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Prof Trevor Marshall
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Many of you have noticed that Soy doesn't always work well in your diets. Well, I finally got around to looking into an isoflavone called Genistein, which is a primary Soy isoflavone. Here is the picture of 1,25-D and Genistein as they dock into the VDR.


The molecule with the green spine is Genistein. Interestingly, it is a partial agonist, forming hydrogen bonds with SER278, TYR143, ARG274 and SER278, the same residues as 1,25-D hydrogen-bonds to. However, it doesn't have the 'tail' of Vitamin D or Benicar, and cannot transcribe those DNA genes which need coactivators requiring helix 12 to be stabilized. Ki calculates at about 0.5 micromolar.

In summary, Genistein will interfere with the operation of the VDR, as well as the PPAR-gamma and PPAR-alpha receptors, all key to the immune system.

This paper implies that 40mg of isoflavones a day is likely to produce concentrations capable of affecting the VDR (about 500 nanomolar). This paper suggests that 20 grams of roasted soyabeans (equiv. 37mg isoflavones) will give more than enough plasma concentration to mess up an already compromised immune system.

---------------------------
(Scientists who want to build this discovery into their own papers should cite:
Marshall TG, Lee RE, Marshall FE: Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theor Biol Med Model. 2006 Jan 10;3(1):1, together with the URL for this thread)

John McDonald
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Trevor,

Just to be sure on this, does this mean that we should add all soy products to the do-not-eat list?

scooker48
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Dr. Marshall,

Isn't this found in green tea?

Sherry

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Thanks Dr. M for looking at that more closely. Something has made me aware that fermented soy is okay because it has released most of the "bad" stuff. Would this be at all accurate? There are so many constituents in soy......

Prof Trevor Marshall
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Any problems will be dose-dependent. Anything up above the cited "20 grams of roasted soybeans," or 40mg of isoflavones, is likely to be a problem.

Benicar should be able to take back the VDR, especially at higher Benicar doses (eg 40mg q6h).

You should aim to keep soy content in diet below this level. As the body recovers during the MP, any potential problems will be reduced.

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John asked, "Just to be sure on this, does this mean that we should add all soy products to the do-not-eat list?"

Greg said, "Something has made me aware that fermented soy is okay because it has released most of the "bad" stuff."

You'll want to minimize your intake of soy because it is immunosuppressive and focus on fermented soy products for other health reasons.

I stopped eating processed soy products some time ago because they made my stomach feel odd....I could tell I'd eaten something unnatural.

Please see Why you should minimize your consumption of soy and soy products for an article by Dana Carpender that discusses other heath risks of soy products and offers suggestions for vegetarians about products that might be safer (in limited quantities).

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Sherry,

Yes, green tea contains genistein. Genistein is found abundantly in soy beans. The amount in green tea beverages varies, depending on how green tea is brewed and the type of green tea used.

Prof Trevor Marshall
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Genistein seems to be low in concentration in Green Tea. I am still trying to find out reliable concentration data, but as far as I can see, Green Tea is OK, because the concentration of Genistein is not high enough to be a problem. I would welcome anybody sharing numerical data on this:)

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Dr Trevor Marshall wrote: The molecule with the green spine is Genistein. Interestingly, it is a partial agonist, forming hydrogen bonds with SER278, TYR143, ARG274 and SER278, the same residues as 1,25-D hydrogen-bonds to. However, it doesn't have the 'tail' of Vitamin D or Benicar, and cannot transcribe those DNA genes which need coactivators requiring helix 12 to be stabilized. Ki calculates at about 0.5 micromolar.

Trevor, since it misses the 'tail', do you know which genes aren't transcribed?

Sincerely, Frans

Prof Trevor Marshall
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Frans,
This really is an imponderable question right now. The conference I recently attended at the Salk Institute discussed "Diseases of Transcription" and really impressed on me that we know very little about the exact transcription coactivators, and the heterodimeric conformations of these Type 1 Nuclear Receptors. Between them, they are probably transcribing 10,000 genes, maybe 100,000 genes.

As I summarize in my recent presentations, the two words I use to describe the Nuclear Receptors are "Redundancy and Complexity." Most scientists would say that unless a molecule's tail exerts forces on helix 12, preventing its folding, then no genes would be transcribed. As somebody who has been well-taught statistics, when I have a sample size of 100,000 or so, then I rarely use the word "never." And that is why I say these may be "partial" agonists. We just don't know yet enough about how the Nuclear receptors work. The co-location of the interatomic forces on all the same residues alerts me to the possibility of some as-yet-undocumented, actions...

lionel forbes
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ahh gosh, i used to consume heaps of soy milk, but i gave it up 3 years before mp, in order to conquer epilepsy,because soy is the food highest in phytates, a substance that binds to magnesium -required to calm nerve and muscle- and other minerals . this proceedure worked.

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Lionel,
That's a load of hogwash. Phytates? Show me exactly how they work. In fact, show me exactly how chelation 'works'. IMO the 'side-effects' of the drugs being used in those procedures are what folk see and feel. We know now exactly how the immune system is weakened by the chronic bacteria. The fallacies underlying these other concepts disappear into oblivion as one starts to reconcile them with the knowledge that pathogens are fundamentally responsible, not mercury, or phosphorus, or...

Never mind. These concepts will disappear in time. As Max Planck said "Science advances one funeral at a time":):)

Jacko
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Do you think this study has any significance in this? It was odd that they found the hormonal effects of soy protein isolate were independent of isoflavone content.

http://jn.nutrition.org/cgi/content/full/135/3/584

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dr marshall,

i decided to add my question to this thread, because if i understand correctly:?, resveratrol may have an effect similar to genistein on the VDR.  i have been very interested in resveratrol for a few years, now, and decided to see what i could find in relationship to vitamin d.  i quickly found a couple of abstracts:  here and here

if you have time, could you please explain what effect you think this substance has on the VDR ....if it suppresses innate immunity or stimulates it?  i am curious and can't understand this stuff unless it's explained simply..................thanks so much......sun

 

Natalia
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Dear Research Team

As a soy sauce lover I am concerned about my soy sauce consumption interfering with the MP. While I note the above comments about the fermentation process lowering the amount of genistein in soy products, I have come across some studies which have found that while the fermentation lowers the overall content of isoflavone (thus genistein), it appears to increase its bioavailability. The studies were carried out by measuring the isoflavone content of urine of subjects who had eaten either fermented and unfermented soy products. (References are listed below)

Could someone from the research team please have a look at this and advise on the  appropriate amount of fermented soy that can be consumed? I would loath to give it up but am concerned at these findings.

Thanks

Natalia


Here are the references to the relevant articles that I came across (there are probably more):
Hutchins AM, Slavin JL, Lampe JW. (1995) ‘Urinary isoflavonoid phytoestrogen and lignan excretion after consumption of fermented and unfermented soy products.’ J Am Diet Assoc. 1995 May;95(5):545-51.

JL Slavin, SC Karr, AM Hutchins and JW Lampe, (1998) ‘Influence of soybean processing, habitual diet, and soy dose on urinary isoflavonoid excretion,’ American Journal of Clinical Nutrition, Vol 68, 1492S-1495S.

Last edited on Mon Jul 9th, 2007 02:46 by Natalia

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Natalia, I also like a bit of soy sauce here and there, in cooking and even on home made dim sims.

would someone be able to give us a "yes its fine in low ammounts" or "no, dont have it at all"

i am learning so much about food that its getting crazy. over the dinner table i can tell my husband whats in what food and why its good or bad while on the MP.:)

thanks,

Sophie

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Dr. Marshall has said that any problems with the genistein in soy products will be dose-dependent and amounts higher than 20 grams of roasted soybeans or 40mg of isoflavones, is likely to be a problem.

The Benicar blockade somewhat offsets genistein's effect on the immune system and as the body recovers during the MP, any potential problems will be reduced.

If you think your consumption of soy sauce, based on these figures and its supposedly higher bioavailability, leads to a high level of genestein then you should reduce your intake. This is a small price to pay to avoid jeopardizing your return to health.

Natalia
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Megan,

As the effect of the genistein in soy sauce is dependent on both its concentration (which is different in soy sauce to soy beans) and its bioavailability (which appear to be greater than in soy beans), it is difficult for a lay person to hazard a guess as to how much soy sauce is 'safe' based on current data. Further information on concentration and bioavailability needs to be deduced in a lab to give a meaningful result.

If anyone on the research team returns to the question of soy sauce and genistein content in future, it would be great to obtain firmer figures on the question of how much soy sauce is 'safe' (as has been done for roasted soy beans)- as soy sauce is a common cooking ingredient. This would take the guess work out of eating soy sauce for many patients who are probably compromising their treatment because they think that fermented soy is 'safe' and are being too liberal with it. (Mind you I, for one, have cut back after this discussion).

Cheers


Natalia

Last edited on Tue Jul 31st, 2007 05:44 by Natalia

RxAngel
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Well, poopie.

I have just moved to Wichita, KS (more details, if interested, under my normal post, RxAngel), where there is a large population of Vietnamese, and have fallen in love with Pho, their noodle soup, and some of their other lighter dishes, and I have been craving this since I've been here, and much of it is soy based, and has tofu as an ingredient (I never thought I'd even consider tofu, being a beef-eating, venison-eating, good ole Texas gal).

I also discovered some time ago that Soy milk doesn't have Vitamin D, and I have found some cereals that aren't supplemented with Vit. D, so I have also been eating that, as well as graham crackers dipped in the milk (one of my favorite nighttime snacks that I had to give up b/c I couldn't find milk without Vit. D).

I have noticed that my irritable bowel is much better, and that my stomach doesn't bother me nearly as much when I eat these foods.

So, what's a girl to do?  Stop eating the soy-based products, even though I am feeling much better intestinally?

Thanks for all of your research and hard work, even though I can't eat mushrooms, salmon, shrimp..........  :(  .......I know, a small price to pay to rid the body of these creepy bugs floating around.

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Are you sure your decrease in gastric symptoms is due to your new food preferences? Or is it because you have taken a break from the MP and immunopathology?

Soy products vary greatly. Those that are low in quality should be avoided completely. Higher quality products should be limited to 40mg of isoflavones a day to ensure your immune system is able to function properly. :)

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RX Angel

Pho soup generally contains fish sauce. Vietnamese and Thai foods are fairly heavily laced with fish sauce which is unfortunate as they were my favourite foods.....:(

Moxie

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Does anyone know how I could find out how much isoflavones are in soy milk as I still use a small amount(even though I'm hoping to cut it out altogether) and  is not printed in the nutritional information. I only use Bonsoy which is supopsed to be the best quality.

Thanks Joolz

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A Japanese source I do not have permission to reprint states the isoflavone content of 200ml of soya bean milk is 52.1mg.

julian.paul.adams
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I have been taking Genistein suppliements for my prostate cancer. :shock:

Julian: please go to Julian's questions < click

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SHould we completely cut out Soy?? It seems that almost EVERYTHING has soy in it, especially organic products. It is so hard now to go food shopping. Yellow #5, soy, flax, and sunflower oil is in just about everything. I feel like I'm running out of options......Like tonight I made taco salad with organic ingrediants and low and behold as soon as I finished eating I started to get nausea and GI pains and headed right to the bathroom, well there was sunflower oil in the taco mix and the tortilla chips. I dont know if it is from that, but I'm thinking it could be because I have never had a reaction like that to these products that I have been using for years.

Shandy 

Natalia
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Shandym,

I don't know if you could digest the meal so quickly, but it would be a good idea to stay away from all of soy, flax and sunflower oil. In Phase 1 I had strong reactions to meals made with vegetable oil (which ofcourse usually includes sunflower or soy oil). This is gastronomically crippling as most restaurants (especially asian ones) cook with vegetable oil, so I avoid eating out now.

Some mediterranean products  state that they only contain olive oil so they should be safe. Also having control over your food preparation really helps on the MP (although yes it is boring). To this end perhaps it may be safer to eat foods that are less processed.

 Anyway best of luck in the kitchen!

Natalia

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Interesting paper on the synergy between resveratrol and 1,25D.  Resveratrol upregulates expression of the VDR but doesn't lead to cell proliferation like genistein.  So genestein upregulates VDR, then blocks its functioning. On the other hand, it appears that resveratrol upregulates VDR, but doesn't seem to interfere with its functioning (at least not to the same extent as genestein).

J. Steroid Biochem. Mol. Biol. 2003 Feb; vol. 84(2-3) pp. 149-57

Phytoestrogen regulation of a Vitamin D3 receptor promoter and 1,25-
dihydroxyvitamin D3 actions in human breast cancer cells.

Wietzke JA, Welsh J

1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a steroid hormone 
derived from Vitamin D(3), is a negative growth regulator of breast 
cancer cells, and Vitamin D(3) analogs represent a novel treatment 
approach for human cancer. Elucidation of Vitamin D(3) receptor (VDR) 
regulation may reveal strategies to sensitize cancer cells to the 
effects of 1,25-dihydroxyvitamin D(3) and Vitamin D(3) analogs. We 
have previously characterized an estrogen responsive promoter region 
(800 bp upstream of exon 1c) in the human VDR gene, and the present 
studies examined regulation of this VDR promoter region by two 
phytoestrogens, resveratrol (present in red wine) and genistein 
(present in soy). We transiently transfected a VDR promoter luciferase 
construct into the estrogen receptor (ER) positive human breast cancer 
cell lines T47D and MCF-7, and treated with 0.4-4 microM resveratrol 
or 5-500 nM genistein. Both phytoestrogens up-regulated the 
transcription of the VDR promoter, as measured by reporter gene 
activity, approximately two-fold compared to vehicle treated cells.
Co-
treatment with the anti-estrogen tamoxifen (TAM) in T47D cells and 
transfection in an estrogen receptor negative breast cancer cell line 
demonstrated that the effects of phytoestrogens on the VDR promoter 
are dependent on estrogen receptor. Resveratrol and genistein also 
increased VDR protein expression as detected by Western blotting. 
Treatment with resveratrol had no effect on cell number or cell cycle 
profile, while treatment with genistein increased cell number. Because 
resveratrol could up-regulate VDR without increasing breast cancer 
cell growth, we hypothesized that resveratrol mediated increase in VDR 
expression would sensitize breast cancer cells to the effects of 1,25-
dihydroxyvitamin D(3) and Vitamin D(3) analogs. In support of this 
hypothesis, both T47D and MCF-7 cells pre-treated with resveratrol 
exhibited increased VDR mediated transactivation of a Vitamin D(3) 
responsive promoter compared to cells pre-treated with vehicle. In 
addition, co-treatment with resveratrol enhanced the growth inhibitory 
effects of 1,25-dihydroxyvitamin D(3) and the Vitamin D(3) analog 
EB1089.
These data support the concept that dietary factors, such as 
phytoestrogens, may impact on breast cancer cell sensitivity to 
Vitamin D(3) analogs through regulation of the VDR promoter.

PMID: 12710998
URL  - http://www.ncbi.nlm.nih.gov/pubmed/12710998?dopt=Citation

Bane
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How red wine may shield brain from stroke damage

http://www.eurekalert.org/pub_releases/2010-04/jhmi-hrw042110.php

Researchers at Johns Hopkins say they have discovered the way in which red wine consumption may protect the brain from damage following a stroke.

Two hours after feeding mice a single modest dose of resveratrol, a compound found in the skins and seeds of red grapes, the scientists induced an ischemic stroke by essentially cutting off blood supply to the animals' brains. They found that the animals that had preventively ingested the resveratrol suffered significantly less brain damage than the ones that had not been given the compound.

Sylvain Doré, Ph.D., an associate professor of anesthesiology and critical care medicine and pharmacology and molecular sciences at the Johns Hopkins University School of Medicine, says his study suggests that resveratrol increases levels of an enzyme (heme oxygenase) already known to shield nerve cells in the brain from damage. When the stroke hits, the brain is ready to protect itself because of elevated enzyme levels. In mice that lacked the enzyme, the study found, resveratrol had no significant protective effect and their brain cells died after a stroke.

"Our study adds to evidence that resveratrol can potentially build brain resistance to ischemic stroke," says Doré, the leader of the study, which appears online in the journal Experimental Neurology.

Red wine has gotten a lot of attention lately for its purported health benefits. Along with reducing stroke, moderate wine consumption has been linked to a lowered incidence of cardiovascular disease — the so-called French paradox. Despite diets high in butter, cheese and other saturated fats, the paradox goes, the French have a relatively low incidence of cardiovascular events, which some have attributed to the regular drinking of red wine.

Doré cautions against taking resveratrol supplements, available alongside vitamins and minerals and on websites touting its benefits, because it is unclear whether such supplements could do harm or good. He has not tested resveratrol in clinical trials. And while resveratrol is found in red grapes, it's the alcohol in the wine that may be needed to concentrate the amounts of the beneficial compound. Doré also cautions that drinking alcohol carries risks along with potential benefits.

He also notes that even if further research affirms the benefits of red wine, no one yet knows how much would be optimal to protect the brain, or even what kind of red wine might be best, because not all types contain the same amount of resveratrol. More research is needed, he says.

Doré says his research suggests that the amount needed could end up being quite small because the suspected beneficial mechanism is indirect. "Resveratrol itself may not be shielding brain cells from free radical damage directly, but instead, resveratrol, and its metabolites, may be prompting the cells to defend themselves," he suggests.

"It's not likely that brain cells can have high enough local levels of resveratrol to be protective," he says. The resveratrol is needed to jump-start this protective enzymatic system that is already present within the cells. "Even a small amount may be sufficient," Doré says.

Doré says his ongoing research also suggests some therapeutic benefits to giving resveratrol to mice after a stroke to limit further neuronal damage.



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