10 replies to this topic

[Logjam]

I know there is some major interest in Parkinsons on this forum.  I'm going to point out another major indication that there is a gene called DYRK1A that may very well be one of the ones behind it.  It acts like a bit of a tumor suppressor in several tissues.  I'll put it in list format then cite some references.  DYRK1A inhibitors are in development for these indications.  Certain natural ones are being tested in Downs with some success like EGCG (a very promiscuous compound, but it inhibits DYRK1A).

1. The gene for DYRK1A is one of the genes on the extra chromosome of Downs syndrome.  Many researchers posit that it is the one that is foundational to Downs.
2. Most downs children get early onset Alzheimers or Parkinsons.  They also get diabetes much more often.
3. All 3 of these diseases are associated in other ways.  Alzheimer's is regularly characterized as "diabetes of the brain."

In fact, another natural DYRK1A inhibitor was used prior to the great depression.  They had no idea it was a DYRK1A inhibitor.  It was forgotten, but see see http://www.ncbi.nlm..../pubmed/1742748.  It's not clear this paper even knows so.  Harmine is one of the most potent DYRK1A inhibitors known.

1. Very old Parkinsons research before it was understood: http://www.ncbi.nlm..../pubmed/1742748
2. Alzheimers: http://www.ncbi.nlm....pubmed/27073990
3. Downs: http://link.springer...0401-008-0419-6
4. Model of Downs: http://www.nature.co...ncomms1090.html
5. Diabetes: http://www.ncbi.nlm....pubmed/26953159 (Harvard), http://www.nature.com/ncomms/2015/151026/ncomms9372/full/ncomms9372.html (Novartis sponsored), http://www.nature.com/nm/journal/v21/n4/full/nm.3820.html (Mt. Sinai)
6. T2D & Downs link: http://adc.bmj.com/c...7/2/183.14.full
7. Parkinsons & Downs: 

The connections are not terribly surprising, but they're remarkably supportive.

 

The connection between DYRK1A and diabetes is very strong considering that 3 researchers found that its inhibition leads to increased beta cell proliferation (something others said is basically impossible), along with its overexpression in Downs and increased frequency in Downs-afflicated individuals.

 

Parkinsons is marginally weaker, but it was effective in early studies.  It is worthwhile to note that Downs patients show signs of symptoms that are Alzheimer's and Parkinsons-like: http://link.springer...6414-0_8#page-1

 

It might be worthwhile to investigate DYRK1A inhibition for Parkinsons, Alzheimers, and diabetes.  I doubt there are any Downs people here, but we may have loved ones who are. 

 

Edited by Logjam, 04 July 2016 - 01:54 AM.

[45rpm]

A potent and inexpensive DYRK1A is the chemical EGCG from green tea.

 

http://www.sindromed...tor-rescues.pdf

 

A while back, I was comparing the various brands of green tea extract and I strongly suggest the Life Extension brand.

Edited by 45rpm, 04 July 2016 - 07:48 AM.

[ceridwen]

My DYRK is neutral I have PSEN2 instead. That is if I am reading my genome correctly.

[ceridwen]

I am pre-diabetic with lots of diabetes in the family. Mostly to do with bad diet.

[ceridwen]

I have both good and bad genes for T2D. Slightly more good than bad.
I am an APOE4 carrier.

[Logjam]

EGCG has shown _some_ positive traits in a few studies for Downs, but it hasn't really been investigated for diabetes RE: DYRK1A.  It might actually achieve something, and there are a few small reasons to believe it like http://www.sciencedi...21342201300098X , but nothing has examined its effects in light of its DYRK1A inhibition.  Keep in mind that DYRK1A inhibitors, and kinase inhibitors in general tend to have an optimum window.  We're talking very small concentrations like nano or micromolar.

 

For example, on the diabetes studies, they used concentrations like 5-15uM.  More or less was less effective to totally ineffective.  See attached.  You'll see after 10-15uM it falls off.

 

The compound most investigated for diabetes and Alzheimers and Parkinsons is Harmine, which is an herbal extract that is legal in most jurisdictions.  The other one is 5-iodotubercidin / 5-IT, which would have to be synthesized in a lab.  Interestingly, 5-IT was more effective than Harmine, and also a GSK3 inhibitor, which the study didn't point out, but another study said that GSK3 inhibition enhanced the effect of DYRK1A inhibition RE: diabetes with "Exemplar compounds GNF7156 and GNF4877."  I'm not sure of the safety profile on 5-IT.  It might be an interesting compound: http://www.apexbt.co...CFUEkhgodag8Ifg

 

DYRK1A + GSK: "However, our findings demonstrate that dual inhibition of GSK3B and DYRK1A more robustly stimulates β-cell proliferation"

http://www.nature.co...ncomms9372.html

 

GSK3: "The purine analog 5- iodotubercidin, also a GSK3 inhibitor, likewise stimulates glycogen synthesis and antagonizes inactivation of glycogen synthase by glucagon and vasopressin in rat liver cells."

http://www.google.co...9065897A1?cl=en

 

Alzheimers:

http://journals.plos...al.pone.0019264

https://www.tgen.org...px#.V3q5RjkrIy4

 

Diabetes:

http://www.mountsina...ost-in-diabetes

https://www.nibr.com...s-replicate-lab & http://www.nature.com/ncomms/2015/151026/ncomms9372/full/ncomms9372.html

http://www.ncbi.nlm....pubmed/26953159

 

These studies are performed in immunosuppressed mice with removed pancreases or killed beta cells, but critically, the cells that replicated were human.  This is very new.  DYRK1A definitely does something, and it's probably what makes beta cells so 'reluctant' to replicate.  Interestingly in a few studies from awhile back, p57 downregulation is what causes hyperinsulinism of infancy:

 

http://www.uphs.upen...14/01/kaestner/

http://www.ncbi.nlm....pubmed/11723059

 

And DYRK1A downregulation also downregulates p57.   See attached.

 

I believe this is interesting.  It's almost certainly one of the genes on the extra chromosome that causes most of the harm in Downs when upregulated (because there's an extra copy, basically).  So it would be almost shocking if it didn't have some link in Alzheimers and Parkinsons if upregulated.

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Edited by Logjam, 04 July 2016 - 07:55 PM.

[nightlight]

As always, whenever a new therapeutic biochemical mechanism is found for Parkinson's or Alzheimer's, such as DYRK1A inhibition in this thread, it turns out without fail that the ancient medicine, tobacco smoke, pushes the same biochemical lever in the same direction as the new drugs. In this case, tobacco smoke is by far (by orders of magnitude) the most potent source of harmine among the commonly used substances e.g. see this paper.

 

"Coincidentally" the Big Pharma has invested over decades billions of dollars in producing and peddling antismoking junk science, creating and sponsoring "grass roots" antismoking organizations, buying antismoking laws and regulations, antismoking politicians and bureaucrats.

Edited by nightlight, 05 July 2016 - 12:03 AM.

[Logjam]

I really don't think that's so.  Tobbaco has B-Carbolines (https://en.wikipedia...E.B2-carbolines), but not Harmine in particular.

 

The only B-Carboline with DYRK1A activity is harmine.  Nothing else.  Smoking also does cause at least cancer through well-understood mechanisms.

 

There's plenty of bullshit in big pharma, but the anti-smoking sentiment probably isn't an example.  

 

Dr Stewart noted that the rate of proliferation of adult beta cells that harmine achieved in the study are comparable with those seen during the first year of life, at approximately 2%.

And although this is an important development, he noted that if there are fewer islets to begin with, "you might want to have a drug that would make them [even] faster."

"So now we're trying to make enhanced structural versions of the harmine family of drugs that are more potent and drive proliferation faster than the 1.5% we've been seeing."

"Those are the next big hurdles: making a stronger, more potent version of harmine and figuring out a way to specifically target beta cells. We're making some progress on both," he noted. However, this is "many years" from anything that could be used clinically, he concluded.

http://www.medscape.com/viewarticle/841364

Edited by Logjam, 05 July 2016 - 12:11 AM.

[nightlight]

I really don't think that's so.  Tobbaco has B-Carbolines (https://en.wikipedia...E.B2-carbolines), but not Harmine in particular.

 

Bear also in mind that Harmine from tobacco smoke goes directly into arterial bloodstream, while oral delivery with other substances (processed in stomach, intestines and liver) is far less efficient. Tobacco smoke also delivers rich complex of other alkaloids finely tuned (often for synergistic & harmonious action) by billions of life-long test subjects over the last 8 millennia.

 

Smoking also does cause at least cancer through well-understood mechanisms.

 

Your "well-understood mechanisms" = "correlations on non-randomized samples" (aka epidemiological junk science). In little publicized experiments (hence, the hard science), the effect of tobacco smoke is precisely the opposite (which implies self-medication confounding) -- e.g. with dogs exposed to real lung carcinogen radon, the tobacco smoke was highly protective: 7 times more dogs in non-smoking test group got lung cancer than dogs in smoking group. Similar protective and life extending effects of tobacco smoke (with & without co-exposures to other substances) were observed in many experiments since 1950s on variety of lab animals. There was a long thread here on this topic, see this post for links to highlights (including the mentioned dogs & other experiments) of that discussion.

[normalizing]

nightlight is right about some of that stuff. most of the cancer causing effects of tobacco smoke are coming from the radioactive residues and additives put in popular tobacco products not found in natural tobacco that has been smoked for thousands of years by various cultures, people. if you pull out the ingredients of popular tobacco products with all the additives they put in (most are proven carcinogenic), add the pesticides and crap they put and spray the plants before harvest (again cancer causing agents) and add the radioactive residues found in soils and/or left over from sprays and chemicals you get a disaster! but also i will mention this too, even in natural tobacco, ingesting anything high heat is likely to cause some damage perhaps even cancer as shown in many studies on consuming hot foods, teas, various drinks and smoke too. but i suppose thats negligible in comparison to other more potent stuff out there

[Logjam]

Pretty much anything you set on fire is empirically demonstrated to be a problem.  Even plant matter.   See http://www.ncbi.nlm....les/PMC3002194/