Article

Effect of minoxidil on proliferation and apoptosis in dermal papilla cells of human hair follicle

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Abstract

Minoxidil has been widely used to treat androgenetic alopecia, but little is known about its pharmacological activity or about the identity of its target cells in hair follicles. We hypothesized that minoxidil has direct effects on the proliferation and apoptosis of dermal papilla cells (DPCs) of human hair follicle. To elucidate the mechanism of topical minoxidil action in terms of stimulating hair growth. We evaluated cell proliferations in cultured DPCs by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and measured the expressions of extracellular signal-regulated kinase (ERK), Akt, Bcl-2, and Bax by Western blot. We also measured elongation of hair follicles in organ culture. Minoxidil significantly increased the proliferation of DPCs. The levels of ERK phosphorylation and of phosphorylated Akt increased significantly 1 h post-treatment; percentage increase of ERK phosphorylation was 287% at 0.1 microM and 351% at 1.0 microM of minoxidil, and that of Akt phosphorylation was 168% at 0.1 microM and 257% at 1.0 microM of minoxidil. 1.0 microM of minoxidil increased Bcl-2 expression over 150%, while 1.0 microM of minoxidil decreased Bax expression by more than 50%. Moreover, a significant elongation of individual hair follicles in organ culture was observed after adding minoxidil. Minoxidil promotes the survival of human DPCs by activating both ERK and Akt and by preventing cell death by increasing the ratio of Bcl-2/Bax. We suggest that minoxidil stimulates the growth of human hairs by prolonging anagen through these proliferative and anti-apoptotic effects on DPCs.

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... HNG 50 nM significantly increased hair shaft elongation by 163.9 ± 22.7% on the 21st day ( Figure A1, 2). MS 1 μM was used as the positive control, which also significantly increased hair fiber elongation by 166.0 ± 30.7% on the 21st day as reported ( Figure A1, 2) [22,23]. Vibrissa follicles treated with HNG or MS showed early catagen shape, while those of untreated controls showed late catagen shape on the 21st day ( Figure A1) [24]. ...
... HNG 50 nM significantly increased hair shaft elongation by 163.9 ± 22.7% on the 21st day (Figures 2 and A1). MS 1 µM was used as the positive control, which also significantly increased hair fiber elongation by 166.0 ± 30.7% on the 21st day as reported (Figures 2 and A1) [22,23]. Vibrissa follicles treated with HNG or MS showed early catagen shape, while those of untreated controls showed late catagen shape on the 21st day ( Figure A1) [24]. ...
... HNG 50 nM significantly increased hair shaft elongation by 163.9 ± 22.7% on the 21st day ( Figure A1, 2). MS 1 μM was used as the positive control, which also significantly increased hair fiber elongation by 166.0 ± 30.7% on the 21st day as reported (Figure A1, 2) [22,23]. Vibrissa follicles treated with HNG or MS showed early catagen shape, while those of untreated controls showed late catagen shape on the 21st day ( Figure A1) [24]. ...
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The hair follicle goes through repetitive cycles including anagen, catagen, and telogen. The interaction of dermal papilla cells (DPCs) and keratinocytes regulates the hair cycle and hair growth. Humanin was discovered in the surviving brain cells of patients with Alzheimer’s disease. HNG, a humanin analogue, activates cell growth, proliferation, and cell cycle progression, and it protects cells from apoptosis. This study was performed to investigate the promoting effect and action mechanisms of HNG on hair growth. HNG significantly increased DPC proliferation. HNG significantly increased hair shaft elongation in vibrissa hair follicle organ culture. In vivo experiment showed that HNG prolonged anagen duration and inhibited hair follicle cell apoptosis, indicating that HNG inhibited the transition from the anagen to catagen phase mice. Furthermore, HNG activated extracellular signal-regulated kinase (Erk)1/2, Akt, and signal transducer and activator of transcription (Stat3) within minutes and up-regulated vascular endothelial growth factor (VEGF) levels on DPCs. This means that HNG could induce the anagen phase longer by up-regulating VEGF, which is a Stat3 target gene and one of the anagen maintenance factors. HNG stimulated the anagen phase longer with VEGF up-regulation, and it prevented apoptosis by activating Erk1/2, Akt, and Stat3 signaling.
... Although various therapeutic options for alopecia are available, none of them provide satisfying results because the pathogenesis and mechanisms of alopecia are heterogeneous and complicated. Minoxidil and finasteride are approved by the US Food and Drug Administration (FDA) for male pattern alopecia [19,20]. However, these drugs generally need to be used continuously for the benefits to be maintained, and unpleasant side effects like migraines and depression sometimes occur. ...
... The Water-Soluble Tetrazolium-1 (WST-1) assay (EZ-Cytox Cell Viability Assay Kit; ITSbio, Korea) was used as described in the manufacturer's protocol to determine cell viability. HDP cells (1 × 10 4 cells/well) were seeded on a 96-well, clear, flat-bottom ultra-low attachment microplate (Corning Inc., USA) to obtain spherical structures, and the cells were treated with the indicated doses of loliolide (1,5,10,20,50, and 100 μg/ml) for 48 h. Subsequently, the WST-1 solution was added to each well, and cell viability was examined by measuring absorbance at 450 nm using an iMark microplate reader (Bio-Rad Laboratories, USA). ...
... AKT is the serine/threoninespecific kinase involved in the proliferation of various cell types like DP cells [26,27]. Moreover, various therapeutic candidates for alopecia treatment have demonstrated hair growth-promoting effects via AKT activation in DP cells [20,27,35]. Based on this knowledge, we conducted experiments to examine the effects of loliolide on the hair inductive properties of HDP cells. ...
Article
The literature indicates that LINC00174 inhibits the growth of colorectal cancer (CRC) cells, but its research needs to be enriched. We tried to explore the function and mechanism of LINC00174 in CRC cell proliferation and migration. Bioinformatics analysis predicted the binding relationship and expressions of lncRNA, miRNA and mRNA. Clinical study analyzes the relationship between LINC00174 and clinical data characteristics of CRC patients. The expressions of LINC00174, miR-3127-5p and E2F7 were verified by RT-qPCR, and the combination of the two was verified by dual luciferase analysis and RNA immunoprecipitation as needed. Western blot was used to detect the expression of EMT-related protein and E2F7 protein. Functional experiments were used to evaluate the function of the target gene on CRC cells. LINC00174 was up-regulated in CRC clinical samples and cells and was related to the clinical characteristics of CRC patients. High-expression of LINC00174, contrary to the effect of siLINC00174, promoted cell viability, proliferation, migration and invasion, up-regulated the expressions of N-Cadherin, Vimentin, E2F7, and inhibited the expression of E-Cadherin. MiR-3127-5p was one of the targeted miRNAs of LINC00174 and was down-regulated in CRC samples. In addition, miR-3127-5p mimic partially reversed the malignant phenotype of CRC cells induced by LINC00174. Besides, E2F7 was a target gene of miR-3127-5p, and LINC00174 repressed miR-3127-5p to regulate E2F7. Our research reveals that LINC00174 affected the biological characteristics of CRC cells through regulated miR-3127-5p/ E2F7 axis.
... In particular, it is known that the level of cyclin D1, a target gene of the Wnt/β-catenin pathway, increases with the progression from G0/G1 to S phase during the cell cycle (Prall et al., 1997). The phosphoinositide 3-kinase (PI3K)/Akt pathway plays a key role in the proliferation of several types of cells, including cancer cells, keratinocytes, and DPCs (Han et al., 2004;Hong et al., 2012;Wang et al., 2017). Previous studies have shown that minoxidil can prevent apoptosis of DPCs by activating Akt and delay the transition of the hair cycle into the regression phase by activating the Wnt/β-catenin pathway in DPCs (Han et al., 2004;Kwack et al., 2011). ...
... The phosphoinositide 3-kinase (PI3K)/Akt pathway plays a key role in the proliferation of several types of cells, including cancer cells, keratinocytes, and DPCs (Han et al., 2004;Hong et al., 2012;Wang et al., 2017). Previous studies have shown that minoxidil can prevent apoptosis of DPCs by activating Akt and delay the transition of the hair cycle into the regression phase by activating the Wnt/β-catenin pathway in DPCs (Han et al., 2004;Kwack et al., 2011). On the other hand, DHT inhibits the Wnt/β-catenin pathway in DPCs, which in part contributes to AGA (Kang et al., 2015). ...
... The PI3K/Akt pathway plays an important role in the proliferation and survival of various types of cells, and the activation of Akt by minoxidil increases the proliferation of human DPCs (Han et al., 2004;Jin et al., 2007). To evaluate whether vanillic acid could activate Akt, DPCs were stimulated with vanillic acid (10 µg/mL) for 0-120 min. ...
Article
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The hair cycle (anagen, catagen, and telogen) is regulated by the interaction between mesenchymal cells and epithelial cells in the hair follicles. The proliferation of dermal papilla cells (DPCs), mesenchymal-derived fibroblasts, has emerged as a target for the regulation of the hair cycle. Here, we show that vanillic acid, a phenolic acid from wheat bran, promotes the proliferation of DPCs via a PI3K/Akt/Wnt/β-catenin dependent mechanism. Vanillic acid promoted the proliferation of DPCs, accompanied by increased levels of cell-cycle proteins cyclin D1, CDK6, and Cdc2 p34. Vanillic acid also increased the levels of phospho(ser473)-Akt, phospho(ser780)-pRB, and phospho(thr37/46)-4EBP1 in a time-dependent manner. Wortmannin, an inhibitor of the PI3K/Akt pathway, attenuated the vanillic acid-mediated proliferation of DPCs. Vanillic acid-induced progression of the cell-cycle was also suppressed by wortmannin. Moreover, vanillic acid increased the levels of Wnt/β-catenin proteins, such as phospho(ser9)-glycogen synthase kinase-3β (GSK-3β), phospho(ser552)-β-catenin, and phospho(ser675)-β-catenin. We found that vanillic acid increased the levels of cyclin D1 and Cox-2, which are target genes of β-catenin, and these changes were inhibited by wortmannin. To investigate whether vanillic acid affects the downregulation of β-catenin by dihydrotestosterone (DHT), implicated in the development of androgenetic alopecia, DPCs were stimulated with DHT in the presence and absence of vanillic acid for 24 h. Western blotting and confocal microscopy analyses showed that the decreased level of β-catenin after the incubation with DHT was reversed by vanillic acid. These results suggest that vanillic acid could stimulate anagen and alleviate hair loss by activating the PI3K/Akt and Wnt/β-catenin pathways in DPCs.
... The Minoxidil ® (pyrimidine derivate) lotion 2% was the first drug to receive approval by the FDA for AGA treatment in males (1988) and in females (1991) [36,37]. Minoxidil ® lotion 5% received approval in 1997 for males who suffered AGA followed by approval of the 5% foam in 2006 [36,37]. ...
... The Minoxidil ® (pyrimidine derivate) lotion 2% was the first drug to receive approval by the FDA for AGA treatment in males (1988) and in females (1991) [36,37]. Minoxidil ® lotion 5% received approval in 1997 for males who suffered AGA followed by approval of the 5% foam in 2006 [36,37]. Minoxidil ® prolongs the anagen and increases the HF diameter through activation of prostaglandin endoperoxide synthase-1, which increases the level of prostaglandin E2 [36]. ...
... Minoxidil ® prolongs the anagen and increases the HF diameter through activation of prostaglandin endoperoxide synthase-1, which increases the level of prostaglandin E2 [36]. Minoxidil ® increases the survival of DPCs by increasing the Bcl-2/Bax ratio and by activating ERK and Akt [37]. ...
Article
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The number of articles evaluating platelet-rich plasma (PRP) efficacy in androgenic alopecia (AGA) have exponentially increased during the last decade. A systematic review on this field was performed by assessing in the selected studies the local injections of PRP compared to any control for AGA. The protocol was developed in accordance with the Preferred Reporting for Items for Systematic Reviews and Meta-Analyses-Protocols (PRISMA-P) guidelines. A multistep search of the PubMed, MEDLINE, Embase, PreMEDLINE, Ebase, CINAHL, PsycINFO, Clinicaltrials.gov, Scopus database, and Cochrane databases was performed to identify studies on hair loss treatment with platelet-rich plasma. Of the 163 articles initially identified, 123 articles focusing on AGA were selected and, consequently, only 12 clinical trials were analyzed. The studies included had to match predetermined criteria according to the PICOS (patients, intervention, comparator, outcomes, and study design) approach. In total, 84% of the studies reported a positive effect of PRP for AGA treatment. Among them, 50% of the studies demonstrated a statistically significant improvement using objective measures and 34% of the studies showed hair density and hair thickness improvement, although no p values or statistical analysis was described. In total, 17% of the studies reported greater improvement in lower-grade AGA, while 8% noted increased improvement in higher-grade AGA. Only 17% of the studies reported that PRP was not effective in treating AGA. The information analyzed highlights the positive effects of PRP on AGA, without major side effects and thus it be may considered as a safe and effective alternative procedure to treat hair loss compared with Minoxidil® and Finasteride®.
... Minoxidil (pyrimidine derivate) lotion 2% was the first drug with FDA approval for treatment of AGA in males (1988) and females (1991) [12,13]. Minoxidil as 5% lotion was approved in 1997 for AGA in males and as 5% foam in 2006 [12,13]. ...
... Minoxidil (pyrimidine derivate) lotion 2% was the first drug with FDA approval for treatment of AGA in males (1988) and females (1991) [12,13]. Minoxidil as 5% lotion was approved in 1997 for AGA in males and as 5% foam in 2006 [12,13]. Minoxidil extends the anagen period and increases HF diameter through activation of prostaglandinendoperoxide synthase-1, which increases the level of prostaglandin E2 [12]. ...
... Minoxidil extends the anagen period and increases HF diameter through activation of prostaglandinendoperoxide synthase-1, which increases the level of prostaglandin E2 [12]. Minoxidil improves the survival of dermal papilla cells (DPCs) by activating ERK and Akt and by increasing the Bcl-2/Bax ratio [13]. ...
Article
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Tissue engineering in hair regrowth aims to develop innovative and not-invasive procedures to advance the hair regrowth. A placebo-controlled, randomized, evaluator-blinded, half-head group study to compare hair regrowth with micrografts containing human hair follicle mesenchymal stem cells (HF-MSCs) vs. placebo was reported. After 58 weeks, 27 patients displayed in the targeted area an increase of hair count and hair density, respectively, of 18.0 hairs per 0.65 cm2 and 23.3 hairs per cm2 compared with baseline, while the control area displayed a mean decrease of 1.1 hairs per 0.65 cm2 and 0.7 hairs per cm2 (control vs. treatment: P
... In DPCs, the mechanisms of action of minoxidil that have been identified clude inhibition of progression of the catagen phase by activation of the Wn pathway and inhibition of apoptosis by activation of Akt and Erk [22,23]. Chan cycle and cell cycle-related proteins are involved in the survival and death of m cells [24,25]. ...
... To examine the efficacy of natural products in promoting hair growth or inhibi hair loss, DPC proliferation was measured, owing to the importance of DPCs as regula of hair growth and regeneration [14,15,23]. We investigated whether the hair growth ef of BDB was induced by the stimulation of DPC proliferation. ...
... To examine the efficacy of natural products in promoting hair growth or inhibiting hair loss, DPC proliferation was measured, owing to the importance of DPCs as regulators of hair growth and regeneration [14,15,23]. We investigated whether the hair growth effect of BDB was induced by the stimulation of DPC proliferation. ...
Article
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Various studies addressing the increasing problem of hair loss, using natural products with few side effects, have been conducted. 5-bromo-3,4-dihydroxybenzaldehyde (BDB) exhibited anti-inflammatory effects in mouse models of atopic dermatitis and inhibited UVB-induced oxidative stress in keratinocytes. Here, we investigated its stimulating effect and the underlying mechanism of action on hair growth using rat vibrissa follicles and dermal papilla cells (DPCs), required for the regulation of hair cycle and length. BDB increased the length of hair fibers in rat vibrissa follicles and the proliferation of DPCs, along with causing changes in the levels of cell cycle-related proteins. We investigated whether BDB could trigger anagen-activating signaling pathways, such as the Wnt/β-catenin pathway and autophagy in DPCs. BDB induces activation of the Wnt/β-catenin pathway through the phosphorylation of GSG3β and β-catenin. BDB increased the levels of autophagic vacuoles and autophagy regulatory proteins Atg7, Atg5, Atg16L, and LC3B. We also investigated whether BDB inhibits the TGF-β pathway, which promotes transition to the catagen phase. BDB inhibited the phosphorylation of Smad2 induced by TGF-β1. Thus, BDB can promote hair growth by modulating anagen signaling by activating Wnt/β-catenin and autophagy pathways and inhibiting the TGF-β pathway in DPCs.
... During years, hair follicle dermal papilla cells have been mainly studied in the context of hair growth induction and in the development of skin equivalents [48][49][50][51][52]. However, their therapeutic potential extends far beyond hair and skin tissue engineering applications, since these cells have been reported to differentiate to various mesenchymal lineages in 2D monolayer cell cultures [14][15][16][17][18]. ...
... The skin is a large self-renewing organ that contains different stem cells niches, one of them, the hair follicle dermal papilla, located in the bulge of the hair follicle. During years, follicle dermal papilla cells have been studied in the context of hair growth induction, epidermal regeneration in response to skin injury, as well as in the development of skin equivalents [48][49][50][51][52]. However, it seems that HFDPC could also be used as a source of stem cells for tissue engineering applications since they have been reported to be able to differentiate to all mesenchymal lineages in 2D monolayer cell cultures [14][15][16][17][18]. First studies showed that rodent dermal papilla cells have a broad differentiation potential, similar to bone marrow derived mesenchymal stem cells [16,61]. ...
Article
Full-text available
Hair follicle dermal papilla cells (HFDPC) are a specialized cell population located in the bulge of the hair follicle with unique characteristics such as aggregative behavior and the ability to induce new hair follicle formation. However, when expanded in conventional 2D monolayer culture, their hair inductive potency is rapidly lost. Different 3D culture techniques, including cell spheroid formation, have been described to restore, at least partially, their original phenotype, and therefore, their hair inductive ability once transplanted into a recipient skin. Moreover, hair follicle dermal papilla cells have been shown to differentiate into all mesenchymal lineages, but their differentiation potential has only been tested in 2D cultures. In the present work, we have cultured HFDPC in the 3D self-assembling peptide scaffold RAD16-I to test two different tissue engineering scenarios: restoration of HFDPC original phenotype after cell expansion and osteogenic and adipogenic differentiation. Experimental results showed that the 3D environment provided by RAD16-I allowed the restoration of HFDPC signature markers such as alkaline phosphatase, versican and corin. Moreover, RAD16-I supported, in the presence of chemical inductors, three-dimensional osteogenic and adipogenic differentiation. Altogether, this study suggests a potential 3D culture platform based on RAD16-I suitable for the culture, original phenotype recovery and differentiation of HFDPC.
... In this context, we also have found that apoptosis signals were significantly reduced by D-panthenol treatment in cultured hair follicle cells (Figures 2A and 6B). Dermal papilla is considered to resist apoptosis, associated with high levels of Bcl-2 and a lack of death receptors during the entire hair cycle in mice and humans [45][46][47][48]. However, they may be susceptible to apoptosis under certain experimental conditions [49,50] and it has been reported that minoxidil prevented cellular apoptosis in dermal papilla cells [46]. ...
... Dermal papilla is considered to resist apoptosis, associated with high levels of Bcl-2 and a lack of death receptors during the entire hair cycle in mice and humans [45][46][47][48]. However, they may be susceptible to apoptosis under certain experimental conditions [49,50] and it has been reported that minoxidil prevented cellular apoptosis in dermal papilla cells [46]. Our data suggest that the reduction of the apoptotic markers by D-panthenol treatment could explain at least in part the cellular mechanism of its clinical anti-hair loss efficacy. ...
Article
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Dexpanthenol (D-panthenol) is a precursor of vitamin B5 (pantothenic acid) and is widely used for dietary supplements and topical applications. D-panthenol has long been used in hair care products for the purpose of anti-hair loss, its effects and the underlying mechanisms, however, were barely reported. In this study, the effects of D-panthenol on human hair follicle cells, including dermal papilla cells (hDPCs) and outer root sheath cells (hORSCs), were investigated. D-panthenol enhanced the cell viability, increasing the cellular proliferation marker Ki67 in cultured hDPCs. The markers for apoptosis (Caspase3/9) and cell senescence (p21/p16), reported to be expressed in aged or resting phase follicles, were significantly reduced by D-panthenol. Anagen-inducing factors (ALP; β-catenin; versican), which trigger or elongate the anagen phase, were stimulated by D-panthenol. On the other hand, D-panthenol reduced TGF-β1 expressions in both mRNA and protein levels. The expression of VEGF, which is important for peripheral blood vessel activation; was up-regulated by D-panthenol treatment. In cultured hORSCs, cell proliferation and viability were enhanced, while the mRNA expression of cell senescence markers (p21/p16) was significantly down-regulated. The expressions of both VEGF and its receptor (VEGFR) were up-regulated by D-panthenol. In conclusion, our data suggest that the hair growth stimulating activity of D-panthenol was exerted by increasing the cell viability, suppressing the apoptotic markers, and elongating the anagen phase in hair follicles.
... Additionally, phosphorylation of ERK and Akt was significantly increased by treatment with SP extract. The role of phosphorylated ERK and Akt in mediating cell survival and apoptosis is well established (Han et al. 2004). Bcl-2 family consists of anti-apoptotic proteins such as Bcl-2 as well as pro-apoptotic proteins such as Bax (Adams and Cory 1998). ...
... Phosphorylated ERK and Akt are known to translocate into the nucleus, and regulate cell survival by modulating the expression of Bcl-2 and Bax (Chang et al. 2003). In addition, the main active target cell of minoxidil is the dermal papilla cells, and the probable mechanisms of action are the activation of both ERK and Akt, as well as the increase of Bcl-2/Bax ratio (Han et al. 2004). Kwon et al. (2007) also reported similar results that minoxidil plus all-trans retinoic acid promoted hair growth by facilitating the phosphorylation of ERK and Akt and increasing the ratio of Bcl-2/Bax. ...
Article
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Context: Although Salvia plebeia (SP) R. Brown (Labiatae) is known to possess various biological activities, the effects of SP on hair growth have not been elucidated. Objective: To investigate the hair growth potential of SP extract by using human dermal papilla cells (hDPCs) and C57BL/6 mice. Materials and methods: The entire SP plant sample was ground into powder and extracted with 99.9% methyl alcohol. Various concentrations of SP extract were added to hDPCs to evaluate the proliferation, migration, and factors related to hair growth and cycling. Effect of topical SP administration on hair regrowth was tested in vivo in male C57BL/6 mice for 21 days. Results: SP extract significantly increased the proliferation of cultured hDPCs at doses of 15.6 and 31.3 μg/mL compared to control group by 123% and 132%, respectively. Expression of hepatocyte growth factor increased while the level of TGF-β1 and SMAD2/3 decreased when treated with SP extract. At the molecular level, the extract activated Wnt/β-catenin signalling by raising β-catenin and phospho-GSK3β expression. SP extract also exerted anti-apoptotic and proliferative effects in hDPCs by increasing the Bcl-2/Bax ratio and activating cell proliferation-related proteins, ERK and Akt. Finally, the extract caused an induction of the anagen phase leading to significantly enhanced hair growth in treated male mice. Discussion and conclusion: Our results indicate that SP extract has the capacity to activate hDPCs into a proliferative state to promote hair growth. Further research is necessary to determine the bioactive components and their mechanisms of action responsible for SP-related hair growth effect.
... It is suggested that the effect of Kuntai capsule on the climacteric syndrome may be related to the ovarian function, Kuntai capsule may improve the ovarian function during climacteric transition. Yang et al. [13] showed that the efficacy of the Kuntai capsule in the treatment of climacteric syndrome was similar to that of estrogen, and had no effect on vital signs, liver and kidney function, and endometrial thickness. Chen et al. [4] pointed out that the Kuntai capsule was more effective than the low-dose estrogen in treating some symptoms (numbness, depression, dizziness, fatigue, muscle and joint pain, headache) of climacteric transition. ...
... In addition to its originally intended effects, it showed hair-growth stimulation as a side effect and is thus used to treat hair loss [17]. Several studies have reported that minoxidil promotes nutrient supply through vasodilation around hair follicles, such as through potassium channel opening [9,18,19]; induces hair growth; and promotes DP cell growth [20]. However, minoxidil provides a short-term improvement, and discontinuing treatment may result in rapid hair loss [17,21]. ...
Article
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Minoxidil is the most widely used treatment for hair growth, but has been associated with several side effects. In this study, we investigated the effects of heat-killed Enterococcus faecalis EF-2001 on hair loss prevention and regrowth using human dermal papilla cells and male C57BL/6 mice. To examine the effects of EF-2001, we used minoxidil as the positive control. In the in vitro experiments, EF-2001 treatment (75–500 μg/mL) led to the proliferation of human dermal papilla cells in a concentration-dependent manner. In the in vivo experiment, the topical application of 200 µL EF-2001 on the dorsal surface of C57BL/6 male mice led to hair growth. Changes in hair regrowth were examined by visual comparison and hematoxylin and eosin staining of skin sections. We also determined the expression levels of marker genes (Wnt) and growth factors (fibroblast growth factor, insulin growth factor 1, and vascular endothelial growth factor) in the skin tissues of the back of each mouse using a quantitative polymerase chain reaction. EF-2001 accelerated the progression of hair regrowth in mice and promoted hair-follicle conversion from telogen to anagen, likely by increasing the expression levels of growth factors and marker genes.
... 4 Minoxidil promotes the survival of dermal papilla cells by increasing Bcl-2/Bax ratio and by activating ERK and Akt. 5 Oral finasteride induces the prolongation of anagen phase of hairs, which results in gradual thickening and elongation of the hairs. 6 Finasteride reduces the pattern hair loss associated with increased expression of caspases 7 and apoptosis inhibitors and for this reason it is suggested to activate anagen hair growth. ...
Article
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Background Androgenetic alopecia (AGA) is a common hair loss disorder affecting both men and women. Despite multiple therapeutic options, treatment of AGA remains unsatisfactory. Platelet rich plasma (PRP) is an autologous concentrate of plasma with a greater count of platelets than that of whole blood and is effective in promoting hair regrowth. Objective This randomized controlled clinical trial was conducted to evaluate the efficacy and safety of PRP therapy in male androgenetic alopecia (AGA). Materials and Methods This study was conducted at the Department of Dermatology & Venereology, Bangabandhu Sheikh Mujib Medical University from October 2016 to October 2017. Fifty four male patients with AGA diagnosed by dermatologist were enrolled by consecutive sampling. The participants were divided into two groups by odd (group- A) and even numbering (Group-B). Group-A patients were treated with PRP injections on their scalp at 4 weeks interval for 3 sessions and group-B patients were treated with topical 5% minoxidil lotion for the same duration. All patients were followed up at 8th and 12th week. At each follow-up hair was counted in prefixed area of treatment, history was taken and clinical examinations were performed to detect any adverse effects of these therapies. Results Among 54 male AGA patients, there was no significant difference (P>0.05) in mean age. Positive family history of AGA was found in 74.04% and 70.37% patients in group-A and group-B respectively. According to Norwood- Hamilton classification, in group-A 29.63% patients were in Stage II and in group-B 25.93% patients were in stage II. At the beginning, in group-A and group-B mean hair count/sq.cm was 15.41±1.16 and 15.56±1.88 respectively. At 8th week, mean hair count/sq.cm of group-A and group-B was 17.42±1.10 and 16.15±1.87 and at 12th week, the hair growth of group-A was increased to 19.14±1.06/sq.cm which was significantly higher (P<0.05) compared to group-B (17.62±2.07/sq.cm). 81.48% patient complaints mild pain followed by erythema at the injection site in group-A and 66.66% patient complaints of transient hair fall at the beginning in group-B. Conclusion PRP was more efficacious than topical 5% minoxidil lotion in male AGA.
... Based on such knowledge, minoxidil induces the initiation of the anagen phase and prolongs its duration (Messenger and Rundegren, 2004). Minoxidil stimulates peripheral vasodilation around the hair follicle and promotes dermal papilla cells survival and proliferation (Han et al., 2004). It can also induce prostaglandin-endoperoxide synthase-1 and upregulate vascular endothelial growth factor (Lachgar et al., 1998). ...
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Objective: Although azelaic acid is effective for treatment of acne and rosacea, the biological activity of azelaic acid and the effect of its combination therapy with minoxidil were not elucidated with regard to hair growth. Materials and methods: In this study, mouse vibrissae follicles were dissected on day 10 after depilation. Then, the bulb and bulge cells of the hair follicle were treated with minoxidil and azelaic acid for 10 days to evaluate Sonic hedgehog (Shh) protein expression. Moreover, bulge and bulb cells of the hair follicles were cultivated and the expression of Gli1, Gli2, and Axin2 mRNA levels was evaluated using real-time polymerase chain reaction (PCR) analysis. We further investigated the protective effects of azelaic acid against ultraviolet B (UVB) irradiation in cultured bulb and bulge cells by determining catalase activity. An irradiation dose of 20 mJ/cm2 UVB for 4 sec was chosen. Results: The results showed that catalase activity significantly (p<0.05) increased in the bulge cells after exposure to 2.5 mM and 25 mM azelaic acid. Meanwhile, treatment of the bulb cells with azelaic acid (2.5 and 25 mM) did not cause significant changes in catalase activity. We also found that azelaic acid (25 mM) alone upregulated Gli1 and Gli2 expression in the bulge cells and 100 µ minoxidil caused Gli1 and Axin2 overexpression in the bulb region of the hair follicle. Moreover, minoxidil (100 µM) alone and in combination with azelaic acid (25 mM) led to Shh protein overexpression in the hair follicles in vitro and in organ culture. Conclusion: Our results indicated a potential role for azelaic acid in the protection of bulge cells from UVB damage and its combination with minoxidil may activate hair growth through overexpression of Shh protein.
... These hair follicles have been shown to produce increased amounts of keratin in response to growth factors; thus, growth factors are considered as key molecules that participate in hair growth initiation and suppression [1][2][3]. Dermal papilla, located at the base of the hair follicle, has its own blood supply and thus plays a crucial role in regulating numerous growth factors in response to various physiological conditions [4,5]. It has been reported that various causes of hair loss, including emotional stress, hormone imbalance, and nutritional deficiency, are characterized by the condensation of the dermal papilla along with impaired ability to produce growth factors [6][7][8]. ...
Article
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Human hair follicle dermal papilla cells (DPCs) are a specialized population of cells located in the hair follicles and regulate hair growth and development, particularly by releasing numerous growth factors in response to various physiological conditions. In the present study, we aimed to test whether nonanal, a scent compound from plants, stimulated growth factors in DPCs and to delineate the underlying mechanisms involved. We found that nonanal promoted DPC proliferation in a dose-dependent manner. Meanwhile, it also increased the intracellular cyclic adenosine monophosphate (cAMP) levels and the expression of various growth factor genes such as vascular endothelial growth factor, keratinocyte growth factor, and insulin-like growth factor 1. Furthermore, nonanal treatment stimulated DPC migration. Notably, the benefits of nonanal use were abrogated by cAMP inhibition. Our results reveal the potential of nonanal in preventing hair loss and suggest that its effects are cAMP-mediated in DPCs.
... Western blot analysis was performed to evaluate the expression of various factors that are closely associated to cell apoptosis and proliferation as reported previously 19,23 . CZ dose dependently enhanced phosphorylation process of Akt and ERK, increased Bcl-2 expression, and reduced Bax expression (Fig. 2). ...
Article
Background: Chrysanthemum zawadskii (CZ) belongs to the genus Chrysanthemum, also known as 'Gu-Jeol-Cho' in Korea. CZ has been used as herbal remedy to manage cough, hypertensive disorders, pharyngitis, bronchitis, gastroenteritis, pneumonia, bladder diseases and common cold. However, its effect on hair growth has not been documented. Objective: The aim of present study was to elucidate the beneficial effects of CZ on hair growth. Methods: Proliferation of follicular dermal papilla (DP) cells from human scalp skin was evaluated by MTT assay. The expression of various molecules in DP cells was checked by western blot assay. Effect of CZ extract on the hair growth was evaluated by hair organ culture and C57BL/6 mice model. Results: Cultivation of DP cells with CZ extract increased cellular proliferation, increased expression of phosphorylated protein kinase B (p-Akt), p-ERK, B-cell lymphoma 2, and decreased expression of Bax. Treatment of human hair follicles with CZ extract significantly enhanced hair growth. Additionally, CZ markedly shortened telogen period, increased anagen transformation and stimulated hair growth in the animal study. Conclusion: These results suggest that CZ extract has an effect of promoting hair growth and may therefore be a useful a therapeutic remedy for preventing hair loss.
... 27,28) . It has been reported that minoxidil promotes the proliferation of hair follicles through MAPK kinase (ERK, JNK, and p38) signaling pathways 29,30) . It has been reported that increased cell apoptosis in the hair cells precedes the transition into catagen stage from anagen stage in hair cycle and the Bax/Bcl-xL/Bcl-2 are expressed in the hair cells of which are involved in hair growth 31,32) . ...
... increases hair follicle size. [5,6] Finasteride also promotes anagen phase by increasing hair diameter and elongating hair length. [7] It decreases serum and scalp levels of DHT and given as a dose of 1 mg daily. ...
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Introduction: Plasma derivatives have been practiced a lot in orthopedics, burns, and sport medicine. Microneedling (MN) with platelet-rich plasma (PRP) therapy has been proven to improve the micro-circulation and thus improve hair growth. The role of concentrated growth factor (CGF) for hair growth has not been mentioned anywhere in the literature for hair growth which we tried to prove in our article by comparing it with various other studies. Materials and methods: This is a retrospective randomized study involving 20 male patients whose ages ranged from 21 years to 56 years. PRP was prepared using the dual-spin method and injected after activation; post-MN, CGF gel was applied topically. Four sessions were performed, and a follow-up was done after 6 months. Statistical analysis was done using the Statistical Package for the Social Sciences software version 21 for Windows (SPSS, IBM Corp, Armonk, NY, USA). Paired t-test was used for the various comparisons. Results: Hair loss reduced by the end of the first month. At the end of 6 months, postfirst session, microscopic examination showed statistically significant difference in the hair count compared to those during the baseline. Discussion: PRP having platelet-derived growth factor and vascular endothelial growth factor acts on stem cells in the follicles, stimulating the development of new follicles and promoting neovascularization. CGF helps stimulating cell proliferation and matrix remodeling due to numerous growth factors in a concentrated form. Thus, this therapy combined helps to boost the hair growth in a very significant way. Summary: This study provides the preliminary evidence of efficacy of PRP along with MN and CGF in treating androgenetic alopecia by promoting angiogenesis along with vascularization and promotes hair follicles to enter and extend the anagen phase. Most of the results obtained show improved results with this therapy. A larger case study for the same can further be done for a stronger recommendation of the use of CGF for hair growth therapy further.
... Minoxidil® (pyrimidine derivate) prolongs the anagen phase and increases HF diameter through activation of prostaglandin endoperoxide synthase-1, which increases the level of prostaglandin E2 [15]. Minoxidil® increases the survival of DPCs by increasing the Bcl-2/Bax ratio and by activating ERK and Akt [16]. ...
Article
Objectives: A retrospective case-series study comparing autologous activated platelet-rich plasma (AA-PRP) versus autologous non-activated platelet-rich plasma (A-PRP) in hair re-growth was reported. Methods: 90 patients, 63 males showing AGA in stage I–V by the Norwood–Hamilton scale and 27 females with AGA in stage I–III by the Ludwig scale, treated since 2013, were analyzed. 57 patients were treated with A-PRP injections and 33 patients were treated with AA-PRP in three sessions spaced 30 days average. Assessment of hair re-growth was evaluated in different weeks (Ws) after the treatment, summarized in four phases: T0, before the first infusion, T1 - 12 Ws, T2 - 23 Ws, T3 - 44 Ws, T4 - 58 Ws after the last treatment. Results: 12 Ws, 23 Ws, 44 Ws, and 58Ws after the last treatment, hair density measurements for patients treated with A-PRP and AA-PRP were 65 ± 5 and 28 ± 4 hairs/cm2 at T1, 28 ± 2 and 15 ± 3 hairs/cm2 at T2, 25 ± 3 and 14 ± 3 hairs/cm2 at T3, 23 ± 3 and 13 ± 3 hairs/cm² at T4. Conclusion: The effects of A-PRP and AA-PRP in hair re-growth during a long-term follow-up, was demonstrated.
... Growth factors, DPCs and signal channels play important roles at extending hair follicles anagen. For example, it was reported that minoxidil has been shown to prolong the hair anagen phase by promoting the survival of DPCs [19], and improving angiogenesis by stimulating the expression of vascular endothelial growth factor (VEGF), potassium channels, extracellular signal-related kinase (ERK) and protein kinase B (AKT) [7,20]. Finasteride extended the hair anagen phase by increasing the expression of caspases and apoptosis inhibitors [21,18]. ...
Article
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Previously, we have demonstrated that policosanol from Chinese wax suppressed testosterone(T)-induced alopecia in mice. However, the underlying mechanism remained to be determined. Herein, we investigated the mechanism of policosanol against androgenetic alopecia (AGA). AGA was induced in Kunming mice by subcutaneous administration of testosterone propionate for 60 d. Policosanol (0.5 %, 1% or 2%) was applied topically on the back of mice. Finasteride (2%) was applied topically as a positive control. The serum T and estradiol (E2) concentrations were determined by ELISA after 28 and 60 days of treatment. The cutaneous expression or activity of key mediators of hair growth, such as alkaline phosphatase (ALP), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), was measured. MTS assay was performed to evaluate cell proliferation in cultured human dermal papilla cells (DPCs) treated with dihydrotestosterone (DHT). Western blotting was performed to evaluate the protein expression of Bax, Bcl2, TGF-β2, caspase-9, and caspase-3. We found lower T and T/E2 ratio in mice treated with policosanol than in the model group. Policosanol suppressed premature hair follicle entry into the regression phase, as shown by improving VEGF and EGF expression and ALP activity. The MTS assay showed that policosanol markedly inhibited the apoptosis of DHT-treated DPCs. Western blotting showed that policosanol significantly reduced the protein expression of TGF-β2, cleaved caspese-9, cleaved caspase-3, and Bax, and increased that of Bcl2. The optimal effect was obtained with 12.50 g/mL policosanol. In conclusion, policosanol prevents androgenetic alopecia by regulating hormone levels and suppressing premature hair follicle entry into the regression phase.
... Although the action mechanism of MXD remains unclear, it has been found to induce hair growth by inducing angiogenesis (increased gene expression of vascular endothelial growth factor (VEGF)), vasodilation (increased nutrient supply), and the opening of ATPsensitive K + channels (KATP channels) (Meisheri et al., 1988;Buhl et al., 1992;Lachgar et al., 1998). MXD has also been reported to extend the anagen phase by activating the Wnt/catenin pathway and improving hair loss by inhibiting apoptosis in DPCs (Han et al., 2004;Kwack et al., 2011). Finasteride has been demonstrated to prevent androgenic alopecia (also called male pattern hair loss) by inhibiting the activity of 5-reductase type II, which affects male hormone metabolism (Mysore and Shashikumar, 2016). ...
Article
Alopecia is a distressing condition caused by the dysregulation of anagen, catagen, and telogen in the hair cycle. Dermal papilla cells (DPCs) regulate the hair cycle and play important roles in hair growth and regeneration. Myristoleic acid (MA) increases Wnt reporter activity in DPCs. However, the action mechanisms of MA on the stimulation of anagen signaling in DPCs is not known. In this study, we evaluated the effects of MA on anagen-activating signaling pathways in DPCs. MA significantly increased DPC proliferation and stimulated the G2/M phase, accompanied by increasing cyclin A, Cdc2, and cyclin B1. To elucidate the mechanism by which MA promotes DPC proliferation, we evaluated the effect of MA on autophagy and intracellular pathways. MA induced autophagosome formation by decreasing the levels of the phospho-mammalian target of rapamycin (phospho-mTOR) and increasing autophagy-related 7 (Atg7) and microtubule-associated protein 1A/1B-light chain 3II (LC3II). MA also increased the phosphorylation levels of Wnt/β-catenin proteins, such as GSK3β (Ser9) and β-catenin (Ser552 and Ser675). Treatment with XAV939, an inhibitor of the Wnt/β-catenin pathway, attenuated the MA-induced increase in β-catenin nuclear translocation. Moreover, XAV939 reduced MA-induced effects on cell cycle progression, autophagy, and DPC proliferation. On the other hand, MA increased the levels of phospho (Thr202/Tyr204)-extracellular signal regulated kinases (ERK). MA-induced ERK phosphorylation led to changes in the expression levels of Cdc2, Atg7 and LC3II, as well as DPC proliferation. Our results suggest that MA promotes anagen signaling via autophagy and cell cycle progression by activating the Wnt/β-catenin and ERK pathways in DPCs.
... Minoxidil can induce hair growth through various suggested mechanisms. For example, minoxidil may work by prolonging the anagen phase, showing antiapoptotic markers in the skin [13] . Furthermore, minoxidil can augment dermal papilla's vascular supply by increasing vascular endothelial growth factor [14] . ...
... As comparing groups that treated with PTX in different concentrations with negative control group showed significant increase in means follicles count ( (31,32). ...
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Objective: Hair is the human body's major esthetic display component, especially in cultural and social interactions. Alopecia starts to be diagnosed medically at a level that about 25 to 40 percent of the person's hair is dropped. Throughout this research, the potency of topical pentoxifylline in stimulating regrowth in hair loss caused by cyclophosphamide was established. Methods: The study was performed by treatment with pentoxifylline topically in male Swiss albino rats. The animals divided into seven groups with six animals in each group. To induce alopecia Cyclophosphamide used at a dose of (125 mg/kg) intraperitoneal. The animals in this study have hair clippered at day one and at day six of experiment to induce entrance of hair follicles into anagen phase. All groups injected cyclophosphamide at day 15 of experiment except control group injected only distilled water. The treatment period was fourteen days for rats used in this study. All animals in groups of study sacrificed at day 29 of experiment. Results: Hair weight assessment showed improvement in hair growth with increasing pentoxifylline concentration in groups. Strong follicular proliferation was demonstrated by histopathology and gross morphological observations of hair growth in shaved areas.
... To investigate the therapeutic effect of KY19382, we utilized a hair (Libecco & Bergfeld, 2004;Messenger & Rundegren, 2004;Price, 1999;Rossi et al., 2016). Existing drugs that control the proliferation of hair cells can be difficult for treating patients with miniaturized or absent hair follicles (Han et al., 2004). Therefore, we aimed to develop a drug that is effective in promoting hair regrowth and hair follicle neogenesis by inducing markers for hair induction such as ALP and activating hair follicle stem cells via the Wnt/β-catenin pathway. ...
Article
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Background and purpose: The promotion of hair regeneration and growth heavily depends on the activation of Wnt/β-catenin signaling in the hair follicle, including dermal papilla (DP). KY19382, one of the newly synthesized analogs of indirubin-3'-monoxime (I3O), was identified as a Wnt/β-catenin signaling activator via inhibition of the interaction between CXXC-type zinc finger protein 5 (CXXC5) and Dishevelled (Dvl) interaction. Given the close relationship between the Wnt/β-catenin signaling and hair regeneration, we investigated the effect of KY19382 on hair re-growth and hair follicle neogenesis. Experimental approach: In vitro hair induction effects of KY19382 was performed in human dermal papilla cells. The hair elongation effects of KY19382 was confirmed through the human hair follicle and vibrissa culture system. In vivo hair regeneration abilities of KY19382 was identified in three models: hair regrowth, wound-induced hair follicle neogenesis (WIHN) and hair patch assays using C57BL/6 mice. The hair regeneration abilities were analyzed by immunoblotting, alkaline phosphatase (ALP) and immunohistochemical staining. Key results: KY19382 activated Wnt/β-catenin signaling and elevated the ALP expression and proliferation marker PCNA in DP cells. KY19382 also increased hair length in ex vivo cultured mouse vibrissa and human hair follicles and induced hair regrowth in mice. Moreover, KY19382 significantly promoted the generation of de novo hair follicles as shown by WIHN and hair patch assays. Conclusion and implications: These results indicate that KY19382 is a potential therapeutic drug that exhibits effective hair regeneration ability via activation of the Wnt/β-catenin signaling for alopecia treatments.
... With a dense cell structure surrounded by ECM [11], and its own blood supply, dermal papilla cells (DPCs) can regulate a variety of growth factors to cope with various physiological conditions [12,13]. Previous studies have shown that DPCs in hair follicles can induce and promote hair growth [14,15]. ...
Article
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The extracellular matrix (ECM) is important for maintaining cell phenotype and promoting cell proliferation and differentiation. In order to better solve the problem of skin appendage regeneration, a combination of mechanical/enzymatic digestion methods was used to self-extract dermal papilla cells (DPCs), which were seeded on silk fibroin/sodium alginate scaffolds as seed cells to evaluate the possibility of skin regeneration/regeneration of accessory organs. Scanning electron microscopy (SEM) graphs showed that the interconnected pores inside the scaffold had a pore diameter in the range of 153–311 μm and a porosity of 41–82%. Immunofluorescence (IF) staining and cell morphological staining proved that the extracted cells were DPCs. The results of a Cell Counting Kit-8 (CCK-8) and Calcein-AM/PI live-dead cell staining showed that the DPCs grew well in the composite scaffold extract. Normal cell morphology and characteristics of aggregation growth were maintained during the 3-day culture, which showed that the silk fibroin/sodium alginate (SF/SA) composite scaffold had good cell-compatibility. Hematoxylin-eosin (H&E) staining of tissue sections further proved that the cells adhered closely and aggregated to the pore wall of the scaffold, and retained the ability to induce differentiation of hair follicles. All these results indicate that, compared with a pure scaffold, the composite scaffold promotes the adhesion and growth of DPCs. We transplanted the SF/SA scaffolds into the back wounds of SD rats, and evaluated the damage model constructed in vivo. The results showed that the scaffold inoculated with DPCs could accelerate the repair of the skin and promote the regeneration of the hair follicle structure.
... [3][4][5] Minoxidil can prolong the anagen phase and to promote survival of dermal papilla cells and increase in hair follicle size. 6,7 Important actions of minoxidil on the hair follicles include -increased expression of vascular endothelial growth factor (VEGF) mRNA in the dermal papillae, activation of cytoprotective prostaglandin synthase-1, an enzyme that stimulates hair growth and increased expression of hepatocyte growth factor (HGF) m-RNA which is another hair growth promoter and vasodilatory effects. ...
Article
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Androgenic alopecia (AGA) is a type of progressive hairloss, where there is androgen mediated conversion of susceptible terminal hairs into vellus hairs, in genetically predisposed individuals. To compare efficacy of Topical 5% Minoxidil alone versus Topical 5% Minoxidil with Autologous Platelet Rich Plasma (PRP) therapy in patients with Androgenetic Alopecia. This is aProspective study conducted in Department of Dermatology GMERS Medical College, Gandhinagar, Gujarat. A convenience sample of 62 men in the age group of 20-40 with Grade 2-5 AGA according to Hamilton- Norwood Grading were selected and was divided into 2 groups of 31 each. Presitting digital photographs and dermoscopic photos were taken. Autologous PRP was prepared using 18 ml of patients blood after double spin centrifugation and injected by Nappage technique. Results were assessed at the baseline and at the end of each sitting on the basis of change in hair density, photographic evaluation and patient’s self satisfaction. Highly significant increase in hair density was achieved after 4 months of treatment. At T4 (Fourth Session of treatment) Group B showed higher hair density (42.97± 8.96) as compared to Group A (36.94 ± 11.57) which was statistically significant at P = 0.03 Group B showed better improvement as compared to Group A.PRP treatment has a positive therapeutic effect on male Androgenetic alopecia without major side effects.
... [1,5,15] Minoxidil appears to prolong anagen phase and to promote survival of dermal papilla cells and increase in hair follicle size. [16,17] Finasteride also promotes hair growth of anagen hairs leading to gradual increase in hair diameter and hair elongation [18] and appears to activate anagen hair growth. [19,20] Presently, there are limited published data regarding PRP's potential effect on hair. ...
Article
This study aimed to evaluate the possible protective effect of platelet-rich plasma (PRP) on ischemia reperfusion (I/R)-induced ovarian injury in a rat model. Forty adult female albino rats were randomly assigned to four groups: control, ischemia, I/R, and I/R + intraperitoneal PRP. Induction of ischemia was done by bilateral ovarian torsion for 3 h, while reperfusion was done by subsequent detorsion for another 3 h. PRP was injected 30 min before detorsion. Histological assessment and measurement of ovarian anti-Mullerian hormone (AMH) were done to assess the degree of tissue damage and the remaining ovarian reserve. Ovarian malondialdehyde (MDA) and total antioxidant capacity (TAC) levels were measured to evaluate the oxidant-antioxidant balance. Tumor necrosis factor-α (TNF-α) was measured to assess degree of inflammation. Immunohistochemical assessment of ovarian vascular endothelial growth factor-A (VEGF-A) was also done. PRP treated I/R group revealed a significant decrease in MDA (P = 0.007), TNF-α (P = 0.001), and a significant increase in TAC (P = 0.001) and VEGF-A (P = 0.003) in comparison to the untreated I/R group. Furthermore, limited vascular congestion and inflammatory infiltration were observed after PRP treatment. However, no significant difference was detected in AMH after PRP treatment. Our results denoted that PRP may help in preservation of ovarian function and structure during surgical conservative detorsion of the torsioned ovary. These protective effects could be attributed to its ability to reduce oxidative stress, inflammation and also to its high content of growth factors especially VEGF.
... RGE and ginsenoside-Rb1 enhanced the proliferation of hair matrix keratinocytes, human hair-follicle dermal papillary cells (hDPCs). Treated hair with RGE or ginsenoside-Rb1 exhibited substantial cell proliferation and the associated phosphorylation of ERK and AKT [16], it was recently demonstrated that ERK activation plays an important role in the proliferation of hDPCs [42] and AKT mediates critical signals for cell survival and also regulates the survival of DPCs as an antiapoptotic molecule [9,16,44] proliferation and the prolongation of the survival in the hDPCs by red ginseng may be mediated by the ERK and AKT signaling pathway [9,16]. ...
Chapter
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The hair follicle is the unique organ that has the capacity of undergoing cyclic transformations following periods of growth (anagen), regression (catagen), and rest (telogen) regenerating itself to restart the cycle. The dynamic capacity of hair to growth and rest enables mammals to control hair growth and length in different body side and to change their coats. Unlike what is observed in many animals in which the pelage synchronously passes from one phase of the cycle to other all stages of growth cycle are simultaneously found in the human pelage, the growth pattern is a mosaic where the hair cycling staging of one hair root is completely independent of it nearest hair follicle, meaning that each follicular unit (FU) can contain follicles in different stages at any given time. A variety of factors, such as nutritional status, hormones, exposure to radiations, chemotherapy or radiotherapy, environmental pollution or drugs may affect hair growth, and affects the number of hairs, this progressive hair loss has a cosmetic and social impact that often significantly affects social and psychological well-being of the patient that suffers from this hair loss. Although a number of therapies, such as finasteride and minoxidil, are approved medications, a wide variety of classes of phytochemicals and natural products, including those present in ginseng are being testing. The purpose of this chapter is to focus on study the potential of ginseng and its metabolites in hair loss.
... Minoxidil is an adenosine triphosphate sensitive potassium channel opener, and is one of the only two drugs for alopecia treatment approved by Food and Drug Administration [35]. It has been confirmed that minoxidil can increase the blood flow of balding scalps, prolong the anagen stage and enhance hair growth by activating Erk and Akt signaling which enhance the survival of cultured dermal papilla cells, and increase in the Bcl-2/Bax ratio protecting cells against cell death [36][37][38]. However, no literature has reported its effect or mechanism of action on central or peripheral nervous system. ...
Article
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Background: Vernonia anthelmintica (L.) willd is a traditional urgur herb in China for a long history. Its alcohol extract (AVE) has been proved to promote hair follicle growth in C57BL/6 mice. We conducted this study to investigate the hair-growth effects of AVE in stressed mice and its possible mechanism of action. Methods: The hair-follicle growth effects of AVE were examined by in vivo and in vitro study. We exposed C57BL/6 male mice to chronic restraint stress to induce murine hair follicle growth inhibition. The effects of AVE were examined by histological analysis, immunofluorescence for Ki67 and cytokeratin 19 immunoreactivity, western blot assay in tyrosinase and related proteins expressions and immunofluorescence for nerve fibers. In organ culture of mouse vibrissae follicles, we used substance P as a catagen-inducing factor of hair follicle growth, and measured the elongation of hair shafts and expression of neurokinin-1 receptor protein by application of AVE. Results: Our results showed that AVE counteract murine hair follicle growth inhibition caused by chronic restraint stress via inducing the conversion of telogen to anagen and inhibiting catagen premature, increasing bulb keratinocytes and bulge stem cells proliferation, promoting melanogenesis, and reducing the numbers of substance P and calcitonin gene-related peptide nerve fibers. Furthermore, AVE also counteracted murine hair follicle growth inhibition caused by substance P in organ culture. Conclusion: These results suggest that AVE counteract stress-induced hair follicle growth inhibition in C57BL/6 mice in vivo and in vitro, and may be an effective new candidate for treatment of stress-induced hair loss.
... Treatment of HHDPCs with cisplatin induces production of reactive oxygen species and decreases of Bcl-2/Bax ratios, leading to HHDPC apoptosis and massive hair loss (Luanpitpong et al., 2011). Tea polyphenol epigallocatechin-3-gallate (Kwon et al., 2007) and MNX (Han et al., 2004) enhanced proliferation and inhibited apoptosis (by increasing Bcl-2/Bax ratios) of dermal papilla cells, thereby stimulating hair growth. In mice, 6-gingerol in ginger suppresses cultured human hair elongation and delays telogen-to-anagen transition of hair follicles by inhibitory and pro-apoptotic activities on dermal hair cells (Miao et al., 2013). ...
Article
This study aimed to investigate the underlying mechanisms of red ginseng extract (RGE) on regulating hair growth and hair follicle development. Results from in vitro studies showed that RGE treatment simultaneously enhanced viability and inhibited apoptosis in human hair dermal papilla cells. Moreover, RGE administration promoted telogen-to-anagen transition, prolonged anagen in hair follicular cycling, and increased the size of hair follicles and skin thickness in a C57BL/6 mouse model. Furthermore, RGE treatment significantly upregulated the expression of β-catenin, phospho-glycogen synthase kinase 3β, cyclin D1, cyclin E, and Bcl-2, phospho-extracellular signal-regulated protein kinase, and phospho-Akt, which are associated with promoting hair growth. In addition, RGE enhanced skin health by activation of antiox-idant defense systems. Our data demonstrates that hair regenerative mechanisms of RGE may be mediated by stimulating dermal papilla cell proliferation and enhancing skin functions.
... 4 Minoxidil acts by promoting enhanced dermal vascularity, and has antiapoptotic, and mitogenic effects. [5][6][7] Finasteride, on the other hand, blocks 5α-reductase, reduces levels of dihydrotestosterone, and prolongs anagen, leading to thickening of miniaturized hairs and increasing hair counts. 8,9 Dutasteride is another non-FDA-approved treatment for AGA . ...
Article
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Background: Male-type baldness is a common chronic hair loss disorder among males. Male type baldness is characterized by stepwise miniaturization of the hair follicle, due to alteration in the hair cycle dynamics, leading to transformation of the terminal hair follicle into a vellus one. Platelet-rich plasma (PRP) seems to be a new technique which may improve hair regrowth. We planned a randomized, double-blinded placebo control trial to see the efficacy of PRP with and without topical minoxidil and to compare with placebo and standard treatment. Materials and methods: The study design was a randomized, double-blind placebo control trial. The sample size was calculated, and randomization was done. Patients with male type baldness were allocated into four groups; first group topical minoxidil only, the second group PRP with minoxidil, the third group normal saline (NS), and fourth group PRP only. Interventions were done monthly for 3 months and patients were followed up for the next 2 months. Effects of interventions were assessed by hair density, patient self-assessment, and clinical photography. Results: A total of 80 patients were included. The maximum improvement was found in PRP with minoxidil group. Increase in hair density (in descending order) was PRP with minoxidil group, PRP-alone group, minoxidil-alone group, while a decrease in hair density was found in NS group, after 5 months. The maximum patient satisfaction was found in PRP with minoxidil group followed by (in descending order), PRP-alone group, minoxidil-alone group, and NS group. Limitation: Long-term follow up of patients was not done. Hair counts and hair thickness estimation were not estimated. Conclusion: In our study, we found PRP with topical minoxidil is more effective than PRP alone and topical minoxidil alone.
... Another important effect of PRP is reduction of hair follicle microinflammation associated with hair loss during AGA [1,57]. PRP growth and transcription factors signal the follicle to enter the anagen versus catagen phase, playing a role in regeneration and renewal; these effects partly overlap those of other effective AGA therapies such as minoxidil [58] or finasteride [59], justifying combined therapy approaches [44]. ...
Article
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Platelet-rich plasma (PRP) represents a novel therapy tested and is used more and more frequently in dermatology and cosmetic surgery for a variety of conditions, including androgenic alopecia (AGA), a common condition with a complex pathogenesis involving genetic factors, hormonal status and inflammation. We performed an extensive literature search which retrieved 15 clinical trials concerning the use in AGA of PRP therapy, alone or in combination, in male, female or mixed patient groups. A quantitative statistical meta-analysis of n = 17 trial groups proved significant increases in hair density from 141.9 ± 108.2 to 177.5 ± 129.7 hairs/cm2 (mean ± SD) following PRP (p = 0.0004). To the best of our knowledge, this is the first meta-analysis that proved a statistically significant correlation between the number of PRP treatments per month and the percentage change in hair density (r = 0.5, p = 0.03), as well as a negative correlation between the mean age of treatment group and the percentage change in hair density (r = −0.56, p = 0.016). Other factors considered for analysis were the PRP preparation method, amount used per treatment, hair diameter, terminal hairs and pull test. We conclude that PRP represents a valuable and effective therapy for AGA in both males and females if patients are rigorously selected.
... Minoxidil, which is widely used as a treatment for alopecia, has been used for more than 30 years to promote hair growth, but it has side effects such as decreased sexual function. Additionally, minoxidil has a concentration-dependent effect on the differentiation and proliferation of normal human keratinocytes [25] and induces significant DPC proliferation [26]. ...
Article
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Alopecia is a chronic inflammatory skin disease with various causes. Lespedeza bicolor extract (LBE) has been reported to have anti-inflammatory and antioxidative effects. In this study, the activity and mechanisms of LBE as a hair growth agent were investigated. Effects of cell proliferation, cytotoxicity, and cell cycle regulation of LBE and its active component protocatechuic acid (PCA) were evaluated in human dermal papilla cells (DPCs). Hair regeneration effects of LBE in 6-week-old C57BL/6 male mice were also determined using positive control 5% minoxidil. The dose-dependent proliferation of DPCs was estimated in response to LBE treatment (0.8–20 µg/mL). Additionally, significant extension of the anagen phase during the hair cell cycle upon LBE treatment was observed histologically and morphologically. Cell cycle arrest gene expression was determined by quantitative real-time polymerase chain reaction. Lespedezabicolor could be a potent treatment against alopecia through enhancing DPC proliferation and hair regrowth via anagen phase arrest.
... Each stage has distinct morphological features, such as cell proliferation and differentiation, hair growth, and elimination. Human hair follicle dermal papilla (HDP) cells, a type of specialized fibroblast cell in the hair bulb, play an essential role in controlling hair growth and in conditions such as androgenic alopecia [3,4]. Therefore, factors affecting HDP function are important targets for ameliorating alopecia. ...
Article
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Background: Despite advances in medical treatments, the proportion of the population suffering from alopecia is increasing, creating a need for new treatments to control hair loss and prevent balding. Treatments based on plant-derived compounds could potentially prevent hair loss. Human hair follicle dermal papilla (HDP) cells, a type of specialized fibroblast in the hair bulb, play an essential role in controlling hair growth and in conditions such as androgenic alopecia. We examined the effect of Bacillus/Trapa japonica fruit ferment filtrate extracts (TJFs) on HDP cells to determine whether activation of the Akt/ERK/GSK-3β signaling pathway improved HDP cell proliferation. Methods: We prepared TJFs using various methods. The extract properties were analyzed using WST-1, Lowry, and cell migration assays as well as immunofluorescence staining. We also determined the cell cycle stage and performed western blotting and an in ovo chick chorioallantoic membrane assay. Last, we constructed an organotypic three-dimensional cell culture model for immunohistochemical use. Results: Our study confirmed that the TJFs contained numerous peptides and five unknown fractions. The TJFs stimulated HDP cell proliferation and migration via the Akt/ERK/GSK-3β signaling pathway. To verify that the Akt/ERK/GSK-3β pathway affected HDP cell proliferation, we treated HDP cells with LY294002 (an Akt inhibitor), BIO (a GSK-3β inhibitor), and PD98059 (an ERK inhibitor). The TJFs also induced cell cycle progression, inhibited type І 5α-reductase, decreased apoptosis, and enhanced angiogenesis (vascular expansion). In addition to these signaling pathways, proteins including insulin-like growth factor-1 and keratinocyte growth factor, stimulating hair growth, were detected in the three-dimensional cell culture model. Conclusions: Our results confirmed that TJFs enhance HDP cell proliferation via the Akt/ERK/GSK-3β signaling pathway, suggesting a potential treatment for alopecia.
Article
Aims Hair follicles play a critical role in the process of hair growth. The dermal papilla cells (DPCs) are an important component in the hair follicle regeneration and growth. This study investigated the effects of ginsenoside Rb1 on the growth of cultured mink hair follicles and DPCs. Main methods The mink hair follicles were treated with ginsenoside Rb1 for 9 days and their lengths were measured every three days. Real-time PCR was used to determine the mRNA expression of vascularization endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGF-R2) and TGF-β1. In addition, the levels of proteins were detected by western blot. Cell proliferation was determined by immunofluorescence staining of proliferation marker Ki-67 and cell cycle analysis was performed on flow cytometry. Moreover, cell migration was evaluated by wound healing assay. Key findings Ginsenoside Rb1 promoted the growth of hair follicles, and proliferation and migration of DPCs. Ginsenoside Rb1 improved the expression levels of VEGFA and VEGF-R2, while attenuated the TGF-β1 expression both in hair follicles and DPCs. Furthermore, ginsenoside Rb1 facilitated the activation of PI3K/AKT/GSK-3β signaling pathway in hair follicles and DPCs. Significance The results reveals a crucial role of PI3K/AKT/GSK-3β signaling pathway in ginsenoside Rb1-induced growth of hair follicles and DPCs.
Article
Introduction: Androgenetic alopecia (AGA) is a common, chronic hair loss disorder. Platelet-rich plasma (PRP) is a novel therapeutic tool for AGA. The objective of this study was to assess the clinical efficacy and safety of autologous activated PRP injections in AGA. Methods: Twenty-four AGA patients were enrolled in the study. All the patients received 4 PRP treatments at baseline (T1), 3 weeks (T2), 6 weeks (T3), and at 14 weeks (T5). We evaluated hair density (hairs/cm2) at 6 time points (T1-T3, T4 [9 weeks], T5, and T6 [7 months]) and patient satisfaction was assessed at T6 with a patient satisfaction questionnaire. Hair count (hairs/0.48 cm2) was assessed using dermoscopic photographs and hair density (hairs/cm2) was calculated accordingly. Results: Twenty-three men and one woman were included with baseline hair density of 102.25 ± 18.463. Hair density significantly increased at all time points with p < 0.001 compared to the baseline. Patients were satisfied with a mean result rating of 72.92 on a linear analogue scale of 0-100. Other than mild pain felt during injections, no remarkable adverse effects were noted. Conclusions: PRP injections may have a positive therapeutic effect on AGA without major side effects.
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Houttuynia cordata (HC) is a traditional oriental herbal medicinal plant widely used as a component of complex prescriptions in Asia for alopecia treatment. The effect of HC on hair growth and its underlying mechanism, however, have not been demonstrated or clarified. In this study, we investigated the hair growth promoting effect of HC in cultured human dermal papilla cells (hDPCs). HC extract was found to stimulate the proliferation of hDPCs and this stimulation might be in part a consequence of activated cellular energy metabolism, because treatment of HC extract increased the generation of nicotinamide adenine dinucleotide (NADH) and ATP through increasing the mitochondrial membrane potential (ΔΨ). In the context of cell cycle, HC extract increased the expression of CDK4 and decreased the expression of CCNA2 and CCNB1, implying that HC extract might induce G1 phase progression of DPCs which resulted in enhanced proliferation. HC extract increased the expression of Bcl2 essential for maintaining hair follicle anagen stage and cell survival. On the contrary, the expression of p16 and p21 was down-regulated by HC extract. In addition, HC extract enhanced the secretion of platelet-derived growth factor (PDGF)-aa and vascular endothelial growth factor (VEGF) and induced phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Furthermore, HC extract prolonged anagen stage in organ cultured human hair follicles. Our data strongly suggest that HC extract could support hair growth by stimulating proliferation of DPCs and elongating anagen stage, resulted from enhanced cellular energy metabolism and modulation of gene expression related to cell cycle, apoptosis, and growth factors. Graphical Abstract Fullsize Image
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The efficacy of minoxidil (MXD) ethanolic solutions (1%‐5% w/v) in the treatment of androgenetic alopecia is limited by adverse reactions. The toxicological effects of repeated topical applications of escalating dose (0.035%‐3.5% w/v) and of single and twice daily doses (3.5% w/v) of a novel hydroxypropyl‐β‐cyclodextrin MXD GEL formulation (MXD/HP‐β‐CD) and a MXD solution were investigated in male rats. The cardiovascular effects were evaluated by telemetric monitoring of ECG and arterial pressure in free‐moving rats. Ultrasonographic evaluation of cardiac morphology and function, and histopathological and biochemical analysis of the tissues, were performed. A pharmacovigilance investigation was undertaken using the EudraVigilance database for the evaluation of the potential cancer‐related effects of topical MXD. Following the application of repeated escalating doses of MXD solution, cardiac hypertrophy, hypotension, enhanced serum natriuretic peptides and K+‐ion levels, serum liver biomarkers, and histological lesions including renal cancer were observed. In addition, the administration of a twice daily dose of MXD solution, at SF rat vs human = 311, caused reductions in the systolic, diastolic, and mean blood pressure of the rats (−30.76 ± 3%, −28.84 ± 4%, and −30.66 ± 5%, respectively, vs the baseline; t test P < .05). These effects were not reversible following washout of the MXD solution. Retrospective investigation showed 32 cases of cancer associated with the use of topical MXD in humans. The rats treated with MXD HP‐β‐CD were less severely affected. MXD causes proliferative adverse effects. The MXD HP‐β‐CD inclusion complex reduces these adverse effects.
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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.
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Gray hair is a visible sign of tissue degeneration during aging. Graying is attributed to dysfunction of melanocyte stem cells (McSCs) that results in depletion of their melanin‐producing progeny. This non‐lethal phenotype makes the hair follicle and its pigment system an attractive model for investigating mechanisms that contribute to tissue aging as well as therapeutic strategies to combat this process. One potential combination therapeutic is RT1640, which is comprised of two drugs that are known to stimulate hair growth (cyclosporine A (CsA) and minoxidil), along with RT175, a non‐immunosuppressive immunophilin ligand that is implicated in tissue regeneration. Using the ionizing radiation‐induced acute mouse model of hair graying, we demonstrate that RT1640, over CsA alone, promotes regeneration of the hair pigment system during and following treatment. In non‐irradiated mice, RT1640 is also physiologically active and successfully speeds hair growth and expands the McSC pool. It appears that this effect relies on the combined activities of the three drugs within RT1640 to simultaneously activate hair growth and McSCs as RT175 alone was insufficient to induce hair cycling in vivo, yet sufficient to drive the upregulation of the melanogenic program in vitro. This study sets the stage for further investigation into RT1640 and its components in McSC biology and, ultimately, melanocyte hypopigmentary disorders associated with disease and aging.
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Introduction Mini-invasive therapies based on autologous non-activated Platelet-Rich Plasma (ANA-PRP), Low-Level Laser Therapy (LLL-T), and Micro-Needling Technique (MN-T) used in combining for hair re-growth need to be standardized. Objectives The work aims to show in vivo outcomes resulted from retrospective case-series study in which ANA-PRP + MN-T + LLL-T were used in combined in patients affected by Androgenic alopecia. Methods 23 patients were treated, of which 13 males were classified in stage I - V by the Norwood–Hamilton scale, and 10 females were classified in stage I - III by the Ludwig scale. Assessment of hair re-growth was evaluated with photography, physician’s and patient’s global assessment scale, and standardized phototrichograms during a follow-up: T0 - baseline, T1 - 12 weeks, T2 - 23 weeks, T3 - 44 weeks, T4 - 58 weeks. Results Interesting outcomes represented by a hair density increase of 81 ± 5 hairs/cm² and 57 ± 7 hairs/cm² respectively at T1 and T2 compared with baseline (173 ± 5 hairs/cm² at T1 and 149 ± 9 hairs/cm² at T2 versus 92 ± 2 hairs/cm² at baseline) were observed using computerized trichograms. Conclusions The effect of the combined use of MN-T, LLL-T, and ANA-PRP has been demonstrated.
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Hair loss is becoming increasingly prevalent as dietary and living habits change. The search for natural products to limit hair loss has led to tapping into traditional cosmetic knowledge. We studied three plants of the Polynesian cosmetopoeia, Bidens pilosa, Calophyllum inophyllum and Fagraea berteroana, to determine their ability to promote hair growth. Their chemical content was characterized by liquid chromatography coupled to mass spectrometry (LC-MS). Their proliferative activity on dermal papilla cells (DPCs) was assessed via MTT assay and molecular targets were evaluated by RT-qPCR analysis of seven factors involved in the modulation of the hair cycle, CCND1, LEF1, DKK1, WNT5A PPARD, TGFΒ1, PPARD and RSPO2. Our results show that our extracts significantly increased proliferation of dermal papilla cells. Furthermore, LC-MS/MS analysis revealed a diversity of molecules, flavonoids, iridoids and organic acids, some known for hair-inducing properties. Finally, specific extracts and fractions of all three plants either upregulated CCND1, LEF1 and PPARD involved in stimulating hair follicle proliferation and/or lowered the gene expression levels of hair growth inhibiting factors, DKK1 and TGFB1. Our findings suggest that extracts from B. pilosa, C. inophyllum and F. berteroana are interesting candidates to stimulate hair growth.
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Objectives Para rubber (Hevea brasiliensis (Willd. ex A. Juss.) Müll. Arg.)) is the important crop of the word. It has been vastly used in biomedical products. However, its pharmacologically application besides the latex is sparely to be explored especially the seed. Cellular biological activities of the standardized para rubber seed oil for hair loss treatment were therefore assessed. Methods Para rubber seed oil was prepared and standardized using GC/MS on the basis of its pharmacologically active fatty acids. The oil was safety assessed in human dermal papilla and DU‐145 human prostate carcinoma. Cellular antioxidant activity was determined as well as proliferation stimulating efficacy and inhibitory effect against 5α‐reductase. Results Oleic acid, fatty acid of cutaneous benefits, was majorly detected in the oil and followed by linoleic, palmitic, and stearic acids. The standardized para rubber seed oil was proved to be safe on human follicle dermal papilla and DU‐145 human prostate carcinoma at the concentration of 0.1‐50 and 0.1‐100 µg/mL, respectively. The standardized para rubber seed oil stimulated the cell proliferation and posed cellular antioxidant activity in human dermal papilla at a comparable potency to minoxidil, dutasteride and vitamin C at the same tested concentration. In addition, the standardized para rubber seed oil inhibited 5α‐reductase as examined in DU‐145 human prostate carcinoma, although at a lesser degree than the standards at the same tested concentration. Conclusions The standardized para rubber seed oil is evidenced as the safe and efficient bio‐oil to be used for hair growth stimulating or reduce/suppress hair loss treatment.
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Coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was declared a pandemic by the World Health Organization, and COVID‐19 continues to have a major impact on society. Numerous studies have reported impaired health sequelae after COVID‐19 recovery, one of which is hair loss. Individuals with hair loss experience a substantial mental burden, which potentially hinders their social life. However, few studies have systematically analyzed the details including hair loss. Therefore, we conducted a narrative review using PubMed on the frequency, associated comorbidities, disease characteristics, and treatment of hair loss after SARS‐CoV‐2 infection (HLASCI). Two search strings were used to identify 28 articles. Of note, most of the literature identified on COVID‐19 sequelae reported an emergence/occurrence of hair loss. HLASCI is speculated to be composed of a heterogeneous population, with the onset or exacerbation of telogen effluvium (TE), anagen effluvium, androgenetic alopecia (AGA), and alopecia areata (AA) reported as possible underlying mechanisms. Among these, acute TE is thought to be the primary cause of HLASCI, with COVID‐19 treatment and TE improvement being considered crucial for HLASCI management. An association between COVID‐19 and AA exacerbation has also been implicated with still insufficient evidence. Spontaneous recovery of TE can be expected once infection reduces; however, faster improvement in symptoms is expected to reduce the mental and social burden of patients. An additional search string identified 11 articles about TE treatment which suggested that the use of minoxidil may be beneficial. Topical minoxidil has been widely used for AGA patients, who have been speculated to exhibit poor resistance to SARS‐CoV‐2. Topical minoxidil may provide relief from HLASCI, but future clinical research is warranted to confirm this observation.
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Hair loss is a distressing condition that may not be life-threatening but has an indisputable impact on psychological well-being of an individual. African plant resources have a great potential for use in hair growth promotion. Here, the effect of tara tannin from tara (Caesalpinia spinosa) pods on hair growth promotion was investigated in vitro using hair follicle dermal papilla cells (HFDPC). The noncytotoxic concentration of tara tannin was determined by subjecting HFDPCs to cytotoxicity assay. Then, ATP production was evaluated and quantitative polymerase chain reaction (qPCR) of hair growth promotion molecular markers was performed to determine the promotion effect on hair growth. Results showed that 5 µM tara tannin stimulated HFPDC proliferation, accompanied by an increase in ATP production. Fluorescent staining revealed an increase in ß-catenin in tara-tannin-treated cells. QPCR results confirmed that 5 µM tara tannin upregulated the expression of ß-catenin (CTNBB), alkaline phosphatase (tissue-nonspecific isozyme) (ALPL), neural cell adhesion molecule 1 (NCAM1), and fibroblast growth factor 1 (FGF1) in HFDPCs. These genes’ expression was upregulated in dermal papilla during the anagen phase of the hair cycle. DNA microarray analysis of tara-tannin-treated pigment cell B16F10 cells (72 h) revealed that cell cycle was one of the most significant signaling pathways modulated. Cell cycle analysis showed that cells were mostly in the G1 phase, consistent with HFDPCs during hair morphogenesis. The results of this study indicated that tara tannin may be used as treatment for alopecia by promoting hair growth.
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Diffuse alopecia wields a significant psychosocial burden by virtue of its clinical presentation and visibility. Patterned alopecia is an umbrella term with the focus point being androgen-mediated alopecias - androgenetic alopecia/male pattern baldness/male androgenetic alopecia and female pattern hair loss/female androgenetic alopecia, both of which have a genetic susceptibility that alters the follicular sensitivity to circulating androgens. Diffuse alopecia affects nearly half the population based on weighted averages. It may present with hair shedding and hair thinning (miniaturization) or a combination. With the female variant, the role of androgens is not fully delineated; hence, the term female pattern hair loss which has replaced prior nomenclature. Managing patterned hair loss has seen a sea change in the last decade, moving well beyond the FDA-approved modalities - topical minoxidil and oral finasteride. Through this short review, the authors have attempted to condense existing information into a ready reference.
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Background: Enhancing blood flow and cell proliferation in the hair dermis is critical for treating hair loss. This study was designed to aid the development of alternative and effective solutions to overcome alopecia. Specifically, we examined the effects of Morus alba. L root extract (MARE, which has been used in traditional medicine as a stimulant for hair proliferation) on dermal fibroblasts and other cell types found in the epidermis. Methods: We first optimized the concentration of MARE that could be used to treat human dermal fibroblasts (HDFs) without causing cytotoxicity. After optimization, we focused on the effect of MARE on HDFs since these cells secrete paracrine factors related to cell proliferation and angiogenesis that affect hair growth. Conditioned medium (CM) derived from MARE-treated HDFs (MARE HDF-CM) was used to treat human umbilical vein endothelial cells (HUVECs) and hair follicle dermal papilla cells (HFDPCs). Results: Concentrations of MARE up to 20 wt% increased the expression of proliferative and anti-apoptotic genes in HDFs. MARE HDF-CM significantly improved the tubular structure formation and migration capacity of HUVECs. Additionally, MARE HDF-CM treatment upregulated the expression of hair growth-related genes in HFDPCs. CM collected from MARE-treated HDFs promoted the proliferation of HFDPCs and the secretion of angiogenic paracrine factors from these cells. Conclusion: Since it can stimulate the secretion of pro-proliferative and pro-angiogenic paracrine factors from HDFs, MARE has therapeutic potential as a hair loss preventative.
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Alopecia is defined as hair loss in a part of the head due to various causes, such as drugs, stress and autoimmune disorders. Various therapeutic agents have been suggested depending on the cause of the condition and patient sex, and age. Minoxidil (MXD) is commonly used topically to treat alopecia, but its low absorption rate limits widespread use. To overcome the low absorption, we suggest microneedles (MNs) as controlled drug delivery systems that release MXD. We used hyaluronic acid (HA) to construct MN, as it is biocompatible and safe. We examined the effect of HA on the hair dermal papilla (HDP) cells that control the development of hair follicles. HA enhanced proliferation, migration, and aggregation of HDP cell by increasing cell-cell adhesion and decreasing cell substratum. These effects were mediated by the cluster of differentiation (CD)-44 and phosphorylation of serine-threonine kinase (Akt). In chemotherapy-induced alopecia mice, topical application of HA tended to decrease chemotherapy-induced hair loss. Although the amount of MXD administered by HA-MNs was 10% of topical treatment, the MXD-containing HA-MNs (MXD-HA-MNs) showed better effects on the growth of hair than topical application of MXD. In summary, our results demonstrated that HA reduces hair loss in alopecia mice, and that delivery of MXD and HA using MXD-HA-MNs maximizes therapeutic effects and minimize the side effects of MXD for the treatment of alopecia. Statement of significance : (1) Significance, This work reports a new approach for treatment of alopecia using a dissolving microneedle (MN) prepared using hyaluronic acid (HA). The HA provided a better environment for cellular functions in the hair dermal papilla cells. The HA-MNs containing minoxidil (MXD) exhibited a significant reduction of hair loss, although amount of MXD contained in them was only 10% of topically applied MXD., (2) Scientific impact, This is the first report demonstrating the direct anti-alopecia effects of HA administrated in a transdermal route and the feasibility of novel therapeutics using MXD-containing HA-MNs. We believe that our work will excite interdisciplinary readers of Acta Biomaterialia, those who are interested in the natural polymers, drug delivery, and alopecia.
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Background: Photobiomodulation is a promising therapy for hair loss with negligible side effects. However, the reported effects of photobiomodulation therapy for hair loss are inconsistent. Objective: To assess the curative effect of photobiomodulation therapy for the treatment of hair loss. Methods: A systematic review of self-controlled studies and randomized controlled trials was conducted. ScienceDirect, PubMed, and Wiley Online Library were searched from the earliest date to May 30, 2021. Results: Thirty-six studies (966 patients) were included. Two to 4 meta-analyses with different indices were performed separately on 4 groups of studies to test the effectiveness of the following hair loss treatments: ultraviolet light for alopecia areata (AA), red light for androgenetic alopecia (AGA), infrared light for AA, and infrared light for AGA. All meta-analyses showed that treatments were superior to control (p < .05). Conclusion: The meta-analyses strongly suggested that photobiomodulation therapies with ultraviolet and infrared light were effective for treating AA, and photobiomodulation therapies with red light and infrared light were effective for treating AGA.
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Sweet potato shochu oil is one of the by-products of sweet potato shochu production. We investigated the functionality and industrial use of shochu oil as a food-derived raw material. Because of the increased incidence of self-consciousness in people owing to thinning hair, in this study, we examined the hair growth-inducing effects of shochu oil. Minoxidil, the only topical medication approved for hair growth treatment in Japan, was used as a control for the evaluation of hair growth-promoting activity of shochu oil. Human follicle dermal papilla cells treated with shochu oil showed upregulated expression of vascular endothelial growth factor in a concentration-dependent manner, indicating that shochu oil induced the activation of the hair growth cycle. In vivo, epidermal treatment with shochu oil also promoted hair growth in C3H mice. More than 35 components were detected in shochu oil via gas chromatography–mass spectrometry. The main components, accounting for 98.5% of shochu oil, were as follows, in order of decreasing concentration: ethyl palmitate, ethyl linoleate, ethyl oleate, ethyl stearate, ethyl caprate, ethyl laurate, ethyl myristate, and ethyl α-linolenate. Among these, ethyl palmitate, ethyl linoleate, and ethyl α-linolenate promoted hair growth in C3H mice. These results indicate that shochu oil can be used as a hair restorer. To the best of our knowledge, this study is the first to demonstrate the hair growth-promoting activity of shochu oil.
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The Ras oncogene regulates cellular proliferation, differentiation, transformation, and survival through multiple downstream signals. Ras signals through its effector phosphoinositide 3 (PI3) kinase to the Pak protein kinase (p65pak), but the steps from Ras to Pak remain to be elucidated. PI3 kinase can stimulate the small G protein, Rac, a direct activator of Pak, as well as the Akt proto-oncogene, a serine-threonine protein kinase. We found that activated Akt stimulated Pak, whereas a dominant negative Akt inhibited Ras activation of Pak in transfection assays. Akt stimulation of Pak was not inhibited by dominant negative mutants of either Rac or Cdc42 suggesting that Akt activated Pak through a GTPase-independent mechanism. We also developed a novel cell-free system to study Ras activation of Pak. In this system Ras activated Pak only in the presence of a crude cell extract but failed to activate Pak when Akt was immunodepleted from the extract. Akt protects cells from apoptosis through phosphorylation of downstream targets such as the Bcl-2 family member, Bad. We found that activated Pak decreased apoptosis and increased phosphorylation of Bad, whereas dominant negative Pak increased apoptosis and decreased phosphorylation of Bad. These studies define a new oncogene-mediated cell survival signal.
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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-beta 1 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.
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Keratinocyte apoptosis is a central element in the regulation of hair follicle regression (catagen), yet the exact location and the control of follicular keratinocyte apoptosis remain obscure. To generate an "apoptomap" of the hair follicle, we have studied selected apoptosis-associated parameters in the C57BL/6 mouse model for hair research during normal and pharmacologically manipulated, pathological catagen development. As assessed by terminal deoxynucleotide transferase dUTP fluorescein nick end-labeling (TUNEL) stain, apoptotic cells not only appeared in the regressing proximal follicle epithelium but, surprisingly, were also seen in the central inner root sheath, in the bulge/isthmus region, and in the secondary germ, but never in the dermal papilla. These apoptosis hot spots during catagen development correlated largely with a down-regulation of the Bcl-2/Bax ratio but only poorly with the expression patterns of interleukin-1beta converting enzyme, p55TNFR, and Fas/Apo-1 immunoreactivity. Instead, a higher correlation was found with p75NTR expression. During cyclophosphamide-induced follicle dystrophy and alopecia, massive keratinocyte apoptosis occurred in the entire proximal hair bulb, except in the dermal papilla, despite a strong up-regulation of Bax and p75NTR immunoreactivity. Selected receptors of the tumor necrosis factor/nerve growth factor family and members of the Bcl-2 family may also play a key role in the control of follicular keratinocyte apoptosis in situ.
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The Ras oncogene regulates cellular proliferation, differentiation, transformation, and survival through multiple downstream signals. Ras signals through its effector phosphoinositide 3 (PI3) kinase to the Pak protein kinase (p65(pak)), but the steps from Ras to Pak remain to be elucidated. PI3 kinase can stimulate the small G protein, Rac, a direct activator of Pak, as well as the Akt proto-oncogene, a serine-threonine protein kinase. We found that activated Akt stimulated Pak, whereas a dominant negative Akt inhibited Ras activation of Pak in transfection assays. Akt stimulation of Pak was not inhibited by dominant negative mutants of either Rac or Cdc42 suggesting that Akt activated Pak through a GTPase-independent mechanism. We also developed a novel cell-free system to study Ras activation of Pak. In this system Ras activated Pak only in the presence of a crude cell extract but failed to activate Pak when Akt was immunodepleted from the extract. Akt protects cells from apoptosis through phosphorylation of downstream targets such as the Bcl-2 family member, Bad. We found that activated Pak decreased apoptosis and increased phosphorylation of Bad, whereas dominant negative Pak increased apoptosis and decreased phosphorylation of Bad. These studies define a new oncogene-mediated cell survival signal.
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One ubiquitous and very important signaling molecule inside cells is the phosphorylated lipid PtdIns(3,4,5)P. The biochemical pathways that deliver the signals from this lipid contain kinases (which add phosphates to other molecules) with regulatory properties that have seemed impossibly complex and diverse. In his commentary, Downward describes how new results reported in this week's issue of Science ([ Pullen et al .][1] and [ Stephens et al .][2]) and in Current Biology reveal that two of these kinases are actually regulated similarly, lending some welcome common themes to these pathways. [1]: http://www.sciencemag.org/cgi/content/short/279/5351/707 [2]: http://www.sciencemag.org/cgi/content/short/279/5351/710
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Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.
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AKT1 (c-AKT, PKBα) is the cellular homolog of the protein-serine/threonine kinase oncogene, v-akt. AKT1 is activated through the insulin and platelet-derived growth factor signaling pathways in transfected fibroblasts, but little is known about the regulation of endogenous AKT1 in tumor cells. AKT1 levels were higher in a panel of human breast carcinoma cell lines than in breast epithelial cells, particularly those with higher HER2 expression. AKT1 activity was increased by either estradiol or IGF-I in estrogen-dependent MCF-7 cells, and both factors acted synergistically to increase AKT1 activity and promote cell proliferation. Stimulation of AKT1 activity by estradiol and IGF-I was blocked by the antiestrogen ICI 182780 and by the phosphatidylinositol-3-kinase inhibitor wortmannin. MCF-7 cells transfected with AKT1 exhibited partial estrogen- and IGF-I-independent growth and were more responsive to the combination of IGF-I and estradiol. AKT1-overexpressing MCF-7 cells were less sensitive to apoptosis induced by wortmannin. These findings suggest that AKT1 is a downstream effector of estrogen- and IGF-I-dependent proliferation and survival in hormone-responsive MCF-7 breast carcinoma cells.
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Minoxidil sulfate and pinacidil are K channel openers and are considered to promote hair growth. However, there have been no studies on the single channel current of isolated cells from hair follicles. Therefore, we characterized the single K channel current of outer root sheath cells and dermal papilla cells and the effect of K channel openers on K currents by patch clamp. We also carried out86Rb efflux studies to observe macroscopic K channel currents. In physiological saline, these two cells showed two types of K channels, large and small conductance Ca2+-activated K channels, both intact cell-attached and excised inside-out patches. In symmetrical 150 mM K solution, unitary conductances were 246 and 70 pS, respectively. Intracellular ATP (up to 5 mM) or glibenclamide (20 nM), a specific ATP-sensitive K channel blocker, did not block these channels. Minoxidil sulfate (5 μg/ml) or pinacidil (10 μM) did not open these two types of K channels or increase86Rb efflux. These results suggest that minoxidil sulfate or pinacidil did not activate K channel current in hair follicles, and that the drug effect on hair growth might be mediated by other mechanisms such as increased blood flow.
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The mechanism by which minoxidil, an adenosine-triphosphate-sensitive potassium channel opener, induces hypertrichosis remains to be elucidated. Minoxidil has been reported to stimulate the production of vascular endothelial growth factor, a possible promoter of hair growth, in cultured dermal papilla cells. The mechanism of production of vascular endothelial growth factor remains unclear, however. We hypothesize that adenosine serves as a mediator of vascular endothelial growth factor production. Minoxidil-induced increases in levels of intracellular Ca(2+) and vascular endothelial growth factor production in cultured dermal papilla cells were found to be inhibited by 8-sulfophenyl theophylline, a specific antagonist for adenosine receptors, suggesting that dermal papilla cells possess adenosine receptors and sulfonylurea receptors, the latter of which is a well-known target receptor for adenosine-triphosphate-sensitive potassium channel openers. The expression of sulfonylurea receptor 2B and of the adenosine A1, A2A, and A2B receptors was detected in dermal papilla cells by means of reverse transcription polymerase chain reaction analysis. In order to determine which of the adenosine receptor subtypes contribute to minoxidil-induced hair growth, the effects of subtype-specific antagonists for adenosine receptors were investigated. Significant inhibition in increase in intracellular calcium level by minoxidil or adenosine was observed as the result of pretreatment with 8-cyclopentyl-1,3-dipropylxanthine, an antagonist for adenosine A1 receptor, but not by 3,7-dimethyl-1-propargyl-xanthine, an antagonist for adenosine A2 receptor, whereas vascular endothelial growth factor production was blocked by both adenosine A1 and A2 receptor antagonists. These results indicate that the effect of minoxidil is mediated by adenosine, which triggers intracellular signal transduction via both adenosine A1 and A2 receptors, and that the expression of sulfonylurea receptor 2B in dermal papilla cells might play a role in the production of adenosine.
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Minoxidil in combination with propranolol and diuretics controlled the blood-pressure in a group of hypertensive patients who were resistant to treatment with large doses of standard drugs. The main problem was fluid retention but subjective side-effects were fewer than in a comparable group on other drugs.
Article
The opening of intracellular potassium channels has been suggested as a mechanism regulating hair growth. Enhancing the flux of potassium ions is a mechanism shared by several structurally diverse antihypertensive agents including minoxidil sulfate (the active metabolite of minoxidil), pinacidil, P-1075 (a potent pinacidil analog), RP-49,356, diazoxide, cromakalim, and nicorandil. Of these drugs, minoxidil, pinacidil, and diazoxide have been reported to elicit hypertrichosis in humans. This potassium channel hypothesis was examined by testing these drugs for effects on hair growth both in vitro and in vivo. For the in vitro studies, mouse vibrissae follicles were cultured for 3 d with drug and the effects on hair growth were measured by metabolic labeling. All drugs, except diazoxide, enhanced cysteine incorporation into the hair shafts of the cultured vibrissae. Diazoxide was poorly soluble and thus was tested only at low doses. Minoxidil, P-1075, cromakalim, and RP-49,356 were also evaluated in vivo by measuring hair growth effects in balding stumptail macaque monkeys. The drugs were administered topically to defined sites on balding scalps once per day for 4-5 months and the amount of hair grown was determined by monthly measurements of shaved hair weight. Three of the drugs produced significant increases in hair weight whereas, the RP-49,356 had no effect. These studies provide correlative evidence that the opening of potassium channels is an important regulatory mechanism for hair growth. This provides the impetus for further studies on this potentially important mechanism affecting hair biology.
Article
Topical minoxidil is a trichogenic agent that stimulates the hair follicle via the vasoactive metabolite minoxidil sulfate without any evidence of antiandrogen activity or an effect on the immune system. Less than 5% of the applied dose is absorbed. The therapeutic effect on hair regrowth is demonstrated for androgenetic alopecia in males and females, by a computer-assisted image analysis counting technique of nonvellus hairs from a photographic print. Patients with severe alopecia areata respond poorly to topical minoxidil treatment. The most common adverse reactions are limited to irritant and allergic contact dermatitis on the scalp. The use of retinoic acid with topical minoxidil has been disappointing relative to the increase in systemic exposure. The value of topical minoxidil as an adjunct for the hair transplant procedure and its effect on hair loss from chemotherapy are being evaluated.
Article
To explore an easily accessible and reproducible model for examining the effect of minoxidil on hair growth, we studied the effect of minoxidil on the natural hair cycles of rats from birth to 80 days of age. During the 1st and 2nd postnatal cycles, the hair follicles grew very rapidly and the size of anagen follicles were markedly enlarged. In the 3rd cycle (50 days to approximately 100 days of age), duration of the telogen phase lasted approximately 20 days. Topical minoxidil, 1%, 3%, or 5% solution, applied on the backs of the rats from 23 days (weaning) to 80 days, induced a remarkable shortening of the telogen phase in the 3rd cycle. Although the dose-dependent response was very minimal, rats treated with 3% or 5% minoxidil showed similar effects in the 4th cycle. Minoxidil, however, did not induce prolongation of the anagen phase, but increased the rate of DNA synthesis in the anagen bulb during the 2nd and 3rd cycles. These results suggest that minoxidil specifically stimulates the secondary germ of the telogen follicles, resulting in rapid progression to anagen follicles.
Article
Minoxidil, a potent vasodilator, stimulates the growth of terminal hair from vellus or miniaturized follicles in balding scalp. To study minoxidil's action on isolated follicles we developed and validated an organ culture system using mouse whisker follicles. Control follicles cultured without minoxidil showed macroscopic changes including kinking of the hair shafts and bending of the follicles. Necrosis was evident in the differentiating epithelial elements forming the cuticle, cortex, and inner root sheath. These abnormalities were eliminated or greatly reduced in minoxidil-treated follicles. The morphology of these follicles was consistent with the production of new hair during culture. Direct measurement demonstrated that minoxidil-treated follicles grew significantly longer than control follicles during the 3-d culture. Minoxidil increased the incorporation of radiolabeled cysteine and glycine in follicles compared with control treatment. Doses of minoxidil up to 1 mM caused increased cysteine incorporation, while higher doses were inhibitory. Experiments with labeled thymidine indicated that minoxidil induced proliferation of hair epithelial cells near the base of the follicle. Autoradiography also showed that cysteine accumulated in the keratogenous zone above the dermal papilla. These studies demonstrate that organ cultured follicles are suitable for determining minoxidil's mechanism of action and may be useful for studying other aspects of hair biology. The results also show that minoxidil's effect on hair follicles is direct. This suggests that minoxidil's action in vivo includes more than just increasing blood flow to hair follicles.
Article
The mechanism by which minoxidil, whether given orally or applied topically, stimulates hair growth remains undetermined. Possible indirect drug action, such as vasodilatation and increased blood flow to the dermal papilla, or possible local irritation related to minoxidil or to one or more components of the vehicle used for topical application has been suggested. Possible sites of direct drug action include either the dermal papilla of the follicle or hair matrix cells or possibly both. Morphometric studies of control scalp biopsies taken from young male patients with androgenetic alopecia reveal that the primary morphologic event in androgenetic alopecia is miniaturization of terminal hair follicles. Shortening and diminution of follicle size is undoubtedly accompanied by shortening of the hair growth cycle (decreased anagen time). Morphometric evaluation of scalp biopsies of patients receiving topical minoxidil in a vehicle composed of propylene glycol, water and ethanol has revealed growth of larger normally formed follicles when compared with pretreatment biopsies from the same individual. There has been no suggestion in any morphologic studies of minoxidil-treated patients for development of new follicles (follicular neogenesis). Because the dermal papilla of the hair follicle apparently controls both growth and differentiation of hair matrix cells and because there are no observable dysplastic or atypical changes in follicular germinal epithelium during or after application of topical minoxidil, it is concluded that the most probable site for the action of minoxidil is on the specialized mesenchymal cells of the follicular dermal papilla.
Article
Dermal papillae were isolated from human hair follicles and primary cell cultures were established from the papilla explants. The cultured papilla cells spread slowly, initially as a monolayer, and eventually formed multi-layered parallel arrays of fibroblast-like cells. At the edges of expanding colonies the cells were large and flattened and showed a tendency to form clumps. The behaviour of human dermal papilla cells in culture is very similar to that reported in cultures of papilla cells from rat vibrissa follicles.
Article
Mammalian hairs are formed by differentiation and keratinization of cells produced in the epidermal matrix (Figs 3, 4). Using the rodent vibrissa follicle as a model, transplantation studies have shown that the dermal papilla, a discrete population of specialized fibroblasts, is of prime importance in the growth of hair. Papillae induce hair growth when implanted into follicles and can interact with skin epidermis to form new hair follicles. When grown in culture, papilla cells display singular morphological and behavioural characteristics compared with connective tissue cells from other skin sources. We report here that serially cultured adult papilla cells can induce the growth of hair when implanted into follicles which otherwise would not grow hairs. This finding presents an opportunity to characterize properties distinguishing the papilla cell population from other skin fibroblasts, and, more specifically, those which control hair growth. The eventual application of this work to human hair replacement techniques can also be envisaged.
Article
A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
Article
The hair follicle undergoes a cycle of growing, regressing, and resting phases (anagen, catagen, telogen, respectively). As the follicle enters catagen, the cells of the lower, cycling portion undergo a process of controlled cell death (apoptosis). Understanding the mechanism of apoptosis in the follicle should give insight into one of the control steps of hair cycling. In this study we sought the expression of bcl-2, a protooncogene associated with apoptosis control, in the cycling follicle of the adult mouse. Using a monoclonal antibody to the mouse protein we immunolocalized bcl-2 gene product in the cycling pelage follicle of the C57/B6 adult mouse. The protein was expressed in the follicular papilla (a non-cycling portion of the follicle) throughout the cycle-including telogen. The cycling follicular epithelium, however, showed positive antibody staining in anagen, which decreased in catagen and disappeared in telogen. In anagen the cells of the bulb, bulge, and basal layer of the outer root sheath expressed the bcl-2 protein. Understanding the action of this apoptosis-inhibiting molecule should serve to elucidate the dynamics of follicular cycling.
Article
We have conducted studies using primary mouse epidermal keratinocyte and whole hair follicle cultures to investigate the mechanism of the hypertrichotic activity of potassium channel openers. In a time course study, the extent of stimulation of epidermal keratinocyte DNA synthesis by minoxidil increased as the rate of DNA synthesis in control cultures declined. Minoxidil stimulation of DNA synthesis in 7-day cultures required prolonged (> 1 day) exposure to the agent. Pinacidil and diazoxide also stimulated DNA synthesis in mouse epidermal keratinocyte cultures. In addition, minoxidil, pinacidil, diazoxide, and cromakalim stimulated DNA synthesis in whole-organ cultures of mouse hair follicles. These results suggest that potassium channel openers retard the loss of proliferative activity of differentiating keratinocytes and support the hypothesis that these agents stimulate hair growth through a direct effect on hair follicles.
Article
Evolutionarily conserved from yeast to man, mitogen-activated protein kinase (MAPK) pathways respond to a variety of disparate signals which induce differentiation, proliferation, or changes in intracellular enzyme regulation. Recent advances have identified two new mammalian MAPK relatives, JNK1 and p38, and the pathways which are responsible for their activation.
Article
There is considerable evidence to suggest that the opening of K+ channels plays an important role in stimulating mitogenesis. K+ channel blockers have been shown to inhibit mitogenesis in vitro, mitogens increase cytosolic membrane K+ channel permeability, K+ channel openers stimulate hair growth in vivo, and the Ras/Raf signal transduction pathway induces K+ channel activity. Paradoxically, however, K+ channel openers such as minoxidil have been reported in vitro not to modulate, or even to inhibit, mitogenesis in a range of cell types. Only untherapeutic concentrations have stimulated mitogenesis. These experiments, however, appear to have been carried out in the presence of aminoglycoside antibiotics, which inhibit potassium channel activity. We now report that in the absence of aminoglycoside antibiotics, minoxidil at 10 microg/ml (0.05 mM) causes a significant stimulation of proliferation of NIH 3T3 fibroblasts maintained over a 10-d period in 5% fetal calf serum-supplemented medium. Further, we show that in the presence of 100 microg streptomycin per ml, minoxidil at 10 microg/ml produces an initial inhibition of proliferation, which apparently confirms, in NIH 3T3 fibroblasts, that the inhibition of mitogenesis by minoxidil in the presence of streptomycin is an artifact. The potentiation of NIH 3T3 cell growth by minoxidil can be attributed to the opening of potassium channels, because the potassium channel blocker tolbutamide (5 mM) or combinations of the blockers tolbutamide (1 mM)/tetraethylammonium (2 mM) or glibenclamide (1 microM)/apamin (10 nM) block the minoxidil-induced stimulation of growth. We also demonstrate that minoxidil is able to significantly potentiate the mitogenic effects of both platelet-derived growth factor and insulin-like growth factor 1 on NIH 3T3 fibroblasts in the presence of CPSR-2 (a cytokine free serum substitute). Thus we have shown that minoxidil potentiates the mitogenic effects of fetal calf serum in vitro on NIH 3T3 fibroblasts by opening potassium channels and is also able to potentiate the mitogenic effects of the growth factors platelet-derived growth factor and insulin-like growth factor 1.
Article
Nearly all cell surface receptors utilize one or more of the mitogen-activated protein kinase cascades in their repertoire of signal transduction mechanisms. Recent advances in the study of such cascades include the cloning of genes encoding novel members of the cascades, further definition of the roles of the cascades in responses to extracellular signals, and examination of cross-talk between different cascades.
Article
The dermal papilla (DP) consists of a discrete population of specialized fibroblasts that are important in the morphogenesis of the hair follicle in the embryo and in the control of the hair growth cycle in the adult. This mitotically quiescent and long-lived cell population expresses gene products that promote cell survival such as Bcl-2, and thus normally might be protected from apoptosis. We investigated whether cultured DP fibroblasts are able to undergo apoptosis by treatment with the protein kinase inhibitor staurosporine. Involvement of the PKC signaling pathway in DP fibroblast survival/death was investigated by inhibition (staurosporine and Bisindolylmaleimide (Bis) treatment) or activation (TPA; 12-O-tetradecanoylphorbol-13-acetate treatment) of PKC and characterization of DP-expressed PKC isoforms by RT-PCR. We determined that cultured DP fibroblasts undergo apoptosis, in a dose-related manner, when treated with staurosporine but not when treated with Bis, an inhibitor with narrow PKC isoform specificity. TPA confers partial and transient resistance to staurosporine-induced DP apoptosis. Staurosporine and Bis each induced G1 arrest, whereas TPA treatment of cultured DP resulted in increased entry into S-phase. The differential responses to individual inhibitors and activators of PKC may be related to the multiple PKC isoforms that DP fibroblasts express. Flow cytometric analysis indicates that the mechanism of staurosporine-induced apoptosis may be through decrease of Bcl-2 in treated DP cells or through modulation of cell cycle regulators. Correlation between sensitivity to induction of apoptosis and proliferation suggests that dermal papilla cells may normally be protected from apoptosis in vivo by their mitotically quiescent state.
Article
Minoxidil is the most used drug with proved effects in the treatment of androgenetic alopecia (AGA), but little is known about its pharmacological activity and target cells in hair follicles. As AGA is characterized by follicle atrophy, accelerated hair cycles and hair fiber thinning, we postulated that keratinocyte proliferation/differentiation is affected and we tested Minoxidil's effects on those parameters. Normal human keratinocytes (NHK) of follicular or epidermal origin were cultured in the presence of Minoxidil (0, 0.1, 1, 10, 100, 1,000 microM) during 5-8 days in various media (high-/low-calcium content, with or without serum). Proliferation was assessed by mitochondrial dehydrogenase activity (XTT), BrdU incorporation, lysosome numeration (neutral red incorporation) and total protein dosage. Drug-induced cytotoxicity was measured by lactate dehydrogenase release in culture supernatant, and pro-differentiating effects were evaluated by relative involucrin expression (ELISA dosage). On this basis, we showed that Minoxidil had biphasic effects on the proliferation and differentiation of NHK: Minoxidil stimulated NHK proliferation at micromolar doses, while antiproliferative, pro-differentiative and partially cytotoxic effects were observed with millimolar concentrations. We can hypothesize that Minoxidil hypertrichotic activity in vivo is possibly mediated by the maintenance of proliferative potential in follicular keratinocytes precociously committed to differentiation.
Article
The hair follicle dermal papilla which controls hair growth, is characterized in the anagen phase by a highly developed vascular network. We have demonstrated in a previous study that the expression of an angiogenic growth factor called vascular endothelial growth factor (VEGF) mRNA varied during the hair cycle. VEGF mRNA is strongly expressed in dermal papilla cells (DPC) in the anagen phase, but during the catagen and telogen phases. VEGF mRNA is less strongly expressed. This involvement of VEGF during the hair cycle allowed us to determine whether VEGF mRNA expression by DPC was regulated by minoxidil. In addition, the effect of minoxidil on VEGF protein synthesis in both cell extracts and DPC-conditioned medium, was investigated immunoenzymatically. Both VEGF mRNA and protein were significantly elevated in treated DPC compared with controls. DPC incubated with increasing minoxidil concentrations (0.2, 2, 6, 12 and 24 mumol/L) induced a dose-dependent expression of VEGF mRNA. Quantification of transcripts showed that DPC stimulated with 24 mumol/L minoxidil express six times more VEGF mRNA than controls. Similarly, VEGF protein production increases in cell extracts and conditioned media following minoxidil stimulation. These studies strongly support the likely involvement of minoxidil in the development of dermal papilla vascularization via a stimulation of VEGF expression, and support the hypothesis that minoxidil has a physiological role in maintaining a good vascularization of hair follicles in androgenetic alopecia.
Article
By means of skin organ culture, some biological characteristics of hair follicle elongation were examined. When skin sections from 6-day-old C3H mice were cultured, spontaneous elongation of hair follicles was maintained. Without insulin, hair follicle elongation was poorly maintained irrespective of the presence of serum at 20%. Insulin could be replaced by IGF-I at 100 ng/ml. During in vitro elongation of hair follicles, bromodeoxyuridine was incorporated into germinal epithelial cells around dermal papillae. Skin sections from 4-week-old C3H mice did not show hair follicle elongation in complete medium. However, when 0.5 mM minoxidil was added to the medium, concentration dependent thickening and elongation of hair follicles was observed. In contrast, in vitro elongation of newborn pelage hair follicles was not enhanced by minoxidil. These results suggest that this system with the use of skin sections from 4-week-old C3H mice would be a potential in vitro model of human androgenic alopecia in which the anagen phase is suppressed but the suppression is partially released by minoxidil.
Mitogen-activated protein kinase pathways
  • Robinson