Inhibition of NAD+ Synthesis by Oncogenic URI Causes Liver Tumorigenesis

[stef2011]

http://www.ncbi.nlm.nih.gov/pubmed/25453901
Inhibition of De Novo NAD+ Synthesis by Oncogenic URI Causes Liver Tumorigenesis through DNA Damage

Highlights

    •URI causes NAD+ depletion-dependent DNA damage leading to HCC development
    •Restoring NAD+ pools in vivo protects from DNA damage and HCC
    •URI inhibits AhR/ER transcriptional activity-mediated de novo NAD+ synthesis
    •URI-mediated de novo NAD+ synthesis inhibition may occur in human HCC

Summary

Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD+) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD+ pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD+ can be prophylactic or therapeutic in HCC.

[stef2011]

you can already buy in longecity group if customs between US and canada are not strict, on longecity you can have a lower price than us in europe

[sorte]

I have a normal well being, but I was thinking about using it in dna damage prevention context so anti cancer.

[stef2011]

so you may try little more than 100mg like 100mg as you wake up and 100mg before bed and see if you feel any effect, which, i stress again, are difficult to detect unless a single problem like my eyes

[stef2011]

i dont think so and i also think if you are fit you wont see a lot of difference maybe only mental clarity

i think i got some damage from peg, eye view has got so much worse after peg, so maybe nr repaired some dna damage and i felt improvement much faster or maybe it is the rerum/resevratrol/pterostilbene combo.

eye view is really improving day by day so i can see how it works from it, when you could read nothing, not even bus stop very big writing or metro writing about train arriving well it is so easy to see improvement

in any case i think that between 40-45yo there is a benefit in preventing aging because it is a fact nr increases nad blood levels and that aging decreases nad

as to doing:
https://globenewswire.com/news-release/2015/08/12/760019/10145720/en/Results-from-First-Human-Clinical-Study-Demonstrate-ChromaDex-s-NIAGEN-R-Nicotinamide-Riboside-Effectively-Increases-the-Co-enzyme-NAD-and-is-Safe.html

The oral presentation and poster presented data which indicate that single doses of NIAGEN® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses. Increases in blood NAD+ tended to be sustained for longer times at higher doses.

[sorte]

thanks Stef, 4x24 is a bit better price. I wonder if 100mg a day would be significant amount.

[stef2011]

maybe if we make a big group buying 100 bottles minimum we can get good deals, i emailed bigvits uk if they can supply this product, now they dont have it but brands life extensions and jarrows are on their website

longecity has better deals but their in US and if we get customs the price gets much higher if they stop it

[cure4life]

I would like to be in a group. But I'm in Canada :(

[stef2011]

life extension europe, they have cheap prices around 22€ from time to time buying 4 bottles.it is 100mg per cap and 30cap bottles, now it is about 24€ 4 bottles.
they have premium subscriptions but i dotn understand how it works and if this applies to nr too, sent an email no answer

jarrows is cheaper, about 44€ for 60 caps when you buy 4 products from them.they also have pterostilbene, similar to resveratrol but more absorbable 60caps 5bottles 24€.swanson pterostilbene is about 12€ 30 caps
https://www.smeetsengraas.nl/jarrow-formulas/nicotinamide-riboside/

[sorte]

Anyone has a link to some cheaper Nicotinamide-Riboside ?

[sorte]

got it. like that one ?

http://www.amazon.com/Niagen-Nicotinamide-Riboside-60-capsules/dp/B00L5Q951S

or

http://www.amazon.com/Life-Extension-Regenerator-Nicotinamide-Riboside/dp/B00NPXDXNA

[cure4life]

I just bought some Niacinamide 500mg 90 tablets for about 10$  will this have similar affect?  I was told niacinamide is the same as nicotinamide.

[studyforhope]

This is the wrong supplement as outlined above. It might have rather negativb effects. It has to be Nicotinamid Riboside.

[stef2011]

ok thank you very much

we forget about nam then especially if it goes against sirtuin activation, slowing aging/promoting general health is so much important than clearing hbsag

[sorte]

studyforhope: so 300mg of NAD+ would be still good for us in anti aging context but do not expect that it will affect hbv ?

It's quite expensive a 30 pills/100mg, around 20 pounds in UK :/
If 100mg a day would have any benefits ?

[studyforhope]

You cannot buy NAD+. You can buy NADH, in 10 or 20 mg doses, but it is not going where it should, while the Nicotinamid Riboside is properly processed to increase intranuclear NAD+ concentrations.

[studyforhope]

The link worked.

The doses required for a meaningful effect on hbv seem much too high.
also, sirtuin inhibition is not healthy.

[studyforhope]

Yes this link worked.

it appears that the NAM doses required to inhibit hbv expression are too high for practical use and it must be kept in mind that any truly relevant inhibition must be very intense to have the effect of a useful contribution to hbv control or functional cure.
also in general, sirtuin inhibition is not a healthy strategy, sirtuin activation is the normally desired effect, as it is achieved with resveratrol and Nicotinamid riboside.

[stef2011]

https://drive.google.com/file/d/0B8E77QizhkLQOWZON3pyalBJN2M/view?usp=sharing

i ve share it by my google drive, its the full paper on this link

[studyforhope]

Nicotinamide has to be seen entirely different than nicotinamide riboside. Resorption, uptake and intracellular processing and distribution are very different.

Nicotinamid has also been reported to be somewhat toxic.
I need to get that mouse paper in full version.the link only loads the first page for me.

[studyforhope]

NR in typical dose will not affect your alt.

[stef2011]

anyway i guess we should go with safe highest dose which is around 3g and check that ast/alt don t change

[stef2011]

https://drive.google.com/file/d/0B8E77QizhkLQOWZON3pyalBJN2M/view?usp=sharing

here s the full study but too complicated for me to understand doses used

Materials and methods
Drugs and antibodies
Nicotinamide was purchased from Sigma-Aldrich (Sigma-
Aldrich, Missouri, USA). Nicotinamide was prepared in a
1 M phosphate-buffered saline (PBS) solution and stored at
-20 °
Nicotinamide was diluted in 500mcg/l PBS
and injected through the caudal vein once daily for 5 days
in each group at a specified dose (0mcg/g, 10mcg/g, 100mcg/g,200mcg/g body weight). Twenty-four hours after the last
injection, the mice were euthanized to collect serum and liver samples

[stef2011]

i am on 500mg spread during the day because some got response only on this dose so even if 300mg worked for me i want to be sure i get max effect for eyes view.nad+increase 50% whatever the dose but doses over 300mg sustain levels for longer

as regards nicotinamide effect on hbv: is it the same taking nicotinamide or nicotinamide riboside?

[studyforhope]

Nr is indeed a metabolic precursor to nad+, placing it where it is needed for the critical effect, which is in the cell nucleus. Several enzymes participate in the various transformations from nicotinic acid aka niacin to the final product nicotinamidadenindinucleotide. Nr is an intermediate in this pathway, very bioavailable.

[studyforhope]

I see no reason why ifn could not be used together with nicotinamide riboside.

I use 300 mg twice a day btw, a relatively high dose. Objective effects are hard to report.

[sorte]

studyforhope: Stef mentioned something about ALT increase, but my ALT on peginf is now 120 IU so not very high.
Any specific reason why you take it ? Or it's just because of it's anti-aging features ?

[stef2011]

No clear answer, nr is more expensive so they will not tell you if they re the same
Study for hcc is on nr, antiage is on nr too, so we cannot say nicotinamide has the same effect

Some researcher said nicotinamide is then transformed to nr in our body, dont remember if the liver makes it, but i havent seen a study on these pathways

[stef2011]

we don t know if it has any effect yet, probably none but  nicotinamide is very cheap vit b3, high doses slow release can make high alt, better fast release.

check ast-alt if you try it, it is a very strong antibacterial and anti tbc too, it increases neutrophils potency according to latest research

i guess doses are 3g but i dont know, not mentioned, 3g is also borderline to make higher alt, it is rare but it can happen and in case of high alt best stop it

[cure4life]

What is he riboside part? Is nicotinamide-riboside (NR) different from the form of b3 nicotinamide?  

[cure4life]

Is it correct to say that NR is the building blocks for NAD? And if so is one more beneficial than the other?

[joc2011]

how can we order this? Whats the dose?