REVERSE: Reversing Negatives and Counter-Reversing Positives (IBE-Sponsored)

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  1. Quote Originally Posted by Iron Lungz View Post
    Read his STOKED! log... it's a great read!
    Getting Your Anabolic Furnace STOKED! (Sponsored)
    And I can't (or won't) speak for Ike, but I believe it may in fact, be too early to compare the two. And plus, our Reverse is set up differently than STOKED! If you notice, it is more of a staple supplement compared to the latter.
    Thanks, Iron!

    Quote Originally Posted by Imeniaan View Post
    Ike ?? , as in Hurricane Ike or as in Tina Turner ?? Just kidding!

    Strategic,

    have you tried stoked? Which product has the better bioavailability and why, Stoked or Reverse. What product do you recommend, or is it too early to tell??

    Thanks.
    Imeniaan, I fully agree with Iron. REVERSE and STOKED! were designed with different objectives in mind, so a direct comparison may not be accurate. Both are excellent products.
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  2. Quote Originally Posted by strategicmove View Post
    Thanks, Iron!



    Imeniaan, I fully agree with Iron. REVERSE and STOKED! were designed with different objectives in mind, so a direct comparison may not be accurate. Both are excellent products.
    Agreed. STOKED is aimed at the testosterone boosting effects, with the bioavail enhancers you get a SIRT1 suppression. With Reverse, we are aiming for the SIRT1 expression, which is why we acytilated it. When you ingest Reverse, the acytilation causes hydrolysis, essentially making the ester a coat of armor, removed for pure unadulterated Resveratrol.

    Okay... I hope all that makes sense... I have 3 cups of Kava Kava in me... so things are a little fuzzy.

    Adams
    The Historic PES Legend
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  3. I was wondering if you're getting any lethargy shortly after dosing? I'm using four cap of Reverse before bed and have been getting awesome sleep with it. It cleared up my skin which was breaking out from Diesel Test Hardcore and seems to have balance my mood substantially.

  4. Quote Originally Posted by slow-mun View Post
    I was wondering if you're getting any lethargy shortly after dosing? I'm using four cap of Reverse before bed and have been getting awesome sleep with it. It cleared up my skin which was breaking out from Diesel Test Hardcore and seems to have balance my mood substantially.
    No, I have not experienced lethargy immediately post-REVERSE intake. I always make sure, though, I take a capsule last thing before bed daily. I usually add one tablet (1000mg) of a Vitamin -C supplement (actually a blend of 1000mg Vitamin C plus 10mg of Dihydroquercetin). I take this vitamin-c supplement with REVERSE, only because resveratrol helps recycle vitamin c (just like dihydroquercetin does).

    Is there any particular reason you take four capsules of REVERSE at once, and not split them into two servings?
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  5. October 17, 2008 - October 20, 2008
    Days 14 - 17


    Results:

    The past couple of days have seen a continuation of sustained feelings of well-being (this aspect may be due to resveratrol, similar to rhodiola rosea, beneficially impacting levels of serotonin, norepinephrine, and endogenous feel-good opioids such as beta-endorphins). Vasodilation/vascularity, physical and mental endurance, as well as excellent motor function remain at high levels. Furthermore, the enhanced immune-system strength and immune response have played an important role in keeping me symptom-free in the current flu-season. REVERSE has been quite impressive so far, and I am enjoying every single day on it!
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  6. You should consider teaching as a job strag

  7. Quote Originally Posted by strategicmove View Post
    No, I have not experienced lethargy immediately post-REVERSE intake. I always make sure, though, I take a capsule last thing before bed daily. I usually add one tablet (1000mg) of a Vitamin -C supplement (actually a blend of 1000mg Vitamin C plus 10mg of Dihydroquercetin). I take this vitamin-c supplement with REVERSE, only because resveratrol helps recycle vitamin c (just like dihydroquercetin does).

    Is there any particular reason you take four capsules of REVERSE at once, and not split them into two servings?
    I'm taking resveratrol twice a day already. Reverse is my bedtime dose and four caps seems to make me pretty lethargic. Truth be told, my decent results didn't begin until I added Reverse. The other resveratrol product has been used for about two months with little results.

  8. Quote Originally Posted by Steveoph View Post
    You should consider teaching as a job strag
    I doubt that would be a strategic move!
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  9. Quote Originally Posted by slow-mun View Post
    I'm taking resveratrol twice a day already. Reverse is my bedtime dose and four caps seems to make me pretty lethargic. Truth be told, my decent results didn't begin until I added Reverse. The other resveratrol product has been used for about two months with little results.
    REVERSE is it!
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  10. Thank you sir for the excellent info! I just ordered my first bottle from NP. I'm going to run it the same way for 25 days.
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  11. Quote Originally Posted by eros62d View Post
    Thank you sir for the excellent info! I just ordered my first bottle from NP. I'm going to run it the same way for 25 days.
    That's good to hear. Keep us updated on your progress!

  12. Quote Originally Posted by eros62d View Post
    Thank you sir for the excellent info! I just ordered my first bottle from NP. I'm going to run it the same way for 25 days.
    Same here, put an order a few days ago, if Strategic thinks Reverse is than there's no further debate about it

  13. I think I'm gonna give this a try also in 2 months or so when I run out of my current supplies. Thinking of stacking this with a GH booster (x-dream?) and some RPN products for a "rejuvenation stack" to run for 3 months or so..

  14. Quote Originally Posted by eros62d View Post
    Thank you sir for the excellent info! I just ordered my first bottle from NP. I'm going to run it the same way for 25 days.
    Awesome! In fact, you can stay on one capsule a day maintenance afterwards.
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  15. Quote Originally Posted by dragonfly View Post
    Same here, put an order a few days ago, if Strategic thinks Reverse is than there's no further debate about it
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  16. wow, how have I missed this for so long?!?!?

    Delsolrob reporting to duty...I'm getting caught up now:-)

  17. Quote Originally Posted by Steveoph View Post
    You should consider teaching as a job strag
    x 2...I truly enjoy reading Ikes posts!

  18. Sorry i'm about a year late
    Millennium Sport Technologies Representative/Sponsored Athlete
    www.millenniumsport.net

  19. Quote Originally Posted by CTDeuce View Post
    Sorry i'm about a year late
    Not quite! Yet, better late than ...! Welcome, bud!
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  20. Quote Originally Posted by delsolrob View Post
    wow, how have I missed this for so long?!?!?...
    I understood the thread's stealth mode was deactivated only today! Appreciate your company, bud!
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  21. Quote Originally Posted by 1HP View Post
    ...Thinking of stacking this with a GH booster (x-dream?) and some RPN products for a "rejuvenation stack" to run for 3 months or so..
    Should be a nice stack!
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  22. Fantastic detail Strat.

    I love to read your posts/reviews (though I only understand about 25% of it )


    Trust in the LORD with all your heart, And lean not on your own understanding; In all your ways acknowledge Him, And He shall direct your paths . Proverbs 3:5-6

  23. Quote Originally Posted by mmowry;
    Fantastic detail Strat.
    Thanks!

    Quote Originally Posted by mmowry;
    I love to read your posts/reviews (though I only understand about 25% of it )
    I actually fare only slightly better! I understand about 33.3% of them! Thanks for keeping us company!
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  24. Yo Strategie! Beautiful and well written log so far bud! If anyone could give this product the log it deserves, it is you. I love how you can explain effects, and then explain the reason for said effects. Will be a followin' closely.

  25. Out of curiosity Ike, do you usually get sick during the flu season? And at other time during the year. I'm one of those people that almost never gets sick; if I start feeling a tingle at the back of my throat I just get 10hours of sleep, load up on vitamin C and it fails to get me.

  26. Quote Originally Posted by Steveoph;
    Out of curiosity Ike, do you usually get sick during the flu season? And at other time during the year....
    Not frequently. I generally try to take a combination of adaptogens and vitamin c year round.
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  27. October 21, 2008 - October 26, 2008
    Days 18 - 23


    Results:

    A full six days of REVERSE update, and only two days to go!
    Daily updates did not make sense here, because the product, by its nature is designed to work on a cumulative-time basis. As in the earlier reports, the (short-term) benefits that I have noticed from the use of REVERSE appear to coalesce around its anti-inflammatory action (probably via its function as a specific cyclooxygenase-1 (COX-1) inhibitor. COX is the enzyme that triggers the conversion of arachidonic acid into prostaglandins, pro-inflammatory compounds that compromise the immune system and may initiate dangerous cell multiplication. For those interested in the details, resveratrol also demonstrates significant anti-cancer properties by stifling the activation of the COX-2 enzyme); its propensity to enhance vasodilation (likely via cAMP modulation and reduced propensity for platelet aggregation, with its positive impact on lipid peroxidation); its ability to improve endurance (via enhanced cardiovascular function and mitochondrial support); its positive action of mental and cognitive performance; its positive impact on skin tone, elasticity, and optics; its subtle-but-noticeable positive impact on visual perception; as well as its beneficial result on immune response.

    The results appear to improve over time, implying a need to use the product short-to-long-term. I still have another two days on REVERSE, and would provide a final review during the next update.


    For those interested in further details and studies, resveratrol appears (in cell cultures) to act as an estrogen agonist in certain conditions, and as an estrogen antagonist in certain other conditions:


    Endocrinology. 2000 Oct;141(10):3657-67.

    Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta.

    Bowers JL, Tyulmenkov VV, Jernigan SC, Klinge CM.

    Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Kentucky 40292, USA.

    Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis. At least some of these activities are mediated through the interaction of phytoestrogens with estrogen receptors alpha and beta (ERalpha and ERbeta). Resveratrol, trans-3,5,4'-trihydroxystilbene, is a phytoestrogen in grapes that is present in red wine. Resveratrol was shown to bind ER in cytosolic extracts from MCF-7 and rat uteri. However, the contribution of ERalpha vs. ERbeta in this binding is unknown. Here we report that resveratrol binds ERbeta and ERalpha with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2). Thus, resveratrol differs from other phytoestrogens that bind ERbeta with higher affinity than ERalpha. Resveratrol acts as an estrogen agonist and stimulates ERE-driven reporter gene activity in CHO-K1 cells expressing either ERalpha or ERbeta. The estrogen agonist activity of resveratrol depends on the ERE sequence and the type of ER. Resveratrol-liganded ERbeta has higher transcriptional activity than E2-liganded ERbeta at a single palindromic ERE. This indicates that those tissues that uniquely express ERbeta or that express higher levels of ERbeta than ERalpha may be more sensitive to resveratrol's estrogen agonist activity. For the natural, imperfect EREs from the human c-fos, pS2, and progesterone receptor (PR) genes, resveratrol shows activity comparable to that induced by E2. We report that resveratrol exhibits E2 antagonist activity for ERalpha with select EREs. In contrast, resveratrol shows no E2 antagonist activity with ERbeta. These data indicate that resveratrol differentially affects the transcriptional activity of ERalpha and ERbeta in an ERE sequence-dependent manner.


    Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):14138-43.

    Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor.

    Gehm BD, McAndrews JM, Chien PY, Jameson JL.

    Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611, USA.

    The phytochemical resveratrol, which is found in grapes and wine, has been reported to have a variety of anti-inflammatory, anti-platelet, and anti-carcinogenic effects. Based on its structural similarity to diethylstilbestrol, a synthetic estrogen, we examined whether resveratrol might be a phytoestrogen. At concentrations (approximately 3-10 microM) comparable to those required for its other biological effects, resveratrol inhibited the binding of labeled estradiol to the estrogen receptor and it activated transcription of estrogen-responsive reporter genes transfected into human breast cancer cells. This transcriptional activation was estrogen receptor-dependent, required an estrogen response element in the reporter gene, and was inhibited by specific estrogen antagonists. In some cell types (e.g., MCF-7 cells), resveratrol functioned as a superagonist (i.e., produced a greater maximal transcriptional response than estradiol) whereas in others it produced activation equal to or less than that of estradiol. Resveratrol also increased the expression of native estrogen-regulated genes, and it stimulated the proliferation of estrogen-dependent T47D breast cancer cells. We conclude that resveratrol is a phytoestrogen and that it exhibits variable degrees of estrogen receptor agonism in different test systems. The estrogenic actions of resveratrol broaden the spectrum of its biological actions and may be relevant to the reported cardiovascular benefits of drinking wine.

    Cancer Res. 2001 Oct 15;61(20):7456-63.

    Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models.

    Bhat KP, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM.

    Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, USA.

    Trans-3,4',5-trihydroxystilbene (resveratrol), a phytoalexin present in grapes and grape products such as wine, has been identified as a chemopreventive agent. Recent studies performed with MCF-7 human breast cancer cells have demonstrated superestrogenic effects with resveratrol. In contrast, studies performed using estrogen receptor-transfected cell lines have shown that resveratrol acts as a mixed agonist/antagonist. The major objective of this study was to characterize the estrogen-modulatory effects of resveratrol in a variety of in vitro and in vivo mammary models. Thus, the effect of resveratrol alone and in combination with 17beta-estradiol (E2) was assessed with MCF-7, T47D, LY2, and S30 mammary cancer cell lines. With cells transfected with reporter gene systems, the activation of estrogen response element-luciferase was studied, and using Western blot analysis, the expression of E2-responsive progesterone receptor (PR) and presnelin 2 protein was monitored. Furthermore, the effect of resveratrol on formation of preneoplastic lesions (induced by 7,12-dimethylbenz(a)anthracene) and PR expression (with or without E2) was evaluated with mammary glands of BALB/c mice placed in organ culture. Finally, the effect of p.o. administered resveratrol on N-methyl-N-nitrosourea-induced mammary tumors was studied in female Sprague Dawley rats. As a result, in transient transfection studies with MCF-7 cells, resveratrol showed a weak estrogenic response, but when resveratrol was combined with E2 (1 nM), a clear dose-dependent antagonism was observed. Similar mixed estrogenic/antiestrogenic effects were noted with S30 cells, whereas resveratrol functioned as a pure estrogen antagonist with T47D and LY2 cells. Furthermore, in MCF-7 cells, resveratrol induced PR protein expression, but when resveratrol was combined with E2, expression of PR was suppressed. With T47D cells, resveratrol significantly down-regulated steady-state and E2-induced protein levels of PR. With LY2 and S30 cells, resveratrol down-regulated presnelin 2 protein expression. Using the mouse mammary organ culture model, resveratrol induced PR when administered alone, but expression was suppressed in the presence of E2 (1 nM). Furthermore, resveratrol inhibited the formation of estrogen-dependent preneoplastic ductal lesions induced by 7,12-dimethylbenz(a)anthracene in these mammary glands (IC50 = 3.2 microM) and reduced N-methyl-N-nitrosourea-induced mammary tumorigenesis when administered to female Sprague Dawley rats by gavage. Therefore, in the absence of E2, resveratrol exerts mixed estrogen agonist/antagonist activities in some mammary cancer cell lines, but in the presence of E2, resveratrol functions as an antiestrogen. In rodent models, carcinogen-induced preneoplastic lesions and mammary tumors are inhibited. These data suggest that resveratrol may have beneficial effects if used as a chemopreventive agent for breast cancer.

    J Cell Physiol
    . 1999 Jun;179(3):297-304.

    Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells.

    Lu R, Serrero G.

    Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore 21201, USA.

    Resveratrol is a natural phytoalexin compound found in grapes and other food products. In this study, the effect of resveratrol on the growth of human breast cancer cells was examined. Results show that resveratrol inhibits the growth of estrogen receptor(ER)-positive MCF-7 cells in a dose-dependent fashion. Detailed studies with MCF-7 cells demonstrate that resveratrol antagonized the growth-promoting effect of 17-beta-estradiol (E2) in a dose-dependent fashion at both the cellular (cell growth) and the molecular (gene activation) levels. At 5 x 10(-6) M, resveratrol abolished the growth-stimulatory effect mediated by concentrations of E2 up to 10(-9) M. The antiestrogenic effect of resveratrol could be observed at a concentration of 10(-6) M and above. The antiestrogenic effect of resveratrol was also demonstrated at the molecular level. Resveratrol in a dose-dependent fashion antagonized the stimulation by E2 of progesterone receptor gene expression in MCF-7 cells. Moreover, expression of transforming growth factor-alpha and insulin-like growth factor I receptor mRNA was inhibited while the expression of transforming growth factor beta2 mRNA was significantly elevated in MCF-7 cells cultivated in the presence of resveratrol (10(-5) M). In summary, our results show that resveratrol, a partial ER agonist itself, acts as an ER antagonist in the presence of estrogen leading to inhibition of human breast cancer cells.
    In terms of the anti-inflammatory effects of resveratrol:



    J Agric Food Chem. 1999 Dec;47(12):4842-6.

    Resveratrol is a potent inhibitor of the dioxygenase activity of lipoxygenase.

    Pinto MC, García-Barrado JA, Macías P.

    Departamento Bioquímica y Biología Molecular, Facultad Ciencias, Universidad de Extremadura, 06080 Badajoz, Spain.

    Resveratrol is a naturally occurring phytoalexin, present in grapes and other food products, with important antioxidant properties. Although still under debate, it is generally assumed that resveratrol has protective effects against heart diseases and probably tumor development. Lipoxygenase is a dioxygenase with peroxidase activity involved in the synthesis of mediators in inflammatory, atherosclerotic, and carcinogenic processes. Lipoxygenase activity is also involved in the generation of flavors and aromas in foods from animal or vegetal sources. The results presented here show that resveratrol was a potent inhibitor of the dioxygenase activity of lipoxygenase, with an IC(50) = 13 microM. Simultaneously, resveratrol was oxidized by the peroxidase activity of lipoxygenase with a V(max) = 0.28 microM min(-1) and a k(M) = 16.6 microM. Furthermore, oxidized resveratrol was as efficient a lipoxygenase inhibitor as in its reduced form. From the data obtained it can be concluded that both resveratrol and its oxidized form can act as inhibitors of the dioxygenase activity of lipoxygenase. In contrast, the hydroperoxidase activity of lipoxygenase was not inhibited by resveratrol. These results suggest that resveratrol may be used as an antioxidant food additive and as a pharmacological agent to prevent the generation of eicosanoids involved in pathological processes.
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  28. J. Biol. Chem., Vol. 279, Issue 21, 22727-22737, May 21, 2004
    Resveratrol is a Peroxidase-mediated Inactivator of COX-1 but Not COX-2
    A MECHANISTIC APPROACH TO THE DESIGN OF COX-1 SELECTIVE AGENTS*

    Lawrence M. Szewczuk , Luca Forti, Lucia A. Stivala||, and Trevor M. Penning**
    From the Department of Biochemistry & Biophysics and the **Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the Dipartimento di Chimica, Universitá di Modena e Reggio Emilia, 41100 Modena, Italy, and the ||Dipartimento di Medicina Sperimentale, sez. Patologia Generale, Universitá di Pavia Piazza Botta, 10-27100 Pavia, Italy
    Received for publication, December 30, 2003 , and in revised form, March 12, 2004.
    Abstract

    Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a phytoalexin found in grapes that has anti-inflammatory, cardiovascular protective, and cancer chemopreventive properties. It has been shown to target prostaglandin H2 synthase (COX)-1 and COX-2, which catalyze the first committed step in the synthesis of prostaglandins via sequential cyclooxygenase and peroxidase reactions. Resveratrol discriminates between both COX isoforms. It is a potent inhibitor of both catalytic activities of COX-1, the desired drug target for the prevention of cardiovascular disease, but only a weak inhibitor of the peroxidase activity of COX-2, the isoform target for nonsteroidal anti-inflammatory drugs. We have investigated the unique inhibitory properties of resveratrol. We find that it is a potent peroxidase-mediated mechanism-based inactivator of COX-1 only (kinact = 0.069 ± 0.004 s-1, Ki(inact) = 1.52 ± 0.15 µM), with a calculated partition ratio of 22. Inactivation of COX-1 was time- and concentration-dependent, it had an absolute requirement for a peroxide substrate, and it was accompanied by a concomitant oxidation of resveratrol. Resveratrol-inactivated COX-1 was devoid of both the cyclooxygenase and peroxidase activities, neither of which could be restored upon gel-filtration chromatography. Inactivation of COX-1 by [3H]resveratrol was not accompanied by stable covalent modification as evident by both SDS-PAGE and reverse phase-high performance liquid chromatography analysis. Structure activity relationships on methoxy-resveratrol analogs showed that the m-hydroquinone moiety was essential for irreversible inactivation of COX-1. We propose that resveratrol inactivates COX-1 by a "hit-and-run" mechanism, and offers a basis for the design of selective COX-1 inactivators that work through a mechanism-based event at the peroxidase active site.



    Titre du document / Document title
    Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test
    Auteur(s) / Author(s)
    TORRES-LOPEZ Jorge E. ; ORTIZ Mario I. ; CASTANEDA-HERNANDEZ Gilberto ; ALONSO-LOPEZ Rosario ; ASOMOZA-ESPINOSA Raquel ; GRANADOS-SOTO Vinicio ;
    Résumé / Abstract
    The peripheral antinociceptive effect of the selective COX-2 inhibitor celecoxib in the formalin-induced inflammatory pain was compared with that of resveratrol (COX-1 inhibitor) and diclofenac (non-selective COX inhibitor). Rats received local pretreatment with saline, celecoxib, diclofenac or resveratrol followed by 50 μl of either 1% or 5% formalin. Peripheral administration of celecoxib did not produce antinociception at either formalin concentration. In contrast, diclofenac and resveratrol produced a dose-dependent antinociceptive effect in the second phase of both 1% and 5% formalin test. The peripheral antinociception produced by diclofenac or resveratrol was due to a local action, as drug administration in the contralateral paw was ineffective. Results indicate that the selective COX-2 inhibitor celecoxib does not produce peripheral antinociception in formalin-induced inflammatory pain. In contrast, selective COX-1 and non-selective COX inhibitors (resveratrol and diclofenac, respectively) are effective drugs in this model of pain.
    Revue / Journal Title
    Life sciences ISSN 0024-3205 CODEN LIFSAK
    Source / Source
    2002, vol. 70, no14, pp. 1669-1676 [8 page(s) (article)]
    Langue / Language
    Anglais
    Editeur / Publisher
    Elsevier, Amsterdam, PAYS-BAS (1973) (Revue)
    Localisation / Location
    INIST-CNRS, Cote INIST : 10194, 35400010072495.0070


    Selective mechanism-based inactivation of COX-1 by M-hydroquinones
    Lawrence M Szewczuk, University of Pennsylvania

    Date: 2004

    Abstract
    Prostaglandin H2 synthase (COX) catalyzes the bis -dioxygenation of arachidonic acid (AA) to yield prostaglandin (PG) G2 (c ycloox ygenase reaction) followed by the peroxidative cleavage of PGG2 to yield PGH2 (peroxidase reaction). These sequential reactions represent the first committed steps in the biosynthesis of all prostanoids, which are known mediators of platelet aggregation, vascular homeostasis, and inflammation. There are two known COX isoforms, which differ mainly in expression patterns. COX-1 is constitutively expressed and involved in "housekeeping" functions, whereas COX-2 is induced in response to inflammatory stimuli and is hence the desired target for the nonsteroidal anti-inflammatory drugs (NSAIDs). These agents block the cyclooxygenase reaction only and attenuate prostaglandin synthesis. Resveratrol (3,4' ,5-trihydroxy-trans -stilbene) is a natural product found in grapes, which is present at concentrations up to 100 μM in red wines. It is reported to have cancer chemopreventive, anti-inflammatory, and cardiovascular protective properties and was shown to inhibit COX-1 and COX-2. This resulted in a decrease in PG synthesis by COX-1 only. Resveratrol is unique in that it is a potent inhibitor of both the cyclooxygenase and peroxidase reactions of COX-1. Resveratrol was also noncompetitive with AA indicating that drug binding occurred at a site other than that of NSAID action. Finally, resveratrol was able to discriminate between the two COX isoforms since it only weakly inhibited the peroxidase activity of COX-2. The goal of this dissertation was to determine the mechanism by which resveratrol selectively inhibits the cyclooxygenase and peroxidase reactions of COX-1. In doing so, a novel class of COX-1 mechanism-based inactivators was discovered, namely the m -hydroquinones. These compounds are oxidized at the peroxidase active site to an unstabilized semiquinone radical that irreversibly inactivates the cyclooxygenase and peroxidase activities of COX-1 through a "hit-and-run" mechanism. This radical was subsequently trapped as the resveratrol dihydrodimer cis -[varepsilon]-viniferin. In contrast, the m -hydroquinones acted only as co-reductants to the COX-2 peroxidase. The selective inactivation of COX-1 by resveratrol can account for the cardioprotective effects associated with red wine consumption (the "French Paradox"), since this isoform is responsible for the production of a potent vasoconstrictor and platelet aggregator, thromboxane A2 (TXA2 ), by the platelet. In addition, red wine contains high concentrations of other dietary m -hydroquinones, namely the catechins and epicatechins, which were also shown to be selective COX-1 mechanism-based inactivators.

    J. Biol. Chem., Vol. 279, Issue 21, 22727-22737, May 21, 2004

    Resveratrol is a Peroxidase-mediated Inactivator of COX-1 but Not COX-2
    A MECHANISTIC APPROACH TO THE DESIGN OF COX-1 SELECTIVE AGENTS*
    Lawrence M. Szewczuk , Luca Forti, Lucia A. Stivala||, and Trevor M. Penning**
    From the Department of Biochemistry & Biophysics and the **Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the Dipartimento di Chimica, Universitá di Modena e Reggio Emilia, 41100 Modena, Italy, and the ||Dipartimento di Medicina Sperimentale, sez. Patologia Generale, Universitá di Pavia Piazza Botta, 10-27100 Pavia, Italy
    Received for publication, December 30, 2003 , and in revised form, March 12, 2004.
    Abstract

    Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a phytoalexin found in grapes that has anti-inflammatory, cardiovascular protective, and cancer chemopreventive properties. It has been shown to target prostaglandin H2 synthase (COX)-1 and COX-2, which catalyze the first committed step in the synthesis of prostaglandins via sequential cyclooxygenase and peroxidase reactions. Resveratrol discriminates between both COX isoforms. It is a potent inhibitor of both catalytic activities of COX-1, the desired drug target for the prevention of cardiovascular disease, but only a weak inhibitor of the peroxidase activity of COX-2, the isoform target for nonsteroidal anti-inflammatory drugs. We have investigated the unique inhibitory properties of resveratrol. We find that it is a potent peroxidase-mediated mechanism-based inactivator of COX-1 only (kinact = 0.069 ± 0.004 s-1, Ki(inact) = 1.52 ± 0.15 µM), with a calculated partition ratio of 22. Inactivation of COX-1 was time- and concentration-dependent, it had an absolute requirement for a peroxide substrate, and it was accompanied by a concomitant oxidation of resveratrol. Resveratrol-inactivated COX-1 was devoid of both the cyclooxygenase and peroxidase activities, neither of which could be restored upon gel-filtration chromatography. Inactivation of COX-1 by [3H]resveratrol was not accompanied by stable covalent modification as evident by both SDS-PAGE and reverse phase-high performance liquid chromatography analysis. Structure activity relationships on methoxy-resveratrol analogs showed that the m-hydroquinone moiety was essential for irreversible inactivation of COX-1. We propose that resveratrol inactivates COX-1 by a "hit-and-run" mechanism, and offers a basis for the design of selective COX-1 inactivators that work through a mechanism-based event at the peroxidase active site.


    Mol Nutr Food Res
    . 2005 May;49(5):405-30.

    Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications.

    de la Lastra CA, Villegas I.

    Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain. [email protected]

    Resveratrol is a phytoalexin polyphenolic compound found in various plants, including grapes, berries, and peanuts. Multiple lines of compelling evidence indicate its beneficial effects on neurological, hepatic, and cardiovascular systems. Also one of the most striking biological activities of resveratrol soundly investigated during the late years has been its cancer-chemopreventive potential. In fact, recently it has been demonstrated that this stilbene blocks the multistep process of carcinogenesis at various stages: tumor initiation, promotion, and progression. One of the possible mechanisms for its biological activities involves downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of activated immune cells, or inhibiting such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) via its inhibitory effects on nuclear factor (kappa)B (NF-(kappa)B) or the activator protein-1 (AP-1). More recent data provide interesting insights into the effect of this compound on the lifespan of yeast and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. It is worthy to note that the phenolic compound possesses a low bioavailability and rapid clearance from the plasma. As the positive effects of resveratrol on inflammatory response regulation may comprise relevant clinical implications, the purpose of this article is to review its strong anti-inflammatory activity and the plausible mechanisms of these effects. Also, this review is intended to provide the reader an up-date of the bioavailability and pharmacokinetics of resveratrol and its impact on lifespan.
    Product Educator | USPowders
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  29. Somehow, I habitually gravitate toward commenting on resveratrol, as if REVERSE were just resveratrol. In line with an earlier assertion of mine in this log, REVERSE's effectiveness must be seen in its full context as a synergistic blend of resveratrol plus carefully selected compounds, that are significantly potent in their own rights. Without those compounds, REVERSE's versatile effectiveness would be compromised. I thought it would make sense to drop this comment in advance of my final update, so my resveratrol bias can be put in appropriate perspective.
    Product Educator | USPowders
    Statements made by this online persona are the sole property of the owner, and do not necessarily reflect USPowders’ opinion as a whole.

  30. What would you think of Reverse + GSE (95%)?

    Good combo? Would you add in anything else for general health?

    Say a general antioxidant like Noxidant, or maybe oral SOD supplementation (GliSODin)?
  

  
 

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