Article

Topical application of the Wnt/β-catenin activator methyl vanillate increases hair count and hair mass index in women with androgenetic alopecia

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Abstract

Background: Activation of the WNT/β-catenin pathway has emerged as a potential therapeutic target in androgenetic alopecia (AGA). Methyl vanillate (MV) - a safe plant-derived ingredient - has been recently shown to activate the WNT/β-catenin signaling. Objectives Two distinct substudies were conducted. First, we designed a 6-month, uncontrolled, open-label clinical study to investigate whether topically applied MV may increase hair count and hair mass index (HMI) in female AGA. Second, we conducted a molecular study on the effect of MV on WNT10B mRNA expression in scalp biopsies of women with AGA. Methods: A total of 20 Caucasian women (age range: 25-57 years) with AGA (Sinclair grade 1-2) were included. The research product was an alcohol-free formulation supplied in the form of a spray containing 0.2% MV as the active ingredient. Results: In the clinical study, hair count and HMI were found to increase at 6 months by 6% (P < 0.01) and 12% (P < 0.001), respectively, compared with baseline. No participant discontinued treatment due to adverse effects, and the overall patient satisfaction was good. At the molecular level, the topical application of the research product resulted in a 32% increase in WNT10B mRNA expression levels in the temporal scalp area (P < 0.001). Conclusion: Our pilot data suggest that topical MV can increase hair count and HMI by inducing WNT10B expression in the scalp, potentially serving as a novel treatment strategy for female AGA.

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... Low-level laser therapy (LLLT) also seems to improve hair regrowth in the conditions of AGA, AA, and chemotherapy-induced alopecia [133]. There are studies demonstrating the positive effects of natural bioactive compounds on AGA [24,30,52,55,56,58,[134][135][136][137][138]. A recently published study demonstrates that a 5-mer peptide (GLYYF; P5) has the potential to promote hair growth when topically applied [139]. ...
... Hence, 23 the predicted target genes largely overlap. Nevertheless, miR-29s exhibit different regula- 24 tions, and thus, their functions may be different from each other [199]. These miRNAs 25 accommodate diverse functions. ...
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Androgenetic alopecia (AGA) remains an unsolved problem for the well-being of humankind, although multiple important involvements in hair growth have been discovered. Up until now, there is no ideal therapy in clinical practice in terms of efficacy and safety. Ultimately, there is a strong need for developing a feasible remedy for preventing and treating AGA. The Wnt/β-catenin signaling pathway is critical in hair restoration. Thus, AGA treatment via modulating this pathway is rational, although challenging. Dickkopf-related protein 1 (DKK1) is distinctly identified as an inhibitor of canonical Wnt/β-catenin signaling. Thus, in order to stimulate the Wnt/β-catenin signaling pathway, inhibition of DKK1 is greatly demanding. Studying DKK1-targeting microRNAs (miRNAs) involved in the Wnt/β-catenin signaling pathway may lay the groundwork for the promotion of hair growth. Bearing in mind that DKK1 inhibition in the balding scalp of AGA certainly makes sense, this review sheds light on the perspectives of miRNA-mediated hair growth for treating AGA via regulating DKK1 and, eventually, modulating Wnt/β-catenin signaling. Consequently, certain miRNAs regulating the Wnt/β-catenin signaling pathway via DKK1 inhibition might represent attractive candidates for further studies focusing on promoting hair growth and AGA therapy.
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... Vanillic acid, a phenolic acid, is a major component of wheat bran, which has been reported to exhibit anti-oxidative and hepatoprotective activity (Itoh et al., 2009;Amin et al., 2017). In patients with AGA, methyl vanillate with a structure similar to that of vanillic acid could promote hair growth by activating the Wnt/β-catenin pathway (Tosti et al., 2016). However, biological activity of vanillic acid in DPCs has not been investigated. ...
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... ingredient is a suspected Wnt-activator given the concomitant 32% increase in Wnt10B expression in the temporal scalp [14]. Treatment of mice with amniotic membrane has similarly shown up regulation of anagen stimulatory signals, specifically, increased FGF7 and proliferating cell nuclear antigen. ...
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... 38 Likewise, methyl vanillate treatment resulted in a 6% increase in hair count and 12% increase in hair mass index. 39 The same is true for comparisons of this study against our previous efficacy trial of SO extract, where participants were also from a different ethnic background (Japanese). Nevertheless, an improvement in shed hair after MTP3 treatment was evident compared to our previous trial of FGF5-inhibiting SO extract: 80% reduction in hair fall at day 112 for the MTP3-treated groups vs. 68% at 4 months. ...
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Chapter
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Chapter
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Androgenetic alopecia (AGA) is the commonest form of hair loss in men. Alopecia areata (AA) is an organ-specific autoimmune disease. Studies revealed that Dickkopf 1 (DKK-1), a powerful suppressor of the Wnt/β-catenin signaling pathway, induced anagen-to-catagen transition in mice. Moreover, in vitro studies suggested that DKK-1 played a role in dihydrotestosterone (DHT)-induced balding. To evaluate the tissue levels of DKK-1 in patients with AGA and AA, to assess its possible role as a pathogenetic mechanism in both disorders. This study included 24 patients with AGA, 31 patients with AA, and 33 healthy controls. Scalp biopsies were taken from all participants for the detection of tissue DKK-1 levels. Tissue DKK-1 levels were significantly higher in patients with AGA than in controls (P = 0.000) as well as in patients with AA than in controls (P = 0.001). In addition, they were significantly higher in patients with AGA than in patients with AA (P = 0.000). DKK-1 was higher in male than in female patients with AGA. DKK-1 was negatively correlated with disease duration in AGA. In conclusion, this study suggests an important role for DKK-1 in the pathogenesis of AGA and AA through documenting higher tissue DKK-1 levels in patients with both hair disorders compared to controls and suggests that DKK-1 may be a promising therapeutic target for these hair diseases. © 2015 Wiley Periodicals, Inc.
Purpose of review: The authors will review the current literature on efficacy and safety of 5-alpha reductase inhibitors (5αRIs) for androgenetic alopecia (AGA). Recent findings: The 5αRI finasteride and dutasteride are effective in treating AGA and promoting hair regrowth. 5αRI can be given orally, topically and more recently through mesotherapy. However, there has been an increasing concern about permanent sexual adverse events such as impotence and infertility. Most of these reports are published as case reports, and two studies reporting persistent sexual side-effects after discontinuation of finasteride had serious method limitations, as patients were recruited from a website. To our knowledge, permanent sexual adverse events have yet to be published in higher quality studies, such as randomized controlled trials. Although patients treated with 5αRIs have an increased incidence of sexual adverse events, these events decrease if discontinued or over time with continued therapy. Summary: Sexual side-effects are uncommon and resolve spontaneously in most patients even without discontinuing therapy. Significant effort is underway to find delivery systems that optimize delivery and reduce systemic absorption of topical 5αRs including hydroxypropyl chitosan and liposomal and nanoparticulate systems.
Article
WNT-β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.
Article
Introduction: Androgenic alopecia (AGA) is the major type of scalp hair loss affecting 60 - 70% of the population worldwide. It is caused by two potent androgens, namely testosterone (T) and 5α-dihydrotestosterone (5α-DHT). Till date, only two FDA-approved synthetic drugs, minoxidil and finasteride, are used to cure AGA with only 35 and 48% success, respectively; therefore, a search for new drug based on the mechanism of androgens action is still needed. Areas covered: Relevant literature was reviewed to identify current therapeutic targets and treatments for AGA. The potential targets are classified into three categories: i) 5α-reductase; ii) androgen receptor and iii) growth-factor-producing genes related to hair growth. Expert opinion: Relevant assay systems using the right targets are required in order to obtain specific and effective drugs for AGA treatment. It is unlikely that single targeted agents will be sufficient for treating AGA, and therefore, it would be a challenge to obtain compounds with multiple activities.
Article
Background: Androgenetic alopecia (AGA) is one of the most common chronic problems seen by dermatologists worldwide. It is characterized by progressive hair loss, especially of scalp hair, and has distinctive patterns of loss in women versus men, but in both genders the central scalp is most severely affected. It often begins around puberty and is known to effect self-esteem and the individual's quality of life. In contrast to the high prevalence of AGA, approved therapeutic options are limited. In addition to the scarce pharmacologic treatments, there are numerous nonprescription products claimed to be effective in restoring hair in androgenetic alopecia. Objectives: The purpose of this paper is to review published medical and non-medical treatments for male and female AGA using the American College of Physicians evidence assessment methods. MEDLINE, EMBASE and Cochrane Library were searched for systematic reviews, randomized controlled trials, open studies, case reports and relevant studies of the treatment of male and female AGA. The relevant articles were classified according to grade and level of evidence. Results: The medical treatments with the best level of evidence classification for efficacy and safety for male AGA are oral finasteride and topical minoxidil solution. For female AGA, topical minoxidil solution appears to be the most effective and safe treatment. The medical treatments corresponding to the next level of evidence quality are some commonly used therapeutic non-FDA-approved options including oral and topical anti-hormonal treatments. Surgical treatment of follicular unit hair transplantation is an option in cases that have failed medical treatment although there is high variation in outcomes. Limitations: Some articles, especially those concerning traditional herbs claimed to promote hair regrowth, were published in non-English, local journals. Conclusions: An assessment of the evidence quality of current publications indicates that oral finasteride (for men only) and topical minoxidil (for men and women) are the best treatments of AGA.
Article
Valproic acid (VPA), a widely used anticonvulsant, inhibits glycogen synthase kinase 3β and activates the Wnt/β-catenin pathway, which is associated with hair growth cycle and anagen induction. To assess the efficacy of topical VPA for treating androgenetic alopecia (AGA), we performed a randomized, double-blind, placebo-controlled clinical trial. Male patients with moderate AGA underwent treatment with either VPA (sodium valproate, 8.3%) or placebo spray for 24 weeks. The primary end-point for efficacy was the change in hair count during treatment, which was assessed by phototrichogram analysis. Of the 40 patients enrolled in the study, 27 (n = 15, VPA group; n = 12, placebo group) completed the entire protocol with good compliance. No statistical differences in age, hair loss duration and total hair count at baseline were found between the groups. The mean change in total hair count was significantly higher in the VPA group than in the placebo group (P = 0.047). Both groups experienced mostly mild and self-limited adverse events, but their differences in prevalence rates were similar between the two groups (P = 0.72). A subject treated with topical VPA developed ventricular tachycardia, but it did not seem to be related to the VPA spray. Topical VPA increased the total hair counts of our patients; therefore, it is a potential treatment option for AGA.
Article
β-Catenin, the transducer of Wnt signaling, is critical for the development and growth of hair follicles. In the absence of Wnt signals, cytoplasmic β-catenin is phosphorylated by glycogen synthase kinase (GSK)-3 and then degraded. Therefore, inhibition of GSK-3 may enhance hair growth via β-catenin stabilization. Valproic acid is an anticonvulsant and a mood-stabilizing drug that has been used for decades. Recently, valproic acid was reported to inhibit GSK-3β in neuronal cells, but its effect on human hair follicles remains unknown. To determine the effect of VPA on human hair growth. We investigated the effect of VPA on cultured human dermal papilla cells and outer root sheath cells and on an in vitro culture of human hair follicles, which were obtained from scalp skin samples of healthy volunteers. Anagen induction by valproic acid was evaluated using C57BL/6 mice model. Valproic acid not only enhanced the viability of human dermal papilla cells and outer root sheath cells but also promoted elongation of the hair shaft and reduced catagen transition of human hair follicles in organ culture model. Valproic acid treatment of human dermal papilla cells led to increased β-catenin levels and nuclear accumulation and inhibition of GSK-3β by phosphorylation. In addition, valproic acid treatment accelerated the induction of anagen hair in 7-week-old female C57BL/6 mice. Valproic acid enhanced human hair growth by increasing β-catenin and therefore may serve as an alternative therapeutic option for alopecia.
Article
To properly assess the progression and treatment response of alopecia, one must measure the changes in hair mass, which is influenced by both the density and diameter of hair. Unfortunately, a convenient device for hair mass evaluation had not been available to dermatologists until the recent introduction of the cross-section trichometer, which directly measures the cross-sectional area of an isolated bundle of hair. We sought to evaluate the accuracy and sensitivity of the HairCheck(®) device, a commercial product derived from the original cross-section trichometer. Bundles of surgical silk and human hair were used to evaluate the ability of the HairCheck(®) device to detect and measure small changes in the number and diameter of strands, and bundle weight. Strong correlations were observed between the bundle's cross-sectional area, displayed as the numeric Hair Mass Index (HMI), the number of strands, the silk/hair diameter, and the bundle dry weight. HMI strongly correlated with the number and diameter of silk/hair, and the weight of the bundle, suggesting that it can serve as a valid indicator of hair mass. We have given the name cross-section trichometry (CST) to the methodology of obtaining the HMI using the HairCheck(®) system. CST is a simple modality for the quantification of hair mass, and may be used as a convenient and useful tool to clinically assess changes in hair mass caused by thinning, shedding, breakage, or growth in males and females with progressive alopecia or those receiving alopecia treatment.
Article
Introduction: Androgenetic alopecia (AGA) is the most common form of hair loss, however current treatment options are limited and moderately effective. In the past few years, there has been an increased interest in deciphering the molecular mechanisms responsible for this disorder, which has opened the possibility of novel treatments that promise to not only stimulate hair growth, but also to induce formation of new hair follicles. Areas covered: The future holds more effective topical treatments with less systemic side effects (such as topical 5-alfa-reductase inhibitors), prostaglandin analogs and antagonists, medications which act through the Wnt signaling pathway, stem cells for hair regeneration, platelet-rich plasma (PRP) and more effective ways of transplanting hair. A comprehensive search was made using PubMed, GoogleScholar and Clinicaltrial.gov using different combination of key words, which included AGA treatment, new treatments for AGA, Wnt pathway, prostaglandins, PRP and stem cells for hair regrowth. Expert opinion: In the near future, treatments with topical 5-alfa-reductase inhibitors and prostaglandin agonists or antagonists are expected. More evidence is needed to verify the efficacy of PRP. Although hair follicle bioengineering and multiplication is a fascinating and promising field, it is still a long way from being available to clinicians.
Article
The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future.
Article
Androgenetic alopecia (AGA) is characterized by vellus transformation of scalp hairs, corresponding to hair follicle miniaturization during repeated hair cycles with shortened anagen phase. This phenomenon is mediated mainly by androgen. Then, the multi-step molecular pathway of androgen can be involved in the pathogenesis of AGA. The expression of type II 5α-reductase is higher in dermal papilla cells from AGA and beard than those from other sites. On the other hand, type I 5α-reductase expression is relatively low. Next, hormone binding assays and RT-PCR demonstrated that androgen receptor (AR) expression is significantly higher in bald dermal papilla cells than non-bald cells. Additionally, AR coactivator Hic-5/ARA55 is highly expressed in dermal papilla cells of hair follicles from androgen-sensitive sites such as AGA and beard. Collectively, the enhanced expression of type II 5α-reductase, AR and Hic-5/ARA55 can upregulate sensitivity to androgen of dermal papilla cells in AGA. Furthermore, in the coculture of AR-overexpressing human dermal papilla cells from AGA and normal human keratinocytes, R1881 suppresses keratinocyte growth through androgen-inducible TGF-β1, indicating that TGF-β1 is one of the key players in pathogenesis of AGA. TGF-β2 and DKK-1 has been reported to be androgen-induced suppressor of growth of follicular epithelial cells. We expect that more pathogenic mediators will be identified in the future, enabling easier understanding of AGA pathogenesis and providing new therapeutic targets from aspect of andrology.
Article
Wnt/beta-catenin and NF-kappaB signaling mechanisms provide central controls in development and disease, but how these pathways intersect is unclear. Using hair follicle induction as a model system, we show that patterning of dermal Wnt/beta-catenin signaling requires epithelial beta-catenin activity. We find that Wnt/beta-catenin signaling is absolutely required for NF-kappaB activation, and that Edar is a direct Wnt target gene. Wnt/beta-catenin signaling is initially activated independently of EDA/EDAR/NF-kappaB activity in primary hair follicle primordia. However, Eda/Edar/NF-kappaB signaling is required to refine the pattern of Wnt/beta-catenin activity, and to maintain this activity at later stages of placode development. We show that maintenance of localized expression of Wnt10b and Wnt10a requires NF-kappaB signaling, providing a molecular explanation for the latter observation, and identify Wnt10b as a direct NF-kappaB target. These data reveal a complex interplay and interdependence of Wnt/beta-catenin and EDA/EDAR/NF-kappaB signaling pathways in initiation and maintenance of primary hair follicle placodes.
Article
Signaling by the Wnt family of secreted glycolipoproteins via the transcriptional coactivator beta-catenin controls embryonic development and adult homeostasis. Here we review recent progress in this so-called canonical Wnt signaling pathway. We discuss Wnt ligands, agonists, and antagonists, and their interactions with Wnt receptors. We also dissect critical events that regulate beta-catenin stability, from Wnt receptors to the cytoplasmic beta-catenin destruction complex, and nuclear machinery that mediates beta-catenin-dependent transcription. Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications.
Article
Hair follicle morphogenesis is initiated by a dermal signal that induces the development of placodes in the overlying epithelium. To determine whether WNT signals are required for initiation of follicular development, we ectopically expressed Dickkopf 1, a potent diffusible inhibitor of WNT action, in the skin of transgenic mice. This produced a complete failure of placode formation prior to morphological or molecular signs of differentiation, and blocked tooth and mammary gland development before the bud stage. This phenotype indicates that activation of WNT signaling in the skin precedes, and is required for, localized expression of regulatory genes and initiation of hair follicle placode formation.
Article
Hair loss or hair thinning is a common complaint in clinical dermatology, and patients seeking advice for hair loss are not necessarily bald. Because the effects of treatment attempts are hard to measure, there is need for a sensitive tool to monitor hair loss and treatment responses. Such a method must be able to analyze the biologic parameters of hair growth, which are: (i) hair density (n per cm2); (ii) hair diameter (microm); (iii) hair growth rate (mm per day); and (iv) anagen/telogen ratio. Herein we present the TrichoScan as a method that combines epiluminescence microscopy with automatic digital image analysis for the measurement of human, and potentially animal hair, in situ. The TrichoScan is able to analyze all four parameters of hair growth with a so-called intraclass correlation of approximately 91% within the same TrichoScan operator and an intraclass correlation of approximately 97% for different TrichoScan operators. The application of the technique is demonstrated by comparing the hair parameters in individuals without apparent hair loss, men with untreated androgenetic alopecia, and men after treatment with finasteride (1 mg per day). We were able to detect a significant increase in hair counts and cumulative hair thickness 3 and 6 mo after treatment. Advantages of the TrichoScan are that it can be used for clinical studies to compare placebo versus treatment, to compare different capacities of hair growth promoting substances, to study androgenetic alopecia and other forms of diffuse hair loss, and to study the effects of drugs and laser treatment on hypertrichosis and hirsutism.
Article
Dermal papilla cells of the hair follicle can be maintained in an active, hair-inducing state in vitro when cocultured with cells secreting Wnt3a. By inducing cultured dermal papilla cells to secrete Wnt themselves, we demonstrate that this activity is a direct effect of Wnt signaling to dermal papilla cells. We further demonstrate that the effects of Wnt3a are exerted through activation of the beta-catenin signal transduction pathway and do not require alternative Wnt transduction cascades. Once dermal papilla cells have lost hair-inducing properties in vitro, neither treatment with Wnt nor expression of a truncated and activating form of beta-catenin is sufficient to restore these properties to the cultured cells.
Androgenetic alopecia
  • Piraccini
Piraccini BM, Alessandrini A. Androgenetic alopecia. G Ital Dermatol Venereol 2014; 149: 15-24.