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Control Epstein-barr virus reactivation with Arginine !!

epstein barr arginine virus

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#1 Lufega

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Posted 31 January 2012 - 04:54 PM


Who would have thought ? Herpes activation is knows to depend on arginine concentration but Epstein-barr, while belonging to the herpesviridae family, reacts differently to this amino. Herpes infections are also known to reactivate epstein barr.

Herpes simplex virus type 1 infection activates the Epstein-Barr virus replicative cycle via a CREB-dependent mechanism.

Abstract

The reactivation of latent Epstein-Barr virus (EBV) to lytic replication is important in pathogenesis and requires virus-host cellular interactions. However, the mechanism underlying the reactivation of EBV is not yet fully understood. In the present study, herpes simplex virus type 1 (HSV-1) was shown to induce the reactivation of latent EBV by triggering BZLF1 expression. The BZLF1 promoter (Zp) was not activated by HSV-1 essential glycoprotein-induced membrane fusion. Nevertheless, Zp was activated within 6h post HSV-1 infection in virus entry-dependent and replication-independent manners. Using a panel of Zp deletion mutants, HSV-1 was shown to promote Zp through a cyclic adenosine monophosphate (cAMP) response element (CRE) located in ZII. The phosphorylated cAMP response element-binding (phos-CREB) protein, the cellular transactivator that binds to CRE, also increased after HSV-1 infection. By transient transfection, cAMP-dependent protein kinase A and HSV-1 US3 protein were found to be capable of activating Zp in CREB- and CRE-dependent manners. The relationship between EBV activation and HSV-1 infection revealed a possible common mechanism that stimulated latent EBV into lytic cycles in vivo.


So, HSV-1 induces EBV ractivation by increased expression of the BZLF1 gene, which is inhibited by arginine at the right concentration. See below study.

Down-regulation of spontaneous Epstein-Barr virus reactivation in the P3HR-1 cell line by L-arginine.


Abstract

We tested the hypothesis that inhibition of Epstein-Barr virus (EBV) reactivation is controlled in part by nitric oxide (NO) generated from L-arginine (Arg). The spontaneous reactivation of EBV in the Burkitt's lymphoma (BL) cell line P3HR-1 was inhibited when the cells were cultured in L-Arg-supplemented medium. The expression of EBV early antigen (EA), immediate-early BZLF1 mRNA and the protein ZEBRA, and production of infectious virus were reduced by L-Arg supplementation in a dose-dependent manner. We demonstrated that inducible NO synthase (iNOS) mRNA was constitutively expressed in P3HR-1 cells, as quantitated by the reverse transcription-polymerase chain reaction. L-Arg supplementation enhanced iNOS and NOx expression in the cells. A specific NOS inhibitor, NG-monomethyl-L-Arg enhanced the expression of ZEBRA and early BMRF1 protein EA-D in the cells. L-Arg supplementation also inhibited the spontaneous EBV reactivation in another BL cell line EB1 and a B lymphoblastoid cell line OB. These results indicated that L-Arg induces iNOS and generates NO, which inhibits EBV reactivation in EBV-positive cells.


Question is, which of the two evils do you prefer ? ;)
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#2 nowayout

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Posted 31 January 2012 - 06:48 PM

Chronic use of L-arginine (6 months in the study I am thinking of) has been found to have harmful effects on blood vessels, diminishing their elastricity and ability to dilate (i.e., the opposite of the short term efefct of L-arginine). There is an old thread on this somewhere on these forums.

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#3 Lufega

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Posted 31 January 2012 - 08:21 PM

Chronic use of L-arginine (6 months in the study I am thinking of) has been found to have harmful effects on blood vessels, diminishing their elastricity and ability to dilate (i.e., the opposite of the short term efefct of L-arginine). There is an old thread on this somewhere on these forums.


Link ? Wouldn't mind reading that. Then there is this post on ergo. log. Seems that arginine is beneficial all around.

L-Arginine: 'the best anti-aging remedy'

#4 nowayout

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Posted 01 February 2012 - 01:22 AM

Chronic use of L-arginine (6 months in the study I am thinking of) has been found to have harmful effects on blood vessels, diminishing their elastricity and ability to dilate (i.e., the opposite of the short term efefct of L-arginine). There is an old thread on this somewhere on these forums.


Link ? Wouldn't mind reading that. Then there is this post on ergo. log. Seems that arginine is beneficial all around.



Arginine initially improves but then worsens peripheral arterial disease over 6 months. Check out the graphs in the article - they should be disturbing to anybody still innocently supplementing arginine. People on argine did worse than placebo.

L-Arginine Supplementation in Peripheral Arterial Disease

No Benefit and Possible Harm
Andrew M. Wilson, MBBS, PhD; Randall Harada, MD; Nandini Nair, MD, PhD; Naras Balasubramanian, PhD; John P. Cooke, MD, PhD From the Division of Cardiovascular Medicine (A.M.W., R.H., N.N., J.P.C.) and Department of Biostatistics (N.B.), Stanford University School of Medicine, Stanford, Calif.

Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University Medical Center, Falk Cardiovascular Research Institute, 300 Pasteur Dr, Stanford, CA 94305. E-mail john.cooke@stanford.edu

Received December 20, 2006; accepted May 3, 2007.

Background— L-Arginine is the precursor of endothelium-derived nitric oxide, an endogenous vasodilator. L-Arginine supplementation improves vascular reactivity and functional capacity in peripheral arterial disease (PAD) in small, short-term studies. We aimed to determine the effects of long-term administration of L-arginine on vascular reactivity and functional capacity in patients with PAD.

Methods and Results— The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study was a randomized clinical trial of oral L-arginine (3 g/d) versus placebo for 6 months in 133 subjects with intermittent claudication due to PAD in a single-center setting. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. L-Arginine supplementation significantly increased plasma L-arginine levels. However, measures of nitric oxide availability (including flow-mediated vasodilation, vascular compliance, plasma and urinary nitrogen oxides, and plasma citrulline formation) were reduced or not improved compared with placebo. Although absolute claudication distance improved in both L-arginine- and placebo-treated patients, the improvement in the L-arginine-treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024).

Conclusions— In patients with PAD, long-term administration of L-arginine does not increase nitric oxide synthesis or improve vascular reactivity. Furthermore, the expected placebo effect observed in studies of functional capacity was attenuated in the L-arginine-treated group. As opposed to its short-term administration, long-term administration of L-arginine is not useful in patients with intermittent claudication and PAD.


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#5 Lufega

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Posted 01 February 2012 - 01:33 AM

L-Arginine Supplementation in Peripheral Arterial Disease No Benefit and Possible Harm


So, if you don't have PAD, then you're in the clear.

#6 nowayout

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Posted 01 February 2012 - 12:19 PM

L-Arginine Supplementation in Peripheral Arterial Disease No Benefit and Possible Harm


So, if you don't have PAD, then you're in the clear.


No, because it is possible, even probable, that arginine may cause harm to blood vessels of healthy people in the same way.

If the mechanism is development of tolerance to increased NO, then healthy people will most likely show the same adaptation, possibly even faster because they are healthy. If you then stop taking arginine, you may be in big trouble, since now your blood vessels will be unable to dilate sufficiently, at least until you have adapted back (which your body may not be able to do completely). Another mechanism of harm while taking arginine might be oxidative damage to blood vessels due to the higher levels of NO from the arginine. NO is a ROS, after all.

I know arginine is big in the bodybuilding industry and people have been brainwashed into the belief that it is very beneficial. My sense is that these people are going to get a nasty surprise in the long run, even if it is eventually blamed on some of the other crap everyone is taking.

It is also well established that arginine may be harmful if you have HSV. Most carriers of Epstein-Barr (i.e., the majority of the population) who have intact immune systems don't ever have to worry about reactivation, and many do have HSV knowingly or unknowingly . Why would you take a possibly harmful supplement for something so unlikely to happen.

Edited by viveutvivas, 01 February 2012 - 12:28 PM.


#7 Lufega

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Posted 01 February 2012 - 06:13 PM

If the mechanism is development of tolerance to increased NO, then healthy people will most likely show the same adaptation, possibly even faster because they are healthy. If you then stop taking arginine, you may be in big trouble, since now your blood vessels will be unable to dilate sufficiently, at least until you have adapted back (which your body may not be able to do completely). Another mechanism of harm while taking arginine might be oxidative damage to blood vessels due to the higher levels of NO from the arginine. NO is a ROS, after all.

...

It is also well established that arginine may be harmful if you have HSV. Most carriers of Epstein-Barr (i.e., the majority of the population) who have intact immune systems don't ever have to worry about reactivation, and many do have HSV knowingly or unknowingly . Why would you take a possibly harmful supplement for something so unlikely to happen.


You're assuming that PAD is caused by arginine or some NO related mechanism ? PAD involves atherosclerotic plaques, inflammation, etc. That causes narrowing of the arteries and decreased flow. Arginine was tested, naturally, as it can dilate the arteries, confering some kind of benefit. Why is arginine harmful in a pathologic state ? Who knows! But you can't extrapolate these results to a healthy, non-PAD population based on these assumptions.

While NO is a free radical, it's a very essential one to life. You can't simply group this one along with the other ROS as bad and you can't ignore arginine as a health promoter, given all the things it can do. Some people believe that Epstein-barr can remain in a persistant, reactivating state. It's been blamed for CFS and other problems. I'm not telling anyone to start popping arginine pills. If you decide to and are positive for HSV-1, keeping your thyroid function in shape is all you really need to do to keep herpes in check.

If you can, try to come up with some studies, even anecdotal, where arginine supplements harmed healthy people, after long-term use.

Edited by Lufega, 01 February 2012 - 06:14 PM.

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#8 Lufega

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Posted 01 February 2012 - 07:04 PM

The problem in the study was Tolerance. The study group build tolerance to Arginine supplementation. That's a fact that's well known in this forum. Cycle everything and take breaks. However, the Arginine itself wasn't harmful or toxic directly. In fact, given all the positive results with using Arginine in the short-term, I would totally use it if I have PAD. Maybe I would do something like 30 day rounds (as used in the short-term studies), take a week or two break, then back on it again. I do this now for most supplements I use, even magnesium.

However, given that PAD is caused by atherosclerosis and inflammation, an anti-inflammatory diet is in order here.

http://coolinginflam...flammatory diet

#9 nowayout

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Posted 02 February 2012 - 12:07 AM

If you can, try to come up with some studies, even anecdotal, where arginine supplements harmed healthy people, after long-term use.


A young healthy guy in these forums claimed to have gotten varicose veins after having used arginine.

#10 nowayout

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Posted 02 February 2012 - 12:10 AM

The problem in the study was Tolerance.


It was more than just tolerance, since the treatment group did worse than placebo, indicating that some harm was occurring besides just tolerance.

In any case, if you cycle arginine, you run the risk of starting your off-cycle with rebound hypertension due to a sudden decrease in available NO. Just doesn't seem smart to me.

#11 niner

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Posted 02 February 2012 - 12:58 AM

I would come down on the cautious side on this one, considering the PAD results. To muddy the waters, here's another "long term" (6 months) study in unhealthy people, though they may not be as unhealthy as the PAD cohort. Here, the results looked good.

J Cardiovasc Pharmacol. 2010 Jun 7. [Epub ahead of print]
Effect of Long-Term L-Arginine Supplementation on Arterial Compliance and Metabolic Parameters in Patients with Multiple Cardiovascular risk Factors: Randomized, Placebo-Controlled Study.
Guttman H, Zimlichman R, Boaz M, Matas Z, Shargorodsky M.

1Israel Institute For Biological Research, 2Department of Medicine, 3Epidemiology and Research Unit, 4Biochemistry and 5Endocrinology Unit, 6The Brunner Institute for Cardiovascular Research, 7E. Wolfson Medical Center, and 8Sackler School of Medicine, Tel Aviv University, Israel.

OBJECTIVES:

This study was designed to determine the effect of long-term L-arginine supplementation on arterial compliance, inflammatory and metabolic parameters in patients with multiple cardiovascular risk factors.
METHODS:

In this randomized, placebo-controlled trial, 90 patients were randomly assigned to two groups: Group 1 received daily oral L-arginine, Group 2 received matching placebo capsules. Patients were evaluated for lipid profile, glucose, HbA1C, insulin, hs-CRP, renin and aldosterone .Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, Minnesota).
RESULTS:

Although large artery elasticity index (LAEI) did not differ significantly between the groups at baseline (10.64.3 vs.11.64.5 ml/mm HgX100, p=0.346), at the end of the study LAEI was significantly greater in patients treated with L-arginine than in the placebo group (12.73.4 vs. 8.02.8 ml/mm HgX10, p<0.0001). Systemic vascular resistance was significantly lower in patients treated with L-arginine than in the placebo group after 6 months. Small artery elasticity index (SAEI) did not differ significantly between the groups at baseline or at the end of the study. Serum aldosterone decreased significantly in Group 1 from 10.76.3 to 8.45.0 ng/ml (p=0.008), but did not change in the placebo group.
CONCLUSION:

L-arginine supplementation improves LAEI in patients with multiple cardiovascular risk factors. This improvement was associated with a decrease in systolic blood pressure, peripheral vascular resistance as well as a decrease in aldosterone levels. The results suggest that long term L-arginine supplementation has beneficial vascular effects in pathologic disease states associated with endothelial dysfunction.

PMID: 20531213


I'd like to see some studies in healthy people, and I'd like to see them run longer. That probably won't happen any time soon, so I guess you have to roll the dice if you want to use Arg.

#12 Lufega

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Posted 02 February 2012 - 02:37 AM

I did a little pubmeding to look for studies on healthy subjects and didn't find anything but I also found no studies suggesting harm. I did take something out of the study viveutvias posted and that is to thread carefully with Arginine since you can become tolerant to NO production. Again, I think rotating and taking breaks should circumvent this problem. The reason the treatment group did worse than the control IS because of tolerance. When you develop tolerance to Arginine, that means that less NO was produced compared to the control group. Ofcourse this made things worse ! In fact, if you look at one of the tables that compared adverse effects, you'll see that 3 persons in the arginine group developed infections. NO is used by macrophages to kill pathogens. It disrupts their DNA or something. This suggests there was probably less NO available, causing some sort of short-term immune deficient state.

Keep in mind though, when the arteries are blocked by atherosclerosis, the body compensates by vasodilating them as much as they can (More NO production). Arginine supplementation increased NO production further to the point where levels topped off and tolerance set it. I doubt this will happen in people with healthy arteries. Another example of this is seen is protein folding diseases. Autophagy here is revved to the max. If you make these people fast, autophagy does not increase further. Even if you use trehalose, you can't increase autophagy that much, if at all.

#13 Lufega

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Posted 02 February 2012 - 03:01 AM

The tolerance issue could be caused by a problem with substrate availability. The issue with tolerance is mediated by oxidative stress (superoxide anion and peroxynitrite) due to a decrease in tetrahydrobiopterin. Folic acid (10 mg) and vitamin C can restore tetrahydrobiopterin levels and corrent the issue of tolerance. I wish that PAD study was redone with additional folic acid and vitamin C supplementation. Keep in mind that this study looked at the effect of nitroglycerine, which is what is used in emergency setting, not Arginine but you can assume that the mechanisms involved are similar.

Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study.

Gori T, Burstein JM, Ahmed S, Miner SE, Al-Hesayen A, Kelly S, Parker JD.

Source

Division of Cardiology, Department of Medicine, Mount Sinai Hospital, and the University of Toronto, Toronto, Canada.

Abstract

BACKGROUND:

In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bioavailability of tetrahydrobiopterin. Recent studies proposed that folic acid is involved in the regeneration of tetrahydrobiopterin in different disease states. Therefore, we investigated whether folic acid administration would prevent this phenomenon. We also sought to determine if folic acid supplementation could prevent the development of tolerance to GTN.
METHODS AND RESULTS:

On the first visit, 18 healthy male volunteers (aged 19 to 32 years) were randomized to receive either oral folic acid (10 mg once a day) or placebo for 1 week in a double-blind designed study. All subjects also received continuous transdermal GTN (0.6 mg/h). On the second visit, forearm blood flow was measured with venous occlusion strain gauge plethysmography in response to incremental infusions of acetylcholine (7.5, 15, and 30 microgram/min), N-monomethyl-L-arginine (1, 2, and 4 micromol/min), and GTN (11 and 22 nmol/min). Folic acid prevented GTN-induced endothelial dysfunction, as assessed by responses to intraarterial acetylcholine and N-monomethyl-L-arginine (P<0.01). Moreover, in the subjects treated with folic acid plus transdermal GTN, responses to intraarterial GTN were significantly greater than those observed after transdermal GTN plus placebo (P<0.05).
CONCLUSION:

Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.


Edited by Lufega, 02 February 2012 - 03:15 AM.


#14 Lufega

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Posted 03 February 2012 - 01:33 AM

Lysine can also prevent Arginine tolerance and this study again mentions vitamin C.

Continuous exposure to L: -arginine induces oxidative stress and physiological tolerance in cultured human endothelial cells.

Abstract

The therapeutic benefits of L: -arginine (ARG) supplementation in humans, often clearly observed in short-term studies, are not evident after long-term use. The mechanisms for the development of ARG tolerance are not known and cannot be readily examined in humans. We have developed a sensitive in vitro model using a low glucose/low arginine culture medium to study the mechanisms of ARG action and tolerance using two different human endothelial cells, i.e., Ea.hy926 and human umbilical venous endothelial cells. Cultured cells were incubated with different concentrations of ARG and other agents to monitor their effects on endothelial nitric oxide synthase (eNOS) expression and function, as well as glucose and superoxide (O (2) (·-) ) accumulation. Short-term (2 h) exposure to at least 50 μM ARG moderately increased eNOS activity and intracellular glucose (p < 0.05), with no change in eNOS mRNA or protein expression. In contrast, 7-day continuous ARG exposure suppressed eNOS expression and activity. This was accompanied by increase in glucose and O (2) (·-) accumulation. Co-incubation with 100 μM ascorbic acid, 300 U/ml polyethylene glycol-superoxide dismutase (PEG-SOD), 100 μM L: -lysine or 30 μM 5-chloro-2-(N-2,5-dichlorobenenesulfonamido)-benzoxazole (a fructose-1,6-bisphosphatase inhibitor) prevented the occurrence of cellular ARG tolerance. Short-term co-incubation of ARG with PEG-SOD improved cellular nitrite accumulation without altering cellular ARG uptake. These studies suggest that ARG-induced oxidative stress may be a primary causative factor for the development of cellular ARG tolerance.


Edited by Lufega, 03 February 2012 - 01:33 AM.


#15 gizmobrain

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Posted 03 June 2012 - 05:46 PM

Hmmm... I haven't thought about this in a while, but I had a bad case of mononucleosis when I was 15. Isn't this usually caused by being infected with EBV?

Any idea how this might effect me long term? Anything to avoid? I'd hate to reactivate it.

Edited by zrbarnes, 03 June 2012 - 05:47 PM.


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#16 nameless

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Posted 03 June 2012 - 07:05 PM

I'm not sure if there is any real significance to being infected with EBV, as I've read (and been told by my doctor) that nearly everyone has at some point. Not that everyone has had full blown mono, but most adults have been exposed to EBV.

My doc's recommendation was sleep well, eat well, etc, etc.

I also had a different doctor who felt EBV was significant, but she had no idea what to do about it than simply... sleep well, eat well, etc.

I recall one of my blood tests with off the charts high EBV, but only as a past infection. If you ever feel super sickly, mono-like again, maybe ask your doctor to run some tests. Besides antivirals, which are rather icky from a side effect profile, not sure what they'd do though.





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