+ Reply to Thread
Page 4 of 4 FirstFirst ... 2 3 4
Results 31 to 35 of 35
  1. #31
    Senior Member
    Join Date
    May 2014
    Posts
    803

    Default

    Quote Originally Posted by Tenma View Post
    Totally agree with that statement. I think the key to long term prevention is simultaneously combat dht using drugs working by those two mechanisms.


    Thats why cb/ru + dut is the best combo for long term maintenance.


    Swooping, do you see something on the horizon regarding all these fascinating research about the strong connection between cellular senescence and aga? Therapeutically speaking, of course
    Yes I agree, prevention is your best bet by doing these things to keep those cells in a healthy condition. I don't see anything on the horizon for a full reversal cure, at least not from a drug form whatsoever. Ultimately a cell based therapy or genetic engineering would be the perfect answer for AGA in my opinion.

  2. #32
    Doctor Representative 35YrsAfter's Avatar
    Join Date
    Aug 2012
    Location
    Alpharetta, GA
    Posts
    1,361

    Default

    Quote Originally Posted by Swooping View Post
    Yes I definitely agree with you on that. I very doubt that it would be possible to have a drug short term which will cure AGA. Something like estrogen that doesn't go systematic would be of great help indeed, would use immediately! I would already if it wouldn't bring boobs with it .
    I'm surprised I don't hear of men derma rolling estrogen.

    Chuck

  3. #33
    Senior Member
    Join Date
    May 2014
    Posts
    803

    Default

    "The consensus about what stress signal(s) after activation of the androgen receptor lead to premature senescence in AGA is not completely known. However literature points much to ROS or DNA damage or a intertwining effect of them both. This stress is to much for the cells to handle and then major pathways get activated which lead to senescence."

    This is indeed a pretty big question at the moment, however if you look at the previous study we can perhaps dig a bit further into why the cells get stressed and senescence pathways like P53/pRB/P16ink4a set in. This is the study I'm talking about; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164265/

    Microarray analysis of androgenetic and senescent alopecia: Comparison of gene expression shows two distinct profiles
    Hair/skin development and function is the most significant physiological function altered in both AGA and SA (senescent alopecia), however, the DEGs (differentially expressed genes) in this category differed in the two diseases. Table 1 shows the 34 genes in this category that are differentially regulated in AGA that contribute to hair follicle development, morphology and cycling (BARX2, EGFR, INHBA, MSX2, OVOL1, KRTs, KRTAPs, RUNX3 and TIMP3). Many of these genes required for hair follicle homeostasis are significantly under expressed in AGA but not in SA compared to normal scalp tissue (Table 1 and Figure S1). Our data (Table 1 & Figure S1) showed that the Androgen Receptor (AR) is up regulated in AGA, but not in SA. Previous studies [4] have shown that genetic variability in AR is a prerequisite for the development of early-onset AGA. A novel AGA susceptibility locus has been identified at 17q21.31 [5]. In our dataset, the DEAD box polypeptide 5 (DDX5), a transcriptional regulator of AR [6] is down regulated in AGA and maps to this locus. The most significant pathway altered in AGA is Notch Signaling which consists of 29 genes (Table 1) including HES1, Notch2, Notch4 and PROX1 that are known to play a role in cell fate determination [7]. The down regulated genes in this pathway in AGA include CNTN1, JAG1, NOTCH2 and PSEN1 and the genes that are up regulated include DTX3, HES and NOTCH4. The expression patterns of Notch signaling pathway genes including Notch 2 and JAG1 were validated by real-time PCR (Figure S1). Jagged1 (JAG1) gene which encodes a ligand for Notch receptor maps to chromosome 20p a susceptibility locus for male-pattern baldness [8]. A reciprocal negative feedback regulation exists between Notch and AR-dependent pathways in the prostate [9]. The activation of AR and the concomitant loss of Notch signaling may be contributing factors to hair follicle miniaturization and may serve as the mechanistic link between prostate cancer and AGA. Thus, modulating the Notch signaling pathway in AGA may lead to future therapies.
    This is the table with differentially expressed genes in androgenetic alopecia with changes of -2 or +2 , basically the ones that stand out the most; http://www.ncbi.nlm.nih.gov/pmc/arti...ort=objectonly



    Obviously as said there is evidence again that the androgen receptor is fcked in AGA, they found a 2.46 fold increase of this compared to control as you can see in the link just above and in the picture here above where I underlined it in purple. I underlined the Aryl hydrocarbon receptor nuclear translocator-like 2 because that one is the most differentially expressed in this research paper with a fold change of -12.13. This gene encodes a protein that is a co-factor in transcriptional regulation by hypoxia-inducible factor 1 (HIF-1A). We'll come back to this later.

    Now they say that the most significant pathway altered in androgenetic alopecia is NOTCH signalling which consists of 29 genes. Furthermore they refer to a other study which found a suspectibility locus for AGA at chromosome 20p, and JAGGED1 (JAG1) gene is a ligand for the NOTCH receptor and maps to this. They propose that activation of the androgen receptor leads to loss of NOTCH signalling which results in miniaturization;

    In conclusion, we found that canonical Notch signaling is required for late-stage granular layer differentiation and correct filaggrin processing in the epidermis. Importantly, Notch signaling loss in hair follicle lineages leads to DNA damage response and loss of stem cell characteristics, which is possibly due to aberrant activation of bulge stem cells.
    Remember DNA damage? Obviously a signal which can lead very well to senescence by pathways like P53/P16/P21 etc like described in this thread.

    Nonetheless, let's dig a bit further and connect the dots a bit further ourself from the information in this study. We have;

    - Altered androgen receptor 2.46 fold
    - Altered Aryl hydrocarbon receptor nuclear translocator-like 2 -12.13 fold
    - NOTCH signalling most significant pathway altered (29 genes)

    Let's propose a hypothesis and try to connect those 3 together. First we are going to look at if NOTCH and the androgen receptor have interactions with each other as proposed;


    .The AR and Notch receptors play essential roles in the regulation of prostate development and homeostasis. Notch signaling initiates when receptor-bearing cells interact with Notch ligands present in neighboring cells. Notch activation causes an increase in HEY1 expression and HEY1 accumulates in the nucleus repressing AR transcriptional activity. In a reciprocal way, the activation of AR upon androgen binding downregulates the expression of Notch1 receptor and its ligand Jagged1, and upregulates Sel1L, a negative regulator of Notch.
    NOTCH is also expressed abundantly in hair follicles. I underlined here evidence that the activation of AR upon androgen binding can for instance downregulate NOTCH signalling and the ligand JAGGED1 which maps to a suspectible locus in AGA. I'm not going to go to deep into this, but there are many studies which show androgen receptor interaction with NOTCH, you can look them up yourself if you want.

    So yes perhaps in AGA because of an overexpressed androgen receptor there is loss of NOTCH signalling. Now we go to the second point , can NOTCH signalling be connected to the Altered Aryl hydrocarbon receptor nuclear translocator-like 2 with a -12.13 fold gene expression in AGA? As I this gene encodes a protein that is a co-factor in transcriptional regulation by hypoxia-inducible factor 1 (HIF-1A). HIF-1A is also abundantly expressed in the hair follicle.

    Let's look up what HIF-1A is ;

    The protein encoded by HIF1 is a bHLH - PAS transcription factor found in mammalian cells growing at low oxygen concentrations. It plays an essential role in cellular and systemic responses to hypoxia.[5] This is one of the class of hypoxia inducible factors, a family that includes Hif1a, Hif2a, and Hif3a. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia.
    Now what many people don't really know is that the hair follicle is in a moderately to severe hypoxia state. Yes you hear that right, the cells like a hypoxic environment in the hair follicle, they like to bath in low oxygen. Especially the connective tissue which consists of the dermal papilla's too. HIF-1A is a regulator which protects this hypoxia state , thus loss of HIF-1A in your hair follicle would completely shred your hair follicle because your cells wouldn't cope with a higher oxygen environment. There are several studies which show this a good short summary;

    Hypoxia is believed to promote an undifferentiated state in several stem and precursor cell populations (Mohyeldin et al., 2010) and our results suggest that the lower stem cell niche of human hair follicles may also be in hypoxic environment. As a portion of CD34+ stem/progenitor cells is located in this hypoxic environment and have been demonstrated to disappear during androgenetic alopecia, we hypothesized that the induction of hypoxia signaling in suboptimal conditions would help maintain hair follicle stem cell functionality and hence prevent alopecia or at least favor neogenesis. Hypoxia signaling is mediated by the hypoxia-inducible transcription factor 1 (HIF1), composed of an αβ heterodimer. The α subunit was reported to be abundantly expressed in human hair follicles (Rosenberger et al. 2007) and is regulated in an oxygen-dependent manner through prolyl-4-hydroxylase-mediated hydroxylation, which mediates proteosomal degradation (Jaakkola et al., 2001).[B]
    So we know that androgen receptor activation can lead to loss of NOTCH signalling. Does NOTCH signalling have something in common with HIF-1a?

    Jup.. It does; http://www.ncbi.nlm.nih.gov/pubmed/16256737

    Hypoxia requires notch signaling to maintain the undifferentiated cell state.
    In addition to controlling a switch to glycolytic metabolism and induction of erythropoiesis and angiogenesis, hypoxia promotes the undifferentiated cell state in various stem and precursor cell populations. Here, we show that the latter process requires Notch signaling. Hypoxia blocks neuronal and myogenic differentiation in a Notch-dependent manner. Hypoxia activates Notch-responsive promoters and increases expression of Notch direct downstream genes. The Notch intracellular domain interacts with HIF-1alpha, a global regulator of oxygen homeostasis, and HIF-1alpha is recruited to Notch-responsive promoters upon Notch activation under hypoxic conditions. Taken together, these data provide molecular insights into how reduced oxygen levels control the cellular differentiation status and demonstrate a role for Notch in this process.
    That's right there is evidence in several studies that HIF-1A needs NOTCH signalling to maintain a hypoxia state.

    So we could propose now and take this study further that there is a correlation between the 3 of them,

    AR> LOSS NOTCH SIGNALLING > LOSS HIF-1A > SENESCENCE PATHWAYS

    What will that do? Well HIF-1A has major interactions with senescence and P53 etc there are many studies about this;

    http://www.nature.com/jid/journal/v1...d2013113a.html

    An interesting corollary to this is that within tissues, oxygen gradients often exist with stem cells residing in the most hypoxic regions (83). It is tempting to think then that these cells, which are known to be more resistant to oxidative stress as a mechanism of self-preservation (84, 85), benefit from their hypoxic environments by avoiding senescence, which would be detrimental to the regenerative capacity of the tissue.
    So yes, perhaps loss of notch signalling due to activation of the androgen receptor leads to loss of HIF-1A in the hair follicle if this would happen, your cells would get stressed as hell (Insane ROS/oxidative stress and possibly DNA DAMAGE) and pathways related to senescence would get activated which would trigger SASP again, an inflammatory response.

  4. #34
    Doctor Representative 35YrsAfter's Avatar
    Join Date
    Aug 2012
    Location
    Alpharetta, GA
    Posts
    1,361

    Default

    Quote Originally Posted by Swooping View Post
    Yes you hear that right, the cells like a hypoxic environment in the hair follicle, they like to bath in low oxygen. Especially the connective tissue which consists of the dermal papilla's too. HIF-1A is a regulator which protects this hypoxia state , thus loss of HIF-1A in your hair follicle would completely shred your hair follicle because your cells wouldn't cope with a higher oxygen environment. There are several studies which show this a good short summary;
    As a side note, I remember reading a study where researchers attempted to keep hair follicles alive in vitro for as long as possible. The maximum length of time they eventually were able to keep the follicles alive was around 44 days, if memory serves me. They tried a variety of solutions and along the way discovered that oxygen actually killed the follicles.

    With that in mind I think it's wise that hair transplant patients avoid hyperbaric chambers post-op.

    35YrsAfter also posts as CITNews and works at Dr. Cole's office - Cole Hair Transplant, 1045 Powers Place, Alpharetta, Georgia 30009 - Phone 678-566-1011
    The contents of my posts are my opinions and not medical advice
    Last edited by 35YrsAfter; 02-23-2015 at 03:47 AM.

  5. #35
    Senior Member
    Join Date
    May 2014
    Posts
    803

    Default

    Quote Originally Posted by 35YrsAfter View Post
    As a side note, I remember reading a study where researchers attempted to keep hair follicles alive in vitro for as long as possible. The maximum length of time they eventually were able to keep the follicles alive was around 44 days, if memory serves me. They tried a variety of solutions and along the way discovered that oxygen actually killed the follicles.

    With that in mind I think it's wise that hair transplant patients avoid hyperbaric chambers post-op.

    35YrsAfter also posts as CITNews and works at Dr. Cole's office - forhair.com - Cole Hair Transplant, 1045 Powers Place, Alpharetta, Georgia 30009 - Phone 678-566-1011 - email 35YrsAfter at chuck@forhair.com
    The contents of my posts are my opinions and not medical advice
    Please feel free to call or email me with any questions. Ask for Chuck
    Interesting 35YrsAfter, thanks. Dermal papilla cells in culture thrive way better too in culture under hypoxic conditions than normoxic conditions. This is a good read too about hypoxia and stem cells; http://www.cell.com/cell-stem-cell/p...10)00341-3.pdf

    Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche
    The defining hallmark of stem cells is their ability to self-renew and maintain multipotency. This capacity depends on the balance of complex signals in their microenvironment. Low oxygen tensions (hypoxia) maintain
    undifferentiated states of embryonic, hematopoietic, mesenchymal, and neural stem cell phenotypes and also influence proliferation and cell-fate commitment. Recent evidence has identified a broader spectrum
    of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells. These findings have important implications on our understanding of development, disease, and tissue-engineering
    practices and furthermore elucidate an added dimension of stem cell control within the niche.

Similar Threads

  1. Androgenetic Alopecia Pathway Update and Finding The Cure
    By AnteUp in forum Cutting Edge / Future Treatments
    Replies: 26
    Last Post: 12-10-2014, 08:42 PM
  2. Has anybody heard of this - mexispatent? Lotion for androgenetic alopecia...
    By JJacobs152 in forum Cutting Edge / Future Treatments
    Replies: 3
    Last Post: 11-13-2013, 01:14 AM
  3. My androgenetic alopecia
    By ili in forum Introduce Yourself & Share Your Story
    Replies: 2
    Last Post: 01-09-2012, 06:57 AM
  4. Androgenetic alopecia and telogen effluvium?
    By arizona in forum Introduce Yourself & Share Your Story
    Replies: 1
    Last Post: 07-02-2010, 09:39 AM

Posting Permissions

  • You may not post new threads
  • You may not post replies
  • You may not post attachments
  • You may not edit your posts

» IAHRS

hair transplant surgeons

» The Bald Truth

» Recent Threads

1800 graft repair case results by Dr. Lindsey
Yesterday 08:38 AM
Last Post By Dr. Lindsey
Yesterday 08:38 AM
Navigating the German Job Market as a Kenyan Citizen
11-04-2023 06:31 AM
Last Post By Keegan212
Yesterday 03:51 AM
DR HAKAN DOGANAY/ 4500 GRAFTS / Implanter Pen+FUE
03-26-2024 04:15 PM
Last Post By Hakan Doganay, MD
03-26-2024 04:15 PM
The Mane Event for Thursday, June 15th, 2023
06-15-2023 02:59 PM
Last Post By gisecit34
03-26-2024 08:05 AM