Glycogen Phosphorylase Inhibitor Promotes Hair Growth via Protecting from Oxidative-Stress and Regulating Glycogen Breakdown in Human Hair follicles.

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

Combining multiomics to analyze the molecular mechanism of hair follicle cycle change in cashmere goats from Inner Mongolia.

Sheep body size can directly reflect the growth rates and fattening rates of sheep and is also an important index for measuring the growth performance of meat sheep.Inner Mongolia Cashmere Goat is a local excellent breed of cashmere and meat dual-purpose, which is a typical heterogeneous indumentum. The hair follicles cycle through periods of vigorous growth (anagen), a regression caused by apoptosis (catagen), and relative rest (telogen). At present, it is not clear which genes affect the cycle transformation of hair follicles and unclear how proteins impact the creation and expansion of hair follicles.we using multi-omics joint analysis methodologies to investigated the possible pathways of transformation and apoptosis in goat hair follicles. The results showed that 917,1,187, and 716 proteins were specifically expressed in anagen, catagen andtelogen. The result of gene ontology (GO) annotation showed that differentially expressed proteins (DEPs) are in different growth cycle periods, and enriched GO items are mostly related to the transformation of cells and proteins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment result indicated that the apoptosis process has a great impact on hair follicle's growth cycle. The results of the protein interaction network of differential proteins showed that the ribosomal protein family (RPL4, RPL8, RPS16, RPS18, RPS2, RPS27A, RPS3) was the core protein in the network. The results of combined transcriptome and proteomics analysis showed that there were 16,34, and 26 overlapped DEGs and DEPs in the comparison of anagen VS catagen, catagen VS telogen and anagen VS telogen, of which API5 plays an important role in regulating protein and gene expression levels. We focused on API5 and Ribosomal protein and found that API5 affected the apoptosis process of hair follicles, and ribosomal protein was highly expressed in the resting stage of hair follicles. They are both useful as molecular marker candidate genes to study hair follicle growth and apoptosis,and they both have an essential function in the cycle transition process of hair follicles. The results of this study may provide a theoretical basis for further research on the growth and development of hair follicles in Inner Mongolian Cashmere goats.

The expression of congenital Shoc2 variants induces AKT-dependent crosstalk activation of the ERK1/2 pathway.

The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-Regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary variants in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these variants affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. In cells expressing the Shoc2 NSLH mutants, we found that the AKT signaling pathway triggers the PAK activation, followed by phosphorylation of Raf-1/MEK1/2 and activation of the ERK1/2 signaling axis. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide additional evidence for the role of Shoc2 as a "gatekeeper" in controlling the selection of downstream effectors within the EGFR signaling network.

Effects of Seasonality and Pregnancy on Hair Loss and Regrowth in Rhesus Macaques.

Several studies have examined the etiology of alopecia, or hair loss, in rhesus macaques. While outcomes differ across studies, some commonalities have emerged. Females, particularly pregnant females, show more alopecia than males, and alopecia follows a seasonal pattern. Much research has explored causes of hair loss; however, alopecia can result from lack of hair growth in addition to hair loss. To better understand how sex, reproductive state, and season affect alopecia, we followed 241 rhesus macaques (Macaca mulatta) in outdoor breeding groups over one year, recording both alopecia severity and presence of hair regrowth. We found that both alopecia and hair regrowth followed a seasonal pattern; alopecia was highest in spring and lowest in late summer, while regrowth started in spring and peaked in late summer. Reproductive state also correlated with both alopecia and hair growth. Females in their third trimester had the highest average level of alopecia and the lowest amount of hair regrowth. Regrowth resumed postpartum, regardless of whether females were rearing an infant. Results indicate that the seasonal pattern of alopecia is due in part to the seasonal limitations on hair regrowth, and that breeding, which also occurs seasonally in rhesus macaques, may further suppress hair regrowth.

Keratin Microspheres as Promising Tool for Targeting Follicular Growth.

Skin is the body barrier that constrains the infiltration of particles and exogenous aggression, in which the hair follicle plays an important role. Recent studies have shown that small particles can penetrate the skin barrier and reach the hair follicle, making them a potential avenue for delivering hair growth-related substances. Interestingly, keratin-based microspheres are widely used as drug delivery carriers in various fields. In this current study, we pursue the effect of newly synthesized 3D spherical keratin particles on inducing hair growth in C57BL/6 male mice and in human hair follicle dermal papilla cells. The microspheres were created from partially sulfonated, water-soluble keratin. The keratin microspheres swelled in water to form spherical gels, which were used for further experiments. Following topical application for a period of 20 days, we observed a regrowth of hair in the previously depleted area on the dorsal part of the mice in the keratin microsphere group. This observation was accompanied by the regulation of hair-growth-related pathways as well as changes in markers associated with epidermal cells, keratin, and collagen. Interestingly, microsphere keratin treatment enhanced the cell proliferation and the expression of hair growth markers in dermal papilla cells. Based on our data, we propose that 3D spherical keratin has the potential to specifically target hair follicle growth and can be employed as a carrier for promoting hair growth-related agents.

Pressure alopecias: A review.

Pressure-induced alopecias (PAs) are an infrequent group of scarring and nonscarring alopecias that occur after ischemic obstruction of capillaries that leads to circumscribed areas of hair loss. Initially described after prolonged surgeries or immobilization, type 1 PA occurs after sustained external pressure to the skin, mainly the scalp prominences. Alopecia induced by cosmetic procedures, referred in this review as type 2 PA, is reported with increased frequency in literature and predominantly emerges from pressure exerted by the volume of injectables. It is important to differentiate type 2 PA from vascular occlusion-induced alopecia because they represent distinct entities. Clinically, PA may present with erythema, swelling, and tenderness; however, alopecia might be the sole manifestation. Crusts and ulceration are associated with a worse outcome and a higher risk of scarring alopecia. Prompt diagnosis is paramount to prevent complications. Trichoscopy, although considered nonspecific, may provide relevant clues for an accurate diagnosis. Hair regrows in most cases, but prognosis depends on ischemia severity and timely treatment with reperfusion therapies or mobilization. Treatment of hair loss is usually not necessary because the disease in most cases is self-limited and reversible. The role of topical minoxidil and corticosteroids remains unknown.

Demonstration of direct immunofluorescence on three substrates in a case of pemphigus.

Direct immunofluorescence (DIF) on skin is considered as the gold standard in the diagnosis of pemphigus. However, alternate substrates can be used. We demonstrate DIF on three substrates, skin biopsy specimen, anagen hair and scrapings of oral erosions. Collection of alternative substrates can be more acceptable to young patients as it is less invasive. It may also be used to detect relapses in cases of pemphigus.

Effects of the Complex of Panicum miliaceum Extract and Triticum aestivum Extract on Hair Condition.

Proso millet (Panicum miliaceum L.) and common wheat (Triticum aestivum L.) have been used as major crops in multiple regions since ancient times, and they contain various nutrients that can affect human hair health. This study investigated the various biological effects of a complex of millet extract and wheat extract (MWC) on hair health. Human immortalized dermal papilla cells (iDPCs) for an in vitro study and an anagen-synchronized mouse model for an in vivo study were employed. These findings revealed that the application of the MWC in vitro led to an increase in the mRNA levels of antioxidant enzymes (catalase and SOD1), growth factors (IGF-1, VEGF, and FGF7), and factors related to hair growth (wnt10b, ß-catenin) while decreasing inflammatory cytokine mRNA levels (IL-6 and TNFα). The mRNA levels of hair follicles (HFs) in the dorsal skin of the mouse model in the early and late telogen phases were also measured. The mRNA levels in the in vivo study showed a similar alteration tendency as in the in vitro study in the early and late telogen phases. In this model, MWC treatment elongated the anagen phase of the hair cycle. These findings indicate that the MWC can suppress oxidative stress and inflammation and may elongate the anagen phase by enhancing the growth factors involved in the wnt10b/ß-catenin signaling pathway. This study suggests that the MWC might have significant potential as a functional food for maintaining hair health.

LncRNAs regulate the cyclic growth and development of hair follicles in Dorper sheep.

Introduction: Hair follicles in Dorper sheep are characterized by seasonal cyclic growth and development, consequently resulting in hair shedding during spring. The cyclic growth and development of hair follicles are regulated by several influencing factors such as photoperiods, hormones, age of the animal, genes, long non-coding RNAs (lncRNAs), and signaling pathways. Methods: In the present study, skin samples of five shedding sheep (S), used as experimental animals, and three non-shedding sheep (N), used as controls, were collected at three time points (September 27, 2019; January 3, 2020; and March 17, 2020) for RNA sequencing (RNA-seq) technology. Nine different groups (S1-vs-S2, S1-vs-S3, S2-vs-S3, N1- vs-N2, N1-vs-N3, N2-vs-N3, S1-vs-N1, S2-vs-N2, and S3-vs-N3) were compared using FDR < 0.05 and log 21 FC >as thresholds to assess the differences in the expression of lncRNAs. Results and discussion: In total, 395 differentially expressed (DE) lncRNAs were screened. Cluster heatmap analysis identified two types of expression patterns, namely, high expression during the anagen phase (A pattern) and high expression during the telogen phase (T pattern). Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that the target genes were largely enriched in the Estrogen signaling pathway, PI3K-Akt signaling pathway, Fc gamma R-mediated phagocytosis, and cell adhesion molecules (CAMs), which are associated with hair follicle cyclic growth and development-related pathways. In addition, 17 pairs of lncRNAs-target genes related to hair follicle cyclic growth and development were screened, and a regulatory network was constructed. Altogether, candidate lncRNAs and their regulated target genes were screened that contributed to sheep hair follicle cyclic growth and development. We believe these findings will provide useful insights into the underlying regulatory mechanisms.

Medication-induced hair loss: An update.

This article discusses drug-induced hair loss, which can occur with many drugs including cytotoxic agents, biologics, and immunomodulating agents, among others. It outlines the diagnosis and management of drug-induced alopecia, with a focus on recently implicated drugs.

A Rare Type of Radiation-Induced Alopecia: Proton-Induced Alopecia.

Introduction: Radiation-induced alopecia (RIA) is a side effect resulting from cranial radiation therapy (RT) and it can be temporary or permanent. In cancer patients, RIA is a less frequent event than chemotherapy-induced alopecia, although the former is more likely to cause permanent hair loss. It is characterized initially by intense anagen effluvium caused by acute dose-dependent damage to the matrix cells of anagen follicles. Proton therapy (PT) is a specific type of RT used in the treatment of brain tumors, which sometimes can cause proton-induced alopecia (PIA), a rare subtype of RIA. Below, we report a case of a patient who presented PIA following PT treatment of a meningioma of the frontal region. Case Presentation: A 38-year-old female patient presented to our trichology outpatient clinic for widespread hair loss in the frontal region. Following a diagnosis of meningioma of the frontal region 3 years ago, adjuvant radiotherapy treatment of the frontal region with scanning beam PT (mean dose of 45 Gy) was performed. Two weeks after the end of treatment, the patient came to our attention with diffuse hair loss at the level of the PT-treated area. Trichoscopy showed flame hairs, broken hairs, black dots, and pigtail hairs. A diagnosis of PIA was established, and topical treatment with minoxidil 5% solution twice a day was initiated. At the follow-up visit after 4 months, the patient had total hair regrowth. Conclusion: PIA is a subtype of RIA still poorly studied in the literature. Hair loss is caused by aggression by radiations of the hair follicle in the anagen phase, leading to an interruption of the mitotic activity of the matrix cells. The cells of the follicular bulb are characterized by marked mitotic activity at this stage and are consequently more susceptible to cytotoxic damage. All this causes tightening of the proximal portion of the hair shaft, increasing its fragility and susceptibility to breakage.

Prospective Efficacy and Safety Study of an Innovative Kerascalp Hair Growth Serum in Mild-to-Moderate Alopecia in India: Regrowth Study.

BACKGROUND AND AIM: Male and female pattern baldness, commonly known as androgenetic alopecia is the most common type of alopecia, often predetermined genetically, which generally affects the scalp and is characterized by progressive terminal hair loss, known as miniaturization. This study aimed to assess the safety and efficacy of Kerascalp hair serum, a unique combination of esculin, ximenynic acid, and lauric acid, extracted from natural sources in subjects with mild to moderate androgenetic alopecia. METHODS: An open-label, single-arm clinical study was conducted on healthy males and females aged 18-60 years. Each subject applied the hair serum once daily for 90 days. The efficacy of hair serum was evaluated in terms of the following outcome variables: anagen and telogen ratio (A:T ratio), hair thickness, hair density, hair fall, and hair strength assessment. Subjects were assessed on day 0, day 30, day 60, day 90, and on follow-up day 120. RESULTS: Thirty subjects completed all assessment visits. After using the hair serum for 90 days, statistically significant (p<0.0001) improvement was observed in A:T ratio, hair density, hair thickness, and hair strength; a statistically significant reduction (p<0.0001) in hair fall was also observed. Moreover, improvement in general appearance of hair (in terms of hair volume and density) and scalp (in terms of itchiness, redness, roughness, and dryness) was recorded through dermatological assessment at each treatment visit and at follow-up visit compared to baseline. No adverse event was recorded during the study period, and on follow-up. CONCLUSIONS: The results of this clinical study suggest that a 90 days treatment with a phyto-ingredient-based Kerascalp hair serum is safe and effective in significantly improving A:T ratio, hair density, hair thickness, and hair strength, while reducing hair shedding. The improvement in the test parameters persists, even 30 days after stopping the usage of the serum.

Commonly prescribed medications associated with alopecia.

BACKGROUND: The diagnosis and treatment of medication-associated alopecia often challenges patients and physicians. While numerous studies on the topic exist, limited information on the strength and magnitude of these studies exists. OBJECTIVES: We investigated the most commonly prescribed medications with high levels of evidence to support associations with alopecia. METHODS: A list of most commonly prescribed medications was compiled using the "Top 100 Prescriptions, Sales" (Intercontinental Marketing Services) and "Top 200 Names Searched" (RxList.com). PubMed, Embase, and Web of Science were searched for "generic drug name" AND "alopecia" and "generic drug name" AND "hair loss." Two reviewers independently reviewed articles for drug, study type and level of evidence, and number of alopecia cases. RESULTS: A total of 192 unique drugs were investigated, with 110 yielding positive search results. Of these, 13 were associated with alopecia in studies with strong levels of evidence (adalimumab, infliximab, budesonide, interferon ß-1α, tacrolimus, enoxaparin, zoster vaccine, lamotrigine, docetaxel, capecitabine, erlotinib, imatinib, and bortezomib). LIMITATIONS: Only full-length articles available in the English language were included. The methodology used relied on lists of drugs based on their sales rather than number of prescriptions, which likely overrepresented expensive drugs. CONCLUSIONS: Few studies with high levels of evidence have been conducted on the topic of medication-associated alopecia. The mechanisms of hair loss must be further identified to provide effective management.

A very mild phenotype in six individuals of a three-generation family with the novel HRAS variant c.176C > G p.(Ala59Gly): Emergence of a new HRAS-related RASopathy distinct from Costello syndrome.

Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in HRAS. The vast majority of affected patients share recurring variants affecting HRAS codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the HRAS variant c.176C>T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome-like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS-related RASopathy for patients carrying HRAS variants affecting codons 58, 59, 60.

Dietary marine-derived ingredients for stimulating hair cell cycle.

In normal condition human hair growth occurs through three phases, anagen (growth phase included about 85 % of hairs, last from 2 to 6 years), catagen (transitional phase lasting up to 2 weeks) and telogen (resting phase which last from 1 to 4 months). Natural dynamics of the hair growth process can be impaired by several factors, such as genetic predisposition, hormonal disorders, aging, poor nutrition or stress, which can lead to the slowdown in the growth of hair or even hair loss. The aim of the study was to assess the hair growth promotion effect of marine-derived ingredients, hair supplement Viviscal® and its raw components (marine protein complex AminoMarC®, shark and oyster extract). Cytotoxicity, production of alkaline phosphatase and glycosaminoglycans, as well as expression of genes involved in hair cycle-related pathways were investigated using dermal papilla cells, both immortalized and primary cell lines. Tested marine compounds showed no evidence of cytotoxicity under in vitro conditions. Viviscal® significantly increased proliferation of dermal papilla cells. Moreover, tested samples stimulated cells to produce alkaline phosphatase and glycosaminoglycans. Increased expression of hair cell cycle-related genes was also observed. The obtained results indicate that marine-derived ingredients stimulate hair growth through anagen activation.

The effects of GPR40 agonists on hair growth are mediated by ANGPTL4.

GPR40 is found primarily in pancreatic ß cells, and is well known to regulate insulin secretion. Despite numerous studies on GPR40, the role and functions of GPR40 related to hair growth are not yet known. The current study investigated hair growth promoting effect of the GPR40 agonists and its mechanism of action using various bio-informatics tools, in vitro and animal experiments. GPR40 may affect the hair cycle, according to clustering and Gene Set Enrichment Analysis (GSEA). Hair growth effect of GPR40 was validated by telogen-to-anagen transition and vibrissae organ culture in the mouse. GPR40 was predominantly expressed in the outer root sheath (ORS) in anagen stage, suggesting that ORS cell is the target of GPR40 agonists. To investigate the mechanism of action for GPR40 agonists' hair growth effect, Gene Ontology (GO) enrichment analysis was performed and it revealed that GPR40 agonists were associated with angiogenesis. ANGPTL4, known for promoting angiogenesis, was highly up-regulated after GPR40 agonists treatment in the hORS cells, and also increased the proliferation and migration. Furthermore, GPR40 agonists promoted hair growth by inducing angiogenesis via ANGPTL4 in the animal experiment. GPR40 agonists activated MAPK and peroxisome proliferator-activated receptors (PPARγ) pathway in hORS cells, while the inhibition of MAPK pathway attenuated ANGPTL4 expression. Finally, GPR40 agonists increased hair growth via autocrine effects in the ORS cells, and induced angiogenesis through paracrine effects by upregulating ANGPTL4 via p38 and PPARγ pathways. As a result, GPR40 agonists have potential as a therapeutic drug for hair loss treatment.

MiR-21 regulated hair follicle cycle development in Cashmere goats by targeting FGF18 and SMAD7.

Increasing Cashmere production can add value because it is the primary product of Cashmere goats. Recent years, peoples find miRNAs are crucial in regulating the development of hair follicle. Following Solexa sequencing, many miRNAs were distinguishingly expressed in telogen skin samples of goats and sheep in earlier study. But the method through which miR-21 controls the growth of hair follicles is still ambiguous. Bioinformatics analysis was used to predict the target genes of miR-21. The mRNA level of miR-21 in telogen Cashmere goat skins was higher than in anagen, according to the results of qRT-PCR, and the target genes expressed similarly with miR-21. Western blot showed similar trend, the protein expression of FGF18 and SMAD7 were lower in anagen samples. The Dual-Luciferase reporter assay confirmed miRNA-21's relationship with its target gene, and the consequences indicated found FGF18 and SMAD7 have positive correlations with miR-21. Western blot and qRT-PCR distinguished the expression of protein and mRNA in miR-21 and its target genes. According to the consequence, we found that target genes expression was increased by miR-21 in HaCaT cells. This study identified that miR-21 might take part in the development of Cashmere goat's hair follicles by targeting FGF18 and SMAD7.