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Effect of caffeine and testosterone on the proliferation of human hair follicles in�vitro
Abstract
Androgenetic alopecia (AGA) is a common problem in men of all ages, affecting approximately 50% at 50 years of age. The underlying cause is an androgen-dependent miniaturization of genetically predetermined hair follicles. Here, the hair organ culture model was used 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 AGA patients, were cultivated for 120-192 h in vitro with normal William's E medium (control) or William's E medium containing different concentrations of testosterone and/or caffeine. Hair shaft elongation was measured daily and at the end of cultivation, cryosections of follicles were stained with Ki-67 to evaluate the degree and localization of keratinocyte proliferation.
Significant growth suppression was found in hair follicles treated with 5 microg/ml testosterone. This was counteracted by caffeine in concentrations of 0.001% and 0.005%. Moreover, caffeine alone led to a significant stimulation of hair follicle growth. These results were confirmed immunohistochemically by Ki-67 staining.
Androgen-dependent growth inhibition of ex vivo hair follicles from patients suffering from AGA was present in the human hair organ culture model, a constellation which may serve for future studies to screen new substances against androgen-dependent hair loss. Caffeine was identified as a stimulator of human hair growth in vitro; a fact which may have important clinical impact in the management of AGA.
... Constituents: Caffeine, sterols, diterpenes, triacylglycerol, phospholipids, keratin [120,149]. ...
... Mechanism: Acts by downregulating TGF-β2 and upregulating IGF-in the hair follicle, stimulating proliferation and inhibiting apoptosis [120,149,150]. ...
... Application: Hair elongation because of prolongation of the anagen phase and proliferation of keratinocytes. The topical application of caffeine is more effective than a 5% topical solution of minoxidil for AGA [120,149]. It also imparts shine, increases elasticity, revitalizes the scalp, and stops hair loss. ...
Polymer, lipid, and natural protein-based hair care nanocarriers are in preclinical testing. Nanomedicine has enhanced therapeutic efficacy and decreased side effects. This review examines herbal nanomedicine for hair care. We also reviewed the hair cycle, its morphology, and the mechanisms of herbal-based medicine that regulate the hair cycle to treat hair loss. Nano-formulations have better solubility, permeability, therapeutic efficacy, and prolonged distribution than standard herbal medicines. This review also discussed the nanotechnology barrier and nano formulations for hair loss and growth and includes a recent herbal nanomedicine study. Researchers interested in using herbs to treat hair problems and clinically translating hair care products may find the results presented significant.
... The HOCM has, for example, been used to study the influence of regulating factors such as TGF-β and IGF-1 in female hair follicles [56,57]. Regarding caffeine, HOCMs have been used to investigate the effects of caffeine on testosterone-induced growth suppression in male hair follicles [59] and on the hair follicle cycle with a particular focus on the maintenance of the anagen phase in male and female hair follicles [22]. ...
... To assess the effects of testosterone (5 ng/mL-5 μg/ mL) and caffeine (10-1,500 μg/mL) on hair follicle growth, scalp biopsies from the vertex area of males with AGA were taken, and the hair follicles together with their root sheaths were microdissected and maintained in the HOCM for up to 8 days [59]. Hair shaft elongation (daily) and keratinocyte proliferation (end of study) were recorded. ...
... The mechanism of action of caffeine and testosterone on the anagen duration of hair follicles in vitro, affecting the hair cycle regulation factors IGF-1 and TGF-β2 as well as the proliferation nuclear marker protein Ki67 (antigen KI-67 or MKI67 [Ki-Kiel]), is depicted in Figure 1. The protein Ki67 can be assessed by immunocytochemical labeling and is a marker of hair matrix keratinocyte proliferation [22,59]. All in all, the beneficial effects of caffeine on hair follicles seen in vitro have been recognized by the current European S3 guideline for the treatment of AGA [64], stating that "in male and female human scalp hair follicles caffeine led to an enhanced hair shaft elongation." ...
Caffeine, particularly after ingestion, is well known to exert various pharmacological effects. A growing body of evidence implicates the ingestion of caffeine with beneficial effects on several diseases. The easy penetration of caffeine across the skin barrier and into human skin makes caffeine an ideal compound for topical application. Hair loss is known to negatively affect the quality of life and predispose to depression and anxiety. Androgenetic alopecia (AGA) is the most common type of hair loss in both men and women. To date, only few approved drug-based treatments for AGA exist, and these are inevitably associated with side effects. Therefore, the development of topical treatments based on well-tolerated natural ingredients such as caffeine to alleviate hair loss may provide a much-needed alternative to drug-based approaches.
... This finding may be related to an unsustainable, hypermetabolic state induced by caffeine that imposes negative effects on the skin and hair. [11] hair disordErs Of the dermatological implications of caffeine, one of the most widely reported has been caffeine's impact in hair growth. Androgenetic alopecia (AGA) is a frequently diagnosed hair disorder and suspected to be the result of both genetic predisposition and androgen-mediated anagen phase shortening with follicular miniaturization. ...
... [12,13] Demonstrating this mechanism, ex vivo hair follicles obtained from the scalp biopsies of patients with AGA were inhibited by the application of 5 µg/ml testosterone. [11] This effect was mitigated by concomitant treatment of 0.0001% and 0.005% concentrated caffeine. Hair follicles treated with caffeine alone experienced pronounced growth in culture compared to hair follicles in a control medium during an extended cultivation window, as measured by hair shaft elongation measurements and confirmed with Ki-67 immunohistochemistry (P < 0.001). ...
... Although these findings demonstrate the positive effect of caffeine on hair growth, over-treating hair follicles with caffeine (concentrations >0.01%) cause a decrease in hair growth. [11] This is believed to be secondary to a hypermetabolic state induced by excess caffeine. This occurrence is crucial in determining the proper strength of future topical caffeine applications. ...
Introduction: Caffeine is a naturally occurring methylxanthine alkaloid, with numerous molecular properties that make its application to the field of dermatology promising. Purpose: This review aims to describe the dermatological implications and applications of caffeine. Methods: PubMed was searched for literature related to caffeine use in dermatology using the search terms “caffeine and dermatology.” Results: Caffeine may stimulate the hair growth in androgenetic alopecia and may prevent the risks of incident rosacea and both nonmelanoma and melanoma skin cancers. Numerous limitations exist for caffeine's application in dermatology, including few well-designed, clinically based trials in the treatment of hair loss, blurring of caffeine's potential therapeutic effects through combination with other active ingredients, potential for recall bias in prospective questionnaire-based studies, and lack of reporting on absolute effects in data analysis. Conclusion: Caffeine's numerous effects at the cellular level have potential application in the treatment of disorders related to the skin and hair. Caffeine may be beneficial in the treatment of hair loss and prevention of rosacea and skin cancer, but numerous limitations restrict the practical application of these findings.
... Products containing caffeine are promising tools for potential treatments for AGA both in vitro and in vivo models. In ex-vivo models, they stimulate human HG of HF obtained from patients affected by AGA [80]. Specifically, a work by Fisher et al. (2007) showed caffeine enhancement of hair shaft elongation, prolonging anagen duration and hair matrix keratinocyte proliferation; moreover, female HFs show a higher sensitivity to caffeine than male HFs [80]. ...
... In ex-vivo models, they stimulate human HG of HF obtained from patients affected by AGA [80]. Specifically, a work by Fisher et al. (2007) showed caffeine enhancement of hair shaft elongation, prolonging anagen duration and hair matrix keratinocyte proliferation; moreover, female HFs show a higher sensitivity to caffeine than male HFs [80]. Caffeine counteracts testosterone-enhanced TGF-2 protein expression in male HFs and reduces TGF-2 expression in female HFs, while it enhances intrafollicular IGF-1 protein expression in both sexes [80]. ...
... Specifically, a work by Fisher et al. (2007) showed caffeine enhancement of hair shaft elongation, prolonging anagen duration and hair matrix keratinocyte proliferation; moreover, female HFs show a higher sensitivity to caffeine than male HFs [80]. Caffeine counteracts testosterone-enhanced TGF-2 protein expression in male HFs and reduces TGF-2 expression in female HFs, while it enhances intrafollicular IGF-1 protein expression in both sexes [80]. Accordingly, it enhances hair shaft elongation, prolongs anagen duration, and promotes the proliferation of hair matrix keratinocytes [81] (Table 4). ...
Abstract: Hair loss is a disorder in which the hair falls out from skin areas such as the scalp and the body. Several studies suggest the use of herbal medicine to treat related disorders, including alopecia. Dermal microcirculation is essential for hair maintenance, and an insu�cient blood supply can lead to hair follicles (HF) diseases. This work aims to provide an insight into the ethnohistorical records of some nutritional compounds containing flavonoids for their potential beneficial features in repairing or recovering from hair follicle disruption. We started from a query for “alopecia” OR “hair
loss” AND “Panax ginseng C.A. Mey.“ (or other six botanicals) terms included in Pubmed and Web of Sciences articles. The activities of seven common botanicals introduced with diet (Panax ginseng C.A.
Mey., Malus pumila Mill cultivar Annurca, Co�ea arabica, Allium sativum L., Camellia sinensis (L.) Kuntze, Rosmarinum o�cinalis L., Capsicum annum L.) are discussed, which are believed to reduce the rate of hair loss or stimulate new hair growth. In this review, we pay our attention on the molecular mechanisms underlying the bioactivity of the aforementioned nutritional compounds in vivo, ex vivo and in vitro studies. There is a need for systematic evaluation of the most commonly used plants to confirm their anti-hair loss power, identify possible mechanisms of action, and recommend their best adoption.
... The newly growing hair is weaker-thinner and shorter and after several cycles, they stop to growth and hair loss can be observed [69]. In several studies tea polyphenols, essential oils and caffeine present in tea plant leaves inhibit the activity of 5α-reductase, which results in a decreased DHT formation [97,99]. The former compounds were also found stimulate hair roots and extend the hair growth phase (anagen phase) [77]. ...
... Fischer and co-investigators performed an in vitro study, which have shown that external application of caffeine in a concentration of 0.001% and 0.005% led to a significant stimulation of human hair follicle growth. It was concluded that caffeine reduces smooth muscle tension near the hair follicle and therefore significantly increases delivery of nutrients through the microcirculation of the papillae of the hair [99]. ...
... -Significant decrease in sebum production -The highest efficiency was achieved after 8 weeks of treatment (60% of sebum reduction) -Significant improvement already after 1 week of treatment (sebum production decreased by 10%) [98] Hair follicles from 14 biopsies, taken from the vertex areas from male with androgenic alopecia Caffeine External application of caffeine in a concentration of 0.001 and 0.005% -Significant stimulation of hair follicle growth -Reduction of a smooth muscle tension near the hair follicle -Significant increase of the nutrients delivery to a hair papillae [99] Placebo controlled study 30 mice ...
Studies on the cosmetic applications of plant extracts are increasingly appearing in the scientific literature, which is due to the growing popularity of skincare products around the world. In the light of the observed changes, a return to natural treatment and skincare with cosmetics free of harmful substances or toxic preservatives is visible. Currently, tea extracts, due to their rich composition and various biological actions, play an important role among the dietary supplements and cosmetics. This review is intended to collect the reports on the properties of the tea plant, its extracts and preparations in cosmetology: for skin care products and for the treatment of selected dermatological diseases. Particular attention is paid to its antioxidant, anti-hyaluronidase, anti-inflammatory, slimming, hair-strengthening, photoprotective and sealing blood vessels properties.
... The EE (%) and LC (%) of β-arbutin was determined to be 68% and 73.4%, respectively, for a 0.4% β-arbutin concentration (Table 1). Entrapment efficiency is influenced by fabrication processes, preparation, methods, the physiochemical properties of β-arbutin [13,[35][36][37], and numerous formulation variables [13]. In the present study, the use of β-arbutin concentrations of 0.5% and 0.6% caused a slight reduction in the drug-loading capacity of the nanoparticles. ...
... The skin's appendages also serve as potential points of entry and penetration into the SC [18]. Funnel-shaped hair follicles, for instance, extend up to 200 nm into the skin [35]. Their large surface area disrupts the epidermal barrier within the lower regions of the skin structure and act as efficient reservoirs for drugs and nanoparticles. ...
Background: There has been an increase in demand for cosmetic skin-whitening products with efficacy toward lightening skin tone. β-arbutin is an inhibitor of tyrosinase enzyme activity within the skin’s melanocytes, and so has shown considerable promise as a skin-lightening agent. It is, however, both hydrophilic and hygroscopic, which hinders its penetration of the skin to reach these melanocytes. Chitosan (CS) possesses considerable penetration-enhancing properties when utilized in topical delivery formulations. The strong affinity of positively charged chitosan nanoparticles toward negatively charged biological membranes can be exploited to achieve site-specific targeting. Objective: To investigate the use of chitosan nanoparticles (CSNPs) as carrier units to enhance the topical delivery of β-arbutin. Method: CSNPs containing β-arbutin were prepared using an ionic cross-linking method, and entrapment efficiency and loading capacity were evaluated at numerous β-arbutin concentrations. Further characterization involved using FTIR, XRD, TEM, and TGA, and in vitro permeation studies were conducted using in vitro Franz diffusion cells. Results: β-arbutin chitosan nanoparticles were successfully formulated with a size range of 211–289 d.nm, a polydispersity index between 0.2–0.3, and zeta potential in the range 46.9–64.0 mV. The optimum encapsulation efficiency (EE) and loading capacity (LC) of β-arbutin were 68% and 73%, respectively. TEM revealed the nanoparticles to be spherical in shape. FTIR spectra revealed characteristic chitosan-related peaks appearing at 3438.3 cm−1 (-OH stretching) and 3320 cm−1 (-CH stretching), together with 1598.01 cm−1 (-NH2) specific to β-arbutin nanoparticles. XRD analysis revealed an increase in crystallinity and TGA analyses identified increasing thermal stability with increasing β-arbutin concentration. In vitro studies indicated higher permeation and improved penetration of β-arbutin loaded in CSNPs compared to its free form. Conclusion: CSNPs present considerable promise as effective carriers for improved topical delivery of β-arbutin.
... Benefi cial changes in the mechanical properties of individual scalp fi bers were observed after the caffeine preparation. Fisher et al. (24) took hair follicles from the vertex areas from 14 male patients. Hair follicles were cultivated for 120-192 h in vitro with normal William's E medium (control) or William's E medium containing different concentrations of caffeine (0.001-0.15%). ...
... They showed that caffeine concentrations ranging from 0.001% to 0.005% led to in vitro stimulation of human hair follicle growth. The stimulating effects of caffeine on hair growth can also be explained due to the caffeine phosphodiesterase inhibition activity with consequent increase of cAMP intracellular concentration and stimulating cellular metabolism (24). ...
Plants are a rich source of a wide variety of bioactive compounds that can be used for the preparation of cosmetics. Natural cosmetics with plant components such as vitamins, polyphenols, and alkaloids have become more and more popular. Alkaloids are important secondary metabolites in plants. They are known to possess therapeutic properties. Alkaloids can be used in the production of tonics, creams, lotions, face and hair masks, compresses for skin problems with numerous inflammations, and discoloration and antiaging products, as well as for reducing the formation of cellulitis. Alkaloids are also used in the production of ampoules for cosmetologists and aesthetic medicine doctors. However, at higher doses, they may exhibit toxic properties. Several studies have been carried out in evaluation of the activity of alkaloids from various plants for their use in cosmetics. This review describes alkaloids (caffeine, capsaicin, berberine, piperine, spilanthol, and anatabine) derived from various plants that are used in cosmetics, as well as their reported activities.
... 1 Androgenetic alopecia (AGA) represents a common form of hair loss, affecting around 50% of men by the age of 50 years. 2 In line with the general perception, recent observational studies suggest that stress may exacerbate hair loss in AGA; 3 however, biological evidence to support this theory has been lacking. As indicated by the fact that hair cortisol level has been adopted to assess stress exposure, the hair follicle (HF) is a stress-associated miniorgan. ...
... 3 Higher caffeine concentration did not always exhibit more favourable effects on organ-cultured HFs vs. lower concentrations. 2 In addition, considering the diverse effects of caffeine, 7 an optimal and stable caffeine concentration needs to be achieved locally, not systemically. Topically applied caffeine can penetrate via HFs. ...
Linked Article: Fischer et al. Br J Dermatol 2021; 184:96–110.
... In the management of AGA, topically applied caffeine reportedly inhibits the miniaturization of hair follicles and stimulates hair growth. In an in vitro study by Fisher et al, 17 low doses of caffeine were shown to counteract the growth suppression of human hair follicles treated with testosterone. Moreover, caffeine alone led to a significant stimulation of hair follicle growth. ...
... Moreover, caffeine alone led to a significant stimulation of hair follicle growth. 17 The role of caffeine in human hair biology was further explored by Fisher et al, 18 who discovered new growth-promoting effects of caffeine on the human hair follicles at different levels: molecular, cellular, and organ. These findings are supportive of the potential clinical impact of caffeine in male AGA patients. ...
Androgenetic alopecia is the most common form of hair loss. This condition affects both men and women causing significant psychological distress and a decrease in the quality of life. The objective of this study was to investigate the clinical efficacy and patient satisfaction of a topical compounded formulation (minoxidil 10%, finasteride 0.1%, biotin 0.2%, and caffeine citrate 0.05% hydroalcoholic solution) in male androgenetic alopecia patients. A total of five individual, prospective case studies were conducted in the private hair transplant practice of Dr. James C. Marotta. Patients were provided with the topical formulation and instructed to apply a measured 1-mL dose to the entire frontal, parietal, and occipital scalp, twice daily for 6 months. Patients visited the practice periodically (90 days, 120 days, and 180 days post-treatment) for clinical evaluation, photographic assessment, and measurement of their treatment satisfaction by the Men's Hair Growth Questionnaire. By the end of the study, at 180 days, the dermatologist-in-charge concluded that the topical treatment was successful for all five patients. Although moderate, the clinical improvements were visually noticeable as most patients had thicker, more voluminous hair; improved scalp coverage; and improved general hair appearance. These results were consistent with the photographic assessment, which demonstrated a global average increase of +1.05 in the patients' hair density. According to the patients' self-assessment, the topical compounded formulation was effective following 3 months and 6 months of continuous treatment. At 120 days, the patients' satisfaction was neutral or negative, which was likely due to negligible differences in the patients' hair growth and appearance in 90 days compared to 120 days. The results from this study suggest that the new hair-loss topical solution may be considered a safe and effective treatment option in male AGA patients.
... In the management of AGA, topically applied caffeine reportedly inhibits the miniaturization of hair follicles and stimulates hair growth. In an in vitro study by Fisher et al, 17 low doses of caffeine were shown to counteract the growth suppression of human hair follicles treated with testosterone. Moreover, caffeine alone led to a significant stimulation of hair follicle growth. ...
... Moreover, caffeine alone led to a significant stimulation of hair follicle growth. 17 The role of caffeine in human hair biology was further explored by Fisher et al, 18 who discovered new growth-promoting effects of caffeine on the human hair follicles at different levels: molecular, cellular, and organ. These findings are supportive of the potential clinical impact of caffeine in male AGA patients. ...
Androgenetic alopecia (AGA) is the most common form of hair loss. This condition affects both men and women causing significant psychological distress and a decrease in the quality of life. The objective of this study is to investigate the clinical efficacy and patient satisfaction of a topical compounded formulation (minoxidil 10%, finasteride 0.1% and biotin 0.2% hydroalcoholic solution) in male AGA patients. A total of five individual, prospective case studies were conducted in the private hair transplant practice of Dr Marotta. Patients were provided with the topical formulation and instructed to apply a measured 1 mL to the entire frontal, parietal and occipital scalp, twice daily for 6 months. Patients visited the clinic periodically (90, 120 and 180 days post-treatment) for clinical evaluation, photographic assessment and measurement of their treatment satisfaction by the Men’s Hair Growth Questionnaire (MCHQ). By the end of the study, at 180 days, the dermatologist in charge concluded that the topical treatment was successful for all five patients. Although moderate, the clinical improvements were visually noticeable as most patients had thicker, more voluminous hair; improved scalp coverage and improved general hair appearance. These results were consistent with the photographic assessment, which demonstrated a global average increase of +1.05 in the patients’ hair density. According to the patients’ self-assessment, the topical compounded formulation was effective following 3 months and 6 months of continuous treatment. At 120 days, the patients’ satisfaction was neutral or negative, which was likely due to negligible differences in the patients’ hair growth and appearance in just 1 month (3-4 months). The results from this study suggest that the new hair loss topical solution may be considered a safe and effective treatment option in male AGA patients.
... The hair follicle (HF) is a mini organ of the skin, extending from the epidermis into the lower dermis, tubular in shape and widening into a bulb at its lower end. Its anatomy, structure physiological role and regenerative nature is well described [1][2][3], although many aspects of its biology remain unclear [4]. Enclosed by the follicle bulb sits the dermal papilla (DP), consisting of spindle-shaped fibroblast cells referred to dermal papilla cells (DPC); connective tissue components and a capillary network. ...
... The anagen or the fibre growth stage is characterised by intense metabolic activity within the DP and the rapid proliferation (mitosis) of HMKs within the bulb. The mitotic rate of HMKs is amongst the highest in the human body [1]. Simultaneously, the bulb melanocytes produce melanin, which is transferred to the cortical cells via melanocyte dendrites. ...
It is known that hair growth disorders and hair loss can cause personal distress and affect well-being. Whilst clinical conditions remain a target for medical research, current research on hair follicle biology and hair growth control mechanisms also provides opportunities for a range of non-medical and cosmetic interventions that have a modulating effect on the scalp and follicle function. Furthermore, an improvement of the hair fibre characteristics (cuticle structure, cortex size and integrity) could add to the overall positive visual effect of the hair array. Since phytochemicals are a popular choice because of their traditional appeal, this review provides a critical evaluation of the available evidence of their activity for hair benefit, excluding data obtained from animal tests, and offers recommendations on improving study validity and the robustness of data collection in pre-clinical and clinical studies.
© 2019 Society of Cosmetic Scientists and the Société Française de Cosmétologie.
... A review by Kriteeka Saini et al. [62] investigated the effect of vitamin D supplementation on hair growth and found that vitamin D plays a role in various signaling pathways for hair follicle growth and differentiation. Other nutritional supplements, such as biotin, caffeine, melatonin, and zinc, have been proposed as potential therapies for hair loss, but the exact therapeutic mechanisms remain unclear [63][64][65][66]. While nutritional supplements are often used off-label or as adjuvant therapy in treating FPHL, a large body of evidence is s\ll needed to support their efficacy. ...
Pattern hair loss can occur in both men and women, and the underlying molecular mechanisms have been continuously studied in recent years. Male androgenetic alopecia (M-AGA), also termed male pattern hair loss, is the most common type of hair loss in men. M-AGA is considered an androgen-dependent trait with a background of genetic predisposition. The interplay between genetic and non-genetic factors leads to the phenotype of follicular miniaturization. Although this similar pattern of phenotypic miniaturization can also be found in female pattern hair loss (FPHL), the corresponding genetic factors in M-AGA do not account for the phenotype in FPHL, indicating that there are different genes contributing to FPHL. Therefore, the role of genetic factors in FPHL is still uncertain. Understanding the genetic mechanism that causes FPHL is crucial for the future development of personalized treatment strategies. This review aims to highlight the differences in the ethnic prevalence and genetic background of FPHL, as well as the current genetic research progress in nutrition, Wnt signaling, and sex hormones related to FPHL.
... Wzmacnia ich strukturę, wygładza, dodaje blasku oraz ociepla ich barwę. Ponadto kofeina zmniejsza niekorzystny wpływ stresu na cebulki włosów, znacznie ograniczając ich wypadanie [47]. ...
Na ilość spożywanej kawy przez konsumentów ma wpływ przede wszystkim jej niepowtarzalny, dość głęboki smak i delikatny aromat, w którym wyczuwalne są nuty korzenne lub czekoladowe oraz jej właściwości wynikające z zawartości kofeiny i polifenoli. Doniesienia naukowe wskazują, że umiarkowana konsumpcja kawy może być częścią zdrowej diety i aktywnego trybu życia, co wiąże się z szeregiem pożądanych zjawisk fizjologicznych w tym sprawności psychicznej i fizycznej. Artykuły naukowe przedstawiają szerokie spektrum pozytywnego wpływu cennych związków zawartych w tym napoju na organizm człowieka, m.in. zmniejszenie śmiertelnościz powodu chorób sercowo-naczyniowych, cukrzycy typu 2, jak również nowotworów czy też obniżeniu ryzyka zachorowalności na chorobę Parkinsona i Alzheimera. Jej dobroczynne właściwości wykorzystywane są również w kosmeteologii.
... As a result, it triggers cell proliferation that helps to reverse hair follicle miniaturization. In various in vitro studies, topical caffeine at various concentrations was able to halt hair follicle growth suppression and stimulate growth [96,97]. A trial in 210 males with AGA demonstrated that caffeine-related growth was not any less than growth seen with 5% minoxidil solution [90]. ...
Androgenetic alopecia (AGA), also known as male pattern hair loss (MPHL) or female pattern hair loss (FPHL), is the most common form of alopecia worldwide, and arises from an excessive response to androgens. AGA presents itself in a characteristic distribution unique to both sexes. Despite its prevalence, AGA can be quite challenging to treat. The condition is chronic in nature and stems from an interplay of genetic and environmental factors. There are only two US Food and Drug Administration (FDA)-approved drugs for the condition: topical minoxidil and oral finasteride. However, numerous non-FDA-approved treatments have been shown to be effective in treating AGA in various studies. Some of these treatments are relatively new and still to be explored, thus emphasizing the need for an updated review of the literature. In this comprehensive review, we discuss the evaluation of AGA and the mechanisms of action, costs, efficacies, and safety profiles of existing, alternative, and upcoming therapeutics for this widespread condition.
... Caffeine, a hydrophilic alkaloid with high bioactivity and capacity to penetrate the lipid skin barrier, has recently attracted increased attention as an active cosmetic agent possessing antioxidant, anticellulite, antiphotoaging, and hair growth-stimulating properties [31,39]. As mechanisms of action, the improvement of local microcirculation in the scalp skin and the inhibition of the 5-α-reductase, an enzyme converting testosterone into dihydrotestosterone, which suppresses the hair shaft elongation, were hypothesized and then proven at molecular, cellular, and in vitro hair organ culture levels [40,41]. The conclusion was that enhanced hair shaft elongation, prolonged the anagen phase of the hair cycle, and stimulated hair matrix keratinocyte proliferation. ...
Plant-derived secondary metabolites (polyphenols/terpenes/alkaloids) and microbial exometabolites/membrane components of fermented tropical fruits are known as highly bioavailable biomolecules causing skin and hair improvement effects (wound healing, anti-inflammatory, antioxidant, antidiabetic, antiacne, skin/hair microbiota balancing, hair growth-promoting, and hair loss-inhibiting). Caffein is considered as a hair growth promoter. A randomized placebo- and caffein-controlled clinical trial on the efficacy of fermented papaya (FP) plus fermented mangosteen (FM) towards human hair quality and loss was conducted. Shampoo and lotion hair care products containing FP, FM, and caffein as active agents were developed and applied to 154 subjects of both sexes with clinically confirmed androgenic or diffuse alopecia for 3 months. Their clinical efficacy was assessed subjectively by questionnaires filled in by dermatologists/trichologists, and by the objective trichomicroscopical calculations. Hair and scalp skin quality was determined by microbiota pattern and ATP, SH-groups, protein, and malonyl dialdehyde quantification. Comparative clinical data showed that the experimental hair care cosmetics significantly inhibited hair loss, increased hair density/thickness, and improved hair follicle structure versus placebo and caffein controls. The cosmetics with FP and FM substantially normalized the microbiota pattern and increased ATP content in hair follicle, while inhibiting lipid peroxidation in the scalp skin, and SH-group formation in the hair shaft.
... It possesses two activities of relevance for hair growth -Indirect, via 5AR inhibition and direct, by stimulation of hair growth parameters. Employing the hair organ culture model wherein hair follicles from the vertex area of male AGA patients were cultivated, Fischer et al. demonstrated that caffeine in concentrations of 0.001% and 0.005% not only counteracted the testosterone-induced hair follicle growth suppression, but also induced significant follicular growth independently [83]. In their next study published recently, Fischer et al. elaborated on caffeine's in-vitro effect at the cytokine level in hair follicles cultivated from both men and women with AGA. ...
... According to some in vitro studies, caffeine actively works as a healthy hair growth promoter in the case of androgen-dependent hair growth inhibition. The excess quantity of this hormone around the hair follicles tends to reduce the growth of hairs by the lack of hair nutrients supply [192,202,203]. Moreover, the combination of the Saberry®, i.e., extract of amla in powder form (the main components are amino acids such as alanine, aspartic acid, glutamic acid, lysine, and proline) and peanut shell powder (luteolin is the major active constituent) with selenium micronutrient, coconut freeze-dried water, and sandalwood fragrance loaded hair serum has been found to show an excellent effect on hair texture and reduce the hair fall in 90 days of the therapy [204]. ...
The growth and demand for cosmeceuticals (cosmetic products that have medicinal or drug-like benefits) have been enhanced for the last few decades. Lately, the newly invented dosage form, i.e., the pharmaceutical-based cosmetic serum has been developed and widely employed in various non-invasive cosmetic procedures. Many pharmaceutical-based cosmetic serums contain natural active components that claim to have a medical or drug-like effect on the skin, hair, and nails, including anti-aging, anti-wrinkle, anti-acne, hydrating, moisturizing, repairing, brightening and lightening skin, anti-hair fall, anti-fungal, and nail growth effect, etc. In comparison with other pharmaceutical-related cosmetic products (creams, gels, foams, and lotions, etc.), pharmaceutical-based cosmetic serums produce more rapid and incredible effects on the skin. This chapter provides detailed knowledge about the different marketed pharmaceutical-based cosmetic serums and their several types such as facial serums, hair serums, nail serums, under the eye serum, lip serum, hand, and foot serum, respectively. Moreover, some valuable procedures have also been discussed which provide prolong effects with desired results in the minimum duration of time after the few sessions of the serum treatment.
... Reduces apoptosis and necrosis. [119,127,128] Epigallocatechin gallate (Camellia sinensis (L.) Kuntze) ...
Hair health is associated with personal distress and psychological well-being. Even though hair loss (alopecia) does not affect humans' biological health, it affects an individual's social well-being. So, treatment for hair problems and improving hair health are obligatory. Several pharmacological and cosmeceutical treatment procedures are available to manage hair loss and promote growth. Several factors associated with hair health include genetics, disease or disorder, drugs, lifestyle, chemical exposure, and unhealthy habits such as smoking, diet, and stress. Synthetic and chemical formulations have side effects, so people are moving towards natural compounds-based remedies for their hair problems. The history of using phytochemicals for hair health has been documented anciently. However, scientific studies on hair loss have accelerated in recent decades. The current review summarizes the type of alopecia, the factor affecting hair health, alopecia treatments, phytochemicals' role in managing hair loss, and the mechanisms of hair growth-stimulating properties of phytochemicals. The literature survey suggested that phytochemicals are potent candidates for developing treatment procedures for different hair problems. Further detailed studies are needed to bring the scientific evidence to market.
... Bioactive compounds in coffee, such as caffeine, trigonelline, and chlorogenic acid, have several skin benefits. They can retard aging process due to ultraviolet radiation, prevent skin photo-damage by acting as antioxidants [54][55][56], and can promote hair growth by inhibiting 5α-reductase enzymes [57]. This suggests that coffee pulp extract might convey these potential benefits. ...
In the cosmetic and pharmaceutical industries, it has been increasingly popular to use alternative solvents in the extraction of bioactive compounds from plants. Coffee pulp, a by-product of coffee production, contains different phenolic compounds with antioxidant properties. The effects of polyols, amplitude, extraction time, solvent concentration, and liquid–solid ratio on total phenolic content (TPC) using ultrasound-assisted extraction (UAE) were examined by single-factor studies. Three main factors that impact TPC were selected to optimize the extraction conditions for total phenolic content (TPC), total flavonoid content (TFC), total tannin content (TTC), and their antioxidant activities using the Box-Behnken design. Different extraction methods were compared, the bioactive compounds were identified and quantified by liquid chromatography triple quadrupole mass spectrometer (LC-QQQ), and the cytotoxicity and cellular antioxidant activities of the extract were studied. According to the response model, the optimal conditions for the extraction of antioxidants from coffee pulp were as follows: extraction time of 7.65 min, liquid–solid ratio of 22.22 mL/g, and solvent concentration of 46.71 %. Under optimized conditions, the values of TPC, TFC, TTC, 1,1-diphenyl-2-picryl-hydrazil (DPPH) radical scavenging assay, 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical scavenging assay, and Ferric reducing antioxidant power assay (FRAP) were 9.29 ± 0.02 mg GAE/g sample, 58.82 ± 1.38 mg QE/g sample, 8.69 ± 0.25 mg TAE/g sample, 7.56 ± 0.27 mg TEAC/g sample, 13.59 ± 0.25 mg TEAC/g sample, and 10.90 ± 0.24 mg FeSO4/g sample, respectively. Compared with other extraction conditions, UAE with propylene glycol extract (PG-UAE) was significantly higher in TPC, TFC, TTC, DPPH, ABTS, and FRAP response values than UAE with ethanol (EtOH-UAE), maceration with propylene glycol (PG-maceration), and maceration with ethanol (EtOH -maceration) (p
... Previous studies have determined that caffeine inhibits the activity of the 5α-reductase enzyme and contributes to a renewed growth phase for human hair. Thus, caffeine was identified as a stimulator of human hair growth in vitro, which may have an important clinical impact on managing androgenetic alopecia [53]. Lademann et al. [54] and Teichmann et al. [55] demonstrated that shampoo containing caffeine efficiently penetrated into the hair follicles of the human scalp and affected hair growth. ...
The aging process encompasses gradual and continuous changes at the cellular level that slowly accumulate with age. The signs of aging include many physiological changes in both skin and hair such as fine lines, wrinkles, age spots, hair thinning and hair loss. The aim of the current study was to investigate the anti-aging potential of coffee berry extract (CBE) on human dermal fibroblast (HDF) and hair follicle dermal papilla (HFDP) cells. Coffee berry was extracted by 50% ethanol and determined for chemical constituents by HPLC technique. Cytotoxicity of the extract was examined on both cells by MTT assay. Then, HDF cells were used to evaluate antioxidant properties by using superoxide dismutase activity (SOD) and nitric oxide inhibition as well as anti-collagenase inhibition assays. The effectiveness of anti-hair loss properties was investigated in HFDP cells by considering cell proliferation, 5α-reductase inhibition (5AR), and growth factor expression. The results showed that caffeine and chlorogenic acid were identified as major constituents in CBE. CBE had lower toxicity and cell proliferation than caffeine and chlorogenic acid on both cells. CBE showed SOD and nitric oxide inhibition activities that were higher than those of caffeine but lower than those of chlorogenic acid. Interestingly, CBE had the highest significant anti-collagenase activity, and its 5AR inhibition activity was comparable to that of chlorogenic acid, which was higher than caffeine. CBE also stimulated hair-related gene expression, especially insulin-like growth factor 1 (IGF-1), keratinocyte growth factor (KGF) and vascular endothelial growth factor (VEGF). The results confirmed that CBE provided anti-aging activity on both skin and hair cells and could be beneficial for applications in cosmeceuticals.
... Caffeine was chosen as a reference for this work because it is commonly used in hair care products and is claimed to stimulate hair growth and prevent hair loss. Fischer et al. showed that caffeine leads to a significant stimulation of hair follicle growth, reduces the negative influence of testosterone [32], and increases IGF-1 protein expression in male and female hair follicles in vitro [33]. In addition, the substance decreases the activity of the enzyme 5-reductase, which is responsible for the conversion of testosterone into dihydrotestosterone [34]. ...
... Which not only improves the scalp but also appears to help maintain hair condition from 5reductase inhibition activity. This enzyme can convert testosterone to active dihydrotestosterone (DHT) that contributes to baldness, thus renewing the hair growth phase [3]. According to a recent study, it showed that caffeine concentrations from 0.001 to 0.005% resulted in the in vitro growth of hair follicle cells due to caffeine phosphodiesterase. ...
Nowadays, Thai consumers are more alert and caring about their hair health. As a result, products that care and promote hair and scalp are in high demand. One of the most interesting products is the hair care line. One of the important substances that help in reducing hair loss and promoting hair regrowth is coffee extract. This research focuses on value creation of coffee products from the northern Thailand into a cosmeceutical product. Variety of coffee by-product are studied in terms of Caffeine content and antioxidant activity, which benefit the hair growth and scalp care function. In addition, product development technique has been implemented to develop the hair serum prototype that comply with customer’s requirement. The results show that the active ingredient can be extracted from a variety part of coffee by- product. The coffee bean extraction yields the highest amount of Caffeine, while the red coffee fruit extraction yields the highest amount of antioxidant activity. However, when compare in terms of performance/cost of material, the extraction of fall grade cherry coffee is the most cost effective source for both active ingredients for this serum development. In the meantime, the market demand was collected based on 252 sample size using online questionnaires. The results show that the sample group gave importance to the factor of no irritation to the scalp as the first concern, while the safety issue as the second and the properties of the product ranked the third on customer’s needs. Then the prototype was developed and verified in terms of active ingredient concentration and product stability. Furthermore, product was validated in terms of hair growth and skin irritation. Finally, the prototype was analyzed with 3 focus groups: (1) hair loss prevention group (2) hair loss solution group and (3) beauty service provider/ product supplier. According to these focus group evaluation, it shows that all three test participants were satisfied with prototype’s sensory. Some issues that could be improved are viscosity and stickiness. Additionally, marketing mix was evaluated on these group to estimate potential product-package design, selling price and place, as well as the promotion technique.
... 6,13,14 Among the ingredients with a potential for cosmetic use against AGA are Hexyl nicotinate (NHE), which enhances cutaneous blood flow [15][16][17] and caffeine for its inhibitory effect on phosphodiesterase resulting in increased cAMP levels in cells 18 as a proposed mechanism of the stimulation of the proliferation of hair follicles. 19 The non-inferiority of a caffeine-based 0.2% topical liquid to minoxidil 5% in the treatment of men with AGA has been demonstrated. 20 Polyphenols (Dihydroquercetin-glycoside [DHQG] and Epigallocatechingallate-glucoside [EGCG2]) induced a stimulation of the metabolism of human fibroblast dermal papilla cells, proliferation and anti-apoptotic effect of the outer root sheath cells, and activation of the Wnt/β-catenin pathway. ...
Background:
Considerable parts of the global population are affected by androgenetic alopecia (AGA).
Aims:
The efficacy of a foam containing nicotinic acid hexyl ester, polyphenols, zinc, glycine, and caffeine in comparison with a vehicle control foam was assessed in a double-blind vehicle-controlled study in men with AGA over 6 months.
Patients/methods:
Sixty-two men with AGA were assigned either to the active ingredients (verum) or the vehicle group. They applied the products twice daily on affected scalp areas over 6 months. Automated phototrichograms were obtained at baseline, after 3 and 6 months. In addition, a clinical rating by a dermatologist and by the subjects themselves was documented using standardized questionnaires.
Results:
The reduction of the telogen rate from T0 to T6 was significantly stronger in the verum group compared to the vehicle group. The reduction was significant from T0 to T3 and T6 in the verum group, but in the vehicle group only from T0 to T3, not to T6. Significantly increased hair density was noticed in both groups at all time points, but the change from T0 to T6 did not differ significantly between the groups. Cosmetic acceptance of the foam and its application regimen was generally good in both groups. Slight reddening and burning after application of verum in six cases was probably due to the presence of hexyl nicotinate.
Conclusion:
The study demonstrated a reduction of the telogen rate by a cosmetic foam in men affected by AGA, indicating a benefit for cosmetic intervention against male pattern hair loss.
... The newly grown hairs become weaker, wafer-thinner and shorter; but after some cycles, hair growth gets stopped, and alopecia can be observed (Mnich et al. 2009). Several studies have proved that tea polyphenols impede the activity of 5αreductase, causing a reduction in the formation of DHT (Fischer et al. 2007;Koch et al. 2019). The compounds present in green tea also help to revitalize hair roots and expand the phase of hair growth (i.e., anagen phase) (Majewska et al. 2010). ...
Due to its wide range of properties, green tea has extensively been
turned out as an important substance to be examined experimentally by the analysts. Out of its various properties, the antineoplastic activity of green tea is exclusively acknowledged. Green tea shows therapeutic potential in case of cancers of cervical, lung, colon, liver, stomach, leukemia, prostate, breast, and many other organs. Green tea
extract possesses some carcinoma preventive bioactive components such as polyphenols, proline, lysine, catechin, ascorbic acid, and
epigallocatechin-3-gallate. Earlier investigations have favoured the
relationship between the reasonable intake of green tea polyphenols and the decreased cancer possibility. Various mechanisms have been
proposed to determine the application of green tea components as an
anticancer agent. These mechanisms incorporate modulation of the
immune system and cell signalling pathways, regulation of cell cycle,
anti-oxidant activity, and inhibition of receptor tyrosine kinase pathway. Further, drug tolerance and several harmful side effects have long been a crucial complication in the treatment of tumor. The treatment by chemotherapy has also been transformed from single-drug remedy to multiple-drug remedy. Earlier research results indicated that the amalgam of green tea and chemo-remedial drugs could synergistically intensify the effectiveness of therapy and lessen the worse after-effects of antitumor agents in tumor sufferer. Therefore, we have focused on the use of green tea constituents either alone or in combination with other agents for the treatment of different types of cancers with upgraded life expectancy.
... Because mouse vibrissa HFs were shown to be an ideal in vitro model system for studying the hair cycle [26,61], we tested the effect of DHT on the hair cycle in vibrissa HF organ cultures. DHT not only inhibited hair growth and induced hair regression, but also caused HFs to enter catagen prematurely [62]. ...
Androgenic alopecia (AGA), also known as male pattern baldness, is one of the most common hair loss diseases worldwide. The main treatments of AGA include hair transplant surgery, oral medicines, and LDL laser irradiation, although no treatment to date can fully cure this disease. Animal models play important roles in the exploration of potential mechanisms of disease development and in assessing novel treatments. The present study describes androgen receptor (AR) in C57BL/6 mouse hair follicles that can be activated by dihydrotestosterone (DHT) and translocate to the nucleus. This led to the design of a mouse model of androgen-induced AGA in vivo and in vitro. DHT was found to induce early hair regression, hair miniaturization, hair density loss, and changes in hair morphology in male C57BL/6 mice. These effects of DHT could be partly reversed by the AR antagonist bicalutamide. DHT had similar effects in an ex vivo model of hair loss. Evaluation of histology, organ culture, and protein expression could explain the mechanism by which DHT delayed hair regrowth.
... Furthermore, the caffeine contents in black tea ranges from 2.79 to 2.93% and this is because many factors control it such as water temperature and extraction method (Horžić et al. 2009;Komes and Ganić 2009). It has been reported that caffeine inhibits phosphodiesterase, that in turn encourages cell proliferation in the hair matrix by increasing the level of cAMP in the cell and thus stimulate its metabolism, this would impede the negative effect of dihydrotestosterone DHT on hair follicle and promotes the elongation of hair fiber (Bansal, Manchanda, and Pandey 2012;Fischer, Hipler, and Elsner 2007). Moreover, flavanoids of black tea such as EGCG have high affinity for estrogen alpha receptor and consequently they possess hair growth promoting activity (Hou et al. 2013). ...
Consuming functional foods and drinks such as kombucha tea is believed to give many beneficial effects for promoting immunity and preventing cancer. The fermented tea with sugar and symbiotic culture of yeast and bacteria is also useful in the topical application for hair re-growth. This study aims to investigate hair re-growth properties of kombucha black tea and chamomile with and without methylsulfonylmethane. Treatments were applied topically to denuded Balb/c mice and observed for hair growth initiation time, density and length in 15 and 30 days in addition to microbiological identification of the main yeast and bacteria. Results showed significantly better hair density and length in groups treated with kombucha black tea with and without MSM, followed by kombucha chamomile tea with and without MSM respectively. In addition, it has been found that MSM promotes hair growth significantly when combined with kombucha ferments. Microbiological analysis indicated the presence of Zygosaccharomyces bailii and Acetobacter genus in the tea broth. Black tea kombucha with MSM can be used as a natural alternative therapy for hair fall and a cost-effective treatment with fewer side effects compared to the synthetic drugs.
... Earlier investigations have shown that caffeine in concentrations of 0.001% and 0.005% inhibits the activity of 5-α-reductase (4) and phosphodiesterase. This increases the intracellular concentration of cyclic adenosine monophosphate (5), stimulating microcirculation, cellular metabolism, and delivery of nutrients to the hair follicle, thereby contributing to strengthened and more rapid human hair growth (1,6). It has been documented that the application of caffeine on the skin leads to its fast absorption and occurrence in the blood. ...
Caffeine is extensively used in cellulite and hair growth cosmetic products. Regulations in the field of cosmetics require manufacturers to list caffeine in the ingredient list on product labels, but its exact content in these products is not declared. On the other hand, daily exposure to caffeine from all sources may approach health reference values. For that reason, it is important to know the exact caffeine content in products for skin and hair care. Cosmetics are often viscous or semisolid products of very complex chemical composition. To analyze caffeine in these complex sample matrices by liquid chromatographic methods, an extraction step is often necessary. This article presents the applicability of the solid-phase extraction (SPE) procedure for the caffeine extraction and high-performance liquid chromatography (HPLC) determination in anticellulite gels, shampoos, and hair balsam. The samples of gels were centrifuged after ammonia addition to precipitate carbomer. In cellulite reduction, gel caffeine content was found to be in the range of 0.7-1.7%, whereas in the hair-care products, it was about 1.0%.
... Caffeine enhances cellular proliferation, counteracts the inhibitory effects of testosterone on hair growth, promotes hair shaft elongation, extends anagen duration, and stimulates hair matrix keratinocyte proliferation [86] Amino acids Oral l-cystine (70 mg) in combination with retinol was assessed for the treatment of diffuse alopecia and resulted in enhanced hair density and anagen rate [87]. Oral l-cystine was also trailed in combination with histidine, copper, and zinc is taken 4 times daily which results in improved mean change in total hair count after 50 weeks) in 24 patients having AGA [88] Curcumin A 5% topical hexane extract of Curcuma aeruginosa (CA) was compared to placebo, 5% minoxidil. ...
Androgens have an intense consequence on the human scalp and body hair. Scalp hair sprouts fundamentally in awol of androgens whereas the body hair hike is vulnerable to the activity of androgens. Androgenetic alopecia (AGA) invoked as males emulate Alopecia due to the cause of the dynamic reduction of scalp hair. Androgens are medium of terminus growth of hair although the body. Local and system androgens convert the extensive terminal follicles into lesser vellus like structure. The out start of this type of alopecia is intensely irregular and the reason behind this existence of enough circulating steroidal hormones androgens and due to genetic predisposition. Effective treatments are available in the market as well as under clinical and preclinical testing. Many herbal formulations are also available but not FDA approved. Different conventional and NDDS formulations are already available in the market. To avoid various systemic side effects of both Finasteride and Minoxidil, topical formulations and natural products (nutrients, minerals, vitamins) now a days are being widely used to treat Androgenic alopecia. CAM (complementary and alternative medicine) provides the option to elect favorable, low-risk, adjuvant and alternative therapies. Herein, we offer a widespread review of topical marketed formulations, natural products, and CAM treatment options for AGA.
Graphic Abstract
... Moreover, caffeine alone led to a significant stimulation of hair follicle growth. 2 There are now numerous over-the-counter hair care products available containing caffeine in combination with a variety of additional chemicals. Some of the products include: Ultrax Labs Hair Surge Caffeine Hair Loss Hair Growth Stimulating Shampoo (caffeine, ketoconazole, saw palmetto), Alpecin C1 Hair Energizer Shampoo with Caffeine (caffeine, panthenol, niacinamide), Alter Ego-Super Hair Follicle Stimulation Blend (Kenyan coffee, green tea, nettle tea), Syoss Men Hair Growth Shampoo with Keratin & Caffeine (caffeine, keratin), and Diamax (caffeine, panthenol, niacinamide). ...
... Alkaloids are the nitrogenous compounds of considerable medicinal and cosmetic value found in herbs. Alkaloid caffeine (Coffea arabica) which contains purine ring is used in alopecia associated with dihydrotestosterone (Fischer et al. 2007). Styphnolobium japonicum contains alkaloid oxymatrine which may be used to prevent keloid and deposition of collagen (Fan et al. 2012). ...
The cosmetic industry is a high-valued and evergreen multibillion dollar industry with more specialized and advanced products adding up every year. The major product categories in the cosmetic industry are skin care, hair care, perfumes, deodorants, toiletries, and make-up. Of these, skin care products top the list, accounting around 36 % of the global cosmetic market. Natural products, a treasure of medicinally active compounds are used for treating various skin ailments, infections, inflammation and as a protectant of UV irradiation and pollution. The hybrid of cosmetic and pharmaceutical compounds, known as cosmeceuticals, possesses therapeutic as well as beautification potential based on its key ingredients. Natural products are well regarded as a rich source of cosmeceuticals. Different classes of natural compounds originating from animal, plant, and marine algal sources are placed under the category of high-valued cosmetic ingredients. The extraction of fatty acid components from botanicals and other natural sources opens up a big market in the cosmetic industry. The present chapter introduces the recent advancement and strategies followed in the cosmeceutical industry, and the role of plant tissue culture in enhancing the production of pharmaceutically valued natural products along with the current regulatory policies.
... The Ki67 protein is a reliable marker of cell proliferation, being present in all active phases of the cell cycle and absent in quiescent or resting phases [28][29][30]. Its expression is associated with increased hair growth, showing a decrease in Ki67-positive hair-matrix keratinocytes at the onset of catagen that has been linked to changes in differentiation markers in the outer and inner root sheaths [31], and increasing or decreasing in association with changes in hair-follicle proliferation in response to caffeine or testosterone, respectively [32,33]. ...
Abstract
OBJECTIVE: Human hair changes with age: fibre diameter and density decrease, hair growth slows and shedding increases. This series of controlled studies examined the effect on hair growth parameters of a new leave-on hair treatment (LOT) formulated with Dynagen (containing hydrolysed yeast protein) and zinc salts. METHODS: Hair growth data were collected from healthy women aged 18 to 65 years. The LOT effect on hair growth was measured in a randomized double blind study and in hair samples; its effect on follicle cell proliferation was assessed by quantifying Ki67 expression in scalp biopsies. The LOT effect on plucking force was determined in an ex vivo model. The effect of Dynagen on the expression of the tight junction marker claudin 1 was analysed in cultured follicles. The effect on protease activity of zinc salts used in the LOT was examined in vitro. RESULTS: Hair growth rate decreased with increasing subject age. The LOT significantly increased hair growth rate, fibre diameter, bundle cross-sectional area, Ki67 expression and the plucking force required to remove hair. Dynagen significantly increased claudin 1 expression in cultured follicles. Protease activity was reduced by zinc salts. CONCLUSION: The Dynagen-based LOT increases hair-fibre diameter, strengthens the follicular root structure and increases hair growth rate
Caffeine is a bitter, white crystalline purine, a methylxanthine alkaloid, chemically related to the adenine and guanine bases of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Caffeine is found in different concentrations in seeds, leaves, and nuts of more than 60 different plant species. It acts as a naturally occurring pesticide since it can paralyze and kill predator insects feeding on the plant [1]. Humans consume caffeine as a stimulant, mainly in coffee beans, tea extracts, in products containing kola or guarana seeds, in the form of soft drinks or energy drinks, or even in everyday food. Caffeine is the world’s most widely consumed psychoactive compound or central nervous system (CNS) stimulant, and in the USA, more than 90% of adults consume an average of 2.4 mg/kg of caffeine daily [2].
Alopecia or hair loss is a widespread issue that has significant effects on personal well-being for both genders nationally and internationally. In addition, alopecia causes extreme emotional stress and negatively impacts the psychological health and self-esteem of cancer patients suffering from chemotherapy-induced alopecia. Unfortunately, available synthetic medications are costly, invasive, or have extreme adverse effects. On the contrary, natural and herbal hair loss products are widely available in the local and international markets in variable pharmaceutical forms with different mechanisms of action, namely, androgen antagonists, nutritional supplements, vasodilators, and 5α-reductase inhibitors or dihydrotestosterone blockers. Thus, it is of great importance to encourage researchers to investigate these natural alternatives that can act as potent therapeutic agents having diverse mechanisms of action as well as limited side effects. Currently, natural remedies are considered a fast-rising pharmaceutical segment with demand from a wide range of consumers. In this study, we present a review of reported herbal remedies and herb combinations recommended for hair loss and their mode of action, along with an overview of available market products and formulations, their composition, and declared effects. In addition, a general outline of the different forms of alopecia, its causes, and recommended treatments are mentioned as well. This was all done with the aim of assisting further studies with developing standardized natural formulations for alopecia as many were found to lack standardization of their bioactive ingredients and efficiency confirmation.
Introduction: Hair follicle regeneration and control of growth cycling is a small but growing field of study. Here we considered some of the more common in vitro and ex vivo hair follicle models that are available for examining follicle growth and cycling, epithelial-mesenchymal signaling, stem cell activity, and follicular neogenesis. Methods: Cited literature was selected using the Pubmed database and the associated MESH terms, or conference proceedings. Results: A variety of in vitro and ex vivo assay models have been developed over the last 35 years. In vitro research started with simple 2D culture of dermal papilla or dermal sheath cells, but this has now progressed to 3D single cell type aggregate cultures that more accurately reflect the gene and protein expression profiles of dermal papilla and dermal sheath cells in vivo. Combining hair follicle mesenchyme and epithelial cells together in 3D “organoid” cultures enables formation of rudimentary proto-hair follicles. More recently, 3D cultured skin equivalents incorporating hair follicle-like structures have been produced from adult cells as well as induced pluripotent stem cells (iPSCs). Ex vivo models are focused on amputated or full-length hair follicles microdissected from scalp skin, follicular units, or whole scalp skin explant culture. Conclusions: Each of the culture systems described holds potential for modelling different aspects of hair follicle growth and regeneration. Potentially, several methods may also be used to provide cells or tissue constructs for treating hair loss. The advantages and limitations of each approach are explored in this review.
Androgenetic alopecia (AGA) is the most common cause of hair loss in men, often requiring medical attention. The US FDA approved topical minoxidil and oral finasteride to treat AGA. Topical minoxidil requires a long-term application to observe improvement; oral finasteride may cause undesirable side effects. Therefore, natural products may be an alternative when patients are skeptical about these two conventional treatments. Physicians may also suggest natural products in conjunction with topical minoxidil or oral finasteride to enhance clinical outcomes. This article reviews the prospect of natural products in treating male AGA. A systematic search was conducted in PubMed, CINAHL, Scopus, Web of Science, and EMBASE (Ovid) on July 19, 2021. In addition, the bibliographies of selected articles were hand-searched to identify relevant studies. After deduplication and screening, 11 clinical studies meet the criteria for detailed review. The selected clinical studies suggest that saw palmetto, caffeine, melatonin, marine extracts, rosemary oil, procyanidin, pumpkin seed oil, and cannabidiol (CBD) oil might be considered in male AGA treatment.
Hair loss is a common complaint that is often stressful for patients and a challenge for practitioners to treat. Fortunately, innovations in the field have contributed to growing evidence for several promising topical, oral, and light and energy-based therapies. We have reviewed the current literature about the efficacy of these treatments, including topical agents (finasteride, latanoprost, spironolactone, caffeine, and metformin), oral minoxidil, nutraceuticals, platelet-rich plasma, low-level laser therapy, fractional lasers, and laser-assisted drug delivery. In addition, several debates related to these treatments have been discussed, including post-finasteride syndrome, effects of biotin supplementation on laboratory testing, standardization of platelet-rich plasma and low-level laser therapy, and combination treatment to enhance hair transplantation.
Objectives:
The hair follicle is composed of more than 20 kinds of cells, and mesoderm derived dermal papilla cells and keratinocytes cooperatively contribute hair growth via Wnt/β-catenin signaling pathway. We are to investigate β-catenin expression and regulatory mechanism by CBD in alopecia hair tissues and dermal papilla cells.
Methods:
We performed structural and anatomical analyses on alopecia patients derived hair tissues using microscopes. Pharmacological effect of CBD was evaluated by β-catenin expression using RT-PCR and immunostaining experiment.
Results:
Morphological deformation and loss of cell numbers in hair shaft were observed in alopecia hair tissues. IHC experiment showed that loss of β-catenin expression was shown in inner shaft of the alopecia hair tissues, indicating that β-catenin expression is a key regulatory function during alopecia progression. Consistently, β-catenin expression was decreased in testosterone or PMA treated dermal papilla cells, suggesting that those treatments are referred as a model on molecular mechanism of alopecia using dermal papilla cells. RT-PCR and immunostaining experiments showed that β-catenin expression was decreased in RNA level, as well as decreased β-catenin protein might be resulted from ubiquitination. However, CBD treatment has no changes in gene expression including β-catenin, but the decreased β-catenin expression by testosterone or PMA was restored by CBD pretreatment, suggesting that potential regulatory effect on alopecia induction of testosterone and PMA.
Conclusion:
CBD might have a modulating function on alopecia caused by hormonal or excess of signaling pathway, and be a promising application for on alopecia treatment.
Alopecia (Baldness) is a very usual trouble in current time. It accompanied by intensive weaking of the scalps hair and follows a specific pattern. Hereditary predisposition plays a very important role in alopecia in spite of not completely understood. Alopecia can be typed to various categories according to etiology, may be due to hereditary factors, autoimmune disease and drugs or chemicals. There are many options of strategies of treatment according to the type and causes of alopecia. Chemical or synthetic medications apply for management of hair loss are accompanied with the wide range of undesirable effects. Naturally occurring drugs also play important role in alopecia management with minimal side effects.
Bei legalen Drogen handelt es sich um Substanzen, die einfach und rechtmäßig erhältlich sind. Der Konsum und Besitz von diesen Substanzen und der Handel mit ihnen sind straffrei und sie können im Supermarkt, am Kiosk oder in der Tankstelle um die Ecke erworben werden. Doch Vorsicht: Legal bedeutet auf keinen Fall, dass diese Substanzen harmlos sind, denn den Körper interessiert das kleine Wörtchen „legal“ kein bisschen, und nur weil diese Suchtmittel ohne strafrechtliche Folgen zu erwerben sind, rechtfertigt dies die negativen Folgen für Gesundheit und Lebensqualität nicht.
Alopecia (Baldness) is a very usual trouble in current time. It accompanied by intensive weaking of the scalps hair and follows a specific pattern. Hereditary predisposition plays a very important role in alopecia in spite of not completely understood. Alopecia can be typed to various categories according to etiology, may be due to hereditary factors, autoimmune disease and drugs or chemicals. There are many options of strategies of treatment according to the type and causes of alopecia. Chemical or synthetic medications apply for management of hair loss are accompanied with the wide range of undesirable effects. Naturally occurring drugs also play important role in alopecia management with minimal side effects.
Since an important commercial interest lies in the nutritional value of various vitamin and amino acid supplements, an important question that arises is whether increasing the content of an already adequate diet with specific amino acids, vitamins, and/or trace elements may further promote hair growth and pigmentation. Pharmacy aisles and Internet drugstores are full of nutritional supplements promising full, thick, luscious hair for prices that range from suspiciously cheap to dishearteningly exorbitant. It would appear that unless hair loss is due to a specific nutritional deficiency, there is only so much that nutritional therapies can do to enhance hair growth and quality. However, there are internal and external factors, such as aging and environmental stressors, that influence hair health to such a degree that nutritional therapy may boost hair that is suffering from these problems. Protein is the main component of hair with the primary component of the hair fiber being keratin that is made from amino acids. The most abundant of these is cysteine which gives the hair fiber much of its strength through the linking of the sulfur in cysteine molecules of adjacent keratin proteins together in disulfide bonds. Meanwhile, the hair follicle exhibits a high rate of metabolism. As a group, B complex vitamins are important for metabolic functions and therefore required to utilize other nutrients like carbohydrates and amino acids: biotin (vitamin H), calcium pantothenate (B5), niacinamide (B3), folic acid, and vitamins B6 (pyridoxal phosphate) and B12 (cobalamin). Further insights into the role of oxidative stress could open additional strategies for interventions into age-dependent hair and pigmentation loss. Specifically, the body possesses endogenous defense mechanisms, such as antioxidative enzymes (superoxide dismutase, catalase, glutathione peroxidase) and nonenzymatic antioxidative molecules (vitamins E and C, glutathione, ubiquinone), protecting it from free radicals. With age, the production of free radicals increases, while the endogenous defense mechanisms decrease. This imbalance leads to the progressive damage of cellular structures, ultimately resulting in the aging phenotype.
The culture of microdissected hair follicles (HFs) and scalp skin enriched in terminal HFs are the best currently available preclinical assays for studying hair and skin biology/pathology in the human system. While microdissected HF organ culture only allows the testing of compounds added into the culture medium, mimicking a systemic application, the scalp skin organ culture also is suitable to test topical and intradermal applications. Here, we describe different methods for isolation of human scalp HFs, the procedures for culturing the scalp skin and microdissected HFs and we also outline different delivery techniques (e.g., topical, systemic) to test active and control substances.
Background:
Human hair is highly responsive to stress, and human scalp hair follicles (HFs) contain a peripheral neuroendocrine equivalent of the systemic hypothalamic-pituitary-adrenal (HPA) stress axis. Androgenetic alopecia (AGA) is supposed to be aggravated by stress. We used corticotropin-releasing hormone (CRH), which triggers the HPA axis, to induce a stress response in human ex vivo male AGA HFs. Caffeine is known to reverse testosterone-mediated hair growth inhibition in the same hair organ culture model.
Objectives:
To investigate whether caffeine would antagonize CRH-mediated stress in these HFs.
Methods:
HFs from balding vertex area scalp biopsies of men affected by AGA were incubated with CRH (10-7 mol L-1 ) with or without caffeine (0·001% or 0·005%).
Results:
Compared to controls, CRH significantly enhanced the expression of catagen-inducing transforming growth factor-β2 (TGF-β2) (P < 0·001), CRH receptors 1 and 2 (CRH-R1/2) (P < 0·01), adrenocorticotropic hormone (ACTH) (P < 0·001) and melanocortin receptor 2 (MC-R2) (P < 0·001), and additional stress-associated parameters, substance P and p75 neurotrophin receptor (p75NTR ). CRH inhibited matrix keratinocyte proliferation and expression of anagen-promoting insulin-like growth factor-1 (IGF-1) and the pro-proliferative nerve growth factor receptor NGF-tyrosine kinase receptor A (TrkA). Caffeine significantly counteracted all described stress effects and additionally enhanced inositol trisphosphate receptor (IP3 -R), for the first time detected in human HFs.
Conclusions:
These findings provide the first evidence in ex vivo human AGA HFs that the stress mediator CRH induces not only a complex intrafollicular HPA response, but also a non-HPA-related stress response. Moreover, we show that these effects can be effectively antagonized by caffeine. Thus, these data strongly support the hypothesis that stress can impair human hair physiology and induce hair loss, and that caffeine may effectively counteract stress-induced hair damage and possibly prevent stress-induced hair loss. What is already known about this topic? Caffeine stimulates hair growth in male and female human hair follicles (HFs) in vitro. What does this study add? For the first time, corticotropin-releasing hormone induction of the hypothalamic-pituitary-adrenal (HPA) stress axis is documented in male human HFs from biopsies (balding vertex area) of men with androgenetic alopecia. First time, the non-HPA neurogenic stress axis is shown in the same male human HFs. Caffeine counteracts both stress axes. Inositol trisphosphate receptor was newly identified in human HFs. What is the translational message? Stress can impair human hair physiology and induce hair loss. Caffeine may effectively counteract stress-induced hair damage and possibly prevent stress-induced hair loss.
The term stimulant refers to a diverse array of natural and synthetic compounds whose use results in varying degrees of euphoria, as well as heightened attention, wakefulness, and libido, in addition to sympathomimetic effects. Certain stimulants are FDA approved for various medical and psychiatric conditions and are therefore available via prescription. While some stimulants have relatively benign physiological profiles, such as caffeine, use of other stimulants such as amphetamines or cocaine can result in significant negative physiological and/or psychiatric consequences such as stroke or myocardial infarction, psychosis, and movement disorders, and also carry a high risk for physiological dependence and the development of use disorders (addiction). As a result of their non-medical and abuse potential, a robust illicit stimulant trade remains active worldwide. There are no pharmacotherapies that are FDA approved for the treatment of any stimulant use disorder, but several behavioral therapies, such as contingency management, have demonstrated promise. This chapter reviews the mechanisms of action of various stimulants, diagnostic features of different stimulant intoxication/withdrawal/use disorders, and evidence-based treatment modalities for these diagnostic entities. The stimulants of particular focus in this chapter will be caffeine, cocaine, as well as amphetamine and amphetamine-type (AAT) stimulants.
Die androgenetische Alopezie gehört bei vielen Männern zum Älterwerden, aber auch bei Frauen tritt Alopezie auf. Für die Behandlung kommen etablierte und aufstrebende Optionen infrage — wenn der Haarausfall gestoppt ist, zudem auch eine Haartransplantation.
Background: Hair loss encompasses a group of scarring and nonscarring diseases with limited treatment options. Understanding the pathogenesis of alopecias has led to the experimental use of phosphodiesterase inhibitors (PDEi).
Objective: To perform a systematic review of literature surrounding the use of PDEi for alopecia.
Materials and methods: A search was conducted using PubMed in February 2019 on PDEi and alopecia. Inclusion criteria were clinical trials, prospective or retrospective studies, case series and case reports written in English, using PDEi in human subjects for the treatment of alopecia.
Results: Fifteen articles were included for review – eight discussing the use of topical caffeine 0.2%–2.5% for the treatment of androgenetic alopecia (AGA) and telogen effluvium (TE), one using injectable caffeine for AGA, one using topical sildenafil for pediatric alopecia areata (AA), and five using oral apremilast for adult AA.
Conclusions: Preliminary results using topical caffeine for AGA or TE are promising with minimal adverse events. However, these studies are primarily single-center trials with few patients. Studies using topical or systemic PDEi for AA demonstrate limited success. Current research using PDEi for alopecia is limited, however new clinical trials are being conducted.
Objectives
While the effect of ultraviolet radiation (UVR) on human skin has been extensively studied, very little is known on how UVR impacts on hair follicle (HF) homeostasis. Here, we investigated how solar spectrum UVR that hits the human skin surface impacts on HF biology, and whether any detrimental effects can be mitigated by a widely used cosmetic and nutraceutical ingredient, caffeine.
Methods
Human scalp skin with terminal HFs was irradiated transepidermally ex vivo using either 10 J/cm² UVA (340‐440 nm) + 20 mJ/cm² UVB (290–320 nm) (low dose) or 50 J/cm² UVA + 50 mJ/cm² UVB (high dose) and organ‐cultured under serum‐free conditions for 1 or 3 days. 0.1% caffeine (5.15 mM) was topically applied for 3 days prior to UV exposure with 40 J/cm² UVA + 40 mJ/cm² UVB and for 3 days after UVR. The effects on various toxicity and vitality read‐out parameters were measured in defined skin and HF compartments.
Results
Consistent with previous results, transepidermally UVR exerted skin cytotoxicity and epidermal damage. Treatment with high and/or low UVA+UVB doses also induced oxidative DNA damage and cytotoxicity in human HFs. In addition, it decreased proliferation and promoted apoptosis of HF outer root sheath (ORS) and hair matrix (HM) keratinocytes, stimulated catagen development, differentially regulated the expression of HF growth factors, and induced perifollicular mast cell degranulation. UVR‐mediated HF damage is more severe after irradiation with high UVR dose and reached also deeper HF compartments. The topical application of 0.1% caffeine did not induce skin or HF cytotoxicity and stimulated the expression of IGF‐1 in the proximal HF ORS. However, it promoted keratinocyte apoptosis in selected HF compartments. Moreover, caffeine provided protection towards UVR‐mediated HF cytotoxicity and dystrophy, keratinocyte apoptosis, and negative modulation of the catagen‐promoting growth factor.
Conclusion
Our study highlights the clinical relevance of our scalp UV irradiation ex vivo assay and provides the first evidence that transepidermal UV radiation negatively affects important human HF functions, suggesting that it is a sensible prophylactic strategy to integrate agents such as caffeine that can act as HF photoprotectants into sun‐protective cosmeceutical and nutraceutical formulations.
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Human skin organ culture (hSOC) is a simple but highly instructive and clinically relevant skin research method. It has been used for decades to study the development, differentiation, and function as well as the response to wounding or test agents of intact human skin in the presence of its appendages and all resident cell populations. hSOC has also proven useful in toxicological and oncological studies and studies of skin aging (both chronological aging and photoaging), skin energy metabolism, skin immunology, pigmentation biology, and cutaneous (neuro-)endocrinology and neurobiology. The pathobiology and treatment of various dermatoses can also be assessed ex vivo by organ-culturing intact lesional human skin. In addition to morphological analyses by routine histochemistry, quantitative (immuno)histomorphometry has proven to be an excellent tool for quantitating and localizing protein expression patterns in defined skin compartments and distinct cell populations using a relatively small amount of precious human tissue. Finally, more recent technological advances, such as siRNA-mediated gene silencing and sensory reinnervation of hSOCs, have further extended the range of methodological applications for the ex vivo study of human skin; it has emerged as the ultimate preclinical assay system for investigative dermatology, including the testing of drugs, cosmeceuticals and nutraceuticals and more, and is just one step below human skin xenotransplant in vivo mouse models and clinical trials. Here, we critically review the renaissance and variety of hSOC assays, their applications and limitations, and we critically compare them with 3D skin “equivalent” assays. The review closes with perspectives on how this ancient but highly informative and physiologically relevant ex vivo skin research method may be further developed in the future.
We report for the first time the successful maintenance and growth of human hair follicles in vitro. Human anagen hair follicles were isolated by microdissection from human scalp skin. Isolation of the hair follicles was achieved by cutting the follicle at the dermo-subcutaneous fat interface using a scalpel blade. Intact hair follicles were then removed from the fat using watchmakers’ forceps.
Isolated hair follicles maintained free-floating in supplemented Williams E medium in individual wells of 24-well multiwell plates showed a significant increase in length over 4 days. The increase in length was seen to be attributed to the production of a keratinised hair shaft, and was not associated with the loss of hair follicle morphology. [methyl-3H]thymidine autoradiography confirmed that in vitro the in vivo pattern of DNA synthesis was maintained; furthermore, [35S]methionine labelling of keratins showed that their patterns of synthesis did not change with maintenance.
The importance of this model to hair follicle biology is further demonstrated by the observations that TGF-βl has a negative growth-regulatory effect on hair follicles in vitro and that EGF mimics the in vivo depilatory effects that have been reported in sheep and mice.
Hair has many useful biologic functions, including protection from the elements and dispersion of sweat-gland products (e.g., pheromones). It also has psychosocial importance in our society, and patients with hair loss (alopecia) (Table 1) or excessive hair growth often suffer tremendously. Not surprisingly, the demand for drugs that alter hair growth and appearance has led to a multibillion-dollar industry, yet few drugs that are effective for these purposes are available. However, recent progress in our understanding of the biology and pathology of hair follicles should lead to more effective therapies for disorders of hair growth. Structure and Function of Hair . . .
Nearly 50 years ago, Chase published a review of hair cycling in which he detailed hair growth in the mouse and integrated hair biology with the biology of his day. In this review we have used Chase as our model and tried to put the adult hair follicle growth cycle in perspective. We have tried to sketch the adult hair follicle cycle, as we know it today and what needs to be known. Above all, we hope that this work will serve as an introduction to basic biologists who are looking for a defined biological system that illustrates many of the challenges of modern biology: cell differentiation, epithelial-mesenchymal interactions, stem cell biology, pattern formation, apoptosis, cell and organ growth cycles, and pigmentation. The most important theme in studying the cycling hair follicle is that the follicle is a regenerating system. By traversing the phases of the cycle (growth, regression, resting, shedding, then growth again), the follicle demonstrates the unusual ability to completely regenerate itself. The basis for this regeneration rests in the unique follicular epithelial and mesenchymal components and their interactions. Recently, some of the molecular signals making up these interactions have been defined. They involve gene families also found in other regenerating systems such as fibroblast growth factor, transforming growth factor-beta, Wnt pathway, Sonic hedgehog, neurotrophins, and homeobox. For the immediate future, our challenge is to define the molecular basis for hair follicle growth control, to regenerate a mature hair follicle in vitro from defined populations, and to offer real solutions to our patients' problems.
While the androgens, including dihydrotestosterone (DHT), have been implicated in the development of androgenetic alopecia (AGA), the exact mechanism by which they exert their effect(s) is unknown. Since apoptosis is an integral component of the normal cycling of human hair, we investigated individuals clinically affected by AGA to assess whether objective differences in the expression of apoptosis-related immunohistochemical markers could be observed in scalp biopsies. Specimens from 16 alopecic male patients were stained with bd-2 and the terminal deoxynucleotidyltransferase dUTP fluorescein nick end-labeling (TUNEL) method was used to assess apoptotic activity in affected and unaffected areas ofthe scalp. Immunoreactivity was analyzed by quantifying staining differences within the same individual. Sections from 3 human volunteers were used to establish the method validity. Significant differences in the bcl-2 staining index (0.67 versus 0.42, p < 0.05) and TUNEL expression (5.7 versus 10.2, p < 0.05) were observed between the areas of the scalp that were clinically affected (frontal) and unaffected (occipital) by AGA. The Gaussian distributions of bcl-2 and TUNEL staining suggest that a relatively uniform population of follicles exists at the frontal hairline and/or that synchrony of follicular cycling occurs in AGA. The apoptosis "hot spot" revealed by TUNEL staining in the bulge-isthmus region of the murine follicle is also identifiable in the human follicle.
Androgenetic alopecia occurs in men and women, and is characterised by the loss of hair from the scalp in a defined pattern. Determining factors appear to be genetic predisposition coupled with the presence of sufficient circulating androgens. The prevalence of this condition is high (up to 50% of white males are affected by 50 years of age) and, although there are no serious direct health consequences, the loss of scalp hair can be distressing. Knowledge of the pathogenesis of androgenetic alopecia has increased markedly in recent years. Pre-programmed follicles on the scalp undergo a transformation from long growth (anagen) and short rest (telogen) cycles, to long rest and short growth cycles. This process is coupled with progressive miniaturisation of the follicle. These changes are androgen dependent, and require the inheritance of several genes. To date, only one of these genes, which encodes the androgen receptor (AR), has been identified. Of the many treatments available for androgenetic alopecia, only two (finasteride and minoxidil) have been scientifically shown to be useful in the treatment of hair loss. However, these therapies are variable in their effectiveness. Discovery of the involvement of the AR gene, and the identification of other genes contributing to the condition, might lead to the development of new and more effective therapies that target the condition at a more fundamental level.
Caffeine is a major biologically active constituent in coffee and tea. Because caffeine has been reported to inhibit carcinogenesis in UVB-exposed mice, the cancer-preventing effect of caffeine has attracted considerable attention. In the present study, the effect of caffeine in quiescent (G0 phase) cells was investigated. Pretreatment with caffeine suppressed cell proliferation in a dose-dependent manner 36 h after addition of fetal bovine serum as a cell growth stimulator. Analysis by flow cytometry showed that caffeine suppressed cell cycle progression at the G0/G1 phase, i.e., 18 h after addition of fetal bovine serum, the percentages of cells in G0/G1 phase in 1 mm caffeine-treated cells and in caffeine-untreated cells were 61.7 and 29.0, respectively. The percentage of cells in G0/G1 phase at 0 h was 75.5. Caffeine inhibited phosphorylation of retinoblastoma protein at Ser780 and Ser807/Ser811, the sites where retinoblastoma protein has been reported to be phosphorylated by cyclin-dependent kinase 4 (cdk4). Furthermore, caffeine inhibited the activation of the cyclin D1-cdk4 complex in a dose-dependent manner. However this compound did not directly inhibit the activity of this complex. In addition, caffeine did not affect p16INK4 or p27Kip1 protein levels, but inhibited the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase 3β. Our results showed that caffeine suppressed the progression of quiescent cells into the cell cycle. The inhibitory mechanism may be due to the inhibition of cell growth signal-induced activation of cdk4, which may be involved in the inhibition of carcinogenesis in vivo.
We have previously reported that the effects of caffeine on alveolar macrophages are dose-dependent; thus, at low concentrations caffeine prevents apoptosis and at moderate concentrations, the cells proceed into apoptosis. In the current study, the mechanism of caffeine action via prostaglandin synthesis and cyclic adenosine monophosphate (cAMP) was investigated using moderate concentrations of caffeine. The results show that the combination of caffeine with indomethacin, an inhibitor of prostaglandin synthesis, mediated caffeine’s effect by increasing cellular viability and lowering superoxide anion production and DNA fragmentation. However, addition of exogenous prostaglandin E2 (PGE2) to the culture in the presence of caffeine had the opposite effect, in which the viability was decreased and anion superoxide production was increased. Incubation of macrophages with exogenous dibutyryl cAMP showed nearly similar effects to caffeine. At low concentrations (<50 μmol/L), higher viability and lower superoxide production pattern were evident and at higher concentrations (>50 μmol/L) the cells proceeded into apoptosis. Therefore, it is suggested that caffeine exerts its effects on macrophages by altering cAMP level and prostaglandin synthesis.
Background: Androgenetic alopecia (male pattern hair loss) is caused by androgen-dependent miniaturization of scalp hair follicles, with scalp dihydrotestosterone (DHT) implicated as a contributing cause. Finasteride, an inhibitor of type II 5α-reductase, decreases serum and scalp DHT by inhibiting conversion of testosterone to DHT. Objective: Our purpose was to determine whether finasteride treatment leads to clinical improvement in men with male pattern hair loss. Methods: In two 1-year trials, 1553 men (18 to 41 years of age) with male pattern hair loss received oral finasteride 1 mg/d or placebo, and 1215 men continued in blinded extension studies for a second year. Efficacy was evaluated by scalp hair counts, patient and investigator assessments, and review of photographs by an expert panel. Results: Finasteride treatment improved scalp hair by all evaluation techniques at 1 and 2 years (P < .001 vs placebo, all comparisons). Clinically significant increases in hair count (baseline = 876 hairs), measured in a 1-inch diameter circular area (5.1 cm2 ) of balding vertex scalp, were observed with finasteride treatment (107 and 138 hairs vs placebo at 1 and 2 years, respectively; P < .001). Treatment with placebo resulted in progressive hair loss. Patients’ self-assessment demonstrated that finasteride treatment slowed hair loss, increased hair growth, and improved appearance of hair. These improvements were corroborated by investigator assessments and assessments of photographs. Adverse effects were minimal. Conclusion: In men with male pattern hair loss, finasteride 1 mg/d slowed the progression of hair loss and increased hair growth in clinical trials over 2 years. (J Am Acad Dermatol 1998;39:578-89.)
To investigate the relation between androgens and hair growth, testosterone-1,2-³H metabolism was assessed under standardized conditions in growing (anagen) and resting (telogen) hair roots from 10 anatomical sites from 4 women and 14 men, 6 of whom had varying degrees of male pattern baldness. A micromethod was developed to quantitate androgen metabolism in only a few hair roots.
In all hairs examined, 5α-reduced and 17-ketosteroids were the major metabolites of testosterone. No significant relation was found between androgen-mediated growth of hair and the capacity to form 5α-metabolites, e.g., scalp hair of women performed 5α-reduction to approximately the same degree as beard hair from men. The formation of 17-ketometabolites was decreased in telogen hairs from all body sites, whereas the formation of dihydrotestosterone was decreased in telogen hairs only from the scalp.
In general a higher formation of 5α-reduced metabolites and 17-ketosteroid metabolites was observed at all sites of the scalp of bald men as compared to hair obtained from the corresponding sites of women and nonbalding men, and a significantly higher rate of metabolism was found at the frontal area of the bald men. It is not clear at present whether these changes are secondary to the balding process or are related causally to the hair loss.
On the basis of these studies it is concluded that regional differences in androgen-mediated hair growth cannot be the result of variations in testosterone metabolism in the hair follicles.
We demonstrated the conversion of testosterone-4-14C to dihydrotestosterone (17β-Phydroxy-5α-androstan-17-one), the tissue-active androgen, with 50–200 μg of freeze-dried human hair follicles plucked from various regions. All of the hair follicles thus far tested contained the 5α-reductase activity. Under optimal conditions, the 5α-reductase activity in growing hair follicles ranged from 10–20 nmoles/100 mg dry wt/hr. In the scalp, the growing follicles showed 3–8 times higher values than the resting. In other regions such as the beard, axilla, chest, pubis, arms and legs, the growing follicles showed nearly the same activities as those of the scalp or even higher, whereas the activities of the resting follicles varied considerably.
Summary Background and objectives A considerable portion of the hair follicle remains attached to plucked hair and can be used for follicle cell culture. In this study we have phenotyped these cells in an attempt to identify the stem cell fraction. Reports in the literature have indicated that this cell population may be positive for cytokeratin (CK) 19. Because stem cells in general need to be protected from apoptosis, the presence of the apoptosis-suppressing Bcl-2 protein, together with the absence of the apoptosis-promoting Bax and the CK profile may be used as an indicator of the stem cell population in the hair follicle, and in cultures of hair follicle cells. Methods Hair follicles from skin biopsies and plucked hair were derived from the scalps of healthy volunteers. Follicular cells were cultured from the plucked hairs. These hair follicles, plucked hairs and cultured cells were examined for their CK profiles, which are indicative of the type of cell (basal ⁄ stem cells) and for their status with respect to the proliferation marker Ki-67, Bax and Bcl-2. Results We found coexpression for CK19 and Bcl-2, but not Bax in two distinct areas, localized in the upper and lower third of the follicle from both skin biopsies and plucked hairs, while proliferation markers were negative in these areas. CK19 and Bcl-2 were also coexpressed in combination in a fraction of the follicular cell culture. The skin basal cell marker CK14 could be found throughout the outer root sheath of the hair follicle from both skin biopsies and plucked hairs, as well as in the follicular cell culture. Conclusions Thus, CK19 ⁄ Bcl-2-positive and Bax-negative cells can be obtained from cells derived from plucked hair and are retained in cultures made from these cells. If this phenotype represents follicular stem cells, our finding endorses the assumption that stem cells are located in the bulge area of the hair follicle, as we did not find them in or near the dermal papilla.
The need for a widely accepted, accurate, and reproducible standard of classification for male pattern baldness has increased with the advent and increasing popularity of hair transplant surgery. This report establishes such a classification, and reports its use in determining the incidence of male pattern baldness at various ages in 1,000 white adult male subjects. The action of testosterone as an incitant in male pattern baldness is well known, but this study points out the continued effect of time, even in later years. Since most hair transplant surgery is peformed on subjects with male pattern baldness, and because the success of hair transplant surgery is largely dependent on proper patient selection, a complete understanding of male pattern baldness is essential for consistently good results with hair transplantation.
The expression of a cell proliferation-associated human nuclear antigen was immunohistochemically studied in human anagen hair and hair follicles using the monoclonal antibody Ki-67. The reaction of Ki-67 in mature anagen hair follicles was observed in the hair matrix cells and outer root sheath (ORS) cells. Nuclear staining was seen in a small number of matrix cells and in some ORS cells; this finding corresponded to the thymidine or bromodeoxyuridine labeling studies previously reported. In addition, there were two different patterns of cytoplasmic staining in the ORS: strong staining of the innermost cells (IMC) and weaker staining of the other ORS cells in the isthmus. Ki-67 reactivity of the IMC layer was observed at each stage of anagen and was regularly seen from the upper bulb to the isthmus. Ki-67 is a commercially available antibody that detects cycling cells. However, the IMCs in anagen hair follicles showed cytoplasmic labeling by Ki-67 from the matrix cells in the upper bulb to the distal portion of the isthmus.
The factors that regulate hair follicle growth are still poorly understood. In vitro models may be useful in elucidating some aspects of hair follicle biology. We have developed an in vitro human hair growth model that enables us to maintain isolated human hair follicles for up to 10 days, during which time they continue to grow at an in vivo rate producing a keratinised hair fibre. We have shown that epidermal growth factor (EGF) in our system mimics the in vivo depilatory action of EGF in sheep, and suggest that this occurs as a result of EGF stimulating outer root sheath (ORS) cell proliferation which results in the disruption of normal mechanisms of cell-cell interaction in the hair follicle. We identify transforming growth factor-beta (TGF-beta) as a possible negative regulator of hair follicle growth and show that physiological levels of insulin-like growth factor-I (IGF-I) can support the same rates of hair follicle growth as supraphysiological levels of insulin. Furthermore, in the absence of insulin hair follicles show premature entry into a catagen-like state. This is prevented by physiological levels of IGF-I. Finally we demonstrate that the hair follicle is an aerobic glycolytic, glutaminolytic tissue and discuss the possible implications of this metabolism.
Androgens, in combination with a genetic susceptibility, have been demonstrated to be required for the development of androgenetic alopecia. Disturbances in androgen metabolism or target organ sensitivity are thought to underlie the pathophysiology of the condition. Observations of patients with disorders of androgen metabolism or function have determined the basic physiology involved in regulation of hair growth by androgens at selective body sites. More recently, in vitro studies of scalp skin and hair follicles have begun to define specific alterations in androgen metabolism at the local level that may play a key role in pathogenesis. The prominent role of 5-reductase in these studies suggests that inhibitors of this enzyme may provide new therapeutic opportunities for patients with androgenetic alopecia.
In this study, 12 women and 12 men, ages 18-33 y, with androgenetic alopecia were selected for biopsies from frontal and occipital scalp sites. The androgen receptor, type I and II 5alpha-reductase, cytochrome P-450-aromatase enzyme were measured and analyzed in hair follicles from these scalp biopsies. Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles. There are marked quantitative differences in levels of androgen receptors and the three enzymes, which we find to be primarily in the outer root sheath of the hair follicles in the two genders. Androgen receptor content in female frontal hair follicles was approximately 40% lower than in male frontal hair follicle. Cytochrome P-450-aromatase content in women's frontal hair follicles was six times greater than in frontal hair follicles in men. Frontal hair follicles in women had 3 and 3.5 times less 5alpha-reductase type I and II, respectively, than frontal hair follicles in men. These differences in levels of androgen receptor and steroid-converting enzymes may account for the different clinical presentations of androgenetic alopecia in women and men.
Androgenetic alopecia (male pattern hair loss) is caused by androgen-dependent miniaturization of scalp hair follicles, with scalp dihydrotestosterone (DHT) implicated as a contributing cause. Finasteride, an inhibitor of type II 5alpha-reductase, decreases serum and scalp DHT by inhibiting conversion of testosterone to DHT.
Our purpose was to determine whether finasteride treatment leads to clinical improvement in men with male pattern hair loss.
In two 1-year trials, 1553 men (18 to 41 years of age) with male pattern hair loss received oral finasteride 1 mg/d or placebo, and 1215 men continued in blinded extension studies for a second year. Efficacy was evaluated by scalp hair counts, patient and investigator assessments, and review of photographs by an expert panel.
Finasteride treatment improved scalp hair by all evaluation techniques at 1 and 2 years (P < .001 vs placebo, all comparisons). Clinically significant increases in hair count (baseline = 876 hairs), measured in a 1-inch diameter circular area (5.1 cm2) of balding vertex scalp, were observed with finasteride treatment (107 and 138 hairs vs placebo at 1 and 2 years, respectively; P < .001). Treatment with placebo resulted in progressive hair loss. Patients' self-assessment demonstrated that finasteride treatment slowed hair loss, increased hair growth, and improved appearance of hair. These improvements were corroborated by investigator assessments and assessments of photographs. Adverse effects were minimal.
In men with male pattern hair loss, finasteride 1 mg/d slowed the progression of hair loss and increased hair growth in clinical trials over 2 years.
Hair loss is a common and distressing symptom. With the approval of two drugs that promote hair growth — finasteride and minoxidil — we can now treat patients with some types of hair loss. Both drugs influence the hair-growth cycle and increase the length and diameter of existing hair, although their mechanisms of action differ. In this article, I will focus on the treatment of two common problems, androgenetic alopecia and alopecia areata, both of which involve a reversible alteration of the hair-growth cycle. The Hair-Growth Cycle Hair growth is cyclic, with phases of growth (anagen), involution (catagen), and rest . . .
The regression phase of the hair cycle (catagen) is an apoptosis-driven process accompanied by terminal differentiation, proteolysis, and matrix remodeling. As an inhibitor of keratinocyte proliferation and inductor of keratinocyte apoptosis, transforming growth factor beta1 (TGF-beta1) has been proposed to play an important role in catagen regulation. This is suggested, for example, by maximal expression of TGF-beta1 and its receptors during late anagen and the onset of catagen of the hair cycle. We examined the potential involvement of TGF-beta1 in catagen control. We compared the first spontaneous entry of hair follicles into catagen between TGF-beta1 null mice and age-matched wild-type littermates, and assessed the effects of TGF-beta1 injection on murine anagen hair follicles in vivo. At day 18 p.p., hair follicles in TGF-beta1 -/- mice were still in early catagen, whereas hair follicles of +/+ littermates had already entered the subsequent resting phase (telogen). TGF-beta1-/- mice displayed more Ki-67-positive cells and fewer apoptotic cells than comparable catagen follicles from +/+ mice. In contrast, injection of TGF-beta1 into the back skin of mice induced premature catagen development. In addition, the number of proliferating follicle keratinocytes was reduced and the number of TUNEL + cells was increased in the TGF-beta1-treated mice compared to controls. Double visualization of TGF-beta type II receptor (TGFRII) and TUNEL reactivity revealed colocalization of apoptotic nuclei and TGFRII in catagen follicles. These data strongly support that TGF-beta1 ranks among the elusive endogenous regulators of catagen induction in vivo, possibly via the inhibition of keratinocyte proliferation and induction of apoptosis. Thus, TGF-betaRII agonists and antagonists may provide useful therapeutic tools for human hair growth disorders based on premature or retarded catagen development (effluvium, alopecia, hirsutism).
Androgenetic alopecia (AGA) is the most common type of hair loss in men and women. This continuous process results in a type of alopecia that follows a definite pattern in those individuals who are genetically predisposed. At present the predisposing genes are unknown but the relatively strong concordance of the degree of baldness in fathers and sons is not consistent with a simple Mendelian trait and a polygenic basis is therefore most likely. AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive HF. Today we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss in AGA. However, recent experimental and clinical advances enable us to explain some pathogenetic steps leading to androgenetic hair loss. Among other steroidogenic isoenzymes such as 17b- and 3b- hydroxysteroid dehydrogenases, the type 2 5a-reductase within the dermal papilla plays a central role by the intrafollicular conversion of T to DHT.
In this study, the effect of two concentration ranges of the cAMP phosphodiesterase inhibitor, caffeine, on alveolar macrophage function was investigated by measuring survival rate, superoxide anion production and DNA fragmentation. The results show caffeine induced apoptosis in alveolar macrophages in a dose dependent manner. The survival rate of the cells exposed to low concentrations of caffeine (<5 mM) increased remarkably with a peak at 2.5 mM. At this concentration, caffeine failed to affect superoxide anion production and DNA degradation. However, at higher concentrations (5-20 mM), at which the viability was higher than the control, a significant increase in both superoxide production and DNA degradation, as judged by agarose gel and diphenylamine reaction, was obtained for 3 and 24 h of culture. The effect of caffeine on survival rate was also time dependent. At low caffeine concentrations, macrophages survived with a viability of 90-97% after 3 days. At moderate concentrations, the cells maintained viability up to 24 h but at concentrations higher than 20 mM, caffeine inhibited cell survival and killed a fraction of the population. The results suggest that low concentrations of caffeine prevent apoptosis of macrophages, whereas at moderate concentrations caffeine induces apoptosis in these cells. The results are discussed in relation to the mechanism of cAMP.
For topical treatment of androgenetic alopecia (AGA) in women, solutions containing either estradiol benzoate, estradiol valerate, 17beta- or 17alpha-estradiol are commercially available in Europe and some studies show an increased anagen and decreased telogen rate after treatment as compared with placebo. At present it is not precisely known how estrogens mediate their beneficial effect on AGA-affected hair follicles. We have shown recently that 17alpha-estradiol is able to diminish the amount of dihydrotestosterone (DHT) formed by human hair follicles after incubation with testosterone, while increasing the concentration of weaker steroids such as estrogens. Because aromatase is involved in the conversion of testosterone to estrogens and because there is some clinical evidence that aromatase activity may be involved in the pathogenesis of AGA, we addressed the question whether aromatase is expressed in human hair follicles and whether 17alpha-estradiol is able to modify the aromatase activity. Herewith we were able to demonstrate that intact, microdissected hair follicles from female donors express considerably more aromatase activity than hair follicles from male donors. Using immunohistochemistry, we detected the aromatase mainly in the epithelial parts of the hair follicle and not in the dermal papilla. Furthermore, we show that in comparison to the controls, we noticed in 17alpha-estradiol-incubated (1 nM) female hair follicles a concentration- and time-dependent increase of aromatase activity (at 24 h: 1 nM = +18%, 100 nM = +25%, 1 micro M = +57%; 24 h: 1 nM = +18%, 48 h: 1 nM = +25%). In conclusion, our ex vivo experiments suggest that under the influence of 17alpha-estradiol an increased conversion of testosterone to 17beta-estradiol and androstendione to estrone takes place, which might explain the beneficial effects of estrogen treatment of AGA.
Androgenetic alopecia (AGA) is the most common type of hair loss in men. The relative strong concordance of the degree of baldness in fathers and sons is not consistent with a smiple Mendelian trait and a polygenic basis is considered to be most likely. So far the predisposing genes for AGA are unknown and we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss, but AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive hair follicles. The type 2 5aR plays a central role by the intrafollicular conversion of T to DHT. Due to the inceasing knowledge in this field, this article shall privide an critical overwiew of recent discoveries.
Androgenetic alopecia (AGA) is hereditary and androgen-dependent, progressive thinning of the scalp hair that follows a defined pattern. While the genetic involvement is pronounced but poorly understood, major advances have been achieved in understanding principal elements of the androgen metabolism involved: androgen-dependent processes are predominantly due to the binding of dihydrotestosterone (DHT) to the androgen receptor (AR). DHT-dependent cell functions depend on the availability of weak androgens, their conversion to more potent androgens via the action of 5 alpha-reductase, low enzymatic activity of androgen inactivating enzymes, and functionally active AR present in high numbers. The predisposed scalp exhibits high levels of DHT, and increased expression of the AR. Conversion of testosterone to DHT within the dermal papilla plays a central role, while androgen-regulated factors deriving from dermal papilla cells are believed to influence growth of other components of the hair follicle. Current available treatment modalities with proven efficacy are oral finasteride, a competitive inhibitor of type 2 5 alpha-reductase, and topical minoxidil, an adenosine-triphosphate-sensitive potassium channel opener which has been reported to stimulate the production of vascular endothelial growth factor in cultured dermal papilla cells. Since the clinical success rate of treatment of AGA with modulators of androgen metabolism or hair growth promoters is limited, sustained microscopic follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is considered a possible cofactor in the complex etiology of AGA.
Androgenetic alopecia (AGA) is the most common form of hair loss in men and women. This continuous process results in a form of alopecia that follows a definite pattern in those individuals who are genetically predisposed. Although clinically different, the pathogenetic pathways leading to this type of hair loss are thought to be similar in both sexes. A genetic predisposition is a feature of AGA, but the predisposing genes are still unknown. Our understanding, however, of the hormonal effects on hair growth is far more advanced. AGA can be defined as a dihydrotestosterone (DHT)-dependent process with continuous miniaturization of sensitive hair follicles. So far, we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss. However, the local androgen metabolism plays a central role in the intrafollicular conversion of weak androgens, such as DHEAS, to more potent androgens such as T or DHT within the hair follicle. The dermal papilla plays a central role by exhibiting an array of important steroidogenic isoenzymes. Provided that the dermal papilla (DP) cell triggers and regulates the growth of hair follicles, this physiological role may be reflected by metabolic differences, which could account for differences in androgen sensitivity as observed in hair follicles from different body sites, and in conditions such as male pattern baldness. The observation of STS, 17beta-HSD, 3beta-HSD, 3alpha-HSD and type 2 5alpha-R-activity within the DP could be a clue to understanding the regulation of androgen action in the human hair follicle by local androgen modification on target cell level. Hence, some of the intrafollicular steroidogenic enzymes would be potential pharmaceutical targets for the treatment of AGA or hirsutism.
The proliferation of keratinocytes in the hair follicle varies from slowly cycling, intermittently proliferating stem cells in the bulge to rapidly proliferating, transient cells in the bulb. To better understand the biological differences between these two compartments, we sought to identify differentially expressed genes using cDNA macroarray analysis. Cyclin D1 was one of 13 genes increased in the bulge compared to the bulb, and its differential expression was corroborated by quantitative real-time polymerase chain reaction (PCR) on the original samples. Using immunohistochemical staining, laser-capture microdissection (LCM) and quantitative real-time PCR, we localized cyclin D1 to the suprabasal cells of the telogen bulge and anagen outer root sheath (ORS). Surprisingly, cyclin D1, D2, and D3 were not detectable by immunohistochemistry in the rapidly proliferating hair-producing cells of the anagen bulb (matrix cells), while these cells were strongly positive for Ki-67 and retinoblastoma protein. In contrast, pilomatricoma, a tumor thought to be derived from matrix cells, was positive for cyclin D1, D2, and D3. Our results suggest that cyclin D1 may mediate the proliferation of stem cells in the bulge to more differentiated transient amplifying cells in the suprabasal ORS. In contrast, non-cyclin D1-proteins appear to control cell division of the highly proliferative bulb matrix cells. This non-cyclin D1-mediated proliferation may provide a protective mechanism against tumorigenesis, which is overridden in pilomatricomas. Our data also demonstrate that the combination of DNA macroarray, LCM and quantitative real-time PCR is a powerful approach for the study of gene expression in defined cell populations with limited starting material.
Although it is universally accepted that dihydrotestosterone causes baldness, how it does so is not well understood. I propose that 3 mechanisms are at work: miniaturization by a dihydrotestosterone-induced acceleration of the mitotic rate of the matrix that leaves less and less time for differentiation; an increased telogen shedding as a result of the shortening of the hair cycles that increases the telogen number per unit of time; and the increased number and duration of the lag phase or kenogen. That this last mechanism is related to dihydrotestosterone is unclear.
Caffeine is a major biologically active constituent in coffee and tea. Because caffeine has been reported to inhibit carcinogenesis in UVB-exposed mice, the cancer-preventing effect of caffeine has attracted considerable attention. In the present study, the effect of caffeine in quiescent (G0 phase) cells was investigated. Pretreatment with caffeine suppressed cell proliferation in a dose-dependent manner 36 h after addition of fetal bovine serum as a cell growth stimulator. Analysis by flow cytometry showed that caffeine suppressed cell cycle progression at the G0/G1 phase, i.e., 18 h after addition of fetal bovine serum, the percentages of cells in G0/G1 phase in 1 mM caffeine-treated cells and in caffeine-untreated cells were 61.7 and 29.0, respectively. The percentage of cells in G0/G1 phase at 0 h was 75.5. Caffeine inhibited phosphorylation of retinoblastoma protein at Ser780 and Ser807/Ser811, the sites where retinoblastoma protein has been reported to be phosphorylated by cyclin-dependent kinase 4 (cdk4). Furthermore, caffeine inhibited the activation of the cyclin D1-cdk4 complex in a dose-dependent manner. However this compound did not directly inhibit the activity of this complex. In addition, caffeine did not affect p16INK4 or p27Kip1 protein levels, but inhibited the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase 3beta. Our results showed that caffeine suppressed the progression of quiescent cells into the cell cycle. The inhibitory mechanism may be due to the inhibition of cell growth signal-induced activation of cdk4, which may be involved in the inhibition of carcinogenesis in vivo.
A considerable portion of the hair follicle remains attached to plucked hair and can be used for follicle cell culture. In this study we have phenotyped these cells in an attempt to identify the stem cell fraction. Reports in the literature have indicated that this cell population may be positive for cytokeratin (CK) 19. Because stem cells in general need to be protected from apoptosis, the presence of the apoptosis-suppressing Bcl-2 protein, together with the absence of the apoptosis-promoting Bax and the CK profile may be used as an indicator of the stem cell population in the hair follicle, and in cultures of hair follicle cells.
Hair follicles from skin biopsies and plucked hair were derived from the scalps of healthy volunteers. Follicular cells were cultured from the plucked hairs. These hair follicles, plucked hairs and cultured cells were examined for their CK profiles, which are indicative of the type of cell (basal/stem cells) and for their status with respect to the proliferation marker Ki-67, Bax and Bcl-2.
We found coexpression for CK19 and Bcl-2, but not Bax in two distinct areas, localized in the upper and lower third of the follicle from both skin biopsies and plucked hairs, while proliferation markers were negative in these areas. CK19 and Bcl-2 were also coexpressed in combination in a fraction of the follicular cell culture. The skin basal cell marker CK14 could be found throughout the outer root sheath of the hair follicle from both skin biopsies and plucked hairs, as well as in the follicular cell culture.
Thus, CK19/Bcl-2-positive and Bax-negative cells can be obtained from cells derived from plucked hair and are retained in cultures made from these cells. If this phenotype represents follicular stem cells, our finding endorses the assumption that stem cells are located in the bulge area of the hair follicle, as we did not find them in or near the dermal papilla.
We have previously reported that the effects of caffeine on alveolar macrophages are dose-dependent; thus, at low concentrations caffeine prevents apoptosis and at moderate concentrations, the cells proceed into apoptosis. In the current study, the mechanism of caffeine action via prostaglandin synthesis and cyclic adenosine monophosphate (cAMP) was investigated using moderate concentrations of caffeine. The results show that the combination of caffeine with indomethacin, an inhibitor of prostaglandin synthesis, mediated caffeine's effect by increasing cellular viability and lowering superoxide anion production and DNA fragmentation. However, addition of exogenous prostaglandin E2 (PGE2) to the culture in the presence of caffeine had the opposite effect, in which the viability was decreased and anion superoxide production was increased. Incubation of macrophages with exogenous dibutyryl cAMP showed nearly similar effects to caffeine. At low concentrations (<50 micromol/L), higher viability and lower superoxide production pattern were evident and at higher concentrations (>50 micromol/L) the cells proceeded into apoptosis. Therefore, it is suggested that caffeine exerts its effects on macrophages by altering cAMP level and prostaglandin synthesis.
This study was conducted to evaluate the effect of caffeine on the meiotic maturation of porcine oocytes. Oocyte-cumulus complexes were collected from slaughterhouse-derived ovaries and cultured for 24, 32 or 48 h in medium 199 supplemented with 10% fetal calf serum, 10 microg/ml FSH, 50 microg/ml sodium pyruvate and 50 microg/ml gentamicin in the presence or absence of 2.5 mM caffeine. Caffeine inhibited the meiotic resumption of pig oocytes effectively after 24 h of culture, and 95.5% of oocytes were arrested at the germinal vesicle (GV) stage (control 17.8%, p < 0.05). Prolonged culture with caffeine up to 32 h or 48 h, however, resulted in a significant decrease in the inhibitory effect (GV: 13.8% and 8.2%). The number of oocytes at metaphase II after 48 h of culture in the presence of caffeine was significantly lower than that in the control medium (65.3% vs 94.7%, p < 0.05). The withdrawal of caffeine after 24 h of culture resulted in the resumption of meiotic maturation, and the oocytes reached metaphase II after 48 h. However, the ability of caffeine-treated oocytes to develop to blastocysts after artificial activation was lower than that of the control (5.5% vs 9.1%, p < 0.05). Caffeine treatment significantly increased cAMP levels in the oocytes after 24 h of culture, while both Cdc2 kinase and MAP kinase activation were inhibited in the oocytes. These results suggest that caffeine, similarly to other purine derivatives, prolongs the meiotic arrest of porcine oocytes at the GV stage, perhaps by its action of increasing the cAMP level and by the suppression of Cdc2 kinase and MAP kinase activities in the oocytes.
Minoxidil induces new hair growth in approximately one-third of patients with androgenetic alopecia after 1 year of treatment. With several conflicting reports in the literature based on small-scale studies, the current study aimed to clarify whether organ culture of human scalp anagen VI hair follicles is a suitable in vitro test system for reproducing, and experimentally dissecting, the recognized in vivo hair-growth-promoting capacity of minoxidil. Hair shaft elongation was studied in terminal anagen VI hair follicles microdissected from the occipital scalp of 36 healthy adults. A total of 2300 hair follicles, approximately 65 per individual, were tested using modifications of a basic organ culture protocol. It is shown here that minoxidil does not significantly increase hair shaft elongation or the duration of anagen VI in ex vivo culture despite several enhancements on the conventional methodology. This disparity to what is seen clinically in minoxidil responders may be explained by the following: (i) use of occipital (rather than frontotemporal or vertex) hair follicles; (ii) use of, already maximally growing, anagen VI hair follicles; (iii) a predominance of hair follicles from minoxidil unresponsive-donors; (iv) use of minoxidil rather than its sulfate metabolite; and/or (v) use of a suboptimal minoxidil dosage. This disparity questions the usefulness of standard human hair follicle organ culture in minoxidil research. Unexpectedly, minoxidil even inhibited hair shaft elongation in the absence of insulin, which may indicate that the actual hair-growth-modulatory effects of minoxidil depend on the concomitant local presence/absence of other growth modulators.
Interferon (IFN)-gamma appears to be an important hair cycle modulator in mice. It is unclear whether it has similar hair growth modulatory functions in human hair follicles.
To study whether IFN-gamma can be exploited to modulate the growth, pigmentation and/or cycling of organ-cultured human anagen scalp hair follicles, as an in vitro indicator system for how IFN-gamma affects human hair growth in vivo. This was correlated with the hair follicle expression patterns of IFN-gamma receptors alpha and beta. In addition, we wanted to establish a new, simple tool for the rapid experimental induction of catagen in vitro.
Normal human scalp hair follicles in the anagen VI stage of the hair cycle were cultured according to the method of Philpott et al., with or without IFN-gamma (50-1000 IU mL(-1)). Hair shaft elongation and pigmentation changes were measured, complemented by quantitative histomorphometry to assess changes in hair follicle cycling (hair cycle score), proliferation (Ki-67), melanogenesis (Masson-Fontana) and apoptosis (TUNEL). IFN-gamma receptors were also localized by immunofluorescence and EnVision technique. As transforming growth factor (TGF)-beta2 is a recognized key inducer of catagen in human hair follicles, TGF-beta2 expression was investigated by tyramide signal amplification and reverse transcription-polymerase chain reaction in anagen hair follicles treated with vehicle (phosphate-buffered saline) or IFN-gamma.
IFN-gamma rapidly inhibited hair elongation in cultured human anagen hair follicles and induced morphological signs of catagen transformation after only 4 days of culture, i.e. faster than with other reported catagen-inducers (e.g. TGF-beta2). Proliferation was inhibited, apoptosis was increased and follicular melanogenesis was switched off in hair bulb keratinocytes treated in situ with IFN-gamma. Anagen hair follicles displayed strong IFN-gamma receptor alpha-like immunoreactivity, while the immunoreactivity for IFN-gamma receptor beta in the hair matrix was only weak. TGF-beta2 immunoreactivity and mRNA transcript levels were enhanced in hair follicles treated with IFN-gamma.
These data suggest that IFN-gamma is a potent catagen inducer in normal human scalp hair follicles, which express cognate receptors, and show that IFN-gamma administration offers an excellent tool for experimental catagen induction in organ-cultured human hair follicles. This catagen induction probably occurs at least in part via upregulation of the recognized catagen-stimulatory growth factor TGF-beta2.
An ex vivo model of male skin – caffeine conteracts testosterone effects Human hair growth in vitro
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13 Tsianakas A, Hüsing B, Moll I, et al. An ex vivo model of male skin – caffeine conteracts testosterone effects. Arch Dermatol Res 2005; 296: 450. 14 Philpott MP, Green MR, Kealey T. Human hair growth in vitro. J Cell Sci 1990; 97: 463–471.
Interferon-gamma is a potent inducer of catagen-like changes in cultured human anagen hair follicles
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Ito T, Ito N, Saathoff M, et al. Interferon-gamma is a potent
inducer of catagen-like changes in cultured human anagen
hair follicles. Br J Dermatol 2005; 152: 623–631.
An ex vivo model of male skin - caffeine conteracts testosterone effects
- Tsianakas
Tsianakas A, Hüsing B, Moll I, et al. An ex vivo model of
male skin -caffeine conteracts testosterone effects. Arch
Dermatol Res 2005; 296: 450.
Interferon-gamma is a potent inducer of catagen-like changes in cultured human anagen hair follicles
- Ito