Re: mechanism of muscle wasting

[Guest guest]

More questions please!! lol...well, let me try to respond as well as I can.Salicylates include aspirin, of course, and asacol. An abstract (below) and some relevant websites:http://www.eurekalert.org/pub_releases/2004-10/jdc-mdf101404.phphttp://www.wangonet.org/Hard/Resources/medinfo/Aspirin.htmhttp://hab.hrsa.gov/tools/palliative/chap4.html

DR Kotler in NYC is studing the use of Asacol to see if it prevents lipoatrophy

VergelDirectorProgram for Wellness Restoration, PoWeRA 501 © 3 non profit national organizationLinks to our web sites:www.nelsonvergel.comwww.powerusa.orgwww.facialwasting.orgwww.salvagetherapies.orgJoin our free listservers by sending a blank email to:pozhealth-subscribe fuzeonsupport-subscribe

[Guest guest]

At 12:29 PM 10/19/2004 -0400, you wrote:

>, what are these salicylate drugs you refer to (brand names, generic

>names)? Also, what dose of L-carnitine is thought to normalize TNF

>levels, and is it sufficient to have lipoatrophy to assume one has

>upregulated TNF (do you mean TNF-alpha?), or does one need a test, and if

>yes, what is that test?

>Finally, what dose of NAC would have efficacy in preventing muscle wasting?

>No-one more thing! Is it thought that muscle wasting and structural fat

>wasting are caused by some of the same mechanisms?

>thanks--Hugo

More questions please!! lol...well, let me try to respond as well as I can.

Salicylates include aspirin, of course, and asacol. An abstract (below) and

some relevant websites:

http://www.eurekalert.org/pub_releases/2004-10/jdc-mdf101404.php

http://www.wangonet.org/Hard/Resources/medinfo/Aspirin.htm

http://hab.hrsa.gov/tools/palliative/chap4.html

The studies on TNF (yes, -alpha, not -beta) and carnitine are from De

Simone et al. from about 1993. In those studies, they used 6 grams per day

for a month, which was an intentionally high dose as they had few people

and a short study period. Essentially, they found that this dosage

normalized TNF if it was high but didn't depress it further if it was

normal (unlike pentoxifylline or thalidomide). This is relevant in that TNF

may activate NF-kappaB which, in turns, drives production of new HIV.

Another study (albeit in mice) was conducted in 1995 showed similar

benefits (abstract below). Sadly, there isn't a lot of more recent research

into carnitine. Another form, acetylcarnitine, was shown beneficial in

managing neuropathy by Mike Youle and his colleagues in London.

I'm not sure that NAC would prevent muscle wasting, certainly not alone.

(By NAC you mean N-acetylcysteine as opposed to acetylcarnitine?) It can

help replenish glutathione, however, and offset the massive sulfur

depletion observed by Droge's group. Dosage is unclear but people somewhat

arbitrarily have settle on about 1800 mg/day.

Tests are available for TNF level and intracellular glutathione, but I'm

not sure how readily available they are.

As to the last question, I can only answer from the perspective of HIV

disease. And no, the mechanisms I think are somewhat different. In HIV

disease, muscle wasting is probably more akin to inflammatory products,

increased TNF and so forth. However, treatment suppresses HIV. Then,

though, the problems can range from myopathy associated with AZT use to

mitochondrial damage in general by nucleoside analogs.

With regard to fat wasting, d4T (Zerit) is particularly rough on

adipocytes, it appears, and may explain much of the peripheral lipoatrophy.

So I think there may be some underlying common problems that range from

endocrine disturbances, reverals in cortisol/DHEA ratio to systemic damage

from impaired gut function to liver and kidney damage. Circulatory troubles

may also arise. And of course there is a lot of activity, particularly in

the hippocampus, when HIV invades the central nervous system, as well as

the peripheral nervous tissues. These may all distally conspire to have an

impact on the overall syndrome known inaccurately as " lipodystrophy. "

M.

**

Pande V, Ramos MJ. Nuclear factor kappa B: a potential target for anti-HIV

chemotherapy. Curr Med Chem. 2003 Aug;10(16):1603-1615.

CEQUP/Departamento de Quimica, Faculdade de Ciencias, Universidade do

Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.

The Nuclear Factor Kappa B (NF-kappaB) is a lymphoid-specific transcription

factor, which is sequestered in the cytoplasm by the protein IkappaB.

NF-kappaB plays a major role in the regulation of HIV-1 gene expression.

Upon activation, NF-kappaB is released from IkappaB, moves to the nucleus,

and binds to its sites on the HIV long terminal repeat to start

transcription of integrated HIV genome. The present review focuses on the

NF-kappaB as a potential target for the development of chemotherapy against

HIV-1. Beginning from the viral-binding to reverse transcription,

integration, and gene expression, to the virion maturation, the life cycle

of HIV presents drug-targets at all the stages. As a result, many drugs

have been developed and have entered clinical trials. Some of the most

important of these are reverse transcriptase and protease inhibitors, which

have been used mostly in clinical studies in the form of combined therapy.

But, this combined therapy has presented the problem of resistance, due to

mutations in the virus. However, targeting NF-kappaB for the suppression of

virus does not present the problem of resistance, as NF-kappaB is a normal

part of the human T-4 cell, and is not subject to mutations, as is the

virus. An overview of the NF-kappaB system and its role in HIV-1 is

presented, followed by a critical review of its current and potential

synthetic inhibitors. The drugs studied against NF-kappaB fall mainly into

three categories: (1) Antioxidants, against oxidative stress conditions,

which aid in NF-kappaB activation, (2) IkappaB phosphorylation and

degradation inhibitors (the phosphorylation and degradation of IkappaB is

necessary to make NF-kappaB free and move to the nucleus), and (3)

NF-kappaB DNA binding inhibitors. The antioxidants include

N-Acetyl-L-cysteine (NAC), alpha-Lipoic acid, glutathione monoester,

pyrrolidine dithiocarbamate, and tepoxalin, of which NAC is the best

studied. The IkappaB phosphorylation and degradation inhibitors, which have

been studied in the context of HIV-1 include the salicylates (sodium

salicylate, and acetylsalicylic acid (aspirin)). Finally, the NF-kappaB DNA

binding inhibitors, which have received attention only recently, are

reviewed. These include the most potential, aurine tricarboxylic acid

(ATA), a chelating agent, which has been found to inhibit NF-kappaB DNA

binding at a low concentration of 30 micro M. The probable mechanism of

action of these drugs is discussed alongwith relevant suggestions and

conclusions.

**

Winter BK, Fiskum G, Gallo LL. Effects of L-carnitine on serum triglyceride

and cytokine levels in rat models of cachexia and septic shock. Br J

Cancer. 1995 Nov;72(5):1173-1179.

Department of Biochemistry and Molecular Biology, Washington

University Medical Center, Washington, DC 20037, USA.

Inappropriate hepatic lipogenesis, hypertriglyceridaemia, decreased fatty

acid oxidation and muscle protein wasting are common in patients with

sepsis, cancer or AIDS. Given carnitine's role in the oxidation of fatty

acids (FAs), we anticipated that carnitine might promote FA oxidation, thus

ameliorating metabolic disturbances in lipopolysaccharide (LPS)- and

methylcholanthrene-induced sarcoma models of wasting in rats. In the LPS

model, rats were injected with LPS (24 mg kg-1 i.p.), and treated with

carnitine (100 mg kg-1 i.p.) at -16, -8, 0 and 8 h post LPS. Rat health was

observed, and plasma inflammatory cytokines and triglycerides (TG) were

measured before and 3 h post LPS. In the sarcoma model, rats were implanted

subcutaneously with tumour, and treated continuously with carnitine (200 mg

kg-1 day-1 i.p.) via implanted osmotic pumps. Tumour burden, TG and

cytokines were measured weekly for 4 weeks. Carnitine treatment

significantly lowered the tumour-induced rise in TG (% rise) in the sarcoma

model (700 +/- 204 vs 251 +/- 51, P < 0.03) in control and carnitine groups

respectively. Levels of interleukin-1 beta (IL-1 beta), interleukin-6

(IL-6) and tumour necrosis factor-alpha (TNF-alpha) (pg ml-1) were also

lowered by carnitine in both LPS (IL-1 beta: 536 +/- 65 vs 378 +/- 44:

IL-6: 271 +/- 29 vs 222 +/- 32; TNF-alpha: 618 +/- 86 vs 367 +/- 54, P < or

= 0.02) and sarcoma models (IL-1 beta: 423 +/- 33 vs 221 +/- 60; IL-6: 222

+/- 18 vs 139 +/- 38; TNF-alpha: 617 +/- 69 vs 280 +/- 77, P < or = 0.05)

for control and carnitine groups respectively. We conclude that carnitine

has a therapeutic effect on morbidity and lipid metabolism in these disease

models, and that these effects could be the result of down-regulation of

cytokine production and/or increased clearance of cytokines.

[Guest guest]

was very right in mentioning Wilhelm Droge ... and cysteine Cytokine-induced loss of muscle happens in Rheumatoid Arthritis and other conditions associalted with immune system activation.

Just another point of interest, when mitochondria are damaged, as in HIV or in HCV, fats are not processed well, and the accumulation of fatty acids in the cells is irritating, causing a rise in TNFa.

When L-carnitine is provided, fat-burning is improved, the cells are less irritated, and TNFa levels drop. It is not that L-carnitine has a direct effect on TNFa; it is that the cells are in better shape thanks to improved health, so less cytokine (distress) signalling is happening.

Droge W, Holm E.

Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. FASEB J. 1997 Nov;11(13):1077-89

Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.

The combination of abnormally low plasma cystine and glutamine levels, low natural killer (NK) cell activity, skeletal muscle wasting or muscle fatigue, and increased rates of urea production defines a complex of abnormalities that is tentatively called "low CG syndrome." These symptoms are found in patients with HIV infection, cancer, major injuries, sepsis, Crohn's disease, ulcerative colitis, chronic fatigue syndrome, and to some extent in overtrained athletes. The coincidence of these symptoms in diseases of different etiological origin suggests a causal relationship. The low NK cell activity in most cases is not life-threatening, but may be disastrous in HIV infection because it may compromise the initially stable balance between the immune system and virus, and trigger disease progression. This hypothesis is supported by the coincidence observed between the decrease of CD4+ T cells and a decrease in the plasma cystine level. In addition, recent studies revealed important clues about the role of cysteine and glutathione in the development of skeletal muscle wasting. Evidence suggests that 1) the cystine level is regulated primarily by the normal postabsorptive skeletal muscle protein catabolism, 2) the cystine level itself is a physiological regulator of nitrogen balance and body cell mass, 3) the cyst(e)ine-mediated regulatory circuit is compromised in various catabolic conditions, including old age, and 4) cysteine supplementation may be a useful therapy if combined with disease-specific treatments such as antiviral therapy in HIV infection.

Publication Types:

• Review

• Review, Academic

Charlie Smigelski RD Boston

[Guest guest]

Charlie,

Are there cystine supplements and is it another amino acid like glutothione? Thanks.

Larry Smyle

-------------- Original message --------------

was very right in mentioning Wilhelm Droge ... and cysteine Cytokine-induced loss of muscle happens in Rheumatoid Arthritis and other conditions associalted with immune system activation. Just another point of interest, when mitochondria are damaged, as in HIV or in HCV, fats are not processed well, and the accumulation of fatty acids in the cells is irritating, causing a rise in TNFa. When L-carnitine is provided, fat-burning is improved, the cells are less irritated, and TNFa levels drop. It is not that L-carnitine has a direct effect on TNFa; it is that the cells are in better shape thanks to improved health, so less cytokine (distress) signalling is happening. Droge W, Holm E.Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. FASEB J. 1997 Nov;11(13):1077-89Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.The combination of abnormally low plasma cystine and glutamine levels, low natural killer (NK) cell activity, skeletal muscle wasting or muscle fatigue, and increased rates of urea production defines a complex of abnormalities that is tentatively called "low CG syndrome." These symptoms are found in patients with HIV infection, cancer, major injuries, sepsis, Crohn's disease, ulcerative colitis, chronic fatigue syndrome, and to some extent in overtrained athletes. The coincidence of these symptoms in diseases of different etiological origin suggests a causal relationship. The low NK cell activity in most cases is not life-threatening, but may be disastrous in HIV infection because it may compromise the initially stable balance between the immune system and virus, and trigger disease progression. This hypothesis is supported by the coincidence observed between the decrease of CD4+ T cells and a decrease in the plasma cystine level. In addition, recent studies revealed important clues about the role of cysteine and glutathione in the development of skeletal muscle wasting. Evidence suggests that 1) the cystine level is regulated primarily by the normal postabsorptive skeletal muscle protein catabolism, 2) the cystine level itself is a physiological regulator of nitrogen balance and body cell mass, 3) the cyst(e)ine-mediated regulatory circuit is compromised in various catabolic conditions, including old age, and 4) cysteine supplementation may be a useful therapy if combined with disease-specific treatments such as antiviral therapy in HIV infection.Publication Types:• Review• Review, AcademicCharlie Smigelski RD Boston Welcome to our PozHealth group!If you received this email from someone who forwarded it to you and would like to join this group, send a blank email to PozHealth-subscribe and you will get an email with intructions to follow. You can chose to receive single emails or a daily digest (collection of emails). You can post pictures, images, attach files and search by keyword old postings in the group.For those of you who are members already and want to switch from single emails to digest or viceversa, visit www.yahoogroups.com, click on PozHealth, then on "edit my membership" and go down to your selection. The list administrator does not process any requests, so this is a do-it-yourself easy process ! :)Thanks for joining. You will learn and share a lot in this group!NOTE: I moderate, approve or disapprove emails before they are posted. Please follow the guidelines shown in the homepage. I will not allow rudeness, sexually explicit material, attacks, and anyone who does not follow the rules. If you are not OK with this, please do not join the group. Forward this email to anyone who may benefit from this information! Thanks!In Health, Vergel (powertx@...)List Founder and Moderator

[Guest guest]

At 12:59 AM 10/23/2004 +0000, lsmyle@... wrote:

>Charlie,

>Are there cystine supplements and is it another amino acid like

>glutothione? Thanks.

Actually, yes but let's clarify a little. I know it was probably just a

misspelling, but here we go!

First:

Cystine is the OXIDIZED form of the amino acid cysteine. Different forms of

the same amino acid.

The supplement form that seems best for people to take has an acetyl group

attached and is known as N-acetylcysteine or NAC. Cysteine (and NAC)

contain sulfur so a lot of the products have a bit of a smell. If it has a

LOT of smell, it ain't good.

This amino acid, when paired with glycine and glutamic acid produces

glutathione. So glutathione is NOT an amino acid but rather a small peptide

made of three amino acids.

(Now don't get this all mixed up with carnitine and acetylcarnitine! Which

are also helpful for other reasons. I take NAC and acetylcarnitine daily,

along with other stuff.)

M.