harold
Established Member
- Reaction score
- 11
Hey guys,
Maybe I have missed it but I have never seen this brought up before and I think it could well be pretty damn important.
From the list of poster presenations at the 2006 European Hair Research Society:
http://content.karger.com/ProdukteDB/pr ... =92842.pdf
comes this:
Role of Reactive Oxygen Species (ROS) on
Androgen-Inducible TGF-Beta1 Regulation
of Dermal Papilla Cells
H.G. Yoo, Y.J. Kang, S.R. Lee, H.K. Pyo, O.S. Kwon,
K.H. Kim, H.C. Eun, K.H. Cho
Department of Dermatology, Seoul National University,
College of Medicine, Laboratory of Cutaneous Aging and Hair
Research, Clinical Research Institute, Seoul National
University Hospital and Institute of Dermatological Science,
Seoul National University, Seoul, Korea
Little is known about the roles of androgen on the regulation of
redox states in dermal papilla cells, a cellular process known to profoundly
increase with aging. The androgen receptor (AR) has been reported to modulate TGF-B1/Smad signaling and to be overexpressed
in androgen-dependent scalp areas of patients with androgenetic
alopecia. The rat vibrissae dermal papilla cell line (DP-6)
over-expressed with AR was investigated to evaluate the role of
ROS on androgen-induced increase of TGF-B1 secretion. AR stablytransfected
DP-6 cells were incubated with R1881 or dihydrotestosterone
(DHT). Flow cytometry and laser scanning confocal microscopy
were undertaken to measure ROS production and an ELISA assay to
evaluate TGF-B1 secretion after androgen treatment. A TGF-B1 promoter
activity assay was also performed whether to be influenced by
pretreatment of ROS scavengers. Androgen markedly increased ROS
generation and the androgen-inducible ROS augmented TGF-B1
secretion from dermal papilla cells. Treatment with ROS scavenger or
several species of inhibitors decreased ROS production and TGF-B1
expression. Luciferase reporter assays showed suppression of
TGF-B1 promoter signaling by ROS scavengers. In conclusion, our
study shows for the first time that androgen-induced TGF-B1 accumulation
in dermal papilla cells would be mediated by ROS production
and prevented by antioxidants or ROS inhibitors.
So what we know about androgenetic alopecia from recent years:
DHT -> androgen receptor -> TGF-B1 secretion and inhibition of dermal papilla proliferation
Now this paper seems to say that the picture actually goes a little more like this
DHT -> androgen receptor -> oxidative stress and damage -> TGF-B1 secretion and inhibition of dermal papilla proliferation
So it looks to me like the binding of DHT to the androgen receptor directly leads to the generation of oxidants which damage the follicle which prompts it to secrete TGF-B1 initiating apoptosis.
Neutralising the ROS reduced the increased production of TGF-B1. Interestingly procyanidin b2 (from memory, possibly it was b3) that has been in all those Japanese studies was shown to downregulate TGF-B1 production and is an antioxidant. Green tea extract, grape seed extract, melatonin are all of course antioxidants.
If this stuff is true and if the free radical theory of aging is more or less correct then androgenetic alopecia is more of an aging/degenerative type disease than we are used to thinking of it IMO. Even though a very young man can go very bald his hair follicles are being "attacked" and "aged" in the same way that UV light ages the skin.
Kinda scary but it also potentially opens up a brand new arsenel in the form of topical antioxidants and should make those who have been using GTE, GSE and other topicals feel more confident in that decision.
These next posters talked a little about how dermal papilla from balding scalp are more sensitive to oxidative stress than those taken from non-balding scalp and the relation between TGF_B1 and oxidative stress:
Study of Cell Senescence in Cultured
Primary Balding and Non-Balding
Dermal Papilla Cells
A.W. Bahta
Dermatology (QMUL), London, UK
The dermal papilla (DP) expresses androgen receptors and is
known to control normal hair growth. The paradox of androgen action
in human hair growth is well established but the molecular mechanisms
are poorly understood. DP cells derived from frontal (balding)
human scalp hair follicles (BDPC) are used to study androgenetic
alopecia. Cultured BDPC are known to have a much slower rate of
growth in vitro than DP from non-balding sites (NBDPC), however,
the cause of this has not been reported. In this study we have investigated
the growth of human BDPC and NBDPC in vitro. We observed
that BDPC have a limited life span of 2–6 passages. We observed that
from passage 2 onwards BDPC but not NBDPC showed a large flattened
morphology characteristic of senescent fibroblasts and that
once they had assumed this morphology they could no longer be
passaged. We showed that these BDPC but not NBDPC of the same
passage expressed senescence-associated B-galactosidase activity at
pH-6. Moreover, stress-induced premature senescence was induced
with more prominent characteristic behaviour in BDPC than NBDPC
after exposure to sub-cytotoxic levels of H2O2 a known inducer of
oxidative stress. Finally BDPC also expressed a wide range of oxidative
stress markers including HSP27, Super Oxide Dismutase and
Catalase. These data suggest that the well documented, slower in vitro
proliferative rate of BDPC is due in part to premature senescence.
Moreover, our observation that cultured BDPC express markers of
oxidative stress and their response to H2O2 suggest that oxidative
stress may play a major role in male pattern hair loss. Others and we
have observed that DHT is able to induce TGF-B1 in BDPC. TGF-B1
is known to induce oxidative stress and this may therefore, link androgens
with oxidative stress and help explain the paradox of androgen
action on hair growth.
So not only is TGF-B1 being secreted in response to oxidative stress but it is also causing it:
DHT -> androgen receptor -> oxidative stress and damage -> TGF-B1 secretion -> oxidative stress and apoptosis of dermal papillae
Immortalisation and Characterisation of
Balding and Non-Balding Dermal Papilla Cell
Lines and their Response to Oxidative Stress
A.W. Bahta
Dermatology (QMUL), London, UK
The dermal papilla (DP) expresses androgen receptors and is known
to control normal hair growth. The paradox of androgen action in human
hair growth is well established but the molecular mechanisms in hair follicles
are poorly understood. DP cells derived from frontal (balding)
human scalp hair follicles (BDPC) are used to study androgenetic alopecia.
However, cultured BDPC are very difficult to obtain, grow very
slowly in vitro and have a limited life span of 2–6 passages before they
senescence. We have recently shown that BDPC express senescenceassociated
B galactosidase activity at pH-6. Moreover, stress induced
premature senescence was induced with more prominent characteristic
behaviour in BDPC than non-balding DPC (NBDPC) after exposure to
sub-cytotoxic levels of H2O2. However, the limited life span of BDPC
represents a substantial obstacle for biochemical analysis, genetic
manipulation and screens. We therefore, generated immortalised balding
and non-balding human DP cells (IBDPC, INBDPC) by ectopic expression
of human telomerase. The IBDPC have undergone more than 90
passages without showing any phenotypic changes. As with the primary
DPC, the IBDPC maintained their aggregating characteristics and
expressed wnt7a, wnt3a, androgen receptor and 5a reductase type 2
mRNA. We established an in vitro co-culture system by growing IBDPC
and INBDPC with keratinocytes (KC) to study the androgen effects in
hair follicles. Androgen suppressed the growth of KC when grown with
IBDPC and this could be partially reversed using a neutralising antibody
to TGF-B1. In addition we have also observed that IBDPC retains
increased sensitivity towards H2O2 than INBDPC cell lines. Therefore,
immortalised DP cell lines show similar characteristics to primary DPC
and they will be of major help to us in our attempt to understand the
actions of androgens on hair growth and enable the development of better
treatment for androgen dependent hair disorders.
Another study that showed that 12 months without treatment may be enough to cause permanent damage to future capacity for hair growth:
The Use of Placebo or Untreated Controls in Male Pattern Hair Loss Studies Leads to a
Significant and Permanent Loss of Hair
Another showed that the combination of Vit B12 and minoxidil was more effective than minoxidil by itself:
Topical Administration of Cyanocobalamin
(Vitamin B12) Showed Suppression of
Potassium Channel Inhibitor (Tolbutamide)
and Induction of Murine Hair Anagen Phase
and Synergistic Effect with Minoxidil
Another showed that oxidative stress is also heavily involved in the greying of hair (more reason for topical antioxidants):
Age-Associated Alterations in Human Scalp Hair Follicle Melanocytes – An in Vitro Study
"The decrease in catalase expression with age further suggests that disruption of anti-oxidant defence mechanisms in melanocytes may contribute to loss of pigmentation with age."
Cheap and easily available eucalyptus oil was shown to upregulate VEGF in the scalp:
Effects of Eucalyptus Extract on Hair Properties and their Molecular Mechanisms
Finally though I have seen it elsewhere there was finally something indicating that there was some actual research going tto be published on the whole caffeine/hair growth thing which I think is important especially given the controversy over whether caffeine as an adenosine antagonist might do more harm than good and interfere with the effects of minoxidil:
Effect of Testosterone in Ex Vivo Human
Hair Follicles from Male Patients with Androgenetic Alopecia
T.W. Fischer1,2, U.C. Hipler1, P. Elsner1
1Department of Dermatology and Allergology, Friedrich-
Schiller-University, Jena, 2Department of Dermatology and
Venerology, University Hospital Schleswig-Holstein,
University of Lübeck, Lübeck, Germany
Androgenetic alopecia (Androgenetic Alopecia) is a common problem in men of all
ages, starting at the age of 20 and affecting about 50% at the age of
50. The underlying cause is an androgen-dependent miniaturization of
genetically predetermined hair follicles, modulated by dihydrotestosterone
(DHT) and the expression of androgen receptor (AR). Here, we
used ex vivo hair follicles from balding areas of men with Androgenetic Alopecia and
cultivated them in vitro to investigate the effects of testosterone and
caffeine, the latter being a promising candidate for hair growth stimulation.
Hair follicles from 14 biopsies, taken from the vertex areas
from male Androgenetic Alopecia patients, were cultivated for 120–192 h in the presence
of normal William’s E medium (control) or William’s E medium
containing different concentrations of testosterone and/or caffeine.
The outcome parameters were hair shaft elongation and keratinocyte
proliferation assessed by Ki-67 staining of longitudinal hair follicle
cryosections. Testosterone which is metabolized by intrafollicular
5--reductase to DHT lead to significant growth suppression at
the concentration of 5
g/ml. This suppression was neutralized by
caffeine in concentrations of 0.001 and 0.005%. Moreover, caffeine
alone lead to a significant stimulation of hair follicle growth compared
to normal medium. The results were confirmed by proliferation
assessment with Ki-67 staining. Androgen-dependent growth inhibition
of ex vivo hair follicles from patients suffering from Androgenetic Alopecia was
present in the human hair organ culture model. This model imitates
the clinical situation of Androgenetic Alopecia in vitro and may serve for future studies
to screen new substances against androgen-dependent hair loss.
Caffeine counteracted the inhibitory effect of testosterone and was
identified as a stimulator of human hair growth in vitro, a fact which
may have important impact on clinical management of Androgenetic Alopecia.
Hope you got something out of that. For me the most important, and possibly even revolutionary part, was the link between the balding process and oxidative stress.
hh
Maybe I have missed it but I have never seen this brought up before and I think it could well be pretty damn important.
From the list of poster presenations at the 2006 European Hair Research Society:
http://content.karger.com/ProdukteDB/pr ... =92842.pdf
comes this:
Role of Reactive Oxygen Species (ROS) on
Androgen-Inducible TGF-Beta1 Regulation
of Dermal Papilla Cells
H.G. Yoo, Y.J. Kang, S.R. Lee, H.K. Pyo, O.S. Kwon,
K.H. Kim, H.C. Eun, K.H. Cho
Department of Dermatology, Seoul National University,
College of Medicine, Laboratory of Cutaneous Aging and Hair
Research, Clinical Research Institute, Seoul National
University Hospital and Institute of Dermatological Science,
Seoul National University, Seoul, Korea
Little is known about the roles of androgen on the regulation of
redox states in dermal papilla cells, a cellular process known to profoundly
increase with aging. The androgen receptor (AR) has been reported to modulate TGF-B1/Smad signaling and to be overexpressed
in androgen-dependent scalp areas of patients with androgenetic
alopecia. The rat vibrissae dermal papilla cell line (DP-6)
over-expressed with AR was investigated to evaluate the role of
ROS on androgen-induced increase of TGF-B1 secretion. AR stablytransfected
DP-6 cells were incubated with R1881 or dihydrotestosterone
(DHT). Flow cytometry and laser scanning confocal microscopy
were undertaken to measure ROS production and an ELISA assay to
evaluate TGF-B1 secretion after androgen treatment. A TGF-B1 promoter
activity assay was also performed whether to be influenced by
pretreatment of ROS scavengers. Androgen markedly increased ROS
generation and the androgen-inducible ROS augmented TGF-B1
secretion from dermal papilla cells. Treatment with ROS scavenger or
several species of inhibitors decreased ROS production and TGF-B1
expression. Luciferase reporter assays showed suppression of
TGF-B1 promoter signaling by ROS scavengers. In conclusion, our
study shows for the first time that androgen-induced TGF-B1 accumulation
in dermal papilla cells would be mediated by ROS production
and prevented by antioxidants or ROS inhibitors.
So what we know about androgenetic alopecia from recent years:
DHT -> androgen receptor -> TGF-B1 secretion and inhibition of dermal papilla proliferation
Now this paper seems to say that the picture actually goes a little more like this
DHT -> androgen receptor -> oxidative stress and damage -> TGF-B1 secretion and inhibition of dermal papilla proliferation
So it looks to me like the binding of DHT to the androgen receptor directly leads to the generation of oxidants which damage the follicle which prompts it to secrete TGF-B1 initiating apoptosis.
Neutralising the ROS reduced the increased production of TGF-B1. Interestingly procyanidin b2 (from memory, possibly it was b3) that has been in all those Japanese studies was shown to downregulate TGF-B1 production and is an antioxidant. Green tea extract, grape seed extract, melatonin are all of course antioxidants.
If this stuff is true and if the free radical theory of aging is more or less correct then androgenetic alopecia is more of an aging/degenerative type disease than we are used to thinking of it IMO. Even though a very young man can go very bald his hair follicles are being "attacked" and "aged" in the same way that UV light ages the skin.
Kinda scary but it also potentially opens up a brand new arsenel in the form of topical antioxidants and should make those who have been using GTE, GSE and other topicals feel more confident in that decision.
These next posters talked a little about how dermal papilla from balding scalp are more sensitive to oxidative stress than those taken from non-balding scalp and the relation between TGF_B1 and oxidative stress:
Study of Cell Senescence in Cultured
Primary Balding and Non-Balding
Dermal Papilla Cells
A.W. Bahta
Dermatology (QMUL), London, UK
The dermal papilla (DP) expresses androgen receptors and is
known to control normal hair growth. The paradox of androgen action
in human hair growth is well established but the molecular mechanisms
are poorly understood. DP cells derived from frontal (balding)
human scalp hair follicles (BDPC) are used to study androgenetic
alopecia. Cultured BDPC are known to have a much slower rate of
growth in vitro than DP from non-balding sites (NBDPC), however,
the cause of this has not been reported. In this study we have investigated
the growth of human BDPC and NBDPC in vitro. We observed
that BDPC have a limited life span of 2–6 passages. We observed that
from passage 2 onwards BDPC but not NBDPC showed a large flattened
morphology characteristic of senescent fibroblasts and that
once they had assumed this morphology they could no longer be
passaged. We showed that these BDPC but not NBDPC of the same
passage expressed senescence-associated B-galactosidase activity at
pH-6. Moreover, stress-induced premature senescence was induced
with more prominent characteristic behaviour in BDPC than NBDPC
after exposure to sub-cytotoxic levels of H2O2 a known inducer of
oxidative stress. Finally BDPC also expressed a wide range of oxidative
stress markers including HSP27, Super Oxide Dismutase and
Catalase. These data suggest that the well documented, slower in vitro
proliferative rate of BDPC is due in part to premature senescence.
Moreover, our observation that cultured BDPC express markers of
oxidative stress and their response to H2O2 suggest that oxidative
stress may play a major role in male pattern hair loss. Others and we
have observed that DHT is able to induce TGF-B1 in BDPC. TGF-B1
is known to induce oxidative stress and this may therefore, link androgens
with oxidative stress and help explain the paradox of androgen
action on hair growth.
So not only is TGF-B1 being secreted in response to oxidative stress but it is also causing it:
DHT -> androgen receptor -> oxidative stress and damage -> TGF-B1 secretion -> oxidative stress and apoptosis of dermal papillae
Immortalisation and Characterisation of
Balding and Non-Balding Dermal Papilla Cell
Lines and their Response to Oxidative Stress
A.W. Bahta
Dermatology (QMUL), London, UK
The dermal papilla (DP) expresses androgen receptors and is known
to control normal hair growth. The paradox of androgen action in human
hair growth is well established but the molecular mechanisms in hair follicles
are poorly understood. DP cells derived from frontal (balding)
human scalp hair follicles (BDPC) are used to study androgenetic alopecia.
However, cultured BDPC are very difficult to obtain, grow very
slowly in vitro and have a limited life span of 2–6 passages before they
senescence. We have recently shown that BDPC express senescenceassociated
B galactosidase activity at pH-6. Moreover, stress induced
premature senescence was induced with more prominent characteristic
behaviour in BDPC than non-balding DPC (NBDPC) after exposure to
sub-cytotoxic levels of H2O2. However, the limited life span of BDPC
represents a substantial obstacle for biochemical analysis, genetic
manipulation and screens. We therefore, generated immortalised balding
and non-balding human DP cells (IBDPC, INBDPC) by ectopic expression
of human telomerase. The IBDPC have undergone more than 90
passages without showing any phenotypic changes. As with the primary
DPC, the IBDPC maintained their aggregating characteristics and
expressed wnt7a, wnt3a, androgen receptor and 5a reductase type 2
mRNA. We established an in vitro co-culture system by growing IBDPC
and INBDPC with keratinocytes (KC) to study the androgen effects in
hair follicles. Androgen suppressed the growth of KC when grown with
IBDPC and this could be partially reversed using a neutralising antibody
to TGF-B1. In addition we have also observed that IBDPC retains
increased sensitivity towards H2O2 than INBDPC cell lines. Therefore,
immortalised DP cell lines show similar characteristics to primary DPC
and they will be of major help to us in our attempt to understand the
actions of androgens on hair growth and enable the development of better
treatment for androgen dependent hair disorders.
Another study that showed that 12 months without treatment may be enough to cause permanent damage to future capacity for hair growth:
The Use of Placebo or Untreated Controls in Male Pattern Hair Loss Studies Leads to a
Significant and Permanent Loss of Hair
Another showed that the combination of Vit B12 and minoxidil was more effective than minoxidil by itself:
Topical Administration of Cyanocobalamin
(Vitamin B12) Showed Suppression of
Potassium Channel Inhibitor (Tolbutamide)
and Induction of Murine Hair Anagen Phase
and Synergistic Effect with Minoxidil
Another showed that oxidative stress is also heavily involved in the greying of hair (more reason for topical antioxidants):
Age-Associated Alterations in Human Scalp Hair Follicle Melanocytes – An in Vitro Study
"The decrease in catalase expression with age further suggests that disruption of anti-oxidant defence mechanisms in melanocytes may contribute to loss of pigmentation with age."
Cheap and easily available eucalyptus oil was shown to upregulate VEGF in the scalp:
Effects of Eucalyptus Extract on Hair Properties and their Molecular Mechanisms
Finally though I have seen it elsewhere there was finally something indicating that there was some actual research going tto be published on the whole caffeine/hair growth thing which I think is important especially given the controversy over whether caffeine as an adenosine antagonist might do more harm than good and interfere with the effects of minoxidil:
Effect of Testosterone in Ex Vivo Human
Hair Follicles from Male Patients with Androgenetic Alopecia
T.W. Fischer1,2, U.C. Hipler1, P. Elsner1
1Department of Dermatology and Allergology, Friedrich-
Schiller-University, Jena, 2Department of Dermatology and
Venerology, University Hospital Schleswig-Holstein,
University of Lübeck, Lübeck, Germany
Androgenetic alopecia (Androgenetic Alopecia) is a common problem in men of all
ages, starting at the age of 20 and affecting about 50% at the age of
50. The underlying cause is an androgen-dependent miniaturization of
genetically predetermined hair follicles, modulated by dihydrotestosterone
(DHT) and the expression of androgen receptor (AR). Here, we
used ex vivo hair follicles from balding areas of men with Androgenetic Alopecia and
cultivated them in vitro to investigate the effects of testosterone and
caffeine, the latter being a promising candidate for hair growth stimulation.
Hair follicles from 14 biopsies, taken from the vertex areas
from male Androgenetic Alopecia patients, were cultivated for 120–192 h in the presence
of normal William’s E medium (control) or William’s E medium
containing different concentrations of testosterone and/or caffeine.
The outcome parameters were hair shaft elongation and keratinocyte
proliferation assessed by Ki-67 staining of longitudinal hair follicle
cryosections. Testosterone which is metabolized by intrafollicular
5--reductase to DHT lead to significant growth suppression at
the concentration of 5
g/ml. This suppression was neutralized by
caffeine in concentrations of 0.001 and 0.005%. Moreover, caffeine
alone lead to a significant stimulation of hair follicle growth compared
to normal medium. The results were confirmed by proliferation
assessment with Ki-67 staining. Androgen-dependent growth inhibition
of ex vivo hair follicles from patients suffering from Androgenetic Alopecia was
present in the human hair organ culture model. This model imitates
the clinical situation of Androgenetic Alopecia in vitro and may serve for future studies
to screen new substances against androgen-dependent hair loss.
Caffeine counteracted the inhibitory effect of testosterone and was
identified as a stimulator of human hair growth in vitro, a fact which
may have important impact on clinical management of Androgenetic Alopecia.
Hope you got something out of that. For me the most important, and possibly even revolutionary part, was the link between the balding process and oxidative stress.
hh
