Androgen Receptor–Mediated Paracrine Signaling Induces Regression of Blood Vessels in the Dermal Papilla in Androgenetic Alopecia

Deng, Zhili; Chen, Mengting; Liu, Fangfen; Wang, Yunying; Xu, San; Sha, Ke; Peng, Qinqin; Wu, Zheng; Xiao, Wenqin; Liu, Tangxiele; Xie, Hongfu; Li, Ji

doi:10.1016/j.jid.2022.01.003

Cited by 21 publications

(17 citation statements)

References 44 publications

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“…The intracellular level of AR was diminished in the alopecia area of the PROTAC‐MNs group, as indicated by the decreased AR expression level ( Figure b) and AR staining signal in HFs (Figure 4c). Furthermore, relative AR mRNA, which was known to be upregulated in AGA regions, [ 6,4 ] presented higher expression level in Model, Blank‐MNs, and Minoxidil group (Figure 4d), thereby restoring the factors involved in the regulation of the hair follicle cycle. For example, the mRNA expression level of TGF‐β1 in the PROTAC‐MNs group, a well‐known catagen inducer promoting apoptotic cell death of HFs, was obviously lower than in the Model group or the Blank‐MNs group (Figure 4e).…”

Section: Resultsmentioning

confidence: 99%

“…The demand to discover novel therapies is urgent given the insufficient efficacy and systemic side effects of minoxidil and finasteride, the only two drugs recognized by the FDA for AGA treatment. [3,15] Since androgen dependence is a main contributor to AGA, [4,5] AR destruction is a reasonable approach for driving the telogen-to-anagen conversion of HFs in AGA treatment. In recent years, AR-PROTAC has raised a huge interest in the regulation of AR-causing diseases because of its accurate targeted protein degradation ability.…”

Section: Biocompatibility Evaluation Of Protac-mnsmentioning

confidence: 99%

“…[ 1–3 ] The etiology of AGA is complex, in which the androgen dependence is assumed to play an essential role in the occurrence and development of AGA. [ 4–6 ] It has been reported that significantly higher androgen receptors (ARs) were expressed in the dermal papilla cells (DPCs) of balding scalps of AGA patients, resulting in their sensitivity to androgens, [ 7–9 ] which can initiate the hair growth regulation, like the Wnt/β ‐catenin signaling pathway and growth factors through binding of the ARs and androgens, thereby leading to the shortening of the anagen phase and the progressive miniaturization of thinning hair, eventually suppressing hair growth. [ 10–12 ]…”

Section: Introductionmentioning

confidence: 99%

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PROTAC Degraders of Androgen Receptor‐Integrated Dissolving Microneedles for Androgenetic Alopecia and Recrudescence Treatment via Single Topical Administration

et al. 2022

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Androgenetic alopecia (AGA) is a transracial and cross‐gender disease worldwide with a youth‐oriented tendency, but it lacks effective treatment. The binding of androgen receptor (AR) and androgen plays an essential role in the occurrence and progression of AGA. Herein, novel proteolysis targeting chimera degrader of AR (AR‐PROTAC) is synthesized and integrated with dissolving microneedles (PROTAC‐MNs) to achieve AR destruction in hair follicles for AGA treatment. The PROTAC‐MNs possess adequate mechanical capabilities for precise AR‐PROTAC delivery into the hair follicle‐residing regions for AR degradation. After applying only once topically, the PROTAC‐MNs achieve an accelerated onset of hair regeneration as compared to the daily application of the first‐line topical drug minoxidil. Intriguingly, PROTAC‐MNs via single administration still realize superior hair regeneration in AGA recrudescence, which is the major drawback of minoxidil in clinical practice. With the degradation of AR, the PROTAC‐MNs successfully regulate the signaling cascade related to hair growth and activate hair follicle stem cells. Furthermore, the PROTAC‐MNs do not cause systemic toxicity or androgen deficiency‐related chaos in vivo. Collectively, these AR‐degrading dissolving microneedles with long‐lasting efficacy, one‐step administration, and high biocompatibility provide a great therapeutic potential for AGA treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Biocompatibility Evaluation Of Protac-mnsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PROTAC Degraders of Androgen Receptor‐Integrated Dissolving Microneedles for Androgenetic Alopecia and Recrudescence Treatment via Single Topical Administration

et al. 2022

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“…Immunofluorescence. Immunofluorescence of skin sections was conducted as previously described (61). Briefly, ear skins from mice were fixed in 4% paraformaldehyde (PFA) and then frozen in OCT.…”

Section: Methodsmentioning

confidence: 99%

Aberrant amino acid metabolism promotes neurovascular reactivity in rosacea

Liu¹,

Xiao²,

Chen³

et al. 2022

JCI Insight

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Rosacea is a chronic skin disorder characterized by abnormal neurovascular and inflammatory conditions on the central face. Despite increasing evidence suggests that rosacea is associated with metabolic disorders, the role of metabolism in rosacea pathogenesis remains unknown. Here, via targeted metabolomics approach, we characterized significantly altered metabolic signatures in rosacea patients, especially for amino acid-related metabolic pathways. Among these, glutamic acid and aspartic acid are highlighted and positively correlated with the disease severity in rosacea patients. We further demonstrated that glutamic acid and aspartic acid can facilitate the development of erythema and telangiectasia, typical features of rosacea, in the skin of mice. Mechanistically, glutamic acid and aspartic acid stimulate the production of vasodilation-related neuropeptides from peripheral neuron and keratinocytes, and induce the release of nitric oxide from endothelial cells and keratinocytes. Interestingly, we provided evidence showing that doxycycline can improve the symptoms of rosacea patients possibly by targeting amino acid metabolic pathway. These findings reveal that abnormal amino acid metabolism promotes neurovascular reactivity in rosacea, and raise the possibility of targeting dysregulated metabolism as a promising strategy for clinical treatment.

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“…Prostaglandin D2 may also contribute to follicular miniaturization and AGA (Garza et al 2012). Another recent work documented that androgen receptor signaling in the HF induces TGF-β expression which then inhibits angiogenesis (Deng et al 2022). Thus the link between the vascular system and HF regeneration was highlighted in AGA.…”

Section: Dysregulation Of Hair Regeneration In Agamentioning

confidence: 99%

Regulation and dysregulation of hair regeneration: aiming for clinical application

et al. 2022

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Hair growth and regeneration represents a remarkable example of stem cell function. Recent progress emphasizes the micro- and macro- environment that controls the regeneration process. There is a shift from a stem cell-centered view toward the various layers of regulatory mechanisms that control hair regeneration, which include local growth factors, immune and neuroendocrine signals, and dietary and environmental factors. This is better suited for clinical application in multiple forms of hair disorders: in male pattern hair loss, the stem cells are largely preserved, but androgen signaling diminishes hair growth; in alopecia areata, an immune attack is targeted toward the growing hair follicle without abrogating its regeneration capability. Genome-wide association studies further revealed the genetic bases of these disorders, although the precise pathological mechanisms of the identified loci remain largely unknown. By analyzing the dysregulation of hair regeneration under pathological conditions, we can better address the complex interactions among stem cells, the differentiated progeny, and mesenchymal components, and highlight the critical role of macroenvironment adjustment that is essential for hair growth and regeneration. The poly-genetic origin of these disorders makes the study of hair regeneration an interesting and challenging field.

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Androgen Receptor–Mediated Paracrine Signaling Induces Regression of Blood Vessels in the Dermal Papilla in Androgenetic Alopecia

Cited by 21 publications

References 44 publications

PROTAC Degraders of Androgen Receptor‐Integrated Dissolving Microneedles for Androgenetic Alopecia and Recrudescence Treatment via Single Topical Administration

PROTAC Degraders of Androgen Receptor‐Integrated Dissolving Microneedles for Androgenetic Alopecia and Recrudescence Treatment via Single Topical Administration

Aberrant amino acid metabolism promotes neurovascular reactivity in rosacea

Regulation and dysregulation of hair regeneration: aiming for clinical application

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