the mRNA expression of 15 SLC transporters in 107 IBD patients (53
Crohn's disease and 54 ulcerative colitis) and 23 control subjects.
Messenger RNA expression was evaluated using the quantitative reverse
transciption-PCR technique. We observed that in ileum of IBD patients,
mRNA levels for SERT, ENT1, ENT2, and OATP2B1 were significantly
elevated while for ASBT and OCTN2 they were significantly lower. In
colon, mRNA levels for ENT1, ENT2, CNT2, OATP2B1, and OATP4A1 were
significantly higher, while mRNA levels for OCTN2 were significantly
decreased. In inflamed colon of IBD patients the mRNA expression levels
of ENT1, ENT2, CNT2, OATP2B1, OATP4A1, and PEPT1 were significantly
higher. We conclude that intestinal SLC mRNA levels are dysregulated in
IBD patients, which may be linked to the inflammation of the tissue and
provides an indication about the role of inflammatory signalling in
regulation of SLC expression.

PMID: 19487253

Does the study distinguish if OCTN2 (carnitine transporter) reduction
causes IBD or that OCTN2 is simply reduced during inflammation? Since
carnitine is an antioxidant and is essential for metabolism of long
chain fatty acids (LCFAs), lack of it could cause inflammation. On the
other hand, during inflammation, cell many not want to metabolize
LCFAs since they are prone to peroxidation.

In article
<edd2ecbf-aa30-45c8-84fe-d0af18522...@p20g2000vbl.googlegroups.com>,

Given that supplemental carnitine in liposomes has alleviated TNBS
colitis in mice when TNBS downregulates OCTN2, I'd say it's causative
[PMID 17065219].  The other limiting factor might be glutamine (via the
Atb0+ transporter).

colitis in mice when TNBS downregulates OCTN2, I'd say it's causative
[PMID 17065219].  The other limiting factor might be glutamine (via
the
Atb0+ transporter).

Thanks, I'll try glutamine next for the burning tongue syndrome that I
have been experiencing for the last 8 years. In the last two years it
has reduced mostly by avoiding trigger foods of which there are many
including organic fruits and veggies.

Per your advice, I recently added carnitine and alpha lipoic acid
(ALA) and they both reduce the tongue burn. And of the two, ALA seems
to be more effective. It also seems my "food allergies" which manifest
itself as itching, sharp intermittent shooting pains and hand
numbness  have been reduced, at least for black pepper and raw
hazelnuts. And I can ingest more beans before incurring a heartburn.

But I am wondering if I have the OCTN1 vs OCTN2 defect which would
prevent the plant derived antioxidant, ergothioniene, from being
accumulated in related tissues (ie skin, gut, endothelial lining,
eyes, joints, immune cells, nervous system). OCTN1 variants are also
linked to CD, RA, lupus, psoriasis and leukemia.

Recent I experimented with cooked vs raw bananas and strawberries. For
some reason cooked cause less tongue burn than raw ones. Anyone else
experience this? What might be the reason?

Have you noticed that an apple or potato turns brown when cut or
bruised. Supposedly, the enzyme tyrosinase converts some polyphenols
into quinones. Quinones are quite reactive and apparently have anti-
viral, bacterial, insect and worm properties.

In humans, a similar process is used to produce melanin. Here tyrosine
is oxidized by tyrosinase into quinones and then further into melanin.
Supposedly ingested dietary polyphenols are also oxidized into
quinones. And neurotransmitters (ie adrenaline) are also oxidized into
quinones. Coincedentally, I get bloating and nerve pain from elevated
stress. And according to some abstracts, vitiligo (white skin) may be
related to quinones also.

Does anyone have links that describe the metabolism of dietary
polyphenols and if it involves carnitine or ergothioniene? Also can
anyone suggest some low molecular weight, non-phenolic based,
antioxidants effective against quinones and hydrogen peroxide (H2O2)?
Thx

Background Info: Various members in my family have suffered Crohn's
Disease, Psoriasis, Dermatitis, Breast Cancer, Leukemia, Cataracts,
etc. Starting 2001, I also experienced gut inflammation, rhoids/
fissures, pain near terminal ileum, IBS, CFS, neuropathy, CTS, RLS,
sciatica, heartburns, sore joints and food allergies that peaked in
late 2007. About half a year ago I starting developing vitiligo on my
hands.

---------
Catechin metabolism: glutathione conjugate formation catalyzed by
tyrosinase, peroxidase, and cytochrome p450.
The metabolic pathways of dietary flavonoids are still largely
unknown. In the present work, mass spectrometry and UV-vis
spectroscopy studies were used to show that the naturally occurring
flavonoid catechin underwent enzymatic oxidation by tyrosinase in the
presence of glutathione (GSH) to form mono-, bi-, and tri-glutathione
conjugates of catechin and mono- and bi-glutathione conjugates of a
catechin dimer. A hydroxylated catechin adduct was also detected.
Using UV spectroscopy, it was shown that the catechol B-ring of
catechin was oxidized by tyrosinase to form an o-quinone which could
be reduced back to catechin with potassium borohydride or reacted with
GSH to form glutathione conjugates. The catechin-glutathione
conjugates formed had much lower distribution coefficient values than
catechin itself. When peroxidase and hydrogen peroxide were used
instead of tyrosinase, only mono-glutathione conjugates were formed
but not bi-glutathione conjugates or hydroxylated adducts. (1)H NMR
evidence showed that three different mono-glutathione conjugates on
ring B of catechin were formed by peroxidase and hydrogen peroxide.
Rat liver microsomes and NADPH or cumene hydroperoxide also catalyzed
catechin-glutathione conjugate formation which was prevented by
benzylimidazole, a P450 2E1 inhibitor. Catechin cytotoxicity toward
isolated hepatocytes was also markedly enhanced by hydrogen peroxide
or cumene hydroperoxide and was prevented by benzylimidazole,
suggesting that catechin could be metabolically activated by P450
peroxidase activity to form cytotoxic quinoid species. PMID: 11453730

In article
<5160df3e-a793-440f-b8b6-7c780a27d...@v38g2000vbb.googlegroups.com>,

You should try reading the references and the earlier posts I've made on
the subject.  Carnitine might only be effective 1) if you can get it
across the cell membrane (like in liposomes or by boosting OCTN2
expression via intermittent fasting, exercise, PPARalpha agonists or
other means I've discussed) and 2) if you consume carnitine in
conjunction with butyrate - *however* if your colitis is due to a virus
then butyrate may only aggravate its replication (especially in
conjunction with a vitamin D3 deficiency).

 And of the two, ALA seems

Pepper is going to activate TRPV's which isn't exactly antiinflammatory
for some people.

In digestive disorders I think it might be a *gain* of function and it
might be a problem due to antibodies against bacteria cross-reacting
with the receptor.  This has been discussed here before as well.

A loss of transport via OCTN1 might occur due to antibodies blocking it
- and upregulating the receptor might only result in more antibody
problems - but this is but one interpretation.

These fruits are too sweet.  Sugar feeds inflammation.  Cooking fruit is
particularly problematic as it generates all sorts of advanced glycation
end products.

I don't see why you don't simply try eliminating these foods first if
they're giving you trouble.  None of them are essential to a balanced
diet.

People actually take worm eggs to force Crohn's into remission.  It
works well for me.  <www.ovamed.de>

Vitiligo is not simply "white skin."  It's loss of pigmentation.  It can
happen due to loss of beta-endorphins, vitamin D3, catalase and - if I'm
not mistaken - even cAMP can be involved.  There appears to be a link to
Parkinson's.

Might I suggest testing for anti-folate receptor antibodies and folate
levels.  A folate deficiency would inhibit your ability to make proper
use of Vitamin D3.  In combination with a carnitine deficiency, that
could explain the neuropathy, the cancer, the autoimmunity and the
cataracts.  You might want to run a general metabolic panel if you
haven't already, particularly looking at carnitine, vitamin D3 and B
vitamins.  I've discussed how to address various parts of these problems
before.

I didn't find any pubmed abstracts relating TRPV and Piper Nigrum
(black pepper). Do you have a link? The only spice that I take
frequently and which has never caused itching is turmeric. Currently I
am trying black pepper since it and ginkgo may be helpful for
vitiligo. Below are some abstracts for black pepper.

Amides from Piper nigrum L. with dissimilar effects on melanocyte
proliferation in-vitro.
Melanocyte proliferation stimulants are of interest as potential
treatments for the depigmentary skin disorder, vitiligo. Piper nigrum
L. (Piperaceae) fruit (black pepper) water extract ...  contains
several amides with the ability to stimulate melanocyte proliferation.
This finding supports the traditional use of P. nigrum extracts in
vitiligo and provides new lead compounds for drug development for this
disease.
PMID: 17430636

UV irradiation affects melanocyte stimulatory activity and protein
binding of piperine.
Piperine, the major alkaloid of black pepper (Piper nigrum L.;
Piperaceae), stimulates melanocyte proliferation and dendrite
formation in vitro. This property renders it a potential treatment for
the skin depigmentation disorder vitiligo... If UVA radiation is used
with piperine in the treatment of vitiligo, application of the
compound and irradiation should be staggered to minimize
photoisomerization. This approach is shown to effectively induce
pigmentation in a sparsely pigmented mouse strain. PMID: 17387768

Stimulation of mouse melanocyte proliferation by Piper nigrum fruit
extract and its main alkaloid, piperine.
During a herbal screening programme to find potential repigmenting
agents for the treatment of vitiligo, Piper nigrum L. fruit (black
pepper) extract was found to possess growth-stimulatory activity
towards cultured melanocytes ...This is the first full report on such
an activity of black pepper and piperine. PMID: 10575373

Antioxidant efficacy of black pepper (Piper nigrum L.) and piperine in
rats with high fat diet induced oxidative stress.
The present study was aimed to explore the effect of black pepper
(Piper nigrum L.) on tissue lipid peroxidation, enzymic and non-
enzymic antioxidants in rats fed a high-fat diet. ...The data indicate
that supplementation with black pepper or the active principle of
black pepper, piperine, can reduce high-fat diet induced oxidative
stress to the cells. PMID: 15231065

Modulatory effect of Piperine on mitochondrial antioxidant system in
Benzo(a)pyrene-induced experimental lung carcinogenesis.
... Oral supplementation of piperine (50 mg/kg body weight)
effectively suppressed lung carcinogenesis in Benzo(a)pyrene (B(a)P)
induced mice as revealed by the decrease in the extent of
mitochondrial lipid peroxidation and concomitant increase in the
activities of enzymatic antioxidants (superoxide dismutase, catalase
and glutathione peroxidase) and non enzymatic antioxidant (reduced
glutathione, vitamin E and vitamin C) levels when compared to lung
carcinogenesis bearing animals. Our data suggests that piperine may
extent its chemopreventive effect by modulating lipid peroxidation and
augmenting antioxidant defense system. PMID: 14971727

Effect of piperine on the inhibition of nitric oxide (NO) and TNF-
alpha production.
Effect of piperine which is an alkaloid present in plants such as
Piper nigrum and Piper longum on the production of nitric oxide (NO)
and tumor necrosis factor-alpha (TNF-alpha) level was analyzed using
in vitro as well as in vivo systems. The level of nitrite in the LPS
stimulated Balb/C mice (95.3 microM) was reduced in the piperine
treated animals (25 microM) significantly. Nitrite level in the
Concanavalin-A (Con-A) treated control animals (83.1 microM) was also
significantly reduced to 18.5 microM in the piperine treated mice. The
drastically elevated levels of TNF-alpha in the lipopolysaccharide
(LPS) stimulated animals (625.8 pg/mL) was lowered in the piperine
treated animals (105.8 pg/mL). Piperine also inhibited the Con-A
induced TNF-alpha production. Piperine could inhibit the nitrite
production by in vitro activated macrophages (116.25 microM) to the
normal level (15.67 microM) at concentration of 5 microg/mL. In vitro
L929 bioassay also revealed the inhibition of TNF-alpha production by
the piperine treatment. PMID: 19180797

Black pepper and its pungent principle-piperine: a review of diverse
physiological effects.
Black pepper (Piper nigrum) is one of the most widely used among
spices. It is valued for its distinct biting quality attributed to the
alkaloid, piperine. Black pepper is used not only in human dietaries
but also for a variety of other purposes such as medicinal, as a
preservative, and in perfumery. Many physiological effects of black
pepper, its extracts, or its major active principle, piperine, have
been reported in recent decades. Dietary piperine, by favorably
stimulating the digestive enzymes of pancreas, enhances the digestive
capacity and significantly reduces the gastrointestinal food transit
time. Piperine has been demonstrated in in vitro studies to protect
against oxidative damage by inhibiting or quenching free radicals and
reactive oxygen species. Black pepper or piperine treatment has also
been evidenced to lower lipid peroxidation in vivo and beneficially
influence cellular thiol status, antioxidant molecules and antioxidant
enzymes in a number of experimental situations of oxidative stress.
The most far-reaching attribute of piperine has been its inhibitory
influence on enzymatic drug biotransforming reactions in the liver. It
strongly inhibits hepatic and intestinal aryl hydrocarbon hydroxylase
and UDP-glucuronyl transferase. Piperine has been documented to
enhance the bioavailability of a number of therapeutic drugs as well
as phytochemicals by this very property. Piperine's bioavailability
enhancing property is also partly attributed to increased absorption
as a result of its effect on the ultrastructure of intestinal brush
border. Although initially there were a few controversial reports
regarding its safety as a food additive, such evidence has been
questionable, and later studies have established the safety of black
pepper or its active principle, piperine, in several animal studies.
Piperine, while it is non-genotoxic, has in fact been found to possess
anti-mutagenic and anti-tumor influences. PMID: 17987447

No doubt sugars feed inflammation. And I too would have expected
cooked fruits to be more inflammatory. But for some reason cooked
fruits cause me less problems. In fact, others in the crohns-colitis
group have also suggested eating cooked vs raw fruits and veggies,
especially when flairing. Could this is related to the polyphenol-
generated quinones? In addition, regular vitamins with citrus
bioflavonoids and soy derivatives (www.iherb.com/Now-Foods-Vit-Min-75-
Iron-Free-180-Tablets/829) give me heartburn, hand numbness and
restless legs. But not hypoallegenic ones (www.iherb.com/Twinlab-
Allergy-Multi-Caps-200-Capsules/2315).

In my case, it seems all foods cause problems to varying degree,
including hypoallegenic-, amino acid-, MCT-, glutamine-, taurine-,
carnitine-based nutritional formulas (EleCare, which does have some
soy oil).  Milk products (inc yogurt, kefir), red meats, eggs,
tropical & citrus fruits, brassica veggies, onion, chilies, some beans
(soy & kidney), nuts (esp peanuts & cashews), chocolate, extra virgin
olive oil, black tea, alcohol (inc red wine), MSG and processed foods
are most offensive to me. I have tried a number of diets. The most
inflammatory were Atkin & Paleo-type (chol = 450). Least inflammatory
was the lettuce diet. Fasting to skin and bones, even less. The least
inflammatory, practical diet thus far has been high in beans (lentils,
pinto), salads, limited fruits and no oils/fats (chol < 170). While
diet has been an important factor, it does not seem to fix some
underlying problem.

I was also consindering this route at one time, but the cost is
prohibitive. What are you most allergic to? What have you found most
effective? Have you had any luck with antioxidants such as ALA, NAC,
CoQ10, E, C, taurine, melatonin, etc?

Since I get lots of sun exposure, I don't think D3 is a factor. Thanks
for other possible factors that I can follow up on. Below pubmed
article are mainly tyrosinase related, however they could also
indicate insufficient antioxidant capacity due to OCTN polymorphisms.

PM Abstract: Vitiligo puzzle: the pieces fall in place.
Over the years, the role of biochemical, immunological, genetic, and
other biological aspects in the pathogenesis of vitiligo has been
studied. So far, no convincing model describing the interplay of these
contributing factors has been formulated. Based on existing research,
we propose that vitiligo has a multi-factorial etiology, characterized
by multiple steps, but always involving an increase of external or
internal phenol/catechol concentration, serving as a preferred
surrogate substrate of tyrosinase, competing with its physiological
substrate tyrosine. The conversion of these substrates into reactive
quinones is reinforced by a disturbed redox balance (increasing
hydrogen peroxide). Such reactive quinones can be covalently bound to
the catalytic centre of tyrosinase (haptenation). This could give rise
to a new antigen, carried by Langerhans cells to the regional lymph
node, stimulating the proliferation of cytotoxic T cells. However, the
activation of such cytotoxic cells is only a first step in skin
melanocyte killing, which also depends on a shift in the balance
between immune defence and tolerance, e.g. resulting from a decrease
in properly functioning T-regulatory cells. With this new model, based
on a synthesis of several of the existing theories, in mind, the
external and internal factors involved in the etiopathogenesis of
vitiligo are reviewed, against the background of reported clinical
data, experimental studies and existing and potential new therapies. A
similar complex mechanism may also lead to some other autoimmune
diseases. PMID: 17850508

PM Abstact: The reaction of alpha-synuclein with tyrosinase: possible
implications for Parkinson disease.
Oxidative stress appears to be directly involved in the pathogenesis
of Parkinson disease. Several different pathways have been identified
for the production of oxidative stress conditions in nigral
dopaminergic neurons, including a pathological accumulation of
cytosolic dopamine with the subsequent production of toxic reactive
oxygen species or the formation of highly reactive quinone species. On
these premises, tyrosinase, a key copper enzyme known for its role in
the synthesis of melanin in skin and hair, has been proposed to take
part in the oxidative chemistry related to Parkinson disease. A study
is herein presented of the in vitro reactivity of tyrosinase with
alpha-synuclein, aimed at defining the molecular basis of their
synergistic toxic effect. The results presented here indicate that, in
conformity with the stringent specificity of tyrosinase, the exposed
tyrosine side-chains are the reactive centers of alpha-synuclein. The
reactivity of alpha-synuclein depends on whether it is free or
membrane bound, and the chemical modifications on the tyrosinase-
treated alpha-synuclein strongly influence its aggregation properties.
On the basis of our results, we propose a cytotoxic model which
includes a possible new toxic role for alpha-synuclein exacerbated by
its direct chemical modification by tyrosinase. PMID: 18390556

Pubmed: The metabolism and toxicity of quinones, quinonimines, quinone
methides, and quinone-thioethers.
Quinones are ubiquitous in nature and constitute an important class of
naturally occurring compounds found in plants, fungi and bacteria.
Human exposure to quinones therefore occurs via the diet, but also
clinically or via airborne pollutants. For example, the quinones of
polycyclic aromatic hydrocarbons are prevalent as environmental
contaminants and provide a major source of current human exposure to
quinones. The inevitable human exposure to quinones, and the inherent
reactivity of quinones, has stimulated substantial research on the
chemistry and toxicology of these compounds. From a toxicological
perspective, quinones possess two principal chemical properties that
confer their reactivity in biological systems. Quinones are oxidants
and electrophiles, and the relative contribution of these properties
to quinone toxicity is influenced by chemical structure, in particular
substituent effects. Modification to the quinone nucleus also
influences quinone metabolism. This review will therefore focus on the
differences in structure and metabolism of quinones, and how such
differences influence quinone toxicology. Specific examples will be
discussed to illustrate the diverse manner by which quinones interact
with biological systems to initiate and propagate a toxic response.
MID: 12093358

That's because capsaicin in pepper is the TRPV1 agonist.  You'll find
plenty on that.

If Parkinson's is due to an autoimmune targetting of neuromelanin then
boosting your melanin production without quelling your autoimmunity will
cause problems.

I think it's related to fiber and fermentation in the gut.

Do it the natural way.  It's free.

Try an intermittent fast.

I react to all but about a dozen foods.

I literally take dozens of supplements.

You might try low-dose naltrexone, folinic acid shots (Tregs have folic
acid receptors), carnitines, a PPARalpha agonist (which fasting will
give you), testosterone, melatonin (although there's evidenc it's
dangerous in Parkinson's), magnesium, butyrate.  A lot of this depends
on what a nutritional panel shows you.

CoQ10 can be a problem if you have a yeast issue.

It is if you can't convert it.  For instance, low folic acid will lead
to a much faster vitamin D breakdown.  You might even have adequate
serum levels of folate and a problem with anti-folate receptor
antibodies preventing enough folate from getting into the CNS.  If
that's the case, all your serum levels might be normal but you could
have a considerable deficit for vitamin D and folic acid in the brain.