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Objective: To investigate the relationship between homocysteine (HCY) and androgenetic alopecia (AGA)., Methods: A case control study and two observational experiments on mice were conducted. In the first part, a total of 528 Chinese AGA patients and 500 age-matched healthy controls were included. Serum HCY levels of AGA and controls were compared. In the second part, eight mice were divided into two groups. Both groups of mice had their hair removed. AGA group received a DHT injection, and the other as control group. HCY levels in hair follicles (HFs) were detected by ELISA and compared. In the third part, twelve mice were divided into three groups and fed with different concentrations of methionine. After 4 weeks, serum HCY levels, parameters related to hair growth through observation and HE staining, and expression of immunohistochemistry (IHC) hair-growth-related markers Ki67, VEGF, IGF-1, Krt27, FGF9, and TGF-β1 were compared among the three groups., Results: In the first part, HCY levels were higher in AGA than the controls of both genders. However, there was no difference in HCY levels between groups with varying severity. Rates of hyperhomocysteinemia was higher in AGA patients than the controls. Logistic regression analysis showed serum HCY levels was positively correlated with the incidence of AGA. In the second part, HCY of the HFs in the AGA group was significantly higher than that in the control group. The third part showed that the increase in serum HCY levels inhibited the growth of mice hair, with the less expressed stimulative markers Ki67, VEGF, IGF-1, Krt27, and FGF9, while there was no difference in the expression of inhibitory markers TGF-β1., Conclusion: There is a potential relationship between HCY and AGA. HCY had an inhibitory effect on hair growth. Further studies are necessary to explore the specific mechanism., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

The purpose of this research was to identify the role of keratin proteins in causing inherited as well as pathogenic alopecia, pinpoint deleterious SNPs, and predict structural changes affecting protein-protein interactions in hair disorders. To elucidate the role of keratin proteins and genetic mutations in alopecia by analyzing protein structures through bioinformatics and identifying a mutation in the LPAR6 gene. It sought to identify the microorganisms linked to alopecia and conducted a comprehensive bioinformatics analysis of proteins with unknown experimental structures and molecular simulation analysis. The study identified a genetic mutation (c.188 A > T, p.Asp63Val) in the LPAR6 gene associated with hereditary hair loss. Pathogenic alopecia was identified to be associated with S. aureus and two ic keratinophilic fungi namely M. canis, and T. violaceum. Additionally, among 14 proteins lacking prior structural information, four proteins namely Keratin, type II cuticular Hb3 (KR1), Keratin, type II cuticular Hb6 (KR2), Keratin, type II cytoskeletal 74 (KR3) and Keratin, type II cuticular Hb1 (KR4) exhibited common 'K-head' and 'F' domains. Docking analysis revealed five distinct binding sites (C1-C5) for each protein. The 'K-head' displayed the highest predicted binding affinities with Vina scores of -5.6 for KR2 and - 4.7 for KR4 whereas the 'F' domain showed Vina scores of -6.0 for KR3 and - 5.7 for KR2. This research underscores the crucial role of keratin proteins in both hereditary and pathogenic alopecia, emphasizing their significance for future investigations., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study presents a comprehensive comparative proteomic analysis aimed at elucidating the molecular mechanisms underlying male androgenetic alopecia (AGA) and female AGA. Scalp samples from both male AGA and female AGA patients, along with their respective normal controls, were subjected to proteomic analysis, followed by bioinformatics investigations. Our findings revealed distinct proteomic profiles between male AGA and female AGA, with a total of 68 differentially expressed proteins identified in male AGA and 84 in female AGA. Among these, specific proteins were altered in male AGA and female AGA, highlighting the sex-specific molecular pathways involved in the pathogenesis of pattern hair loss. Protein-protein interaction network analyses further delineated the most impacted biological processes, including cytoskeleton organization, stress response, and metabolic pathways, with particular emphasis on the differing altered stress responses and metabolic states associated with hair loss between sexes. Our study not only uncovered the complex molecular landscape of male AGA and female AGA but also identified potential biomarkers and therapeutic targets, offering new insights into the sex-specific pathogenesis of pattern hair loss., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Alopecia, or hair loss, is an emerging global disease. Its etiopathogenesis includes nutritional deficiencies, oxidative stress, and deficiency of physiological factors. Around 2% of the general population has the probability of developing alopecia at any one period. Vitamin D and interleukin-6 (IL-6) have a major role in alopecia. The present goal of research is to investigate the role of vitamin D and IL-6 in the saliva of patients with non-scarring alopecia., Methodology: The study involved 51 cases of non-scarring alopecia and 50 healthy controls with an age range between 18 and 40 years. A detailed history and clinical examination were done. Salivary vitamin D and IL-6 were determined to compare within the groups., Results: The average vitamin D level in cases (104.64 ± 46.95 pmol/L) was significantly lower as compared to controls (223 ± 12.03 pmol/L) (p < 0.001). Whereas the average amount of IL-6 was significantly higher (170.54 ± 63.68 ng/L) than the control group (56.38 ± 46.52 ng/L) (p < 0.001). No correlation of vitamin D level with IL-6 was detected in study subjects., Conclusion: Vitamin D significantly influences the development of non-scarring alopecia. Patients with non-scarring alopecia had low amount of vitamin D indicate its role in etiology of hair loss. IL-6 may cause a collapse of the hair bulb, having a significant part in the pathogenesis of alopecia indicating chronic inflammatory or autoimmune condition. This research will aid in diagnosing scalp disease using salivary biomarkers and improve the treatment of alopecia., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vitamin D is a crucial vitamin that participates in various biological processes through the Vitamin D Receptor (VDR). While there are studies suggesting that VDR might regulate hair growth through ligand-independent mechanisms, the efficacy of Vitamin D in treating hair loss disorders has also been reported. Here, through in vivo experiments in mice, in vitro organ culture of hair follicles, and cellular-level investigations, we demonstrate that 1,25-(OH) 2 D 3 promotes mouse hair regeneration, prolongs the hair follicle anagen, and enhances the proliferation and migration capabilities of dermal papilla cells and outer root sheath keratinocytes in a VDR-dependent manner. Transcriptome analysis of VDR-knockout mouse skin reveals the involvement of HIF-1α, NLRP3, and IL-1β in these processes. Finally, we confirm that 1,25-(OH) 2 D 3 can counteract the inhibitory effects of DHT on hair growth. These findings suggest that 1,25-(OH) 2 D 3 has a positive impact on hair growth and may serve as a potential therapeutic agent for androgenetic alopecia (AGA)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chronic stress is a common cause of hair loss, involving inflammatory responses and changes in cellular signaling pathways. This study explores the mechanism of action of the SDF-1/CXCR4 signaling axis in chronic stress-induced hair loss. The research indicates that SDF-1 promotes hair follicle growth through the PI3K/Akt and JAK/STAT signaling pathways. Transcriptome sequencing analysis was conducted to identify differentially expressed genes in the skin of normal and stressed mice, with key genes SDF-1/CXCR4 selected through machine learning and a protein-protein interaction network established. A chronic stress mouse model was created, with injections of SDF-1 and AMD3100 administered to observe hair growth, weight changes, and behavioral alterations and validate hair follicle activity. Skin SDF-1 concentrations were measured, differentially expressed genes were screened, and pathways were enriched. Activation of the PI3K/Akt and JAK/STAT signaling pathways was assessed, and siRNA technology was used in vitro to inhibit the expression of SDF-1 or CXCR4. SDF-1 promoted hair follicle activity, with the combined injection of SDF-1 and AMD3100 weakening this effect. The activation of the PI3K/Akt and JAK/STAT signaling pathways was observed in the SDF-1 injection group, confirmed by Western blot and immunofluorescence. Silencing SDF-1 through siRNA-mediated inhibition reduced cell proliferation and migration abilities. SDF-1 promotes hair growth in chronic stress mice by activating the PI3K/Akt and JAK/STAT pathways, an effect reversible by AMD3100. The SDF-1/CXCR4 axis may serve as a potential therapeutic target for stress-induced hair loss.

Background: Androgenetic alopecia (AGA) is a common form of hair loss. Androgens, such as testosterone and dihydrotestosterone, are the main causes of AGA. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) can reduce AGA. However, preparing therapeutic doses of MSCs for clinical use is challenging. Induced pluripotent stem cell-derived MSCs (iMSCs) are homogenous and easily expandable, enabling scalable production of EVs. Hyaluronic acid (HA) can exert various functions including free radical scavenging, immune regulation, and cell migration. Herein, we examined whether hyaluronic acid (HA) stimulation of iMSCs could produce EVs with enhanced therapeutic outcomes for AGA., Methods: EVs were collected from iMSCs primed with HA (HA-iMSC-EVs) or without HA (iMSC-EVs). The characteristics of EVs were examined using dynamic light scattering, cryo-transmission electron microscopy, immunoblotting, flow cytometry, and proteomic analysis. In vitro, we compared the potential of EVs in stimulating the survival of hair follicle dermal papilla cells undergoing testosterone-mediated AGA. Additionally, the expression of androgen receptor (AR) and relevant growth factors as well as key proteins of Wnt/β-catenin signaling pathway (β-catenin and phosphorylated GSK3β) was analyzed. Subsequently, AGA was induced in male C57/BL6 mice by testosterone administration, followed by repeated injections of iMSC-EVs, HA-iMSC-EVs, finasteride, or vehicle. Several parameters including hair growth, anagen phase ratio, reactivation of Wnt/β-catenin pathway, and AR expression was examined using qPCR, immunoblotting, and immunofluorescence analysis., Results: Both types of EVs showed typical characteristics for EVs, such as size distribution, markers, and surface protein expression. In hair follicle dermal papilla cells, the mRNA levels of AR, TGF-β, and IL-6 increased by testosterone was blocked by HA-iMSC-EVs, which also contributed to the augmented expression of trophic genes related to hair regrowth. However, no notable changes were observed in the iMSC-EVs. Re-activation of Wnt/β-catenin was observed in HA-iMSC-EVs but not in iMSC-EVs, as shown by β-catenin stabilization and an increase in phosphorylated GSK3β. Restoration of hair growth was more significant in HA-iMSC-EVs than in iMSC-EVs, and was comparable to that in mice treated with finasteride. Consistently, the decreased anagen ratio induced by testosterone was reversed by HA-iMSC-EVs, but not by iMSC-EVs. An increased expression of hair follicular β-catenin protein, as well as the reduction of AR was observed in the skin tissue of AGA mice receiving HA-iMSC-EVs, but not in those treated with iMSC-EVs., Conclusions: Our results suggest that HA-iMSC-EVs have potential to improve AGA by regulating growth factors/cytokines and stimulating AR-related Wnt/β-catenin signaling., (© 2024. The Author(s).)

Androgenetic alopecia (AGA) is characterized by microinflammation and abnormal immune responses, particularly in the upper segment of hair follicles (HFs). However, the precise patterns of immune dysregulation remain unclear, partly due to limitations in current analysis techniques to preserve tissue architecture. The infundibulum, a major part of the upper segment of HFs, is associated with significant clusters of immune cells. In this study, we investigated immune cells around the infundibulum, referred to as peri-infundibular immune infiltration (PII). We employed spatial transcriptome profiling, a high-throughput analysis technology, to investigate the immunological disruptions within the PII region. Our comprehensive analysis included an evaluation of overall immune infiltrates, gene set enrichment analysis (GSEA), cellular deconvolution, differential expression analysis, over-representation analysis, protein-protein interaction (PPI) networks, and upstream regulator analysis to identify cell types and molecular dysregulation in immune cells. Our results demonstrated significant differences in immune signatures between the PII of AGA patients (PII-A) and the PII of control donors (PII-C). Specifically, PII-A exhibited an enrichment of CD4 + helper T cells, distinct immune response patterns, and a bias toward a T helper (Th) 2 response. Immunohistochemistry revealed disruptions in T cell subpopulations, with more CD4 + T cells displaying an elevated Th2 response and a reduced Th1-cytotoxic response compared to PII-C. These findings reveal the unique immune landscapes of PII-A and PII-C, suggesting potential for the development of innovative treatment approaches.

Dermal papilla cells (DPCs) exhibit self-recovery ability, which may be involved in hair growth. Therefore, we tested whether DPCs subjected to temporary growth-inhibiting stress (testosterone, 17β-estradiol, mitomycin C, or undernutrition) treatments exhibit self-recovery behavior that can activate hair follicle growth, and examined the changes in cell proliferation capacity and gene expression. Related proteins were identified and their relationships with the hair cycle was examined using a mouse model. Recovery-period DPCs (i.e., from day 3 after loading) were subjected to microarray analysis to detect genetic variations common to each stress treatment. Co-culture of recovery-period DPCs and outer root sheath cells (ORSCs) confirmed the promotion of ORSC proliferation, suggesting that the activation of hair follicle growth is promoted via signal transduction. Chitinase 3-like 1 (CHI3L1) and C-X-C motif chemokine 5 (CXCL5) exhibited ORSC proliferation-promoting effects. Measurement of protein content in the skin during each phase of the hair cycle in mice revealed that CHI3L1 and CXCL5 secretion increased immediately after anagen transition. In a hair-loss mouse model treated with testosterone or 17β-estradiol, CHI3L1 and CXCL5 secretion was lower in treated telogen skin than in untreated skin. Our results suggest that CHI3L1 and CXCL5 secreted by recovery-state DPCs promote hair growth., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Prostaglandin E 2 (PGE 2 ) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF 2α , has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, to enhance PGE 2 levels while improving hair loss, we found dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using DeepZema ® , an AI-based drug development program. Here, we investigated whether DPP improved hair loss in human follicle dermal papilla cells (HFDPCs) damaged by dihydrotestosterone (DHT), which causes hair loss. We found that DPP enhanced wound healing and the expression level of alkaline phosphatase in DHT-damaged HFDPCs. We observed that DPP significantly down-regulated the generation of reactive oxygen species caused by DHT. DPP recovered the mitochondrial membrane potential in DHT-damaged HFDPCs. We demonstrated that DPP significantly increased the phosphorylation levels of the AKT/ERK and activated Wnt signaling pathways in DHT-damaged HFDPCs. We also revealed that DPP significantly enhanced the size of the three-dimensional spheroid in DHT-damaged HFDPCs and increased hair growth in ex vivo human hair follicle organ culture. These data suggest that DPP exhibits beneficial effects on DHT-damaged HFDPCs and can be utilized as a promising agent for improving hair loss.

Aging (senescence) is an unavoidable biological process that results in visible manifestations in all cutaneous tissues, including scalp skin and hair follicles. Previously, we evaluated the molecular function of adenosine in promoting alopecia treatment in vitro. To elucidate the differences in the molecular mechanisms between minoxidil (MNX) and adenosine, gene expression changes in dermal papilla cells were examined. The androgen receptor (AR) pathway was identified as a candidate target of adenosine for hair growth, and the anti-androgenic activity of adenosine was examined in vitro. In addition, ex vivo examination of human hair follicle organ cultures revealed that adenosine potently elongated the anagen stage. According to the severity of alopecia, the ratio of the two peaks (terminal hair area/vellus hair area) decreased continuously. We further investigated the adenosine hair growth promoting effect in vivo to examine the hair thickness growth effects of topical 5% MNX and the adenosine complex (0.75% adenosine, 1% penthenol, and 2% niacinamide; APN) in vivo. After 4 months of administration, both the MNX and APN group showed significant increases in hair density (MNX + 5.01% ( p < 0.01), APN + 6.20% ( p < 0.001)) and thickness (MNX + 5.14% ( p < 0.001), APN + 10.32% ( p < 0.001)). The inhibition of AR signaling via adenosine could have contributed to hair thickness growth. We suggest that the anti-androgenic effect of adenosine, along with the evaluation of hair thickness distribution, could help us to understand hair physiology and to investigate new approaches for drug development.

Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are primary cicatricial alopecia that cause a major impact on quality of life due to irreversible hair loss and symptoms as itching, burning and pain. They are characterized by permanent loss of hair follicle stem cells (HFSCs) by pathomechanisms still poorly understood, resulting in poor efficacy of currently available treatments. Caveolae are flask-shaped lipid rafts invaginated within the plasma membrane of multiple cell types. Although their role in the HF physiology and pathophysiology is relatively unknown, we have previously demonstrated that the primary structural component of caveolae (caveolin-1 or Cav1) is upregulated in FFA. Thus, we propose to investigate the expression and localization of caveolae-associated structural proteins (Cav1, Cav2, and Cavin-1) and HFSCs (identified by K15) in both LPP and FFA. We analyzed 4 patients with LPP biopsied in affected and non-affected (NA) scalp, 4 patients with FFA biopsied in affected scalp and 4 healthy controls. Affected scalp of LPP and FFA demonstrated increased levels of Cav1 and Cavin-1 compared with HC and LPP-NA. Moreover, Cav1, Cav2 and Cavin1 all exhibit high colocalization with K15 and their expression appears to be negatively correlated, supporting the hypothesis that these proteins are important players in LPP/FFA and may serve as therapeutic targets in future treatments., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patterned hair loss (PHL) or androgenetic alopecia is a condition affecting about 50% of people worldwide. Several pharmacological medications have been developed over the years, but few studies have investigated their effectiveness. Therefore, new, safer and more effective strategies are required. Recent investigations showed that Annurca apple extract application could induce keratin production and promote hair growth thanks to the high amount of procyanidin B2 contained in. Hence, this study aimed to investigate the role of an Annurca apple extract in preventing PHL by testing it on human follicle dermal papilla cells (HFDPCs) for the first time. Treatment of HFDPCs with Annurca apple extract counteracted intracellular reactive oxygen species accumulation by increasing the activity of antioxidant enzymes such as superoxide dismutase 2 and catalase. Furthermore, treatment with Annurca apple extract increased β-catenin and fibroblast growth factor 2, which are involved in hair growth stimulation. These data suggest that Annurca apple extract may be a potential therapeutically useful nutraceutical product for preventing or treating hair loss by reducing oxidative stress and inducing the expression of hair growth-related factors., (© 2024 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Hair follicle development and hair growth are regulated by multiple factors and multiple signalling pathways. The hair follicle, as an important skin appendage, is the basis for hair growth, and it has the functions of safeguarding the body, perceiving the environment and regulating body temperature. Hair growth undergoes a regular hair cycle, including anagen, catagen and telogen. A small amount of physiological shedding of hair occurs under normal conditions, always in a dynamic equilibrium. Hair loss occurs when the skin or hair follicles are stimulated by oxidative stress, inflammation or hormonal disorders that disrupt the homeostasis of the hair follicles. Numerous researches have indicated that oxidative stress is an important factor causing hair loss. Here, we summarize the signalling pathways and intervention mechanisms by which oxidative stress affects hair follicle development and hair growth, discuss existing treatments for hair loss via the antioxidant pathway and provide our own insights. In addition, we collate antioxidant natural products promoting hair growth in recent years and discuss the limitations and perspectives of current hair loss prevention and treatment., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Chemotherapy-induced alopecia (CIA) represents one of the most severe side effects of chemotherapy, which forces some patients to reject cancer treatment. The exact pathophysiological mechanisms of CIA are not clearly understood, which makes it difficult to discover efficient preventive or therapeutic procedures for this adverse effect. N-acetylcysteine (NAC) has a strong antioxidant activity as it stimulates glutathione synthesis and acts as an oxygen radical scavenger. The current study tried to investigate the efficacy of NAC in preserving biochemical parameters and hair follicle structure against cyclophosphamide (CYP) administration. In total, 40 adult female C57BL/6 mice were induced to enter anagen by depilation (day 0) and divided into four groups: group I (control), group II (CYP) received a single dose of CYP [150 mg/kg body weight (B.W.)/intraperitoneal injection (IP)] at day 9, group III (CYP & NAC) received a single dose of CYP at day 9 as well as NAC (500 mg/kg B.W./day/IP) from day 6-16, and group IV (NAC) received NAC from day 6-16. CYP administration in group II induced an increase in malondialdehyde (MDA), decrease in superoxide dismutase (SOD), histological hair follicle dystrophy, disruption of follicular melanogenesis, overexpression of p53, and loss of ki67 immunoreactivity. NAC coadministration in group III reversed CYP-induced alterations in the biochemical parameters and preserved hair follicle structure, typical follicular melanin distribution as well as normal pattern of p53 and ki67 expression. These findings indicated that NAC could be used as an efficient and safe therapeutic option for hair loss induced by chemotherapy., (© 2024. The Author(s).)

Hypotrichosis is a genetic disorder characterized by a diffuse and progressive loss of scalp and/or body hair. Nonetheless, the causative genes for several affected individuals remain elusive, and the underlying mechanisms have yet to be fully elucidated. Here, we discovered a dominant variant in a disintegrin and a metalloproteinase domain 17 (ADAM17) gene caused hypotrichosis with woolly hair. Adam17 (p.D647N) knockin mice mimicked the hair abnormality in patients. ADAM17 (p.D647N) mutation led to hair follicle stem cell (HFSC) exhaustion and caused abnormal hair follicles, ultimately resulting in alopecia. Mechanistic studies revealed that ADAM17 binds directly to E3 ubiquitin ligase tripartite motif-containing protein 47 (TRIM47). ADAM17 variant enhanced the association between ADAM17 and TRIM47, leading to an increase in ubiquitination and subsequent degradation of ADAM17 protein. Furthermore, reduced ADAM17 protein expression affected the Notch signaling pathway, impairing the activation, proliferation, and differentiation of HFSCs during hair follicle regeneration. Overexpression of Notch intracellular domain rescued the reduced proliferation ability caused by Adam17 variant in primary fibroblast cells.

Objective: To summarize the dynamic and synchronized changes between the hair cycle and dermal adipose tissue as well as the impact of dermal adipose tissue on hair growth, and to provide a new research idea for the clinical treatment of hair loss., Methods: An extensive review of relevant literature both domestic and international was conducted, analyzing and summarizing the impact of dermal adipose precursor cells, mature dermal adipocytes, and the processes of adipogenesis in dermal adipose tissue on the transition of hair cycle phases., Results: Dermal adipose tissue is anatomically adjacent to hair follicles and closely related to the changes in the hair cycle. The proliferation and differentiation of dermal adipose precursor cells promote the transition of hair cycle from telogen to anagen, while mature adipocytes can accelerate the transition from anagen to catagen of the hair cycle by expressing signaling molecules, with adipogenesis in dermal adipose tissue and hair cycle transition signaling coexistence., Conclusion: Dermal adipose tissue affects the transition of the hair cycle and regulates hair growth by secreting various signaling molecules. However, the quantity and depth of existing literature are far from sufficient to fully elucidate its prominent role in regulating the hair cycle, and the specific regulatory mechanisms needs to be further studied.

Background/aim: Hair-follicle keratinocytes contain high levels of cysteine, which is derived from methionine, rapidly proliferate, and form the hair shaft. The high proliferation rate of hair-follicle keratinocytes resembles that of aggressive cancer cells. In the present study, we determined the effect of a methionine-deficient diet on hair loss (alopecia) in mice with or without homocysteine supplementation., Materials and Methods: Mice were fed a normal rodent diet (2020X, ENVIGO) (Group 1); a methionine-choline-deficient diet (TD.90262, ENVIGO) (Group 2); a methionine-choline-deficient diet with a 10 mg/kg/day supply of homocysteine administered by intra-peritoneal (i.p.) injection for 2 weeks (Group 3). In Group 2, mice were fed a methionine-choline-deficient diet for an additional 2 weeks but with 10 mg/kg/day of i.p. l-homocysteine and the mice were observed for two additional weeks. Subsequently, the mice were fed a standard diet that included methionine. Hair loss was monitored by photography., Results: After 14 days, hair loss was observed in Group 2 mice on a methionine-restricted diet but not in Group 3 mice on the methionine-restricted diet which received i.p. homocysteine. In Group 2, at 2 weeks after methionine restriction, hair loss was not rescued by homocysteine supplementation. However, after restoration of methionine in the diet, hair growth resumed. Thus, after 2 weeks of methionine restriction, only methionine restored hair loss, not homocysteine., Conclusion: Hair maintenance requires methionine in the diet. Future experiments will determine the effects of methionine restriction on hair-follicle stem cells., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Androgenic alopecia (AGA) is the most common non-scarring alopecia disorder. Given its increasing incidence and onset during adolescence, AGA significantly impacts both the physical and psychological well-being of affected individuals. Emerging evidence suggests a pivotal role of metabolites in AGA. This study aims to elucidate the causal relationship between metabolites and AGA using Mendelian randomization (MR) analysis., Methods: We conducted a two-sample Mendelian randomization (TSMR) analysis based on a genome-wide association study (GWAS) to assess the causality of 452 metabolites on AGA. The main approach employed for inferring causal effects was inverse variance weighted (IVW), which was complemented by MR-Egger regression, weighted median, as well as MR pleiotropy residual sum and outlier (MR-PRESSO) approaches. Additionally, sensitivity analyses were performed to ensure result robustness. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) in GWAS dataset comprising 452 metabolites., Results: Notably, we identified Scyllo-inositol and Alpha-ketoglutarate as the most potent protective factors against AGA, while Heme* and 2-palmitoylglycerophosphocholine* emerged as significant risk factors for AGA. Furthermore, sensitivity analysis revealed no heterogeneity in these findings., Conclusions: Overall, our research suggests a potential causal link between metabolites and AGA, offering a more comprehensive insight into the pathogenesis of AGA and present additional strategies for prevention and treatment., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

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 (H 2 O 2 )-induced HDPCs. The senescence-associated β-galactosidase staining assay also demonstrated that the antioxidant abilities of PG effectively mitigated H 2 O 2 -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.

ANTXR1 is one of two cell surface receptors mediating the uptake of the anthrax toxin into cells. Despite substantial research on its role in anthrax poisoning and a proposed function as a collagen receptor, ANTXR1's physiological functions remain largely undefined. Pathogenic variants in ANTXR1 lead to the rare GAPO syndrome, named for its four primary features: Growth retardation, Alopecia, Pseudoanodontia, and Optic atrophy. The disease is also associated with a complex range of other phenotypes impacting the cardiovascular, skeletal, pulmonary and nervous systems. Aberrant accumulation of extracellular matrix components and fibrosis are considered to be crucial components in the pathogenesis of GAPO syndrome, contributing to the shortened life expectancy of affected individuals. Nonetheless, the specific mechanisms connecting ANTXR1 deficiency to the clinical manifestations of GAPO syndrome are largely unexplored. In this study, we present evidence that ANTXR1 deficiency initiates a senescent phenotype in human fibroblasts, correlating with defects in nuclear architecture and actin dynamics. We provide novel insights into ANTXR1's physiological functions and propose GAPO syndrome to be reconsidered as a progeroid disorder highlighting an unexpected role for an integrin-like extracellular matrix receptor in human aging., (© 2024. The Author(s).)

Although topical application of minoxidil is a widely used, FDA-approved therapy for androgenetic alopecia (AGA) treatment, it suffers from low bioavailability, the requirement for frequent long-term use, and side effects. With a similar structure as minoxidil, kopexil and kopyrrol are less toxic and have been commercialized, but show an inferior hair regeneration effect compared to minoxidil. Herein, we developed a hyaluronic acid (HA)-based dissolvable microneedles (MNs) delivery platform integrated with kopexil and kopyrrol coencapsulated nanoliposomes (KK-NLPs) to effectively and safely treat AGA. Facilitated by nanoliposomes and MNs, the encapsulated KK-NLPs performed efficient skin penetration and enhanced cellular internalization into human dermal papilla cells. Furthermore, within the target cells, the codelivered kopexil and kopyrrol show synergistic effects by orchestrating an upregulation in the expression of Ki67, β-catenin, vascular endothelial growth factor (VEGF), and CD31. These molecular responses collectively foster cell proliferation, migration, and antioxidative effects, thereby facilitating the expedited progression of hair follicles (HFs) into the anagen phase and promoting peripheral angiogenesis. Notably, the KK-NLPs-integrated MNs treatment group exhibits noteworthy enhanced hair regeneration in vivo , with identical or superior therapeutic effects at a much lower dosage than that of minoxidil. These results suggest the great potential of this kopexil and kopyrrol codelivery nanoliposomes-integrated MNs platform for AGA treatment in a safe and efficient way.

Background: Male-pattern baldness (MPB) is the most common cause of hair loss in men. It can be categorized into three types: type 2 (T2), type 3 (T3), and type 4 (T4), with type 1 (T1) being considered normal. Although various MPB-associated genetic variants have been suggested, a comprehensive study for linking these variants to gene expression regulation has not been performed to the best of our knowledge., Results: In this study, we prioritized MPB-related tissue panels using tissue-specific enrichment analysis and utilized single-tissue panels from genotype-tissue expression version 8, as well as cross-tissue panels from context-specific genetics. Through a transcriptome-wide association study and colocalization analysis, we identified 52, 75, and 144 MPB associations for T2, T3, and T4, respectively. To assess the causality of MPB genes, we performed a conditional and joint analysis, which revealed 10, 11, and 54 putative causality genes for T2, T3, and T4, respectively. Finally, we conducted drug repositioning and identified potential drug candidates that are connected to MPB-associated genes., Conclusions: Overall, through an integrative analysis of gene expression and genotype data, we have identified robust MPB susceptibility genes that may help uncover the underlying molecular mechanisms and the novel drug candidates that may alleviate MPB., (© 2024. The Author(s).)

Psychosocial stress is increasing, causing a growing number of people to suffer from hair loss. Stress-related corticotropin-releasing hormone (CRH) is associated with hair loss, but the mechanism by which hair follicles respond to stress and CRH remain poorly understood. The aim of the study is to elucidate the association between CRH and stress-related hair regenerative disorders, and reveal the potential pathological mechanisms. A chronic unpredictable stress mouse model and a chronic social defeat stress mouse model were used to examine the role of CRH and stress-related hair regrowth. Chronic unpredictable stress and chronic social defeat stress increased the expression of CRH and CRH receptors (CRHRs), and contributed to the onset of hair-cycle abnormalities. Psychoemotional stress and stress-related CRH blocked hair follicle regrowth, which could be restored by astressin, a CRHR antagonist. Long-term exposure to either chronic unpredictable stress or CRH induced a decrease in autophagy, which could be partially rescued by astressin. Activating CRHR, by stress or CRH administration, decreased autophagy via the mTOR-ULK1 signaling pathway to mediate hair regenerative disorders, which could be partially reversed through enhancing autophagy by administration of brefeldin A. These findings indicate that CRH-mediated autophagy inhibition play an important role in stress-induced hair regenerative disorders. CRH regulates the local hypothalamic-pituitary-adrenal axis of hair follicles, but also plays an independent pathogenic role in stress-related hair regenerative disorders through CRH-mediated autophagy inhibition. This work contributes to the present understanding of hair loss and suggests that enhancing autophagy may have a therapeutic effect on stress-induced hair loss., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Hair loss occurs due to various biological and environmental causes, which can have psychosocial consequences. The Wnt/β-catenin signaling is well-known for its role in hair growth and regeneration, as it induces the proliferation and differentiation of hair cells. When the leucine-rich G protein-coupled receptor 5 (Lgr5) interacts with the R-spondins, the frizzled receptor (FZD), a Wnt receptor, becomes stabilized, resulting in an increased β-catenin activity., Aim: We investigated whether the octapeptide that binds to Lgr5 enhances proliferation and differentiation of human primary hair cells through the activation of Wnt/β-catenin signaling., Methods: The binding affinity of the octapeptide to Lgr5 was evaluated using surface plasmon resonance (SPR). We confirmed changes in proliferation and related factors like β-catenin activation and growth factors (GFs) expression in human hair follicle dermal papilla cells (HHFDPCs). Additionally, we observed the proliferation and the expression of differentiation markers in human hair follicle outer root sheath cells (HHFORSCs), human hair follicle germinal matrix cells (HHFGMCs), and human hair follicle stem cells (HHFSCs). We used three-dimensional HHFDPC spheroid culture treated with dihydrotestosterone (DHT) to create in vitro conditions that mimic androgenetic alopecia, and we studied the effects of octapeptide on Wnt expression and HHFSC differentiation., Results: The binding of the octapeptide to Lgr5 was confirmed using SPR analysis. In HHFDPCs, treatment with octapeptide resulted in a concentration-dependent increase in proliferation. We also observed increased nuclear translocation of β-catenin and increased expression of its downstream targets. HHFDPCs treated with octapeptide exhibited increased expression of growth factors and phosphorylation of Akt and ERK. In addition, we confirmed that octapeptide increased proliferation and induced differentiation in HHFORSCs, HHFGMCs, and HHFSCs. Under the HHFDPC spheroid culture conditions, we found that octapeptide restored the inhibition of Wnt-5a and Wnt-10b expressions by DHT. In HHFSCs treated with HHFDPC spheroid culture media, we observed that octapeptide recovered the inhibition of differentiation by DHT., Conclusion: We found that octapeptides activated the Wnt/β-catenin signaling and induced the proliferation and differentiation of human primary hair cells by acting as an exogenous ligand for Lgr5. In addition, octapeptides recovered inhibited hair regeneration characters by DHT in androgenetic alopecia-mimic in vitro model. These findings suggest that octapeptides may be a promising therapeutic option for treating hair loss., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Androgenetic alopecia (AGA) is a prevalent systemic disease caused by diverse factors, for which effective treatments are currently limited. Herein, the oleogel (OG) containing copper-curcumin (CuR) nanoparticles is developed, designated as CuRG, which is also combined with traditional naturopathic scraping (Gua Sha, SCR) as a multifunctional therapy for AGA. With the assistance of lipophilic OG and SCR, CuR can efficaciously penetrate the epidermal and dermal regions where most hair follicles (HFs) reside, thereby releasing curcumin (CR) and copper ions (Cu 2+ ) subcutaneously to facilitate hair regeneration. Concomitantly, the mechanical stimulation induced by SCR promotes the formation of new blood vessels, which is conducive to reshaping the microenvironment of HFs. This study validates that the combination of CuRG and SCR is capable of systematically interfering with different pathological processes, ranging from improvement of perifollicular microenvironment (oxidative stress and insufficient vascularization), regulation of inflammatory responses to degradation of androgen receptor, thus potentiating hair growth. Compared with minoxidil, a widely used clinical drug for AGA therapy, the designed synergistic system displays augmented hair regeneration in the AGA mouse model., (© 2024 Wiley‐VCH GmbH.)

The prevalence of alopecia has increased recently. Hair loss is often accompanied by the resting phase of hair follicles (HFs). Dermal papilla (DP) plays a crucial role in HF development, growth, and regeneration. Activating DP can revive resting HFs. Augmenting WNT/β-catenin signaling stimulates HF growth. However, the factors responsible for activating resting HFs effectively are unclear. In this study, we investigated epidermal cytokines that can activate resting HFs effectively. We overexpressed β-catenin in both in vivo and in vitro models to observe its effects on resting HFs. Then, we screened potential epidermal cytokines from GEO DATASETs and assessed their functions using mice models and skin-derived precursors (SKPs). Finally, we explored the molecular mechanism underlying the action of the identified cytokine. The results showed that activation of WNT/β-catenin in the epidermis prompted telogen-anagen transition. Keratinocytes infected with Ctnnb1-overexpressing lentivirus enhanced SKP expansion. Subsequently, we identified endothelin 1 (ET-1) expressed higher in hair-growing epidermis and induced the proliferation of DP cells and activates telogen-phase HFs in vivo. Moreover, ET-1 promotes the proliferation and stemness of SKPs. Western blot analysis and in vivo experiments revealed that ET-1 induces the transition from telogen-to-anagen phase by upregulating the PI3K/AKT pathway. These findings highlight the potential of ET-1 as a promising cytokine for HF activation and the treatment of hair loss., (© 2024 Federation of American Societies for Experimental Biology.)

We had previously investigated the expression and functional role of C-X-C Motif Chemokine Ligand 12 (CXCL12) during the hair cycle progression. CXCL12 was highly expressed in stromal cells such as dermal fibroblasts (DFs) and inhibition of CXCL12 increased hair growth. Therefore, we further investigated whether a CXCL12 neutralizing antibody (αCXCL12) is effective for androgenic alopecia (AGA) and alopecia areata (AA) and studied the underlying molecular mechanism for treating these diseases. In the AGA model, CXCL12 is highly expressed in DFs. Subcutaneous (s.c.) injection of αCXCL12 significantly induced hair growth in AGA mice, and treatment with αCXCL12 attenuated the androgen-induced hair damage in hair organ culture. Androgens increased the secretion of CXCL12 from DFs through the androgen receptor (AR). Secreted CXCL12 from DFs increased the expression of the AR and C-X-C Motif Chemokine Receptor 4 (CXCR4) in dermal papilla cells (DPCs), which induced hair loss in AGA. Likewise, CXCL12 expression is increased in AA mice, while s.c. injection of αCXCL12 significantly inhibited hair loss in AA mice and reduced the number of CD8 + , MHC-I + , and MHC-II + cells in the skin. In addition, injection of αCXCL12 also prevented the onset of AA and reduced the number of CD8 + cells. Interferon-γ (IFNγ) treatment increased the secretion of CXCL12 from DFs through the signal transducer and activator of transcription 3 (STAT3) pathway, and αCXCL12 treatment protected the hair follicle from IFNγ in hair organ culture. Collectively, these results indicate that CXCL12 is involved in the progression of AGA and AA and antibody therapy for CXCL12 is promising for hair loss treatment.

Androgenetic alopecia (AGA), one of the most common forms of hair loss, lacks satisfactory treatment methods in modern society. This study employed an experimental design combining in vitro and in vivo approaches to explore the effects of Cyanidin-3-O-glucoside (C3G) and Carboxypyranocyanidin-3-O-glucoside (Vitisin A) on AGA. In human dermal papilla cells (HDPCs), both anthocyanins demonstrated inhibitory effects on androgen receptors, significantly reduced dihydrotestosterone (DHT) induced apoptosis of HDPCs, and regulated the secretion of Fibroblast growth factor 7 and Transforming growth factor beta 1. In vitro transdermal experiment revealed that both C3G and Vitisin A could penetrate mice skin, aided by the application of cream. Furthermore, in vivo experiments with mice indicated that application of C3G or Vitisin A cream effectively improved hair follicles miniaturization, regression, and apoptosis caused by DHT. The repression of Wnt10b and β-catenin expression induced by DHT was prevented by C3G and Vitisin A in both cell and mouse model. Consequently, these findings suggest that C3G and Vitisin A could be considered as alternative methods for alleviating AGA., Competing Interests: Declaration of competing interest The authors state that they have no conflicts of interest related to this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Androgenetic alopecia (AGA) has become a widespread problem that leads to considerable impairment of the psyche and daily life. The currently approved medications for the treatment of AGA are associated with significant adverse effects, high costs, and prolonged treatment duration. Therefore, natural products are being considered as possible complementary or alternative treatments. This review aims to enhance comprehension of the mechanisms by which natural products treat AGA. To achieve this, pertinent studies were gathered and subjected to analysis. In addition, the therapeutic mechanisms associated with these natural products were organized and summarized. These include the direct modulation of signaling pathways such as the Wnt/β-catenin pathway, the PI3K/AKT pathway, and the BMP pathway. Additionally, they exert effects on cytokine secretion, anti-inflammatory, and antioxidant capabilities, as well as apoptosis and autophagy. Furthermore, the review briefly discusses the relationship between signaling pathways and autophagy and apoptosis in the context of AGA, systematically presents the mechanisms of action of existing natural products, and analyzes the potential therapeutic targets based on the active components of these products. The aim is to provide a theoretical basis for the development of pharmaceuticals, nutraceuticals, or dietary supplements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

The plant Justicia procumbens is traditionally used in Asia to treat fever, cough, and pain. Previous studies have reported its anticancer and anti-asthmatic properties. However, its potential for preventing androgenic alopecia (AGA) has not yet been reported. AGA is a widespread hair loss condition primarily caused by male hormones. In this study, we examined the hair loss-preventing effects of an aqueous extract of J. procumbens (JPAE) using human hair follicle dermal papilla cell (HFDPC) and a mouse model of testosterone-induced AGA. JPAE treatment increased HFDPC proliferation by activating the Wnt/β-catenin signaling pathway. Additionally, JPAE increased the expression of Wnt targets, such as cyclin D1 and VEGF, by promoting the translocation of β-catenin to the nucleus. Administration of JPAE reduced hair loss, increased hair thickness, and enhanced hair shine in an AGA mouse model. Furthermore, it increased the expression of p-GSK-3β and β-catenin in the dorsal skin of the mice. These findings imply that JPAE promotes the proliferation of HFDPC and prevents hair loss in an AGA mouse model. JPAE can therefore be used as a functional food and natural treatment option for AGA to prevent hair loss., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Alopecia is a prevalent problem of cutaneous appendages and lacks effective therapy. Recently, researchers have been focusing on mesenchymal components of the hair follicle, i.e. dermal papilla cells, and we previously identified biglycan secreted by dermal papilla cells as the key factor responsible for hair follicle-inducing ability. In this research, we hypothesized biglycan played an important role in hair follicle cycle and regeneration through regulating the Wnt signalling pathway. To characterize the hair follicle cycle and the expression pattern of biglycan, we observed hair follicle morphology in C57BL/6 mice on Days 0, 3, 5, 12 and 18 post-depilation and found that biglycan is highly expressed at both mRNA and protein levels throughout anagen in HFs. To explore the role of biglycan during the phase transit process and regeneration, local injections were administered in C57BL/6 and nude mice. Results showed that local injection of biglycan in anagen HFs delayed catagen progression and involve activating the Wnt/β-catenin signalling pathway. Furthermore, local injection of biglycan induced HF regeneration and up-regulated expression of key Wnt factors in nude mice. In addition, cell analyses exhibited biglycan knockdown inactivated the Wnt signalling pathway in early-passage dermal papilla cell, whereas biglycan overexpression or incubation activated the Wnt signalling pathway in late-passage dermal papilla cells. These results indicate that biglycan plays a critical role in regulating HF cycle transit and regeneration in a paracrine and autocrine fashion by activating the Wnt/β-catenin signalling pathway and could be a potential treatment target for hair loss diseases., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dermal papilla cells (DPCs) undergo premature ageing in androgenetic alopecia and senescent alopecia. As critical components of hair follicle reconstruction, DPCs are also prone to senescence in vitro, resulting in a diminished hair follicle inductivity capacity. Dermal sheath cup cells (DSCCs), a specific subset of hair follicle mesenchymal stem cells, intimately linked to the function of DPCs. The primary objective of this research is to investigate the anti-ageing effect of exosomes derived from DSCCs (Exo DSCCs ) on DPCs. Exosomes were utilized to treat H 2 O 2 -induced DPCs or long-generation DPCs(P10). Our findings demonstrate that Exo DSCCs(P3) promote the proliferation, viability and migration of senescent DPCs while inhibiting cell apoptosis. The expression of senescence marker SA-β-Gal were significantly downregulated in senescent DPCs. When treated with Exo DSCCs(P3) , expression of inducibility related markers alkaline phosphatase and Versican were significantly upregulated. Additionally, Exo DSCCs(P3) activated the Wnt/β-catenin signalling in vitro. In patch assay, Exo DSCCs(P3) significantly promoted hair follicle reconstruction in senescent DPCs. In summary, our work highlights that Exo DSCCs(P3) may restore the biological functions and improve the hair follicle induction ability of senescent DPCs. Therefore, Exo DSCCs(P3) may represent a new strategy for intervening in the ageing process of DPCs, contributing to the prevention of senile alopecia., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Stress has been considered as a potential trigger for hair loss through the neuroendocrine-hair follicle (HF) axis. Neurotensin (NTS), a neuropeptide, is known to be dysregulated in the inflammatory-associated skin diseases. However, the precise role of NTS in stress-induced hair loss is unclear. To investigate the function and potential mechanisms of NTS in stress-induced hair growth inhibition, we initially detected the expression of neurotensin receptor (Ntsr) and NTS in the skin tissues of stressed mice by RNA-sequencing and ELISA. We found chronic restraint stress (CRS) significantly decreased the expression of both NTS and Ntsr in the skin tissues of mice. Intracutaneous injection of NTS effectively counteracted CRS-induced inhibition of hair growth in mice. Furthermore, NTS regulated a total of 1093 genes expression in human dermal papilla cells (HDPC), with 591 genes being up-regulated and 502 genes being down-regulated. GO analysis showed DNA replication, cell cycle, integral component of plasma membrane and angiogenesis-associated genes were significantly regulated by NTS. KEGG enrichment demonstrated that NTS also regulated genes related to the Hippo signalling pathway, axon guidance, cytokine-cytokine receptor interaction and Wnt signalling pathway in HDPC. Our results not only uncovered the potential effects of NTS on stress-induced hair growth inhibition but also provided an understanding of the mechanisms at the gene transcriptional level., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In a world where hair loss, acne, and skin whitening are common concerns, ethosomes emerge as a captivating breakthrough in cosmetic drug delivery., Method: This review provides a comprehensive overview of the ethosomal system and assesses its potential as an effective nanocarrier for delivering active ingredients to the skin. The focus is on exploring their applications in various pathologies, particularly skin disorders such as acne, hair loss, and skin pigmentation., Results: Ethosomes are a novel type of vesicular nanocarrier composed of high concentrations of ethanol (20-45%) and phospholipids. Their unique structure and composition make them an ideal choice for transporting active ingredients through the skin, offering targeted and effective treatment. The inclusion of ethanol in ethosomes' composition gives them distinctive properties, including flexibility, deformability, and stability, facilitating deep penetration into the skin and enhancing medication deposition. Moreover, ethosomes improved theoverall drug-loading capacity, and specificity of target treatment CONCLUSION: Ethosomes represent a unique and suitable approach for delivering active cosmetic ingredients in the treatment of hair loss, acne, and skin whitening, presenting a versatile alternative to traditional dermal delivery systems. Despite the challenges associated with their complex preparation and sensitivity to temperature and humidity, the remarkable potential benefits of ethosomes cannot be ignored. Further research is crucial to unlock their full potential, understand their limitations, and refine their formulations and administration methods. Ethosomes hold the promise of transforming the way we address these cosmetic concerns, offering an exciting glimpse into the future of advanced skincare solutions., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

The health of hair is directly related to people's health and appearance. Hair has key physiological functions, including skin protection and temperature regulation. Hair follicle (HF) is a vital mini-organ that directly impacts hair growth. Besides, various signaling pathways and molecules regulate the growth cycle transition of HFs. Hair and its regeneration studies have attracted much interest in recent years with the increasing rate of alopecia. Mesenchymal stem cells (MSCs), as pluripotent stem cells, can differentiate into fat, bone, and cartilage and stimulate regeneration and immunological regulation. MSCs have been widely employed to treat various clinical diseases, such as bone and cartilage injury, nerve injury, and lung injury. Besides, MSCs can be used for treatment of hair diseases due to their regenerative and immunomodulatory abilities. This review aimed to assess MSCs' treatment for alopecia, pertinent signaling pathways, and new material for hair regeneration in the last 5 years.

Hair loss is a debilitating condition associated with the depletion of dermal papilla cells (DPCs), which can be replenished by dermal sheath cells (DSCs). Hence, strategies aimed at increasing the populations of DPCs and DSCs hold promise for the treatment of hair loss. In this study, we demonstrated in mice that introduced exogenous DPCs and DSCs (hair follicle mesenchymal stem cells) could effectively migrate and integrate into the dermal papilla and dermal sheath niches, leading to enhanced hair growth and prolonged anagen phases. However, the homing rates of DPCs and DSCs were influenced by various factors, including recipient mouse depilation, cell passage number, cell dose, and immune rejection. Through in vitro and in vivo experiments, we also discovered that the CXCL13/CXCR5 pathway mediated the homing of DPCs and DSCs into hair follicle niches. This study underscores the potential of cell-based therapies for hair loss by targeted delivery of DPCs and DSCs to their respective niches and sheds light on the intriguing concept that isolated mesenchymal stem cells can home back to their original niche microenvironment.

Androgenetic alopecia (AGA), also known as male pattern baldness, is a common hair loss condition influenced by genetic and hormonal factors. Variations in gene expression and androgen responsiveness have been observed between the frontal and occipital regions of AGA patients. However, obtaining and cultivating frontal hair follicles is challenging. Therefore, no matched frontal and occipital dermal papilla (DP) cell lines have been reported yet. This study aimed to establish matched immortalized human frontal and occipital scalp DP cell lines from AGA patients. Simian virus 40 large T antigen (SV40T-Ag) and human telomerase reverse transcriptase (hTERT) were introduced into primary human DP cells. The obtained cell lines were characterized by assessing their gene expression patterns, androgen receptor (AR) levels, and the presence of 5-alpha reductase (5αR). Additionally, we examined their response to dihydrotestosterone (DHT) and evaluated cell viability. The conditioned medium from the frontal DP cell line inhibited human hair follicle growth, leading to reduced keratinocyte proliferation and increased apoptosis. Furthermore, when the cells were cultured in a 3D environment mimicking in vivo conditions, the 3D cultured frontal DP cell line exhibited weaker sphere aggregation than the occipital DP cell line due to the increased expression of matrix metalloproteinase 1 (MMP1), MMP3, and MMP9. Additionally, the expression of DP signature genes was inhibited in the 3D cultured frontal DP cell line. These matched frontal and occipital DP cell lines hold significant potential as valuable resources for research on hair loss. Their establishment allows us to investigate the differences between frontal and occipital DP cells, contributing to a better understanding of the molecular mechanisms underlying AGA. Furthermore, these cell lines may be valuable for developing targeted therapeutic approaches for hair loss conditions., (© 2023. The Author(s).)

Peptidylarginine deiminases (PADs) transform a protein arginine residue into the non-standard amino acid citrulline. This calcium-dependent post-translational modification of proteins is called citrullination or deimination. As described in this special issue, PADs play a role in various physiological processes, and PAD deregulations are involved in many human diseases. Three PADs are expressed in the epidermis, where their roles begin to be deciphered. PAD1 and PAD3 are involved in keratinocyte differentiation, particularly in the epidermal barrier function, keratins, filaggrin and filaggrin-related proteins being the most abundant deiminated epidermal proteins. Reduced amounts of deiminated proteins and PAD1 expression may be involved in the pathogenesis of psoriasis and atopic dermatitis, two very frequent and chronic skin inflammatory diseases. The trichohyalin/PAD3/transglutaminase three pathway is important for hair shaft formation. Mutations of the PADI3 gene, leading to a decreased activity or abnormal localization of the corresponding isotype, are the cause of a rare hair disorder called uncombable hair syndrome, and are associated with the central centrifugal cicatricial alopecia, a frequent alopecia mainly affecting women of African ancestry. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

Androgenetic alopecia (AGA) is the most common type of hair loss caused by dihydrotestosterone (DHT) binding to androgen receptors in dermal papilla cells (DPCs). Photobiomodulation (PBM) is a promising treatment for AGA but suffers from inconsistent outcomes and inconsistent effective light parameters. This study investigated the impact of red light at various irradiances on normal and DHT-treated DPCs. Our results suggested that red light at 8 mW/cm 2 was most effective in promoting DPCs growth. Furthermore, a range of irradiances from 2 to 64 mW/cm 2 modulated key signaling pathways, including Wnt, FGF, and TGF, in normal and DHT-treated DPCs. Interestingly, 8 mW/cm 2 had a greater impact on these pathways in DHT-treated DPCs and altered the Shh pathway, suggesting that the effect of PBM varies with the cellular environment. This study highlights specific factors that influence PBM effectiveness and provides insight into the need for personalized PBM treatment approaches., (© 2023 Wiley-VCH GmbH.)

Background: Exosomes are small extracellular vesicles with potential roles in modulating the hair growth cycle and are an emerging therapy for patients with alopecia. In recent years, researchers have made significant progress in deciphering the network of cellular interactions and signaling pathways mediated by the transfer of exosomes. This has opened the door to a wide range of potential therapeutic applications with an increasing focus on its application in precision medicine., Aim: To evaluate current published evidence, both preclinical and clinical, on the use of exosomes for hair restoration., Methods: In January 2023, a systematic search was conducted using PubMed, Embase, and the Cochrane Library. Records were identified, screened, and assessed for eligibility as per the PRISMA guideline., Results: We identified 16 studies (15 preclinical and 1 clinical) showing varying degrees of efficacy using exosomes derived from sources including adipose-derived stem cells (ADSCs) and dermal papilla cells (DPCs). Applications of exosomes isolated from ADSCs (ADSC-Exo) and DPCs have shown early promising results in preclinical studies corroborated by results obtained from different model systems. Topical ADSC-Exo has been tried successfully in 39 androgenetic alopecia patients demonstrating significant increases in hair density and thickness. No significant adverse reactions associated with exosome treatment have been reported thus far., Conclusions: Although current clinical evidence supporting the use of exosome treatment is limited, there is a growing body of evidence suggesting its therapeutic potential. Further studies are warranted to define its mechanism of action, optimize its delivery and efficacy, and to address important safety concerns., (© 2023 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Hair loss caused by the abnormal functions of hair follicles in skin can seriously impact the quality of an individual's life. The development of sophisticated skin tissue-engineered constructs is required to enable the function recovery of hair follicles. However, effective hair regrowth in skin substitutes still remains a great challenge. In this study, a 3D multicellular micropattern was successfully fabricated by arranging the hair follicle-related cells orderly distributed in the interval of vascular-cell networks via bioprinting technology. By combining the stable biomimetic micropattern structure and the bio-inducing substrate incorporated with magnesium silicate (MS) nanomaterials, the 3D multicellular micropattern possessed significant follicular potential and angiogenic capacity in vitro . Furthermore, the 3D multicellular micropattern with MS incorporation contributed to efficient hair regrowth during skin tissue regeneration in both immunodeficient mice and androgenetic alopecia (AGA) mice models. Thus, this study proposes a novel 3D micropatterned multicellular system assembling a biomimetic micro-structure and modulating the cell-cell interaction for hair regeneration during skin reconstruction.

Despite advancements in medical research, androgenetic alopecia (AGA) remains a humankind problem that still needs to be overcome. To date, clinical practice lacks an ideal treatment for AGA. The Wnt/β-catenin signaling pathway is evidenced to play a key role in hair regrowth, hence, modulating this signaling pathway for AGA therapy appears to be rational. One of the major inhibitors of the canonical Wnt/β-catenin signaling pathway is dickkopf-related protein 1 (DKK1). In this report, we have selected a small interfering RNA (siRNA) targeting DKK1 in vitro via qPCR and then tested its efficacy in vivo on the depilated dorsal skin of the mice. The changes in hair growth in different groups were observed over time. Moreover, the visual observation of the hair growth and hematoxylin and eosin (HE) staining showed that DKK1-targeting siRNA reveals non-inferior results compared with the mice treated with the Food and Drug Administration (FDA)-approved, commercially available minoxidil (5%) topical solution that was used as a positive control. Both- positive control and DKK1-targeting siRNA groups demonstrated significantly superior results compared with the control group that received negative control siRNA. Consequently, siRNAs targeting DKK1 may promote hair growth regulation in the AGA population via potentially activating the Wnt/β-catenin signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The hair growth cycle consists of the anagen, catagen, and telogen phases, and hair follicle dermal papilla (HDP) cells of human hair play a role in the initiation and maintenance of the anagen phase. Reduction in HDP cells contributes to hair loss; however, the limited treatment options are associated with negative side effects. Therefore, a naturally derived substance with hair loss-preventing properties is needed., Aim: We investigated the hair growth-stimulating activities of Plantago asiatica L. extract (PAE) and its molecular mechanism in HDP cells., Methods: Cell proliferation was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide solution. Relative mRNA and protein expression levels of hair growth factors were determined using quantitative real-time polymerase chain reaction and western blotting, respectively. Additionally, a tube formation assay was performed in human umbilical vein endothelial cells (HUVEC)., Results: Plantago asiatica L. extract significantly increased the cell proliferation and expression of hair growth factors, including keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2) and MYC, in HDP cells. Moreover, PAE led to the accumulation of β-catenin by promoting the phosphorylation of glycogen synthase kinase-3 beta (GSK-3β) at Ser9 and cAMP response element-binding protein (CREB) at Ser133 via phosphorylation of extracellular signal-regulated kinase (ERK) (Thr202/Tyr204). PAE also increased tube formation in HUVECs, which promoted angiogenesis for the anagen phase., Conclusions: Plantago asiatica L. extract amplified tube formation and production of growth factors (KGF, VEGF) via the activation of GSK-3β/β-catenin and mitogen-activated protein kinase (MAPK)/CREB signaling pathways, demonstrating its potential to safely promote hair growth by inducing the anagen phase., (© 2023 J2KBIO. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Objective: To determine the expression level of Sonic hedgehog (Shh) in the passage of hair follicle stem cells (HFSCs), analyze the effect of Shh overexpression on the proliferation activity of HFSCs, and explore the survival of HFSCs after Shh overexpression and its effect on hair follicle regeneration., Methods: Hair follicles from the normal area (H1 group) and alopecia area (H2 group) of the scalp donated by 20 female alopecia patients aged 40-50 years old were taken, and the middle part of the hair follicle was cut under the microscope to culture, and the primary HFSCs were obtained and passaged; the positive markers (CD29, CD71) and negative marker (CD34) on the surface of the fourth generation HFSCs were identified by flow cytometry. The two groups of HFSCs were transfected with Shh-overexpressed lentivirus. Flow cytometry and cell counting kit 8 assay were used to detect the cell cycle changes and cell proliferation of HFSCs before and after transfection, respectively. Then the HFSCs transfected with Shh lentivirus were transplanted subcutaneously into the back of nude mice as the experimental group, and the same amount of saline was injected as the control group. At 5 weeks after cell transplantation, the expression of Shh protein in the back skin tissue of nude mice was detected by Western blot. HE staining and immunofluorescence staining were used to compare the number of hair follicles and the survival of HFSCs between groups., Results: The isolated and cultured cells were fusiform and firmly attached to the wall; flow cytometry showed that CD29 and CD71 were highly expressed on the surface of the cells, while CD34 was lowly expressed, suggesting that the cultured cells were HFSCs. The results of real-time fluorescence quantitative PCR and Western blot showed that the expression levels of Shh protein and gene in the 4th, 7th, and 10th passages of cells in H1 and H2 groups decreased gradually with the prolongation of culture time in vitro . After overexpression of Shh, the proliferation activity of HFSCs in the two groups was significantly higher than that in the blank group (not transfected with lentivirus) and the negative control group (transfected with negative control lentivirus), and the proliferation activity of HFSCs in H1 group was significantly higher than that in H2 group before and after transfection, showing significant differences ( P <0.05). At 5 weeks after cell transplantation, Shh protein was stably expressed in the dorsal skin of each experimental group; the number of hair follicles and the expression levels of HFSCs markers (CD71, cytokeratin 15) in each experimental group were significantly higher than those in the control group, and the number of hair follicles and the expression levels of HFSCs markers in H1 group were significantly higher than those in H2 group, and the differences were significant ( P <0.05)., Conclusion: Lentivirus-mediated Shh can be successfully transfected into HFSCs, the proliferation activity of HFSCs significantly increase after overexpression of Shh, which can secrete and express Shh continuously and stably, and promote hair follicle regeneration by combining the advantages of stem cells and Shh.

Many people suffer from hair loss and abnormal skin pigmentation, highlighting the need for simple assays to support drug discovery research. Current assays have various limitations, such as being in vitro only, not sensitive enough, or unquantifiable. We took advantage of the bilateral symmetry and large size of mouse whisker follicles to develop a novel in vivo assay called "whisker follicle microinjection assay". In this assay, we plucked mouse whiskers and then injected molecules directly into one side of the whisker follicles using microneedles that were a similar size to the whiskers, and we injected solvent on the other side as a control. Once the whiskers grew out again, we quantitatively measured their length and color intensity to evaluate the effects of the molecules on hair growth and coloring. Several chemicals and proteins were used to test this assay. The chemicals minoxidil and ruxolitinib, as well as the protein RSPO1, promoted hair growth. The effect of the clinical drug minoxidil could be detected at a concentration as low as 0.001%. The chemical deoxyarbutin inhibited melanin production. The protein Nbl1 was identified as a novel hair-growth inhibitor. In conclusion, we successfully established a sensitive and quantitative in vivo assay to evaluate the effects of chemicals and proteins on hair growth and coloring and identified a novel regulator by using this assay. This whisker follicle microinjection assay will be useful when investigating protein functions and when developing drugs to treat hair loss and abnormal skin pigmentation.

Pathological hair loss (also known as alopecia) and shortage of hair follicle (HF) donors have posed an urgent requirement for HF regeneration. With the revelation of mechanisms in tissue engineering, the proliferation of HFs in vitro has achieved more promising trust for the treatments of alopecia and other skin impairments. Theoretically, HF organoids have great potential to develop into native HFs and attachments such as sweat glands after transplantation. However, since the rich extracellular matrix (ECM) deficiency, the induction characteristics of skin-derived cells gradually fade away along with their trichogenic capacity after continuous cell passaging in vitro. Therefore, ECM-mimicking support is an essential prelude before HF transplantation is implemented. This review summarizes the status of providing various epidermal and dermal cells with a three-dimensional (3D) scaffold to support the cell homeostasis and better mimic in vivo environments for the sake of HF regeneration. HF-relevant cells including dermal papilla cells (DPCs), hair follicle stem cells (HFSCs), and mesenchymal stem cells (MSCs) are able to be induced to form HF organoids in the vitro culture system. The niche microenvironment simulated by different forms of biomaterial scaffold can offer the cells a network of ordered growth environment to alleviate inductivity loss and promote the expression of functional proteins. The scaffolds often play the role of ECM substrates and bring about epithelial-mesenchymal interaction (EMI) through coculture to ensure the functional preservation of HF cells during in vitro passage. Functional HF organoids can be formed either before or after transplantation into the dermis layer. Here, we review and emphasize the importance of 3D culture in HF regeneration in vitro. Finally, the latest progress in treatment trials and critical analysis of the properties and benefits of different emerging biomaterials for HF regeneration along with the main challenges and prospects of HF regenerative approaches are discussed.

Oleanolic acid (OA) is a pentacyclic triterpenoid with favourable physiological activity. It is widely distributed in more than 200 species of plants. OA has garnered significant interest because of its potential biological activities, such as antioxidant, bacteriostatic, and hair growth-promoting effects. To study the effect of OA on hair growth and related mechanisms, we investigated hair growth in mice with testosterone-induced androgenetic alopecia (AGA) that were treated with three different concentrations of OA. The antioxidant, bacteriostatic, and cytotoxic effects of OA were evaluated. We found that mice with testosterone-induced AGA treated with 1% or 0.5% OA showed significantly enhanced hair growth and increased vascular endothelial growth factor/glyceraldehyde-3-phosphate dehydrogenase ratio and levels of fibroblast growth factor receptor and insulin-like growth factor 1. Using an immunofluorescence staining assay, we demonstrated that β-catenin, a key Wnt signalling transducer, was highly expressed in the OA-treated groups. These results suggest that OA may promote hair growth by stimulating hair matrix cell proliferation via the Wnt/β-catenin pathway and lowering the levels of tumour necrosis factor-alpha, and transforming growth factor-beta 1, dihydrotestosterone, and 5α-reductase., Competing Interests: The authors report no conflicts of interest in this work.

Androgenetic alopecia is a condition that results in hair loss in both men and women. This can have a significant impact on a person's psychological well-being, which can lead to a decreased quality of life. We conducted a systematic review to evaluate the efficacy of using stem cells in androgenic alopecia. The search was conducted in MEDLINE via PubMed, Web of Science, and Scopus databases. The review was performed on data pertaining to the efficacy of using different types of stem cells in androgenic alopecia: quantitative results of stem cell usage were compared to the control treatment or, different types of treatment for female and male androgenetic alopecia. Of the outcomes, the density of hair was analyzed. Fourteen articles were selected for this review. During and after treatment with stem cells, no major side effects were reported by patients with alopecia. The use of stem cells in androgenic alopecia seems to be a promising alternative to the standard treatment or it could play the role of complementary therapy to improve the effect of primary treatment. However, these results should be interpreted with caution until they can be reproduced in larger and more representative samples.