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Androgenetic alopecia and microinflammation
... Firstly, the improvement with MNX and/or FIN is limited and tends to plateau after one to two years of continuous use. The success rate of treatment for AGA barely exceeds 30% using either of these agents; which brings the second reason to the fore, i.e., a high possibility of other pathophysiologic pathways being involved in this condition [8]. Indeed, there is now sufficient evidence supporting the role of factors other than hormones contributing significantly to the pathogenesis of AGA (vide infra). ...
... Follicular micro-inflammation and fibrosis are being increasingly recognized to play an important role in AGA, especially in the early phases. Several studies have reported mild to moderate lympho-histiocytic inflammatory infiltrate in the peri-infundibular region of HF taken from subjects with AGA compared with controls [8]. The term 'microinflammation' has been proposed, to differentiate the gradual, subtle, and indolent process occurring in AGA from the prominent inflammation and fibrosis characteristically seen in classical cicatricial alopecias. ...
... The role of keratinocytes and Langerhans cells acting as antigen presenting cells (APC) and inducing T lymphocyte infiltration and proliferation mediated by various pro-inflammatory cytokines has been suggested. Further, perifollicular fibrosis (appreciable on cross-sectional scalp biopsy of scalp with AGA as 'fibrotic streamers') seems to result from cytokine mediated activation of collagenases, such as matrix metalloproteinases (MMPs) [8,21], and may end with complete destruction of the affected follicles in advanced cases. Further support for the role of micro-inflammation in AGA has come from studies that documented significantly superior results in improving hair growth with combinations of MNX with antimicrobials and/or antiinflammatory agents (like zinc pyrithione, ketoconazole, hydrocortisone, diclofenac, tea tree oil) compared with use of MNX alone [22]. ...
... 32,33 The term microinflammation was proposed by Mahé et al, because the process involves a slow, subtle, and indolent course, in contrast to the inflammatory and destructive process in the classical inflammatory scarring alopecias. 34 Morphometric studies in patients with MPHL treated with minoxidil showed that 55% of those with microinflammation had regrowth in response to treatment, in comparison to 77% in those patients without inflammation and fibrosis. 33 Finally, the more recently described fibrosing alopecia in a pattern distribution, 35 a condition in which patients with PHL have additional clinical and histological features of inflammation and fibrosis limited to the area of PHL, provides the respective evidence. ...
... Alternatively, keratinocytes themselves may respond to chemical stress from irritants, pollutants, and ultraviolet (UV) irradiation by producing radical oxygen species and nitric oxide and by releasing intracellularly stored IL-1α. 34 This proinflammatory cytokine by itself has been shown to inhibit the growth of isolated hair follicles in culture. 37 Moreover, adjacent keratinocytes, which express receptors for IL-1, start to engage in the transcription of IL-1 responsive genes: mRNA coding for IL-1β, TNFbeta, and IL-1α, and for specific chemokine genes, such as IL-8, and monocyte chemoattractant protein-1 (MCP-1) and MCP-3, themselves mediators for the recruitment of neutrophils and macrophages, they have been shown to be upregulated in the epithelial compartment of the human hair follicle. ...
... The antigens are selectively destroyed by infiltrating macrophages or natural killer cells. 34 On the occasion that the causal agents persist, sustained inflammation is the result, together with connective tissue remodeling, where collagenases such as matrix metalloproteinase (also transcriptionally driven by proinflammatory cytokines) play an active role. 34 Eventually, permanent alopecia is the result of irreversible damage to the putative site of follicular stem cells in the bulge area of the outer-root sheath in the superficial portion of the hair follicle. ...
Pattern hair loss (PHL) is the most frequent cause of hair loss in men and women, accounting for 65% of consultations in a hair referral center. PHL is understood to represent a hereditary, age-dependent progressive thinning of the scalp hair, which follows distinct clinical patterns with notable differences depending on sex and age of onset. Clinical and investigative advances have helped us to understand some of the pathogenic steps, leading to PHL. Besides genetic factors and peculiarities of androgen metabolism, additional pathogenic factors that are suspected include microbiomata, oxidative stress, and microinflammation. While further suspects are likely to be exposed, individual diversity of causal agents, as well as of the sequence of events, or combined factors, must be kept in mind. A large number of therapeutic molecules claimed to be active and patented in this field, and their limited efficacy in offering a definitive cure of PHL confirm the complexity of PHL. The aim of therapy is to retard progression of hair thinning and increase hair coverage of the scalp. As yet, two FDA-approved drugs are available for this purpose, oral finasteride, and topical solution of minoxidil. Variations in posology and formulation allow for an enhancement of patient comfort and treatment efficacy. Antiandrogen treatments in women with normal androgen levels have questionable efficacy while having health risks.
... AGA is a non-scarring alopecia with symmetrical and progressive thinning of the hairs (miniaturization) in the parietal and vertex regions, sparing the occipital area [5][6][7][8][9]. Even though AGA is not considered an inflammatory alopecia and does not progress to scarring, a certain degree of perifollicular fibrosis and inflammatory lymphocytic infiltrate in the perifollicular region (sometimes referred as 'microinflammation') can be seen [9][10][11]. The 'microinflammation' found in AGA is suggested as a potential pathogenic factor in the development of the disease, but is distinct from the lichenoid lymphocytic infiltrate of LPP [11]. ...
... Even though AGA is not considered an inflammatory alopecia and does not progress to scarring, a certain degree of perifollicular fibrosis and inflammatory lymphocytic infiltrate in the perifollicular region (sometimes referred as 'microinflammation') can be seen [9][10][11]. The 'microinflammation' found in AGA is suggested as a potential pathogenic factor in the development of the disease, but is distinct from the lichenoid lymphocytic infiltrate of LPP [11]. ...
Fibrosing alopecia in a pattern distribution (FAPD) has been described as a diffuse alopecia in the central region of the scalp with clinical and histopathological features of both androgenetic alopecia (AGA) and lichen planopilaris (LPP). Review cases that met clinical and microscopic criteria for FAPD with a minimum follow-up period of 18 months. We evaluated 28 histopathologic criteria in 35 scalp biopsies from 22 patients. The cases were separated into two groups according to the presence or absence of cicatricial fibrous tract (CFT). Low terminal to vellus hair ratio was seen in 45% of samples and 55% of biopsies presented lichenoid inflammation. Among 9 patients with CFT, four developed well-defined areas of alopecia in the follow-up. A wide range of histological features were observed and very few cases showed alterations of both AGA an LPP simultaneously. FAPD is a term that could be used either when diagnostic signs of LPP are not present or perifollicular fibrosis and higher terminal to vellus hair ratio forbid an undisputed AGA diagnosis. The presence of CFT and lichenoid inflammation may be a warning sign for actual LPP with initially diffuse distribution on the scalp and potentially scarring outcome.
... In addition to the above factors, micro-inflammation, degeneration of the arrector pili muscle, chronic scalp tension and stress have also been implicated in the development of AGA. [35][36][37] Chronic scalp tension hypothesis has shown that the scalp is in chronic tension induced by the galea aponeurotica, with the attendant inflammatory response for alopecia-prone tissues. Oxidative stress, on the other hand, brought about by physically and psychologically stressful life events, has been found to aid both the development and progression of AGA with decreased superoxide dismutase activity. ...
... Chronic inflammation has been suggested as a link since it has been implicated in abnormal lipid metabolism, [46] and inflammatory infiltrates have also been observed around the hair follicles in patients who have AGA. [35] Another possible connection is altered sensitivity to androgens as ARs and the 5-alpha reductase enzyme are both present in adipose tissue. It has been suggested that their dysfunction is a link between AGA and dyslipidaemia. ...
This study reviewed the current knowledge on the epidemiology, pathophysiology, clinical presentations, diagnosis, treatment, quality-of-life assessment and recent trends in androgenetic alopecia (AGA). Relevant articles on AGA from PubMed, Google Scholar, Medline and Scopus from 1950 to 2024 were obtained and scrutinized.. Key search words included each term like ‘androgenetic alopecia’, ‘androgenic alopecia’, ‘pattern baldness’ and ‘pattern hair loss’ AND each term like ‘epidemiology’, ‘pathophysiology’, ‘genetics’, ‘hormones’, ‘micronutrient’, ‘stress and inflammation’, ‘growth factors’, ‘clinical features’, ‘staging’, ‘cardiovascular associations’, ‘diagnosis’ and ‘management’ were used in the search. AGA is a non-scarring hair loss that is exemplified by a progressive decline of hair follicles, or non-functional or dead hair follicles in the scalp in a defined pattern. It is the most common hair loss, more common in men but can also present in younger age as premature AGA. Hormones, genetics, micronutrient deficiency, microinflammation and stress have been implicated, while psychosocial distress and cutaneous correlate of cardiovascular diseases have become sources of relentless research. AGA is a patterned hair loss that is more prevalent in Men. It results from the interactions between hormonal, genetic and other factors which determine the extent of hair loss and associated disorders (psychosocial and cardiovascular). As results of more research become available, the extent of AGA, its comorbidities as well as the full spectrum of their manifestations will continue to be sources of health education and more holistic examination by dermatologists and patients.
... Apart from the cosmetic implication, there is growing evidence that AGA may be a part of a systemic microinflammation milieu [4]. Research revealed that AGA patients tend to have an atherogenic lipid profile [5]. ...
... been investigated as an indicator of systemic inflammation in cardiovascular disease [7]. It is now thought that miniaturization of hair follicles in AGA is a result of an indolent, painless, silent inflammatory process, given the term "microinflammation" to be differentiated from the usual inflammatory process [4]. Dyslipidemia in AGA patients has been studied in multiplicity of research, with proved decreased HDL levels in AGA patients in most controlled studies [5]. ...
Introduction
Both Androgenetic alopecia (AGA) and age-related macular degeneration (AMD) shared the microinflammatory milieu and increased oxidative stress as important criteria in their pathogenesis. The monocyte/high density lipoprotein (HDL) ratio (MHR) seems to be an easy-to-calculate prognostic marker of microinflammation.
Objectives
To assess MHR in patients with AGA and its correlation to AMD in these patients, if any.
Methods
Forty patients with AGA aged 40 years or more of both sexes and 40 control subjects participated in this case-control study. General, dermatological, and ophthalmologic examination, MHR evaluation and optical coherence tomography (OCT) were performed.
Results
The mean MHR was significantly higher in AGA patients (6.98 ± 2.21) than in controls (3.82 ± 0.68) (P < 0.001). AMD was significantly higher in patients than controls (P < 0.001). Eighty percent of AGA patients were diagnosed with AMD versus 20% of control subjects. The presence of AMD in AGA was significantly related to the degree of severity of AGA in male patients (P = 0.02). The MHR was significantly higher in AGA patients found to have AMD (9.37 ± 1.1 and 7.01 ± 1.42 in the wet and dry type respectively) than those without AMD (P < 0.001).
Conclusions
AMD may develop more frequently in those with AGA. The MHR seems to be a missing link between both conditions, and could be utilized as a potential biomarker for predicting AMD in AGA patients.
... This result supports the notion that the HF from PAs is characterized by low-grade microin ammation, which might not be easily distinguished from that of CDs [41]. Several factors, including sex, age, disease severity, and the de ned region for analysis, may contribute to discrepancies in the prevalence and degree of in ammation among studies. ...
... Although various factors have been proposed to trigger microin ammation in AGA scalps [41], the exact contribution of these factors in the disturbance in immune homeostasis of the HF has not been established. Marked hyperplasia of Langerhans' cells within the HF and connective tissue sheath at the lower infundibulum and an increase in antigen-presenting cell-related genes, including class II HLA, have been associated with AGA balding scalps, consistent with our ndings [19,38,39]. ...
Peri-infundibular immune infiltration (PII) is a crucial cluster of immune cells associated with human hair follicles (HFs), with potential importance in HF-immune interactions. Androgenetic alopecia (AGA) is characterized by microinflammation and abnormal immune responses, especially in the PII region. However, the precise patterns of immune dysregulation remain unclear due to limitations in current analysis techniques preserving tissue architecture. Here, we utilized spatial transcriptome profiling, a high-throughput analysis technology, to investigate the immunological disturbances within the PII region. We evaluated overall immune infiltrates, conducted gene set enrichment analysis (GSEA), cellular deconvolution, differential expression analysis, over-representation analysis, protein-protein interaction (PPI) network, and upstream regulator analysis to identify cell types and molecular dysregulation in immune cells. Our results demonstrated significant differences in immune signature between the PII of AGA patients (PII-A) and the PII of control donors (PII-C). PII-A exhibited enrichment in CD4 + helper T cells, distinct immune response patterns, and a bias toward the T helper (Th) 2 response. Immunohistochemistry confirmed the disturbed T cell subpopulations, with increased CD4 + T cells displaying elevated Th2 response but reduced Th1-cytotoxic response compared to PII-C. These findings reveal the unique immune landscapes of PII-A and PII-C, suggesting possibilities for the development of innovative treatment approaches.
... In patients with AGA, histopathological studies of the scalp typically reveal peribulbar inflammation (lymphocytes) and perifollicular fibrosis. 9 The Food and drug administration (FDA) has approved minoxidil and finasteride for the treatment of AGA. The treatment aims to retain current hair density, which is why it's important to get started as soon as possible. ...
... Adult healthy male albino mice (weight: 25-30 g and age: [8][9][10][11][12] week) were obtained from the animal house of Iraqi Center for Cancer and Medical Genetics Research, University of Al Mustansiriya, Iraq. ...
Background and Objective: Androgenetic alopecia is an age-related disease. It’s the most prevalent type of non-scarring progressive hair loss, affecting men and women. Here, Convolvulus arvensis ethanolic extract is investigated for its growth-promoting effects in albino mice with testosterone-induced hair loss. Material and Method: 50 adult male albino mice (2-3 month) divided into 5 group 10 mice in each group (I) intact negative control (II) Testosterone gel 1% only (induction group) (III) Testosterone gel 1% + finasteride solution 2% (standard group) (IV) testosterone gel 1% + Convolvulus arvensis cream 3% (extract group) (V) testosterone gel 1% + glycerine cream 15% (vehicle group) testosterone gel 1% was applied topically to the back of the mice to all group except negative control group (I) for 21 days to induce hair loss hair growth promoting effect evaluated by visual observation, histopathological study of follicular density and anagen/telogen ratio and testosterone, dihydrotestosterone serum level. Result: animals in extract group showed less hair loss as compared to those treated with induction and vehicle groups that possess A patch of hair loss, Convolvulus arvensis ethanolic extract increase follicular density and anagen/telogen ratio significantly compared to induction group, these result suggest that extract promotes hair growth and prevent hair loss by inducing the anagen phase in resting hair follicles and might therefore be a potential hair growth-promoting agent.
... radiation, androgenic hormone, 5α-reductase activity promoting substances, stress, diseases, and pollution. 3 Androgenic hormones and 5α-reductase activity are the most important causes of human alopecia namely androgenic alopecia (AGA). Although minoxidil and finasteride are effective in AGA treatment, their adverse side effects such as itching, skin rash, loss of erectile function, and libido also have been reported. ...
... 34,35 Futhermore, ILβ is the major factor to destruct the hair follicle and trigger the microinflammatory chain reaction. 3,36 The results of this study indicated that A. ebracteatus extract effectively inhibited the synthesis of IL-1β. The inhibition result may be due to chemical components that possess an anti-oxidant activity. ...
Introduction:
Miniaturization of the hair follicles is evident on the balding scalp. Approved medications, topical minoxidil and oral finasteride for the treatment of alopecia sometimes come with undesirable adverse effects. The study was to examine the bioactivity of medicinal plants for finding the promising source of anti-hair loss application.
Methods:
Ten ethanolic extracts were prepared form, Acacia concina (Willd.) DC., Acanthus ebracteatus Vahl, Bridelia ovata Decne, Cleome viscosa L., Cocos nucifera L., Hibiscus subdariffla L., Oryza sativa L., Terminalia chebula Retz., Tinospora crispa (L.) Hook. f. & Thomson and cytotoxic tested on dermal papilla cells using MTT assay. The effect of the extracts on cell cycle was also determined using flow cytometry technique. Anti-inflammatory activity was examined by determining IL-1β inhibition in RAW 257.4 cells. In vitro study of androgenic and 5α-reductase inhibitory activities were also determined using MTT assay and enzymatic reaction couple with liquid chromatography-mass spectrometry (LC-MS), respectively.
Results:
Our results revealed that only A. ebracteatus promoted dermal papilla cell proliferation and the S and G2/M phases in cell cycle. A. ebracteatus also showed inhibitory activity against 5α-reductase and testosterone in reducing cell viability of the dermal papilla. Moreover, A. ebracteatus extract strongly inhibited LPS-stimulating IL-1β production in RAW 264.7 cells in a dose-dependent manner.
Conclusion:
Our finding indicated that the ethanolic extract of A. ebracteatus is a promising candidate for anti-hair loss treatment.
... The RAW 264.7 cells are normally used for evaluating anti-inflammatory activity because the macrophage can be stimulated by LPS to produce IL-1β by activating Toll-like receptors 35,36 . Although the release of pro-inflammatory cytokines in dermal papilla cells has been not fully understood, many reports also reveal the determination of those cytokines from dermal papilla cells and they play a crucial role in dermal papilla cell apoptosis and hair follicular damage 1,8,9,37 . AE extracted with 95% ethanol had the highest content of VB of all tested AE extracts. ...
... The prevention of cell apoptosis via down-regulating cAMP was reported as a mechanism of VB on testosterone activity 29 . The decrease in testosterone metabolism diminished inflammation initiating cell apoptosis 1,9 . IL-1β and IL-1α are pro-inflammatory cytokines that indicate cells are undergoing an inflammatory process 45 . ...
Androgenic alopecia is a common type of hair loss, usually caused by testosterone metabolism generating dihydrotestosterone and hair follicular micro-inflammation. These processes induce dermal papilla cells to undergo apoptosis. Currently approved effective medications for alopecia are Finasteride, an oral 5α-reductase inhibitor, Minoxidil, a topical hair growth promoter, and Diclofenac, an anti-inflammatory agent, all of which, however, have several adverse side effects. In our study, we showed the bioactivity of Acanthus ebracteatus Vahl. (AE) extract performed by 95% ethanol, and verbascoside (VB), a biomarker of AE extract. Both AE extract and VB were studied for their effects on dermal papilla cell viability and the cell cycle by using MTT assay and flow cytometry. The effect of an anti-inflammatory activity of AE extract and VB on IL-1β, NO, and TNF-α, released from LPS induced RAW 264.7 cells, and IL-1α and IL-6 released from irradiated dermal papilla cells were detected using ELISA technique. The preventive effect on dermal papilla cell apoptosis induced by testosterone was determined by MTT assay. In controlled in vitro assays it was found that AE extract and VB at various concentrations induced dermal papilla cell proliferation which was indicated by an increase in the number of cells in the S and G2/M phases of the cell cycle. AE extract at 250 µg/mL concentration or VB at 62.50 µg/mL concentration prevented cell apoptosis induced by testosterone at a statistically significant level. In addition, both AE extract and VB greatly inhibited the release of pro-inflammatory cytokines from RAW 264.7 and dermal papilla cells. The release of IL-1β, TNF-α, and NO from RAW 264.7 cells, as well as IL-1α and IL-6 from dermal papilla cells, was also diminished by AE extract 250 µg/mL and VB 125 µg/mL. Our results indicate that AE extract and VB are promising ingredients for anti-hair loss applications. However, further clinical study is necessary to evaluate the effectiveness of AE extract and VB as treatment for actual hair loss.
... By enhancing microcirculation and nutrient delivery to hair follicles, PN could potentially reverse the follicular miniaturization seen in AGA. Additionally, its anti-inflammatory properties may mitigate the microinflammatory processes thought to contribute to hair follicle damage [16]. ...
Androgenetic alopecia (AGA) is a highly prevalent condition that poses a significant challenge to quality of life, yet the US Food and Drug Administration-approved treatments remain limited. Polynucleotides (PN) stimulate tissue regeneration by reducing inflammation, activation of growth factors and accelerating angiogenesis, which are vital for hair regrowth. This study aimed to assess the efficacy of PN in promoting hair regrowth by measuring changes in hair diameter and density in patients with AGA. This prospective study evaluated 28 patients with AGA who received four injection of DOT™ PN (DNA Fragment Optimizing Technology Polynucleotides) at four-week intervals. Hair diameter and density were quantitatively assessed using dermoscopic analysis. Treatment efficacy was also evaluated using patient and dermatologist satisfaction survey. Both hair diameter and density showed significant improvement, with hair diameter increased notably one month post-treatment and continuing to rise throughout the study. Total hair density improvements were evident from one months post-treatment onwards. Additionally, the dermatologist’s assessment indicated stabilization in 60.7% of cases, while the patient assessment score indicated improvement in 82.1% of cases, with no serious side effects. This study demonstrates that PN effectively promotes hair regrowth in AGA patients. This is likely due to increased angiogenesis and anti-apoptotic effects. PN offers a promising new alternative for patients who have not responded to traditional treatments.
... In contrast to traditional scarring alopecia, which is characterized by an inflammatory and destructive process, this one is sluggish, subtle, and indolent. One possible mechanism by which microbial toxins belonging to the genus Demodex, Propionibacterium, Staphylococcus, or Malassezia contribute to the development of an inflammatory response is as follows (25). Despite AGA's reputation as a noninflammatory illness, histological investigations have shown inflammation in the top third of hair follicles, indicating that inflammation may play a pathogenic role in the condition (26). ...
... The early catagen phase, oxidative stress, and apoptosis of hair cells are caused by an abrupt surge of cytokines in the blood. Among these proinflammatory molecules, interleukin (IL)-6 holds a pivotal role, particularly in severe forms of COVID-19 [17], [54]. Elevated levels of IL-6 affect the hair follicles by disrupting their immune privilege, inducing the catagen phase, and inhibiting hair shaft elongation by suppressing matrix cell proliferation, inciting local inflammation [43], [55], [56]. ...
This paper explores the connection between COVID-19 and hair loss, emphasizing its emotional impact. Beyond respiratory effects, the virus causes various skin symptoms, including hair loss (telogen effluvium) in up to one-fifth of patients. The study reviews disruptions in the hair growth cycle induced by COVID-19, suggesting a multifactorial mechanism involving proinflammatory cytokines, the ADE phenomenon, and coagulation cascade activation. Recognizing the psychological impact, the paper uses a comprehensive research methodology to explore the correlation between hair loss and COVID-19. Recommendations for managing COVID-19-induced hair loss include counseling, dietary adjustments, and treatment options like minoxidil and corticosteroids. The study highlights the proactive role of healthcare professionals in addressing COVID-19-related hair loss to enhance patient satisfaction and overall quality of life.
... Although various factors have been proposed to trigger microinflammation in AGA scalps [59], the exact contribution of these factors to the disturbance in immune homeostasis of the HF has not been established. Marked hyperplasia of Langerhans' cells within the HF and connective tissue sheath at the lower infundibulum and an increase in antigenpresenting cell-related genes, including class II HLA, have been associated with AGA balding scalps, consistent with our findings [26,52,54]. ...
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.
... It increases blood flow thus an extra nutrients and oxygen supply to the hair follicle. Moreover, one study found cytoprotective activity resulting from the activation of prostaglandin synthase-1, the main isoform in DPCs [35]. Doses range from 2 to 5%, and like other hair growth stimulators, Minoxidil treatment can cause telogen follicles to fall out and be replaced by new ones [36]. ...
Androgenetic alopecia (AGA) is the most prevalent type of hair loss. Its morbility is mainly psychological although an increased incidence in melanoma has also been observed in affected subjects. Current drug based therapies and physical treatments are either unsuccessful in the long term or have relevant side effects that limit their application. Therefore, a new therapeutic approach is needed to promote regenerative enhancement alternatives. These treatment options, focused on the cellular niche restoration, could be the solution to the impact of dihydrotestosterone in the hair follicle microenvironment. In this context emerging regenerative therapies such as Platelet-rich plasma or Platelet-rich fibrine as well as hair follicle stem cells and mesenchymal stem cell based therapies and their derivatives (conditioned medium CM or exoxomes) are highlighting in the evolving landscape of hair restoration. Nanotechnology is also leading the way in AGA treatment through the design of bioinks and nanobiomaterials whose structures are being configuring in a huge range of cases by means of 3D bioprinting. Due to the increasing number and the rapid creation of new advanced therapies alternatives in the AGA field, an extended review of the current state of art is needed. In addition this review provides a general insight in current and emerging AGA therapies which is intented to be a guidance for researchers highlighting the cutting edge treatments which are recently gaining ground.
... 61 Recently, researchers observed perifollicular inflammation of CD4+ T cells in individuals with FPHL and male AGA; however, specific triggers remain unknown. 62 Histopathology shows miniaturisation of follicles and sebaceous pseudohyperplasia. Arao-Perkins bodies, aggregates of elastic fibres in the fibrous streamers, are common in advanced stages. ...
Alopecia is prevalent among females, categorised as either scarring or non-scarring, depending on the potential for hair follicle regeneration. Various aetiologic factors are implicated in non-scarring alopecia, including genetic predisposition, loss of immune privilege, oxidative damage, and hormonal fluctuations. Telogen effluvium, alopecia areata, and female pattern hair loss are the main causes of non-scarring alopecia in females of all ages. This review covers the aetiology, pathophysiology, and treatment of the most common non-scarring alopecias in females.
... 6,7 This imbalance in the microecological environment may trigger inflammatory responses, serving as a "stressor" that exacerbates the disease progression. 8 In dermatological practices, the use of ultraviolet (UV)-induced fluorescence is a prevalent technique for aiding in disease diagnosis. 9,10 The Wood's lamp, for instance, exemplifies this application, emitting This fluorescence phenomenon is frequently applied in diagnosing scalp conditions, such as tinea capitis. ...
Background
Ultraviolet (UV)‐induced fluorescence technology is widely used in dermatology to identify microbial infections. Our clinical observations under an ultraviolet‐induced fluorescent dermatoscope (UVFD) showed red fluorescence on the scalps of androgenetic alopecia (AGA) patients. In this study, based on the hypothesis that microbes are induced to emit red fluorescence under UV light, we aimed to explore the microbial disparities between the AGA fluorescent area (AF group) and AGA non‐fluorescent area (ANF group).
Methods
Scalp swab samples were collected from 36 AGA patients, including both fluorescent and non‐fluorescent areas. The bacterial communities on the scalp were analyzed by 16S rRNA gene sequencing and bioinformatics analysis, as well as through microbial culture methods.
Results
Significant variations were observed in microbial evenness, abundance composition, and functional predictions between fluorescent and non‐fluorescent areas. Sequencing results highlighted significant differences in Cutibacterium abundance between these areas (34.06% and 21.36%, respectively; p < 0.05). Furthermore, cultured red fluorescent colonies primarily consisted of Cutibacterium spp., Cutibacterium acnes, Staphylococcus epidermidis, and Micrococcus spp.
Conclusions
This is the first study to investigate scalp red fluorescence, highlighting microbial composition variability across different scalp regions. These findings may provide novel insights into the microbiological mechanisms of AGA.
... Growth and transcription factors from PRP signal the follicle to enter the anagen phase of the hair cycle, playing an important role in cellular regeneration and renewal. 4,13,16 According to a meta-analysis published by Georgescu and colleagues 4 , although the total number of PRP treatments and the amount of PRP injected per treatment did not seem to influence the outcome, an increased frequency of application (number of treatments per month) results in greater increases in hair density in patients with AGA. Furthermore, other important factors are the age of the patients and the early start of treatment from diagnosis, with earlier initiation resulting in better outcomes. ...
Androgenetic alopecia (AGA) is currently the primary cause of hair loss in both men and women. It is characterized by a progressive thinning of the hair follicles due to a shortening of the anagen phase of the hair growth cycle. The pathophysiology mainly involves the accumulation of dihydrotestosterone (DHT), a metabolite of testosterone, and a chronic perifollicular inflammatory process. The objective of this study is to evaluate, through a literature review, the validity, protocols, and efficacy of the use of platelet-rich plasma (PRP) in the treatment of patients with AGA. It is a review conducted in the first half of 2024, using the PubMed and BVS databases, employing Descritores em Ciência e Saúde (alopecia, plasma rico em plaquetas, terapia) and Medical Subject Headings (alopecia, platelet-rich plasma, therapy). Inclusion criteria consisted of: a) articles published between 2022 and 2024; b) written in Portuguese or English; c) full-text articles available for free; d) research focused on PRP therapy for the treatment of androgenetic alopecia in men. Twelve articles were included in the synthesis. Overall, the articles indicated that despite the need for standardized protocols, the use of PRP as a treatment for AGA shows promising results in the current context. The therapy demonstrated improvements in hair density and patient satisfaction, suggesting its potential as a viable option for managing androgenetic alopecia. Besides being a safe option with minimal side effects, its combination with other therapies, such as minoxidil, has brought beneficial outcomes for patients with this condition. Keywords: Alopecia, Platelet-Rich Plasma, Therapy
... Evidence has demonstrated a role of inflammation in the pathogenesis of AGA at the clinical, histological, and transcriptomic levels [98][99][100][101]. The term "microinflammation" was adopted because, compared to scarring alopecias, inflammation in AGA is slow and subtle [102]. Evidence sustaining that this "microinflammation" plays an important role in AGA is the fact that drugs with anti-inflammatory effects, for example, minoxidil, can have a therapeutic effect. ...
Androgenetic alopecia is a highly prevalent condition mainly affecting men. This complex trait is related to aging and genetics; however, multiple other factors, for example, lifestyle, are also involved. Despite its prevalence, the underlying biology of androgenetic alopecia remains elusive, and thus advances in its treatment have been hindered. Herein, we review the functional anatomy of hair follicles and the cell signaling events that play a role in follicle cycling. We also discuss the pathology of androgenetic alopecia and the known molecular mechanisms underlying this condition. Additionally, we describe studies comparing the transcriptional differences in hair follicles between balding and non-balding scalp regions. Given the genetic contribution, we also discuss the most significant risk variants found to be associated with androgenetic alopecia. A more comprehensive understanding of this pathology may be generated through using multi-omics approaches.
... Extrinsic factors include ultraviolet radiation, androgenic hormones, 5α-reductase activity-promoting substances, stress, diseases, and pollution [5,6]. It has been believed ...
Although hair loss plays a vital physiological function in present society, their impact on shaping self-esteem is undeniable. Even though there are numerous synthetic drugs available, these days, there are issues with safety, efficiency, and unclear time settings for required outcomes with the current synthetic drug remedies available; therefore, there is growing attention to discovering alternative methods to fight hair loss, primarily through plant-derived formulations. While earlier reports mostly focused on screening compounds or plant extracts affecting 5α-reductase, our research takes a unique direction. We employed a biochemical and molecular biological approach by delving into the complicated biosynthetic pathways involving 17β-hydroxysteroid dehydrogenase (17β-HSD) and 3β-hydroxysteroid dehydrogenase (3β-HSD) in producing testosterone derived from cholesterol. This process conceded requiring experimental results, posing insights into the control of the testosterone/dihydrotestosterone (DHT) production pathway. Our study confirms a discovery platform for finding potential candidates as hair loss inhibitors, highlighting exploring various biochemical mechanisms involving 17β-HSD and 3β-HSD in combination with medicinal plant extracts.
... A multifaceted strategy for treating AGA is required to resolve both issues. Dermal papilla cells (DPCs) produce interleukin (IL-6) and converting growth factor (TGF-2) in response to DHT, which inhibits hair development and causes the catagen stage to begin prematurely in AGA patients [6][7][8][9][10][11]. ...
Hair loss (alopecia) has a multitude of causes, and the problem is still poorly defined. For curing alopecia, therapies are available in both natural and synthetic forms; however, natural remedies are gaining popularity due to the multiple effects of complex phytoconstituents on the scalp with fewer side effects. Evidence-based hair growth promotion by some plants has been reported for both traditional and advanced treatment approaches. Nanoarchitectonics may have the ability to evolve in the field of hair- and scalp-altering products and treatments, giving new qualities to hair that can be an effective protective layer or a technique to recover lost hair. This review will provide insights into several plant and herbal formulations that have been reported for the prevention of hair loss and stimulation of new hair growth. This review also focuses on the molecular mechanisms of hair growth/loss, several isolated phytoconstituents with hair growth-promoting properties, patents, in vivo evaluation of hair growth-promoting activity, and recent nanoarchitectonic technologies that have been explored for hair growth.
... The microinflammation process, especially in the upper segment of the HF, has been proposed as a possible element in the pathogenesis of AGA and FPHL. [49] An inflammatory infiltrate, mainly consisting of CD4+ lymphocytes, is more evident in miniaturized HFs and is correlated with higher apoptosis. [50] FPHL is also associated with higher fasting glucose and factors related to hormones, i.e. prolonged estrogen exposure. ...
Hair follicle (HF) growth is regulated by local and systemic environments. Sex hormones, a systemic factor, paradoxically promote and suppress hair growth in different sites of the body, leading to diseases such as hirsutism, androgenetic alopecia, and female pattern hair loss. The past decades have seen progress in the treatment of sex hormone-related hair diseases, but the pathogenesis of some of these diseases remains obscure and even controversial. We review the biological effects of major sex hormones on hair growth and summarize their known impacts. We discuss the different responses of animal and human HFs to sex hormones, summarize the pathogenesis of sex hormone-related hair diseases, and highlight the benefits of and controversies in the current management of these diseases. Finally, we discuss future research directions such as interactions between sex hormones and the immune system and the possible role of epigenetics in these hair disorders.
... They suggested that the local microbiologic flora and environmental factors like UV light could be responsible for the inflammatory reactions (56). Mahe et al. (59) proposed in a 2001 review that the inflammatory process associated with AGA be referred to as microinflammation in contrast to classical inflammatory process. Furthermore, the presence of peripilar signs around the hair follicle ostium, which reflect perifollicular inflammation, has established the presence of follicular microinflammation in AGA (60,61). ...
Introduction: Androgenetic alopecia (AGA) is a common progressive scalp hair loss disorder that leads to baldness. This study aimed to identify core genes and pathways involved in premature AGA through an in-silico approach.
Methods: Gene expression data (GSE90594) from vertex scalps of men with premature AGA and men without pattern hair loss was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between the bald and haired samples were identified using the limma package in R. Gene ontology and Reactome pathway enrichment analyses were conducted separately for the up-regulated and down-regulated genes. The DEGs were annotated with the AGA risk loci, and motif analysis in the promoters of the DEGs was also carried out. STRING Protein-protein interaction (PPI) and Reactome Functional Interaction (FI) networks were constructed using the DEGs, and the networks were analyzed to identify hub genes that play could play crucial roles in AGA pathogenesis.
Results and discussion: The in-silico study revealed that genes involved in the structural makeup of the skin epidermis, hair follicle development, and hair cycle are down-regulated, while genes associated with the innate and adaptive immune systems, cytokine signaling, and interferon signaling pathways are up-regulated in the balding scalps of AGA. The PPI and FI network analyses identified 25 hub genes namely CTNNB1, EGF, GNAI3, NRAS, BTK, ESR1, HCK, ITGB7, LCK, LCP2, LYN, PDGFRB, PIK3CD, PTPN6, RAC2, SPI1, STAT3, STAT5A, VAV1, PSMB8, HLA-A, HLA-F, HLA-E, IRF4, and ITGAM that play crucial roles in AGA pathogenesis. The study also implicates that Src family tyrosine kinase genes such as LCK, and LYN in the up-regulation of the inflammatory process in the balding scalps of AGA highlighting their potential as therapeutic targets for future investigations.
... The contribution of "microinflammation", which refers to histopathological periinfundibular lymphocytic cell infiltrates, has been suggested in AGA and FPHL pathophysiology [82]. Putative triggers include ultraviolet radiation, environmental pollutants, and perifollicular microbiota [75]. ...
Hair-loss diseases comprise heterogenous conditions with respective pathophysiology and clinicopathological characteristics. Major breakthroughs in hair follicle biology and immunology have led to the elucidation of etiopathogenesis of non-scarring alopecia (e.g., alopecia areata, AA) and cicatricial alopecia (e.g., lichen planopilaris, LPP). High-throughput genetic analyses revealed molecular mechanism underlying the disease susceptibility of hair loss conditions, such as androgenetic alopecia (AGA) and female pattern hair loss (FPHL). Hair loss attracted public interest during the COVID-19 pandemic. The knowledge of hair loss diseases is robustly expanding and thus requires timely updates. In this review, the diagnostic and measurement methodologies applied to hair loss diseases are updated. Of note, novel criteria and classification/scoring systems published in the last decade are reviewed, highlighting their advantages over conventional ones. Emerging diagnostic techniques are itemized with clinical pearls enabling efficient utilization. Recent advances in understanding the etiopathogenesis and management for representative hair diseases, namely AGA, FPHL, AA, and major primary cicatricial alopecia, including LPP, are comprehensively summarized, focusing on causative factors, genetic predisposition, new disease entity, and novel therapeutic options. Lastly, the association between COVID-19 and hair loss is discussed to delineate telogen effluvium as the predominating pathomechanism accounting for this sequela.
... Apart from DHT attacking, persistent inflammation is also an inducement to AGA [66]. A large number of inflammatory cells (macrophages, T cells, etc.) gather around the hair follicle and penetrate into the dermal papilla and release inflammatory factors such as TNF-α and IL-6 [67]. ...
A nanocomposite microneedle (ZCQ/MN) patch containing copper/zinc dual-doped mesoporous silica nanoparticles loaded with quercetin (ZCQ) was developed as a combination therapy for androgenic alopecia (AGA). The degradable microneedle gradually dissolves after penetration into the skin and releases the ZCQ nanoparticles. ZCQ nanoparticles release quercetin (Qu), copper (Cu²⁺) and zinc ions (Zn²⁺) subcutaneously to synergistically promote hair follicle regeneration. The mechanism of promoting hair follicle regeneration mainly includes the regulation of the main pathophysiological phenomena of AGA such as inhibition of dihydrotestosterone, inhibition of inflammation, promotion of angiogenesis and activation of hair follicle stem cells by the combination of Cu²⁺ and Zn²⁺ ions and Qu. This study demonstrates that the systematic intervention targeting different pathophysiological links of AGA by the combination of organic drug and bioactive metal ions is an effective treatment strategy for hair loss, which provides a theoretical basis for development of biomaterial based anti-hair loss therapy.
... [3] Apart from these two main factors, the factors that play a role in the development of AGA are defined as environmental pollution, smoking, ultraviolet rays, decrease in microcirculation, follicular microinflammation, and aging process. [4][5][6][7][8][9] Although the quality of life of patients with AGA is significantly affected, the only treatments approved by the FDA for AGA are oral finasteride and topical minoxidil. In addition to the effective clinical results of these treatments, there are a few disadvantages. ...
... Keratinocytes are shown to respond to chemical stress within minutes by releasing such factors as IL-1, reactive oxygen species (ROS), prostaglandins, and histamine. These diffusible factors potently inhibit hair growth and survival [31]. Oxidative stress in follicular microenvironments, which is a known contributor to PHL [32], can be triggered by several of the main etiologies of alopecia, e.g., drugs, stress, age, and exposure to microbial antigens. ...
The diffusion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inducing coronavirus disease 2019 (COVID-19) has increased the incidence of several dermatological disorders, including hair loss (HL). This article aims to review the literature regarding the incidence of HL and telogen effluvium (TE) in COVID-19 patients and critically appraise the available evidence regarding the role of regenerative strategies like Platelet-Rich Plasma (PRP) and Human Follicle Stem Cells (HFSCs). A literature review regarding the correlation of HL and TE in COVID-19 patients analyzing the biomolecular pathway involved and the role of regenerative strategies was performed using PubMed, MEDLINE, Embase, PreMEDLINE, Scopus, and the Cochrane databases. Observational studies revealed an escalated incidence of pattern HL and TE in COVID-19 patients. Psychological stress, systemic inflammation, and oxidative stress are potential culprits. Proinflammatory cytokines and stress hormones negatively affect the normal metabolism of proteoglycans. Reduced anagenic expression of proteoglycans is a potential mediating mechanism that connects HL to COVID-19. Currently, only one study has been published on PRP against HL in COVID-19 patients. Further controlled trials are required to confirm PRP and HFSCs efficacy in COVID-19 patients.
... 14 The e ect of androgens is well studied and is presumed to be secondary to downstream autocrine and paracrine factors that are secreted after binding to the androgen receptor; 15 however, recent science increasingly supports the contribution of other intrinsic and extrinsic factors, such as environmental aggressors, oxidative stress, aging, mediators of psycho-emotional stress, diet, genetic predispositions, and downstream in ammation. 2,4,5,13,[16][17][18][19][20][21] Sex di erences in hair loss further expand among various racial and ethnic groups. For example, there are di erences in straight and curly hair, including follicle shape and density and growth rates. ...
Objective:
The goal of this study was to assess the perceived efficacy of a standardized nutraceutical to improve hair growth and quality in men and women of various ethnicities with self-perceived hair thinning.
Methods:
This prospective, single-blind study enrolled healthy men aged 20 to 55 years (n=47) and premenopausal women aged 20 to 45 years (n=51) with self-perceived, mild-to-moderate hair thinning and included African American, Asian, Hispanic Caucasian and Non-Hispanic Caucasian participants. The nutraceutical supplement (Nutrafol® Men or Women Capsules, Nutraceutical Wellness Inc., New York, New York) was taken daily for six months. Subjects were evaluated in the clinic at baseline and Weeks 12 and 24 with two self-assessments at Weeks 4 and 8. Study endpoints were standardized digital imaging and investigator rated assessments. Self-assessment questionnaires rated hair growth, hair satisfaction, and lifestyle factors.
Results:
Investigator ratings for baseline hair growth, coverage, density, and volume were significant at Weeks 12 and 24 for all subjects (for each, p<0.001). These significant improvements were seen in 83.7 percent of men and 79.5 percent of women at Week 24. Results were similar across ethnic subgroups with significant benefit at Weeks 12 and 24 (for each, p<0.05). All subjects reported significant improvements in baseline hair appearance/quality, volume/fullness, scalp coverage, thickness, and shedding at Weeks 4, 8, 12 and 24 (for each, p<0.01).
Conclusion:
A standardized nutraceutical supplement improved visible hair growth with less notable shedding based on subjects' and investigators' overall perception of treatment benefit for men and women of various ethnic backgrounds.
... In vitro studies also showed that PRP causes papillary cells of the skin to grow by activating the extracellular signal-regulated kinases (ERK) [49]. Another important effect of PRP is reduction of hair follicle microinflammation associated with hair loss during AGA [1,57]. PRP growth and transcription factors signal the follicle to enter the anagen versus catagen phase, playing a role in regeneration and renewal; these effects partly overlap those of other effective AGA therapies such as minoxidil [58] or finasteride [59], justifying combined therapy approaches [44]. ...
Platelet-rich plasma (PRP) represents a novel therapy tested and is used more and more frequently in dermatology and cosmetic surgery for a variety of conditions, including androgenic alopecia (AGA), a common condition with a complex pathogenesis involving genetic factors, hormonal status and inflammation. We performed an extensive literature search which retrieved 15 clinical trials concerning the use in AGA of PRP therapy, alone or in combination, in male, female or mixed patient groups. A quantitative statistical meta-analysis of n = 17 trial groups proved significant increases in hair density from 141.9 ± 108.2 to 177.5 ± 129.7 hairs/cm2 (mean ± SD) following PRP (p = 0.0004). To the best of our knowledge, this is the first meta-analysis that proved a statistically significant correlation between the number of PRP treatments per month and the percentage change in hair density (r = 0.5, p = 0.03), as well as a negative correlation between the mean age of treatment group and the percentage change in hair density (r = −0.56, p = 0.016). Other factors considered for analysis were the PRP preparation method, amount used per treatment, hair diameter, terminal hairs and pull test. We conclude that PRP represents a valuable and effective therapy for AGA in both males and females if patients are rigorously selected.
... Alguns estudos mostram que a aplicação de antimicrobianos parece melhorar esta doença. 57 Relativamente ao uso de cetoconazol em específico, estudos recentes têm suportado a sua eficácia na AGA: em modelos murinos, verificou-se um aumento do crescimento do cabelo em áreas desnudas; em humanos, objetivou-se um aumento do diâmetro da haste pilosa e um aumento dos cabelos em anafase. O cetoconazol parece exercer a sua ação anti--inflamatória através da inibição da 5-lipooxigenase e, ao controlar a população de Malassezia, ocorrerá uma redução da inflamação local com desaceleração da miniaturização e deflúvio. ...
In recent years, several studies have demonstrated the involvement of the intestinal microbiota in immune-mediated diseases such as diabetes, ulcerative colitis, and multiple sclerosis. There are few data on the follicular microbiome and its role in the pathogenesis of scalp diseases. Some studies show influence of dysbiosis on these diseases, and manipulation of the microbiome may represent a possible therapeu- tic option. This article reviews current knowledge regarding the impact of dysbiosis on dermatological diseases of the scalp, such as seborrheic dermatitis, psoriasis, alopecia areata, androgenetic alopecia, lichen planus pilaris, frontal fibrosing alopecia and decalvant folliculitis. A broader understanding of this may suggest additional treatments beyond conventional therapies.
... Fatty acids, such as palmitic acid and oleic acid, are generated by lipases produced by Malassezia and Cutibacterium acnes; these compounds lead to inflammation [41,42]. In addition, inflammation reduces the efficacy of hair loss treatment and chronic microinflammation of the scalp leads to hair loss [43], suggesting that palmitic acid induces hair loss by triggering inflammation [41]. In the present study, sebum and microbiome changes were observed on the scalp in the AGA group. ...
The skin microbiome and sebum may be associated with inflammation-related diseases of the scalp. To assess the pathogenesis and progression of androgenetic alopecia (AGA), we analyzed the composition of sebum and the bacterial and fungal microbiomes of the scalps of 118 Japanese male individuals with and without AGA, then discussed their roles in the pathogenesis of AGA. Sebum triglyceride and palmitic acid contents were higher in the AGA group than in the non-AGA group. Malassezia restricta, a lipophilic fungus that consumes palmitic acid, was abundant on the scalps of patients with AGA. Cutibacterium, Corynebacterium, and Staphylococcus were the most common genera in both groups, and patients with AGA exhibited scalp dysbiosis (increased abundance of Cutibacterium and decreased abundance of Corynebacterium). Our findings suggest that both sebum and the bacterial and fungal microbiomes of the scalp may be involved in the development of AGA.
Male androgenetic alopecia (MAA) is quite common and worsens with age, with a significant impact on quality of life, and is increasingly a reason for consultation with a dermatologist. The etiopathogenesis of MAA is multifactorial and genetic and hormonal influences stand out. MAA starts with the process of follicular miniaturization in diverse phenotypic patterns. The diagnosis of MAA is basically clinical and currently corroborated by well-established trichoscopic findings. Despite this, therapeutic options are limited, especially when one considers medications with a high level of scientific evidence. This review aims to help the general dermatologist towards a better understanding of MAA providing a basis for good individualized and judicious therapeutic decisions.
Androgenetic alopecia (AGA), the most prevalent clinical hair loss, lacks safe and effective treatments due to downregulated angiogenic genes and insufficient vascularization in the perifollicular microenvironment of the bald scalp in AGA patients. In this study, a hyaluronic acid (HA) based hydrogel-formed microneedle (MN) was designed, referred to as V-R-MNs, which was simultaneously loaded with vascular endothelial growth factor (VEGF) and the novel hair loss drug Ritlecitinib, the latter is encapsulated in slowly biodegradable polyhydroxyalkanoates (PHAs) nanoparticles (R-PHA NPs) for minimally invasive AGA treatment. The integration of HA based hydrogel alongside PHA nanoparticles significantly bolstered the mechanical characteristics of microneedles and enhanced skin penetration efficiency. Due to the biosafety, mechanical strength, and controlled degradation properties of HA hydrogel formed microneedles, V-R-MNs can effectively penetrate the skin's stratum corneum, facilitating the direct delivery of VEGF and Ritlecitinib in a minimally invasive, painless and long-term sustained release manner. V-R-MNs not only promoted angiogenesis and improve the immune microenvironment around the hair follicle to promote the proliferation and development of hair follicle cells, but also the application of MNs to the skin to produce certain mechanical stimulation could also promote angiogenesis. In comparison to the clinical drug minoxidil for AGA treatment, the hair regeneration effect of V-R-MN in AGA model mice is characterized by a rapid onset of the anagen phase, improved hair quality, and greater coverage. This introduces a new, clinically safer, and more efficient strategy for AGA treatment, and serving as a reference for the treatment of other related diseases.
Aging is a complex natural process that leads to a decline in physiological functions, which is visible in signs such as hair graying, thinning, and loss. Although hair graying is characterized by a loss of pigment in the hair shaft, the underlying mechanism of age-associated hair graying is not fully understood. Hair graying and loss can have a significant impact on an individual's self-esteem and self-confidence, potentially leading to mental health problems such as depression and anxiety. Omics technologies, which have applications beyond clinical medicine, have led to the discovery of candidate hair biomarkers and may provide insight into the complex biology of hair aging and identify targets for effective therapies. This review provides an up-to-date overview of recent omics discoveries, including age-associated alterations of proteins and metabolites in the hair shaft and follicle, and highlights the significance of hair aging and graying biomarker discoveries. The decline in hair follicle stem cell activity with aging decreased the regeneration capacity of hair follicles. Cellular senescence, oxidative damage and altered extracellular matrix of hair follicle constituents characterized hair follicle and hair shaft aging and graying. The review attempts to correlate the impact of endogenous and exogenous factors on hair aging. We close by discussing the main challenges and limitations of the field, defining major open questions and offering an outook for future research.
This research aimed to develop an E-course training in accordance with the ADDIE model, from June 2018 to December 2019. The subjects in the research comprised 345 immunization workers. Data were collected using needs analysis questionnaires and open-ended questions about their needs for media usage, core course content, content design and presentation, etc. Data analysis was done using descriptive statistics and content analysis. The results were then considered in conjunction with the operational framework for immunization workers provided by the National Vaccine Institute to create lessons and materials. The first set of lessons was examined by 7 experts and later tried with 10 workers. The results from the trials were used to improve and develop a more complete training course and were further adjusted to meet the needs of those involved before being implemented on a large scale.
The results showed that the content related to vaccines, cold chain system and Adverse Events Following Immunization management were in highest demand, respectively. E-course is divided into 7 topics, each containing media such as animation, infographics, video clips, and diagrams. The training can track learners’ progress and show the number of end-of-unit tests they have taken before passing the determined criteria. Certificates are issued to those who succeed in all the tests. To make an E-course training effective alternatives, further research should be conducted to investigate the effectiveness of E-course training on the knowledge and skills of the workers.
Tripeptide Glycyl-L-histidyl-L-lysine (GHK) is a naturally occurring tripeptide that was initially isolated in the human serum [1] at a concentration of 200 ng/mL and was later isolated in the saliva and urine [2]. GHK is a matrix-derived tripeptide which may originate from several extracellular matrix macromolecules. It spontaneously forms a high-affinity tripeptide- Cu+2 complex with one Cu+2 (II) ion, forming GHK-Cu.
We analyzed the short sequence repeats (SSRs) of the intergenic spacer (IGS) region 1 of the rRNA genes in Malassezia globosa and M. restricta, which predominantly colonize the scalp in androgenetic alopecia (AGA). No AGA‐specific SSRs were found in the M. globosa IGS region, whereas a (CT)6:(AT)8 SSR was predominantly detected in the M. restricta IGS region in the AGA group. Malassezia colonization was higher in the scalps of patients with M. restricta (CT)6:(AT)8 SSRs than in the scalps of patients without M. restricta (CT)6:(AT)8 SSRs. These observations suggest that this specific SSR type in M. restricta is involved in the development or exacerbation of AGA. This article is protected by copyright. All rights reserved.
Smoking and its role in Androgenetic Alopecia has long been debated. Smoking may lead to hair loss by vasoconstriction, by forming DNA adducts, free radical damage to hair follicle, by enhancing senescence and hormonal effects. We have reviewed the available literature on AGA and smoking. Data available show that there is a significant association between smoking and AGA. However, studies demonstrating the benefit of avoidance of smoking in improving hair loss are lacking. Furthermore, large controlled studies with histological documentation are still unavailable to affirm the findings.
Hair folliculogenesis and hair growth mediated by the secretory properties of white adipocytes may pave the way for the adipose-derived (AD) regenerative therapy for androgenetic alopecia (AGA). Quantitative and qualitative secretome profiling of AD stem cells (ADSCs) from different zones of hair growth in patients with AGA were analysed. 1mm punch samples of adipose tissue associated with hair follicles, of three scalp areas (balding, non-balding and transition zone) and one periumbilical sample, were used for ADCS isolation. The ADCS secretome was analysed in conditioned media using a 41plex assay. Among the thirty-five signalling proteins analysed, the levels of VEGF, EGF, IL-6, Eotaxin, MCP-3, IFNγ-inducible Protein-10 and MIP-1α were higher in the balding zone compared with the non-balding and periumbilical zones. In contrast, MCP-1 was lowest in the balding zone in comparison to the other zones. The observed differences in the secretome suggest crosstalk between angiogenic and inflammatory processes underlying AGA etiology and may prove relevant in both the diagnosis of AGA and the application of ADSC secretome for AGA treatment.
Androgenetic alopecia (AGA) affects physical and mental health with limited therapeutic options. Novel materials and delivery methods have considerable potential to improve the current paradigm of treatment. In this study, we used a novel plant nanoparticle of safflower oil body (SOB) loaded with human fibroblast growth factor 10 (hFGF10) to target hair follicles and accelerate hair regeneration in AGA mice with few adverse effects. Our data revealed that the average particle size of SOB-hFGF10 was 226.73 ± 9.98 nm, with a spherical and uniform structure, and that SOB-hFGF10 was quicker to preferentially penetrate into hair follicles than hFGF2 alone. Using a mouse model of AGA, SOB-hFGF10 was found to significantly improve hair regeneration without any significant toxicity. Furthermore, SOB-hFGF10 inhibited dihydrotestosterone (DHT)-induced TNF-α, IL-1β, and IL-6 overproduction in macrophages in relation to hair follicle microinflammation, thereby enhancing the proliferation of dermal papilla cells. Overall, this study provides an applicable therapeutic method through targeting hair follicles and reducing microinflammation to accelerate hair regeneration in AGA.
The hair follicle enjoys the benefits of the “Immune Privilege”, which allows the produced hair not to be recognized as an antigen during anagen stage. The flip side of this privilege is that the hair follicle is insufficiently protected from exogenous, harmful stimuli.
Resting epidermal keratinocytes contain large amounts of interleukin 1 (IL-1), but the function of this cytokine in the skin remains unclear. To further define the role of IL-1 in cutaneous biology, we have generated two lines of transgenic mice (TgIL-1.1 and TgIL-1.2) which overexpress IL-1alpha in basal keratinocytes. There was high-level tissue-specific expression of transgene mRNA and protein and large quantities of IL-1alpha were liberated into the circulation from epidermis in both lines. TgIL-1.1 mice, which had the highest level of transgene expression, developed a spontaneous skin disease characterized by hair loss, scaling, and focal inflammatory skin lesions. Histologically, nonlesional skin of these animals was characterized by hyperkeratosis and a dermal mononuclear cell infiltrate of macrophage/monocyte lineage. Inflammatory lesions were marked by a mixed cellular infiltrate, acanthosis, and, in some cases, parakeratosis. These findings confirm the concept of IL-1 as a primary cytokine, release of which is able to initiate and localize an inflammatory reaction. Furthermore, these mice provide the first definitive evidence that inflammatory mediators can be released from the epidermis to enter the systemic circulation and thereby influence, in a paracrine or endocrine fashion, a wide variety of other cell types.
The ability of glucocorticosteroids to inhibit tissue eosinophilia may be an important feature of their anti‐inflammatory action in allergic diseases. Our previous work showed that an effect of dexamethasone on the release of eosinophils from the bone marrow could explain its inhibitory action on eosinophil accumulation in a mouse air‐pouch model. Thus, it was unclear from that study whether dexamethasone could interfere with the process of eosinophil trafficking. In the present study, therefore, we used a newly developed mouse model to evaluate the effects of systemic treatment with dexamethasone on the recruitment of ¹¹¹ In‐labelled blood eosinophils to sites of cutaneous inflammation in the mouse and whether lipocortin‐1 (LC‐1) was involved.
The i.d. injection of ovalbumin (OVA) in sensitized mice induced a dose‐dependent recruitment of ¹¹¹ In‐labelled blood eosinophils which peaked at 4 to 8 h after antigen challenge. Systemic treatment with dexamethasone (50 μg per mouse, 3 h after antigen) effectively inhibited ¹¹¹ In‐eosinophil recruitment in this reaction by 70 to 85%. Similarly, a 1 h pretreatment with dexamethasone significantly suppressed ¹¹¹ In‐eosinophil induced by platelet‐activating factor (PAF), leukotriene B 4 (LTB 4 ) and the chemokine macrophage inflammatory protein‐1α (MIP‐1α) by 40 to 70%.
Two experimental approaches were used to evaluate the role of LC‐1: treatment with LC‐1 fragment Ac2‐26 and use of an anti‐LC‐1 antiserum. LC‐1 fragment Ac2 ‐26 (100 μg per mouse) failed to affect ¹¹¹ In‐eosinophil recruitment. Moreover, pretreatment of animals with an anti‐LC‐1 antiserum failed to reverse the inhibitory effects of dexamethasone on ¹¹¹ In‐eosinophil recruitment induced by MIP‐1α and by antigen in sensitized mice.
In contrast, the LC‐1 fragment significantly inhibited glycogen‐induced neutrophil recruitment into the peritoneal cavity of mice. Furthermore, the anti‐LC‐1 antiserum reversed the inhibitory effects of dexamethasone on the glycogen‐induced neutrophil recruitment.
Thus, our results suggest that dexamethasone can inhibit the recruitment of eosinophils in mouse skin independent of an action on the bone marrow. However, by use of two different approaches, we showed that LC‐1 does not play a role in mediating the inhibitory action of dexamethasone on eosinophil migration into cutaneous inflammatory reactions in the mouse. These data add further support to a LC‐1‐independent action of dexamethasone on eosinophils in vivo .
British Journal of Pharmacology (1998) 123 , 538–544; doi: 10.1038/sj.bjp.0701625
Male pattern baldness is assumed to result from a combination of normal serum concentrations of androgen and an appropriate genetic background. To study whether inflammation contributes to the development of androgenetic alopecia, direct immunofluorescence and dermatopathologic studies were performed on biopsy specimens from bald scalp of patients, with specimens from uninvolved scalp of these patients or from scalp of volunteers who were not bald serving as controls. Granular deposits of Immunoglobulin M or C3 (or both) were found at the basement membrane in 25 (96%) of 26 study patients and 1 (12%) of 8 control subjects. Granular C3 was also deposited on eccrine myoepithelial cells in 8 (31%) of 26 study patients, but no control subjects. Porphyrins were found in the pilosebaceous canal in 15 (58%) of 26 study subjects and in 1 (12%) of 8 control subjects. These results support an inflammatory pathogenesis of androgenetic alopecia. Propionibacterium acnes is known to produce porphyrins. Ultraviolet radiation may excite microbiologic porphyrins that could activate C3 and, subsequently, the complement cascade producing inflammatory mediators.
Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many disease processes such as arthritis, cancer, periodontitis, and osteoporosis. A matrixin family is defined, comprising at least seven members that range in size from Mr 28,000 to 92,000 and are related in gene sequence to collagenase. All family members are secreted as zymogens that lose peptides of about 10,000 daltons upon activation. Latency is due to a conserved cysteine that binds to zinc at the active center. Latency is overcome by physical (chaotropic agents), chemical (HOCl, mercurials), and enzymatic (trypsin, plasmin) treatments that separate the cysteine residue from the zinc. Expression of the metalloproteinases is switched on by a variety of agents acting through regulatory elements of the gene, particularly the AP-1 binding site. A family of protein inhibitors of Mr 28,500 or less binds strongly and stoichiometrically in noncovalent fashion to inhibit members of the family. The serum protein alpha 2-macroglobulin and relatives are also strongly inhibitory.
Interleukin-8 (IL-8) is a potent chemotactic protein for polymorphonuclear leukocytes (PMN). Here we examine whether PMN synthesize and release IL-8 in response to stimulation by leukotriene B4 (LTB4). PMN isolated from normal heparinized peripheral human blood were incubated in RPMI culture medium at 37 degrees C in 5% CO2, with and without LTB4. The culture supernatants were tested for IL-8 bioactivity through chemotactic activity measurements with and without neutralizing anti-IL-8 serum. Immunoreactive IL-8 was quantified by ELISA, and de novo IL-8 synthesis was evaluated by metabolic labeling with [35S]cysteine followed by immunoprecipitation. LTB4 stimulated PMN to produce IL-8 in a dose- and time-dependent manner. The IL-8 concentrations reached maximal levels after 16 h of incubation with LTB4. Significant increases in IL-8 production occurred with LTB4 doses of 10 to 1,000 nM/ml. Immunoprecipitation of labeled IL-8 documented new synthesis of IL-8 by LTB4-treated PMN. Northern blot analysis of total RNA from PMN using a 30 mer oligonucleotide for IL-8 demonstrated increased mRNA expression in LTB4-stimulated PMN compared with untreated PMN. These data show that peripheral blood PMN can be stimulated by LTB4 to synthesize and secrete biologically active IL-8. PMN and other cells capable of producing LTB4 may induce IL-8 protein production by inflammatory PMN and thereby amplify or perpetuate the acute inflammatory response by recruiting additional PMN into an inflammatory site.
Hair-follicle regression in the bald scalps of stumptailed macaques develops after puberty, which corresponds to an elevation of serum testosterone and dihydrotestosterone. Using the cultured cells from the pre- and postpubertal macaques, we examined the role of dermal papilla cells in testosterone-induced inhibition of outer root sheath cell proliferation. Testosterone showed no effects on proliferation of either dermal papilla cells or outer root sheath cells cultured alone. Testosterone-induced inhibition of outer root sheath cell proliferation occurred only in coculture with dermal papilla cells derived from the bald scalps of adult macaques but not with dermal papilla cells from the hairy occipital scalps of adult macaques or the prebald frontal scalps of juvenile macaques. Furthermore, RU 58841, an androgen receptor blocker, antagonized this testosterone-elicited inhibition. Together our data indicate that the inhibitory effect of testosterone on proliferation of epithelial cells is age dependent, a...
The aims of this study were to investigate: (1) the production of all arachidonic acid metabolites in hair dermal, papilla cells (DPC) and (2) the effects of minoxidil and vascular endothelial growth factor (VEGF) on this production. Eicosanoid synthesis was evaluated in culture medium after incorporation of tritiated arachidonic acid into DPC membrane phospholipids. Compared to controls, exposure of DPC to 1 μM 12-O-tetradecanoyl phorbol 13-acetate did not stimulate arachidonic acid metabolism, however exposure to calcium ionophore A23187, produced large amounts of eicosanoids, consisting mainly of 273% PG6KF(1α), 176% of PGE2 and 68% LTB4. A good correlation was found with ELISA and radioassay techniques for total synthesis of major metabolites. The ELISA technique was also used to investigate the effects of minoxidil and VEGF on DPC production of three arachidonic acid metabolites: prostaglandins 6KF(1α), E2 and leukotriene B4, before and after stimulation with A23187. High concentrations of VEGF induced an activation of the production of these metabolites, and a low concentration of minoxidil (12 μM) inhibited PG6KF(1α), production but stimulated that of PGE2 and LTB4. These data confirm the implication of VEGF and minoxidil in the modulation of eicosanoid production by hair, dermal papilla cells.
To evaluate the androgen control of sebum, subjects with complete androgen insensitivity and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency and decreased dihydrotestosterone (DHT) production had sebum production studied. A hydrophobic polymeric film applied to the forehead was used to measure sebum production through the use of air filled micropores. Sebum scores of normal preadrenarchal children (ages 2-6), and normal age-matched adult males and females, were studied as well as males treated with the 5 alpha-reductase inhibitor, finasteride, for benign prostatic hyperplasia who were studied at baseline and after drug therapy. Androgen insensitive subjects had no sebum production by this methodology, and the results were identical to preadrenarchal children. In contrast, adult male pseudohermaphrodites with 5 alpha-reductase deficiency and a selective decrease in DHT production had sebum production scores identical to normal age-matched males. Males with benign prostatic hyperplasia treated with the 5 alpha-reductase inhibitor, finasteride, to lower DHT levels did not decrease the sebum score from baseline values. The lack of demonstrable sebum in androgen-insensitive subjects clearly demonstrates the absolute androgen control of sebum production. The DHT dependency of the sebaceous gland, however, could not be demonstrated in this study. Two 5 alpha-reductase isoenzymes 1 and 2, have been described. 5 alpha-reductase-2 is the gene responsible for inherited 5 alpha-reductase deficiency. Although the degree of inhibition of DHT in utero and in adulthood in male pseudohermaphrodites with a defect in 5 alpha-reductase-2 enzyme activity caused severe impairment of external genital and prostate differentiation and decreased facial and body hair, it had no demonstrable effect on sebaceous gland development or function. Furthermore, lowering DHT levels in adulthood had no effect on sebum production. If the gland is rich in the enzyme 5 alpha-reductase-2, it is proposed that the sebaceous gland is either exquisitely sensitive to DHT, requiring only small amounts for normal development and function, or that male levels of testosterone compensate for DHT and maintain normal sebaceous gland activity throughout life. It is also possible that 5 alpha-reductase-1 is the enzyme of the sebaceous gland and is unaffected in the inherited condition and by finasteride.
Data from the literature indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, piroxicam, or ibuprofen, induce hair loss in vivo. These NSAIDs are well-known inhibitors of both the cytoprotective isoform of prostaglandin endoperoxide synthase-1 (PGHS-1) and of the inducible form (PGHS-2). By immunohistochemical staining, we found that PGHS-1 is the main isoform present in the dermal papilla from normal human hair follicle (either anagen or catagen), whereas PGHS-2 was only faintly and exclusively expressed in anagen dermal papilla. Thus, PGHS-1 might be the primary target of the hair growth-inhibitory effects of NSAIDS. We thus speculated that activation of PGHS-1 might be a mechanism by which minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxyde) stimulates hair growth in vivo. We demonstrate here that minoxidil is a potent activator of purified PGHS-1 (AC50 = 80 μM), as assayed by oxygen consumption and PGE2 production. This activation was also evidenced by increased PGE2 production by BALB/c 3T3 fibroblasts and by human dermal papilla fibroblasts in culture. Our findings suggest that minoxidil and its derivatives may have a cytoprotective activity in vivo and that more potent second-generation hair growth-promoting drugs might be designed, based on this mechanism.
The presence of 5α-reductase (5α-R) in skin may indicate that the androgen regulation of sebaceous glands and sebum production requires the local conversion of testosterone to dihydrotestosterone. The goals of this study were to identify which isozyme of 5α-R (type 1 or type 2) is expressed in sebaceous glands from facial areas, scalp, and non-acne-prone areas; to determine if 5α-R activity is concentrated in sebaceous glands; to assess whether there are regional differences in this enzyme's activity; and to test the effects of azasteroid inhibitors and 13-cis retinoic acid on 5α-R in these tissues. Sebaceous glands were microdissected from facial skin, scalp, and non-acne-prone skin (arm, breast, abdomen, leg), and the activity of 5α-R was determined. A total of 49 samples from 23 male and 21 female subjects without acne (age range, 16 to 81 years, 56 ± 20 years [mean ± SD]) was analyzed. The biochemical properties of the enzyme in each of the samples tested are consistent with those of the type 1 5α-R. Minimal to no type 2 5α-R was detected. The level of 5α-R activity was significantly higher in the sebaceous glands compared to whole skin in facial skin (p = 0.047), scalp (p = 0.039), and non-acne-prone skin (p = 0.04). Enzyme activity in sebaceous glands from facial skin and scalp was significantly higher than in a comparable amount of sebaceous gland material obtained from non-acne-prone areas (32 ± 6 [mean ± SEM]), 35 ± 7 (mean ± SEM) versus 6.0 ± 3.0 (mean ± SEM) pmol/min/mg protein, p = 0.014 and 0.007, respectively). Finasteride and 13-cis retinoic acid were poor inhibitors of the enzyme with 50% inhibitory concentration values greater than 500 nM. These data demonstrate that in the skin from older patients without acne the type 1 isozyme of 5α-R predominates, its activity is concentrated in sebaceous glands and is significantly higher in sebaceous glands from the face and scalp compared to non-acne-prone areas, and the action of 13-cis retinoic acid in the control of acne is not at the level of 5α-R. Furthermore, we suggest that specific inhibition of the type 1 5α-R may offer a viable approach to the management of sebum production and, hence, acne.
The conversion of testosterone into dihydrotestosterone by steroid 5 alpha-reductase is a key reaction in androgen action, and is essential both for the formation of the male phenotype during embryogenesis and for androgen-mediated growth of tissues such as the prostate. Single gene defects that impair this conversion lead to pseudohermaphroditism in which 46X,Y males have male internal urogenital tracts, but female external genitalia. We have described the isolation of a human 5 alpha-reductase complementary DNA from prostate. Subsequent cloning and genetic studies showed that this gene (designated 5 alpha-reductase 1) was normal in patients with 5 alpha-reductase deficiency. We report here the isolation of a second 5 alpha-reductase cDNA by expression cloning and the polymerase chain reaction. The biochemical and pharmacological properties of this cDNA-encoded enzyme (designated 5 alpha-reductase 2) are consistent with it being the major isozyme in genital tissue. A deletion in this gene is present in two related individuals with male pseudohermaphroditism caused by 5 alpha-reductase deficiency. These results verify the existence of at least two 5 alpha-reductases in man and provide insight into a fundamental hormone-mediated event in male sexual differentiation.
The enzyme steroid 5α-reductase catalyzes the conversion of testosterone into the more powerful androgen, dihydrotestosterone. We previously described the cloning of rat and human cDNAs that encode steroid 5α-reductase and their expression in oocytes and cultured cells. Here, we report the isolation, characterization, and chromosomal mapping of two human steroid 5α-reductase genes. One gene (symbol SRD5A1) is functional, contains five exons separated by four introns, and maps to the distal short arm of chromosome 5. Two informative restriction fragment length polymorphisms are present in exons 1 and 2 of this gene. A second gene (symbol SRD5AP1) has all of the hall-marks of a processed pseudogene and was mapped to the q24-qter region of the X chromosome. In the mouse, a single steroid 5α-reductase gene (Srd5α-1) is linked to Xmv-13 on chromosome 13.
Recently, the search for new and effective agents for the treatment of alopecia has become significantly more intense. The increase in hair biology research worldwide seen in both academic institutions and pharmaceutical companies stems from the desire to profit from the marketing of drugs that have been termed cosmeceuticals. Millions of men and women from every ethnic group suffer from various forms of alopecia, the most common being androgenetic alopecia (AGA), where the target tissue active androgen, 5α-dihydrotestosterone (DHT) aggravates genetically programmed scalp hair follicles, resulting in hair loss. Currently available drugs indicated for other disease processes are still commonly used to treat the various forms of alopecia because no other agents are available; some of these compounds have severe side-effects and many also exhibit minimal efficacy. These prescription drugs were not originally indicated for alopecia and have not been adequately tested in controlled clinical trials to assess for efficacy, safety and toxicity. Despite this, these agents continue to be used clinically for the treatment of patients with various forms of alopecia. To combat the problems associated with the currently prescribed drugs a variety of new agents have emerged in patent applications. This report reviews nearly 70 patent applications submitted since 1995 for AGA, immunomodulatory related hair diseases and antichemotherapeutic alopecia agents (preventing hair loss during chemotherapy) and discusses the mechanisms of action targetted by research and their implications regarding efficacy.
Androgenetic alopecia (AGA) is a common yet poorly understood condition. In particular, the significance of inflammatory cells close to the infrainfundibulum of transitional hairs remains obscure. This study was conducted in 20 men who used a lotion containing the antimicrobials, piroctone olamine and triclosan, regularly for 18 months. At entry, mild pruritus and abnormal hair loss were reported by the volunteers. During treatment, pruritus resolved rapidly. Comparison of clinical photographs and trichograms taken at 3-month intervals suggested signs of hair regrowth with moderate increase in density of transitional hairs. Biopsies taken at 6-month intervals were processed for immunohistochemistry. There was a decrease in the density of activated T cells in the region of the follicular infrainfundibulum and isthmus over time. IgG deposits found within the epithelial sheaths at entry to the study were absent in the subsequent biopsies. The volume of the sebaceous glands, as assessed by computerized morphometry, was not modified by the treatment. It was concluded that inflammation associated with AGA transitional hairs may be driven by the presence of microorganisms harboured in the infrainfundibulum. They may modulate the severity of AGA and may potentially be controllable. This offers a new possibility of prevention and partial reversal of hair loss in AGA.
In 1972, Gery and co-workers1 detected a factor that promotes murine thymocyte proliferation in culture supernatants of human peripheral blood adherent leukocytes. This factor is active across species lines, does not support the growth of interleukin 2 (IL-2)-dependent lymphocyte lines, is produced by monocytic rather than lymphocytic leukocytes, and has subsequently been termed interleukin 1 (IL- 1)2. More recently, it has become evident that IL-1 activities can be produced by virtually every nucleated cell type and, in addition, IL-1 has been reported to have stimulatory effects on the growth and differentiation of numerous cell types. In this review, Joost Oppenheim and his colleagues discuss the biochemical characteristics, gene cloning, cell sources, biological properties and actions of IL-1, and give reasons why this pleitotropic, nonspecific hormone-like cytokine is of considerable concern to immunologists.
The nuclear hormone 1 α,25-dihydroxyvitamin D(3) (VD) is an important regulator of calcium homeostasis and is also a modulator of the cell cycle. The genomic actions of the hormone are mediated by a single transcription factor, the vitamin D(3) receptor (VDR). On the majority of the known VD response elements, VDR binds as heterodimeric complex with the retinoid X receptor (RXR), which is a member of the nuclear receptor superfamily like VDR. RXR supports not only the DNA binding affinity and specificity of VDR, but allosterically also its transactivation properties. Moreover RXR is a partner in other hormone response systems, which supports the idea that the different nuclear hormone signaling pathways are functionally linked.
Three hundred and forty-seven tissue specimens were studied from 23 patients with male pattern alopecia. Characteristic features of pattern alopecia included: the presence of miniature or vellus follicles; a marked enlargement of the sebaceous glands and arrectores pilorum muscles; the presence of connective tissue streamers beneath the vellus follicles; and the thinning of the dermis. A mild perivascular infiltrate of mononuclear cells and mild capillary dilatation was sometimes seen. An increased number of mast cells was often a prominent feature. Histochemical procedures were performed for glycogen, acid mucosaccharides, inorganic substances, and enzymes including alkaline phosphatase, acid phosphatase, beta glucuronidase, cholinesterase, aminopeptidase, oxidases and dehydrogenases. Histochemical studies did not reveal any significantly abnormal enzyme changes other than the altered vascular and nerve supply to the the miniature follicles.
Phorbol ester (TPA) and retinoic acid (RA) are two potent immunomodulatory agents whose actions are mediated through distinct signal transduction pathways involving protein kinase C (PKC) and nuclear RA receptors, respectively. We have investigated the interactions between these two pathways in the regulation of expression of the inflammatory cytokine IL-8 in human skin fibroblasts. TPA (as previously reported) and RA both induced IL-8 mRNA and protein in a time- and dose-dependent manner. IL-8 mRNA induction by TPA (10 nM) was maximal (15-fold) within 6 h, and returned to baseline within 24 h of treatment, although maximal induction (10-fold) by RA (1 microM) did not occur until 24 h posttreatment. Induction of IL-8 by TPA was blocked by 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine, which inhibits PKC and cAMP-dependent protein kinases (PKA), but not by N-(2-ganidinoethyl)-5-isoquinoline sulfonamide, which preferentially inhibits PKA, consistent with the participation of PKC in the induction of IL-8 by TPA. In contrast, induction of IL-8 by RA was inhibited by both 1-(5-isoquinoline sulfonamide and N-(2-gamidinoethyl)-5-isoquinoline sulfonamide, suggesting the participation of PKA in the induction of IL-8 by RA. However, activation of PKA by addition of cAMP analogues was not sufficient to induce IL-8 expression. Induction of IL-8 by RA also did not appear to be mediated indirectly through induction of IL-1, because addition of IL-1R antagonist did not block IL-8 induction by RA. RA and TPA added in combination synergistically enhanced expression of IL-8 mRNA, measured at 6 (2-fold) and 24 h (10-fold) posttreatment. To investigate the mechanism of this synergy, the effect of TPA and RA on fibroblast PKC activation and PKC isozyme levels were determined. TPA, either alone or together with RA, but not RA alone, stimulated phosphorylation of an endogenous 80-kDa PKC substrate. Dermal fibroblasts expressed three PKC isozymes (alpha, (delta, and (epsilon). TPA, but not RA, down-regulated PKC-alpha, neither TPA or RA affected the level of PKC-delta, and both TPA and RA down-regulated PKC-epsilon. This latter effect was enhanced 2-fold by addition of RA and TPA together. These data suggest that modulation of PKC-epsilon may be a common participant in the regulation of IL-8 expression by TPA and RA.
Hair-bearing, transitional, and alopecic scalp from three males and one female with progressive pattern alopecia were examined. Ultrastructural studies disclosed measurable thickening of the follicular adventitial sheaths of transitional and alopecic zones compared with those in the non-alopecic zones. This finding was associated with mast cell degranulation and fibroblast activation within the fibrous sheaths. Immunohistochemically, control biopsies were devoid of follicular inflammation (n = 3), while transitional regions consistently showed the presence of activated T-cell infiltrates about the lower portions of follicular infundibula. These infiltrates were associated with the induction of class II antigens on the endothelial linings of venules within follicular adventitia and with apparent hyperplasia of follicular dendritic cells displaying the CD1 epitope. Inflammatory cells infiltrated the region of the follicular bulge, the putative source of stem cells in cycling follicles. The data suggest that progressive fibrosis of the perifollicular sheath occurs in lesions of pattern alopecia, and may begin with T-cell infiltration of follicular stem cell epithelium. Injury to follicular stem cell epithelium and/or thickening of adventitial sheaths may impair normal pilar cycling and result in hair loss.
Superoxide and hydrogen peroxide are reactive oxygen species (ROS) primarily produced by phagocytic cells as a consequence of the process of phagocytosis. This defensive role, may, however, become one of attack when production of ROS is excessive and overwhelms cellular scavenging systems. This happens in situations such as acute inflammation and results in host cell membrane damage, which is particularly prevalent in the presence of transition metal catalysts such as iron and copper. The skin is uniquely vulnerable to this attack being rich in polyunsaturated fatty acids and exposed to high oxygen tensions and ultraviolet light, both of which promote production of ROS. Additionally, the respiratory burst of infiltrating polymorphonuclear leukocytes and macrophages in inflamed skin will produce high local levels of superoxide that can release "catalytic iron" from storage proteins such as ferritin. The role of iron and ROS in the pathogenesis of inflammatory skin disease is discussed as is the possibility of novel therapeutic strategies based on their removal.
The role of endogenous nitric oxide (NO) in acute inflammation was investigated using two inhibitors of NO synthase (NG-nitro-L-arginine methyl ester(L-NAME) and NG-monomethyl-L-arginine (L-NMMA)) as well as L- or D-arginine. The effect of test compounds was studied on the carrageenin-induced increase in vascular permeability in rat skin and in dextran- and carrageenin-induced paw oedema. Both L-NAME and L-NMMA dose dependently inhibited the increase in vascular permeability and oedema formation. L- but not D-arginine increased these inflammatory responses and reversed the inhibitory effects of L-NAME and L-NMMA. In dexamethasone-treated rats L-arginine enhanced the dextran-induced oedema and the early phase of carrageenin-induced oedema but did not modify the inhibition by dexamethasone of the late phase of carrageenin-induced oedema. These results suggest that endogenous NO is released at the site of acute inflammation and modulates oedema formation. Depending on the time course or on the type of inflammation, NO may be predominantly generated by the constitutive or by the inducible NO synthase.
Twenty-five biopsy specimens from the balding frontal scalp of five patients were studied. Processing included vertical and transverse (horizontal) sectioning, toluidine blue and hematoxylin and eosin staining, and fixed and frozen sectioning. Findings included decreased hair density, increased numbers of vellus hairs, and alteration of the normal follicular architecture. Transverse frozen sectioning with toluidine blue staining appeared to be a rapid and reliable tool for studying androgenic alopecia.
Movement of neutrophils from the bloodstream to inflamed tissue depends on the activation of both the neutrophil and the endothelial cell. Endothelial cells lining the postcapillary venule respond to proinflammatory mediators by expressing adhesion molecules and synthesizing a variety of neutrophil-activating factors. Endothelial cell production of a 77-amino acid variant of interleukin-8 (IL-8) was found to be a requirement for the invasion of neutrophils through a vessel wall model. IL-8 secreted by cytokine- or lipopolysaccharide-stimulated endothelial cells induced the rapid shedding of neutrophil lectin adhesion molecule-1, the up-regulation of leukocyte beta 2 integrins, and the attachment and transmigration of the neutrophils. Thus, endogenous endothelial IL-8 regulates transvenular traffic during acute inflammatory responses.
The "active" edges of patches of alopecia areata and normal areas from the same scalp (i.e., bearing normal terminal hair) from seven patients with alopecia areata were investigated immunohistologically. Similar areas from a further eight patients were examined using light and electronmicroscopy. "Active" and "normal" areas of alopecia areata scalps were immunohistologically similar and varied from normal controls in the number, distribution, and ratio for T4 and T8-positive cells. Similarly the ultrastructural changes seen in the "active" areas when compared to normal controls were also present in the "normal" areas of alopecia areata scalps. The most significant differences found between normal "control" follicles and both "active" and "normal" areas of alopecia areata scalps were the polymorphic nature of the dermal papilla cells and the loss of cellular organization within the dermal papillae taken from alopecia areata scalps. In addition, the junction between the dermal papilla and the bulb of the hair follicle, the dermo-epithelial junction of the hair follicle bulb, demonstrated critical changes in follicles taken from both "active" and "normal" areas of alopecia areata scalps. These results support the suggestion of a subclinical state of alopecia areata and indicate that further work on the etiology of alopecia areata should be directed towards the "normal" areas of alopecia areata scalps, in particular the cells of the dermal papilla and the dermo-epithelial junction of the hair follicle bulb.
Phospholipase A2 (PLA2) is known to play an important intracellular role in inflammatory processes but does it also perform a vital function extracellularly? Here, W. Pruzanski and P. Vadas marshall the evidence supporting PLA2 as a mediator of inflammation, specifically in linking local and systemic effects.
Interleukin 8 (IL-8) is a potent leukocyte chemotactic and activating cytokine produced by keratinocytes, fibroblasts, peripheral blood monocytes (PBMC) and endothelial cells. IL-8 is believed to play an important role in the development of inflammation and is thus an obvious target for therapeutical modulation. We studied the possible effect of an endogenous immune modulator 1,25(OH)2-cholecalciferol (1,25(OH)2-D3) on the IL-1-induced IL-8-production by several types of cells. 1,25(OH)2-D3 inhibited the IL-1-alpha induced IL-8 production and mRNA expression in keratinocytes, fibroblasts and PBMC, but not in endothelial cells. Optimal vitamin concentrations varied between 10(-10) and 10(-11) M. These results suggest a potential role of this hormone in the regulation of chemotactic cytokine production.
The microsomal enzyme steroid 5 alpha-reductase is responsible for the conversion of testosterone into the more potent androgen dihydrotestosterone. In man, this steroid acts on a variety of androgen-responsive target tissues to mediate such diverse endocrine processes as male sexual differentiation in the fetus and prostatic growth in men. Here we describe the isolation, structure, and expression of a cDNA encoding the human steroid 5 alpha-reductase. A rat cDNA was used as a hybridization probe to screen a human prostate cDNA library. A 2.1-kilobase cDNA was identified and DNA sequence analysis indicated that the human steroid 5 alpha-reductase was a hydrophobic protein of 259 amino acids with a predicted molecular weight of 29,462. A comparison of the human and rat protein sequences revealed a 60% identity. Transfection of expression vectors containing the human and rat cDNAs into simian COS cells resulted in the synthesis of high levels of steroid 5 alpha-reductase enzyme activity. Both enzymes expressed in COS cells showed similar substrate specificities for naturally occurring steroid hormones. However, synthetic 4-azasteroids demonstrated marked differences in their abilities to inhibit the human and rat steroid 5 alpha-reductases.
Various chemoattractants have been implicated in the aetiology of the polymorphonuclear leucocyte (PMN) migration into the epidermis seen in early lesions of psoriasis. Using an under-agarose technique, the in vitro chemotactic responses of PMN to the arachidonic acid lipoxygenase product leukotriene B4 (LTB4) were assayed in five groups of subjects: normal healthy volunteers (n = 12), untreated psoriatics (n = 11) and psoriatics treated with topical tar (n = 12), PUVA (n = 11) and UVB phototherapy (n = 10). No significant difference was observed between the responses of control subjects and of untreated psoriatics, nor between the untreated psoriatic group and the PUVA- and UVB-treated groups, respectively. However, comparison of the tar-treated and untreated groups revealed a significantly increased chemotactic response to LTB4 in the tar-treated group (p less than 0.01).
A murine monoclonal antibody (H4/18) raised against cultured human endothelial cells (HEC) prestimulated by the monokine interleukin 1 (IL 1) recognizes a cell surface molecule inducible by IL 1 or by the distinct monokine tumor necrosis factor (TNF) in primary or serially passaged HEC. H4/18 binding is not basally expressed or inducible by IL 1 in an SV-40 transformed HEC line, in human dermal fibroblasts, or in blood leukocytes. Expression of this molecule by HEC in response to IL 1 can be blocked by protein and RNA synthesis inhibitors but not by cyclooxygenase inhibitors. In addition, H4/18 can immunoprecipitate two biosynthetically labeled polypeptides (Mr 100,000 and 120,000) from HEC stimulated with IL 1 but not from control HEC. Thus, the H4/18 binding site appears to be an inducible surface protein specific for HEC. The majority of HEC in a culture can be induced to express the H4/18 binding protein, but expression is transient (peak 4 to 6 hr) and over the next 24 hr declines to near basal levels either in the continued presence of or upon removal of IL 1. The magnitude of the peak response depends upon IL 1 concentration (peak 5 to 10 U/ml), and the response is optimized by the continued presence of IL 1 during the initial 4- to 6-hr induction period. The time of peak H4/18 binding does not appear to be a function of IL 1 concentration. The decline of H4/18 binding from peak levels is prevented by cycloheximide, a protein synthesis inhibitor. HEC maintained in the presence of IL 1 for 24 hr become refractory to restimulation by IL 1; however, IL 1-stimulated cells rested in the absence of IL 1 for 20 hr can be stimulated by fresh IL 1. HEC expression of the H4/18 binding protein is not induced by interleukin 2 or by interferon-alpha, -beta, or -gamma. Induction of H4/18 binding by TNF is also concentration dependent, transient, and dependent upon protein and RNA synthesis. Several observations suggest that IL1 and TNF act independently on HEC. Our TNF is a recombinant protein, expressed from a cloned cDNA and thus free of IL 1 contamination; it also has no activity in a highly sensitive IL 1 assay. Our standard IL 1 preparation is affinity purified and lacks TNF activity on L929 cells. Thus, our monokine preparations are not cross-contaminated. Most interestingly, HEC incubated with IL 1 and refractory to IL1 restimulation can be restimulated by TNF to express H4/18 binding and vice versa.(ABSTRACT TRUNCATED AT 400 WORDS)
Experiments with guinea-pig lung suggest that some of the therapeutic effects of sodium salicylate and aspirin-like drugs are due to inhibition of the synthesis of prostaglandins.
Glucocorticosteroids are highly effective in controlling inflammation and the molecular mechanisms involved are now becoming clear. Activation of glucocorticoid receptors results in increased or decreased transcription of a number of genes involved in the inflammatory process. Of particular importance is the repression of cytokine gene transcription and the direct interaction between the glucocorticoid receptor and other transcription factors activated in chronic inflammation. In this review, Peter Barnes and Ian Adcock discuss recent studies that have increased our understanding of these mechanisms and that may lead to improved anti-inflammatory therapies in the future.
We investigated the populations of activated T (HLA-DR+CD3+) cells and natural killer (CD57-CD16+) cells in the peripheral blood of patients with various types of alopecia areata (AA) and noted any changes that occurred in the said populations after administration of local and systemic corticosteroid therapy. In type 2 (severe multiple AA and alopecia totalis) and type 3 (alopecia universalis), the mean percentages of HLA-DR+CD3+ cells and CD57-CD16+ cells were significantly higher when compared with those of the normal controls. The percentages of both subsets in type 1 (mild AA) and the normal controls were consistent. Twenty-four patients in types 2 and 3 had received corticosteroid treatment, and all patients experienced new hair growth. With the changes in disease activity, the populations of HLA-DR+CD3+ cells in these patients after corticosteroid therapy significantly decreased when compared with those recorded prior to treatment. Subsequent to treatment, the mean percentages of CD57-CD16+ cells decreased to levels that were not significant relative to that of the normal controls. These findings indicate that HLA-DR+CD3+ and CD57-CD16+ cells in the peripheral blood of patients with AA may be correlated with the disease activity of AA.
Keratinocytes can function as antigen-presenting cells/accessory cells and regulate T cells with three distinct outcomes, depending on the nature of the stimulus. In the presence of alloantigen, it appears that a "null" event takes place between T cells and keratinocytes, with neither activation nor induction of tolerance. Using nominal antigen, keratinocytes induce antigen-specific tolerance. In contrast, with bacterial-derived superantigens, phytohemagglutinin, or immobilized CD3 monoclonal antibody, keratinocytes can significantly activate resting autologous T-cell proliferation and cytokine release. To understand these highly divergent responses, we focused on the two-signal model of T-cell activation, with particular emphasis on costimulatory molecules expressed by keratinocytes. Such second signals, as highlighted by the B7 and CD28 receptor families, provide useful insights into the complex interactions involving keratinocytes and T cells. In this review, we summarize recent evidence indicating that keratinocytes regulate T-cell activation in a direct and indirect manner by their mutual expression and responsiveness involving adhesion molecules, cytokines, and costimulatory signals. As investigative momentum continues to grow in the fields of immunology and keratinocyte biology, it is likely that manipulation of CD28:B7 interactions will not only provide a useful model to understand further the complexities of skin immune reactions, but will also serve as the basis for new therapeutic opportunities for numerous T-cell-mediated diseases that involve aberrant reactions with keratinocytes.
Chemokines are thought to play a central role in the recruitment and activation of leukocytes during inflammatory responses. Monocyte chemoattractant protein 1 (MCP-1) is a chemokine of the C-C or beta family that is chemotactic in vitro for monocytes, T cells, and basophils. Its excessive production by keratinocytes has been implicated in psoriasis and other skin diseases. To test the in vivo role of MCP-1 in inflammatory skin disease, we undertook the generation of transgenic mice that express murine MCP-1 in the basal layer of epidermis. Despite production of high levels of functional MCP-1 by basal keratinocytes, documented in vivo and in vitro, these mice did not exhibit spontaneous cutaneous inflammation or any other discernible skin pathology. In contrast, elicited inflammation in the skin of these mice differed qualitatively and quantitatively from that observed in non-transgenic controls. Contact hypersensitivity challenge responses in transgenic animals were characterized by an exaggerated lichenoid infiltration of monocytes and T cells. Additional phenotypic characterization of the normal appearing skin in these mice showed that the only spontaneous change was a dramatic increase and redistribution of CD45+, I-A+ cells that assumed a dendritic morphology in situ, including a subset that expressed markers characteristic of Langerhans cells. Taken together, these data indicate that tissue-specific expression of MCP-1 alone is not sufficient to induce an inflammatory response, though its presence can modify inflammatory and immune events initiated by exogenous stimuli. The recruitment of dendritic and Langerhans cells in the absence of inflammation is a previously unknown consequence of cutaneous MCP-1 production in vivo.
Since the discovery that epidermal cell-derived thymocyte-activating factor was identical to interleukin (IL)-1 alpha and -beta in 1986, these molecules have been implicated in the pathogenesis of skin diseases. In 1995, it has become clear that a group of gene products function to regulate the activity of IL-1. IL-1 alpha and mature 17-kD IL-1 beta (cleaved from precursor by IL-1 beta-converting enzyme) bind to the type 1 IL-1 receptor to transduce a signal. This process can be antagonized at the level of the receptor by two distinct forms of the IL-1 receptor antagonist, which bind to the type I receptor but do not transduce a signal. The process can also be antagonized at the level of the ligand by either cell-bound or soluble type 2 IL-1 receptor. This type 2 IL-1 receptor binds ligand but does not transduce a signal. Keratinocytes can make each of these variables in vitro, and the balance between agonists and antagonists dictates the biologic outcome of a putative IL-1-mediated event. Transgenic mice that overexpress each of these factors individually in epidermis will be useful for enhancing our understanding of the cutaneous biology of IL-1.
The discovery of a second cyclooxygenase has provided fresh impetus to the search for new anti-inflammatory drugs. The second enzyme is effectively absent from healthy tissues but its levels rise dramatically during inflammation. It can be induced in migratory cells by bacterial lipopolysaccharide, cytokines and growth factors. The constitutive cyclooxygenase-1 (COX-1) can thus be considered a "housekeeping" enzyme, in contrast to cyclooxygenase-2 (COX-2) which is activated by tissue damage. Both enzymes have a molecular weight of around 70 kDa and similar Km and Vmax values for their reaction with arachidonic acid. Several non steroid anti-inflammatory drugs which have more than 1,000 fold selectivity for COX-2 over COX-1 are in the early stages of drug development.
The scalp hair of 15 patients, who were treated with etretinate for at least 6 months, was investigated, with the aims of confirming the previously described reduction in the duration of anagen and establishing the mechanism of etretinate alopecia. An increase in hair shedding rate and an increase in plucked telogen count, both of which continued for 6 months of treatment, were found, whereas there was no significant increase in the proportion of new, or regrowing, anagen hairs in a cut sample(NAH). The sustained decrease in the duration of anagen was confirmed, and it was further shown that this decrease was progressive. This would appear to be the main cause of the observed increased shedding associated with etretinate treatment. In relation to the mechanism of the alopecia, it was concluded that an arrest at the onset of anagen and a follicular anchorage defect in telogen were causes. The evidence for an arrest at the onset of anagen was a failure of NAH to rise on treatment, and a large increase in NAH on stopping treatment. The evidence for a follicular anchorage defect was a rise in shed rate very early in treatment, and an observed shed rate greater than expected, on the basis of plucked telogen results, later in treatment.
These pathogenic mechanisms have never been described previously in drug-induced alopecia, or in the majority of hair disorders in general. However, it would seem highly unlikely that these mechanisms are exclusive to etretinate therapy.
The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.
A hereditary, androgen-driven disorder, androgenetic alopecia is the most common form of alopecia in humans: its prevalence is 23-87%. Central alopecia is more severe in men; women are more likely to experience diffuse thinning. The acute onset of alopecia in those with inflammatory diseases of the scalp suggests a variety of etiologies, including the impact of inflammatory cells, release of cytokines, presence of growth factors, and increased interaction of stromal cells. Therapeutic modalities, which are most effective when used in combinations, utilize hair growth promoters, antiandrogens, and androgen blockade agents.
Androgens are major regulators of human hair growth with paradoxically different effects on hair follicles depending on their body site. They stimulate terminal growth in many regions including the face, have no effect on eyelashes, but may cause inhibition and balding on the scalp in genetically disposed individuals. How this occurs is unknown. However, androgens may act on the hair follicle via the cells of the dermal papilla; these would then influence the other cells of the hair follicle by altering the production of regulatory substances such as growth factors and/or extracellular matrix components. Therefore, primary lines of dermal papilla cells have been established from androgen-sensitive hair follicles, such as beard, and control, relatively androgen-independent, non-balding scalp cells and their mechanism of androgen action has been compared. Isolated beard dermal papillae were larger than those from scalp follicles. Although dermal papilla cells did not respond to in vitro androgens by alterations in growth, androgen-dependent dermal papilla cells contained higher levels of specific, low capacity, high affinity androgen receptors than non-balding scalp cells. The ability of the cells to metabolise testosterone to 5 alpha-dihydrotestosterone in culture also varied in parallel to that predicted from studies of hair growth in the 5 alpha-reductase deficiency syndrome. These results support the hypothesis that androgens act via the dermal papilla. They also show that dermal papilla cells retain differences in gene expression in culture which appear to correspond with their androgenic response in vivo. Further studies of such cells should help elucidate why bald men can grow beards!
A549 cells grown under serum free conditions do not express cyclooxygenase 2 (cox 2). However, addition of IL-1 beta results in the induction of cox 2 in a time and dose dependent manner; actinomycin D completely blocks this induction. Dexamethasone completely suppressed the induction of cox 2 only if present during the first 3.5h of IL-1 beta treatment but not if added after 3.5h. Treatment with a neutralising monoclonal antibody (1A, Biogen) specific to lipocortin-1 failed to reverse this inhibition by dexamethasone. However, using this same antibody we were able to reverse completely the effects of dexamethasone on the suppression of PGE2 release. These observations support the idea that glucocorticoids directly regulate cox 2 expression at the transcriptional level and this phenomenon is not mediated by lipocortin-1.
Prostaglandin H synthase (PGHS) is the rate-limiting enzyme in the conversion of arachidonic acid to prostanoids. The human PGHS has two isoforms. PGHS-1 is a house keeping gene whereas PGHS-2 is an inducible gene. We reported here the isolation of the entire PGHS-2 gene and its 5'-flanking region from a human bacteriophage P1 genomic library. The gene containing 10 exons is 7.5 kb in length and located at chromosome 1. The transcriptional start site was mapped at 134 bases upstream from the ATG start codon. Nucleotide sequence of 1.8 kb promoter region contains a TATA box and a number of potential regulatory elements including CRE, NF-kappa B, Sp1 and AP2 sites. Studies of the promoter activity showed that the first 460 nucleotides of 5'-flanking region efficiently drove transcription of the luciferase reporter gene in human umbilical vein endothelial cells upon stimulation with phorbor ester.
We have used a whole-organ culture system to investigate the effects of 1,25(OH)2D3 on human hair follicle growth and hair fiber production. Relatively low concentrations (1-10 nM) of 1,25(OH)2D3 stimulated the cumulative growth of hair follicles and hair fibers, by 52% and 36%, respectively (concentration producing 50% of the maximal response [EC50] values of 0.3 nM). The initial rates of follicle and fiber growth were increased, whereas the respective growth periods were unaffected. At higher concentrations of 1,25(OH)2D3, there was a dose-dependent inhibition of both follicle and fiber growth (IC50 values of 100 nM), in part due to reduction in the growth periods. There was a marked delay between the onset of 1,25(OH)2D-induced hair follicle and hair fiber growth inhibition. Incubation of hair follicles with 100 nM 1,25(OH)2D3 resulted in a rapid, transient inhibition of DNA synthesis (55% inhibition at 24 h), followed by a gradual return to control levels at day 4. Prolonged (> 5 h), incubation in the presence of 100 nM of 1,25 (OH)2D3 was required for follicle growth inhibition to be manifest. Ro 31-7549, a selective inhibitor of protein kinase C, did not prevent 1,25(OH)2D3-induced inhibition of hair follicle growth. These data suggest that 1,25(OH)2D3 may play a physiologic role in maintaining optimal hair follicle activity, and that elevation of 1,25(OH)2D3 may inhibit hair growth in vivo.