Re: An observation on the inflammation story and suggested actions

July 31, 2004

HI ,

Your list of anti-inflammatories looks pretty good, but the

recommendations for fish and fish oil are not taking into

consideration the 1,25d hormone's role in causing inflammation (fish

is high in its precursor, 25D). There's lots of new research on D

metabolism in the last 10 years, but you could start with this paper:

http://www.chestjournal.org/cgi/eletters/123/1/18

Other than the fish, some PWC might definitely want to try some of

those things on that list to reduce inflammation. In my own case, I

have realized that inflammation is responsible for almost ALL of my

symptoms, including hashi's thyroid, migraines, body pain,

depression, the list goes on. They've all stopped since starting the

angiotensin II receptor blocker, Benicar.

Dr. Marshall, who created the protocol which uses Benicar, in

particular is thinking that perhaps Quecertin and Vitamin E (on your

list) could be beneficial to help the really ill PWC transition to

the Marshall Protocol. (and of course, avoiding vitamin d foods and

staying out of the sun, until the D metabolites are rebalanced).

, DVM benefitted from Quercetin before starting the

protocol , and he found some compelling research which I'll post

here:

Biochem Biophys Res Commun. 2002 May 24;293(5):1458-65

Quercetin glucuronide prevents VSMC hypertrophy by angiotensin II

via the inhibition of JNK and AP-1 signaling pathway.

Yoshizumi M, Tsuchiya K, Suzaki Y, Kirima K, Kyaw M, Moon JH, Terao

J, Tamaki T.

Department of Pharmacology, The University of Tokushima School of

Medicine, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.

yoshizu@...

We previously reported that quercetin, a bioflavonoid belonging to

polyphenols, inhibited Angiotensin II (Ang II)-induced vascular

smooth muscle cell (VSMC) hypertrophy through the inhibition of c-

Jun N-terminal kinase (JNK) activation. However, we recently found

that orally administered quercetin appeared in plasma as glucuronide-

conjugated forms in rats and humans. Therefore we examined the

effect of chemically synthesized quercetin glucuronide on Ang II-

induced mitogen-activated protein (MAP) kinase activation and

hypertrophy of cultured rat aortic smooth muscle cells (RASMC). Ang

II activated extracellular signal-regulated kinase (ERK)1/2, JNK,

and p38 in RASMC. Ang II-induced JNK activation was inhibited by

quercetin 3-O-beta-d-glucuronide (Q3GA) whereas ERK1/2 and p38

activations were not affected. Q3GA scavenged 1,1-diphenyl-2-

picrylhydrazyl radical measured by a method of electron paramagnetic

resonance. Q3GA also inhibited Ang II-induced increases in activator

protein-1 (AP-1) DNA binding, a downstream transcription factor of

JNK. Finally, Ang II-induced [3H]leucine incorporation into RASMC

was abolished by Q3GA. These findings suggest that the preventing

effect of Q3GA on Ang II-induced VSMC hypertrophy is attributable in

part to its inhibitory effect on JNK and the AP-1 signaling pathway.

Q3GA would be an active metabolite of quercetin in plasma and may

possess a preventing effect for cardiovascular diseases relevant to

VSMC growth.

Dr. 's comments:

There are many more good references in a pubmed or google search

regarding quercetin and angiotensin.

Briefly, what this above work shows is that quercetin inhibits part

of the inflammatory cascade… specifically, JNK and AP-1

_expression. The AP-1 _expression has many responsibilities, but

one in particular is the regulation of the _expression of

angiotensin II type 1 receptors. So, quercetin reduces the

_expression of angiotensin II type 1 receptors. As you know, these

are the same receptors that Benicar antagonizes.

Quercetin has many other benefits including inhibition of ACE, anti-

inflammation…etc.

Just thought you might be interested. You're obviously on the same

trail that some other great researchers are on.

penny

> Hi Rich,

> You might not remember me by now, but I contributed a couple of

> pseudo-papers last year, the last in June 6, making the case for

> a " blend " of your theory on ethiology with that of Marty Pall.

>

> Since then this is the first time I look back at the forum. I

saw

> your response on the superoxide dismutase reaction being quasi-

> reversible and of course I agree on that. However, if there was

any

> other post from you on the subject which was not threaded to mine,

I

> just can't find it because I can't see how to search all messages

in

> a specific date range for a string.

>

> Now, I'd like to share with you an observation I made while

> reading an article on a good Argentinian site on antioxidants.

> That's a site I have a look periodically that gives good summaries

> on recent research on the topic. (The head of the research group

> there, Alberto Boveris, was the successor of Lester Packer as

> President of the International Society for Free Radical Research

> (SFRR).)

>

> The article is at URL

> http://www.antioxidants.com.ar/12/FrArt171.htm

>

> When I read it, I perceived that CFS looked strikingly like a

non-

> acute, chronic relative of SIRS (systemic inflammatory response

> syndrome). Having in mind your theory and Marty's, I noticed

these

> paragraphs, and particularly the last sentence:

>

> " The common and simultaneous activation of different cytokines is

in

> part mediated by the activation of the nuclear transcription

factor

> NFkB, originally identified in B-lymphocytes in the synthesis of

> kappa chains of globulins. 10

> NFkB is a common factor to cytokines, adhesion molecules and

> inducible nitric oxide synthase (iNOS) which produces NO in large

> amounts. It is also a nuclear transcription factor common to IL-6,

> IL-2, and E-selectin. NFkB is constituted by 3 subunits: the IKB

> inhibitor bound to 2 proteins, the p65, and p50. Certain reactive

> species such as hydrogen peroxide (H2O2), .NO, and ONOO interact

> with NFkB sensible sites (sulfyidril groups). This promotes de

> unbinding of the inhibitor and p65 and p 50 are allowed to enter

the

> nucleus initiating the nuclear transcription of a large number of

> mediators. .NO y H2O2 constitute the main signal molecules that

> stimulate NFkB. 10,11 "

>

> Now, if we bring in the known facts that:

> - GSH scavenges .NO

> - GSH scavenges H2O2 (to form water and GSSG)

> it's clear that a GSH deficiency, by allowing higher levels of .NO

> and H2O2, will allow - all other things being equal - an

increased

> activation of NFkB, and so an increased activation of inflammatory

> cytokines and iNOS.

>

> Now, this is just the inflammation topic that has become so hot

in

> later years for health in general, where we know there are several

> pathways

> NFkB -> iNOS -> .NO

> NFkB -> TNFa -> iNOS -> .NO

> NFkB -> TNFa -> NFkB

>

> Therefore, I keep thinking that excessive production of

> inflammatory cytokines compounded by a depletion of GSH is the

> underlying mechanism of CFS for the vast mayority of PWCs.

> Moreover, I think that embarking in a chicken-or-egg-like

discussion

> of what came first, whether the excess of cytokines or the

depletion

> of GSH, is just byzantine. Because once the condition has set in,

> the various vicious cycles involved will keep it up regardless

what

> component did the kickoff. It would be much more productive to

try

> to break those vicious cycles at as many points as possible,

drawing

> for that purpose on the accumulated knowledge available on the

> inflammation topic.

>

> And here goes my contribution:

>

> Inhibitors of the production of inflammatory cytokines:

> - EPA and DHA (cold-water fish: mackerel, salmon, tuna, herring)

> - GLA (borage oil and evening primrose oil)

> - catechins (green tea)

> - quercetin (green tea, onion, apple)

> - genistein (soy)

>

> Inhibitors of NFkB:

> - alpha-lipoic acid (ALA) - see (*1) below

> - catechins, quercetin, genistein

>

> Inhibitors of iNOS induction:

> - catechins, quercetin, genistein

>

> Inhibitors of iNOS activity:

> - green tea

>

> Scavengers of .NO:

> - green tea

> - red wine (*2)

>

> Scavengers of ONOO-:

> - ALA

> - red wine (*2)

> - green tea

> - GAMMA tocopherol - IMPORTANT, see (*3) below

> - vitamin C

> - Co-Q10

> - NADH

> - uric acid

>

> Booster of GSH levels:

> - ALA

> - N-Acetyl-Cysteine (NAC)

> According to Dr Lester Packer, one of the foremost scientists on

ALA

> (aka tioctic acid), ALA is a more efficient booster of GSH levels

> than NAC.

>

> And of course, following a moderate-carb diet that tilts the

> eicosanoid balance towards the anti-inflammatory side, such as the

> Zone, Omega, Dr Perricone's, Dr Sinatra's.

>

> (*1) Supplementing with ALA requires supplementing with biotin too.

>

> BTW, Lester Packer and Bruce Ames happen to be on the Scientific

> Advisory Board of a company that produces a supplement with ALA,

> Acetyl-L-Carnitine (ALC), and biotin. (I'm not being paid by

them :-)

>

> http://www.juvenon.com/product.html

>

> (*2) There is a possibility that red wine, partly via its

> resveratrol component, could increase the expression of iNOS.

> Together with the fact that PWCs do not tolerate alcohol well, it

> should be advisable to stick to green tea.

>

> The following is a particularly good study

>

> FEBS Lett. 2000 Jan 14;465(2-3):93-7.

> Activity of monomeric, dimeric, and trimeric flavonoids on NO

> production, TNF-alpha secretion, and NF-kappaB-dependent gene

> expression in RAW 264.7 macrophages.

>

> Park YC, Rimbach G, Saliou C, Valacchi G, Packer L.

> Department of Molecular and Cell Biology, 251 Life Sciences

> Addition, University of California, Berkeley, CA 94720-3200, USA.

>

> Flavonoids are potent antioxidants and have been associated with

> lowering the risk of cardiovascular diseases. In this study, the

> effect of flavonoids (monomers, dimers and a trimer) as well as

> French maritime pine bark extract, Pycnogenol, on NO production,

> tumor necrosis factor-alpha (TNF-alpha) secretion and nuclear

factor

> (NF)-kappaB activity was compared. Monomers and dimers repressed

NO

> production, TNF-alpha secretion and NF-kappaB-dependent gene

> expression induced by interferon gamma, whereas the trimeric

> procyanidin C2 and Pycnogenol enhanced these parameters. In

> addition, in unstimulated RAW 264.7 macrophages, both procyanidin

C2

> and Pycnogenol increased TNF-alpha secretion in a concentration-

and

> time-dependent manner. These results demonstrate that procyanidins

> act as modulators of the immune response in macrophages.

>

> PMID: 10631311 [PubMed - indexed for MEDLINE]

>

> J Agric Food Chem. 2000 Nov;48(11):5768-72.

> Protection against nitric oxide toxicity by tea.

>

> Paquay JB, Haenen GR, Stender G, Wiseman SA, Tijburg LB, Bast A.

>

> Department of Pharmacology and Toxicology, Faculty of Medicine,

> University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The

> Netherlands.

>

> It is found that green tea and black tea are able to protect

against

> nitric oxide (NO(*)) toxicity in several ways. Both green tea and

> black tea scavenge NO(*) and peroxynitrite, inhibit the excessive

> production of NO(*) by the inducible form of nitric oxide synthase

> (iNOS), and suppress the LPS-mediated induction of iNOS. The NO(*)

> scavenging activity of tea was less than that of red wine. The

high

> activity found in the polyphenol fraction of black tea (BTP) could

> not be explained by the mixed theaflavin fraction (MTF) or

catechins

> [epicatechin, epigallocatechin, epicatechin gallate,

> epigallocatechin gallate (EGCG)], which were tested separately.

> Synergistic effects between the compounds, or the presence of a

> potent, unidentified NO(*) scavenger, may explain the high

activity

> of BTP. The peroxynitrite scavenging of tea was comparable to that

> of red wine. The main activity was found in the polyphenol

fraction.

> MTF and the catechins were found to be potent peroxynitrite

> scavengers. Tea and tea components were effective inhibitors of

> iNOS. Of the tea components tested, only MTF had an activity

higher

> than that of the tea powders. The polyphenol fractions of tea were

> much more active than the tea powders in suppressing the induction

> of iNOS. On the basis of its abundance and activity, EGCG was the

> most active inhibitor. The protective effect of tea on NO(*)

> toxicity is discussed in relation to the beneficial effect of

> flavonoid intake on the occurrence of cardiovascular heart disease.

>

> PMID: 11087552 [PubMed - indexed for MEDLINE]

>

> (*3) Try to take a vitamin E supplement such that its ALPHA-

> tocopherol content does not exceed one third of the total content

of

> all other E-complex vitamins (all in mg, such that 1.5 UI = 1 mg)

> such as:

>

> http://www.lef.org/newshop/items/item00559.html

> http://www.aor.ca/proddetail.asp?prod_id=162

> http://www.iherb.com/gammae400.html

>

> If you can't get one of the above, look at least for one that gets

> as close to that ratio as possible, such as:

>

> http://www.gnc.com/productDetails.aspx?id=319421 & lang=en

> http://www.iherb.com/gammae.html

>

> This is because gamma-T is a much better scavenger of ONOO- and

> inhibitor of inflammation than alpha-T, and supplementing with

just

> alpha lowers gamma levels. (On the other hand, supplementing with

> gamma actually increases cellular uptake of alpha.) Notably,

gamma-

> T is much more abundant in foods than alpha-T, which in my view is

> no coincidence, but yet another sign that God is wise and good.

>

> The following studies on this point are by none less than Dr Bruce

> Ames.

>

> FASEB J. 2003 May;17(8):816-22.

> Gamma-tocopherol, but not alpha-tocopherol, decreases

> proinflammatory eicosanoids and inflammation damage in rats.

>

> Jiang Q, Ames BN.

>

> Division of Biochemistry and Molecular Biology, University of

> California, Berkeley; and Children's Hospital Oakland Research

> Institute, Oakland, California 94609-1673, USA.

>

> Gamma-tocopherol (gammaT), the major form of vitamin E in U.S.

> diets, and its physiological metabolite 2, 7, 8-trimethyl-2-(beta-

> carboxyethyl)-6-hydroxychroman (gamma-CEHC), in contrast to alpha-

> tocopherol (alphaT), the primary vitamin E in supplements, inhibit

> cyclooxygenase-catalyzed synthesis of prostaglandin E2 (PGE2) in

> activated macrophages and epithelial cells. Here we report that in

> carrageenan-induced inflammation in male Wistar rats,

administration

> of gammaT (33 or 100 mg/kg) and gamma-CEHC (2 mg/pouch), but not

> alphaT (33 mg/kg), significantly reduced PGE2 synthesis at the

site

> of inflammation. gammaT, but not alphaT, significantly inhibited

the

> formation of leukotriene B4, a potent chemotactic agent

synthesized

> by the 5-lipoxygenase of neutrophils. Although gammaT had no

effect

> on neutrophil infiltration, it significantly attenuated the

partial

> loss of food consumption caused by inflammation-associated

> discomfort. Administration of gammaT led consistently to a

> significant reduction of inflammation-mediated increase in 8-

> isoprostane, a biomarker of lipid peroxidation. gammaT at 100

mg/kg

> reduced TNF-alpha (65%;P=0.069), total nitrate/nitrite

(40%;P=0.1),

> and lactate dehydrogenase activity (30%;P=0.067). Collectively,

> gammaT inhibits proinflammatory PGE2 and LTB4, decreases TNF-

alpha,

> and attenuates inflammation-mediated damage. These findings

provide

> strong evidence that gammaT shows anti-inflammatory activities in

> vivo that may be important for human disease prevention and

therapy.

>

> PMID: 12724340 [PubMed - indexed for MEDLINE]

>

> Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11494-9.

> gamma-tocopherol and its major metabolite, in contrast to alpha-

> tocopherol, inhibit cyclooxygenase activity in macrophages and

> epithelial cells.

>

> Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN.

>

> Division of Biochemistry and Molecular Biology, University of

> California, Berkeley, CA 94720, USA.

>

> Cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E(2)

> (PGE(2)) plays a key role in inflammation and its associated

> diseases, such as cancer and vascular heart disease. Here we

report

> that gamma-tocopherol (gammaT) reduced PGE(2) synthesis in both

> lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and IL-

> 1beta-treated A549 human epithelial cells with an apparent IC(50)

of

> 7.5 and 4 microM, respectively. The major metabolite of dietary

> gammaT, 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman

> (gamma-CEHC), also exhibited an inhibitory effect, with an IC(50)

of

> approximately 30 microM in these cells. In contrast, alpha-

> tocopherol at 50 microM slightly reduced (25%) PGE(2) formation in

> macrophages, but had no effect in epithelial cells. The inhibitory

> effects of gammaT and gamma-CEHC stemmed from their inhibition of

> COX-2 activity, rather than affecting protein expression or

> substrate availability, and appeared to be independent of

> antioxidant activity. gamma-CEHC also inhibited PGE(2) synthesis

> when exposed for 1 h to COX-2-preinduced cells followed by the

> addition of arachidonic acid (AA), whereas under similar

conditions,

> gammaT required an 8- to 24-h incubation period to cause the

> inhibition. The inhibitory potency of gammaT and gamma-CEHC was

> diminished by an increase in AA concentration, suggesting that

they

> might compete with AA at the active site of COX-2. We also

observed

> a moderate reduction of nitrite accumulation and suppression of

> inducible nitric oxide synthase expression by gammaT in

> lipopolysaccharide-treated macrophages. These findings indicate

that

> gammaT and its major metabolite possess anti-inflammatory activity

> and that gammaT at physiological concentrations may be important

in

> human disease prevention.

>

> PMID: 11005841 [PubMed - indexed for MEDLINE]

>

> Best regards,

>

August 1, 2004

Penny, there is no evidence as of yet that most CFS patients have a

Vitamin D problem. Just because sarcoid patients do, doesn't mean all

chronically ill patients do, or even most, or even some.

August 1, 2004

Didn't say there was. I was talking about 1,25d and how it impacts

the inflammatory process. Thought might be interested in that.

There's no " evidence " , I guess, that " CFS " is an inflammatory

illness either. But since PWC try all kinds of supplements for

things that are not proven, (because there's no real treatment for

CFS), would it hurt if some people wanted to explore supplements to

reduce inflammation, as outlined in that post? Of course, many of

those things we have already tried, but maybe not enough or in the

right combo? And we don't really know if they'll do the job anyway.

That's why I posted the study on Quercetin.

penny

> Penny, there is no evidence as of yet that most CFS patients have

a

> Vitamin D problem. Just because sarcoid patients do, doesn't mean

all

> chronically ill patients do, or even most, or even some.

August 1, 2004

Hi, .

I certainly do remember you! It's good to see you posting here

again. Thanks for your latest comprehensive post.

I think you've made some good points in your current message.

Yes, I agree that inflammation is an important thing to look at in

CFS. As I think you've already heard, since you were last posting

here, we have been hearing a lot about the work of Trevor Marshall

on sarcoidosis and its possible application to other disorders. His

treatment is very much involved with inflammation. I think we have

yet to see how far-reaching his protocol will be, but it seems to be

helping at least some people with CFS symptoms, particularly those

who know they have a recalcitrant bacterial infection, such as

disseminated Lyme disease. I have not yet had time to study all of

this to the point that I feel as though I have a good understanding

of it.

As I may have said earlier, I think that prior to the onset of

CFS in many PWCs, cortisol is elevated because of some combination

of long-term stress, be it physical, chemical, biological,

psychological or emotional. It is known that elevated cortisol

suppresses the immune system, including the Th1 immune response as

well as the inflammation response (the latter being what

corticosteroid drugs such as prednisone are often used for). So I

don't think that inflammation is a problem initially in CFS, because

the person is unable to generate an inflammatory response initially,

but rather the main problem is a suppression of the Th1 immune

response, as a result of elevated cortisol and depleted

glutathione. I think this combination is what allows the endogenous

viruses (such as EBV and HHV-6) to come out of latency, producing

the initial infection that robs the skeletal muscles of cysteine, so

that they go low in glutathione and suffer partial blockades from

peroxynitrite, producing the fatigue. I think it is very possible

that there are factors that are elevating NO as well, as Marty and

you have emphasized, making the production of peroxynitrite even

more severe. Perhaps bacterial infections get going during this

time, too, and because of the suppression of inflammation by the

elevated cortisol, the immune system doesn't respond to them yet.

After a person develops CFS, there is quite a bit of evidence for

dysfunction in the HPA axis, often leading to lower than normal

cortisol secretion. I think that this is the stage at which

inflammation can develop. I think there is therefore sort of a " one-

two punch " that goes on with infections and the immune system in

CFS. First the viruses produce infections, which the immune system

gets activated about but is unable to defeat, and then later on the

immune system produces inflammation to go after the bacteria, after

the cortisol secretion has dropped.

I think that Dr. Cheney has held the view for some time that you

expressed about it being pointless to try to figure out how a case

of CFS started, once it has gotten going, and that one just needs to

figure out how to treat it. I'm not quite in agreement with that

position yet. I do think we need to focus on treatment, but I still

think it's important to figure out how a given case started, because

if that isn't resolved, I think it might be difficult to achieve

health, and difficult to maintain health once achieved. For

example, it is very important to get the immune system back into

proper operation, because it has to be the day-in, day-out guardian

of our health. It's important to defeat infections by whatever

means will work, such as antivirals, antifungals, antibiotics and

Benicar, but it is equally important to figure out why the immune

system was not able to protect against them in the first place, and

to correct this problem.

I do agree that there are vicious circles in CFS, and that they are

hard to break. I don't think we know what all the vicious circle

even are, yet.

In the absence of a complete understanding of the vicious circles, I

have also been advocating a " brute force, " " full court press " type

of approach to treatment, as I think you are suggesting (check the

archives for my " Suggested General Outline for Dealing with Cases of

CFS. " ) I think Marty has advocated such an approach, too, as have

quite a few of the CFS clinicians (Cheney, Teitelbaum, Corsello,

Conley and others), though they all include different components.

Perhaps the combination of supplements you are suggesting will do

the job for some PWCs. I'm still hopeful that eventually we will be

able to put together the right combination of things to break these

vicious circles, but I don't think this has happened yet. One of

the things that has been happening since you were last posting here

is that some doctors are now doing " fast I.V. pushes " of fairly

significant amounts of glutathione. I've also recently learned that

sublingual troches of 250 mg glutathione are available (Lionville

Pharmacy, Lionville, PA, phone 1-877-363-7474). I think that

together with use undenatured whey protein products, such as

ImmunoPro Rx (www.immunesupport.com), these approaches have the

potential to build glutathione in a fairly aggressive way. Provided

a person can tolerate this, it might be a way to achieve a " critical

mass " and break the vicious circles holding down the glutathione

levels in CFS.

I haven't studied all the details of the things you cited, but I

plan to do so.

Again, it's good to have you back, and thanks for your contributions.

Rich