Genistein, Tyrosine Kinase Inhibitor, for MCAD and Herpes.

[Remy]

I'm always curious if there is a plant based supplement that is similar to pharmaceutical drugs. I recently started taking imatinib for mast cell activation disorder. So I asked Dr Google and found genistein is a tyrosine kinase inhibitor too.

You may remember from my review of Dr Afrin's book that tyrosine kinases regulate growth and differentiation of cells. Different tyrosine kinase inhibitors target different proteins though and I'm not sure that imatinib and genostein target the same one exactly though there does seem to be some overlap in the epidermal growth factor receptors and it definitely decreased Nf-kb.

It also may not matter if they target exactly the same tyrosine kinase protein either since different drugs are effective for different people with MCAD anyway and no one drug, including imatinib, is a winner for everyone. Maybe the tyrosine kinase protein is the reason why?

And this is interesting...genistein also activates AMPK...which is an important enzyme involved in cellular energy homeostasis. I've been having good luck using nicotine lozenges as an AMPK activator in the past month or so.

Even more head scratching-ly, genistein (and tyrosine kinase inhibitors in general) appear to have an anti-herpes effect by preventing viral entry to cells.

Dr Lerner worked a lot with antiviral drugs, thymidine kinase inhibitors, like Valcyte and Valtrex. I don't have a lot of support for this idea but it seems like some viruses may express both thymidine and tyrosine kinases.

Herpes Simplex Virus Entry Is Associated with Tyrosine Phosphorylation of Cellular Proteins

Abstract

The initial step in herpes simplex virus (HSV) entry is binding of virion glycoprotein (g)C and/or gB to cell surface heparan sulfate. After this initial attachment, gD interacts with cell surface receptor or receptors, and the virion envelope fuses with the cell membrane. Fusion requires viral glycoproteins gB, gD, gL, and gH, but the cellular factors that participate in or the pathways activated by viral entry have not been defined. To determine whether signal transduction pathways are triggered by viral–cell fusion, we examined the association of viral entry with tyrosine phosphorylation of cellular proteins. Using immunoprecipitation and Western blotting, we found that at least three cytoplasmic host cell proteins, designated p80, p104, and p140, become tyrosine phosphorylated within 5–10 min after exposure to HSV-1 or HSV-2. However, no phosphorylation is detected when cells are exposed to a mutant virus deleted in gL that binds but fails to penetrate. Phosphorylation is restored when the gL-deletion virus is grown on a complementing cell line. Viral entry and the phosphorylation of p80, p104, and p140 are inhibited when cells are infected with virus in the presence of protein tyrosine kinase inhibitors. Taken together, these studies suggest that tyrosine phosphorylation of host cellular proteins is triggered by viral entry.

I feel like I'd heard of genistein before...and that's because it is a phytoestrogen that is used in many supplements for menopausal women. But I don't think that's a strike against it because phytoestrogens are actually good for those with low estrogen and for those with estrogen dominance. It can compete with the "real" estrogen and keep it from binding in those situations.

So genistein is pretty powerful. Powerful enough for scientists to tell people to not take it with drugs like tamoxifen that block estrogen (even though I'm not sure they understand how phytoestrogens work and the role of estrogen in breast cancer anyway!). So that's encouraging.

I was a little concerned about it coming from soy. But it appears to be fermented soy which I think is OK unless you have a soy allergy. And I took things like phosphatidyl choline in the past that were derived from soy successfully so I don't think that is as much of a concern.

I couldn't find an ideal dose for viral suppression or mast cell disease so I expect it will be like everything else...trial and error and maybe works for some and probably doesn't work for a lot of others unfortunately. But I think it's very interesting and certainly while drugs like imatinib are so hard to come by in terms of price and availability, it might be a viable option to try.

Genistein-induced LKB1-AMPK activation inhibits senescence of VSMC through autophagy induction.

Lee KY, et al. Vascul Pharmacol. 2016.
Show full citation
Abstract

Genistein, the primary isoflavone from soy products, enhances antioxidant enzyme activities and inhibits tyrosine kinase. However, the mechanisms underlying genistein-induced autophagy are not yet completely understood. Autophagy refers to a regulated cellular process for the lysosomal-dependent turnover of organelles and proteins. During starvation or nutrient deficiency, autophagy provides an endogenous mechanism for prolonging survival. Here, we investigated whether genistein exerts autophagic effects through the activation of LKB1-AMPK signaling in VSMCs. Genistein dose- and time-dependently increased the phosphorylation of LKB1 and AMPK in VSMCs. LKB1 and AMPK induced autophagy through the downregulation of mTOR in VSMCs. Genistein-induced autophagy was inhibited in dominant-negative AMPK-transfected cells, whereas it was accelerated in cells transfected with the constitutively active form of AMPK. Increased autophagosome activity was confirmed by a concentration-dependent increase in LC3-II formation on Western blots and by increased perinuclear LC3-II puncta in genistein-treated VSMCs. Furthermore, genistein-induced autophagy attenuated adriamycin-induced SA-b-gal staining. These results suggest that genistein-dependent autophagy diminishes VSMC senescence and genistein may attenuate the VSMC senescence via an LKB1-AMPK-dependent mechanism.
Copyright © 2016 Elsevier Inc. All rights reserved.
PMID

26924458 [PubMed - in process]
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[Who Me?]

You get a degree in sleuthing!

 

[Remy]

Looks like genistein is a pretty good antihistamine and mast cell stabilizer...

I think Dr Theoharides is the one behind Neuroprotek.

Allergy Asthma Proc. 2003 Sep-Oct;24(5):373-7.
The isoflavone genistein inhibits proliferation and increases histamine content in human leukemic mast cells.

Alexandrakis MG1, Kyriakou DS, Kempuraj D, Huang M, Boucher W, Seretakis D, Theoharides TC.

Abstract

Mast cells are involved in allergic inflammation and some rare disorders such as systemic mastocytosis and mast cell leukemia. Certain naturally occurring flavonoids have been shown to inhibit mast cell activation and promote maturation of secretory granules. Here, we report that the isoflavone genistein inhibited the growth of human leukemic mast cells (HMC-1) by 68.8, 51.6, and 30.2% at 10(-4), 10(-5), and 10(-6) M, respectively, at day 3 (p < 0.001). Genistein at 10(-4) M increased the histamine content per 2 x 10(5) cells at day 3 from 5.9 +/- 1.2 micrograms/mL to 11.1 +/- 1.3 micrograms/mL (n = 6; p < 0.0001). These results indicate that genistein can inhibit proliferation and induce maturation of HMC-1 cells.

 

[Who Me?]

Looks like genistein is a pretty good antihistamine and mast cell stabilizer...

I think Dr Theoharides is the one behind Neuroprotek.

Yes. Dr theoharides does neuroprotek. His YouTube video on mast cell is posted her somewhere. It's really interesting and one of the things that led me to start rutin and quercetin.

 

[h3ro]

@Remy Did you give a geniVida supplement a trial? Also how did the imatinib go?

 

[Remy]

@Remy Did you give a geniVida supplement a trial? Also how did the imatinib go?

Genivida is a non soy synthetic genistein. I did not try this formulation but someone with a soy allergy might want to consider it.

Imatinib is going well. I stopped it for a couple of weeks and I could tell a difference without it, so I started it up again. I'm hopeful at some point I'll be able to stop it though because it is pricey and has to be imported.

 

[h3ro]

Genivida is a non soy synthetic genistein. I did not try this formulation but someone with a soy allergy might want to consider it.

Well did you test drive any form of genistein?

 

[Remy]

Well did you test drive any form of genistein?

Yes, I tried the Vital Nutrients brand.

I took a bottle but did not notice any difference when I stopped so I did not repurchase.

I would definitely try again though at menopause because I did not have any ill effects either.

If someone cannot get imatinib, I think it's a reasonable choice to try.

 

[h3ro]

If someone cannot get imatinib, I think it's a reasonable choice to try.

I already ordered some imatinib from India. I hope it doesn't contain all sorts of horrid fillers I can't tolerate. That would be a big bummer.