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(A) Non-balding DPCs isolated from the frontal scalp of normal individuals exhibited a relatively normal appearance at passage 2 compared with balding DPCs isolated from the frontal scalp of AGA patients of the same passage, which exhibited an enlarged, irregular, and flattened morphology. (B) SA-β-Gal activity was increased in balding DPCs. Scale bar = 100 µm. (C) Quantification of SA-β-Gal activity showed that the percentage of SA-β-Gal expression was increased in balding DPCs in all matched-pairs. (D) Balding DPCs exhibited an increase in cell size. (E) Prolongation of the cell doubling time were observed in balding DPCs. The pair 1–4 of the x axis in Figure 1C,D,E means the each age (20, 24, 27 and 40 years), sex (male), site (frontal) matched pairs of normal control (non-AGA males) and AGA patient. Values are means ± SDs from three determinations per experiment from three independent experiments using second-passage DPCs (*P<0.05, **P<0.01 compared with matched controls).
Source publication
The dermal papilla, located in the hair follicle, expresses androgen receptor and plays an important role in hair growth. Androgen/Androgen receptor actions have been implicated in the pathogenesis of androgenetic alopecia, but the exact mechanism is not well known. Recent studies suggest that balding dermal papilla cells exhibit premature senescen...
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Pseudopelade of Brocq (PPB) is a rare, idiopathic self-limiting hair disorder resulting in progressive cicatricial alopecia primarily involving the parietal scalp and vertex. The general pathogenesis of scarring alopecias has been focused on theories of stem cell failure and sebaceous gland destruction. Acquired immunity, Borrelia infection and sen...
Citations
... 50,51 This activated signaling pathway is involved in elevated apoptosis due to stress, subsequently increasing cellular senescence in hair follicles. 52 We found that CRH treatment increased the phosphorylation of JNK, c-jun, Erk1/2, and p38 in both cell types. In contrast, the GL extract treatment reduced the phosphorylation of JNK, c-jun, Erk1/2, and p38 in the CRH-treated cells, indicating the attenuation of stress-induced responses. ...
Corticotropin-releasing hormone (CRH) is a key mediator in stress-induced hair growth inhibition. Here, we investigated the impact of stress-induced senescence and evaluated the potential of Ganoderma lucidum (GL) extract in mitigating CRH-induced senescence in human hair follicle cells (hHFCs). We show that CRH treatment increased the senescence-associated beta-galactosidase (SA-β-GAL) activity and reactive oxygen species (ROS) formation in hHFCs and suppressed alkaline phosphatase (ALP) activity and anagen-inducing genes. However, GL extract restored ALP activity and decreased the expression levels of anagen-related genes in CRH-treated hHFCs. It decreased SA-β-GAL activity, reduced ROS production, and prevented the phosphorylation of MAPK signaling pathways in CRH-related stress response. Moreover, GL reversed the CRH-induced inhibition of two-cell assemblage (TCA) elongation and Ki67 expression. GL extract attenuates stress-induced hair follicular senescence by delaying catagen entry and scavenging ROS. Our findings suggest that GL extract could be used for treating stress-induced hair loss.
... Furthermore, gene association studies have demonstrated strong correlation between AGA phenotypes and AR [39]. The androgen/AR signal caus damage to the DNA in HDPCs in the balding region, which accelerates premature agin [40]. Hence, DHT may contribute to the miniaturization of AGA hair follicles. ...
... Furthermore, gene association studies have demonstrated a strong correlation between AGA phenotypes and AR [39]. The androgen/AR signal causes damage to the DNA in HDPCs in the balding region, which accelerates premature aging [40]. Hence, DHT may contribute to the miniaturization of AGA hair follicles. ...
β-Nicotinamide mononucleotide (NMN) has shown promising effects on intestinal health, and it is extensively applied as an anti-aging and Alzheimer’s disease therapeutic, due to its medicinal properties. The effects of NMN on the growth of mouse hair were observed after hair removal. The results indicated that NMN can reverse the state of hair follicle atrophy, hair thinning, and hair sparsity induced by dihydrotestosterone (DHT), compared to that of minoxidil. In addition, the action mechanisms of NMN promoting hair growth in cultured human dermal papilla cells (HDPCs) treated with DHT were investigated in detail. The incubation of HDPCs with DHT led to a decrease in cell viability and the release of inflammatory mediators, including interleukin-6 (IL-6), interleukin-1Beta (IL-1β) and tumor necrosis factor Alpha (TNF-α). It was found that NMN can significantly lower the release of inflammatory factors induced by DHT in HDPCs. HDPCs cells are protected from oxidative stress damage by NMN, which inhibits the NF-κB p65 inflammatory signaling pathway. Moreover, the levels of androgen receptor (AR), dickkopf-1 (DKK-1), and β-catenin in the HDPCs were assessed using PCR, indicating that NMN can significantly enhance the expression of VEGF, reduced IL-6 levels and suppress the expression of AR and DKK-1, and notably increase β-catenin expression in DHT-induced HDPCs.
... Meantime, the stem cells in hair follicles surrounding the attacked area are also suppressed away from anagen due to the abnormal microenvironment such as excessive inflammation and injured micro vessels. The sustained attack and delayed repair ultimately lead to the necrosis of hair follicles and the spread of alopecia [11][12][13]. So, AGA is a systemic disease caused by a variety of factors, mainly including excessive androgen attack, sustained inflammatory response, and lack of active hair follicle stem cells for hair regeneration. ...
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.
... In parallel, the balding DPC also showed the senescence manifestations such as changes of cell morphological, expression of senescence related β-galactosidase, and upregulation of p16 INK4a /pRb [23,61]. In fact, DHT induces premature ageing of DPCs in balding and non-balding frontal scalp migratory areas, but not beard DPCs [78]. These implied some unveiled relationship between the elevated androgen, AR and the cell senescence in AGA, which has been extensively investigated in other ageing related diseases as following. ...
Androgenetic alopecia (AGA) is the most common type of hair loss and features a progressive miniaturization of hair follicles. Generally, the occurrence of AGA has long been thought to be driven by genetic and androgen predisposition. However, increasingly data proposed ageing and AGA are intimately linked. Elevated senescent cell burden, androgen and oxidative stress induced senescence mechanisms that occur in ageing may be initial targets to improve AGA. This review summarizes the biological links between ageing and AGA, with special focus on cellular senescence. In addition, we discuss the potential therapeutic strategies for improving cellular senescence in AGA, such as inhibiting dermal papilla cells (DPCs) and hair follicle stem cells (HFSCs) senescence driven by androgen and reactive oxygen species (ROS), removing senescent cell and reducing senescence associated secretory phenotype (SASP).
... Thus, one mechanism by which androgen/AR signaling causes senescence is prolonged cell cycle arrest, which the cells are unable to escape from. The association of the androgen/AR complex with the senescence program was first made in androgen-responsive prostate cancer cells [32,74] and human dermal papilla cells [75]. However, there were few reports that demonstrated the association of AR antagonists [76] and androgen depletion in prostate cancer [77] with senescence. ...
Simple Summary
Thyroid cancer is the most common endocrine malignancy and occurs three times more frequently in women than in men. Further, androgen receptor expression is decreased in thyroid cancer cells. These observations suggest that male hormones may play a role in the prevention of thyroid cancer. We show that androgen stimulation of the androgen receptor inhibits the growth of thyroid cancer cells by inducing a state of senescence, in which cells are not killed, but are unable to multiply. Further work will investigate the ability to use androgens to treat thyroid cancer cells, as well as the possibility of treating and eliminating senescent cells using specific drugs.
Abstract
Thyroid cancer (TC) is the most common endocrine malignancy, with an approximately three-fold higher incidence in women. TCGA data indicate that androgen receptor (AR) RNA is significantly downregulated in PTC. In this study, AR-expressing 8505C (anaplastic TC) (84E7) and K1 (papillary TC) cells experienced an 80% decrease in proliferation over 6 days of exposure to physiological levels of 5α-dihydrotestosterone (DHT). In 84E7, continuous AR activation resulted in G1 growth arrest, accompanied by a flattened, vacuolized cell morphology, with enlargement of the cell and the nuclear area, which is indicative of senescence; this was substantiated by an increase in senescence-associated β-galactosidase activity, total RNA and protein content, and reactive oxygen species. Additionally, the expression of tumor suppressor proteins p16, p21, and p27 was significantly increased. A non-inflammatory senescence-associated secretory profile was induced, significantly decreasing inflammatory cytokines and chemokines such as IL-6, IL-8, TNF, RANTES, and MCP-1; this is consistent with the lower incidence of thyroid inflammation and cancer in men. Migration increased six-fold, which is consistent with the clinical observation of increased lymph node metastasis in men. Proteolytic invasion potential was not significantly altered, which is consistent with unchanged MMP/TIMP expression. Our studies provide evidence that the induction of senescence is a novel function of AR activation in thyroid cancer cells, and may underlie the protective role of AR activation in the decreased incidence of TC in men.
... These secretory factors from senescent DPCs induce hair loss by blocking the transition from telogen (resting phase) to anagen (growth phase) through inhibition of follicle neogenesis, differentiation, and growth of hair follicle stem cells [4]. Reducing DHT-induced DPC senescence is important for AGA prevention and previous researchers strongly agree that mitochondrial dysfunction is a crucial factor in inducing senescence in cells exposed to high DHT concentrations [5][6][7]. Since therapeutics regulating DHT production by 5-α-reductase inhibition does not have effect on reducing mitochondrial dysfunction and longterm usage of such treatments often brings side effects such as sexual dysfunction or trichosis, it is worthwhile to develop a new therapeutic strategy with reduced side effects while also maintaining the physiological function of mitochondria in DPCs [8][9][10]. Therefore, understanding the mechanism of DHT-induced mitochondrial dysfunction provides a promising strategy for new AGA treatments that minimize senescence of DPCs exposed to elevated DHT levels. ...
Background
Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs) located in the base of hair follicles. DHT causes DPC senescence in AGA through mitochondrial dysfunction. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the protective role of cyanidins on DHT-induced mitochondrial dysfunction and DPC senescence and the regulatory mechanism involved.
Methods
DPCs were used to investigate the effect of DHT on mitochondrial dysfunction with MitoSOX and Rhod-2 staining. Senescence-associated β-galactosidase activity assay was performed to examine the involvement of membrane AR-mediated signaling in DHT-induced DPC senescence. AGA mice model was used to study the cyanidins on DHT-induced hair growth deceleration.
Results
Cyanidin 3- O -arabinoside (C3A) effectively decreased DHT-induced mtROS accumulation in DPCs, and C3A reversed the DHT-induced DPC senescence. Excessive mitochondrial calcium accumulation was blocked by C3A. C3A inhibited p38-mediated voltage-dependent anion channel 1 (VDAC1) expression that contributes to mitochondria-associated ER membrane (MAM) formation and transfer of calcium via VDAC1–IP3R1 interactions. DHT-induced MAM formation resulted in increase of DPC senescence. In AGA mice models, C3A restored DHT-induced hair growth deceleration, which activated hair follicle stem cell proliferation.
Conclusions
C3A is a promising natural compound for AGA treatments against DHT-induced DPC senescence through reduction of MAM formation and mitochondrial dysfunction.
... DHT and oxidative stress are known as deleterious factors for hair growth. They can induce premature senescence of DPCs and promote HF regression by inhibiting the proliferation of keratinocytes around DPCs [8,9]. DHT is closely linked to androgenetic alopecia. ...
... In this regard, CJFSE can alleviate the viability of HFDPCs reduced by DHT, inhibit 5α-reductase activity converting testosterone to DHT and reduce the secretion of Dkk-1 induced by DHT. In addition, DHT is known to induce premature hair loss by prolonging telogen at the same time as anagen shortening, resulting in hair miniaturization [8]. The present study confirmed that CJFSE mitigated senescence in HFDPCs induced by DHT (Figure 4). ...
Objective:
Hair loss is caused by various factors. Impacts of these factors are often overlapped and intensified. Currently, mitigation of hair loss is being studied by proliferating dermal papilla cells (DPCs) and inhibiting deleterious factors such as dihydrotestosterone (DHT) and oxidative stress on hair growth. Camellia japonica (C. japonica) fruit shell is a discarded part. Its biological activity remains to be elucidated. In this study, we investigated the capacity of C. japonica fruit shell extract (CJFSE) for hair loss mitigation.
Methods:
MTT assay, spheroid culture and quantitative RT-PCR were performed to observe proliferative effect of CJFSE on hair follicle dermal papilla cells (HFDPCs). Effects of CJFSE on DHT-induced hair-loss were confirmed by Dkk-1 ELISA, β-galactosidase (β-gal), and 5α-reductase activity assay. In addition, effects of CJFSE on oxidative stress were confirmed through DPPH and ROS production assays.
Results:
CJFSE increased the proliferation and spheroid size of HFDPCs. Expression levels of VEGF-A, Wnt-1, c-Myc, and Cyclin D1 were upregulated by CJFSE. CJFSE also suppressed 5α-reductase activity and DHT-induced decrease in cell proliferation, Dkk-1 secretion, and β-gal activity. Moreover, CJFSE showed DPPH scavenging activity and ameliorated hydrogen peroxide-induced ROS production and β-gal activity. Finally, gallic acid and protocatechuic acid were observed in CJFSE through HPLC analysis.
Conclusion:
CJFSE has the potential to alleviate hair loss by promoting hair cell growth and suppressing effects of DHT and oxidative stress on hair.
... These proteins interact with each other and activate a series of downstream genes. p53 is involved in the apoptosis of hair follicles during anagenesis [36]. We found that CSCE upregulated bcl-2 expression and downregulated bax and p53 expressions in DHT-incubated cells (Figure 4). ...
Autocrine and paracrine factors play key roles in the process of Androgenetic alopecia (AGA), which are secreted by balding dermal papilla cells (DPCs) after dihydrotestosterone (DHT) induction. Camellia seed cake is an oriental oil extraction byproduct, and its extract has been traditionally used to wash hair in China. This study elucidated the hair growth-promoting effects of Camellia seed cake extract (CSCE) in DHT-treated cultured DPCs and its underlying mechanisms. The effect of CSCE on cell viability and release of inflammatory factors IL-6 and IL-1α was performed on human dermal papilla cells (DPCs) incubated with DHT. Relative expression of bax, bcl-2, p53, androgen receptor (AR) and 5α- reductase type II (SRD5A2) was determined by PCR. Senescence-associated was examined by β-galactosidase (SA-β-Gal) assays. CSCE restored DHT-induced cell damage in a dose-dependent manner, and effectively reduced the production of IL-6 and IL-1α in DHT-treated DPCs. CSCE exhibited an anti-apoptotic effect, which increased the expression of bcl-2, and decreased the expressions of bax and p53 in DHT-incubated DPCs. CSCE also showed an anti-androgenic effect reversing the increase in AR and SRD5A2 expressions in DPCs driven by DHT incubation. In addition, CSCE inhibited the β-galactosidase enzyme activity and slowed down the cell senescence of DPCs which is crucial for AGA progression. In this study, we found that CSCE may have the potential to prevent and alleviate AGA by abrogating the effect of DHT in cultured DPCs.
... In an effort to clarify the mechanisms involved in the etiology of AGA, a recent study found that balding DPCs experience premature senescence in vitro, which is indicated by the production of the proteins p16INK4a and senescence-associated-galactosidase (SA-gal), as well as markers of oxidative and DNA damage [29]. According to a paper, androgen/AR signaling, in conjunction with DNA damage, speeds up the premature senescence of human DPCs from the frontal scalp [30]. The biological characteristics of DPC are positively regulated by Tcf4. ...
... The practical value of Belyaev's concept has been realized in a huge collection of commercial fur colors-e.g., "Amber-gold pastel," "Ashen," "Beige," "Black crystal," "Cobalt," "Erminelike," "Peach," ""Pearl," Platinum," "Purple," "Silver sable-like," "Steel-blue," and "Straw,"-rarely or never seen in the wild [6]. The concept's fundamental importance has found confirmation in a large variety of breeds of dogs [7], cats [8], pigs [9], cows [10], horses [11], sheep [12], goats [13], chickens [14], ducks [15], geese [16], and other domestic animals [17] as well as in artificial shelters and additional feeding for wild animals in wildlife for saving them [18]. On the basis of Belyaev's concept [1], a laboratory model of animal domestication by humans has been created using outbred lines of tame and aggressive rats artificially bred [19] for performance on a standard glove test [20]. ...
... androgen-induced premature aging in adult men [15] → 6 ASMT 3 [3] in conformity with human allergic airway inflammation models using mice: higher risks of inflammatory airway diseases such as asthma because of melatonin deficiency [16] → 10 [3] within a men reproductive health immunohistochemical model using ram's seminal plasma and reproductive tract samples: melatonin excess protects sperm from oxidative DNA damage [17] ← 7 ASMTL 5 [3] as shown by a cohort-based study of prostatic hyperplasia tissue biopsies using quantitative polymerase chain reaction (qPCR): increased risk of prostate cancer [18] → 13 [3] in agreement with a cohort-based study of the sporadic autism patients who had additionally intellectual disability, craniofacial anomaly, or seizure: increased risk of autism spectrum disorders [19] → 8 CD99 3 [3] in a human atherogenesis model using mice administered with vector pcDNA3 carrying the Cd99 gene fragment for extracellular domain: lesser risks of stroke and infarction as most often causes of human death [20] ← 20 [3] within a human disease model using mice: both prevent and delayed progression of acute myeloid leukemia, as well as lowered leukemia engraftment in the bone marrow [21] ← 9 CDY2A 1 [3] in keeping with a qPCR study of men with Y-chromosome microdeletions: male maturation arrest [22] → pursuant to qPCR, histological and cytological studies of the testicular tissue in men with an abnormal karyotype or a Y-chromosome microdeletion: partly repaired fertility in men due to the CDY1 paralog [23] ← 10 CETP 1 [2] according to the CETP promoter of a proband, who is a heterozygote of 18-bp deletion containing TATA box: atherogenesis delay reduces risks of both myocardial infarction and stroke, which are most often causes of human death [24] ← 3 [2] as claimed by a cohort-based study: CETP excess during pregnancy elevates risk for later diabetes development [25] → ...
Belyaev’s concept of destabilizing selection during domestication was a major achievement in the XX century. Its practical value has been realized in commercial colors of the domesticated fox that never occur in the wild and has been confirmed in a wide variety of pet breeds. Many human disease models involving animals allow to test drugs before human testing. Perhaps this is why investigators doing transcriptomic profiling of domestic versus wild animals have searched for breed-specific patterns. Here we sequenced hypothalamic transcriptomes of tame and aggressive rats, identified their differentially expressed genes (DEGs), and, for the first time, applied principal component analysis to compare them with all the known DEGs of domestic versus wild animals that we could find. Two principal components, PC1 and PC2, respectively explained 67% and 33% of differential-gene-expression variance (hereinafter: log2 value) between domestic and wild animals. PC1 corresponded to multiple orthologous DEGs supported by homologs; these DEGs kept the log2 value sign from species to species and from tissue to tissue (i.e., a common domestication pattern). PC2 represented stand-alone homologous DEG pairs reversing the log2 value sign from one species to another and from tissue to tissue (i.e., representing intraspecific and interspecific variation).
