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GDF11 Makes Aged Brains And Muscles Behavior Younger

gdf11 blood transfusion mice mouse parabiosis

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#1 lemonhead

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Posted 05 May 2014 - 02:33 AM


from Science 2.0:

 

GDF11 Makes Aged Brains And Muscles Behavior Younger

 

A protein that can make the failing hearts in aging mice appear more like those of young health mice similarly improves brain and skeletal muscle function in aging mice, according to two papers in Science.
Professors Amy Wagers and Lee Rubin, of Harvard's Department of Stem Cell and Regenerative Biology (HSCRB), report that injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice – they could detect smell as younger mice do.

 

Full news article:

http://www.science20..._younger-135583

 


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#2 PWAIN

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Posted 05 May 2014 - 03:46 AM

Another link:

 

http://www.reuters.c...N0DK0HW20140504

 

Now to find the molecular structure of this and get it synthed. This one would probably be worth injecting if necesssary...

 



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#3 PWAIN

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Posted 05 May 2014 - 04:01 AM

Available here:

 

http://www.mybiosour...ducts_id=538017

 

0.02 mg  /  $320.00 + 1 FREE 8GB USB Flash Drive

 

According to this site:

 

http://www.peprotech.com/en-US/Pages/Product/Recombinant-Proteins/Growth-Factors-Cytokines/Recombinant_Human_GDF-11/120-11#prettyPhoto

 

The ED50 was determined by its ability to inhibit induced alkaline phosphatase production by ATDC-5 chondrogenic cells. The expected ED50 for this effect is 0.08-0.10 µg/ml.

 

So a very low dose is probably in order and that small amount would probably go a long way.

 

Anyone feeling brave???


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#4 lemonhead

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Posted 05 May 2014 - 03:15 PM

You first, PWAIN.

 

Seriously, though, the article reports that they are going to do clinical trials in humans in 3-5 years. I hope they also do longevity studies in various strains of mice and rats. There are almost always side effects, we need to know if there's a downside and if so, how bad it is.

 

 


Edited by lemonhead, 05 May 2014 - 03:16 PM.


#5 bixbyte

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Posted 05 May 2014 - 07:50 PM

There is much research on GDF8 (mysostatin) that makes me apprehensive to believe these early studies of GDF11 with Mice.

 

 GDF11 is closely related to myostatin, a negative regulator of muscle growth.[12][13] Both myostatin and GDF11 are involved in the regulation of cardiomyocyte proliferation. GDF11 is also a negative regulator of neurogenesis,[14][15] the production of islet progenitor cells,[16] the regulation of kidney organogenesis,[17] pancreatic development,[18] the rostro-caudal patterning in the development of spinal cords,[19] and is a negative regulator of chondrogenesis.[20]

 

http://en.wikipedia.org/wiki/GDF11

 

 

Looks like p38 might regulate GDF11 so the effects are only temporary.

 

Growth of cardiomyocytes may also be hindered by myostatin-regulated inhibition of protein kinase p38 and the serine-threonine protein kinase Akt, which typically promote cardiomyocyte hypertrophy.[33] However, increased myostatin activity only occurs in response to specific stimuli,[29][33] such as in pressure stress models, in which cardiac myostatin induces whole-body muscular atrophy.[29][31] 

 

http://en.wikipedia.org/wiki/Myostatin

 

 

I think the study of Mice and the benefits of GDF11 could be short term.


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#6 StevesPetRat

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Posted 05 May 2014 - 07:50 PM

This wiki article seems to make it out to suppress nerve and muscle growth in humans.
http://en.m.wikipedia.org/wiki/GDF11
If anyone can explain the contradiction, oh and then float some cash since I'm just about broke (it seems like this vial would be a one day supply), I would give it a try. Stress and illness have just about annihilated me this past year. I'm down to my high school weight and some of that seems to be in the form of edema.

Oops beat to the punch. That's what happens when you wander off in the middle of a post.

Edited by StevesPetRat, 05 May 2014 - 07:52 PM.


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#7 lemonhead

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Posted 05 May 2014 - 08:20 PM

Here's a nice review article that's available full-text:

McPheron, AC. Metabolic Functions of Myostatin and GDF11. Immunol Endocr Metab Agents Med Chem. 2010 Dec;10(4):217-231.

PMID: PMC3011861

 

It says pretty much the same thing as the wikipedia article. A couple of interesting nuggets: you can make a myostatin knockout mouse, but not a GDF11 knockout - or at least one that reaches maturity - they die perinatally. They don't know what tissue produces the serum GDF11.

 

I'll keep looking...

 


Edited by lemonhead, 05 May 2014 - 08:21 PM.


#8 Phoenicis

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Posted 05 May 2014 - 08:27 PM

Activation of the Growth-Differentiation Factor 11 Gene by the Histone Deacetylase (HDAC) Inhibitor Trichostatin A and Repression by HDAC3

 

Abstract

Vertebral bodies are segmented along the anteroposterior (AP) body axis, and the segmental identity of the vertebrae is determined by the unique expression pattern of multiple Hox genes. Recent studies have demonstrated that a transforming growth factor β (TGF-β) family protein, Gdf11 (growth anddifferentiationfactor 11), and the activin type II receptor, ActRIIB, are involved in controlling the spatiotemporal expression of multiple Hox genes along the AP axis, and that the disruption of each of these genes causes anterior transformation of the vertebrae. Skeletal defects are more severe in Gdf11-null mice than in ActRIIB-null mice, however, leaving it uncertain whether Gdf11 signals via ActRIIB. Here we demonstrate using genetic and biochemical studies that ActRIIB and its subfamily receptor, ActRIIA, cooperatively mediate the Gdf11 signal in patterning the axial vertebrae, and that Gdf11 binds to both ActRIIA and ActRIIB, and induces phosphorylation of Smad2. In addition, we also show that these two receptors can functionally compensate for one another to mediate signaling of another TGF-β ligand, nodal, during left–right patterning and the development of anterior head structure.


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#9 lemonhead

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Posted 05 May 2014 - 08:36 PM

Here's another free article:

 

Endocrinology. 2011 Aug;152(8):2976-86. doi: 10.1210/en.2011-0159. Epub 2011 Jun 14.
 
Abstract

Skeletal muscle wasting is an important public health problem associated with aging, chronic disease, cancer, kidney dialysis, and HIV/AIDS. 1,25-Dihydroxyvitamin D (1,25-D3), the active form of vitamin D, is widely recognized for its regulation of calcium and phosphate homeostasis in relation to bone development and maintenance and for its calcemic effects on target organs, such as intestine, kidney, and parathyroid glands. Emerging evidence has shown that vitamin D administration improves muscle performance and reduces falls in vitamin D-deficient older adults. However, little is known of the underlying mechanism or the role 1,25-D3 plays in promoting myogenic differentiation at the cellular and/or molecular level. In this study, we examined the effect of 1,25-D3 on myoblast cell proliferation, progression, and differentiation into myotubes. C(2)C(12) myoblasts were treated with 1,25-D3 or placebo for 1, 3, 4, 7, and 10 d. Vitamin D receptor expression was analyzed by quantitative RT-PCR, Western blottings and immunofluorescence. Expression of muscle lineage, pro- and antimyogenic, and proliferation markers was assessed by immunocytochemistry, PCR arrays, quantitative RT-PCR, and Western blottings. Addition of 1,25-D3 to C(2)C(12) myoblasts 1) increased expression and nuclear translocation of the vitamin D receptor, 2) decreased cell proliferation, 3) decreased IGF-I expression, and 4) promoted myogenic differentiation by increasing IGF-II and follistatin expression and decreasing the expression of myostatin, the only known negative regulator of muscle mass, without changing growth differentiation factor 11 expression. This study identifies key vitamin D-related molecular pathways for muscle regulation and supports the rationale for vitamin D intervention studies in select muscle disorder conditions.

 

 

I need to go do some stuff, so I'll have to read it later. I'll post anything useful from it if no one beats me to it.

 


Edited by lemonhead, 05 May 2014 - 08:36 PM.

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#10 bixbyte

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Posted 06 May 2014 - 02:38 PM

This wiki article seems to make it out to suppress nerve and muscle growth in humans.
http://en.m.wikipedia.org/wiki/GDF11
If anyone can explain the contradiction, oh and then float some cash since I'm just about broke (it seems like this vial would be a one day supply), I would give it a try. Stress and illness have just about annihilated me this past year. I'm down to my high school weight and some of that seems to be in the form of edema.

Oops beat to the punch. That's what happens when you wander off in the middle of a post.

 

I have an idea for a less costly source of GDF11.

Find someone young that is willing to donate or sell you some blood to inject.

Sounds like becoming a vampire may have positive benefits.



#11 lemonhead

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Posted 06 May 2014 - 03:15 PM

 

This wiki article seems to make it out to suppress nerve and muscle growth in humans.
http://en.m.wikipedia.org/wiki/GDF11
If anyone can explain the contradiction, oh and then float some cash since I'm just about broke (it seems like this vial would be a one day supply), I would give it a try. Stress and illness have just about annihilated me this past year. I'm down to my high school weight and some of that seems to be in the form of edema.

Oops beat to the punch. That's what happens when you wander off in the middle of a post.

 

I have an idea for a less costly source of GDF11.

Find someone young that is willing to donate or sell you some blood to inject.

Sounds like becoming a vampire may have positive benefits.

 

 

 

Unfortunately, they would have to give you half their blood volume.

The 'heterochronic parasymbiotic mice' had their circulatory systems shared for four weeks in this experiment [PMID: 23663781].

 

It looks like people will have to wait for the commercial product, which may be a derivative of GDF11 or some balanced combination of GDF11 and other signalling molecules. Start saving your money now ;). The user called reason made a good point about all the press about this finding and the company developing this technology looking for venture capital. He also raised another issue:  "there is a strong possibility that forcing old tissues to behave as though young by changing the signaling environment - such as by using young blood - will result in a greatly raised risk of cancer."

 

Still, a very interesting result and it is good to be living in a time of such fascinating discoveries.


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#12 bixbyte

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Posted 06 May 2014 - 07:02 PM

I have an idea for a less costly source of GDF11.
Find someone young that is willing to donate or sell you some blood to inject.
Sounds like becoming a vampire may have positive benefits.

 
Unfortunately, they would have to give you half their blood volume.
The 'heterochronic parasymbiotic mice' had their circulatory systems shared for four weeks in this experiment [PMID: 23663781].

 
Both studies examined the effect of GDF11 in two ways.
By using a parabiotic system, in which two mice are surgically joined and the blood of the younger mouse circulates through the older mouse.
By injecting the older mice with GDF11, which in an earlier study by Wagers and Richard Lee, MD, of Brigham and Womens Hospital who is also an author on the two papers released today, was shown to be sufficient to reverse characteristics of aging in the heart.
 
http://www.kurzweila...ce-made-younger
 
Surgically joining the young mouse to an old mouse by their blood circulation system does not prove that GDF11 was totally responsible for the results.

Edited by Michael, 10 June 2014 - 11:43 PM.


#13 lemonhead

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Posted 06 May 2014 - 08:00 PM

This wiki article seems to make it out to suppress nerve and muscle growth in humans.
http://en.m.wikipedia.org/wiki/GDF11
If anyone can explain the contradiction, oh and then float some cash since I'm just about broke (it seems like this vial would be a one day supply), I would give it a try. Stress and illness have just about annihilated me this past year. I'm down to my high school weight and some of that seems to be in the form of edema.

Oops beat to the punch. That's what happens when you wander off in the middle of a post.

 

 

I can't explain the contradiction. I skimmed over a bunch of articles and I just don't get it. I took developmental biology around 25 years ago and they didn't know about GDF11 back then and I can't get access to a lot of the articles because of pay walls. Also, cognitive decline. There, those are my excuses. Certainly not intellectual laziness. (sarcasm)

 

So please, someone out there, tell us the mechanism by which GDF11 works to regenerate muscle tissue. Does it stimulate the recruitment of satellite cells (hyperplastic growth)? I can't find anything that states that it does this.  I'm just a sorry old housewife now, so feed it to me with a spoon, please.



#14 drtom

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Posted 08 May 2014 - 12:19 PM

Plasma probably contains dozens, if not, hundreds of circulating factors.

Some of these have been earmarked by heterochronic parabiosis as being implicated in aging.

For example, eotaxin (aka CCL11) is a chemokine that is known to increase with age in humans. Men have more than women and it tends to stunt neurogenesis.

So, reducing elevated levels of eotaxin late in life may well be beneficial.

 

Conversely, levels of GDF11 fall as humans age.

This suggests (to me) that it is probably heavily involved in early development ("setting up the pattern of growth") and that, following puberty, its work is probably done and so levels wane. Boosting levels in later life may well show remarkable effects, but it may be a two-edged sword. Potent growth factors such as this may stimulate growth of cancers, so caution would be urged. This effect may be difficult to see in mice as they are already "cancer factories".

I believe recombinant GDF11 is available and there is some talk of transdermal patches being developed to give a slow-release, but, for the moment, it is "caveat emptor".

 

DrTom


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#15 maximum411

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Posted 08 May 2014 - 01:52 PM

I completely agree with Dr. Tom- after all, HGH and testosterone both produce "youthful" effects but likely have harmful effects on life span. Interestingly, though, GDF11 reverses cardiac hypertrophy, suggesting that it may be different than other anabolic hormones used in "anti-aging" therapies.


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#16 LexLux

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Posted 12 May 2014 - 06:32 PM

Activation of the growth-differentiation factor 11 gene by the histone deacetylase (HDAC) inhibitor trichostatin A and repression by HDAC3.

[click hyperlink for full text]
Abstract

Histone deacetylase (HDAC) inhibitors inhibit the proliferation of transformed cells in vitro, restrain tumor growth in animals, and are currently being actively exploited as potential anticancer agents. To identify gene targets of the HDAC inhibitor trichostatin A (TSA), we compared the gene expression profiles of BALB/c-3T3 cells treated with or without TSA. Our results show that TSA up-regulates the expression of the gene encoding growth-differentiation factor 11 (Gdf11), a transforming growth factor beta familymember that inhibits cell proliferation. Detailed analyses indicated that TSA activates the gdf11 promoter through a conserved CCAAT box element. A comprehensive survey of human HDACs revealed that HDAC3 is necessary and sufficient for the repression of gdf11 promoter activity. Chromatin immunoprecipitation assays showed that treatment of cells with TSA or silencing of HDAC3 expression by small interfering RNA causes the hyperacetylation of Lys-9 in histone H3 on the gdf11 promoter. Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression.

[...]

 

"To determine whether TSA increases amounts of Gdf11 mRNA in human cells, Northern blot assays were done using RNA prepared from TSA-treated and untreated HeLa cells. Similar to the response in BALB/c-3T3 cells, Gdf11 mRNA was much more abundant in TSA-treated than in untreated HeLa cells (Fig. ?(Fig.1C).1C). However, Gdf11 induction in HeLa cells required a much greater concentration of TSA than did Gdf11 induction in BALB/c-3T3 cells. Similar to HeLa cells, TSA also induced Gdf11 mRNA expression in a normal diploid fibroblast cell line, Flow 2000, although to a lesser extent.

 

To determine whether increases in the abundance of Gdf11 mRNA result in increases in the abundance of Gdf11 protein, we generated a polyclonal anti-Gdf11 antibody and performed a Western blot assay using protein extracts prepared from HeLa cells treated or untreated with TSA. As shown in Fig. ?Fig.1D,1D, TSA clearly increased the amount of Gdf11 protein in HeLa cells."

 

 

Supplements like sodium butyrate and prebiotics like RS and FOS also seem interesting. For sodium butyrate, you can see it go up against drugs like trichostatin A and valproic acid here:

 

http://www.ncbi.nlm....9941/figure/F4/

http://www.ncbi.nlm....9941/figure/F3/

 

The last two citations look at "GDNF" not "GDF-11", but since both are influenced by H3 acetylation, this gives an interesting comparison of the effectiveness of various HDAC inhibitors. Sodium butyrate seems to hold up surprisingly well. 
 

 


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#17 lemonhead

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Posted 12 May 2014 - 07:36 PM

Very interesting! Thanks, LexLux!!!


Edited by lemonhead, 12 May 2014 - 07:48 PM.


#18 LexLux

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Posted 12 May 2014 - 08:24 PM

Anyone know anything about the effective dosage for Na Butyrate and how oral supplementation compares to production of butyrate via fermentation of prebiotics like FOS and RS in the colon? 

 

http://www.direct-ms...olon cancer.pdf

http://onlinelibrary...003.01836.x/pdf

 

As pointed out by Celebes in this thread, Na Butyrate was "the only other HDAC inhibitor shown to facilitate complete fear extinction (apart from vorinostat and valproate):

 

http://www.ncbi.nlm....port=objectonly"

 

Na Butyrate just seems a lot cheaper than the safe HDAC inhibiting drugs and is an endogenous compound. As might have become clear from studies posted earlier, it also seems promising for cancer : http://europepmc.org...hBaWIANGrOQH.24

 

Edited by LexLux, 12 May 2014 - 08:27 PM.


#19 Phoenicis

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Posted 14 May 2014 - 04:48 PM

No one should go running off taking any of these compounds without seeking independent medical advice from a doctor, I just want to bring something up for discussion purposes. 

 

What I want to discuss is butyrate and its prodrug tributyrin - people have noted how quickly butyrate is metabolised, but it seems tributyrin has much better pharmokinetics and the other interesting thing is that tributyrate is sold as a food grade flavor?!  10kg for 200 British pounds? Am I mistaken? Apparently it's naturally present in butter as well. Perhaps selective HDAC 3 inhibitors like this RGFP966 should be studied further? Here it was used to enhance the extinction of cocaine seekinng behavior: http://www.pnas.org/...364110.full.pdf

 

Tributyrin, a Stable and Rapidly Absorbed Prodrug of Butyric Acid, Enhances Antiproliferative Effects of Dihydroxycholecalciferol in Human Colon Cancer Cells

 

 Tanja Gaschott, Dieter Steinhilber*, Vladan Milovic, and Jürgen Stein2

 

"Butyrate, a normal constituent of the colonic luminal contents, is formed by bacterial fermentation of unabsorbed complex carbohydrates in the mammalian digestive tract. In normal colonic mucosa, butyrate serves as a primary energy source, promotes growth of normal colonic epithelial cells in vivo and in vitro and plays a role in preventing certain types of colitis (1). In contrast, in a wide variety of neoplastic cells, butyrate acts as a potent antineoplastic agent, i.e., it inhibits growth and induces differentiation, restoring normal phenotype and function (2). The studies done during the last decade provide multiple lines of evidence that butyrate indeed interferes with the pathogenesis of colorectal cancer. Butyrate inhibits DNA synthesis and arrests growth of neoplastic colonocytes in G1 (3), modifies expression of genes involved in chemotherapy resistance (4) and in cell proliferation/differentiation (5, ,6), and induces apoptosis by a p53-independent pathway (7). At least some of butyrate?s antineoplastic effects in colon cancer cells may be due to its synergistic action with another antiproliferative agent, 1,25-dihydroxyvitamin D3 [dihydroxycholecalciferol; (OH)2D3]. In various cancer cell lines it has been shown that butyrate and (OH)2D3 act synergistically in reducing proliferation and enhancing differentiation of neoplastic cells (8, 9, 10).

 

In spite of its early promise, butyrate is not among the drugs used for cancer treatment. The major problem has been to achieve and maintain its millimolar concentrations in blood. Butyrate is metabolized rapidly as soon as it enters the colonocyte via its active transport system (11, 12, 13), and its plasma concentrations are far below those required to exert its antiproliferative/differentiating actions.

 

A prodrug of natural butyrate, tributyrin, is a neutral short-chain fatty acid triglyceride that is likely to overcome the pharmacokinetic drawbacks of natural butyrate as a drug (14). Because it is rapidly absorbed and chemically stable in plasma, tributyrin diffuses through biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective butyrate over time directly into the cell. Compared with butyrate, tributyrin has more favorable pharmacokinetics (141516) and is well tolerated (17)Liquid tributyrin filled into gelatin capsules and administered orally resulted in millimolar concentrations of butyrate both in plasma and inside the cell (17). In vitro, tributyrin has potent antiproliferative, proapoptotic and differentiation-inducing effects in neoplastic cells (181920). In this study, human colon cancer cells (Caco-2) were used to investigate the effects of tributyrin on growth and differentiation."

 

 

Clinical Trials -

 

1) Phase I study of the orally administered butyrate prodrug, tributyrin, in patients with solid tumors.

 

Butyrates have been studied as cancer differentiation agents in vitro and as a treatment for hemoglobinopathies. Tributyrin, a triglyceride with butyrate molecules esterified at the 1, 2, and 3 positions, induces differentiation and/or growth inhibition of a number of cell lines in vitro. When given p.o. to rodents, tributyrin produces substantial plasma butyrate concentrations. We treated 13 patients with escalating doses of tributyrin from 50 to 400 mg/kg/day. Doses were administered p.o. after an overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses without toxicity greater than grade 2. The time course of butyrate in plasma was assessed on days 1 and 15 and after any dose escalation. Grade 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 and 2 toxicities included diarrhea, headache, abdominal cramping, nausea, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alopecia, odor, dysphoria, and clumsiness. There was no consistent increase in hemoglobin F with tributyrin treatment. Peak plasma butyrate concentrations occurred between 0.25 and 3 h after dose, increased with dose, and ranged from 0 to 0.45 mM. Peak concentrations did not increase in three patients who had dose escalation. Butyrate pharmacokinetics were not different on days 1 and 15. Because peak plasma concentrations near those effective in vitro (0.5-1 mM) were achieved, but butyrate disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a dose of 450 mg/kg/day.

 

2) Clinical and pharmacologic study of tributyrin: an oral butyrate prodrug

 

 

"Purpose

Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50?100 ?M. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 ?M. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule.

Patients and methods

Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter.

Results

The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30?74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 ?M was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression.

Conclusion

Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing."

 

 

3) No results posted here? http://www.clinicalt...ibutyrin&rank=1

 

Hypothesized mechanism of action for tributyrin seems to be: 

 

Tributyrin -> therapeutic levels of Na butyrate in vivo -> HDAC 3 inhibition -> increased GDF 11 expression

 

Activation of the Growth-Differentiation Factor 11 Gene by the Histone Deacetylase (HDAC) Inhibitor Trichostatin A and Repression by HDAC3  

Xiaohong Zhang, Walker Wharton, [...], and Edward Seto

 

"Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression."

[...]

"...To confirm that HDAC3 is involved in the repression of the gdf11 promoter, we used a DNA vector-based RNA interference (RNAi) method to suppress HDAC3 expression in HeLa cells. small interfering RNAs (siRNAs) targeting HDACs 1, 2, and 3 synthesized from the BS/U6 template efficiently inhibited the expression of HDAC1, -2, and -3, respectively, but not of the control protein ?-actin, as monitored by immunoblotting (Fig. ?(Fig.4C).4C). Transfection with the BS/U6 vector (control) had no effect on the abundance of any of the HDACs. In full agreement with the observation that HDAC3 overexpression represses the activity of the gdf11 promoter, depletion of HDAC3 but not HDAC1 or HDAC2 significantly increased the activity of the pGL191 promoter. These results strongly support the premise that HDAC3 represses transcription from the gdf11 promoter."

 

 

Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3.

Abstract

 

Fibroblast growth factor 21 (FGF21) stimulates fatty acid oxidation and ketone body production in animals. In this study, we investigated the role of FGF21 in the metabolic activity of sodium butyrate, a dietary histone deacetylase (HDAC) inhibitor. FGF21 expression was examined in serum and liver after injection of sodium butyrate into dietary obese C57BL/6J mice. The role of FGF21 was determined using antibody neutralization or knockout mice. FGF21 transcription was investigated in liver and HepG2 hepatocytes. Trichostatin A (TSA) was used in the control as an HDAC inhibitor. Butyrate was compared with bezafibrate and fenofibrate in the induction of FGF21 expression. Butyrate induced FGF21 in the serum, enhanced fatty acid oxidation in mice, and stimulated ketone body production in liver. The butyrate activity was significantly reduced by the FGF21 antibody or gene knockout. Butyrate induced FGF21 gene expression in liver and hepatocytes by inhibiting HDAC3, which suppresses peroxisome proliferator-activated receptor-? function. Butyrate enhanced bezafibrate activity in the induction of FGF21. TSA exhibited a similar set of activities to butyrate. FGF21 mediates the butyrate activity to increase fatty acid use and ketogenesis. Butyrate induces FGF21 transcription by inhibition of HDAC3.

 

There are different types of HDAC inhibitors, but lets find out what the down sides of specifically tributyrin and butyrate are -   Anyone know enough about sirtuins to interpret this?:

 

Differential regulation of the Sir2 histone deacetylase gene family by inhibitors of class I and II histone deacetylases.

Abstract  

The Sir2 histone deacetylase gene family consists of seven mammalian sirtuins (SIRTs) which are NAD-dependent histone/protein deacetylases. Sir2 proteins regulate, for instance, genome stability by chromatin silencing in yeast. In mammals, their function is still largely unknown. Due to the NAD+ dependency, Sir2 might be the link between metabolic activity and histone/protein acetylation. Regulation of gene expression also seems to play an important role in Sir2 functions, since increasing the dosage of Sir2 genes increases genome stability in yeast and Caenorhabditis elegans. We observed that the modification of histone/protein acetylation status by several class I and II histone deacetylase (HDAC) inhibitors induces differential changes in gene expression profiles of seven SIRT mRNAs in cultured neuronal cells. SIRT2, SIRT4 and SIRT7 were upregulated, whereas SIRT1, SIRT5 and SIRT6 were downregulated by trichostatin A (TSA) and n-butyrate. The upregulation of SIRT mRNAs was inhibited by actinomycin D. Interestingly, the regulation of SIRT mRNAs was highly similar both in mouse Neuro-2a neuroblastoma cells and post-mitotic rat primary hippocampal and cerebellar granule neurons. Using a chromatin immunoprecipitation technique, we showed that the upregulation of SIRT2 expression with TSA is related to the hyperacetylation of DNA-bound histone H4 within the first 500 bp upstream of the transcription start site of the SIRT2 gene. Chemically different types of HDAC inhibitors, such as TSA, apicidin, SAHA, M344 and n-butyrate induced remarkably similar responses in SIRT1-7 mRNA expression patterns. Differential responses in SIRT mRNA expression profiles indicate that the expression of the Sir2 family of genes is selectively regulated and dependent on histone/protein acetylation status.

 

 

 


Edited by Phoenicis, 14 May 2014 - 04:55 PM.


#20 adamh

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Posted 14 May 2014 - 08:36 PM

I read that milk fats such as butter contain 5% to 7% tributyrin. Rather than buy the stuff purified, perhaps eating more butter and cheese would be a preventative for colon cancer and bring about the other benefits mentioned? The downside would be the high caloric content. The paleo diet is high fat and high protien, I wonder what role tributyrin plays in that diet?



#21 lemonhead

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Posted 15 May 2014 - 12:36 AM

Yes, a reason to eat more butter! I've got some Kerry Gold in the fridge and chronometer says I have 131 calories left for today (but I've reached my fat limit... hmm...)

 

Emmentaler cheese is supposed to contain a lot of butyric acid; I try to get the stinkiest I can afford for my GI issues. Sometimes I find other varieties in the scrap bin at Whole Foods with that characteristic odor.

 

Still, I am seriously considering the Na butyrate supplement. It seems like it could help with more than one of my problems. I need to read more about it, though.

 


Edited by lemonhead, 15 May 2014 - 12:38 AM.


#22 Phoenicis

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Posted 15 May 2014 - 01:50 AM

I want your cat Lemonhead. That is all.



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#23 lemonhead

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Posted 15 May 2014 - 01:56 AM

:)

I must say, he is a great cat; my dark prince, I call him.



#24 Avatar of Horus

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Posted 28 May 2014 - 03:37 PM

Plasma probably contains dozens, if not, hundreds of circulating factors.
Some of these have been earmarked by heterochronic parabiosis as being implicated in aging.
For example, eotaxin (aka CCL11) is a chemokine that is known to increase with age in humans. Men have more than women and it tends to stunt neurogenesis.
So, reducing elevated levels of eotaxin late in life may well be beneficial.

Conversely, levels of GDF11 fall as humans age.
This suggests (to me) that it is probably heavily involved in early development ("setting up the pattern of growth") and that, following puberty, its work is probably done and so levels wane. Boosting levels in later life may well show remarkable effects, but it may be a two-edged sword. Potent growth factors such as this may stimulate growth of cancers, so caution would be urged. This effect may be difficult to see in mice as they are already "cancer factories".
I believe recombinant GDF11 is available and there is some talk of transdermal patches being developed to give a slow-release, but, for the moment, it is "caveat emptor".

DrTom

some details in this topic:
Young Blood Reverses Signs of Aging in Old Mice
 

Posted 04 May 2014 - 07:20 PM
Serious questions for discussion:

- Why does the article state that there were "compounds in the old mice" that "dampened the resilience of the young mice" if it only discussed GDF11? Were there really such compounds identified, and if so, what were they?

- Since young mice apparently came to resemble older mice due to this blood exchange, has it been demonstrated that reintroducing GDF11 reverses the changes experienced in the young mice?

- What causes the changes in blood signalling that accumulate over time? Is there a causal link between changes in signalling and genetic/epigenetic changes that accumulate between youthful and old states, and, if so, which causes the other?

- Are there similar screenings of blood that make statistical distinctions between the blood hormone and cell composition of young from old blood? If so, what did they find? If not, why hasn't it been done?

- HRT would seem to carry an attendant cancer risk. If my understanding of this is correct, would the remark in the article concerning GDF introduction causing cancer be a valid one?

- Finally, do you think the restoration of youthful signalling profiles would make a major difference in life span (as opposed to health span)?
Edited by Vardarac, 04 May 2014 - 07:24 PM.

IMHO these are relevant questions; some of them have been touched upon some time ago in the above topic:
from post #28 on, like #49,#55,#57,#59.
 

This wiki article seems to make it out to suppress nerve and muscle growth in humans.
http://en.m.wikipedia.org/wiki/GDF11
If anyone can explain the contradiction, oh and then float some cash since I'm just about broke (it seems like this vial would be a one day supply), I would give it a try. Stress and illness have just about annihilated me this past year. I'm down to my high school weight and some of that seems to be in the form of edema.

Oops beat to the punch. That's what happens when you wander off in the middle of a post.


I can't explain the contradiction. I skimmed over a bunch of articles and I just don't get it. I took developmental biology around 25 years ago and they didn't know about GDF11 back then and I can't get access to a lot of the articles because of pay walls. Also, cognitive decline. There, those are my excuses. Certainly not intellectual laziness. (sarcasm)

So please, someone out there, tell us the mechanism by which GDF11 works to regenerate muscle tissue. Does it stimulate the recruitment of satellite cells (hyperplastic growth)? I can't find anything that states that it does this. I'm just a sorry old housewife now, so feed it to me with a spoon, please.


I am too examining the activin-inhibin/BMP/GDF/TGF-beta - SMA/mothers against decapentaplegic (SMAD) signaling pathway's possible role of aging (GDF11=BMP11), e.g.: BMP2,4,6, for example:

Liu et al. 2013: Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescence-associated secretory phenotype in vascular smooth muscle cells
http://circres.ahajo...112/10/e99.long


One possible explanation to your question, if the effect is on the level of cell signaling, is that in the TGF-beta superfamily, which is rather large, there is a significant number of 'cross-interactions' between its different but related members and receptors, and therefore the effect can be opposite, as it depends on a number of factors, such as the concentrations of the given proteins and antagonists, their receptors and downstream effectors, and the tissue and cellular context. For example:
Bmp2:
"It has been reported that BMP2/4 acts as a neuroepithelial proliferation signal at very early stages of embryonic central nervous system development, an effect mediated principally by BMPR1A ... Later in development, BMP2/4 induces neuronal and astrocytic differentiation of NSCs, an event coinciding with increased expression of BMPR1B ..." (1)
Another similar case:
"Membrane-bound endoglin is necessary for TGF-β signaling through ALK1 and has been proposed to balance signaling through either ALK1, promoting proliferation, or through ALK5, which inhibits growth of endothelial cells." (2,3)
 

I completely agree with Dr. Tom- after all, HGH and testosterone both produce "youthful" effects but likely have harmful effects on life span. Interestingly, though, GDF11 reverses cardiac hypertrophy, suggesting that it may be different than other anabolic hormones used in "anti-aging" therapies.

I am examining these hormones, GH & T, as well.
And it is very well possible, but I'm not sure (or more exactly, I have not enough information to say for sure) that they are entirely different.
For example one of the early parabiotic studies'

Rejuvenation of aged progenitor cells by exposure to a young systemic environment
Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Nature 2005.
http://www.ncbi.nlm....pubmed/15716955

basis was the study of Iakova et al. (4), which identified that the aging of the liver (or its declining regenerative capacity) is controlled by Brahma (Brm / SMARCA2 protein), a chromatin remodelling factor, whose elevated level facilitates the forming of a Brm-CEBPalpha-Rb-E2F4 protein complex in the promoter of the c-Myc gene, that represses its transcription, thereby switching off the cells ability to divide if needed. An effect that can be counteracted by GH in young age.(5)
And the TGF-beta pathway is capable of a similar blocking effect through the E2F4-Rbl1 protein complex.(6)
 
and in the case of testosterone, which could strengthen the muscle:

Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt signaling pathways
Kovacheva EL, et al. Endocrinology. 2010
http://www.ncbi.nlm....pubmed/20022929
...

as T can induce the expression of follistatin (FST), which may be its effector.(7) And the FST is an antagonist of the TGF-beta ligands, among them the Gdf11.(8)

References:
1) Lee et al. 2008 - Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells
http://www.ncbi.nlm....pubmed/18167341
2) Olsen et al. - Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin
http://www.ncbi.nlm....pubmed/24658374
3) Lebrin et al. - Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction
http://www.ncbi.nlm....pubmed/15385967
4) Iakova et al. 2003 - Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest
http://www.ncbi.nlm....pubmed/12757710
5) Wang et al. 2007 - Growth hormone corrects proliferation and transcription of phosphoenolpyruvate carboxykinase in livers of old mice via elimination of CCAAT/enhancer-binding protein alpha-Brm complex
http://www.ncbi.nlm....pubmed/17107955
6) Chen et al. 2002 - E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression
http://www.ncbi.nlm....pubmed/12150994
7) Braga et al. 2012 - Testosterone inhibits transforming growth factor-β signaling during myogenic differentiation and proliferation of mouse satellite cells: potential role of follistatin in mediating testosterone action
http://www.ncbi.nlm....pubmed/22138414
8) Gokoffski et al. 2011 - Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate
http://www.ncbi.nlm....pubmed/21852401
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#25 Phoenicis

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Posted 28 May 2014 - 04:24 PM

Not advising anyone to do this, I'm asking out of curiosity. 

 

Since both are endogenous, would it be crazy for someone to inject GDF-11 or klotho directly? Could someone, for discussion purposes, speculate on what the potential negative outcomes might be.


Edited by Phoenicis, 28 May 2014 - 04:41 PM.


#26 LexLux

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Posted 02 June 2014 - 08:53 PM

This is just my humble non-medical research, get independent medical advice if anything - 

 

Another HDAC inhibitor - beta-hydroxybutyratethis recent publication has noted that the detrimental effects of HDAC1 inhibition are offset by SIRT1 activation (see pp.49 of the free full text). Similarly to trichostatin A, this HDACi actually also inhibits HDAC3, but it is less potent than butyrate. Tributyrin could be the among the most potent natural HDACis, but I'm not a doctor and cannot comment on it's safety. 

 

Could these then raise GDF-11? This may require further study.

 

Beta-hydroxybutyrate is actually a ketone and can be raised by calorie restriction, fasting, and by medium chain triglycerides. This ketone was traditionally thought of as an alternative source of energy for the brain when glucose levels are low, but has recently been found to act as a signalling molecule and an HDAC inhibitor.

 

A mere 30g/d of MCTs produces a mild ketosis, similar to calorie restriction, one could also reasonably expect similar effects. Aside from more energy and less appetite, these would be -

 

(Ref: John C. Newman, Ketone bodies as signaling metabolites, Trends Endocrinol Metab. 2014 Jan;25(1):42-52. [Be sure to see the full text])

  • lower mTOR activity
  • less IGF-1 signalling
  • more AMPK activity
  • Upregulation of FOXO3
  • more protein acetylation
  • more stress resistance

In Addition 

 


Edited by LexLux, 02 June 2014 - 09:07 PM.

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#27 LexLux

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Posted 04 June 2014 - 07:59 PM

Growth Hormone does not always correlate with and IGF-1 increase. 

 


Edited by LexLux, 04 June 2014 - 08:01 PM.


#28 Avatar of Horus

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Posted 04 June 2014 - 11:37 PM

...
The user called reason made a good point about all the press about this finding and the company developing this technology looking for venture capital. He also raised another issue:  "there is a strong possibility that forcing old tissues to behave as though young by changing the signaling environment - such as by using young blood - will result in a greatly raised risk of cancer."
 
Still, a very interesting result and it is good to be living in a time of such fascinating discoveries.

 
Regarding the cancer thing: that may well be so, but its opposite also seems possible, cf. with the following:

A similar approach to this parabiosis/young systemic environment/blood thing is the so-called stem cell niche, that is the more local tissue/cell environment, and its possible role in aging and rejuvenation/regeneration.
Another study from a member of the team of the above quoted paper:

Rejuvenation of aged progenitor cells by exposure to a young systemic environment
Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Nature 2005.
http://www.ncbi.nlm....pubmed/15716955

is this:

Loss of stem cell regenerative capacity within aged niches
ME Carlson and IM Conboy, Aging Cell(2007) 6.
http://www.ncbi.nlm....pubmed/17381551

Its Abstract:

This work uncovers novel mechanisms of aging within stem cell niches that are evolutionarily conserved between mice and humans and affect both embryonic and adult stem cells. Specifically, we have examined the effects of aged muscle and systemic niches on key molecular identifiers of regenerative potential of human embryonic stem cells (hESCs) and post-natal muscle stem cells (satellite cells). Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf-5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue-specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches. Significantly, this work establishes that hESC-derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo; thus, suggesting that the regenerative outcome of stem cell-based replacement therapies will be determined by a balance between negative influences of aged tissues on transplanted cells and positive effects of embryonic cells on the endogenous regenerative capacity. Comprehensively, this work points toward novel venues for in situ restoration of tissue repair in the old and identifies critical determinants of successful cell-replacement therapies for aged degenerating organs.


That is the role of the young niche/ECM, and the stem cell secreted factors.

And now about the connection of this to cancer, cf. e.g. these two papers:

Human Embryonic-like ECM (hECM) Stimulates Proliferation and Differentiation in Stem Cells While Killing Cancer Cells
Pinney et al. 2011, Int J Stem Cells. 2011 Jun;4(1):70-5., pubmed link: 24298336
Abstract
BACKGROUND AND OBJECTIVES:
There are a number of unique processes seen in the developing fetus that cease post-partum including that tumors rarely form, and scar-less wound healing and digit regeneration occur. In addition, cancer lines have been "reprogrammed" by co-culture with embryonic extracellular matrix (ECM).
METHODS AND RESULTS:
We have developed a naturally secreted human ECM (hECM) with embryonic-like characteristics which is secreted by neonatal fibroblasts grown in microcarrier suspension cultures under hypoxia. This upregulates a number of substances associated with stem cell niches in the body including various laminins, Collagen 4, CXCL12, NID1, NID2, and NOTCH2. hECM has been shown to support proliferation of hESCs and MSCs and diminish or eliminate tumor load in melanoma (B16), adenocarcinoma (MDA-MB-435), colon cancer (HT29) and glioma (C6) in both in vitro and in vivo animal studies. In the tumor chorioallantoic membrane (tumcam) model hECM significantly inhibited tumor growth and in subcutaneous mouse xenograft experiments, tumor growth was inhibited from 70∼90%. Co-cultures of fibroblasts and mesothelioma show support of fibroblast expansion with a concurrent inhibition of mesothelioma. The inhibitory affect is selective for cancer cells and cancer stem cells through the upregulation of Caspase 9 which forces the cells into apoptosis.
CONCLUSIONS:
These data show that hECM has the potential to show benefit in the treatment of various cancers as a coating for biopsy needle, tissue filler post tumor removal, and as an injectable into the tumor site.

KEYWORDS:
Cancer; Embyonic ECM; Extracellular matrix; Stem cells; Tissue-engineered ECM
PMCID:PMC3840969 Free PMC Article

and

Human Wharton's Jelly Stem Cells, its Conditioned Medium and Cell-Free Lysate Inhibit the Growth of Human Lymphoma Cells
Lin et al. 2014, Stem Cell Rev. 2014 May 2. [Epub ahead of print], pubmed link: 24789672
Abstract
Several groups have reported that primitive mesenchymal stem cells from the gelatinous matrix of the Wharton's jelly of the human umbilical cord (hWJSCs) possess tumoricidal properties and inhibit the growth of solid tumours such as human mammary carcinoma, ovarian carcinoma and osteosarcoma. This unique characteristic led to the hypothesis that hWJSCs serve as a natural defence against migrating cancer cells from mother to fetus thus explaining why tumorigenesis in the fetus is rare. However, it is not known whether non-solid malignant hematopoietic cells are also inhibited by hWJSCs and what the exact tumoricidal mechanisms are. We therefore evaluated the influence of hWJSCs and its extracts on Burkitt's lymphoma cells. Cell proliferation (BrdU and Ki67+), viability (MTT) and cell death (Annexin V-Propidium iodide and live/dead) assays showed significant inhibition of lymphoma cell growth after 48 h exposure to hWJSCs or its extracts compared to controls. Increased cell death was observed at sub-G1 and S and decreased proliferation at G2/M phases of the mitotic cycle. Superoxide dismutase and hydrogen peroxide activity were significantly increased and glutathione peroxidase significantly decreased in treated lymphoma cells. Time lapse imaging and confocal z-stack images showed yellow fluorescent in situ hybridization (FISH) signals of lymphoma cell Y chromosomes within the cytoplasm of female red labelled hWJSCs. We hypothesize that the growth of lymphoma cells is inhibited by the molecules secreted by hWJSCs that use oxidative stress pathways to induce cell death followed by engulfment of the apoptotic remains of the lymphoma cells by the hWJSCs.


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#29 pone11

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Posted 30 January 2015 - 03:39 AM

 

No one should go running off taking any of these compounds without seeking independent medical advice from a doctor, I just want to bring something up for discussion purposes. 

 

What I want to discuss is butyrate and its prodrug tributyrin - people have noted how quickly butyrate is metabolised, but it seems tributyrin has much better pharmokinetics and the other interesting thing is that tributyrate is sold as a food grade flavor?!  10kg for 200 British pounds? Am I mistaken? Apparently it's naturally present in butter as well. Perhaps selective HDAC 3 inhibitors like this RGFP966 should be studied further? Here it was used to enhance the extinction of cocaine seekinng behavior: http://www.pnas.org/...364110.full.pdf

 

 

Does anyone know of a commercial source for tributyrin in small doses?

 

I have tried sodium butyrate, and it causes me incredible intestinal distress.  This is true even though I supposed have high butyrate levels measured on my gut tests.



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#30 pone11

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Posted 30 January 2015 - 05:23 AM

 

No one should go running off taking any of these compounds without seeking independent medical advice from a doctor, I just want to bring something up for discussion purposes. 

 

What I want to discuss is butyrate and its prodrug tributyrin - people have noted how quickly butyrate is metabolised, but it seems tributyrin has much better pharmokinetics and the other interesting thing is that tributyrate is sold as a food grade flavor?!  10kg for 200 British pounds? Am I mistaken? Apparently it's naturally present in butter as well. Perhaps selective HDAC 3 inhibitors like this RGFP966 should be studied further? Here it was used to enhance the extinction of cocaine seekinng behavior: http://www.pnas.org/...364110.full.pdf

 

Tributyrin, a Stable and Rapidly Absorbed Prodrug of Butyric Acid, Enhances Antiproliferative Effects of Dihydroxycholecalciferol in Human Colon Cancer Cells

 

 

I can't help but wonder would tributyrin have value in stimulating ketosis, perhaps better than MCT Oil?







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