Celastrol Enhances Atoh1 Expression in Inner Ear Stem Cells and Promotes Their Differentiation

[PolishSoldier87]

Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150060/

In summary, here we demonstrated that Celastrol treatment stimulated expression of the master transcription factor Atoh1 in inner ear stem cells and subsequently derived spheres. Moreover, Celastrol facilitated the commitment of inner ear stem cells to neuronal-like cells, which might hold great therapeutic promise for further exploitations.

https://www.amazon.com/Thunder-God-Vine-Root-20/dp/B0145XJQZ2

 

[JohnAdams]

Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150060/

In summary, here we demonstrated that Celastrol treatment stimulated expression of the master transcription factor Atoh1 in inner ear stem cells and subsequently derived spheres. Moreover, Celastrol facilitated the commitment of inner ear stem cells to neuronal-like cells, which might hold great therapeutic promise for further exploitations.

https://www.amazon.com/Thunder-God-Vine-Root-20/dp/B0145XJQZ2

View attachment 23035

FANTASTISCH!!!!!
"Transcription factor Atoh1 is the key player during HC development and regeneration."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299128/

I'm blown away I didnt find this already I've spent hours and hours searching for ways to increase atoh1. Now is this something we can take in high enough doses to do anything? It's worth looking into!

 

[JohnAdams]

My studies indicate only 1/3 gram is safe oral dose. Seems too low for oral therapeutic effect.

 

[PolishSoldier87]

My studies indicate only 1/3 gram is safe oral dose. Seems too low for oral therapeutic effect.

Pls give me a source.

 

[JohnAdams]

Pls give me a source.

https://ard.bmj.com/content/76/Suppl_2/1080.1

 

[PolishSoldier87]

How many/day do we need? What do you think?

 

[JohnAdams]

Maybe if we stack all known natural substances that have properties implicated in hair cell regeneration then we can do this, like egcg, thunder god root, carrageenan, etc.

I wish more people on this forum would realize that this type of thing potentially holds the greatest chance to help us anytime soon. Those of us with certain types of cochlear damage. It may seem far fetched but what if it is not?

 

[uae96]

I placed an order.

 

[PolishSoldier87]

What do we have to do to make these cells to become hair cells after differentiation?

 

[JohnAdams]

What do we have to do to make these cells to become hair cells after differentiation?

Atoh1. I think. I believe differentiation means becoming hair cells.
I just ordered some deer antler and some thunder god root.

 

[PolishSoldier87]

Atoh1. I think. I believe differentiation means becoming hair cells.
I just ordered some deer antler and some thunder god root.

But I can't find this about hair cells it in this article. It's only about neuronal cells, I think.

English is not my native language and maybe I am wrong.

 

[JohnAdams]

But I can't find this about hair cells it in this article. It's only about neuronal cells, I think.

English is not my native language and maybe I am wrong.

I could be wrong too but I'm under the impression that increasing atoh1 is the primary mechanism behind cochlear hair cell regeneration. My main question is what is up with the scientists that publish these papers? Why don't they ever follow through on this research? If you discovered a mechanism to regenerate hearing wouldn't you follow through? That's Nobel Prize level stuff.

 

[PolishSoldier87]

It's from June 2018 so a new thing.

 

[PolishSoldier87]

I placed an order.

Don't forget to tell us about the effects

From article:
The third-generation of utricular maculae-derived sphere cells was stimulated to differentiate with 50 ng/ml NT-3 and 100 ng/ml BDNF (R & D Systems, Minneapolis, MN, USA).

So maybe its not so stupid to take it with Matrine (NT-3) and Lurong (NT-3, BDNF, IGF-1)

 

[PolishSoldier87]

Neurog1 can partially substitute in Atoh1 function in hair cell differentiation during organ od Corti development.

https://www.ncbi.nlm.nih.gov/m/pubmed/26209643/

Despite the presence of many HCs with stereocilia these mice are deaf.

Combining Neurog1 in one allele with removal of floxed Atoh1 in a self-terminating conditional mutant (Atoh1-Cre; Atoh1(f/kiNeurog1)) mouse results in significantly more differentiated inner HCs and outer HCs that have a prolonged longevity of 9 months compared with Atoh1 self-terminating littermates.

Curcumin, which is found in turmeric, functions as a strong anticancer agent in different cancer models through the modulation of DNMT, HAT/HDAC, and miRNAs that target the Nrf2, Neurog-1, RARβ2, PTEN, and P53 pathways
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924975/

103. Shu L, Khor TO, Lee JH, Boyanapalli SS, Huang Y, Wu TY, et al. Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells. AAPS J. 2011;13:606–14​

Maybe we shouldn't give up curcumin but add it to our set.

 

[JohnAdams]

Neurog1 can partially substitute in Atoh1 function in hair cell differentiation during organ od Corti development.

https://www.ncbi.nlm.nih.gov/m/pubmed/26209643/

Despite the presence of many HCs with stereocilia these mice are deaf.

Combining Neurog1 in one allele with removal of floxed Atoh1 in a self-terminating conditional mutant (Atoh1-Cre; Atoh1(f/kiNeurog1)) mouse results in significantly more differentiated inner HCs and outer HCs that have a prolonged longevity of 9 months compared with Atoh1 self-terminating littermates.

Curcumin, which is found in turmeric, functions as a strong anticancer agent in different cancer models through the modulation of DNMT, HAT/HDAC, and miRNAs that target the Nrf2, Neurog-1, RARβ2, PTEN, and P53 pathways
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924975/

103. Shu L, Khor TO, Lee JH, Boyanapalli SS, Huang Y, Wu TY, et al. Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells. AAPS J. 2011;13:606–14​

Maybe we shouldn't give up curcumin but add it to our set.

that's cool. because curcumin blocks atoh1. I really did feel like curcumin was making me better. I really think you are on to something here. wouldn't that just be so awesome if we actually could pull this off?

 

[PolishSoldier87]

that's cool. because curcumin blocks atoh1. I really did feel like curcumin was making me better. I really think you are on to something here. wouldn't that just be so awesome if we actually could pull this off?

Curcumin blocks atoh1? Pls tell me more about this and provide source if you may.

 

[JohnAdams]

No bullshit.
I get my curcumin at the hippy grocery store called earthfare and am about to go get it this evening and in the middle of this very conversation I look down at my phone and this email popped up.

 

[JohnAdams]

"Furthermore, inhibition of histone acetyltransferase (HAT) activity by curcumin partially blocks the DAPT-induced accumulation of Atoh1 mRNA, further indicating a need for ongoing histone acetylation to induce Atoh1 (Fig. 6B). Curcumin, either on its own or in conjunction with DAPT, had no effect on the expression level of the Notch effectors Hes5 and Hey1 (data not shown)"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813338/

 

[PolishSoldier87]

Ok, so curcumin partially blocks Atoh1. Thanks.

 

[JohnAdams]

Ok, so curcumin partially blocks Atoh1. Thanks.

Seriously what's your confidence level that these substances could heal us?

 

[PolishSoldier87]

Seriously what's your confidence level that these substances could heal us?

This is hard. I don't know if it is possible. But maybe it will improve something. I have lyme. I am very sick and I am desperate to improve my condition.

 

[JohnAdams]

This is hard. I don't know if it is possible. But maybe it will improve something. I have lyme. I am very sick and I am desperate to improve my condition.

damn, sorry to hear that.

 

[PolishSoldier87]

Celastrol, an active constituent of the TCM plant Tripterygium wilfordii Hook.f., inhibits prostate cancer bone metastasis.
https://www.ncbi.nlm.nih.gov/m/pubmed/28195223/

https://www.magicznyogrod.pl/tripterygium_wilfordii_ekstrakt_30_1.html

https://m.alibaba.com/amp/showroom/celastrol-extract.html

 

[PolishSoldier87]

My studies indicate only 1/3 gram is safe oral dose. Seems too low for oral therapeutic effect.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150060/figure/F0001/

As shown in Fig. 1A, the cell viability was significantly increased by treatment with up to 2 μM Celastrol in a dose-dependent manner. However, high concentration of Celastrol (10 μM) displayed remarkable suppressive effect on cell growth, which might be due to ensued cytotoxicity.

 

[PolishSoldier87]

Pure Celastrol
https://www.alibaba.com/product-detail/99-Celastrol-tripterygium-wilfordii-extract_60330216220.html

 

[JohnAdams]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150060/figure/F0001/

As shown in Fig. 1A, the cell viability was significantly increased by treatment with up to 2 μM Celastrol in a dose-dependent manner. However, high concentration of Celastrol (10 μM) displayed remarkable suppressive effect on cell growth, which might be due to ensued cytotoxicity.

Great.....

 

[PolishSoldier87]

Upgraded form od Celastrol.
https://www.ncbi.nlm.nih.gov/m/pubmed/22343423/

We found that liposomal celastrol had high encapsulation efficiency (71.67%) and liposomal celastrol had a higher C(max) and area under the curve, longer t(1/2), and better biodistribution than free celastrol. A cytotoxicity assay indicated that free celastrol had lower 50% inhibiting concentration values than the liposomal celastrol; however, treatment of subcutaneous xenografts with 1 mg/kg of liposomal celastrol induced greater antitumor activity than free celastrol at an equimolar concentration. In addition, a 4 mg/kg dose of liposomal celastrol had fewer severe side effects than free celastrol at the same dose. In this study, we found that the use of liposomes as a carrier of celastrol increased the bioavailability and reduced the side effects of the compound.

So 5mg/kg is safe or not?

 

[JohnAdams]

Upgraded form od Celastrol.
https://www.ncbi.nlm.nih.gov/m/pubmed/22343423/

We found that liposomal celastrol had high encapsulation efficiency (71.67%) and liposomal celastrol had a higher C(max) and area under the curve, longer t(1/2), and better biodistribution than free celastrol. A cytotoxicity assay indicated that free celastrol had lower 50% inhibiting concentration values than the liposomal celastrol; however, treatment of subcutaneous xenografts with 1 mg/kg of liposomal celastrol induced greater antitumor activity than free celastrol at an equimolar concentration. In addition, a 4 mg/kg dose of liposomal celastrol had fewer severe side effects than free celastrol at the same dose. In this study, we found that the use of liposomes as a carrier of celastrol increased the bioavailability and reduced the side effects of the compound.

So 5mg/kg is safe or not?

From what I read it is. But how could I know for sure.

 

[PolishSoldier87]

https://www.sciencedaily.com/releases/2008/08/080830005613.htm
"Brigande and his colleagues were able to produce hair cells by transferring a key gene, called Atoh1, into the developing inner ears of mice. The gene was inserted along with green florescent protein (GFP) which is the molecule that makes a species of jellyfish glow. GFP is often used in research as a "marker" that a scientist can use to determine, in this case, the exact location of the Atoh1 expression. Remarkably, the gene transfer technique resulted in Atoh1 expression in the organ of Corti, where the sensory hair cells form.
Using this method, the researchers were able to trace how the inserted genetic material successfully led to hair cell production resulting in the appearance of more hair cells than are typically located in the ears of early postnatal mice."​

Does it mean that inducing production od Atoh1 will always cause its expression in cochlea?