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Since I have been asking whether or not anyone would want to do a group buy for MG132, I thought I’d make a seperate thread about what exactly it does, and how it can promote hair growth. I’ll also add some bits about how it’s used, and potential sides.
To begin with, we look at some of the studies which show topical proteasome inhibitors stimulate hair growth.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116182/#!po=31.7308
Partial Proteasome Inhibitors Induce Hair Follicle Growth by Stabilizing β-catenin
Abstract
The activation of tissue stem cells from their quiescent state represents the initial step in the complex process of organ regeneration and tissue repair. While the identity and location of tissue stem cells are becoming known, how key regulators control the balance of activation and quiescence remains mysterious. Here, we show that hair cycle timing depends on regulated stability of signaling substrates by the ubiquitin-proteasome system. Topical application of partial proteasomal inhibitors (PaPIs) inhibits epidermal and dermal proteasome activity throughout the hair cycle. PaPIs prevent the destruction of the key anagen signal β-catenin, resulting in more rapid hair growth and dramati cally shortened telogen. PaPIs thus represent a novel class of hair growth agents that act through transiently modifying the balance of stem cell activation and quiescence pathways.
Stem cell activation forms the basis for tissue regeneration and occurs both spontaneously and during injury or stress. The UPS (Ubiquitin/Proteasome System) regulates the stability of key substrates and in turn controls the timing of key developmental events such as cell cycle progression and fertilization.
A PaPI effect on hair cycle has been reported before but was thought to be through BMP2 activation. While PaPIs appear to affect multiple signaling pathways, we find that they preferentially stabilize the Wnt pathway component β-catenin, downstream of DKK. Studies of known signaling pathways in the skin have defined both stem cell activation and quiescence pathways as targets of the UPS, including the role in quiescence for BMP2. However, our study of topically applied PaPIs reveals little detectable alteration of quiescence regulators and argue against derepression of quiescence as the mechanism for PaPI action. Rather, our study identifies β-catenin as the most sensitive of the potential substrates to UPS inhibition. Moreover, because we found that increasing doses of β-catenin in conjunction with PaPIs can accelerate the onset of anagen, we postulate a threshold of β-catenin protein above which anagen is induced. Such a threshold would likely be set by the activity of BMP and NfatC1. Consistent with this model, GSK3βinhibitors dramatically shorten the length of telogen. UPS regulation of the hair cycle is analogous to that of the cell cycle, where the anaphase promoting complex regulates the destruction of G1 substrates to control the cell cycle checkpoints [14]. For the hair cycle, ongoing destruction of β-catenin at the beginning of telogen is critical to maintain the resting phenotype.
We have uncovered a novel mechanism for the PaPIs that have marked effects on normal hair growth cycling.
Our data in hair follicle regulation clearly show that PaPIs function through the stabilization of β-catenin signaling leading to a shortened telogen phase. This is consistent with the previously published role for Wnt signaling in mediating anagen and possessing the ability to ectopically activate anagen. While our data support a central role for PaPIs/GSK3β in acting on the Wnt pathway, we cannot rule out smaller contributions from other pathways. Previous studies on the role of Wnt signaling in hair cycling have clearly demonstrated a role for the Wnt ligand in hair cycling, suggesting that Wnt agonists may have similar effects as PaPIs. However, because Wnts have sustained activity, they are associated with the induction of cancer. Transient stabilization and Wnt pathway activation by reversibly stabilizing β-catenin with PaPIs portends a preferable and potentially safer alternative as a hair growth therapy.
(This last statement here is important, because it backs the reasons for cycling the use of topical ppi’s for 3 week on, 3-4 week off periods. )
RESULTS OF TOPICAL APPLICATION
To determine the effects of PaPIs on skin, we treated murine skin topically with PaPIs starting in the middle of the first anagen cycle every other day for 2 weeks. PaPI-treated skin demonstrated remarkable enhancement of hair growth (Fig. 2A, 2B) through the shortening of the resting (telogen) phase and increased hair growth during anagen. We measured the stage of the hair cycle using skin pigmentation, and correlated that with hair counts. During the anagen growth phase, the length of the guard hair was increased by approximately 20% relative to vehicle control for both PaPIs we tested (Supporting Information Fig. S1, p <.01). This was true at multiple sites along the dorsal back, ruling out a local penetration effect. Interestingly, the length of anagen was relatively unchanged (Fig. 2C) indicating that the growth rate of the hair was increased. Moreover, PaPI treatment also affected the enforcement of the resting or telogen stage. In untreated animals, quiescent hair follicle stem cells in the second telogen typically remain dormant for 21 days until they asynchronously enter anagen. Remarkably, Bortezomib-treated animals re-entered anagen prematurely, with an average return to anagen after 3–5 days. PaPI treatment results in longer hair due to more rapid anagen growth and inhibition of the quiescent telogen phase of the hair cycle.
Now, back in 2007 there was actually a company called NEOSIL that successfully did trials for a topical PPI on humans. They described it as “a powerful stimulator of new hair growth, so poweful that you only need to apply it daily, for 21 days, stop, and watch new hair grow (then repeat the 21 day cycle again sometime later)”.
The results are as follows. Sadly they ran out of funding and jumped ship.
In a randomized, double-blind Phase 2a clinical study, conducted in Germany, 50 men with androgenetic alopecia (Norwood/Hamilton grades III-IV) received once-daily topical treatments of NEOSH101 or placebo over two 14-day treatment periods, which were separated by a one-month drug-free interval. Hair growth was measured using an objective photographic, computer-based analysis for up to 24 weeks after initiation of therapy. Results show that NEOSH101 was safe and well tolerated. A statistically significant increase in total hair count (4.8%, p=0.04), and cumulative hair thickness (3.7%, p=0.02) were observed, with peak effects occurring eight weeks following the second treatment cycle.
“The results of this study are encouraging, particularly the finding of increased numbers of terminal hairs, those hairs that are thicker than 40 microns and desirable for scalp coverage,” said Andria Langenberg, M.D., Vice President of Clinical Development at Neosil. “We plan to initiate a Phase 2b study to evaluate daily treatment with NEOSH101 for a longer treatment period in men with PHL.”
Neosil used OSH 101 (ppi topical) as a candidate drug for hair re-growth in a proprietary screening program. In animal studies, it was observed that topical administration of OSH101 strongly stimulates dormant hair follicles, increases hair follicle thickness, and overall hair growth. The picture to the right demonstrates the increase in the size and thickness of hair follicles treated topically with OSH101 versus untreated controls. The purple colored bulbs are hair follicles. In the untreated control, the follicles remain small and inactive, while the follicles in the treated group were stimulated and show marked increase in their size and thickness. Treatment with OSH101 for 21 days re-grew healthy, thick hair; whereas the untreated control group barely began to re-grow any hair. OSH101 is a powerful stimulator of new hair growth.
OSH101’s hair growth effect was also compared to the hair growth effect of Rogaine®. The two groups were treated with OSH101 and Rogaine® respectively once per day for five days. After an additional sixteen days elapsed, hair growth was measured. OSH101 resulted in much faster and thicker hair growth than Rogaine®.”
Now, because the trials were ditched and we were left in the lurch, people did in fact go on to try topical PPI’s.
Now the very first choice was PSI, which was what NEOSIL used. However, apart from the fact that it’s INCREDIBLY expensive, it would also found that it is pretty unstable in solution. That brings us to PSI’s less expensive sister, MG132, which is comparative to PSI for proteasome Inhibition, and seems to be preferred in the studies too.
Safety? Well we know that long term use of proteasome inhibitors can cause neural issues, Alzheimer’s etc, but all the studies where topical application used in cyclical administration was employed showed a good safety outcome.
I’d also like to draw your attention to this:
https://www.ncbi.nlm.nih.gov/m/pubmed/12119296/
Upon binding to androgen, the androgen receptor (AR) can translocate into the nucleus and bind to androgen response element(s) to modulate its target genes. Here we have shown that MG132, a 26 S proteasome inhibitor, suppressed AR transactivation in an androgen-dependent manner in prostate cancer LNCaP and PC-3 cells. In contrast, MG132 showed no suppressive effect on glucocorticoid receptor transactivation. Additionally, transfection of PSMA7, a proteasome subunit, enhanced AR transactivation in a dose-dependent manner. The suppression of AR transactivation by MG132 may then result in the suppression of prostate-specific antigen, a well known marker used to monitor the progress of prostate cancer. Further mechanistic studies indicated that MG132 may suppress AR transactivation via inhibition of AR nuclear translocation and/or inhibition of interactions between AR and its coregulators, such as ARA70 or TIF2. Together, our data suggest that the proteasome system plays important roles in the regulation of AR activity in prostate cancer cells and may provide a unique target site for the development of therapeutic drugs to block androgen/AR-mediated prostate tumor growth.
There are a few other studies which go into the AR/proteasome inhibition relationship, but essentially we are also looking at this as a potential antiandrogen.
Others have trialed PSI and MG with some success, but mostly on the private forums, so I can’t give you many anecdotal accounts, but there I one that I care across on HLH, and this guy is also a member of the private forum.
He states that he he used MG132 500mg/26ml for the 21 week cycle with some success. Not sure what vehicle he used, but I believe the best route is dmso/ethanol.
0tk1
Newbie
Posts: 2
Joined: 06/01/2014
Im using this drug since mid april. 500mg at 1- 1,25 ml
Soon im up to the 2 months and report vellous.Hair loss is stopped since late april.
Before use mg i was using ru and minoxidil.Today only mg-132
0tk1
Newbie
Posts: 2
Joined: 06/01/2014
Im using this drug since mid april. 500mg at 1- 1,25 ml
Soon im up to the 2 months and report vellous.Hair loss is stopped since late april.
Before use mg i was using ru and minoxidil.Today only mg-132
So with that, I have in fact found suppliers
on alibaba. The best quote I’ve received thus far is $460 US for 1g which is EXCELLENT compared to all others. They have sent me various certificates of authenticity and confirmed 98% purity, but if we go ahead we still may need to test it.
This is a really long shot guys, and it will be expensive even if we go for the cheaper options. I just want to gauge what interest there is here, and if anyone is willing to try.
Thanks for reading this mess of a post.
To begin with, we look at some of the studies which show topical proteasome inhibitors stimulate hair growth.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116182/#!po=31.7308
Partial Proteasome Inhibitors Induce Hair Follicle Growth by Stabilizing β-catenin
Abstract
The activation of tissue stem cells from their quiescent state represents the initial step in the complex process of organ regeneration and tissue repair. While the identity and location of tissue stem cells are becoming known, how key regulators control the balance of activation and quiescence remains mysterious. Here, we show that hair cycle timing depends on regulated stability of signaling substrates by the ubiquitin-proteasome system. Topical application of partial proteasomal inhibitors (PaPIs) inhibits epidermal and dermal proteasome activity throughout the hair cycle. PaPIs prevent the destruction of the key anagen signal β-catenin, resulting in more rapid hair growth and dramati cally shortened telogen. PaPIs thus represent a novel class of hair growth agents that act through transiently modifying the balance of stem cell activation and quiescence pathways.
Stem cell activation forms the basis for tissue regeneration and occurs both spontaneously and during injury or stress. The UPS (Ubiquitin/Proteasome System) regulates the stability of key substrates and in turn controls the timing of key developmental events such as cell cycle progression and fertilization.
A PaPI effect on hair cycle has been reported before but was thought to be through BMP2 activation. While PaPIs appear to affect multiple signaling pathways, we find that they preferentially stabilize the Wnt pathway component β-catenin, downstream of DKK. Studies of known signaling pathways in the skin have defined both stem cell activation and quiescence pathways as targets of the UPS, including the role in quiescence for BMP2. However, our study of topically applied PaPIs reveals little detectable alteration of quiescence regulators and argue against derepression of quiescence as the mechanism for PaPI action. Rather, our study identifies β-catenin as the most sensitive of the potential substrates to UPS inhibition. Moreover, because we found that increasing doses of β-catenin in conjunction with PaPIs can accelerate the onset of anagen, we postulate a threshold of β-catenin protein above which anagen is induced. Such a threshold would likely be set by the activity of BMP and NfatC1. Consistent with this model, GSK3βinhibitors dramatically shorten the length of telogen. UPS regulation of the hair cycle is analogous to that of the cell cycle, where the anaphase promoting complex regulates the destruction of G1 substrates to control the cell cycle checkpoints [14]. For the hair cycle, ongoing destruction of β-catenin at the beginning of telogen is critical to maintain the resting phenotype.
We have uncovered a novel mechanism for the PaPIs that have marked effects on normal hair growth cycling.
Our data in hair follicle regulation clearly show that PaPIs function through the stabilization of β-catenin signaling leading to a shortened telogen phase. This is consistent with the previously published role for Wnt signaling in mediating anagen and possessing the ability to ectopically activate anagen. While our data support a central role for PaPIs/GSK3β in acting on the Wnt pathway, we cannot rule out smaller contributions from other pathways. Previous studies on the role of Wnt signaling in hair cycling have clearly demonstrated a role for the Wnt ligand in hair cycling, suggesting that Wnt agonists may have similar effects as PaPIs. However, because Wnts have sustained activity, they are associated with the induction of cancer. Transient stabilization and Wnt pathway activation by reversibly stabilizing β-catenin with PaPIs portends a preferable and potentially safer alternative as a hair growth therapy.
(This last statement here is important, because it backs the reasons for cycling the use of topical ppi’s for 3 week on, 3-4 week off periods. )
RESULTS OF TOPICAL APPLICATION
To determine the effects of PaPIs on skin, we treated murine skin topically with PaPIs starting in the middle of the first anagen cycle every other day for 2 weeks. PaPI-treated skin demonstrated remarkable enhancement of hair growth (Fig. 2A, 2B) through the shortening of the resting (telogen) phase and increased hair growth during anagen. We measured the stage of the hair cycle using skin pigmentation, and correlated that with hair counts. During the anagen growth phase, the length of the guard hair was increased by approximately 20% relative to vehicle control for both PaPIs we tested (Supporting Information Fig. S1, p <.01). This was true at multiple sites along the dorsal back, ruling out a local penetration effect. Interestingly, the length of anagen was relatively unchanged (Fig. 2C) indicating that the growth rate of the hair was increased. Moreover, PaPI treatment also affected the enforcement of the resting or telogen stage. In untreated animals, quiescent hair follicle stem cells in the second telogen typically remain dormant for 21 days until they asynchronously enter anagen. Remarkably, Bortezomib-treated animals re-entered anagen prematurely, with an average return to anagen after 3–5 days. PaPI treatment results in longer hair due to more rapid anagen growth and inhibition of the quiescent telogen phase of the hair cycle.
Now, back in 2007 there was actually a company called NEOSIL that successfully did trials for a topical PPI on humans. They described it as “a powerful stimulator of new hair growth, so poweful that you only need to apply it daily, for 21 days, stop, and watch new hair grow (then repeat the 21 day cycle again sometime later)”.
The results are as follows. Sadly they ran out of funding and jumped ship.
In a randomized, double-blind Phase 2a clinical study, conducted in Germany, 50 men with androgenetic alopecia (Norwood/Hamilton grades III-IV) received once-daily topical treatments of NEOSH101 or placebo over two 14-day treatment periods, which were separated by a one-month drug-free interval. Hair growth was measured using an objective photographic, computer-based analysis for up to 24 weeks after initiation of therapy. Results show that NEOSH101 was safe and well tolerated. A statistically significant increase in total hair count (4.8%, p=0.04), and cumulative hair thickness (3.7%, p=0.02) were observed, with peak effects occurring eight weeks following the second treatment cycle.
“The results of this study are encouraging, particularly the finding of increased numbers of terminal hairs, those hairs that are thicker than 40 microns and desirable for scalp coverage,” said Andria Langenberg, M.D., Vice President of Clinical Development at Neosil. “We plan to initiate a Phase 2b study to evaluate daily treatment with NEOSH101 for a longer treatment period in men with PHL.”
Neosil used OSH 101 (ppi topical) as a candidate drug for hair re-growth in a proprietary screening program. In animal studies, it was observed that topical administration of OSH101 strongly stimulates dormant hair follicles, increases hair follicle thickness, and overall hair growth. The picture to the right demonstrates the increase in the size and thickness of hair follicles treated topically with OSH101 versus untreated controls. The purple colored bulbs are hair follicles. In the untreated control, the follicles remain small and inactive, while the follicles in the treated group were stimulated and show marked increase in their size and thickness. Treatment with OSH101 for 21 days re-grew healthy, thick hair; whereas the untreated control group barely began to re-grow any hair. OSH101 is a powerful stimulator of new hair growth.
OSH101’s hair growth effect was also compared to the hair growth effect of Rogaine®. The two groups were treated with OSH101 and Rogaine® respectively once per day for five days. After an additional sixteen days elapsed, hair growth was measured. OSH101 resulted in much faster and thicker hair growth than Rogaine®.”
Now, because the trials were ditched and we were left in the lurch, people did in fact go on to try topical PPI’s.
Now the very first choice was PSI, which was what NEOSIL used. However, apart from the fact that it’s INCREDIBLY expensive, it would also found that it is pretty unstable in solution. That brings us to PSI’s less expensive sister, MG132, which is comparative to PSI for proteasome Inhibition, and seems to be preferred in the studies too.
Safety? Well we know that long term use of proteasome inhibitors can cause neural issues, Alzheimer’s etc, but all the studies where topical application used in cyclical administration was employed showed a good safety outcome.
I’d also like to draw your attention to this:
https://www.ncbi.nlm.nih.gov/m/pubmed/12119296/
Upon binding to androgen, the androgen receptor (AR) can translocate into the nucleus and bind to androgen response element(s) to modulate its target genes. Here we have shown that MG132, a 26 S proteasome inhibitor, suppressed AR transactivation in an androgen-dependent manner in prostate cancer LNCaP and PC-3 cells. In contrast, MG132 showed no suppressive effect on glucocorticoid receptor transactivation. Additionally, transfection of PSMA7, a proteasome subunit, enhanced AR transactivation in a dose-dependent manner. The suppression of AR transactivation by MG132 may then result in the suppression of prostate-specific antigen, a well known marker used to monitor the progress of prostate cancer. Further mechanistic studies indicated that MG132 may suppress AR transactivation via inhibition of AR nuclear translocation and/or inhibition of interactions between AR and its coregulators, such as ARA70 or TIF2. Together, our data suggest that the proteasome system plays important roles in the regulation of AR activity in prostate cancer cells and may provide a unique target site for the development of therapeutic drugs to block androgen/AR-mediated prostate tumor growth.
There are a few other studies which go into the AR/proteasome inhibition relationship, but essentially we are also looking at this as a potential antiandrogen.
Others have trialed PSI and MG with some success, but mostly on the private forums, so I can’t give you many anecdotal accounts, but there I one that I care across on HLH, and this guy is also a member of the private forum.
He states that he he used MG132 500mg/26ml for the 21 week cycle with some success. Not sure what vehicle he used, but I believe the best route is dmso/ethanol.
0tk1
Newbie
Posts: 2
Joined: 06/01/2014
Im using this drug since mid april. 500mg at 1- 1,25 ml
Soon im up to the 2 months and report vellous.Hair loss is stopped since late april.
Before use mg i was using ru and minoxidil.Today only mg-132
0tk1
Newbie
Posts: 2
Joined: 06/01/2014
Im using this drug since mid april. 500mg at 1- 1,25 ml
Soon im up to the 2 months and report vellous.Hair loss is stopped since late april.
Before use mg i was using ru and minoxidil.Today only mg-132
So with that, I have in fact found suppliers
on alibaba. The best quote I’ve received thus far is $460 US for 1g which is EXCELLENT compared to all others. They have sent me various certificates of authenticity and confirmed 98% purity, but if we go ahead we still may need to test it.
This is a really long shot guys, and it will be expensive even if we go for the cheaper options. I just want to gauge what interest there is here, and if anyone is willing to try.
Thanks for reading this mess of a post.
Last edited:
