90 replies to this topic

[Anthony_Loera]

Taken Resveratrol since October 2006 (2 grams a day), no joint problems here either.

A

[krillin]

Here's another theory. (Or maybe just an extension of the glutamate theory, since glutamate increases nitric oxide.)

Resveratrol increases iNOS activity, and nitric oxide is likely part of Cipro's tendinitis mechanism.

J Cardiovasc Pharmacol. 2007 Jul;50(1):83-93.
Resveratrol inhibits rat aortic vascular smooth muscle cell proliferation via estrogen receptor dependent nitric oxide production.
Ekshyyan VP, Hebert VY, Khandelwal A, Dugas TR.
Department of Pharmacology, Toxicology & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.

Vascular smooth muscle cell (VSMC) proliferation is pivotal in the progression of hypertension, atherosclerosis, and restenosis. Resveratrol is a grape polyphenol that is implicated as an important contributor to red wine's vascular protective effects. Its antimitogenic action on VSMC is attributed to an array of pleiotropic effects, including modulation of the estrogen receptor (ER). To elucidate the mechanisms underlying resveratrol-mediated ER modulation and its inhibition of VSMC proliferation, we treated VSMC with resveratrol with or without the ER antagonist ICI 182,780 and measured cell proliferation and nitric oxide (NO) production. Resveratrol dose-dependently decreased VSMC DNA synthesis, with a half maximal inhibitory concentration (IC50) of 3.73+/-0.57 microM, and dramatically slowed cell growth, but did not induce VSMC apoptosis. Resveratrol-mediated decrease in proliferation was reversed by cotreatment with ICI 182,780, and resveratrol effectively competed with 17beta-estradiol for binding to the ER, exhibiting an IC50 of 8.92+/-0.14 microM. Resveratrol induced a sustained increase in ER-dependent NO production. Further, resveratrol-mediated decrease in VSMC proliferation was blunted by cotreatment with the general nitric oxide synthase (NOS) inhibitor N5-(1-Iminomethyl)-L-ornithine, dihydrochloride or with the inducible NOS (iNOS)-selective inhibitor S,S'-1,4-phenylene-bis (1,2-ethanediyl)bis-isothiourea, dihydrobromide, but not with the neuronal NOS-selective inhibitor 7-nitroindazole. Though resveratrol did not alter iNOS protein levels, it dose-dependently increased levels of iNOS activity, of the iNOS cofactor tetrahydrobiopterin (BH4), and of guanosine triphosphate cyclohydrolase I protein, the rate-limiting enzyme in BH4 biosynthesis. In addition, all of these effects were abolished by cotreatment with ICI 182,780. Thus, the antimitogenic effects of resveratrol on VSMC may be mediated by an ER-induced increase in iNOS activity.

PMID: 17666920

Resveratrol is also a GABAc antagonist, but I'm not sure if that would have an effect.

[krillin]

Sheesh. I found yet another possibility. Interfering with topoisomerase can hurt tendons. Cipro, resveratrol, and a bunch of other phytochemicals inhibit topoisomerase.

Hum Immunol. 1994 Jun;40(2):101-10.
Severe systemic sclerosis with anti-topoisomerase I antibodies is associated with an HLA-DRw11 allele.
Morel PA, Chang HJ, Wilson JW, Conte C, Saidman SL, Bray JD, Tweardy DJ, Medsger TA Jr.
Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, PA.

SSc is an autoimmune connective tissue disease in which strong HLA associations have not been described. Anti-topo I antibodies are recognized, in general, in SSc patients with diffuse cutaneous involvement, whereas anti-ACAs are found in individuals with limited cutaneous involvement. We studied 95 Caucasian SSc patients, 44 with anti-topo I antibodies and 51 with neither anti-topo I nor ACA, for HLA-DR associations by using DNA typing techniques. We analyzed 181 normal Caucasian individuals in the same fashion. A significant association was observed in the anti-topo-I-positive patients with DRw11 (p = 1.7 x 10(-6), RR 4.2). The distribution of DRw11 alleles in these patients was significantly different from that observed in controls and could be accounted for by an increase in the frequency of the DRB1*1104 allele (p = 1.2 x 10(-9), RR 9.5). The DRw11 alleles were also associated with SSc with more tendon friction rubs (p = 0.006), which is a marker of more severe disease. In addition, a strong association was observed with anti-topo I antibodies and a particular sequence (aa 71-77) of the DQB1 chain (p = 0.02, RR 2.2). HLA associations in the case of SSc patients with anti-topo I antibodies are complex and involve at least two genes: HLA-DRw11, which appears to play a major role in determining the severity of the disease, and a DQ sequence, which associates with the development of the anti-topo I antibodies.

PMID: 7928439

J Agric Food Chem. 2006 Mar 22;54(6):2083-7.
Catalytic inhibition of human DNA topoisomerase II by interactions of grape cell culture polyphenols.
Jo JY, Gonzalez de Mejia E, Lila MA.
Department of Natural Resources and Environmental Sciences, University of Illinois at Urbana-Champaign, 1201 South Dorner Drive, Urbana, Illinois 61801, USA.

Previously, we isolated mixed polyphenolic fractions on a toyopearl matrix (TP-2 to TP-6) from grape cell cultures that were highly potent catalytic inhibitors in a human DNA topoisomerase II assay for cancer chemoprevention. The objectives of this study were to evaluate the potency of, and potential interactions between, individual fractions and some of the purified bioactive polyphenols that comprise these fractions on human DNA topoisomerase II catalytic activity. Treatments that combined anthocyanin-rich fractions (TP-2; 0.5 or 2.0 microg of dried material/mL), fractions containing catechins, procyanidin dimers, and flavanones (TP-4; 0.25 microg of dried material/mL), and/or fractions enriched with procyanidin oligomers and polymers (TP-6; 0.15 or 0.5 microg of dried material/mL) showed additive effects toward catalytic inhibition of the enzyme. Epicatechin gallate (IC50 = 0.029 microM), myricetin (0.39 microM), procyanidin B2 (PB2, 4.5 microM), and resveratrol (65.7 microM), constituents of the most bioactive mixed fraction from grape cell culture (TP-4), each individually provided potent catalytic inhibition of topoisomerase II. In addition, potentiating interactions between the PB2 and the other polyphenolic constituents mentioned above and between myricetin and resveratrol were clearly demonstrated. A synergistic interaction between myricetin and resveratrol was also confirmed with isobolographic analysis at a molar ratio of 1:70.

PMID: 16536579

Mutagenesis. 2006 Sep;21(5):321-5.
Topoisomerase II inhibition and high yield of endoreduplication induced by the flavonoids luteolin and quercetin.
Cantero G, Campanella C, Mateos S, Cortés F.
Department of Cell Biology, Faculty of Biology, University of Seville Seville, Spain.

Luteolin and quercetin are widely distributed plant flavonoids that possess a variety of chemical and biological activities, including free-radical scavenging and antioxidant activity. Recently, both flavonoids have been reported to inhibit DNA topoisomerases I and II (topo I and topo II), a property that, together with their ability to induce DNA and chromosome damage, has made them candidate anticancer compounds. In the present study, we confirmed that both compounds are topo II inhibitors by conducting a comparative study of their effect on topo II activity from Chinese hamster ovary AA8 cells. Because interference with the function of topo II to resolve DNA entanglement at the end of replication results in chromosome malsegregation at mitosis, we investigated whether luteolin and quercetin are effective in inducing endoreduplication in AA8 cells. Concentrations of luteolin and quercetin that inhibited topo II catalytic activity resulted in extraordinarily high yields of metaphases showing diplochromosomes. Given the established relationship of polyploidy with tumor development via aneuploidy and genetic instability, these results question the usefulness of luteolin and quercetin in cancer therapy.

PMID: 16950806

[niner]

Sheesh. I found yet another possibility. Interfering with topoisomerase can hurt tendons. Cipro, resveratrol, and a bunch of other phytochemicals inhibit topoisomerase.

Yikes.

>Severe systemic sclerosis with anti-topoisomerase I antibodies is associated with an HLA-DRw11 allele.

Well, this is with antibodies as opposed to relatively mild inhibitors, so that's pretty good. Do we have evidence that resveratrol or anything else inhibits topo I, as opposed to topo II?

>Catalytic inhibition of human DNA topoisomerase II by interactions of grape cell culture polyphenols.
>Epicatechin gallate (IC50 = 0.029 microM), myricetin (0.39 microM), procyanidin B2 (PB2, 4.5 microM),
>and resveratrol (65.7 microM)

This is not much of a worry, since we'll never see 66uM in resveratrol. Maybe we should worry more about ECG?

>Topoisomerase II inhibition and high yield of endoreduplication induced by the flavonoids luteolin and quercetin.

Potentially scary, but they didn't say what the IC50s were. Humans get a lot of quercetin in the diet, but maybe that's one of the reasons that we have such efficient phase II metabolism...

[krillin]

>Topoisomerase II inhibition and high yield of endoreduplication induced by the flavonoids luteolin and quercetin.

Potentially scary, but they didn't say what the IC50s were. Humans get a lot of quercetin in the diet, but maybe that's one of the reasons that we have such efficient phase II metabolism...

The free full text says they noticed effects at 30 microM and above. They didn't test anything lower.

Both luteolin and quercetin inhibit topo I and II.

Biochem J. 2002 Sep 1;366(Pt 2):653-61.
Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I.
Chowdhury AR, Sharma S, Mandal S, Goswami A, Mukhopadhyay S, Majumder HK.
Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India.

Luteolin, a naturally occurring flavonoid, is abundant in our daily dietary intake. It exhibits a wide spectrum of pharmacological properties, but little is known about its biochemical targets other than the fact that it induces topoisomerase II-mediated apoptosis. In the present study, we show that luteolin completely inhibits the catalytic activity of eukaryotic DNA topoisomerase I at a concentration of 40 microM, with an IC50 of 5 microM. Preincubation of enzyme with luteolin before adding a DNA substrate increases the inhibition of the catalytic activity (IC50=0.66 microM). Treatment of DNA with luteolin before addition of topoisomerase I reduces this inhibitory effect. Subsequent fluorescence tests show that luteolin not only interacts directly with the enzyme but also with the substrate DNA, and intercalates at a very high concentration (>250 microM) without binding to the minor groove. Direct interaction between luteolin and DNA does not affect the assembly of the enzyme-DNA complex, as evident from the electrophoretic mobility-shift assays. Here we show that the inhibition of topoisomerase I by luteolin is due to the stabilization of topoisomerase-I DNA-cleavable complexes. Hence, luteolin is similar to camptothecin, a class I inhibitor, with respect to its ability to form the topoisomerase I-mediated 'cleavable complex'. But, unlike camptothecin, luteolin interacts with both free enzyme and substrate DNA. The inhibitory effect of luteolin is translated into concanavalin A-stimulated mouse splenocytes, with the compound inducing SDS-K+-precipitable DNA-topoisomerase complexes. This is the first report on luteolin as an inhibitor of the catalytic activity of topoisomerase I, and our results further support its therapeutic potential as a lead anti-cancer compound that poisons topoisomerases.

PMID: 12027807

J Biol Chem. 1996 Jan 26;271(4):2262-70.
Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I.
Boege F, Straub T, Kehr A, Boesenberg C, Christiansen K, Andersen A, Jakob F, Köhrle J.
Medizinische Poliklinik, University of Würzburg, Federal Republic of Germany.

Topoisomerases are involved in many aspects of DNA metabolism such as replication and transcription reactions. Camptothecins, which stabilize the covalent intermediate of topoisomerase I and DNA are effective, though toxic, drugs for cancer therapy. In this study, a new class of topoisomerase I inhibitors was identified, and their mode of action was characterized using recombinant human topoisomerase I preparations and human HL-60 leukemic cells. Quercetin and the related natural flavones, acacetin, apigenin, kaempferol, and morin, inhibit topoisomerase I-catalyzed DNA religation. In contrast to camptothecin, these compounds do not act directly on the catalytic intermediate and also do not interfere with DNA cleavage. However, formation of a ternary complex with topoisomerase I and DNA during the cleavage reaction inhibits the following DNA religation step. 3,3',4',7-Tetrahydroxy-substituted flavones stabilize the covalent topoisomerase I-DNA intermediate most efficiently. Enhanced formation of covalent topoisomerase I-DNA complexes was also demonstrated in human HL-60 cells. In contrast, synthetic 3,5'-dibromo- 4'-hydroxy-3-methylflavones bind selectively to topoisomerase I in its non-DNA-bound form and block the following DNA binding step. As a consequence, these synthetic flavonoids are capable of counteracting topoisomerase I-directed effects of camptothecin. Inhibition of DNA binding is obtained by voluminous hydrophobic substituents in 6-position of the flavone structure. Our data show that selective inhibitors of both half-reactions of topoisomerase I can be derived from the flavone structure.

PMID: 8567688

[alterego]

After a few month of not using resveratrol, I started another test with a 99% extract, about 1 to 1.5 grams a day.

I have a light form of rheumatoid arthritis (the autoimmune form).

During the third day, my joint problems increased dramatically. 2 days after stopping, everything went back to normal. It repeats every time I start taking the resveratrol again.
Unnecessary to say that I definitely stop taking it. If anyone has information about the use of resveratrol in a autoimmune context, let me know. I was not able to find anything yet.

A while back, i did a test with a 50% extract yielding 100mg resveratrol that did not have any effect at all, no differences in experience and blood value's.

[maxwatt]

After a few month of not using resveratrol, I started another test with a 99% extract, about 1 to 1.5 grams a day.

I have a light form of rheumatoid arthritis (the autoimmune form).

During the third day, my joint problems increased dramatically. 2 days after stopping, everything went back to normal. It repeats every time I start taking the resveratrol again.
Unnecessary to say that I definitely stop taking it. If anyone has information about the use of resveratrol in a autoimmune context, let me know. I was not able to find anything yet.

A while back, i did a test with a 50% extract yielding 100mg resveratrol that did not have any effect at all, no differences in experience and blood value's.

I find this strange. Reduction of tumor necrosis factor (TNF) and of nfKappa B reduces inflammation and symptoms of rheumatoid arthritis. Resveratrol inhibits both TNS and nfK-B. What you experiences is very similar to what I experienced when I combined luteolin with resveratrol; within 3 days, increase in pain int he affected joints (I've been diagnosed with osteoarthritis.) If you search on the web, you will find testimonials by people who claim resveratrol relieved their rheumatoid arthritis.

Possible explanations that come to mind:

-Coincidence. The pain had nothing to do with resveratrol, but was due to major flareups that coincided with your resveratrol dosing.
-What you have is not really resveratrol, but some other substance. One would have expected 1/5 the dose of resveratrol you had with the 50% extract to possibly have given some hint of this effect of increased pain.
- You may be taking sufficiently Quercetin with the resveratrol - possibly in the form of a citris juice -- to block the action of resveratrol, and perhaps increase TNF and nfK-B. Other foods might do this too.


-

[Hedgehog]

I'm thinking that a good proteolytic enzyme supplement may be the solution to supposed resveratrol induced joint pain...

Which one?

http://www.sigmaaldr...ic_Enzymes.html
http://en.wikipedia.org/wiki/Protease

A enzyme supplement will probably only help u digest food. You can't get foreign enzymes into your body. Otherwise if you eat an egg you would turn into an egg. If you some strong reason you do get a foreign enzyme into your body your immune system would attack it and degrade it rapidly.

[alterego]

After a few month of not using resveratrol, I started another test with a 99% extract, about 1 to 1.5 grams a day.

I have a light form of rheumatoid arthritis (the autoimmune form).

During the third day, my joint problems increased dramatically. 2 days after stopping, everything went back to normal. It repeats every time I start taking the resveratrol again.
Unnecessary to say that I definitely stop taking it. If anyone has information about the use of resveratrol in a autoimmune context, let me know. I was not able to find anything yet.

A while back, i did a test with a 50% extract yielding 100mg resveratrol that did not have any effect at all, no differences in experience and blood value's.

I find this strange. Reduction of tumor necrosis factor (TNF) and of nfKappa B reduces inflammation and symptoms of rheumatoid arthritis. Resveratrol inhibits both TNS and nfK-B. What you experiences is very similar to what I experienced when I combined luteolin with resveratrol; within 3 days, increase in pain int he affected joints (I've been diagnosed with osteoarthritis.) If you search on the web, you will find testimonials by people who claim resveratrol relieved their rheumatoid arthritis.

Possible explanations that come to mind:

-Coincidence. The pain had nothing to do with resveratrol, but was due to major flareups that coincided with your resveratrol dosing.
-What you have is not really resveratrol, but some other substance. One would have expected 1/5 the dose of resveratrol you had with the 50% extract to possibly have given some hint of this effect of increased pain.
- You may be taking sufficiently Quercetin with the resveratrol - possibly in the form of a citris juice -- to block the action of resveratrol, and perhaps increase TNF and nfK-B. Other foods might do this too.


-

Thanks for the heads up!

Well, I don't think it's coincidence, but I suspect interference with other components of my regimen. I do not take quercitine, but quite large amounts of silymarin. And MSM. Maybe I will do another test after washing out the silymarin. Maybe the MSM as well. There is a small amount of luteolin in my multi (2mg a day from 2 to 3 tablets LEF mix), but I did not take this with the res.
The C I take ( 5 grams a day) does contain the almost obligatory citrus flavonoids, so I will buy a version without it next week. And , oh, almost forgot, 2 of the 5 grams of C comes from C with diHydro quercitine.... I will skip that as well before starting the next experiment.

Other flavonoids I take are green tea, blueberry, pomegranate and cacao.....

I agree that the research (not in vivo in humans as far as I know) is very promising. That's why I don't want to dismiss the res to soon.

I trust the powder I bought from Anthony, at least, at a reasonable level.... That's probably not the culprit

Other suggestions are welcome!

[krillin]

A enzyme supplement will probably only help u digest food. You can't get foreign enzymes into your body. Otherwise if you eat an egg you would turn into an egg. If you some strong reason you do get a foreign enzyme into your body your immune system would attack it and degrade it rapidly.

Serrapeptase and nattokinase make it.

Acta Haematol. 1990;84(3):139-43.
Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase.
Sumi H, Hamada H, Nakanishi K, Hiratani H.
Department of Physiology, Miyazaki Medical College, Japan.

The existence of a potent fibrinolytic enzyme (nattokinase, NK) in the traditional fermented food called 'natto', was reported by us previously. It was confirmed that oral administration of NK (or natto) produced a mild and frequent enhancement of the fibrinolytic activity in the plasma, as indicated by the fibrinolytic parameters, and the production of tissue plasminogen activator. NK capsules were also administered orally to dogs with experimentally induced thrombosis, and lysis of the thrombi was observed by angiography. The results obtained suggest that NK represents a possible drug for use not only in the treatment of embolism but also in the prevention of the disease, since NK has a proven safety and can be massproduced.

PMID: 2123064

Respirology. 2003 Sep;8(3):316-20.
Effect of the proteolytic enzyme serrapeptase in patients with chronic airway disease.
Nakamura S, Hashimoto Y, Mikami M, Yamanaka E, Soma T, Hino M, Azuma A, Kudoh S.
Department of Respiratory Medicine, Tokyo Metropolitan Hiroo General Hospital, Japan. hb16104@alto.ocn.ne.jp

OBJECTIVES: The proteolytic enzyme serrapeptase (SER) is widely used in clinical practice in Japan. We investigated the effect of SER on sputum properties and symptoms in patients with chronic airway diseases. METHODS: This study was an open-labelled trial with a non-treatment control group. Patients were randomly assigned to oral treatment with (n = 15) and without (n = 14) SER 30 mg/day for 4 weeks. Patients collected sputum samples for about 4 h in the morning on the day the trial began and 4 weeks later. We measured the amount of sputum by weighing. Part of each sputum sample was weighed and then completely dried and reweighed. The percentage solid component, viscosity and elasticity of the sputum were measured. Mucociliary transportability index was measured using ciliated bovine trachea ex vivo. Sputum smears were also prepared to count sputum neutrophils. Patients' symptoms were assessed by a questionnaire that used a visual analogue scale. RESULTS: After 4 weeks of SER treatment, sputum weight in the morning, percentage solid component, viscosity and elasticity of sputum, sputum neutrophil count, frequency of coughing and frequency of expectoration significantly decreased. The mean mucociliary transportability index increased from 13.3 +/- 1.8 to 24.4 +/- 2.5 (P = 0.0103). CONCLUSIONS: SER may exert a beneficial effect on mucus clearance by reducing neutrophil numbers and altering the viscoelasticity of sputum in patients with chronic airway diseases.

PMID: 12911824

Biotechnol Appl Biochem. 1994 Aug;20 ( Pt 1):101-8.
Intestinal absorption of serrapeptase (TSP) in rats.
Moriya N, Nakata M, Nakamura M, Takaoka M, Iwasa S, Kato K, Kakinuma A.

Biotechnology Research Laboratories, Takeda Chemical Industries Ltd., Osaka, Japan.

A sensitive sandwich enzyme immunoassay (e.i.a.) for serrapeptase (TSP), an orally available anti-inflammatory proteinase, was established using affinity-purified anti-TSP rabbit IgG and its Fab' fragment conjugated with horseradish peroxidase as the first and the second antibodies respectively. TSP in the plasma was determined by the e.i.a. after its oral administration (100 mg/kg) to rats. The peak concentration was observed between 30 min and 2 h after administration. TSP in the plasma samples was trapped on a microtitre plate coated with the affinity-purified anti-TSP rabbit IgG, and the hydrolysis of a synthetic fluorogenic substrate, butoxycarbonyl-Glu(benzyloxy)-Ala-Arg-4-methylcoumaryl-7-amide, by the trapped TSP was fluorometrically measured (proteinase assay). The values obtained by the e.i.a. and those obtained by the proteinase assay correlated well for various plasma samples. These results indicate that orally administered TSP was absorbed from the intestinal tract and transferred into the circulation in an enzymically active form.

PMID: 7917060

Biol Pharm Bull. 1995 Sep;18(9):1194-6.
Transport of nattokinase across the rat intestinal tract.
Fujita M, Hong K, Ito Y, Misawa S, Takeuchi N, Kariya K, Nishimuro S.
Biotechnology Research Laboratories, JCR Pharmaceuticals Co., Ltd., Kobe, Japan.

Intraduodenal administration of nattokinase (NK) at a dose of 80 mg/kg, resulted in the degradation of fibrinogen in plasma suggesting transport of NK across the intestinal tract in normal rats. The action of NK on the cleavage of fibrinogen in the plasma from blood samples drawn at intervals after intraduodenal administration of the enzyme was investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis with an anti-fibrinogen gamma chain antibody. The 270 kDa fragment carrying antigenic sites for the binding of the anti-fibrinogen gamma chain antibody appeared within 0.5 h and was then degraded gradually to a 105 kDa fragment via a 200 kDa fragment. This suggests that fibrinogen was degraded to a 105 kDa fragment via several intermediates (270 and 200 kDa). In parallel with the degradation process, plasma recalcification times were remarkably prolonged NK was also detected in the plasma from blood samples drawn 3 and 5 h after administration of the enzyme by SDS-PAGE and Western blotting analysis with an anti-NK antibody. The results indicate that NK is absorbed from the rat intestinal tract and that NK cleaves fibrinogen in plasma after intraduodenal administration of the enzyme.

PMID: 8845803

[krillin]

If anyone has information about the use of resveratrol in a autoimmune context, let me know. I was not able to find anything yet.

J Proteome Res. 2005 Nov-Dec;4(6):2032-42.
Resetting the epigenetic histone code in the MRL-lpr/lpr mouse model of lupus by histone deacetylase inhibition.
Garcia BA, Busby SA, Shabanowitz J, Hunt DF, Mishra N.
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA.

The baseline level of gene expression varies between healthy controls and systemic lupus erythematosus (SLE) patients, and among SLE patients themselves. These variations may explain the different clinical manifestations and severity of disease observed in SLE. Epigenetic mechanisms, which involve DNA and histone modifications, are predictably associated with distinct transcriptional states. To understand the interplay between various histone modifications, including acetylation and methylation, and lupus disease, we performed differential expression histone modification analysis in splenocytes from the MRL-lpr/lpr mouse model of lupus. Using stable isotope labeling in combination with mass spectrometry, we found global site-specific hypermethylation (except H3 K4 methylation) and hypoacetylation in histone H3 and H4 MRL-lpr/lpr mice compared to control MRL/MPJ mice. Moreover, we have identified novel histone modifications such as H3 K18 methylation, H4 K31 methylation, and H4 K31 acetylation that are differentially expressed in MRL-lpr/lpr mice compared to controls. Finally, in vivo administration of the histone deacetylase inhibitor trichostatin A (TSA) corrected the site-specific hypoacetylation states on H3 and H4 in MRL-lpr/lpr mice with improvement of disease phenotype. Thus, this study is the first to establish the association between aberrant histone codes and pathogenesis of autoimmune disease SLE. These aberrant post-translational histone modifications can therefore be reset with histone deacetylase inhibition in vivo.

PMID: 16335948

J Biol Chem. 2003 Oct 31;278(44):43041-50.
Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression.
Senawong T, Peterson VJ, Avram D, Shepherd DM, Frye RA, Minucci S, Leid M.
Laboratory of Molecular Pharmacology, Department of Pharmaceutical Sciences, College of Pharmacy, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97331, USA.

Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting proteins 1 and 2 (CTIP1 and CTIP2) enhance transcriptional repression mediated by COUP-TF II and have been implicated in hematopoietic cell development and malignancies. CTIP1 and CTIP2 are also sequence-specific DNA-binding proteins that repress transcription through direct, COUP-TF-in-dependent binding to a GC-rich response element. CTIP1- and CTIP2-mediated transcriptional repression is insensitive to trichostatin A, an inhibitor of known class I and II histone deacetylases. However, chromatin immunoprecipitation assays revealed that expression of CTIP2 in mammalian cells resulted in deacetylation of histones H3 and/or H4 that were associated with the promoter region of a reporter gene. CTIP2-mediated transcriptional repression, as well as deacetylation of promoter-associated histones H3/H4 in CTIP2-transfected cells, was reversed by nicotinamide, an inhibitor of class III histone deacetylases such as the mammalian homologs of yeast Silent Information Regulator 2 (Sir2). The human homolog of yeast Sir2, SIRT1, was found to interact directly with CTIP2 and was recruited to the promoter template in a CTIP2-dependent manner. Moreover, SIRT1 enhanced the deacetylation of template-associated histones H3/H4 in CTIP2-transfected cells, and stimulated CTIP2-dependent transcriptional repression. Finally, endogenous SIRT1 and CTIP2 co-purified from Jurkat cell nuclear extracts in the context of a large (1-2 mDa) complex. These findings implicate SIRT1 as a histone H3/H4 deacetylase in mammalian cells and in transcriptional repression mediated by CTIP2.

PMID: 12930829

[maxwatt]

If anyone has information about the use of resveratrol in a autoimmune context, let me know. I was not able to find anything yet.

J Proteome Res. 2005 Nov-Dec;4(6):2032-42.
Resetting the epigenetic histone code in the MRL-lpr/lpr mouse model of lupus by histone deacetylase inhibition.
.....
PMID: 16335948

J Biol Chem. 2003 Oct 31;278(44):43041-50.
Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression.
Senawong T, Peterson VJ, Avram D, Shepherd DM, Frye RA, Minucci S, Leid M.
Laboratory of Molecular Pharmacology, Department of Pharmaceutical Sciences, College of Pharmacy, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97331, USA.

PMID: 12930829

These two studies Krillin turned up seem to indicate resveratrol may be contra-indicated for some autoimmune diseases, where overexpression of histone deacetylase is a problem; aggravating it with SirT1 expression is counter-productive.

For these conditions a Sirtuin antagonist is indicated. Quercetin may be one, and niacinamide is another. If alterego decides to try these supplements, perhaps you could let us know if they relieve rheumatoid arthritis symptoms? A quick Google shows both are used as treatments. Is it possible that they could correct the condition, then be discontinued?

[rhc124]

Isn't quercetin a very weak antagonist while niacinamide a strong antagonist?

[electric buddha]

This could very easily just be a coincidence, but about a month after starting to mix resveratrol powder(400mg) with lecithin I wound up with a sudden pain in my left hip joint down to my knee. I take an hour to hour and a half brisk walk five days a week, and have been on that schedule for about six years now without every having a problem. We had our medical insurance plan change go into effect at that exact moment, so I haven't been able to get an actual diagnosis thanks to being in transition limbo. But for whatever reason, it was almost impossible to get through the pain of walking on it without a cane for about two weeks.

Edited by electric buddha, 17 January 2008 - 07:47 PM.

[krillin]

This could very easily just be a coincidence, but about a month after starting to mix resveratrol powder(400mg) with lecithin I wound up with a sudden pain in my left hip joint down to my knee. I take an hour to hour and a half brisk walk five days a week, and have been on that schedule for about six years now without every having a problem. We had our medical insurance plan change go into effect at that exact moment, so I haven't been able to get an actual diagnosis thanks to being in transition limbo. But for whatever reason, it was almost impossible to get through the pain of walking on it without a cane for about two weeks.

Is it the IT band? If so, ice it and make sure that the heels on your shoes aren't worn out.

[rhc124]

Well it has been about two months since I started this thread and I wanted to give you an update. I am now taking about 2.2g of Resv per day. One gram of powder in the morning with two 300mg tablets (Revgenics 50%) and another two in the afternoon. For the past couple of weeks I have basically had no joint pain. I still feel kind of somthing in my right hip but it is not pain. I have read comments on this board about speculation that maybe resv was doing some kind of healing of the joints. Maybe it has been, I don't know, but for now I do not have any joint pain anymore. I have been on Resv above 1g for about 4 months now. It would be interesting to hear if anyone has seen their joint pain subside after a period or not.

Edited by rhc124, 02 February 2008 - 02:23 AM.

[smithx]

There are some problems with the idea of taking enzymes and thinking they'll do something in some part of the body besides the digestive tract.

First of all, enzymes are proteins, and proteins are not absorbed into the blood whole. Instead they are broken down (by proteolytic enzymes (!) in the small intestine) and only short polypeptides are absorbed into the blood.

So these enzymes had better do their work before they hit the small intestine, or they're gone.

A second problem with the idea of taking enzymes orally is that enzymes work due to their tertiary folding structure, and they usually are easily denatured into inactive forms by such things as intense changes in pH -- the HCl in the stomach, for instance.

So these enzymes had better either be made to work at the acid pH of the stomach, or they'd better do their work before even getting to the stomach.

What's really happening in almost every case where people swallow enzyme pills is that these enzymes are just being broken down and absorbed as any other protein source would be. But they're a lot more expensive than an equivalent quantity of, say, lobster.

[maxwatt]

Well it has been about two months since I started this thread and I wanted to give you an update. I am now taking about 2.2g of Resv per day. One gram of powder in the morning with two 300mg tablets (Revgenics 50%) and another two in the afternoon. For the past couple of weeks I have basically had no joint pain. I still feel kind of somthing in my right hip but it is not pain. I have read comments on this board about speculation that maybe resv was doing some kind of healing of the joints. Maybe it has been, I don't know, but for now I do not have any joint pain anymore. I have been on Resv above 1g for about 4 months now. It would be interesting to hear if anyone has seen their joint pain subside after a period or not.

It sounds like resveratrol was not the cause of joint pain in this case, and did not apparently interfere with the healing of what might have been a typcal over-use injury,

[rhc124]

It sounds like resveratrol was not the cause of joint pain in this case, and did not apparently interfere with the healing of what might have been a typcal over-use injury,

Maxwatt, where did you gather that it was some type of over-use injury. If I had such I would have put that in my initial post. There was no recent injury to my hips nor do I know of having ever injured them (Unfortunatly I currently do not exercise). The joint Pain in my hips kind of came out of nowhere. About every five years I do get pain in my left shoulder, which I think is from football 23 years ago. That flared up as well when I was having the hip pain. Also during this time I had very mild discomfort the the joints of my fingures.

I have spent several months trying to figure what was causing the joint pain. I take a lot of pills so it took awhile to make sure that is was the resveratrol. I can say that it was the only supplement that I take that the pain went away when I stopped taking it, and I tried that several times. Because I believe in REsveratrol I wanted to keep taking it and see what would happen. Well, as stated above, finally the joint pain started subsiding and has now mostly gone away.

Oddly, my left hip was the first to start hurting, almost to the point of not being able to walk. Then my right hip starting hurting but never to the level of the left. The left was the first to stop hurting and now I do not even feel a tingle. Got kind of a tingle in the right. Shoulder seems to be ok now and no problem in the fingures. Remember all this happened over about a 4 month period.

[maxwatt]

It sounds like resveratrol was not the cause of joint pain in this case, and did not apparently interfere with the healing of what might have been a typcal over-use injury,

Maxwatt, where did you gather that it was some type of over-use injury. If I had such I would have put that in my initial post. There was no recent injury to my hips nor do I know of having ever injured them

There were some posts from runners with tendon injuries, I may have confused these. Yours sounds like osteoarthritis. Why it would hurt before it got better I do not know; I think someone suggested that parts of the healing process can be painful.

Edited by Michael, 29 August 2009 - 04:01 PM.
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[sUper GeNius]

I've been having some odd joint pain over the last several weeks. I take about a gram a day of t-res.

I have a funny feeling in finger joints, not quite an ache, but not very intense either. Never had that before. I do crack my knuckles, but never ever had a problem. The other day I had a problem in both shoulders, but more in my right. It felt as though I had been doing lateral weight raises, and over did it one day. Like a slight strain or pull on top of the shoulder, in one small place. Thing is, I have been doing no physical activity at all.

[missminni]

I've been having some odd joint pain over the last several weeks. I take about a gram a day of t-res.

I have a funny feeling in finger joints, not quite an ache, but not very intense either. Never had that before. I do crack my knuckles, but never ever had a problem. The other day I had a problem in both shoulders, but more in my right. It felt as though I had been doing lateral weight raises, and over did it one day. Like a slight strain or pull on top of the shoulder, in one small place. Thing is, I have been doing no physical activity at all.

When I first started taking over a gram a day, my knees, which previously hurt when I would get up from a squat position, started to feel loose and as if they were going to come out of joint if I wasn't very careful how I walked. That lasted for a day. Very soon after I noticed that they no longer hurt when I squatted. I think there is an adjustment that is made by the body when first hi-dosing with res. I think you should take it easy the first few days you hi-dose and let your body adjust.

[krillin]

There are some problems with the idea of taking enzymes and thinking they'll do something in some part of the body besides the digestive tract.

Carefully reread post #41.

[alterego]

Regarding the joint pain:

I think the resveratrol, whether due to interactions with other supps or not, can have a detrimental effect for me and possibly for people with similar constitutions that are predisposed to rheumatoid arthritis. And maybe to other auto-immune issues as well. But it's very difficult to find research in this direction.

Look at it this way. Resveratrol apparently has a very broad range of effects on our biochemistry. Effects that enhance immunity and effects that reduce inflammation markers. Maybe for some reason, if you are predisposed like me, in combination with my gene constitution and food intake, the immune enhancing effect supersedes the inflammation reduction effect. Hence resulting in a nett negative effect of resveratrol. The effect of resveratrol is in my case very similar to the effects of specifically immune enhancing substances multiplied by a magnitude of 10 or so.

On the other hand, we just don't know.

[maxwatt]

Regarding the joint pain:

I think the resveratrol, whether due to interactions with other supps or not, can have a detrimental effect for me and possibly for people with similar constitutions that are predisposed to rheumatoid arthritis. And maybe to other auto-immune issues as well. But it's very difficult to find research in this direction.

Look at it this way. Resveratrol apparently has a very broad range of effects on our biochemistry. Effects that enhance immunity and effects that reduce inflammation markers. Maybe for some reason, if you are predisposed like me, in combination with my gene constitution and food intake, the immune enhancing effect supersedes the inflammation reduction effect. Hence resulting in a nett negative effect of resveratrol. The effect of resveratrol is in my case very similar to the effects of specifically immune enhancing substances multiplied by a magnitude of 10 or so.

On the other hand, we just don't know.

Posts 42 and 43 address this to a degree.
I believe if one has rheumatoid as opposed to osteoarthritis, self-testing with a high dose of resveratrol (over 800 mg) for as little as three days would indicate if it helps or aggravates; if it helps, joint pain and swelling will be reduced. If it aggravates the condition, joint pain and swelling will be noticeably worsened; in that case, stop resveratrol and switch to either quercetin or niacinamide, which will block Sirt1 and improve the situation. Doses and which of the latter to use are still a matter of speculation.

[alterego]

Regarding the joint pain:

I think the resveratrol, whether due to interactions with other supps or not, can have a detrimental effect for me and possibly for people with similar constitutions that are predisposed to rheumatoid arthritis. And maybe to other auto-immune issues as well. But it's very difficult to find research in this direction.

Look at it this way. Resveratrol apparently has a very broad range of effects on our biochemistry. Effects that enhance immunity and effects that reduce inflammation markers. Maybe for some reason, if you are predisposed like me, in combination with my gene constitution and food intake, the immune enhancing effect supersedes the inflammation reduction effect. Hence resulting in a nett negative effect of resveratrol. The effect of resveratrol is in my case very similar to the effects of specifically immune enhancing substances multiplied by a magnitude of 10 or so.

On the other hand, we just don't know.

Posts 42 and 43 address this to a degree.

It gave me another direction to explore indeed. But I highly doubt it is that simple and one-dimensional. I've been taking niacinamide for 2 weeks now and I can't say it gives a big improvement. Maybe it helps a bit on the long term, but certainly it's not as good as the res was bad. I took 250mg a day in one serving, but this suggests that 250mg would not be enough.

I believe if one has rheumatoid as opposed to osteoarthritis, self-testing with a high dose of resveratrol (over 800 mg) for as little as three days would indicate if it helps or aggravates; if it helps, joint pain and swelling will be reduced. If it aggravates the condition, joint pain and swelling will be noticeably worsened; in that case, stop resveratrol and switch to either quercetin or niacinamide, which will block Sirt1 and improve the situation. Doses and which of the latter to use are still a matter of speculation.

That would be good advice indeed.

[alterego]

A small update.

After my unpleasant experience with resveratrol I upped all the supps I already was taking against the joint issues to the level I was taking a few years ago.
My regimen regarding this mainly consists of
- MSM
- NAC
- Nettle leaf
- Glucosamine (several forms)
- 5-Loxin
- Nexrutine
- MSM
- Omega 3

But I must say that during this week my joint issues improved quite a bit, subjectively better then ever before.

So maybe the B3 (and possibly the link with sirtuins) plays a role in my auto-immune joint issues after all. Thanks for the suggestion!
I'll try to find out if it is the B3 indeed that causes the current improvements.

Furthermore, my individual position regarding resveratrol and (my) rheumatic experience with it has become one with great caution.

Edited by alterego, 09 February 2008 - 01:34 PM.

[alterego]

Another small update.

After becomming aware of this, I decided to up the niacinamide dose dramatically to 2 to 3 grams a day. The result has been a huge improvement in my rheumatic arthritis issues.

So, the question develops if this is due to a one dimensional relation with resveratrol, or if the situation is a bit more complex. The review linked above states that the increase of NAD is the main pathway of the actvity of niacinamide in reducing auto immune symtoms. So, the effect of niacinamide on sirtuins might be secondary or even non-existent (with regard to auto immune issues). To make the matter more complicated, niacin, as stated in this paper, has influence on the NAD pathway with the addition to it having effect on additional pathways. One of them being activation of the human sirtuins. This combination of effects is presented as being positive regarding auto immune issues. Specifically, one paragraph in this review describes the potential benefits of resveratrol.

Anyway, I'm still thinking that the use of resveratrol in auto immune context is one of grate caution. The recommendations made by maxwatt above look good in case you are sure that you have a condition of which the progression can be perceived easily, e.g. by following severity of pain level. In all other cases resveratrol might be a big gamble.

I think I will proceed as follows. First I will await my new blood-values to see if the niacinamide has an effect on that level as well. They will arrive next week. Then I will continue using just the niacinamide (with the other supplements I already mentioned) to await the blood-values after 2 or 3 months or so. I want to be reasonably sure of the correlation between the naicinamide and RA progression. After that, I'm planning to swap half of the niacinamide dose with niacine to see what happens then.

Any additional thoughts?

Edited by alterego, 20 July 2008 - 09:39 AM.

[maxwatt]

I'm still thinking that the use of resveratrol in auto immune context is one of grate caution. The recommendations made by maxwatt above look good in case you are sure that you have a condition of which the progression can be perceived easily [...]
Any additional thoughts?

EGCG http://www.scienceda...70429113444.htm

Beneficial in early trials against rheumatoid arthritis. Activates Sirt1 if sufficient anti-oxidants are present. (Vitamin C?) Achieves higher serum levels than resveratrol where conjugation (sulfonation, glucuronidation) is not a problem.

Edited by Michael, 29 August 2009 - 04:03 PM.
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[krillin]

Any additional thoughts?

HDAC inhibitors are another way of inducing IDO.

J Clin Invest. 2008 Jul 1;118(7):2562-2573.
Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice.
Reddy P, Sun Y, Toubai T, Duran-Struuck R, Clouthier SG, Weisiger E, Maeda Y, Tawara I, Krijanovski O, Gatza E, Liu C, Malter C, Mascagni P, Dinarello CA, Ferrara JL.
Department of Internal Medicine and Department of Pediatrics, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA. Department of Pathology, University of Florida, Gainesville, Florida, USA. ItalFarmaco S.p.A, Milan, Italy. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.

Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition-induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases.

PMID: 18568076

Mol Carcinog. 2006 Jun;45(6):443-6.
Dietary agents as histone deacetylase inhibitors.
Myzak MC, Ho E, Dashwood RH.
Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331-6512, USA.

In cancer cells, an imbalance often exists between histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities, and various drug companies are actively seeking competitive HDAC inhibitors for chemotherapeutic intervention. Cancer cells appear to be more sensitive than nontransformed cells to HDAC inhibitors, which disrupt the cell cycle and induce apoptosis via derepression of genes such as P21 and BAX. However, in the search for potent HDAC inhibitors with cancer therapeutic potential, a tendency exists to overlook or dismiss weak ligands that could prove effective in cancer prevention. Butyrate, diallyl disulfide (DADS), and sulforaphane (SFN) are three dietary agents that exhibit HDAC inhibitory activity in vitro and/or in vivo, and other such dietary agents probably will be discovered that affect HDAC activity. We make the distinction between 'pharmacologic' agents that potently derepress gene expression, during therapeutic intervention, and dietary HDAC inhibitors that, as weak ligands, might subtly regulate the expression of genes involved in cell growth and apoptosis. An important issue for future study is to determine the extent to which dietary HDAC inhibitors, by modulating genes such as p21 and Bax, enable normal, nontransformed cells to respond most effectively to external stimuli and toxic insults.

PMID: 16652377