Jane Schastnaya : New Insights Into The Mechanism Of Action Of Minoxidil With Aa | HairLossTalk Forums

Jane Schastnaya : New Insights Into The Mechanism Of Action Of Minoxidil With Aa

Discussion in 'Hair Loss and Alopecia Published Studies' started by Noisette, Jul 21, 2017.

  1. Noisette

    Noisette Established Member

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    Title : " An analysis of gene expression data involving examination of signaling pathways activation reveals new insights into the mechanism of action of minoxidil topical foam in men with androgenetic alopecia " Full Text uploaded . June 2017


    Abstract :
    Androgenetic alopecia is the most common form of hair loss. Minoxidil has been approved for the treatment of hair loss, however its mechanism of action is still not fully clarified. In this study, we aimed to elucidate the effects of 5% minoxidil topical foam on gene expression and activation of signaling pathways in vertex and frontal scalp of men with androgenetic alopecia. We identified regional variations in gene expression and perturbed signaling pathways using in silico Pathway Activation Network Decomposition Analysis (iPANDA) before and after treatment with minoxidil. Vertex and frontal scalp of patients showed a generally similar response to minoxidil. Both scalp regions showed upregulation of genes that encode keratin associated proteins and downregulation of ILK, Akt, and MAPK signaling pathways after minoxidil treatment. Our results provide new insights into the mechanism of action of minoxidil topical foam in men with Androgenetic Alopecia.

    Discussion :
    Our analysis revealed that both genes and non-coding RNAs were differentially expressed between vertex and frontal scalp before and after treatment with MTF 5%.

    We observed variations in gene expression in the two scalp regions before treatment. Several genes, including genes induced by oxidative stress and growth factors (DUSP1, CYR61),26–28 and non-coding RNAs were upregulated in frontal compared to vertex scalp, while the expression of pseudogene MSL3P1 that may be involved in chromatin remodeling and regulation of transcription was decreased. These results suggest that gene expression in hair follicles in vertex versus frontal scalp of patients with Androgenetic Alopecia may not be completely identical and exhibit different molecular signatures.

    In general, vertex and frontal scalp showed similar molecular response to MTF 5% treatment. The strong upregulation of keratin-associated genes in both the vertex and frontal regions was a distinctive feature of responding patients, while patients who showed minimal response to MTF 5% treatment did not exhibit a similar level of upregulation of keratin-associated genes. The expression of several non-coding RNAs was significantly decreased in both scalp regions after treatment. It should be noted that keratinization-related genes were downregulated in the frontal scalp of both responders and placebo control patients. Thus, it is not clear whether the decreased expression of late cornified envelope protein 3D (LCE3D) was caused by the MTF 5% treatment or other as yet unidentified factors. We also observed regional variations in gene expression after treatment with MTF 5%. Collagen type VI alpha 6 chain (COL6A6), fatty acid and lipid metabolism genes (ACOT4, CIDEA) and several non-coding 8 RNAs were upregulated in frontal scalp compared to vertex. The downregulated genes included keratinencoding and keratin-associated genes as well as genes that play a role in cation channel activity and extracellular matrix binding. It is tempting to speculate that these differences in gene expression reflect the underlying mechanism of the response of hair follicles from two scalp regions to MTF 5% treatment. Baseline regional variations between frontal and vertex scalp were also visible upon pathway level examination. Thus, IL-2, which is being studied in the context of alopecia areata,29 and ILK, a key mediator in integrin signal transduction, were upregulated pathways identified in frontal compared to vertex scalp.

    The following pathways were also upregulated in frontal versus vertex scalp before treatment: MAPK (facilitates the survival of dermal papilla cells30), TGF-beta (induces catagen31), JAK/STAT (prevents anagen reentry32), PTEN, Akt (promotes dermal papilla cells survival and anagen initiation33,34). The downregulated pathways included IL-6, which may provoke inflammation, and Presenilin action in Notch and Wnt signaling (NCI) pathways.

    It has been shown that activation of Notch signaling is necessary for keratinocyte differentiation, and Wnt signaling drives hair follicle morphogenesis, hair shaft differentiation, hair cycling induction and maintenance.37–42 ILK, Akt, and MAPK pathways became downregulated in both vertex and frontal scalp of responders after treatment with MTF 5%.

    Previous studies have shown that Akt and MAPK pathways promote dermal papilla cell survival, so the effect of minoxidil on these pathway requires further clarification. JAK/STAT signaling and Ras pathways were downregulated in vertex scalp of patients who responded to MTF 5% treatment. JAK/STAT inhibition should promote hair growth, while Ras pathway regulates cellular proliferation, differentiation, and senescence by stimulating various parallel effector pathways.43 Protein digestion and absorption pathway, which includes several collagen-encoding genes, was significantly upregulated in the frontal scalp of responders.

    MTF 5% treatment also caused upregulation of mTOR pathway in the frontal scalp region. It is known that mTOR pathway promotes hair follicle stem cells proliferation and activation, and is activated at the moment of telogen-to-anagen transition.44,45 9 The results of our analysis suggest that vertex and frontal scalp of

    Androgenetic Alopecia patients showed generally similar response to minoxidil treatment implying that minoxidil can be recommended for both vertex and frontal scalp. However, there were some differences in response to the treatment at the level of gene expression and signaling pathways response. Both scalp regions showed upregulation of genes that encode keratin-associated proteins and downregulation of ILK, Akt, and MAPK signaling pathways after MTF 5% treatment, suggesting that control of inflammation in conjunction with keratin stimulation may contribute to the improvement of hair growth disorders. To our knowledge this is the first time that regional variations in the activation of signaling pathways before and after treatment with MTF 5% has received significant attention. These results were based on available data from a study involving a minoxidil foam product,25 and as such may not be representative of all products containing minoxidil.


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  2. Grasshüpfer

    Grasshüpfer Experienced Member My Regimen

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    Noisette i love you. ;)
    So science is moving forward.
     
  3. c_super2

    c_super2 Established Member

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    How do we control inflammation?
     
  4. Afro_Vacancy

    Afro_Vacancy Senior Member My Regimen

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    Sugar, white flour, vegetable oils.
     
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  5. c_super2

    c_super2 Established Member

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    ok.

    Are there any products or pills that reduce the amount of inflammation in the scalp or is diet sufficient?
     
  6. Afro_Vacancy

    Afro_Vacancy Senior Member My Regimen

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    Yoga, massages, exercise, sleep, good fats supposedly.
     
  7. hairblues

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    I did not read this whole thing

    But some people with Alopecia Areata and other auto immune diseases try something called paleo elimination diet..or Autoimmune protocol diet...its basically about lowering inflammation as that is a trigger supposedly for auto immune response....you can google it, they have a face group page.

    BUT I dont know if inflation in scalp would be affected by diet, this diet is more about inflammation in your intestines from what I understand...but who knows.

    One of the 'theories' with PRP is if you have a biopsy that has inflammation you are more likely to get a positive result...I dont think everyone with Androgenetic Alopecia has inflammation...a lot of women with Androgenetic Alopecia do though. Not sure the reason why...but this is theoretically why more women have positive results with PRP then men..the inflammation.

    Example
    I have inflammation in my scalp biopsy (scant inflammation))
    BUT my physicals, my extensive blood work is perfect..I am picture or health I dont have any signs of inflammation in my body...not for my age--but for any age my Dr is always amazed.
    So good diet and healthy lifestyle in my opinion is not going to lower scalp inflammation

    IF I am understanding this correctly. (Sleepy)
     
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  8. lemoncloak

    lemoncloak Established Member My Regimen

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    She's kinda cute tho
     
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  9. ALightInTheDark

    ALightInTheDark Established Member My Regimen

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    JAK/STAT signaling and Ras pathways were downregulated in vertex scalp of patients who responded to MTF 5% treatment

    So basically,we shouldn't put minoxidil on the Vertex ?
     
  10. hellouser

    hellouser Senior Member My Regimen

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  11. bboy

    bboy Member My Regimen

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    Inhibition of JAK/STAT is what we want. It's it's inhibition that promotes hair growth.
     
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  12. bboy

    bboy Member My Regimen

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    This raises a lot of questions though.

    Firstly why are there difference between the frontal and vertex? Are we actually maybe looking at two variations of the same disease?

    A study I read seems to indicate that MPAK helps shut down DP cells to prevent them from becoming exhausted, so it's overexpression could be contributing to holding DP cells in a quiescent state, more than they should be. But is the difference between the frontal and vertex just a marginal difference between a general difference from what you would see on a non balding scalp?

    Why is minoxidil having opposite effects on certain pathways given the location of the scalp it's applied to?

    Without going into too much broscience it seems minoxidil is a bit of a blunt weapon. It's inhibiting somethings we need and up regulating some things we don't, and it appears to be doing this differently depending on if you apply it to the frontal or vertex scalp. Why?

    And why are there difference between the frontal and vertex to begin with?
     
  13. InBeforeTheCure

    InBeforeTheCure Established Member My Regimen

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    I don't understand the before vs. after results (besides increased expression of hair follicle structural proteins, which is probably trivial), but the frontal vs. vertex comparison shows a blatant signature of reduced Wnt signaling activity in frontal scalp compared to vertex.

    Gene - (Frontal vs. vertex, log2 fold change) vs. (beta-catenin conditional knockout mice bulge, log2 fold change from Lien et al.)

    Fos - 1.93 vs. 1.43
    Dusp1 - 1.18 vs. 1.39

    Mir21 - 1.12 vs. Not Detected
    Fosb - 1.08 vs. 1.13
    Cyr61 - 0.79 vs. 1.56

    Nr4a2 - 0.71 vs. Not Detected
    Atf3 - 0.66 vs. 1.70
    Egr1 - 0.55 vs. 1.35

    Cd69 - 0.50 vs. Not Detected
    Junb - 0.48 vs. 0.88
    Zfp36 - 0.45 vs. 1.04

    Mmp1 - 0.44 vs. Not Detected
    Rgs1 - 0.44 vs. Not Detected
    Snord116-26 - 0.41 vs. Not Detected
    Msl3p1 - -0.59 vs. Not Detected

    Of the 8 genes upregulated in frontal vs. vertex scalp that are detected in the bulge in Lien et al., every single one of them is also upregulated by beta-catenin knockout.
     
  14. InBeforeTheCure

    InBeforeTheCure Established Member My Regimen

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    Both activation and inhibition of Jak/Stat signaling have been shown to promote hair growth, oddly enough...
     
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