The evaluation of JAK inhibitors on effect and safety in alopecia areata: a systematic review and meta-analysis of 2018 patients.

Background: JAK inhibitors treat various autoimmune diseases, but an updated systematic review in treating alopecia areata is currently lacking. Objective: Evaluate the specific efficacy and safety of JAK inhibitors in alopecia areata by systematic review and meta-analysis. Methods: Eligible studies in PubMed, Embase, Web of Science, and Clinical Trials up to May 30, 2022, were searched. We enrolled in randomized controlled trials and observational studies of applying JAK inhibitors in alopecia areata. Results: 6 randomized controlled trials with 1455 patients exhibited SALT50 (odd ratio [OR], 5.08; 95% confidence interval [CI], 3.49-7.38), SALT90 (OR, 7.40; 95% CI, 4.34-12.67) and change in SALT score (weighted mean difference [WSD], 5.55; 95% CI, 2.60-8.50) compared to the placebo. The proportion of 26 observational studies with 563 patients of SALT5 was 0.71(95% CI, 0.65-0.78), SALT50 was 0.54(95% CI 0.46-0.63), SALT90 was 0.33(95% CI, 0.24-0.42), and SALT score (WSD, -2.18; 95% CI, -3.12 to -1.23) compared with baseline. Any adverse effects occurred in 921 of 1508 patients; a total of 30 patients discontinued the trial owing to adverse reactions. Limitations: Few randomized controlled trials met the inclusion criteria and insufficiency of eligible data. Conclusion: JAK inhibitors are effective in alopecia areata, although associated with an increased risk.

Expression and localization of Sox10 during hair follicle morphogenesis and induced hair cycle.

Sox transcription factors play many diverse roles during development, including regulating stem cell states, directing differentiation, and influencing the local chromatin landscape. Sox10 has been implicated in the control of stem/progenitor activity and epithelial-mesenchymal transition, yet it has not been studied in relation to the hair follicle cycle or hair follicle stem cell (HFSC) control. To elucidate the role of Sox10 in hair follicle cycle control, we performed immunohistochemical and immunofluorescence analysis of its expression during hair morphogenesis, the postnatal hair cycle, and the depilation-induced murine hair follicle cycle. During hair follicle morphogenesis, Sox10 was expressed in the hair germ and peg. In telogen, we detected nuclear Sox10 in the hair bulge and germ cell cap, where HFSCs reside, while in anagen and catagen, Sox10 was detected in the epithelial portion, such as the strands of keratinocytes, the outer root sheath (ORS) in anagen, and the regressed epithelial strand of hair follicle in catagen. These results suggest that Sox10 may be involved in early hair follicle morphogenesis and postnatal follicular cycling.

Granulomatous rosacea-like skin rash: extranodal Rosai-Dorfman disease.

We report a 38-year-old man who presented with bilateral conjunctival congestion, hoarseness, and progressively growing pruritic, infiltrated skin lesions that had first begun over the face and neck, and later spread to the trunk and the limbs in 4 months. The clinical appearance of the lesions mimics granulomatous rosacea, acne vulgaris, or pityrosporum folliculitis. Histopathologic examination of the lesions from the face and chest both revealed dense dermal nodular lymphohistiocytic infiltrates which were positive for CD68 and S-100, but negative for CD1a. A systemic work-up for him detected no lymphadenopathy or other systemic involvement. A diagnosis of extranodal Rosai-Dorfman disease was made, and the patient received systemic glucocorticoids, with considerable improvement after 4 months of therapy.

Tranexamic Acid Inhibits Angiogenesis and Melanogenesis in Vitro by Targeting VEGF Receptors.

Melasma is a common but complex skin condition concerning cosmetic problems. Tranexamic acid (TA) has been proved to be effective in treatment of melasma with still unclear mechanisms. Here, we show that VEGF165 enhanced the expression of VEGF receptors (VEGFRs, including VEGFR-1, VEGFR-2 and NRP-1) in human umbilical vein endothelial cells (HUVECs), which was attenuated by TA. VEGF165 also promoted tyrosine phosphorylation of VEGFR-1 and VEGFR-2 in HUVECs, which was again abolished by TA. TA further showed similar effects to neutralization of VEGFR-1 and VEGFR-2 in inhibiting cell proliferation, migration, invasion and tube formation of HUVECs induced by VEGF165, suggesting that TA could inhibit angiogenesis by targeting VEGFRs in HUVECs. In addition, VEGF165 enhanced the expression of VEGFRs and promoted tyrosine phosphorylation of VEGFR-1 and VEGFR-2 in normal human melanocytes, which were also attenuated by TA. Furthermore, TA showed similar effects to neutralization of VEGFR-1 and VEGFR-2 in inhibiting tyrosinase activity, melanin production and even melanogenic proteins induced by VEGF165, suggesting that TA could reduce melanogenesis via inhibiting activation of VEGFRs and subsequent expression of melanogenic proteins in melanocytes. Taken together, we demonstrate that TA can inhibit angiogenesis and melanogenesis in vitro at least in part by targeting VEGFRs, which may offer a new understanding of the pathogenesis of melasma as well as the molecular mechanism for TA in treatment of the disease.

VEGFR-2 Is in a State of Activation in Hair Follicles, Sebaceous Glands, Eccrine Sweat Glands, and Epidermis from Human Scalp: An In Situ Immunohistochemistry Study of Phosphorylated VEGFR-2.

BACKGROUND Recent research reports that VEGFR-2 is expressed in the whole hair follicle, sebaceous glands, eccrine sweat glands, and epidermis. However, phosphorylated VEGFR-2 was not found, and it could not be ascertained whether the activated form of VEGFR-2 actually participates in the biological control of epidermal appendages. In this study we aimed to determine whether the VEGFR-2 pathway is directly involved in the daily regulation of epidermal appendages biology. MATERIAL AND METHODS In this study, we investigated the expression of phosphorylation of VEGFR-2 by immunohistochemical analysis in the epidermis and epidermal appendages in normal human scalp skin. RESULTS Immunohistochemical analysis revealed phosphorylation of VEGFR-2 in a whole hair follicle, mainly in the infundibulum basal layer, hair cortex, and medulla in the isthmus, and matrix in the hair bulb. Phosphorylated VEGFR-2 also was found in the sebaceous glands, eccrine sweat glands, and epidermis. CONCLUSIONS Therefore, we suggest that VEGFR-2 activation is involved in routine regulation of human epidermal appendages.

Expression and localization of VEGFR-2 in hair follicles during induced hair growth in mice.

Recently, VEGFR-2 has been detected not only in vascular and lymphatic endothelial cells but also in some non-vascular endothelial cells, particularly human hair follicles, sebaceous glands, and sweat glands. In addition, VEGFR-2 has been confirmed to play direct roles in hair follicle keratinocyte regulation beyond simply angiogenesis. To elucidate whether VEGFR-2 activation plays a role in hair follicle cycling regulation, immunofluorescence of VEGFR-2 expression was performed during hair cycling of the dorsum of the mouse induced by hair plucking. We observed that staining for VEGFR-2 in hair follicles during anagen II and IV was much stronger than during anagen VI, catagen and telogen. During anagen II, intense staining for VEGFR-2 was observed on the keratinocyte strands of the hair follicle. Subsequently, we detected intense staining for VEGFR-2 in the ORS, IRS and hair bulb during anagen IV. Moderate staining for VEGFR-2 was detected in the ORS and hair bulb, but staining was most intense in IRS during anagen VI. During catagen, staining for VEGFR-2 in the IRS remained intense, while staining in the ORS and hair bulb was significantly weakened and was negative in the dermal papilla. During telogen, we detected VEGFR-2 in germ cells, cap, and club hair adjoining the epidermis. In conclusion, VEGFR-2 was expressed on the hair follicles of the dorsum of the mouse and varied in expression on the mouse hair follicles during hair cycling, suggesting that VEGFR-2 may exert roles in hair cycle regulation in hair follicles on the dorsum of mice.

Unilateral generalized keratosis pilaris following pregnancy.

Keratosis pilaris (KP) is a common inherited disorder characterized by small folliculocentric keratotic papules that may have surrounding erythema, which gives the skin a stippled appearance resembling gooseflesh. The extensor surfaces of the upper arms, thighs, and buttocks commonly are affected, but a generalized presentation may occur. We report the case of a 29-year-old woman with unilateral generalized KP in the second month of her second pregnancy. Both a genetic mutation and pregnancy-induced hormonal changes played possible roles in the development and progress of unilateral generalized KP in this patient.

Acquired progressive lymphangioma in the inguinal area mimicking giant condyloma acuminatum.

Lymphangioma is a benign proliferation of the lymphatic vessels that accounts for approximately 4% of vascular malformations and 26% of benign vascular tumors. Compared to those arising in nongenital areas, lymphangiomas of the vulva and genital areas are more hyperplastic, possibly due to the loose connective tissue, which can cause a cauliflowerlike appearance and may easily be misdiagnosed as genital warts or molluscum contagiosum. We report a case of acquired progressive lymphangioma (APL) of the inguinal area that mimicked giant condyloma acuminatum and showed favorable results following surgical excision. We also provide a review of the literature regarding the pathogenesis, diagnosis, differential diagnosis, and treatment of APL.

Expression of decorin throughout the murine hair follicle cycle: hair cycle dependence and anagen phase prolongation.

Decorin is a prototypical member of the small leucine-rich proteoglycan (SLRP) family, which is involved in numerous biological processes. The role of decorin, as a representative SLRP, in hair follicle morphogenesis has not been elucidated. We present our initial findings on decorin expression patterns during induced murine hair follicle (HF) cycles. It was found that decorin expression is exclusively restricted to the epidermis, outer root sheath and sebaceous glands during the anagen phase, which correlates with the upregulation of decorin mRNA and protein expression in depilated murine dorsal skin. Furthermore, we used a functional approach to investigate the effects of recombinant human decorin (rhDecorin) via cutaneous injection into HFs at various murine hair cycle stages. The local injection of rhDecorin (100 µg/ml) into the hypodermis of depilated C57BL/6 mice at anagen delayed catagen progression. In contrast, rhDecorin injection during the telogen phase caused the premature onset of anagen, as demonstrated by the assessment of the following parameters: (i) hair shaft length, (ii) follicular bulbar diameter, (iii) hair follicle cycling score and (iv) follicular phase percentage. Taken together, our results suggest that decorin may modulate follicular cycling and morphogenesis. In addition, this study also provides insight into the molecular control mechanisms governing hair follicular epithelial-mesenchymal interactions.

Multiple tumors of the follicular infundibulum: a cutaneous reaction pattern?

The etiology of tumor of the follicular infundibulum (TFI) is unknown. Eruptive forms of TFI are rare. We present the case of a 49-year-old woman with multiple lesions on the arms, shoulders, trunk, buttocks, and legs of more than 3 years' duration. On clinical and histologic examination, a diagnosis of multiple TFI was made. Additionally, the patient presented with other rare remarkable features including severe pruritus, the Köbner phenomenon, and underlying inflammatory cell infiltration of the tumors. These findings strongly suggest that eruptive TFI may represent a kind of cutaneous reaction.

VEGF165 modulates proliferation, adhesion, migration and differentiation of cultured human outer root sheath cells from central hair follicle epithelium through VEGFR-2 activation in vitro.

BACKGROUND: The functional state of vasculature is tightly controlled by vascular endothelial growth factor receptor-2 (VEGFR-2). Recent studies revealed that VEGFR-2 is expressed on hair follicle keratinocytes. OBJECTIVE: We proposed to investigate its effect on proliferation, adhesion and migration of cultured human outer root sheath cells from central hair follicle epithelium. METHODS: These studies were undertaken in vitro using human outer root sheath cells from central hair follicle epithelium, immunohistochemistry analysis, immunofluorescence microscopy, western blot analysis, MTT, trans well analysis, and RT-PCR. RESULTS: Our results show that VEGFR-2 is expressed in these cells in vivo and in vitro. Furthermore, proliferation and migration of cultured human outer root sheath cells from central hair follicle epithelium is increased by VEGF165, while homotypic adhesion is decreased but heterotypic adhesion is increased. VEGF165 upregulates integrin ß1 but dowregulates lgr6 expression. In addition, phosphorylation of VEGFR-2, Erk1/2, c-Jun and p38, are increased following VEGF165 treatment and these effects are reversed by a VEGFR-2 neutralizing antibody. CONCLUSION: Our results suggest a role of VEGF/VEGFR-2 beyond angiogenesis in hair follicle regulation.

Role of VEGF receptors in normal and psoriatic human keratinocytes: evidence from irradiation with different UV sources.

Vascular endothelial growth factor (VEGF) promotes angiogenesis and plays important roles both in physiological and pathological conditions. VEGF receptors (VEGFRs) are high-affinity receptors for VEGF and are originally considered specific to endothelial cells. We previously reported that VEGFRs were also constitutively expressed in normal human keratinocytes and overexpressed in psoriatic epidermis. In addition, UVB can activate VEGFRs in normal keratinocytes, and the activated VEGFR-2 signaling is involved in the pro-survival mechanism. Here, we show that VEGFRs were also upregulated and activated by UVA in normal human keratinocytes via PKC, and interestingly, both the activated VEGFR-1 and VEGFR-2 protected against UVA-induced cell death. As VEGFRs were over-expressed in psoriatic epidermis, we further investigated whether narrowband UVB (NB-UVB) phototherapy or topical halomethasone monohydrate 0.05% cream could affect their expression. Surprisingly, the over-expressed VEGFRs in psoriatic epidermis were significantly attenuated by both treatments. During NB-UVB therapy, VEGFRs declined first in the basal, and then gradually in the upper psoriatic epidermis. VEGFRs were activated in psoriatic epidermis, their activation was enhanced by NB-UVB, but turned undetectable after whole therapy. This process was quite different from that by halomethasone, in which VEGFRs and phospho-VEGFRs decreased in a gradual, homogeneous manner. Our findings further suggest that UV-induced activation of VEGFRs serves as a pro-survival signal for keratinocytes. In addition, VEGFRs may be involved in the pathological process of psoriasis, and UV phototherapy is effective for psoriasis by directly modulating the expression of VEGFRs.

Expression and localization of Artemis serine 516 phosphorylation in human scalp skin.

Artemis phosphorylation at serine 516 (Ser516) has important regulatory functions in the repair of radiation-induced DNA damage, V(D)J recombination, p53-dependent apoptosis and cell cycle control. Accordingly, Artemis mutations can lead to Omenn syndrome, which is associated with human radiosensitive severe combined immunodeficiency syndrome and alopecia. In this study, we investigated the expression of Ser516 phosphorylation of Artemis in the epidermis and epidermal appendages in normal human scalp skin. Immunofluorescence analysis revealed Ser516 phosphorylation of Artemis in the upper and middle portion of anagen hair follicle [including outer root sheath (ORS), inner root sheath but not stratum basale], hair matrix, sebaceous glands (secretory and ductal portions), eccrine sweat glands (secretory and ductal portions) and epidermis (stratum basale and stratum granulosum), respectively. Artemis phosphorylation at Ser516 was most prominent in ORS keratinocytes. Therefore, we suggest that phosphorylation of Artemis at Ser516 could be involved in regulation of human epidermal appendages.

VEGF induces proliferation of human hair follicle dermal papilla cells through VEGFR-2-mediated activation of ERK.

Vascular endothelial growth factor (VEGF) is one of the strongest regulators of physiological and pathological angiogenesis. VEGF receptor 2 (VEGFR-2), the primary receptor for VEGF, is thought to mediate major functional effects of VEGF. Previously, we have localized both VEGF and VEGFR-2 in human hair follicles. In this study, we further defined the expression and roles of VEGFR-2 on human hair follicle dermal papilla (DP) cells. The expression of VEGFR-2 on DP cells was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis separately, and localization of VEGFR-2 was defined by immunofluorescence. The effect of VEGF on DP cells was analyzed by MTT assays and specific inhibitors. Finally, the role of VEGF involved in the signaling pathways was investigated by Western blot. RT-PCR and Western blot analysis demonstrated the expression of VEGFR-2 on DP cells. Immunostaining for VEGFR-2 showed strong signal on cultured human DP cells in vitro. Exogenous VEGF(165) stimulated proliferation of DP cells in a dose-dependent manner. Furthermore, this stimulation was blocked by a VEGFR-2 neutralizing antibody (MAB3571) and an ERK inhibitor (PD98059). VEGF(165)-induced phosphorylation of ERK1/2 was abolished by MAB3571 and PD98059, while the phosphorylation of p38, JNK and AKT were not changed by VEGF(165). Taken together, VEGFR-2 is expressed on primary human hair follicle DP cells and VEGF induces proliferation of DP cells through VEGFR-2/ERK pathway, but not p38, JNK or AKT signaling.

VEGF upregulates VEGF receptor-2 on human outer root sheath cells and stimulates proliferation through ERK pathway.

Vascular endothelial growth factor (VEGF) is a key regulator of physiological and pathological angiogenesis. The biological effects of VEGF are mediated by receptor tyrosine kinases. VEGF receptor-2, the primary receptor for VEGF, is thought to mediate most functional effects. In this study, we examined the expression and roles of VEGF receptor-2 on human outer root sheath cells (ORS). The expression of VEGFR-2 was determined at mRNA and protein levels by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Localization of VEGFR-2 in ORS cells was detected by immunofluorescence. The effect of VEGF on ORS cell proliferation was determined by MTT assays. Our data showed the expression of VEGFR-2 on ORS cells at both mRNA and protein levels. Immunostaining for VEGFR-2 demonstrated strong signal on cultured ORS cells. Exogenous VEGF(165) stimulated proliferation of ORS cells and upregulated expression of VEGFR-2 in a dose-dependent manner. Moreover, VEGF(165) induced phosphorylation of VEGFR-2, PLC-γ1, PKC-α, MEK, and p44/42 MAPK (ERK1/2) in a time-dependent manner. Taken together, human ORS cells express functional VEGF receptor-2 and exogenous VEGF(165) upregulates expression of VEGFR-2 and stimulates proliferation of ORS cells via VEGFR-2 mediated ERK signaling pathway.

Expression and location of phospho-Artemis (Serine516) in hair follicles during induced growth of mouse hair.

Artemis has been implicated in having a role in NHEJ, and it is also a multifunctional protein. Previous studies have found Omenn syndrome-like phenotype due to Artemis mutations and associated with alopecia. As Artemis phosphorylation in its c-terminus including Serine516 is prerequisite for the Artemis endonuclease reaction, we postulate that Artemis (Serine516) may be expressed in hair follicle and relate to hair cycling. In this study, hair growth in C57BL/6 mice was induced by plucking the telogen hair on the back. Expression of Artemis (Serine516) in hair follicles during the hair growth cycle was evaluated by immunofluorescence using cryosections and a specific polyclonal anti-Artemis (Serine516) immunoglobulin G (IgG) antibody. It was detected in germ cells, cap, and club hair adjoining the epidermis in telogen. In anagen II, intense staining for Artemis (Serine516) was found in the whole interfollicular epidermis, and in strand keratinocytes. In anagen IV, intense staining for Artemis (Serine516) was detected in basal cells and upper of outer root sheath (ORS) and inner root sheath (IRS). But only upper ORS and lower medulla were stained positive in anagen VI. Upper ORS and lower cortex were positively stained with Artemis (Serine516) in catagen. Based on the phenomenon that the expression of Artemis (Serine516) in mid-anagen and mature anagen was stronger than that in telogen and catagen, we suggest it may take roles in induced growth of mouse hair.

Purse-string suture for round and oval defects: a useful technique in dermatologic surgery.

BACKGROUND: Round and oval skin wounds, like facial pigmented nevi after excision, are traditionally sutured linearly for closure, leaving significant scars, which greatly influences their appearance. OBJECTIVE: This article provides an overview of our experience using intradermal purse-string suture for round and oval defects in the faciocervical region to ascertain whether purse-string suture closure for such defects can result in good functional and cosmetic outcomes. METHODS AND RESULTS: We present 63 cases with different skin lesions in the faciocervical area. The defects of the lesions after excision were closed using intradermal purse-string suture. The wounds showed good final healing without obvious adverse events postoperatively. The result of scar assessment using the Vancouver Scar Scale was satisfying, with a total score of only 1.11. The final cosmetic appearance of the healed wounds seemed to be excellent and acceptable as they were always smaller than the original defects, with minimal scarring. CONCLUSION: Purse-string suture enabled us to repair small, circular wounds easily after excision of skin lesions. It is an excellent alternative to other reconstructions and a rapid, simple method to close skin defects with minimal scarring, achieving an excellent long-term cosmetic and functional outcome.

Activation of VEGFR-2 signaling in response to moderate dose of ultraviolet B promotes survival of normal human keratinocytes.

Mounting evidence indicates that signaling via VEGF receptors (VEGFRs) extends beyond blood vessel formation. Recently, VEGFRs are also found to be constitutively expressed in keratinocytes and epidermal appendages. Here, we show that the expression of VEGFRs (including VEGFR-1, VEGFR-2, and NRP-1) was significantly enhanced by moderate dose of ultraviolet B (UVB) in normal human keratinocytes and epidermis. The elevated expression of VEGFRs by UVB was independent of autocrine stimulation by their natural ligand, VEGF, but mainly mediated through hypoxia and oxidative stress. Moderate dose UVB also promoted tyrosine phosphorylation of VEGFR-1 and VEGFR-2, this effect was again VEGF independent. Both α and δ isoforms of protein kinase C (PKC) were required for UVB-induced phosphorylation of VEGFR-1, but only the δ isoform was required for VEGFR-2 phosphorylation. The phosphorylation of VEGFRs or isoforms of PKC was completely inhibited by PP2, a specific inhibitor for Src family kinases (SFKs), indicating that SFKs are upstream of PKC and VEGFRs. Moderate dose UVB-induced VEGF exerted an anti-apoptotic effect for keratinocytes, whereas high dose UVB-induced VEGF played as an inflammatory factor. Of note, neutralization of VEGFR-2 but not VEGFR-1 exacerbated UVB-induced cell death and reduced survival of keratinocytes. Furthermore, VEGFR-2 neutralization inhibited the activation of ERK1/2 and Akt by UVB, suggesting that VEGFR-2 signaling was involved in the pro-survival mechanism via ERK1/2 and PI3-K/Akt pathway. Taken together, we demonstrate for the first time that VEGFR-2 signaling is activated and promotes survival of keratinocytes under moderate dose of UVB irradiation.