• Journal of Microbiology and Biotechnology
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• 제34권4호
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• pp.812-827
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• 2024

Phloroglucinol (PG) is one of the abundant isomeric benzenetriols in brown algae. Due to its polyphenolic structure, PG exhibits various biological activities. However, the impact of PG on anagen signaling and oxidative stress in human dermal papilla cells (HDPCs) is unknown. In this study, we investigated the therapeutic potential of PG for improving hair loss. A non-cytotoxic concentration of PG increased anagen-inductive genes and transcriptional activities of β-Catenin. Since several anagen-inductive genes are regulated by β-Catenin, further experiments were performed to elucidate the molecular mechanism by which PG upregulates anagen signaling. Various biochemical analyses revealed that PG upregulated β-Catenin signaling without affecting the expression of Wnt. In particular, PG elevated the phosphorylation of protein kinase B (AKT), leading to an increase in the inhibitory phosphorylation of glycogen synthase kinase 3 beta (GSK3β) at serine 9. Treatment with the selective phosphoinositide 3-kinase/AKT inhibitor, LY294002, restored the increased AKT/GSK3β/β-Catenin signaling and anagen-inductive proteins induced by PG. Moreover, conditioned medium from PG-treated HDPCs promoted the proliferation and migration of human epidermal keratinocytes via the AKT signaling pathway. Subsequently, we assessed the antioxidant activities of PG. PG ameliorated the elevated oxidative stress markers and improved the decreased anagen signaling in hydrogen peroxide (H₂O₂)-induced HDPCs. The senescence-associated β-galactosidase staining assay also demonstrated that the antioxidant abilities of PG effectively mitigated H₂O₂-induced senescence. Overall, these results indicate that PG potentially enhances anagen signaling and improves oxidative stress-induced cellular damage in HDPCs. Therefore, PG can be employed as a novel therapeutic component to ameliorate hair loss symptoms.

• 약학회지
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• 제47권1호
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• pp.14-19
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• 2003

The hair cycle consists of three phases, growth (anagen), involution (catagen) and quiescence (telogen) phases. In order to evaluate hair re-growth effect of herbal extracts mixture containing the 70％ ethanol extracts of Polygoni Multiflori Radix, Mori Cortex Radicis, Gingko Biloba Folium and Pine bud, we have examined the induction of the anagen phase and/or elongation of the anagen period using C3H mice. Morphological examination was done by Hattori' and Ogawa's method. Enzyme activities of ${\gamma}$-glutamyl transpeptidase (${\gamma}$-GT) and alkaline phosphatase (ALP) was detected by Bessey-Lovry-Brock's method. Enzyme activity as a biochemical marker of hair cycle was investigated in the third hair cycle period of C3H mice after depilation. 3％ Minoxidil treated group and herbal extract mixture treated group were shown 3 days earlier initiation of anagen than control group. In cycling mouse skin, ${\gamma}$-GT activity is pronounced during anagen and greatly diminished during telogen. Herbal extract mixture has shown promising hair re-growth effect on hair follicular cycles of C3H mice.

• Biomolecules & Therapeutics
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• 제29권6호
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• pp.643-649
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• 2021

Literature has revealed that the delta opioid receptor (DOR) exhibited diverse pharmacological effects on neuron and skin. In the present study, we have investigated whether the activation of DOR has hair-growth promotion effects. Compared with other opioid receptor, DOR was highly expressed in epidermal component of hair follicle in human and rodents. The expression of DOR was high in the anagen phase, but it was low in the catagen and telogen phases during mouse hair cycle. Topical application of UFP-512, a specific DOR agonist, significantly accelerated the induction of the anagen in C₃H mice. Topical application of UFP-512 also increased the hair length in hair organ cultures and promoted the proliferation and the migration of outer root sheath (ORS) cells. Similarly, pharmacological inhibition of DOR by naltrindole significantly inhibited the anagen transition process and decreased hair length in hair organ cultures. Thus, we further examined whether Wnt/β-catenin pathway was related to the effects of DOR on hair growth. We found that Wnt/β-catenin pathway was activated by UFP-512 and siRNA for β-catenin attenuated the UFP-512 induced proliferation and migration of ORS cells. Collectively, result established that DOR was involved in hair cycle regulation, and that DOR agonists such as UFP-512 should be developed for novel hair-loss treatment.

• Biomolecules & Therapeutics
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• 제29권2호
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• pp.211-219
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• 2021

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.

• Biomolecules & Therapeutics
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• 제29권5호
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• pp.545-550
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• 2021

Chemotherapy-induced alopecia and hair loss can be stressful in patients with cancer. The hair grows back, but sometimes the hair tends to stay thin. Therefore, understanding mechanisms regulating hair regeneration may improve the management of chemotherapy-induced alopecia. Previous studies have revealed that chemotherapeutic agents induce a hair follicle vascular injury. As hair growth is associated with micro-vessel regeneration, we postulated that the stimulation of angiogenesis might enhance hair regeneration. In particular, mice treated with 5-fluorouracil (5-FU) showed delayed anagen initiation and reduced capillary density when compared with untreated controls, suggesting that the retardation of anagen initiation by 5-FU treatment may be attributed to the loss of perifollicular micro-vessels. We investigated whether the ETS transcription factor ETV2 (aka ER71), critical for vascular development and regeneration, can promote angiogenesis and hair regrowth in a 5-FU-induced alopecia mouse model. Tie2-Cre; Etv2 conditional knockout (CKO) mice, which lack Etv2 in endothelial cells, presented similar hair regrowth rates as the control mice after depilation. Following 5-FU treatment, Tie2-Cre; Etv2 CKO mice revealed a significant reduction in capillary density, anagen induction, and hair restoration when compared with controls. Mice receiving lentiviral Etv2 injection after 5-FU treatment showed significantly improved anagen induction and hair regrowth. Two-photon laser scanning microscopy revealed that enforced Etv2 expression restored normal vessel morphology after 5-FU mediated vessel injury. Our data suggest that vessel regeneration strategies may improve hair regrowth after chemotherapeutic treatment.

• Biomolecules & Therapeutics
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• 제32권5호
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• pp.640-646
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• 2024

Hair growth cycles are mainly regulated by human dermal papilla cells (hDPCs) and human outer root sheath cells (hORSCs). Protecting hDPCs from excessive oxidative stress and hORSCs from glycogen phosphorylase (PYGL) is crucial to maintaining the hair growth phase, anagen. In this study, we developed a new PYGL inhibitor, hydroxytrimethylpyridinyl methylindolecarboxamide (HTPI) and assessed its potential to prevent hair loss. HTPI reduced oxidative damage, preventing cell death and restored decreased level of anagen marker ALP and its related genes induced by hydrogen peroxide in hDPCs. Moreover, HTPI inhibited glycogen degradation and induced cell survival under glucose starvation in hORSCs. In ex-vivo culture, HTPI significantly enhanced hair growth compared to the control with minoxidil showing comparable results. Overall, these findings suggest that HTPI has significant potential as a therapeutic agent for the prevention and treatment of hair loss.

• 대한약침학회지
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• 제18권4호
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• pp.20-25
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• 2015

Objectives: Recently, thread-embedding therapy (TET) has been widely applied in Korean medicine for cosmetic purposes such as reducing skin wrinkles. An inserted thread was reported to have induced continuous stimulation, followed by support for connective tissue regeneration. However, the potential role of TET in hair-growth has not yet been reported. Methods: We designed this study to evaluate whether TET has a hair-growth-promoting effect. C57 black 6 (C57BL/6) mice were divided into three groups: normal saline-treated, minoxidil-treated, and thread-embedded groups. Normal saline or 5% minoxidil was topically sprayed on the dorsal skin of the mice once a day for 16 days. Medical threads were embedded into the dorsal skin of the mice in a single application. Hair growth activity was evaluated by using dermoscopic and microscopic observations. Sections of the dorsal skin were stained with hematoxylin and eosin. Expressions of bromodeoxyuridine (BrdU), proliferating cell nuclear antigen (PCNA), fibroblast growth factor-7 (FGF-7), and fibroblast growth factor-5 (FGF-5) were detected by using immunohistochemical staining. A reverse transcription-polymerase chain reaction (RT-PCR) analysis was adopted to measure the messenger RNA (mRNA) expressions of FGF-7 and FGF-5. Results: TET enhanced anagen development in the hair follicles of C57BL/6 mice. The expressions of BrdU and PCNA, both of which imply active cellular proliferation, were increased by using TET. Moreover, TET increased the expression of FGF-7, an anagen-inducing growth factor, while decreasing the expression of FGF-5, an anagen-cessation growth factor, both at the protein and the mRNA levels. Conclusion: TET enhanced hair re-growth in C57BL/6 mice. TET regulated the expressions of anagen-associated growth factors and activated the proliferation of hair follicular cells in depilated skin lesions. Considering its long-lasting effect, TET may be a good alternative therapeutic for the treatment of alopecia.

• 동의생리병리학회지
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• 제28권1호
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• pp.16-21
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• 2014

Micro needle roller therapy has been used for cosmetic purposes, such as reducing skin winkles and improving elasticity of skin. It is claimed that micro needle roller therapy has potentials for connective tissue regeneration by facilitating collagen synthesis. Therefore, there seems to be a possibility that connective tissue regenerating potential of micro needle roller therapy could influence the hair growth cycle. This study, we investigated the hair growth-promoting effects of micro needle roller therapy. C57BL/6 mice were devided into three groups as follows: normal saline-treated, minoxidil-treated, and micro needle roller therapy-received group. Hair growth activity was evaluated by handscopic and microscopic observations. Sections of dorsal skin were stained with hematoxylin and eosin. Expression of BrdU, FGF, and VEGF was detected by immunohistochemical staining. Micro needle roller therapy enhanced the development of hair follicle during anagen. Immunohistochemical analysis revealed that micro neeld roller therapy incresed the expression of BrdU and FGF in the hair follicles of C57BL/6 mice. Furthermore, micro needle roller therapy upregulated mRNA expression of VEGFR-2, FGF-2, EGF - growth factors that play a central role in hair follicle development during anagen. These results suggest that Micro needle roller therapy can potentially be used for the treatment of alopecia.

• Applied Microscopy
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• 제27권3호
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• pp.321-332
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• 1997

The dermal papilla is known to playa major role in influencing the form and dynamics of the hair follicle, which probably involves regulatory substances crossing the basal lamina. But little is known about the junctions between the dermal papilla and the surrounding epithelial cells of the hair bulb, or between the connective tissue and the epithelial cells on the outside of the hair follicle. This study was performed to identify the ultrastructural differences between dermoepidermal junction of the skin and connective tissue-epithelial junctions on the outside of the hair follicle and around the dermal papilla of normal anagen hair follicles in the human fetal scalp skin. Electron microscopic findings of dermoepidermal junction in scalp skin showed that basal lamina was very irregular and undulated, and it contained many attachment plaques of hemidesmosomes with sub-basal dense plates, tonofilaments, and anchoring filaments. Also invaginations of plasma membrane of basal keratinocytes were seen. There were clear differences both on the outside of the follicle and around the dermal papilla as compared with similar junction in the skin. In particular, neither hemidesmosomes nor tonofilaments, as seen in dermoepidermal junction, were observed in the dermal papilla. Also attachment plaque, sub-basal dense plate and anchoring filaments were not observed at the junction on the outside of the follicle and the dermal papilla. There were some differences between connective tissue-epithelial junctions on the outside of the hair follicle and around the dermal papilla, ie, smoothness of basal lamina and orthogonal arrangement of collagen fibers were seen in the outside of hair follicle, but not in the dermal papilla. These results indicate that the mechanical connection between the hair follicle and the connective tissue component is much weaker than that between the corresponding components in skin, and it reflects the dynamic processes during the anagen phase of the hair follicle compared to the relatively permanent state of the epidermis.

• Biomolecules & Therapeutics
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• 제28권4호
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• pp.354-360
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• 2020

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, 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.