You should be taking GRAPE SKIN extract NOT grape seed!!

GRAPE SKIN extract is GREAT for MS folks.


Lots of MS folks think that taking "Grape Seed Extract" is good but it is not for the following reason.

IF and ONLY if we accept that increasing GAMMA INTERFERON is BAD for MS folks will my argument prove sound.

I would hope that everyone can accept this as a fact.

Some Gamma Interferon at low levels is necessary for good health and myelin repair.

The medical literature shows that ADDING/INCREASING Gamma Interferon has worsened MS folks in clinical studies.

jackD

: Clin Diagn Lab Immunol 2002 Mar;9(2):470-6

Grape seed extract activates Th1 cells in vitro.

Nair N, Mahajan S, Chawda R, Kandaswami C, Shanahan TC, Schwartz SA.

Division of Allergy, Immunology, and Rheumatology, Department of Medicine, State University of New York at Buffalo and Kaleida Health, 14203, USA.

Although flavonoids manifest a diverse range of biological activities, including antitumor and antiviral effects, the molecular mechanisms underlying these activities await elucidation.

We hypothesize that the flavonoid constituents of a proprietary grape seed extract (GSE) that contains procyandins exert significant antiviral and antitumor effects, by inducing production of the Th1-derived cytokine gamma interferon (IFN-gamma) by peripheral blood mononuclear cells) from healthy donors.

Our results show that GSE significantly induced the transcription of IFN-gamma mRNA as demonstrated by reverse transcription-PCR but had no effect on the Th2-derived cytokine interleukin-6. The enhancing effect of GSE on IFN-gamma expression was further supported by a concomitant increase in the number of cells with intracytoplasmic IFN-gamma as well as the synthesis and secretion of IFN-gamma.

Our results demonstrate that the potentially beneficial immunostimulatory effects of GSE may be mediated through the induction of IFN-gamma.

PMID: 11874895 [PubMed - indexed for MEDLINE

1: Neuroscientist 2002 Dec;8(6):586-95

Matrix metalloproteinases and neuroinflammation in multiple sclerosis.

Rosenberg GA.
Department of Neurology, University of New Mexico Health Sciences Center,
Albuquerque, New Mexico 87131, USA.

Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral proteases that are important in normal development, angiogenesis, wound repair, and a wide range of pathological processes. Growing evidence supports a key role of the MMPs in many neuroinflammatory conditions, including meningitis, encephalitis, brain tumors, cerebral ischemia, Guillain-Barre, and multiple sclerosis (MS).

The MMPs attack the basal lamina macromolecules that line the blood vessels, opening the blood-brain barrier (BBB). They contribute to the remodeling of the blood vessels that causes hyalinosis and gliosis, and they attack myelin. During the acute inflammatory phase of MS, they are involved in the injury to the blood vessels and may be important in the disruption of the myelin sheath and axons. Normally under tight regulation, excessive proteolytic activity is detected in the blood and cerebrospinal fluid in patients with acute MS. Because they are induced in immunologic and nonimmunologic forms of demyelination, they act as a final common pathway to exert a "bystander" effect.

AGENTS THAT BLOCK THE ACTION OF THE MMPS HAVE BEEN SHOWN TO REDUCE THE DAMAGE TO THE BBB AND LEAD TO SYMPTOMATIC IMPROVEMENT IN SEVERAL ANIMAL MODELS OF NEUROINFLAMMATORY DISEASES, INCLUDING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS. SUCH AGENTS MAY EVENTUALLY BE USEFUL IN THE CONTROL OF EXCESSIVE PROTEOLYSIS THAT CONTRIBUTES TO THE PATHOLOGY OF MS AND OTHER NEUROINFLAMMATORY CONDITIONS.

PMID: 12467380 [PubMed - in process]


"Things" that reduce MMP-9s (AKA gelatinase B)

This list of GOOD "things" for MS should seem familiar - This is WHY???

QUERCETIN..........................REDUCES MMP-9s

VIT D3 .................................REDUCES MMP-9s

RESVERATROL (Grape Skin Extract) ...REDUCES MMP-9s
(NOT GRAPE SEED EXTRACT)

GREEN TEA EXTRACT(EGCGs)... REDUCES MMP-9s

ALPHA LIPOIC ACID (R-lipoic/ R-Dihdro-LipoicAcid) ... REDUCES MMP-9s

NAC N-Acetyl-L-Cysteine .......REDUCES MMP-9s

STATIN DRUGS (i.e Zocor) .....REDUCES MMP-9s

Omega-3s (ie Fish oil) ...........REDUCES MMP-9s

Minocycline/Doxycycline.........REDUCES MMP-9s

Curcumin.............................REDUCES MMP-9s

Pycnogenol (Pine bark extract)..REDUCES MMP-9s

Chondroitin sulfate (CS) and CS plus glucosamine sulfate (GS) ..REDUCES MMP-9s

Interferon Betas 1a/1b...........REDUCES MMP-9

(of course Steroids ....REDUCES MMP-9s)

***NOTE*** ( gelatinase B = MMP-9) ***NOTE***


I have lots more information on this MMP - MS - INTERFERON-beta connection and will elaborate it if there is some interest in this subject here.

The techie stuff is here..

http://home.ix.netcom.com/~jdalton/Yongrev.pdf

SEE FIGURE 2 and MS info on page 505


jackD


Lancet Neurol. 2003 Dec;2(12):747-56.

Functional roles and therapeutic targeting of gelatinase B(MMP-9) and chemokines in
multiple sclerosis.

Opdenakker G, Nelissen I, Van Damme J.
GO, IN, and JVD are at the Rega Institute for Medical Research, University
of
Leuven, Belgium

Multiple sclerosis (MS) is a demyelinating disease of the CNS of unknown
cause. Pathogenetic mechanisms, such as chemotaxis, subsequent activation of
autoreactive lymphocytes, and skewing of the extracellular proteinase
balance, are targets for new therapies.

Matrix metalloproteinase gelatinase B (MMP-9) is upregulated in MS and was
recently shown to degrade interferon beta, one of the drugs used to treat
MS.

Consequently, the effect of endogenously produced interferon beta or
parenterally given interferon beta may be increased by gelatinase B(MMP-9)
inhibitors. Blockage of chemotaxis or cell adhesion molecule engagement, and
inhibition of hydoxymethyl-glutaryl-coenzyme-A reductase to lower expression
of gelatinase B(MMP-9), may become effective treatments of MS, alone or in
combination with interferon beta. This may allow interferon beta to be used
at lower doses and prevent side-effects.

PMID: 14636780 [PubMed - in process]


1: Brain. 2003 Jun;126(Pt 6):1371-81.

Gelatinase B/matrix metalloproteinase-9(MMP-9) cleaves interferon-beta and is a
target for immunotherapy.

Nelissen I, Martens E, Van den Steen PE, Proost P, Ronsse I, Opdenakker G.
Rega Institute for Medical Research, Laboratory of Molecular Immunology,
University of Leuven, Leuven, Belgium.

Parenteral administration of interferon (IFN)-beta is one of the currently
approved therapies for multiple sclerosis. One characteristic of this
disease is the increased production of gelatinase B(MMP-9), also called matrix
metalloproteinase (MMP-9) Gelatinase B is capable of destroying the
blood-brain barrier, and of cleaving myelin basic protein into
immunodominant and encephalitogenic fragments, thus playing a functional
role and being a therapeutic target in multiple sclerosis. Here we
demonstrate that gelatinase B(MMP-9) proteolytically cleaves IFN-beta, kills its
activity, and hence counteracts this cytokine as an antiviral and
immunotherapeutic agent. This proteolysis is more pronounced with
IFN-beta-1b than with IFN-beta-1a. Furthermore, the tetracycline
minocycline, which has a known blocking effect in experimental autoimmune
encephalomyelitis, an in vivo model of acute inflammation in multiple
sclerosis, and other MMP inhibitors prevent the in vitro degradation of
IFN-beta by gelatinase B(MMP-9). These data provide a novel mechanism and rationale
for the inhibition of gelatinase B(MMP-9) in diseases in which IFN-beta has a
beneficial effect. The combination of gelatinase B(MMP-9) inhibitors with better
and lower pharmacological formulations of IFN-beta may reduce the
side-effects of treatment with IFN-beta, and is therefore proposed for
multiple sclerosis therapy and the immunotherapy of viral infections.

PMID: 12764058 [PubMed - indexed for MEDLINE]

: Curr Pharm Biotechnol. 2008 Feb;9(1):34-46.

Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis.

Muroski ME, Roycik MD, Newcomer RG, Van den Steen PE, Opdenakker G, Monroe HR, Sahab ZJ, Sang QX.
Department of Chemistry and Biochemistry and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.

Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes involved in an array of physiological and pathological processes from development, morphogenesis, reproduction, wound healing, and aging to inflammation, angiogenesis, neurological disorders, and cancer cell invasion and metastasis. The imbalance between MMP activity and the inhibitory action of tissue inhibitors of metalloproteinases (TIMPs) are implicated in multiple diseases. Secreted in the body in a latent form, upon activation MMP-9 (gelatinase B) acts on many inflammatory substrates, and thus is suspected of contributing to the progression of cardiovascular disease, rheumatoid arthritis, and the subjects of this review, chronic obstructive pulmonary disease (COPD) and multiple sclerosis (MS). COPD is the fourth most common cause of death in the United States. In COPD, increased expression of MMP-9 by inflammatory cells e.g. neutrophils and macrophages is correlated with a variety of processes that cause lung damage. MMP-9 is also important in cytokine and protease modulation; it degrades the serine protease inhibitor alpha(1)-antitrypsin, which thus may lead to lung destruction.

MS affects approximately 400,000 Americans and over a million people worldwide. Upregulation of MMP-9 increases the permeability of the blood brain barrier (BBB), facilitates the infiltration of leukocytes into the central nervous system, and causes myelin sheath degradation and neuronal damage. Early stage clinical trials have shown promising results when MMP-9 is inhibited in MS. These observations lead to the hypothesis that MMP-9 is a potential drug target for both COPD and MS and further development of highly potent and specific MMP-9 inhibitors is warranted.

PMID: 18289055 [PubMed - in process]

Grape Skin Extract - Resveratrol - lowers levels of MMP-9 study.

jackd


1: Acta Pharmacol Sin. 2003 Nov;24(11):1167-71.

Resveratrol inhibits matrix metalloproteinase-9 transcription in U937 cells.

Li YT, Shen F, Liu BH, Cheng GF.

Department of Pharmacology, Institute of Materia Medica, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beijing 100050, China.

AIM: To examine the inhibitory effect of resveratrol on matrix
metalloroteinase-9 (MMP-9) and explore its mechanism.

METHODS: MMP-9 activity was analyzed by gelatin zymography; MMP-9 protein was detected by Western
blot; MMP-9 mRNA expression was investigated by RT-PCR. Activation of activator
protein -1 (AP-1) was measured by electrophoretic mobility shift assay
(EMSA).

RESULTS: MMP-9 activity in U937 cells increased significantly after exposed
to PMA at 10 nmol/L for 24 h without FCS (P<0.01). Resveratrol at 1 and 10
micromol/L showed significant inhibition on MMP-9 activity (P<0.05 and
P<0.01, respectively). Western blot and RT-PCR experiments displayed that MMP-9
protein (P<0.01) and mRNA expression (P<0.01) increased significantly in PMA-treated
U937 cells. Resveratrol at 1 and 10 micromol/L showed inhibitory effects on
MMP-9 protein production and MMP-9 mRNA expression (P<0.05). The activation
of AP-1 induced by PMA was also extensively inhibited by resveratrol at 0.1, 1,and
10 micromol/L.

CONCLUSION: The inhibitory effect of resveratrol on MMP-9
activity may be partly through suppression of activation of nuclear
transcription factor AP-1, and inhibition of MMP-9 mRNA expression and MMP-9
protein production.

PMID: 14627504 [PubMed - in process]

It has suddenly occurred to me that some MS folks may not know what an MMP is or what it does in MS.

So 1st here is what it is and what it does in MS.


This report published in NATURE is titled "MMPs in Biology of the Nervous System". Examine VERY carefuly Figure 2 on page 505.

http://home.ix.netcom.com/~jdalton/Yongrev.pdf (my web space)

SEE FIGURE 2 and MS info on page 505


I have lots of degrees but none in the medical area. I will try to simplify my ignorance and post my misunderstandings so you can fantasize about it.

Simply put MMPs are a family of about 27 (mmp-1 to MMP-27) enzymes that share a common characteristic function and structure of cutting "THINGS" up into little pieces.

Unfortunately for MS folks they (MMP-9s) like to cut a hole in our BBB Blood Brain Barrier and then enter the brain and cut our myelin into three components that the other hungry characters like to dine on.

They (MMPs) all have a zinc ion tip that allows them to break down hydrogen bonds in tissue thus allows absorption of dead or dying tissue to be reabsorbed or sent via the lymph system to others places to exit out the poop shoot.

The MMP-9s usually have an accompanying regulator protein that is suppose to make sure that it only "eat/cuts up" BAD stuff. This is called a TIMP-1. For NORMAL folks there is a one-to-one ratio of MMP-9 to TIMP-1s.

Sad to say for us MS folks that we have lots of MMP-9s that I call ROGUE MMP-9s that have no accompanying regulating timp-1. Just before and during a MS relapse the total MMP-9s level rise significently. The first thing they do is cut a BIG hole in our BBB Blood Brain Barrier!! They then enter and do the following...

They just wander around the brain cutting up anything "active" and when they run into an active transmission cable the eat through it, The outside of that cable is called myelin. (a fatty insulating substance)

The advantage of taking an Interferon Beta is that after about 4 to 6 months of starting beta treatment that the ratio of MMP-s to TIMP-1s goes back to the desirable one-to-one ration.

There are NO effective drugs to lower just MMP-9s. Some drugs were developed but they shut them all (all 27) down and killed the host.

Some antibiotics seem to lower MMP-9s quite well but taking those for long periods of time can be equally deadly. Likewise taking some steroids can lower the MMP-9s quite well but can be equally deadly over the long haul.

jackD



1: Mult Scler 2002 May;8(3):222-8

Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple
sclerosis: implication for pathogenesis.

Liuzzi GM, Trojano M, Fanelli M, Avolio C, Fasano A, Livrea P, Riccio P.

Department of Biochemistry and Molecular Biology, University of Bari, Italy.
m.g.liuzzi@biologia.uniba.it

Matrix metalloproteinase-9 (MMP-9) was detected by zymography and enzyme-linked
immunosorbent assay (ELISA) in matched serum and cerebrospinal fluid (CSF)
samples from patients with neurological diseases. Patients with
relapsing-remitting multiple sclerosis (RR-MS) had serum and CSF MMP-9 levels
comparable to those from patients with inflammatory neurological diseases
(INDs), but higher than patients with non-inflammatory neurological diseases
(NINDs) and healthy donors (HDs). MMP-9 increased in active RR-MS in comparison
with inactive RR-MS implying that MMP-9 in MS is related with clinical disease
activity. A correlation between the CSF/serum albumin (Q(AIb)) and CSF/serum
MMP-9 (Q(MMP-9)) was observed in IND and NIND but not in RR-MS patients,
indicating that CSF MMP-9 levels in NIND and IND patents could be influenced by
serum MMP-9 and blood-brain barrier (BBB) permeability properties. MS patients
had higher values of Q(MMP-9):Q(Alb)(MMP-9 index) than IND and NIND patients
suggesting that in MS the increase in CSF MMP-9 could be due to intrathecal
synthesis of MMP-9.

A significant inverse correlation was found between MMP-9
and its endogenous inhibitor TIMP-1 in RR-MS indicating that in MS patients both
the increase in MMP-9 and the decrease in TIMP-1 serum levels could contribute
to BBB disruption and T-lymphocyte entry into the CNS.

PMID: 12120694 [PubMed - in process]

Here is that info to support the Omega-3 - MMP-9 connection.

jackD

[P03.119] Effect of Omega-3 Fatty Acid Supplementation on Matrix
Metalloproteinase-9 Production in Multiple Sclerosis

Gail Marracci, Lynne Shinto, Adrienne Strehlow, Sara Baldauf-Wagner, Dennis
Bourdette, Portland, OR

OBJECTIVE: To assess the safety and effectiveness of omega-3 fatty acid
supplementation on matrix metalloproteinase-9 (MMP-9) production in multiple
sclerosis (MS).

BACKGROUND: Eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) are
omega-3 fatty acids that have reported immunomodualtory effects, including
effects on MMP-9. Because MMP-9 may contribute to MS disease pathology by
facilitating the migration of inflammatory cells into the CNS, omega-3 fatty
acids may prove to be a useful treatment in MS.

DESIGN/METHODS: This was a pilot open label study. All subjects gave
informed consent prior to study participation. Ten subjects with relapsing
remitting MS received 8 capsules BID with a daily dose of 1900 mg DHA and
2900 mg of EPA. Blood was drawn before and after 1 and 3 months of
supplementation. MMP-9 levels from serum and levels secreted from peripheral
blood mononuclear cells (PBMC) were measured by ELISA at these time points.
DHA and EPA levels were measured by red blood cell fatty acid analysis at
baseline and month 3. Adverse events were monitored by subject reports and
laboratory assessment.

RESULTS: After 3 months of supplementation, there was a 52% decrease in
MMP-9 levels secreted by PBMC (p<0.001), and omega-3 fatty acid blood levels
were significantly increased (EPA, p<0.001; DHA, p<0.001).

CONCLUSIONS: Supplementation with omega-3 fatty acids can significantly
decrease MMP-9 levels secreted from immune cells, and in vitro decrease
MMP-9 activity at physiologic doses. Omega-3 fatty acid supplementation
appears to be safe and well tolerated. Omega-3 fatty acids warrant further
investigation as a potential therapy for MS.

Supported by: National Institutes of Health Grants P50AT00066-01 & M01
RR000334, the Department of Veterans Affairs, the Nancy Davis Center Without
Walls and Vital Nutrients.

Here is the BEST way to reduce IL-12 and a LOT of other NASTY things that foster damage in MS.

CURCUMIN (Tumeric)

It is poorly absorbed by the body BUT if you add some black pepper extract PIPERINE or maybe just some black pepper itself, you can increase absorption rate by 2000%.

Life Extension folks include some Bioperine (their version of PIPERINE extract) with their SUPER CURCUMIN which I take (900 mg).

jackD



http://www.lef.org

http://www.lef.org/newshop/items/item00912.html

: Br J Pharmacol 1999 Sep;128(2):380-4

Curcumin inhibits Th1 cytokine profile in CD4+ T cells by suppressing
interleukin-12 production in macrophages.

Kang BY, Song YJ, Kim KM, Choe YK, Hwang SY, Kim TS.

College of Pharmacy, Chonnam National University, Kwangju 500-757, South Korea.

1 Interleukin-12 (IL-12) plays a central role in the immune system by driving
the immune response towards T helper 1 (Th1) type responses which are
characterized by high IFN-gamma and low IL-4 production. In this study we
investigated the effects of curcumin, a natural product of plants obtained from
Curcuma longa (turmeric), on IL-12 production by mouse splenic macrophages and
the subsequent ability of these cells to regulate cytokine production by CD4+ T
cells. 2 Pretreatment with curcumin significantly inhibited IL-12 production by
macrophages stimulated with either lipopolysaccharide (LPS) or head-killed
Listeria monocytogenes (HKL). 3 Curcumin-pretreated macrophages reduced their
ability to induce IFN-gamma and increased the ability to induce IL-4 in
Ag-primed CD4+ T cells. Addition of recombinant IL-12 to cultures of
curcumin-pretreated macrophages and CD4+ T cells restored IFN-gamma production
in CD4+ T cells. 4 The in vivo administration of curcumin resulted in the
inhibition of IL-12 production by macrophages stimulated in vitro with either
LPS or HKL, leading to the inhibition of Th1 cytokine profile (decreased
IFN-gamma and increased IL-4 production) in CD4+ T cells. 5 These findings
suggest that curcumin may inhibit Th1 cytokine profile in CD4+ T cells by
suppressing IL-12 production in macrophages, and points to a possible
therapeutic use of curcumin in the Th1-mediated immune diseases.

PMID: 10510448 [PubMed - indexed for MEDLINE]


1: Planta Med. 1998 May;64(4):353-6.

Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.

Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS.
Department of Pharmacology, St. John's Medical College, Bangalore, India.

The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low.

Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%.

The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.

Publication Types:
Clinical Trial
PMID: 9619120 [PubMed - indexed for MEDLINE]

GINGER also lowers activity of MMP-9s

jackD

1: J Nutr Biochem. 2008 May;19(5):313-9. Epub 2007 Aug 1. Links
[6]-Gingerol inhibits metastasis of MDA-MB-231 human breast cancer cells.Lee HS, Seo EY, Kang NE, Kim WK.
Department of Sports Sciences, Seoul Sports Graduate University, Seoul 150-034, South Korea.

Gingerol (Zingiber officinale Roscoe, Zingiberaceae) is one of the most frequently and heavily consumed dietary condiments throughout the world. The oleoresin from rhizomes of ginger contains [6]-gingerol (1-[4'-hydroxy-3'-methoxyphenyl]-5-hydroxy-3-decanone) and its homologs which are pungent ingredients that have been found to possess many interesting pharmacological and physiological activities, such as anti-inflammatory, antihepatotoxic and cardiotonic effects. However, the effects of [6]-gingerol on metastatic processes in breast cancer cells are not currently well known. Therefore, in this study, we examined the effects of [6]-gingerol on adhesion, invasion, motility, activity and the amount of MMP-2 or -9 in the MDA-MB-231 human breast cancer cell line. We cultured MDA-MB-231 cells in the presence of various concentrations of [6]-gingerol (0, 2.5, 5 and 10 microM). [6]-Gingerol had no effect on cell adhesion up to 5 microM, but resulted in a 16% reduction at 10 microM. Treatment of MDA-MB-231 cells with increasing concentrations of [6]-gingerol led to a concentration-dependent decrease in cell migration and motility. The activities of MMP-2 or MMP-9 in MDA-MB-231 cells were decreased by treatment with [6]-gingerol and occurred in a dose-dependent manner. The amount of MMP-2 protein was decreased in a dose-dependent manner, although there was no change in the MMP-9 protein levels following treatment with [6]-gingerol. MMP-2 and MMP-9 mRNA expression were decreased by [6]-gingerol treatment.

In conclusion, we have shown that [6]-gingerol inhibits cell adhesion, invasion, motility and activities of MMP-2 and MMP-9 in MDA-MB-231 human breast cancer cell lines.

PMID: 17683926 [PubMed - indexed for MEDLINE]

1: QJM 2002 Dec;95(12):787-796

Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR
genotype: mechanisms for inflammatory damage in chronic disorders?
Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D,
Aganna E, Price CP, Boucher(2) BJ.
Departments of. Clinical Biochemistry, Diabetes and Metabolic Medicine and.
Haematology, Barts and The London, Queen Mary's School of Medicine and
Dentistry, University of London and. Department of Cardiology, 'Barts and
The London' NHS Trust, London, UK.

BACKGROUND:Vitamin-D deficiency and vitamin-D receptor genotype (VDR) are
risk factors for several disorders with inflammatory components, including
coronary heart disease (CHD) and diabetes, though the mechanisms involved
are unclear. Aim: To examine the hypothesis that vitamin D status modulates
the matrix metalloproteinase (MMP) system in a population with a high
prevalence of vitamin D deficiency, a situation affecting susceptibility to
CHD and diabetes.

DESIGN:
Prospective cross-sectional, interventional and embedded studies. METHODS:
Circulating MMP2,9, the inhibitor TIMP-1 and C-reactive protein (CRP) were
measured during studies of vitamin-D deficiency as a risk factor for type 2
diabetes and CHD in 171 healthy British Bangladeshi adults, free of known
diabetes or major illness. Vitamin D status, VDR genotype, body-build, blood
pressure, lipid and insulin profiles, glucose tolerance, fibrinogen, PAI-1,
folate and homocysteine were measured. Vitamin-D-deficient subjects were
re-assessed after 1 years' supplementation. MMP, TIMP-1 and CRP levels were
measured in 41 subjects halfway through 5-year follow-up. Independent
determinants of circulating concentrations of MMP9, TIMP-1 and CRP were
assessed by multiple regression analysis.

RESULTS: Vitamin D status was the sole determinant of circulating MMP9
(inversely) and an independent determinant of CRP (inversely). Determinants
of TIMP-1 were MMP9, systolic blood-pressure (directly) and VDR genotype
(TaqI). Significant reductions in MMP9 (-68%), TIMP-1 (-38%) and CRP (-23%)
concentrations followed vitamin-D supplementation. DISCUSSION: Vitamin-D
insufficiency is associated with increased circulating MMP2,9 and CRP,
correctable by supplementation. This finding provides a possible mechanism
for tissue damage in chronic inflammatory conditions, including CHD and
diabetes.

PMID: 12454321 [PubMed - as supplied by publisher]

1: Equine Vet J Suppl. 2002 Sep;(34):224-9.Links
Inhibition of articular cartilage degradation by glucosamine-HCl and chondroitin sulphate.Orth MW, Peters TL, Hawkins JN.
Department of Animal Science, Michigan State University, East Lansing 48824-1225, USA.

Glucosamine and chondroitin sulphate in many animal and human trials has improved joint health. In vitro studies are beginning to clarify their mode of action. The objective of this research was to: 1) determine at what concentrations glucosamine-HCl (GLN) and/or chondroitin sulphate (CS) would inhibit the cytokine-induced catabolic response in equine articular cartilage explants and 2) to determine if a combination of the 2 was more effective at inhibiting the catabolic response than the individual compounds. Articular cartilage was obtained from carpal joints of horses (age 1-4 years). Cartilage discs (3.5 mm) were biopsied and cultured. Explants were incubated with lipopolysaccharide (LPS) in the presence of varying concentrations of GLN, CS, or both. Control treatments included explants with no LPS and LPS without GLN or CS. Media were analysed for nitric oxide (NO), prostaglandin E2 (PGE2) and keratan sulphate. Cartilage was extracted for analysis of metalloproteinases (MMP). Four experiments were conducted. In all experiments, GLN at concentrations as low as 1 mg/ml decreased NO production relative to LPS stimulated cartilage without GLN over the 4 day period. In general, CS at either 0.25 or 0.5 mg/ml did not inhibit NO production. The addition of CS to GLN containing media did not further inhibit NO production. GLN at concentrations as low as 0.5 mg/ml decreased PGE2 production, whereas CS did not effect on PGE2. The combination of GLN/CS decreased MMP-9 gelatinolytic activity but had no effect on MMP-2 activity. The combination in 2 experiments tended to decrease MMP-13 protein concentrations and decreased keratan sulphate levels in media. Overall, the combination of GLN (1 mg/ml) and CS (0.25 mg/ml) inhibited the synthesis of several mediators of cartilage degradation. These results further support the effort to understand the role of GLN and CS in preserving articular cartilage in athletic horses.

PMID: 12405691 [PubMed - indexed for MEDLINE]


1: Front Biosci. 2006 Jan 1;11:529-43. Links
Matrix metalloproteinases: role in arthritis.Burrage PS, Mix KS, Brinckerhoff CE.
Department of Biochemistry, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756, USA.

The irreversible destruction of the cartilage, tendon, and bone that comprise synovial joints is the hallmark of both rheumatoid arthritis (RA) and osteoarthritis (OA). While cartilage is made up of proteoglycans and type II collagen, tendon and bone are composed primarily of type I collagen. RA is an autoimmune disease afflicting numerous joints throughout the body; in contrast, OA develops in a small number of joints, usually resulting from chronic overuse or injury. In both diseases, inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) stimulate the production of matrix metalloproteinases (MMPs), enzymes that can degrade all components of the extracellular matrix. The collagenases, MMP-1 and MMP-13, have predominant roles in RA and OA because they are rate limiting in the process of collagen degradation. MMP-1 is produced primarily by the synovial cells that line the joints, and MMP-13 is a product of the chondrocytes that reside in the cartilage. In addition to collagen, MMP-13 also degrades the proteoglycan molecule, aggrecan, giving it a dual role in matrix destruction. Expression of other MMPs such as MMP-2, MMP-3 and MMP-9, is also elevated in arthritis and these enzymes degrade non-collagen matrix components of the joints.

Significant effort has been expended in attempts to design effective inhibitors of MMP activity and/or synthesis with the goal of curbing connective tissues destruction within the joints.

To date, however, no effective clinical inhibitors exist.

Increasing our knowledge of the crystal structures of these enzymes and of the signal transduction pathways and molecular mechanisms that control MMP gene expression may provide new opportunities for the development of therapeutics to prevent the joint destruction seen in arthritis.

PMID: 16146751 [PubMed - indexed for MEDLINE]

I posted this in 2001 and it explains why a LOW SATURATED FAT diet may help lower GAMMA INTERFERON levels. (ANY LOW SATURATED FAT DIET)

Also I found out at that time that high levels of gut bacteria could elevate GAMMA INTERFERON. The toxins from high levels of dying bateria in gut elevate GAMMA INTERFERON. Have a couple pints of Yogurt but do not eat a quart at a time.

jackD


Researchers in the Netherlands gave volunteers the liquid caloric
equivalent
> > of a fast-food hamburger and fries. Then ran blood tests to check for
two
> > substances that fight bacteria and viruses.


> > Six hours after the meal, levels of Interferon Gamma, which combats cold
> > viruses, rose fourfold.


> > There was little rise, however in Interleukin-4 levels, which battles
> > fever-causing bacterial infections.


> > But after overnight fasting, Interleukin-4 levels went up fourfold.
> > Meanwhile the Interferon Gamma fell 83% of its normal level.


> > Scientists need to learn more about immune response to food.


> > But for now it may help to FEED A COLD AND STARVE A FEVER.


> > JackD

Based on the preceding I guess you can figure why a veggie diet with no
dairy products would help a MSer feel better. It does not cure the disease
but does eliminate something that could exacerbate the condition.


I do not feel that such a drastic diet is necessary. I eat lean meat about
twice a week and because it is a good source of protein and other things.
The most difficult thing to identify is the hidden saturated fats in
a lot of processed foods.

Jack, thanks for posting everything here, had seen it all over on "Refugees" but had forgotten where it was.

I am going to print out some or all for my neuro. He already uses Omega 3s (EPA/DHA) for treatment of some Interferon related depression, but at lower mg levels. I suspect he'll be upping some doses.

Thanks.