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Sanguisorba Officinalis Root Extract Has FGF5 Inhibitory Activity and Reduces Hair Loss by Causing Prolongation of the Anagen Period
Abstract
Tokushima 770-8503, Japan (Director: Prof. S. Arase) FGF-5 inhibitors with FGF-5-antagonizing activity may be effective against hair loss, as these inhibitors suppress the transition of hair follicles from the anagen to catagen phase caused by FGF-5. We screened 24 substances for their FGF-5-antagonizing activity using both an FGF receptor-1c-transfected Ba/F3 cell line and the C3H mouse, and finally detected Sanguisorba Officinalis Root Extract (SO extract) as a reliable FGF-5 inhibitor. Topical application of SO extract elongated the anagen period in C3H mice. In addition, in a clinical study using 39 volunteers with hair loss, the SO extract significantly decreased the telogen /anagen hair ratio and the number of shed hairs. This extract showed a high degree of usefulness clinically. These findings suggest that FGF-5-antagonizing activity of SO extract observed in vitro and in vivo is closely related to its clinical effects.
... FGF5 inhibition and improving hair loss there is potential for exogenous inhibitors of FGF5 to promote hair growth, as demonstrated by Ito et al. 26 The evidence that FGF5 inhibits hair growth and is involved in the transition from anagen to catagen led us, in our previous work, 27 to screen botanical extracts for FGF5 inhibitory activity. We identified Sanguisorba officinalis root extract (SO extract) as an effective FGF5 inhibitor and demonstrated that SO extract enhanced the multiplication of outer root sheath cells in vitro. ...
... We screened a series of botanical extracts for FGF5 inhibitory activity, including the FGF5 inhibitory SO extract (Maruzen Pharmaceuticals, Onomichi, Japan) described in our previous work, 27 Camellia japonica seed extract (NOF Corporation, Tokyo, Japan) and crude eucalyptus essential oil (EPT extract) (Essentially Australia, Byron Bay, Australia). We also screened a number of isolates from the monoterpene family ( Figure 1) including 3-carene, l-carveol, 1,8-cineole, β-citronellol, dl-rose oxide, geraniol, geranyl acetate, linalool, linalyl acetate, l-menthol, nerol, piperitone, α-terpineol, (−)terpinen-4-ol, (+)terpinen-4-ol and (±)terpinen-4-ol. ...
... We first assessed the ability of test compounds to inhibit FGF5induced proliferation of the engineered FGF receptor 1-expressing BaF3 cell line. 27 The BaF3 cell line used in the study is a cell line engineered to express FGFR1c, originally used to study the splice variant of FGF5 known as FGF5s. 26 The BaF3 cell lineage is IL-3 dependent and responds to the presence of IL-3 by proliferating. ...
Background
There are very few effective, scientifically validated treatments with known mechanisms of action for treatment of hair loss in both men and women. Fibroblast growth factor 5 (FGF5) is an important factor in the irreversible transition from anagen to catagen, and inhibition of FGF5 prolongs anagen phase and reduces hair loss.
Objective
We aimed to screen botanically derived molecules for FGF5 inhibitory activity in vitro and assess efficacy in a clinical setting.
Methods
We screened for FGF5 inhibitory efficacy via a novel 2-step in vitro pipeline consisting of an engineered FGF5 responsive cell line, followed by an activated dermal papillae (DP) cell method. Efficacy in a clinical setting was assessed in a randomized, single-blind, placebo-controlled trial against early- to mid-stage pattern hair loss in men and women.
Results
We observed FGF5 inhibitory activity for a number of compounds from the monoterpenoid family, many showing greater inhibitory efficacy than our previously reported crude plant extracts. Evaluation of a lead candidate in a clinical study over 112 days showed a significant improvement in anagen:telogen (AT) ratio (p = 0.002), reduced hair fall (p = 0.007) and improved visual grading (p = 0.004). Scientifically matched photography on a subgroup of randomly chosen participants highlighted significant improvement in hair density, with increases evident in all tested participants compared to baseline.
Conclusion
Isolates from the monoterpenoid family displayed efficacy in FGF5 inhibition in vitro. A topical formulation containing a leading isolate significantly improved AT ratio, reduced hair fall and increased apparent hair density in the tested population of men and women.
In the context of evolutionary time, cities are an extremely recent development. Although our understanding of how urbanization alters ecosystems is well developed, empirical work examining the consequences of urbanization on adaptive evolution remains limited. To facilitate future work, we offer candidate genes for one of the most prominent urban carnivores across North America. The coyote (Canis latrans) is a highly adaptable carnivore distributed throughout urban and nonurban regions in North America. As such, the coyote can serve as a blueprint for understanding the various pathways by which urbanization can influence the genomes of wildlife via comparisons along urban–rural gradients, as well as between metropolitan areas. Given the close evolutionary relationship between coyotes and domestic dogs, we leverage the well-annotated dog genome and highly conserved mammalian genes from model species to outline how urbanization may alter coyote genotypes and shape coyote phenotypes. We identify variables that may alter selection pressure for urban coyotes and offer suggestions of candidate genes to explore. Specifically, we focus on pathways related to diet, health, behavior, cognition, and reproduction. In a rapidly urbanizing world, understanding how species cope and adapt to anthropogenic change can facilitate the persistence of, and coexistence with, these species.
Alopecia is a common dermatological disorder of patchy hair loss with substantial patient burden. Phytotherapeutic compounds are increasingly used as a source of new therapeutic options. This review aimed to synthesize the evidence on plant species in hair growth and the methodological aspects of in vivo experimental models. The systematic scoping review was conducted following the PRISMA checklist, Joanna Briggs Institute and in accordance with Cochrane. A systematic search was carried out in the Pubmed, Scopus, Web of Science, and SciELO databases. In vivo experiments that evaluated hair growth activity using natural substances of plant origin were included. Data collection and analysis: A total of 1,250 studies were identified, of which 175 were included for qualitative synthesis. Of these, 128 used mice, 37 rats, 10 rabbits, 1 guinea pig, and 1 sheep as animal models. The methodologies mapped were: hair growth analysis, histological analysis, immunohistochemistry, gene expression analysis, Western blot, enzyme-linked immunosorbent assay, and biochemical analysis. Minoxidil and finasteride were the most commonly used positive controls. The studies evaluated plant species (166), algae (11) or isolated substances (31). Overall 152 plant species and 37 isolated substances were identified. This is the first systematic scoping review on methodological aspects of in vivo hair growth activity. We created a checklist to be completed by authors to allow data comparison and reproducibility, facilitate data interpretation by readers and ensure better quality of evidence. This work may become a valuable tool for future research and contribute to significant advances in hair growth studies.
Hair disorders such as hair loss (alopecia) and androgen dependent, excessive hair growth (hirsutism, hypertrichosis) may impact the social and psychological well‐being of an individual. Recent advances in understanding the biology of hair have accelerated the research and development of novel therapeutic and cosmetic hair growth agents. Preclinical models aid in dermocosmetic efficacy testing and claim substantiation of hair growth modulators. The in vitro models to investigate hair growth utilize the hair follicle Dermal Papilla cells (DPCs), specialized mesenchymal cells located at the base of hair follicle that play essential roles in hair follicular morphogenesis and postnatal hair growth cycles. In this review, we have compiled and discussed the extensively reported literature citing DPCs as in vitro model to study hair growth promoting and inhibitory effects. A variety of agents such as herbal and natural extracts, growth factors and cytokines, platelet‐rich plasma, placental extract, stem cells and conditioned medium, peptides, hormones, lipid‐nanocarrier, light, electrical and electromagnetic field stimulation, androgens and their analogs, stress‐serum and chemotherapeutic agents etc. have been examined for their hair growth modulating effects in DPCs. Effects on DPCs’ activity were determined from untreated (basal) or stress induced levels. Cell proliferation, apoptosis and secretion of growth factors were included as primary end‐point markers. Effects on a wide range of biomolecules and mechanistic pathways that play key role in the biology of hair growth were also investigated. This consolidated and comprehensive review summarizes the up‐to‐date information and understanding regarding DPCs based screening models for hair growth and may be helpful for researchers to select the appropriate assay system and biomarkers. This review highlights the pivotal role of DPCs in the forefront of hair research as screening platforms by providing insights into mechanistic action at cellular level, which may further direct the development of novel hair growth modulators. This article is protected by copyright. All rights reserved.
“Hair” refers to the hair shaft and follicle, and “hair follicles” are located under the skin dermis, where control hair growth with hair cycle. Hair follicles consist of dermal papilla, hair matrix cells, dermal sheath cells, hair follicle stem cells, etc. For each cell type as a target cell, hair growth/stimulation mechanisms have been proposed and elucidated through certain growth factors/signaling molecules. Based on these mechanisms, many hair growth–promoting reagents have been developed in the past. However, after launching U.S. Food and Drug Administration–approved drugs, the development of cosmeceutical compounds has been limited. Nevertheless, certain agents have successfully introduced into market as quasi-drugs, with safety and certain efficacy data. Recently, besides topical/oral compounds and drugs, treatments for hair thinning/hair loss have spread into the cosmetic surgery area with methods such as laser treatment and hair transplantation. In the near future, even cell-based therapy using one’s own hair cells may become an option together with topical treatment and/or transplantation surgery.
Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional polypeptide which acts as mitogen, motogen, or morphogen. In this study, we examined the effect of HGF/SF on human hair growth using organ and cell culture systems. HGF/SF was found to stimulate hair length and DNA synthesis in hair follicles at increasing concentrations up to 10 ng/ml (P < 0.05 and P < 0.01, respectively). HGF/SF stimulated [3H]thymidine incorporation by hair bulb-derived keratinocytes with the strongest response at 30 ng/ml of HGF/SF (P < 0.05). Cultured follicular papilla cells secreted HGF/SF, measured by an enzyme-linked immunoassay, in response to interleukin 1-alpha (IL1-alpha, 10 ng/ml), tumor necrosis factor-alpha (TNF-alpha, 10 ng/ml), or tetradecanoylphorbolacetate (100 nM) at levels ranging from 0.2 to 0.3 ng/mg protein/48 h. HGF/SF mRNA expressions, measured by the reverse transcription-polymerase chain reaction, were detected in follicular papilla cells, and were also stimulated by the three reagents. Transforming growth factor-beta (10 ng/ml) suppressed both protein and mRNA levels. These results suggest that hair follicle elongation induced by HGF/SF in organ culture occurs partly due to the mitogenic activity of HGF/SF expressed in follicular papilla cells on hair bulb-derived keratinocytes.
Earlier studies demonstrated that knock-out of fibroblast growth factor-5 gene (Fgf-5) prolonged anagen VI phase of hair cycle, resulting long hairs in the mice. We showed the activities on hair growth of the two Fgf-5 gene products, one of which, FGF-5 suppressed hair growth by inhibiting anagen proceeding and inducing the transition from anagen to catagen, and FGF-5S, a shorter polypeptide with FGF-5-antagonizing activity translated from alternatively spliced mRNA, suppressed this activity of FGF-5. As the results suggested that FGF-5 antagonist would increase hair growth, we synthesized various peptides having partial sequences of human FGF-5 and FGF-5S and determined their FGF-5 antagonist activity. Among them, a decapeptide designated P3 (95-VGIGFHLQIY-104) that aligns with receptor binding sites of FGF-1 and FGF-2 suppressed FGF-5-induced proliferation of BALB/3T3 A31 and NIH/3T3 murine fibroblasts, and FGF receptor-1c (FGFR-1c)-transfected Ba/F3 cell line (FR-Ba/F3 cells). IC50s of this peptide on these cell proliferations were 64, 28, 146 microM, respectively. On the other hand, IC50 of this peptide on binding of FGF-5 to the FGFR-1(IIIc)/Fc chimera was 483 microM. Examination in dorsal depilated mice revealed that the P3 peptide reduced the activity of FGF-5 to recover hair pigmentation and hair follicle lengths. The classification of histologically observed skin sections showed FGF-5-induced delations of anagen procedure had reduced by the P3 peptide. The anti-Ki67 antibody staining of hair follicles was inhibited by administration of FGF-5, and this inhibition by FGF-5 was recovered by administration of the P3 peptide. The P3 peptide alone did not affect hair follicle length and hair cell proliferation. These results indicate that the decapeptide antagonized FGF-5 activity in vivo, and reduced the inhibition of FGF-5 in hair growth, confirming that FGF-5 inhibitors are promising substances against hair loss and/or for promoting hair growth.