Journal of dermatological science最新文献

英文中文

Enhancement of skin barrier function and augmentation of epidermal cell-cell interactions by galactomyces ferment filtrate 半乳酵母菌发酵滤液可增强皮肤屏障功能和表皮细胞-细胞间的相互作用。

IF 4.6

Journal of dermatological science

Pub Date : 2024-08-01 DOI: 10.1016/j.jdermsci.2024.03.011

引用次数: 0

Integration of line-field confocal optical coherence tomography and in situ microenvironmental mapping to investigate the living microenvironment of reconstructed human skin and melanoma models 线场共聚焦光学相干断层成像与原位微环境绘图相结合，研究重建人体皮肤和黑色素瘤模型的活体微环境

IF 4.6

Journal of dermatological science

Pub Date : 2024-08-01 DOI: 10.1016/j.jdermsci.2024.07.001

Background

In tissue engineering, real-time monitoring of tumors and of the dynamics of the microenvironment within in vitro models has traditionally been hindered by the need to harvest the cultures to obtain material to analyze. Line-field confocal optical coherence tomography (LC-OCT) has proven to be useful in evaluating in vivo skin conditions, including melanoma, by capturing dynamic, three-dimensional (3D) information without the need for invasive procedures, such as biopsies. Additionally, the M-Duo Technology® developed by IMcoMET presents a unique opportunity for continuous in situ biomarker sampling, providing insights into local cellular behavior and interactions.

Objective

This study aimed to validate the non-destructive mapping capabilities of two advanced methodologies (LC-OCT by DAMAE Medical and M-Duo Technology® by IMcoMET) to investigate the living microenvironment of in vitro reconstructed human skin (RhS) and melanoma-RhS (Mel-RhS).

Methods

LC-OCT and M-Duo Technology® were compared to conventional analysis of the RhS and Mel-RhS microenvironments.

Results

LC-OCT successfully visualized the distinct layers of the epidermis and tumor structures within the Mel-RhS, identifying keratinocytes, melanocytes, tumor nests, and fibroblasts. The M-Duo Technology® revealed differences in in situ cytokine (IL-6) and chemokine (CCL2, CXCL10, and IL-8) secretion between Mel-RhS and the control RhS. Notably, such differences were not detected through conventional investigation of secreted proteins in culture supernatants.

Conclusion

The combination of LC-OCT's high-resolution imaging and M-Duo Technology®’s in situ microenvironmental mapping has the potential to provide a synergistic platform for non-invasive, real-time analysis, allowing for prolonged observation of processes within Mel-RhS models without the need for culture disruption.

背景在组织工程学中，对肿瘤和体外模型中微环境动态的实时监测历来受到需要收获培养物以获取分析材料的阻碍。事实证明，线场共聚焦光学相干断层扫描（LC-OCT）可以捕捉动态的三维（3D）信息，而无需活检等侵入性程序，从而有助于评估包括黑色素瘤在内的体内皮肤状况。本研究旨在验证两种先进方法（DAMAE Medical 的 LC-OCT 和 IMcoMET 的 M-Duo Technology®）的非破坏性绘图能力，以研究体外重建的人类皮肤 (RhS) 和黑色素瘤-RhS (Mel-RhS) 的活体微环境。结果LC-OCT成功地观察到了表皮的不同层次和Mel-RhS中的肿瘤结构，识别出了角质细胞、黑色素细胞、肿瘤巢和成纤维细胞。M-Duo Technology® 揭示了 Mel-RhS 与对照 RhS 之间原位细胞因子（IL-6）和趋化因子（CCL2、CXCL10 和 IL-8）分泌的差异。结论LC-OCT 的高分辨率成像与 M-Duo Technology® 的原位微环境绘图相结合，有望为非侵入性实时分析提供一个协同平台，从而无需中断培养即可对 Mel-RhS 模型内的过程进行长时间观察。

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引用次数: 0

Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells 局部应用 BCL-2 抑制剂可通过消除衰老细胞改善咪喹莫特诱导的银屑病皮炎。

IF 4.6

Journal of dermatological science

Pub Date : 2024-08-01 DOI: 10.1016/j.jdermsci.2024.06.002

Background

Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs.

Objective

To investigate the role of senescent CD4⁺ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis.

Methods

We explored the expression levels of p16^INK4a and p21, classical markers of cellular senescence, in CD4⁺ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis.

Results

Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16^INK4a and p21 in CD4⁺ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and β chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4^creTet2^f/f mice was milder than that in Tet2^f/f mice in the IMQ-induced psoriasis model.

Conclusion

We revealed the roles of senescent CD4⁺ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αβ repertoire, and regulation of the TET2-Th17 cell pathway.

背景：银屑病是一种炎症性皮肤病，发病机制尚不清楚，治疗需求尚未得到满足：研究衰老的 CD4+ T 细胞在银屑病皮损形成中的作用，并探索衰老剂在治疗银屑病中的应用：我们探讨了细胞衰老的经典标志物--p16INK4a和p21在人类银屑病皮损和咪喹莫特（IMQ）诱导的银屑病皮损的CD4+T细胞中的表达水平。我们使用B细胞淋巴瘤2（BCL-2）抑制剂ABT-737制备了一种衰老凝胶，并评估了其治疗银屑病的疗效：结果：通过多谱系免疫组化（mIHC）染色，我们检测到银屑病皮损的 CD4+ T 细胞中 p16INK4a 和 p21 的表达水平升高。局部使用 ABT-737 凝胶后，IMQ 诱导的银屑病皮损明显减轻，病理改变较轻。从机理上讲，ABT-737凝胶能显著降低IMQ诱导的银屑病皮损中衰老细胞的比例、T细胞受体（TCR）α和β链的表达，以及甲基胞嘧啶二氧酶2（Tet2）的表达。此外，在IMQ诱导的银屑病模型中，CD4creTet2f/f小鼠银屑病皮损的严重程度比Tet2f/f小鼠轻：我们揭示了衰老的CD4+T细胞在银屑病发病中的作用，并强调了外用ABT-737凝胶通过消除衰老细胞、调节TCR αβ 复合物和TET2-Th17细胞通路治疗银屑病的潜力。

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引用次数: 0

Editors Choice 编辑推荐

IF 4.6

Journal of dermatological science

Pub Date : 2024-08-01 DOI: 10.1016/S0923-1811(24)00156-7

引用次数: 0

miR-25–5p in exosomes derived from UVB-induced fibroblasts regulates melanogenesis via TSC2-dominated cellular organelle dysfunction 从 UVB 诱导的成纤维细胞中提取的外泌体中的 miR-25-5p 通过 TSC2 主导的细胞器功能障碍调控黑色素生成

IF 4.6

Journal of dermatological science

Pub Date : 2024-08-01 DOI: 10.1016/j.jdermsci.2024.06.001

Background

Few reports have confirmed whether exosomes derived from fibroblasts can regulate the process of melanogenesis. We wondered whether exosomes derived from fibroblasts could have a potent regulatory effect on melanogenesis and explored the underlying mechanisms.

Objective

This study aimed to find the role of fibroblasts in melanocytes and revealed the related mechanisms.

Methods

RT-qPCR, Western blot analysis were conducted to measure the RNA and protein expression level of various related genes. miRNA sequencing, mass spectrum analysis and subsequent bioinformatics analysis were employed to find the underlying targets. Zebrafish were employed to measure the melanin synthesis related process in vivo. Furthermore, electron microscopy, ROS measurement and dual-luciferase reporter assay were adopted to investigate the relationship between these processes.

Results

We found that exosomes derived from human primary dermal fibroblasts were internalized by human primary melanocytes and MNT1 cells and that the melanin content and the expression of melanin synthesis-related proteins TYR and MITF was inhibited by exosomes derived from UVB-induced human primary dermal fibroblasts. The miRNA expression profile in secreted exosomes changed significantly, with miR-25–5p identified as capable of regulating TSC2 expression via the CDS region. The miR-25–5p-TSC2 axis could affect the melanin content through subsequent cellular organelle dysfunction, such as mitochondrial dysfunction, endoplasmic reticulum stress and dysregulation of lysosomal cysteine proteases.

Conclusion

We unveiled a novel regulatory role of fibroblasts in melanocytes, facilitated by the secretion of exosomes. miR-25–5p within exosomes plays a pivotal role in regulating melanogenesis via TSC2-induced cellular organelle dysfunction.

背景很少有报道证实成纤维细胞产生的外泌体能否调控黑色素的生成过程。本研究旨在发现成纤维细胞在黑色素细胞中的作用，并揭示其相关机制。方法采用RT-qPCR、Western印迹分析等方法检测各种相关基因的RNA和蛋白表达水平，并通过miRNA测序、质谱分析及后续的生物信息学分析寻找相关靶标。利用斑马鱼测量体内黑色素合成的相关过程。结果我们发现，来自人类原发性真皮成纤维细胞的外泌体可被人类原发性黑色素细胞和 MNT1 细胞内化，来自 UVB 诱导的人类原发性真皮成纤维细胞的外泌体可抑制黑色素含量和黑色素合成相关蛋白 TYR 和 MITF 的表达。分泌的外泌体中 miRNA 的表达谱发生了显著变化，其中 miR-25-5p 被确定能通过 CDS 区域调节 TSC2 的表达。miR-25-5p-TSC2轴可通过随后的细胞器功能障碍（如线粒体功能障碍、内质网应激和溶酶体半胱氨酸蛋白酶失调）影响黑色素含量。

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引用次数: 0

Necrosulfonamide promotes hair growth and ameliorates DHT-induced hair growth inhibition Necrosulfonamide 可促进毛发生长，改善 DHT 引起的毛发生长抑制。

IF 4.6

Journal of dermatological science

Pub Date : 2024-08-01 DOI: 10.1016/j.jdermsci.2024.04.004

Background

Alopecia affects patients' appearance and psychology. Mixed-lineage kinase domain-like pseudokinase (MLKL)-mediated necroptosis plays a role in various skin diseases, but its effect on hair growth is unclear.

Objective

To investigate the effects of MLKL on hair growth and its regulatory mechanisms and to determine the potential clinical value of Necrosulfonamide (NSA, a MLKL-targeting inhibitor) in promoting hair growth and counteracting dihydrotestosterone (DHT) inhibition of hair growth.

Methods

The expression level of MLKL was detected in the scalp of androgenetic alopecia (AGA) patients and the skin tissues of mice. Knock down MLKL expression or use NSA to observe hair growth in vivo and in vitro.

Results

In AGA patients, MLKL expression is elevated in the alopecia areas. In mice, MLKL is significantly expressed in the outer root sheath (ORS) cells of hair follicles, peaking during the catagen phase. Knockdown expression of MLKL in mice skin promoted hair growth. NSA enhanced hair growth and prevented hair follicle regression via the Wnt signaling. Reduced MLKL boosts ORS cell proliferation without directly impacting DPCs' growth. Interestingly, NSA boosts DPCs' proliferation and induction when co-cultured with ORS cells. Besides, NSA alleviated the inhibition of DHT on hair growth in vivo and vitro.

Conclusion

NSA inhibited the activation of MLKL in ORS cells, promoted the activation of Wnt signal in DPC cells, and improved the inhibition of hair growth by DHT, illuminating a new alopecia mechanism and aiding anti-alopecia drug development.

背景介绍脱发会影响患者的外观和心理。混系激酶域样假激酶（MLKL）介导的坏死在多种皮肤病中发挥作用，但其对毛发生长的影响尚不清楚：研究MLKL对毛发生长的影响及其调控机制，并确定Necrosulfonamide（NSA，一种MLKL靶向抑制剂）在促进毛发生长和对抗二氢睾酮（DHT）抑制毛发生长方面的潜在临床价值：方法：检测雄激素性脱发（AGA）患者头皮和小鼠皮肤组织中 MLKL 的表达水平。方法：检测雄激素性脱发（AGA）患者头皮和小鼠皮肤组织中 MLKL 的表达水平：结果：在AGA患者中，脱发区域的MLKL表达升高。在小鼠中，MLKL在毛囊的外根鞘细胞中明显表达，在毛发生长期达到高峰。在小鼠皮肤中敲除 MLKL 的表达可促进毛发生长。NSA 通过 Wnt 信号传导促进毛发生长并防止毛囊退化。减少 MLKL 可促进 ORS 细胞增殖，但不会直接影响 DPCs 的生长。有趣的是，当 NSA 与 ORS 细胞共同培养时，它能促进 DPCs 的增殖和诱导。此外，NSA 还能减轻 DHT 对体内和体外毛发生长的抑制作用：结论：NSA抑制了ORS细胞中MLKL的活化，促进了DPC细胞中Wnt信号的活化，改善了DHT对毛发生长的抑制作用，揭示了一种新的脱发机制，有助于抗脱发药物的开发。

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引用次数: 0

JSID2024-1 JSID2024-1

IF 4.6

Journal of dermatological science

Pub Date : 2024-08-01 DOI: 10.1016/S0923-1811(24)00154-3

引用次数: 0

Maximizing the potential of biobanks in dermatology research 最大限度地发挥生物库在皮肤病学研究中的潜力

IF 4.6

Journal of dermatological science

Pub Date : 2024-08-01 DOI: 10.1016/j.jdermsci.2024.03.003

引用次数: 0

Dysregulated tryptophan metabolism and AhR pathway contributed to CXCL10 upregulation in stable non-segmental vitiligo 色氨酸代谢失调和AhR通路导致稳定期非节段性白癜风患者CXCL10上调。

IF 4.6

Journal of dermatological science

Pub Date : 2024-07-01 DOI: 10.1016/j.jdermsci.2024.06.003

Background

Tryptophan metabolism dysregulation has been observed in vitiligo. However, drawing a mechanistic linkage between this metabolic disturbance and vitiligo pathogenesis remains challenging.

Objective

Aim to reveal the characterization of tryptophan metabolism in vitiligo and investigate the role of tryptophan metabolites in vitiligo pathophysiology.

Methods

LC-MS/MS, dual-luciferase reporter assay, ELISA, qRT-PCR, small interfering RNA, western blotting, and immunohistochemistry were employed.

Results

Kynurenine pathway activation and KYAT enzyme-associated deviation to kynurenic acid (KYNA) in the plasma of stable non-segmental vitiligo were determined. Using a public microarray dataset, we next validated the activation of kynurenine pathway was related with inflammatory-related genes expression in skin of vitiligo patients. Furthermore, we found that KYNA induced CXCL10 upregulation in keratinocytes via AhR activation. Moreover, the total activity of AhR agonist was increased while the AhR concentration per se was decreased in the plasma of vitiligo patients. Finally, higher KYAT, CXCL10, CYP1A1 and lower AhR expression in vitiligo lesional skin were observed by immunohistochemistry staining.

Conclusion

This study depicts the metabolic and genetic characterizations of tryptophan metabolism in vitiligo and proposes that KYNA, a tryptophan-derived AhR ligand, can enhance CXCL10 expression in keratinocytes.

背景：在白癜风中观察到色氨酸代谢紊乱。然而，将这种代谢紊乱与白癜风发病机制联系起来仍具有挑战性：旨在揭示白癜风患者色氨酸代谢的特征，并研究色氨酸代谢物在白癜风病理生理学中的作用：采用LC-MS/MS、双荧光素酶报告实验、ELISA、qRT-PCR、小干扰RNA、Western印迹和免疫组化等方法：结果：测定了稳定期非节段性白癜风患者血浆中犬尿氨酸通路的活化和KYAT酶相关的犬尿氨酸（KYNA）偏离。利用公开的微阵列数据集，我们进一步验证了犬尿氨酸通路的激活与白癜风患者皮肤中炎症相关基因的表达有关。此外，我们还发现 KYNA 通过 AhR 激活诱导角质形成细胞中 CXCL10 的上调。此外，在白癜风患者血浆中，AhR 激动剂的总活性增加，而 AhR 本身的浓度降低。最后，通过免疫组化染色观察到白癜风皮损皮肤中 KYAT、CXCL10、CYP1A1 表达较高，而 AhR 表达较低：本研究描述了白癜风患者色氨酸代谢和遗传特征，并提出色氨酸衍生的AhR配体KYNA可增强角朊细胞中CXCL10的表达。

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引用次数: 0

LEKTI domain 6 displays anti-inflammatory action in vitro and in a murine atopic dermatitis model LEKTI 结构域 6 在体外和小鼠特应性皮炎模型中显示出抗炎作用

IF 4.6

Journal of dermatological science

Pub Date : 2024-07-01 DOI: 10.1016/j.jdermsci.2024.03.004

Background

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a serine protease inhibitor consisting of multiple domains. A loss of function mutation is described in Netherton patients that show severe symptoms of atopic lesions and itch.

Objectives

LEKTI domain 6 (LD6) has shown strong serine protease-inhibitory action in in vitro assays and thus it was tested in vitro and in vivo for potential anti-inflammatory action in models of atopic skin disease.

Methods

Human skin equivalents were treated with LD6 and an inflammatory reaction was challenged by kallikrein-related endopeptidase 5 (KLK5). Furthermore, LD6 was tested on dorsal root ganglia cells stimulated with KLK5, SLIGRL and histamine by calcium imaging. The effect of topically administered LD6 (0.4–0.8%) in lipoderm was compared to a topical formulation of betamethasone-diproprionate (0.1%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice sensitized to house dust mite antigen. Endpoints were clinical scoring of the mice as well as determination of scratching behaviour.

Results

KLK5 induced an upregulation of CXCL-8, CCL20 and IL-6 in skin equivalents. This upregulation was reduced by pre-incubation with LD6. KLK5 as well as histamine induced calcium influx in a population of neurons. LD6 significantly reduced the calcium response to both stimuli. When administered onto lesional skin of NC/Nga mice, both LD6 and betamethasone-dipropionate significantly reduced the inflammatory reaction. The effect on itch behaviour was less pronounced.

Conclusion

Topical administration of LD6 might be a new therapeutic option for treatment of lesional atopic skin.

淋巴上皮卡扎尔型相关抑制剂（LEKTI）是一种由多个结构域组成的丝氨酸蛋白酶抑制剂。在出现严重特应性皮炎和瘙痒症状的尼瑟顿患者中，有功能缺失突变的描述。LEKTI 结构域 6 (LD6) 在试验中显示出很强的丝氨酸蛋白酶抑制作用，因此对其进行了测试，以确定其在特应性皮肤病模型中的潜在抗炎作用。用 LD6 处理人体皮肤等效物，并用桔皮素相关内肽酶 5（KLK5）挑战炎症反应。此外，还通过钙成像测试了 LD6 对受 KLK5、SLIGRL 和组胺刺激的背根神经节细胞的作用。比较了局部给药 LD6（0.4%-0.8%）和外用倍他米松二丙酸酯制剂（0.1%）对对屋尘螨抗原敏感的 NC/Nga 小鼠特应性皮炎样病变的治疗效果。终点是对小鼠的临床评分以及搔抓行为的测定。KLK5 可诱导等量皮肤中的 CXCL-8、CCL20 和 IL-6 上调。预孵育 LD6 可降低这种上调。KLK5 和组胺可诱导神经元群体中的钙离子流入。LD6 能明显降低对这两种刺激的钙离子反应。将 LD6 和倍他米松二丙酸酯注射到 NC/Nga 小鼠的病变皮肤上时，都能显著减轻炎症反应。但对瘙痒行为的影响不明显。局部使用 LD6 可能是治疗特应性皮肤病的新疗法。

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