Regeneration of the Cochlea: Notch Inhibition + LLLT — A Theoretical Approach

[Elixir Eksistir]

I do not know which is the best place for this: Research, Treatments, Alternative treatments and research... the last combined both, so I have decided to post here.

First, according with recent research is possible to regenerate the cochela in mammals, and therefore is possible to regenerate the cochela in the humans:
http://www.masseyeandear.org/news/press_releases/archived/new_2014/2014_CHEN_PNAS/

The researchers show that Notch inhibition initiates proliferation of supporting cells that give rise to new hair cells in postnatal mouse cochlea in vivo and in vitro. Through lineage tracing, they identified that a majority of the proliferating supporting cells and cell division-generated hair cells induced by Notch inhibition are originated from the Wnt-responsive leucine-rich repeat-containing G protein coupled receptor 5 (Lgr5+) progenitor cells. They demonstrated that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5+ progenitor cells to mitotically generate new hair cells.

http://www.pnas.org/content/112/1/166.abstract

Abstract
The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic-generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5+) progenitor cells. We demonstrate that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5+ progenitor cells to mitotically generate new HCs. Our study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways.

So I was thiking in stack a regeneration enhancer tool like LLLT with a Notch inhibtor, I've done some research and the Notch inhbitors available are:
Curcumunoids from Turmeric
http://onlinelibrary.wiley.com/doi/10.1002/cncr.21904/pdf
http://www.ncbi.nlm.nih.gov/pubmed/23219912
Genistein
http://www.ncbi.nlm.nih.gov/pubmed/16546962
http://europepmc.org/articles/pmc3792569
And Sulphorane
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783342/


I've been using LLLT for other applications before my tinnitus started, I never thought it would have a too strong effect on the cochlea due to well know claim that cochlear cells are incapable of regeneration... But these new researchs make me think otherwise, perhaps LLLT really can regenerate the cochela if it is combined with substances thats unlock the WNT pathway.

First thing, I don't know how exactly works the mechanism of the cochelar regeneration in mammal
The most basic thing is:
Gamma secretase inhibition---> Notch Inhibition---> WNT activation---->Lgr5

These are the questions:
Can a Notch inhibitor like Curcumin or Genistein lead to Lgr5+?
Is really needed a Gamma Secretase inhibitor?
What happens if there is consumed a substance that has the capacity of activate the WNT pathway?

That would be great if someone can explain these questions

And what are the possible risks?
Well, Notch inhibitors listed doesn't look dangerous.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783342/

And in the otherhand Curcumin is very safe, just google Curcumin+cancer and you will see tons of research about Curcumin anti-cancer properties. I wonder if curcumin can counteract the inner ear repair by others mechanism distinct from notch inhibition.

About Genistein, well it is a flavonoid like Quercetin, Luteolin, Resveratrol and others... flavonoids are very well know anti-oxidants, I don't think that Genistein can be dangerous, on the contrary, it can be good for health.

The problem comes with the WNT pathway, in some cases it has positive positive effects and in other cases it would be dangerous for too much cell proliferation.

About """Natural""" WNT activators I only know Magnesium L-Threonate.

"Well all this bla bla bla sounds good, but I dont have money for a Laser Device"
Me neither. Low Level Laser Therapy (LLLT) now is called, Low Level Light Therapy, because you can use Infrared LEDs instead of Lasers, both are used, I use a Infrared LED illuminator, of 200 MW and 850 nm, not weak but not the most powerful, you can also build your own laser device, on ebay are too much laser diodes.
http://www.ncbi.nlm.nih.gov/pubmed/24155530

So a first and safe approach would be Genistein+LLLT, or Curcumin+LLLT... Perhaps Curcumin+Genistein+LLLT.
Curcumin needs to be taken in a liposomal form because of is poor absoprtion, or take it with Piperine (10 mg of black pepper extract). Piperine increases the curcumin absortion in 2000%.

Perhaps this will not work but I will give it a try....The cochlea can be regenerated!, we need the correct susbtances and tools.

 

[dboy]

Thanks very much for sharing this. The science is way over my head, but I'm really keen to hear more about how you get on. How do you intend to measure success? Obviously improvements in tinnitus would be good, although that is subjective. Audiograms?

Best of luck.

 

[Elixir Eksistir]

Just subjetive improvement
I've done LLLT alone, I think that I will be capable to detect differences from lllt alone and and this "stack".
Is not easy for me to get a High Frequency Audiogram, here are expensive and difficult to find a clinic

 

[dboy]

Just subjetive improvement
I've done LLLT alone, I think that I will be capable to detect differences from lllt alone and and this "stack".
Is not easy for me to get a High Frequency Audiogram, here are expensive and difficult to find a clinic

Would you be willing to make a short post in the LLLT User Experiences thread about you experience with LLLT alone? Lots of us are keen to hear any reports about that (good or bad). Also I posted there an online hearing test you could use to get a rough impression of any improvements. Goes up to 16k if your headphones, etc. are good for this.

http://newt.phys.unsw.edu.au/jw/hearing.html

 

[Elixir Eksistir]

Would you be willing to make a short post in the LLLT User Experiences thread about you experience with LLLT alone? Lots of us are keen to hear any reports about that (good or bad). Also I posted there an online hearing test you could use to get a rough impression of any improvements. Goes up to 16k if your headphones, etc. are good for this.

Thak you!
I will do it, I've used LLLT alone for brain enhancement, hair loss, muscle building, and to take care of my internal organs. LLLT works... to the ears is more difficult, I've experienced improvements in my tinnitus, today I'm not wearing earplugs, and my T has a lower level, today I can live with this, the first two weeks where an horror movie, now I have my mind coming back.

The problem is that I'm doing to muuchs things at the same time, I'm taking c60, a powerful antioxidant. I'm doing TDCS sessions in the back to head, I'm trying to stimulate the dorsal cochlear nucleus, I've notices that my T changes the sound when I hit the DCN.

The last week was very good, I've noticed a rapid improvement with c60+LLLT. Today I will buy Curcumin or Genistein. These new studies about cochlear regeneration are promising... the trick is found the correct substance or susbtances to unlock the mechanism of cochlear regeneration, and then hit the cells with the laser.

There are two compounds that can potentiate the laser, PQQ and Nicotinamide Riboside.
Really, today my T is very low, I want to take retigabine, but I ned a prescription first, then buy it overseas, so I will try with levetiracetam (Keppra) first, the current improvements in my T gives me the force to continue with this fight

Well, here is a compilation of the LLLT efects, and a guide to Do It Yourself with Infrared LEDs.
http://selfhacked.com/2013/11/14/my-review-of-lllt/

 

[dboy]

Ahhhh. I thought you were saying you had used LLLT for tinnitus before, but should have seen that your T is recent. Thanks for all your thoughts on this and the link. I'm looking forward to hearing more about how you get on. I understand about the difficulty of knowing exactly where any improvement comes from when trying multiple treatments. But when you have recent onset T you just gotta try everything to make it go away again - or at least reduce as much as possible. Wishing you success.

 

[Elixir Eksistir]

Very recent, a month with a week. But this improvements of the LLLT+C60 in olive oil in my tinnitus level are not placebo.

 

[linearb]

Very recent, a month with a week. But this improvements of the LLLT+C60 in olive oil in my tinnitus level are not placebo.

respectfully, you are very early in this, and many (perhaps even most) people who develop tinnitus will improve within the first months, in many cases achieving complete remission. So, there's really no way to know if any of the things you are doing is having any effect.

Do you do your own LLLT at home? What device do you have?

 

[Elixir Eksistir]

respectfully, you are very early in this, and many (perhaps even most) people who develop tinnitus will improve within the first months, in many cases achieving complete remission. So, there's really no way to know if any of the things you are doing is having any effect.

Do you do your own LLLT at home? What device do you have?

Yes I know that, but my T level in the first two weeks was very high. The best improvement that I've noticed was in the last week, I was very bad, because my T was stopped in a uncomfortable level without any sign of future improvement... so in a desesperate action I took c60 olive oil and then I do a session of LLLT in the afternoon and another in the night.

The next day after that I woke up in the morning feeling fully rested (I do the LLLT session in my head also)... and as today my T has a low level, the high tone has improved too much, is the low tone (bmmmmmmmmmmm) that bothers me but is not all day this is intermittent, actually there are moments when I not hear any T sound, I only hear it If I put my fingers in my ears, and this is a ZUIIIIIUUII in a very low volumen, before this improvement Iwas feeling a high freq T and without the fingers in my ears... and my energy levels, and emotional state is better now, I'm not feeling depressed.
Well can be this a palcebo effect or an spontaneous remission? Maybe yes.... But I'm also seeing a relantionship between the improvenment and the LLLT session.

Before the T started I was doing LLLT sessions for physical improvement, with some good results, when T started I do some LLLT sesions in the 2nd and 3rd week, but the improvement was inconclusive, not too much, but the improvement of the last week was really good. My T started the 24th of January so is very recent.

I think that the crucial factor was the c60, there are some theories on internet that says that this naomolecule can have great increments in the lifespan and anti-aging properties.... but well this is a obscure zone.

I'm trying to undertand how to improve the laser effects, apparently the notch inhibition required to activate the stems cells in the cochlea requires an specific inhibition by a gamma transferase inhibtor, so a notch inhibition by a diferent mechanism, probably does not produce the same effect... Curcumin is a notch inhibitor but is not a gamma transferase inhibitor, , well curcumin with LLLT will no cause harm, but with this things we need to take some care, because too much cell proliferation an vascularization can do more harm than good.... curcumin is safe because it activates some other biological and celular mechanism is not only a notch inhibitor. Curcumin is a very useful "suplement" for the health.

And finally... I'm not using and infrared laser, I'm using and infrared LED of 830 nm and 200 mw.... sometimes I use a cheap infreared laser of 650 nm.... really low is a the last is a infreared thermometer... I'm thinking in buy some powerful linfreared LED and introduce it under my ear, or buy laser diodes on ebay, there are some cheap and good options, I don't need 500 USD for doing LLLT at home... but if you want to waste more for a really good and potent device well that is good, a device of 808nm is the best option, but 830 nm and 200 mw infrared LED is not bad, the problem with this is that can't introduce it under my ear, that why I'm thinking in buy just LEDs alone or laser diodes from ebay.

Here is an example of a infreared LED for a DIY LLLT at home:
http://www.amazon.com/Crazy-48-LED-Infrared-Vision-Illuminator/dp/B0067S8IZ8
http://www.ebay.com/itm/48-LED-Illu...mera-leds-Indoor-Outdoor-DC-12V-/191343024734
http://www.aliexpress.com/item/48-L...era-Free-Shipping-Dropshipping/956035021.html

As you can see in the last link, this device has a Infrared Wavelenght of 830 nm.

 

[linearb]

Interesting, thanks! That certainly looks cheap to try!

 

[Elixir Eksistir]

Hello
Here is another gamma secretase inhibitor:

Abstract
Ethnopharmacological relevance
The aqueous decoction of Pterocarpus erinaceus has been traditionally used in Benin against memory troubles.

Aim of the study
New strategies are needed against Alzheimer׳s disease (AD), for, to date, AD treatment is symptomatic and consists in drugs treating the cognitive decline. An interesting target is the β-amyloid peptide (Aβ), whose accumulation and progressive deposition into amyloid plaques are key events in AD aetiology.

Identifying new and more selective γ-secretase inhibitors or modulators (none of the existing has proven so far to be selective or fully efficient) appears in this respect of particular interest. We studied the activity and mechanisms of action of Pterocarpus erinaceus kino aqueous extract, after the removal of catechic tannins (KAST).

Methods and results
We tested KAST at non-toxic concentrations on cells expressing the human Amyloid Precursor Protein (APP695), as well as on primary neurons. Pterocarpus erinaceus extract was found to inhibit Aβ release in both models. We further showed that KAST inhibited γ-secretase activity in cell-free and in vitro assays, strongly suggesting that KAST is a natural γ-secretase inhibitor. Importantly, this extract did not inhibit the cleavage of Notch, another γ-secretase substrate responsible for major detrimental side effects observed with γ-secretase inhibitors. Epicatechin was further identified in KAST by HPLC-MS.

Conclusion
Pterocarpus erinaceus kino extract appears therefore as a new γ-secretase inhibitor selective towards APP processing.

http://www.sciencedirect.com/science/article/pii/S0378874115000434

and here is an interesting paper about the Notch inhibition properties of Curcumin:

Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling.
Subramaniam D1, Ponnurangam S, Ramamoorthy P, Standing D, Battafarano RJ, Anant S, Sharma P.
Author information

Abstract
BACKGROUND:
Curcumin inhibits the growth of esophageal cancer cell lines; however, the mechanism of action is not well understood. It is becoming increasingly clear that aberrant activation of Notch signaling has been associated with the development of esophageal cancer. Here, we have determined that curcumin inhibits esophageal cancer growth via a mechanism mediated through the Notch signaling pathway.

METHODOLOGY/PRINCIPAL FINDINGS:
In this study, we show that curcumin treatment resulted in a dose and time dependent inhibition of proliferation and colony formation in esophageal cancer cell lines. Furthermore, curcumin treatment induced apoptosis through caspase 3 activation, confirmed by an increase in the ratio of Bax to Bcl2. Cell cycle analysis demonstrated that curcumin treatment induced cell death and down regulated cyclin D1 levels. Curcumin treatment also resulted in reduced number and size of esophagospheres. Furthermore, curcumin treatment led to reducedNotch-1 activation, expression of Jagged-1 and its downstream target Hes-1. This reduction in Notch-1 activation was determined to be due to the down-regulation of critical components of the γ-secretase complex proteins such as Presenilin 1 and Nicastrin. The combination of a known γ-secretase inhibitor DAPT and curcumin further decreased proliferation and induced apoptosis in esophageal cancer cells. Finally, curcumin treatment down-regulate the expressions of Notch-1 specific microRNAs miR-21 and miR-34a, and upregulated tumor suppressor let-7a miRNA.

CONCLUSION/SIGNIFICANCE:
Curcumin is a potent inhibitor of esophageal cancer growth that targets the Notch-1 activating γ-secretase complex proteins. These data suggest that Notch signaling inhibition is a novel mechanism of action for curcumin during therapeutic intervention in esophageal cancers.

This is an interesting part:

The combination of a known γ-secretase inhibitor DAPT and curcumin further decreased proliferation and induced apoptosis in esophageal cancer cells. Finally, curcumin treatment down-regulate the expressions of Notch-1 specific microRNAs miR-21 and miR-34a, and upregulated tumor suppressor let-7a miRNA.

Combining a Gamma secretase inhibitor and Curcumin, and then hit the Cochlea with LLLT could be a good intervention.

 

[1MW]

LLLT does not regenerate hair cells also is ultra cheap costs 20 euros max at ebay.
Devices cost 4000 euros are from scammers and is not differrent laser from that costs 20 euro.
The price difference are profit for the scammer.

 

[Stink]

Devices cost 4000 euros are from scammers and is not differrent laser from that costs 20 euro.

the strength of the laser is different on those cheap lasers... do your homework before being ignorant

 

[1MW]

hey with 20 euro you get 400mw configurable (0-400mw)
But lasers don't regenerate hair cells can kill hair cells but not regenerate.

 

[linearb]

you can get a powerful laser from a $20 blu ray player.

Chinese companies charging hundreds of dollars or more for "medical" lasers should probably not be trusted.

@Elixir Eksistir , can you tell me about your tDCS device? Did you build your own? I've been looking in to this. TDCS seems more interesting to me than LLLT.

 

[japongus]

hey with 20 euro you get 400mw configurable (0-400mw)
But lasers don't regenerate hair cells can kill hair cells but not regenerate.

Orly? At the low levels of energy they supposedly reach the cochlea?

 

[japongus]

Very recent, a month with a week. But this improvements of the LLLT+C60 in olive oil in my tinnitus level are not placebo.

Are you the author of selfhacked dot com?
Did you buy a DIY laser on ebay etc?
Any positive results on tinnitus?
Did you try notch inhibition?

cheers

 

[linearb]

FYI I experimented with a cheap LED IR array, it spikes the shit out of my tinnitus if I use it on my ears for ~15 mins, which has made me a little ambivalent about the wisdom of using it on a more frequent basis.

 

[soundmachine]

It's not just strength...but wavelength. Putting any "IR" array or DIY laser together has to meet both power and wavelength...otherwise..you probably have worse than a Chinese laser.

For example: 660nm @ 0.5W

 

[linearb]

It's not just strength...but wavelength. Putting any "IR" array or DIY laser together has to meet both power and wavelength...otherwise..you probably have worse than a Chinese laser.

For example: 660nm @ 0.5W

Yes, I am aware, and the LED array I have is in the 830nm range.

 

[soundmachine]

Yes, I am aware, and the LED array I have is in the 830nm range.

830nm may be too long. Check some of the more expensive lasers and see what they are using. Like the famous Walden laser. Seems too low freq. As I understand it, there are ranges of wavelengths for zones of hearing freq.

 

[Zug]

IS "LLLT" FOR TINNITUS BY DR. WILDEN A SCAM?

https://www.tinnitustalk.com/threads/is-lllt-for-tinnitus-by-dr-wilden-a-scam.14011/

This link is broken

 

[JohnAdams]

I do not know which is the best place for this: Research, Treatments, Alternative treatments and research... the last combined both, so I have decided to post here.

First, according with recent research is possible to regenerate the cochela in mammals, and therefore is possible to regenerate the cochela in the humans:
http://www.masseyeandear.org/news/press_releases/archived/new_2014/2014_CHEN_PNAS/


http://www.pnas.org/content/112/1/166.abstract


So I was thiking in stack a regeneration enhancer tool like LLLT with a Notch inhibtor, I've done some research and the Notch inhbitors available are:
Curcumunoids from Turmeric
http://onlinelibrary.wiley.com/doi/10.1002/cncr.21904/pdf
http://www.ncbi.nlm.nih.gov/pubmed/23219912
Genistein
http://www.ncbi.nlm.nih.gov/pubmed/16546962
http://europepmc.org/articles/pmc3792569
And Sulphorane
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783342/


I've been using LLLT for other applications before my tinnitus started, I never thought it would have a too strong effect on the cochlea due to well know claim that cochlear cells are incapable of regeneration... But these new researchs make me think otherwise, perhaps LLLT really can regenerate the cochela if it is combined with substances thats unlock the WNT pathway.

First thing, I don't know how exactly works the mechanism of the cochelar regeneration in mammal
The most basic thing is:
Gamma secretase inhibition---> Notch Inhibition---> WNT activation---->Lgr5

These are the questions:
Can a Notch inhibitor like Curcumin or Genistein lead to Lgr5+?
Is really needed a Gamma Secretase inhibitor?
What happens if there is consumed a substance that has the capacity of activate the WNT pathway?

That would be great if someone can explain these questions

And what are the possible risks?
Well, Notch inhibitors listed doesn't look dangerous.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783342/

And in the otherhand Curcumin is very safe, just google Curcumin+cancer and you will see tons of research about Curcumin anti-cancer properties. I wonder if curcumin can counteract the inner ear repair by others mechanism distinct from notch inhibition.

About Genistein, well it is a flavonoid like Quercetin, Luteolin, Resveratrol and others... flavonoids are very well know anti-oxidants, I don't think that Genistein can be dangerous, on the contrary, it can be good for health.

The problem comes with the WNT pathway, in some cases it has positive positive effects and in other cases it would be dangerous for too much cell proliferation.

About """Natural""" WNT activators I only know Magnesium L-Threonate.

"Well all this bla bla bla sounds good, but I dont have money for a Laser Device"
Me neither. Low Level Laser Therapy (LLLT) now is called, Low Level Light Therapy, because you can use Infrared LEDs instead of Lasers, both are used, I use a Infrared LED illuminator, of 200 MW and 850 nm, not weak but not the most powerful, you can also build your own laser device, on ebay are too much laser diodes.
http://www.ncbi.nlm.nih.gov/pubmed/24155530

So a first and safe approach would be Genistein+LLLT, or Curcumin+LLLT... Perhaps Curcumin+Genistein+LLLT.
Curcumin needs to be taken in a liposomal form because of is poor absoprtion, or take it with Piperine (10 mg of black pepper extract). Piperine increases the curcumin absortion in 2000%.

Perhaps this will not work but I will give it a try....The cochlea can be regenerated!, we need the correct susbtances and tools.

I have independently replicated your research before I found this thread.