FoxO3 restricts liver regeneration by suppressing the proliferation of hepatocytes.

Upon injury, the liver is capable of substantial regeneration from the original tissue until an appropriate functional size. The underlying mechanisms controlling the liver regeneration processes are not well elucidated. Previous studies have proposed that the transcription factor FoxO3 is involved in various liver diseases, but its exact role in the regulation of liver regeneration remains largely unclear. To directly test the detailed role of FoxO3 in liver regeneration, both a constitutive Albumin-Cre driver line and adeno-associated virus serotype 8 (AAV8)-Tbg-Cre (AAV-Cre)-injected adult FoxO3fl/fl mice were subjected to 70% partial hepatectomy (PH). Our data demonstrate that FoxO3 deletion accelerates liver regeneration primarily by limiting polyploidization and promoting the proliferation of hepatocytes during liver regeneration. RNA-seq analysis indicates that FoxO3 deficiency greatly alters the expression of gene sets associated with cell proliferation and apoptosis during liver regeneration. Chromatin immunoprecipitation-PCR (ChIP-PCR) and luciferase reporter assays reveal that FoxO3 promotes the expression of Nox4 but suppresses the expression of Nr4a1 in hepatocytes. AAV8 virus-mediated overexpression of Nox4 and knockdown of Nr4a1 significantly suppressed hepatocyte proliferation and liver regeneration in FoxO3-deficient mice. We demonstrate that FoxO3 negatively controls hepatocyte proliferation through Nox4 upregulation and Nr4a1 downregulation, thereby ensuring appropriate functional regeneration of the liver. Our findings provide novel mechanistic insight into the therapeutic mechanisms of FoxO3 in liver damage and repair.

Effect of Chrysanthemum zawadskii Extract on Dermal Papilla Cell Proliferation and Hair Growth.

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.

Expression Pattern and Role of Klotho in Human Hair Follicles.

BACKGROUND: Klotho protein plays a pivotal role in aging regulation. However, it is unclear whether klotho is expressed in human hair follicles and is correlated with hair growth. OBJECTIVE: The purpose of this study was to determine the expression pattern and role of klotho in human hair follicles. METHODS: We examined the klotho expression patterns in human hair follicles from young and aged donors. Furthermore, we examined the functional roles of klotho on human hair growth using klotho siRNA and klotho recombinant protein. RESULTS: Interestingly, klotho was expressed in human hair follicles at both gene and protein levels. In hair follicles, prominent klotho expression was mainly observed in the outermost regions of the outer root sheath and hair bulb matrix cells. Quantification of klotho protein expression in young and aged donors showed that klotho expression decreased with aging. In human hair follicle organ culture, klotho silencing promoted premature catagen induction and inhibited human hair growth. Otherwise, klotho protein prolonged human hair growth. CONCLUSION: These results indicate that klotho might be an important regulatory factor for human hair growth and hair cycle change.

Subclinical sensitization with diphenylcyclopropenone is sufficient for the treatment of alopecia areata: Retrospective analysis of 159 cases.

BACKGROUND: Contact immunotherapy with diphenylcyclopropenone (DPCP) is presently considered the treatment of choice for extensive alopecia areata. However, a major concern with contact immunotherapy is that it causes various adverse effects (AEs) that contribute to discontinuation of treatment. OBJECTIVE: We investigated whether a modified DPCP treatment protocol can promote hair regrowth with fewer AEs. METHODS: All patients were sensitized with 0.1% DPCP and began treatment with 0.01% DPCP. Thereafter, the DPCP concentration was slowly increased according to the treatment response and AEs. This was a retrospective review of DPCP treatment with modified protocols in 159 patients with alopecia areata. RESULTS: Of the 159 patients, 46 (28.9%) showed a complete response and 59 (37.1%) showed a partial response. No patients had AEs after sensitization. During the treatment, only 3 patients (1.9%) showed severe AEs, and 55 showed moderate AEs; however, all were well controlled with antihistamines alone or antihistamines and medium-potency topical steroids. There was no association between treatment response and AEs. LIMITATIONS: Sample size, subject composition, and the retrospective study design represent potential limitations. CONCLUSION: A modified DPCP treatment protocol with subclinical sensitization could induce a favorable therapeutic response and result in fewer AEs.

Targeting of CXXC5 by a Competing Peptide Stimulates Hair Regrowth and Wound-Induced Hair Neogenesis.

The Wnt/ß-catenin pathway has been implicated in hair follicle development and hair regeneration in adults. We discovered that CXXC-type zinc finger protein 5 (CXXC5) is a negative regulator of the Wnt/ß-catenin pathway involved in hair regrowth and wound-induced hair follicle neogenesis via an interaction with Dishevelled. CXXC5 was upregulated in miniaturized hair follicles and arrector pili muscles in human balding scalps. The inhibitory effects of CXXC5 on alkaline phosphatase activity and cell proliferation were demonstrated using human hair follicle dermal papilla cells. Moreover, CXXC5-/- mice displayed accelerated hair regrowth, and treatment with valproic acid, a glycogen synthase kinase 3ß inhibitor that activates the Wnt/ß-catenin pathway, further induced hair regrowth in the CXXC5-/- mice. Disrupting the CXXC5-Dishevelled interaction with a competitor peptide activated the Wnt/ß-catenin pathway and accelerated hair regrowth and wound-induced hair follicle neogenesis. Overall, these findings suggest that the CXXC5-Dishevelled interaction is a potential target for the treatment of hair loss.

Protective effect of Korean Red Ginseng against chemotherapeutic drug-induced premature catagen development assessed with human hair follicle organ culture model.

BACKGROUND: Chemotherapy-induced alopecia (CIA) is one of the most distressing side effects for patients undergoing chemotherapy. This study evaluated the protective effect of Korean Red Ginseng (KRG) on CIA in a well-established in vitro human hair follicle organ culture model as it occurs in vivo. METHODS: We examined whether KRG can prevent premature hair follicle dystrophy in a human hair follicle organ culture model during treatment with a key cyclophosphamide metabolite, 4-hydroperoxycyclophosphamide (4-HC). RESULTS: 4-HC inhibited human hair growth, induced premature catagen development, and inhibited proliferation and stimulated apoptosis of hair matrix keratinocytes. In addition, 4-HC increased p53 and Bax protein expression and decreased Bcl2 protein expression. Pretreatment with KRG protected against 4-HC-induced hair growth inhibition and premature catagen development. KRG also suppressed 4-HC-induced inhibition of matrix keratinocyte proliferation and stimulation of matrix keratinocyte apoptosis. Moreover, KRG restored 4-HC-induced p53 and Bax/Bcl2 expression. CONCLUSION: Overall, our results indicate that KRG may protect against 4-HC-induced premature catagen development through modulation of p53 and Bax/Bcl2 expression.

Hot water extract of oriental melon leaf promotes hair growth and prolongs anagen hair cycle: In vivo and in vitro evaluation.

Effects of hot water extracts of oriental melon leaves (OML) on promotion of hair growth were investigated. Topical OML extract administration for hair regeneration was investigated using an in vivo model with C57BL/6 mice. Effects of OML extracts on the human hair growth were investigated using a hair follicle organ culture. OML extracts induced a shortened telogen to anagen conversion and promoted hair growth in the C57BL/6 mouse model. Culture of human hair follicles in the presence of OML extracts for 8 days promoted hair growth and prolonged the anagen duration due to induction of hair follicle cell proliferation in the bulb region. OML extracts exert a hair growth promotion effect and, therefore, can be used as a therapeutic agent for prevention of hair loss.

FoxO3a suppresses the senescence of cardiac microvascular endothelial cells by regulating the ROS-mediated cell cycle.

FoxO3a plays an important role in the aging process and decreases with age. However, the potential regulatory roles of FoxO3a in processes involved in cardiac microvascular endothelial cell (CMEC) senescence, and its underlying molecular mechanisms have not been elucidated. This study demonstrates that FoxO3a is deactivated in senescent CMECs together with the inhibition of proliferation and tube formation. Furthermore, the activation of the antioxidant enzymes catalase and SOD, downstream FoxO3a targets, was significantly decreased, thereby leading to cell cycle arrest in G1-phase by increased ROS generation and subsequently the activation of the p27(Kip1) pathway. However, FoxO3a overexpression in primary low-passage CMECs not only significantly suppressed the senescence process by increasing the activation of catalase and SOD but also markedly inhibited ROS generation and p27(Kip1) activation, although it failed to reverse cellular senescence. Moreover, both cell viability and tube formation were greatly increased by FoxO3a overexpression in primary CMECs during continuous passage. In addition, FoxO3a, deficiency in low-passage CMECs, accelerated the senescence process. Collectively, our data suggest that FoxO3a suppresses the senescence process in CMECs by regulating the antioxidant/ROS/p27(Kip1) pathways, although it fails to reverse the cellular senescent phenotype.

Comparison of hair shaft damage after chemical treatment in Asian, White European, and African hair.

BACKGROUND: Diverse causes of extrinsic damage to the hair shaft have been documented and can be roughly divided into physical and chemical causes. Chemical causes of hair damage include bleaching, hair dyeing, and perming. OBJECTIVES: The goal of this study was to investigate differences in patterns of serial damage in Asian, White European (WE), and African hair after chemical stress imposed by straightening and coloring treatments. METHODS: Hairs were divided into control and treatment groups (straightening, coloring, and a combination of straightening and coloring). At 24 hours after the final treatment, patterns of hair damage were evaluated using transmission electron microscopy (TEM) and lipid TEM. Grades of hair cuticle and cortex damage were evaluated by three dermatologists. RESULTS: In the TEM examination, the cuticle of Asian hair proved to be resistant to damage caused by straightening treatments, whereas the WE hair cuticle and cortex were relatively susceptible to stress imposed by coloring treatments. In the combination treatment of straightening and coloring, African hair emerged as the most resistant to stress. In the lipid TEM examination, no notable differences in cell membrane complex damage were observed among the three groups of hairs. CONCLUSIONS: The present study suggests that WE hair is relatively susceptible and African hair is more resistant to chemical stresses, such as those imposed by straightening and coloring.

The ethnic differences of the damage of hair and integral hair lipid after ultra violet radiation.

BACKGROUND: Genetic factors account for the majority of differences in skin color and hair morphology across human populations. Although many studies have been conducted to examine differences in skin color across populations, few studies have examined differences in hair morphology. OBJECTIVE: To investigate changing of integral hair lipids after ultraviolet (UV) irradiation in three human ethnic groups. METHODS: We studied the UV irradiation induced hair damage in hairs of three human populations. UV irradiation had been performed with self-manufactured phototherapy system. Damaged hair samples were prepared at 12 and 48 hours after UVA (20 J/sec) and UVB (8 J/sec) irradiation. We evaluated the changes of hair lipid using scanning electron microscopy (SEM), transmission electron microscopy (TEM), lipid TEM and HP-TLC. After UV irradiation, hair surface damage was shown. RESULTS: African hair showed more severe damage on hair surface than others. The lipid compositions across human populations were similar, but Asian hair had more integral hair lipids than other groups as a whole. Especially, free fatty acid contents were higher than other lipids. After UV irradiation, lipid contents were decreased. These patterns were shown in all human populations. Asian hair has more integral hair lipid than European or African hair. After UV irradiation, European and African hair samples exhibited more damage because they have less integral hair lipids. However, Asian hair samples have less damage. CONCLUSION: We conclude that integral hair lipid may protect the hair against the UV light.

Effects of calcitonin gene-related peptide on the immune privilege of human hair follicles.

The hair follicle is a widely available and instructive miniature organ in the human body that experiences major histocompatibility complex (MHC) class I dependent immune privilege (IP). There are various regulation factors that act on the generation, maintenance, and collapse of hair follicle IP. Neuropeptides such as calcitonin gene-related peptide (CGRP) are created in many organs, including skin, and display various immune regulation effects. The purpose of this study was to investigate the phenotypic effect of CGRP on the hair follicle's IP. First, we used interferon-γ (IFN-γ) to generate ectopic MHC antigen expression model in cultured human hair follicles as previously described. Then, we examined the effects of CGRP on the regulation of ectopic MHC antigen expression in cultured human hair follicles using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical staining techniques. IFN-γ (75 IU/ml) induced ectopic MHC expression. CGRP down-regulated INF-γ-induced ectopic MHC class I mRNA expression. These down-regulated effects were especially evident in 10(-8)M. In addition, CGRP also suppressed the staining intensity related to the expression of MHC class I and MHC class I-pathway related molecules (ß2-microglobulin), but had no effect on MHC class II antigen expression. Taken together, these results indicate that CGRP might be an important regulatory factor for IP maintenance and restoration of IP via suppression of MHC class I antigen.

Qualitative investigation of fresh human scalp hair with full-field optical coherence tomography.

We have investigated depth-resolved cellular structures of unmodified fresh human scalp hairs with ultrahigh-resolution full-field optical coherence tomography (FF-OCT). The Linnik-type white light interference microscope has been home-implemented to observe the micro-internal layers of human hairs in their natural environment. In hair shafts, FF-OCT has qualitatively revealed the cellular hair compartments of cuticle and cortex layers involved in keratin filaments and melanin granules. No significant difference between black and white hair shafts was observed except for absence of only the melanin granules in the white hair, reflecting that the density of the melanin granules directly affects the hair color. Anatomical description of plucked hair bulbs was also obtained with the FF-OCT in three-dimensions. We expect this approach will be useful for evaluating cellular alteration of natural hairs on cosmetic assessment or diagnosis of hair diseases.

Effect of IGF-I on Hair Growth Is Related to the Anti-Apoptotic Effect of IGF-I and Up-Regulation of PDGF-A and PDGF-B.

BACKGROUND: Insulin-like growth factor-I (IGF-I) shares a high degree of structural and functional homology with insulin and is a potent mitogen supporting cell growth and survival in many kinds of the tissues and cells. It also plays a role in some differentiation and anti-apoptotic functions. In previous reports, it has been shown that IGF-I stimulates hair follicle (HF) growth, maintains the anagen stage, and postpones the catagen stage. OBJECTIVE: The exact mechanism of the effect of IGF-I on HF growth is not yet established. Therefore, we investigated the relationships between IGF-I and various other factors (i.e. apoptosis related molecules, pro-inflammatory cytokines, other growth factors, etc.) in the control of HF growth. METHODS: The effect of IGF-I on human hair growth was measured using an organ culture model of human HFs and compared with a control group that did not receive IGF-I. We also measured mRNA expression of factors related to hair growth and apoptosis (which was determined by reverse transcription polymerase chain reaction (RT-PCR). RT-PCR was done on days 2, 4, 6, and 8 of organ culture. RESULTS: In organ cultured human hair follicles, IGF-I had a positive effect on the rate of linear hair growth. IGF-I maintained the anagen phase. IGF-I increased the expression of platelet-derived growth factor (PDGF)-A, PDGF-B and the expression ratio of Bcl-2/Bax. CONCLUSION: The effect of IGF-I on hair growth appears to be related to the upregulation of PDGF-A and PDGF-B and to the anti-apoptotic effect of IGF-I.

Hair shaft damage from heat and drying time of hair dryer.

BACKGROUND: Hair dryers are commonly used and can cause hair damage such as roughness, dryness and loss of hair color. It is important to understand the best way to dry hair without causing damage. OBJECTIVE: The study assessed changes in the ultra-structure, morphology, moisture content, and color of hair after repeated shampooing and drying with a hair dryer at a range of temperatures. METHODS: A standardized drying time was used to completely dry each hair tress, and each tress was treated a total of 30 times. Air flow was set on the hair dryer. The tresses were divided into the following five test groups: (a) no treatment, (b) drying without using a hair dryer (room temperature, 20℃), (c) drying with a hair dryer for 60 seconds at a distance of 15 cm (47℃), (d) drying with a hair dryer for 30 seconds at a distance of 10 cm (61℃), (e) drying with a hair dryer for 15 seconds at a distance of 5 cm (95℃). Scanning and transmission electron microscopy (TEM) and lipid TEM were performed. Water content was analyzed by a halogen moisture analyzer and hair color was measured with a spectrophotometer. RESULTS: Hair surfaces tended to become more damaged as the temperature increased. No cortex damage was ever noted, suggesting that the surface of hair might play a role as a barrier to prevent cortex damage. Cell membrane complex was damaged only in the naturally dried group without hair dryer. Moisture content decreased in all treated groups compared to the untreated control group. However, the differences in moisture content among the groups were not statistically significant. Drying under the ambient and 95℃ conditions appeared to change hair color, especially into lightness, after just 10 treatments. CONCLUSION: Although using a hair dryer causes more surface damage than natural drying, using a hair dryer at a distance of 15 cm with continuous motion causes less damage than drying hair naturally.

Comparison of hair shaft damage after UVA and UVB irradiation.

Sunlight, especially ultraviolet (UV) light-induced hair damage is difficult to avoid during daily life. Concerns about the effects of ultraviolet light on hair are emerging recently. These photochemical changes mainly come from damage to hair proteins and melanins. In this study, we performed experiments to find the patterns of morphological and biochemical changes in UV-light-induced damage to hair by scanning and transmission electron microscopy and hair protein analysis. In our results, morphological damage is significant in UVB-irradiated hairs, while biochemical changes are greater in UVA-irradiated hairs.