Journal of dermatological science最新文献_第6页

Visualization of intradermal blood vessel structures by dual-wavelength photoacoustic microscopy and characterization of three-dimensional construction of livedo-racemosa in cutaneous polyarteritis nodosa 用双波长光声显微镜观察皮肤多发性结节性动脉炎患者的皮内血管结构和活血化瘀三维结构特征

IF 4.6

Journal of dermatological science

Pub Date : 2024-05-01 DOI: 10.1016/j.jdermsci.2024.03.010

Kazuyo Sujino , Keiji Tanese , Yasuko Saito , Junko Kuramoto , Hideaki Iwazaki , Taiichiro Ida , Sadakazu Aiso , Nobuaki Imanishi , Hiroki Kajita , Keitaro Fukuda , Masayuki Amagai , Akiko Tanikawa

Background

Photoacoustic microscopy is expected to have clinical applications as a noninvasive and three-dimensional (3D) method of observing intradermal structures.

Objective

Investigate the applicability of a photoacoustic microscope equipped with two types of pulsed lasers that can simultaneously recognize hemoglobin and melanin.

Methods

16 skin lesions including erythema, pigmented lesions, vitiligo and purpura, were analyzed to visualize 3D structure of melanin granule distribution and dermal blood vessels. 13 cases of livedo racemosa in cutaneous polyarteritis nodosa (cPN) were further analyzed to visualize the 3D structure of dermal blood vessels in detail. Vascular structure was also analyzed in the biopsy specimens obtained from tender indurated erythema of cPN by CD34 immunostaining.

Results

Hemoglobin-recognition signal clearly visualized the 3D structure of dermal blood vessels and melanin-recognition signal was consistently reduced in vitiligo. In livedo racemosa, the hemoglobin-recognition signal revealed a relatively thick and large reticular structure in the deeper layers that became denser and finer toward the upper layers. The numerical analysis revealed that the number of dermal blood vessels was 1.29-fold higher (p<0.05) in the deeper region of the lesion than that of normal skin. The CD34 immunohistochemical analysis in tender indurated erythema revealed an increased number of dermal vessels compared with normal skin in 88.9% (8/9) of the cases, suggesting that vascular network remodeling had occurred in cPN.

Conclusion

The photoacoustic system has an advantage in noninvasively detecting dermal blood vessel structures that are difficult to recognize by two-dimensional histopathology specimen examination and is worth evaluating in various skin diseases.

背景光声显微镜作为一种无创和三维（3D）观察皮内结构的方法，有望在临床上得到应用。方法分析了 16 例皮肤病变，包括红斑、色素病变、白癜风和紫癜，以观察黑色素颗粒分布和真皮血管的三维结构。此外，还进一步分析了 13 例皮肤多动脉炎结节（cPN）中的外生殖器，以详细观察真皮血管的三维结构。结果血红蛋白识别信号可清晰显示真皮血管的三维结构，而黑色素识别信号在白癜风患者中持续减弱。白癜风患者的血红蛋白识别信号在深层显示出相对粗大的网状结构，并向上层变密变细。数值分析显示，病变深层的真皮血管数量是正常皮肤的 1.29 倍（p<0.05）。结论光声系统在无创检测二维组织病理学标本检查难以识别的真皮血管结构方面具有优势，值得在各种皮肤病中进行评估。

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引用次数: 0

Lack of cutis verticis gyrata is associated with c.1279_1290del12 of SLCO2A1 in 43 Japanese patients with pachydermoperiostosis 在 43 名日本腓肠肌症患者中，SLCO2A1 的 c.1279_1290del12 与缺乏腓肠肌有关

IF 4.6

Journal of dermatological science

Pub Date : 2024-05-01 DOI: 10.1016/j.jdermsci.2024.03.008

H. Niizeki , R. Tanaka , T. Nomura , A. Seki , M. Miyasaka , Y. Matsumoto , M. Ishibashi , S. Narumi , K. Nakabayashi , K. Yoshida

引用次数: 0

IL-4-induced decrease in both the number and CTLA-4 expression of Treg impairs suppression of Th2 type inflammation in severe atopic dermatitis IL-4 诱导的 Treg 数量和 CTLA-4 表达的减少会削弱对严重特应性皮炎 Th2 型炎症的抑制作用

IF 4.6

Journal of dermatological science

Pub Date : 2024-05-01 DOI: 10.1016/j.jdermsci.2024.03.007

Bocheng Wang , Zhiying Yu , Jiao Liu , Yuyang Tian , Yijia Ruan , Tinghui Kong , Mingjun Hou , Bihui Yu , Shiqi Ling , Di Wang , Yishan Chen , Yingping Xu , Weiwei Deng , Yunsheng Liang

Background

T_reg plays a pivotal role in the suppression of Th2 cell and the maintenance of immune homeostasis. The precise molecular mechanism underlying the disruption of T_reg suppression of Th2 cell and the promotion of Th2 type inflammation in allergic diseases remains elusive.

Objective

This study aims to investigate the molecular mechanism underlying quantitative and functional changes of T_reg in AD.

Methods

The molecular mechanism was investigated using flow cytometry, mRNA sequencing, co-culture experiments, co-immunoprecipitation, chromatin immunoprecipitation, and bisulfite sequencing in vitro or in AD mice model and patients with AD.

Results

Increased proportion of T_reg was detected in mild and moderate AD. Conversely, characteristic decrease in both the number and CTLA-4 expression of T_reg was relevant to serum IL-4 level in severe AD patients, which was verified under a high concentration of IL-4 treatment in vitro. The underlying mechanism is that IL-4/pSTAT6 pathway recruits DNMT1 and HDAC2 to inhibit transcriptional regulation of Foxp3 and CTLA-4 loci. High level of IL-4 impaired the suppression of T_reg against Th2 cell differentiation mediated by CTLA-4, and blockade of IL-4Rα signaling in T_reg restored T_reg number and suppression of Th2 cell in AD model mice and patients with AD.

Conclusion

The number of T_reg is relevant to stratification of severity and serum IL-4 level in patients with AD. Abnormal high level of IL-4 epigenetically triggers a decrease in both the number and CTLA-4 expression of T_reg. The reduced expression of CTLA-4 on T_reg induced by IL-4 impairs suppression of Th2 cell differentiation.

背景Treg在抑制Th2细胞和维持免疫平衡中发挥着关键作用。本研究旨在探讨 AD 中 Treg 数量和功能变化的分子机制。方法采用流式细胞术、mRNA测序、共培养实验、共免疫沉淀、染色质免疫沉淀和亚硫酸氢盐测序等方法，在体外或AD小鼠模型和AD患者中研究其分子机制。相反，在重度 AD 患者中，Treg 数量和 CTLA-4 表达的特征性减少与血清 IL-4 水平有关，这在体外高浓度 IL-4 治疗中得到了验证。其潜在机制是IL-4/pSTAT6通路招募DNMT1和HDAC2抑制Foxp3和CTLA-4位点的转录调控。高水平的IL-4削弱了CTLA-4介导的Treg对Th2细胞分化的抑制，而阻断Treg中的IL-4Rα信号传导可恢复AD模型小鼠和AD患者的Treg数量和对Th2细胞的抑制。异常高水平的IL-4会从表观遗传学上引发Treg数量和CTLA-4表达的减少。IL-4诱导的Treg上CTLA-4表达的减少会损害对Th2细胞分化的抑制。

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引用次数: 0

KTN1 mediated unfolded protein response protects keratinocytes from ionizing radiation-induced DNA damage KTN1 介导的未折叠蛋白反应保护角质形成细胞免受电离辐射诱导的 DNA 损伤

IF 4.6

Journal of dermatological science

Pub Date : 2024-04-01 DOI: 10.1016/j.jdermsci.2024.02.006

Xinli Niu , Yi Shen , Yunhan Wen, Xing Mi, Jing Xie, Ying Zhang, Zhenhua Ding

Background

The unfolded protein response (UPR) is one of the cytoprotective mechanisms against various stresses and essential for the normal function of skin. Skin injury caused by ionizing radiation (IR) is a common side effect of radiotherapy and it is unclear how UPR affects IR-induced skin injury.

Objectives

To verify the effect of UPR on IR-induced DNA damage in keratinocytes and the relation between an endoplasmic reticulum (ER) protein KTN1 and UPR.

Methods

All experiments were performed on keratinocytes models: HaCaT and HEK-A. ER lumen and the expression levels of KTN1 and UPR pathway proteins (PERK, IRE1α and ATF6) were examined by transmission electron microscopy and immunoblotting, respectively. 4-PBA, an UPR inhibitor, was used to detected its effects on DNA damage and cell proliferation. Subsequently, the effects of KTN1 deletion on UPR, DNA damage and cell proliferation after IR were detected. Tunicamycin was used to reactivate UPR and then we examined its effects on DNA damage.

Results

UPR was activated by IR in keratinocytes. Inhibition of UPR aggravated DNA damage and suppressed cell proliferation after IR. KTN1 expression was upregulated by IR and KTN1 depletion reduced ER expansion and the expression of UPR-related proteins. Moreover, KTN1 depletion aggravated DNA damage and suppressed cell proliferation after IR could reversed by reactivation of UPR.

Conclusion

KTN1 deletion aggravates IR-induced keratinocyte DNA damage via inhibiting UPR. Our findings provide new insights into the mechanisms of keratinocytes in response to IR-induced damage.

未折叠蛋白反应（UPR）是抵御各种压力的细胞保护机制之一，对皮肤的正常功能至关重要。电离辐射（IR）引起的皮肤损伤是放疗的常见副作用，目前还不清楚 UPR 如何影响 IR 诱导的皮肤损伤。为了验证 UPR 对 IR 诱导的角质细胞 DNA 损伤的影响，以及内质网（ER）蛋白 KTN1 与 UPR 的关系。所有实验均在角质形成细胞模型上进行：HaCaT和HEK-A。透射电子显微镜和免疫印迹法分别检测了ER腔和KTN1及UPR通路蛋白（PERK、IRE1α和ATF6）的表达水平。使用 UPR 抑制剂 4-PBA 检测其对 DNA 损伤和细胞增殖的影响。随后，检测了KTN1缺失对IR后UPR、DNA损伤和细胞增殖的影响。使用曲卡霉素重新激活UPR，然后检测其对DNA损伤的影响。IR激活了角质形成细胞的UPR。抑制 UPR 会加重 DNA 损伤并抑制 IR 后的细胞增殖。红外线会上调 KTN1 的表达，而 KTN1 的消耗会减少 ER 的扩张和 UPR 相关蛋白的表达。此外，KTN1缺失加重了DNA损伤，抑制了细胞增殖，但UPR的重新激活可逆转这种情况。KTN1缺失会通过抑制UPR加重IR诱导的角质细胞DNA损伤。我们的发现为角质形成细胞应对红外诱导损伤的机制提供了新的见解。

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引用次数: 0

JSID’s Fellowship Shiseido Research Grant JSID研究金资生堂研究补助金

IF 4.6

Journal of dermatological science

Pub Date : 2024-04-01 DOI: 10.1016/j.jdermsci.2024.03.005

Manabu Ohyama (Secretary-General of JSID)

引用次数: 0

Rh family C glycoprotein contributes to psoriatic inflammation through regulating the dysdifferentiation and cytokine secretion of keratinocytes Rh 家族 C 糖蛋白通过调节角质形成细胞的分化障碍和细胞因子分泌，对银屑病炎症做出了贡献。

IF 4.6

Journal of dermatological science

Pub Date : 2024-04-01 DOI: 10.1016/j.jdermsci.2024.02.007

Wei Liu, Yaqi Wang, Yitian Zhang, Mingzhu Zhou, Hanjiang Gu, Mei Lu, Yumin Xia

Background

Keratinocyte dysdifferentiation and proinflammatory cytokine production play a central role in psoriatic inflammation. According to recent studies, the Rh family C glycoprotein (RHCG) enhances cell proliferation and disrupts cell differentiation. However, the specific role of RHCG psoriasis development remains unclear.

Objective

We here explored the effect of RHCG on keratinocytes under psoriatic inflammation.

Methods

The cell counting kit‑8 assay was conducted to assess proliferation. RHCG protein expression was assessed through western blotting and enzyme-linked immunosorbent assays. The expression of proinflammatory cytokines and differentiation markers was analyzed through a quantitative reverse-transcription polymerase chain reaction.

Results

Both RHCG mRNA and protein levels increased in psoriatic skin. Notably, cultured keratinocytes treated with an M5 cocktail, which mimics psoriatic inflammation, exhibited higher RHCG expression. Furthermore, RHCG overexpression promoted keratinocyte proliferation, accompanied by an increase in the production of interleukin (IL)-1β, IL-6, and IL-8, and tumor necrosis factor-α. RHCG overexpression also resulted in higher expression of keratin 17, a differentiation marker. Conversely, RHCG gene knockdown reduced keratinocyte proliferation and cytokine secretion. RHCG inhibition in cells recovered both keratin 1 and loricrin expression. Additionally, RHCG overexpression facilitated the phosphorylation of nuclear factor-kappa B and extracellular signal-regulated protein kinase signaling pathways. Importantly, when these signaling pathways were inhibited, the effect of RHCG on keratinocytes was attenuated.

Conclusion

These findings support the substantial role of RHCG in psoriatic inflammation development and suggest that RHCG serves as a potential target for psoriasis treatment.

背景：角质细胞分化障碍和促炎细胞因子的产生在银屑病炎症中起着核心作用。根据最近的研究，Rh 家族 C 糖蛋白（RHCG）可促进细胞增殖并破坏细胞分化。然而，RHCG 在银屑病发病中的具体作用仍不清楚：我们在此探讨了 RHCG 对银屑病炎症条件下角质形成细胞的影响：方法：采用细胞计数试剂盒-8测定法评估增殖情况。方法：采用细胞计数试剂盒-8测定法评估细胞增殖情况，通过免疫印迹法和酶联免疫吸附法评估 RHCG 蛋白表达情况。通过逆转录聚合酶链反应定量分析促炎细胞因子和分化标志物的表达：采用细胞计数试剂盒-8 检测法评估增殖情况。通过 Western 印迹和酶联免疫吸附试验评估 RHCG 蛋白的表达。通过逆转录聚合酶链反应定量分析促炎细胞因子和分化标志物的表达：结果：银屑病皮肤中的 RHCG mRNA 和蛋白质水平都有所增加。值得注意的是，经模拟银屑病炎症的 M5 鸡尾酒处理的培养角朊细胞表现出较高的 RHCG 表达。此外，RHCG 的过表达促进了角质形成细胞的增殖，并伴随着白细胞介素（IL）-1β、IL-6、IL-8 和肿瘤坏死因子-α 生成的增加。RHCG 过表达还导致分化标志物角蛋白 17 的高表达。相反，RHCG 基因敲除会减少角质形成细胞的增殖和细胞因子的分泌。抑制细胞中的 RHCG 可恢复角蛋白 1 和 loricrin 的表达。此外，RHCG 的过表达促进了核因子卡巴 B 和细胞外信号调节蛋白激酶信号通路的磷酸化。重要的是，当这些信号通路受到抑制时，RHCG 对角质形成细胞的作用就会减弱：这些发现证实了 RHCG 在银屑病炎症发展过程中的重要作用，并表明 RHCG 是治疗银屑病的潜在靶点。

{"title":"Rh family C glycoprotein contributes to psoriatic inflammation through regulating the dysdifferentiation and cytokine secretion of keratinocytes","authors":"Wei Liu, Yaqi Wang, Yitian Zhang, Mingzhu Zhou, Hanjiang Gu, Mei Lu, Yumin Xia","doi":"10.1016/j.jdermsci.2024.02.007","DOIUrl":"10.1016/j.jdermsci.2024.02.007","url":null,"abstract":"<div><h3>Background</h3><p>Keratinocyte dysdifferentiation and proinflammatory cytokine production play a central role in psoriatic inflammation. According to recent studies, the Rh family C glycoprotein (RHCG) enhances cell proliferation and disrupts cell differentiation. However, the specific role of RHCG psoriasis development remains unclear.</p></div><div><h3>Objective</h3><p>We here explored the effect of RHCG on keratinocytes under psoriatic inflammation.</p></div><div><h3>Methods</h3><p>The cell counting kit‑8 assay was conducted to assess proliferation. RHCG protein expression was assessed through western blotting and enzyme-linked immunosorbent assays. The expression of proinflammatory cytokines and differentiation markers was analyzed through a quantitative reverse-transcription polymerase chain reaction.</p></div><div><h3>Results</h3><p>Both RHCG mRNA and protein levels increased in psoriatic skin. Notably, cultured keratinocytes treated with an M5 cocktail, which mimics psoriatic inflammation, exhibited higher RHCG expression. Furthermore, RHCG overexpression promoted keratinocyte proliferation, accompanied by an increase in the production of interleukin (IL)-1β, IL-6, and IL-8, and tumor necrosis factor-α. RHCG overexpression also resulted in higher expression of keratin 17, a differentiation marker. Conversely, <em>RHCG</em> gene knockdown reduced keratinocyte proliferation and cytokine secretion. RHCG inhibition in cells recovered both keratin 1 and loricrin expression. Additionally, RHCG overexpression facilitated the phosphorylation of nuclear factor-kappa B and extracellular signal-regulated protein kinase signaling pathways. Importantly, when these signaling pathways were inhibited, the effect of RHCG on keratinocytes was attenuated.</p></div><div><h3>Conclusion</h3><p>These findings support the substantial role of RHCG in psoriatic inflammation development and suggest that RHCG serves as a potential target for psoriasis treatment.</p></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140186668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Editor's Choice 编辑推荐

IF 4.6

Journal of dermatological science

Pub Date : 2024-04-01 DOI: 10.1016/S0923-1811(24)00064-1

引用次数: 0

High α-diversity of skin microbiome and mycobiome in Japanese patients with vitiligo 日本白癜风患者皮肤微生物组和霉菌生物组的α-多样性较高。

IF 4.6

Journal of dermatological science

Pub Date : 2024-04-01 DOI: 10.1016/j.jdermsci.2024.02.008

Yasutaka Kuroda , Lingli Yang , Takakazu Shibata , Masahiro Hayashi , Yuta Araki , Makiko Nishida , Takeshi Namiki , Teruhiko Makino , Tadamichi Shimizu , Tamio Suzuki , Tetsuya Sayo , Yoshito Takahashi , Daisuke Tsuruta , Ichiro Katayama

Background

Vitiligo is an acquired pigmentary disorder characterized by depigmented patches on the skin that majorly impact patients' quality of life. Although its etiology involves genetic and environmental factors, the role of microorganisms as environmental factors in vitiligo pathology remains under-researched.

Objectives

Our study explored the presence of characteristic bacterial and fungal flora in vitiligo-affected skin and investigated their potential roles in vitiligo pathogenesis.

Methods

We sequenced bacterial 16S rRNA and the fungal ITS1 region from skin swabs collected at frequently affected sites, namely the forehead and back, of patients with vitiligo. We analyzed bacterial and fungal flora in lesional and non-lesional areas of patients with vitiligo compared with corresponding sites in age- and sex-matched healthy subjects.

Results

Our findings revealed elevated α-diversity in both bacterial and fungal flora within vitiligo lesions compared with healthy controls. Notably, bacterial flora exhibited a distinctive composition in patients with vitiligo, and the proportional representation of Enterococcus was inversely correlated with the degree of vitiligo progression. Gammaproteobacteria, Staphylococcus spp., and Corynebacterium spp. were more abundant in vitiligo patients, with notable Staphylococcus spp. prevalence during the stable phase on the forehead. Conversely, the proportion of Malassezia sympodialis was lower and that of Malassezia globosa was higher in the progressive phase on the back of vitiligo patients.

Conclusion

Our study identified some characteristic bacterial and fungal groups associated with vitiligo activity and prognosis, highlighting the potential roles of microorganisms in pathogenesis and offering insights into personalized disease-management approaches.

背景：白癜风是一种获得性色素脱失症，其特征是皮肤上出现色素脱失斑，严重影响患者的生活质量。虽然其病因涉及遗传和环境因素，但微生物作为环境因素在白癜风病理学中的作用仍未得到充分研究：我们的研究探讨了受白癜风影响的皮肤中存在的特征性细菌和真菌菌群，并研究了它们在白癜风发病机制中的潜在作用：方法：我们从白癜风患者经常受影响的部位（即前额和背部）采集的皮肤拭子中对细菌 16S rRNA 和真菌 ITS1 区进行了测序。我们将白癜风患者皮损区和非皮损区的细菌和真菌菌群与年龄和性别匹配的健康人相应部位的细菌和真菌菌群进行了比较分析：结果：我们的研究结果表明，与健康对照组相比，白癜风皮损区细菌和真菌菌群的α多样性均有所提高。值得注意的是，白癜风患者体内的细菌菌群呈现出独特的组成，肠球菌的比例与白癜风的进展程度成反比。在白癜风患者中，伽马蛋白菌、葡萄球菌属和棒状杆菌属的数量较多，其中葡萄球菌属在前额白癜风稳定期的发病率较高。相反，在白癜风患者背部的进展期，交感马拉色菌的比例较低，而球形马拉色菌的比例较高：我们的研究发现了一些与白癜风活动和预后相关的特征性细菌和真菌群，强调了微生物在发病机制中的潜在作用，并为个性化疾病管理方法提供了启示。

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引用次数: 0

Calcitriol modulates epidermal tight junction barrier function in human keratinocytes 骨化三醇调节人类角质细胞表皮紧密连接屏障功能

IF 4.6

Journal of dermatological science

Pub Date : 2024-04-01 DOI: 10.1016/j.jdermsci.2024.02.001

Juan Valentin Trujillo-Paez , Ge Peng , Hai Le Thanh Nguyen , Masahiro Nakamura , Yoshie Umehara , Hainan Yue , Risa Ikutama , Miho Takahashi , Shigaku Ikeda , Hideoki Ogawa , Ko Okumura , François Niyonsaba

Background

The aberrant expression of tight junction (TJ) proteins play an important role in several diseases with impaired skin barriers, including atopic dermatitis, psoriasis, and chronic wounds. The evidence provided thus far suggests an important role of calcitriol in skin homeostasis. However, it is not known whether calcitriol improves the impaired skin barrier.

Objective

To investigate the effect of calcitriol on TJ barrier function in human primary keratinocytes.

Methods

Normal human primary keratinocytes were stimulated with calcitriol, and the expression of TJ-related proteins was measured by real-time PCR and Western blotting. Immunofluorescence was used to examine the intercellular distribution of TJ-related proteins. TJ barrier function was assessed by the transepithelial electrical resistance (TER) assay.

Results

We demonstrated that calcitriol increased the expression levels of TJ-related proteins, including claudin-4, claudin-7, occludin, and zonula occludens (ZO)− 1. Calcitriol enhanced the distribution of TJ-related proteins at cellcell borders and induced the phosphorylation of pathways involved in the regulation of TJ barrier function, such as atypical protein kinase C (aPKC), Ras-related C3 botulinum toxin substrate 1 (Rac1), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt), as evidenced by the effects of specific inhibitors on the above pathways. Indeed, we confirmed that calcitriol enhanced TER in keratinocyte monolayers.

Conclusion

These findings showed that calcitriol could modify the expression of keratinocyte TJ proteins, contributing to the maintenance of homeostatic barrier function.

背景紧密连接（TJ）蛋白的异常表达在特应性皮炎、银屑病和慢性伤口等多种皮肤屏障受损的疾病中起着重要作用。迄今提供的证据表明，降钙素三醇在皮肤稳态中发挥着重要作用。方法用降钙素三醇刺激正常人的原代角朊细胞，通过实时 PCR 和 Western 印迹检测 TJ 相关蛋白的表达。免疫荧光用于检测 TJ 相关蛋白在细胞间的分布。结果我们发现，钙三醇提高了TJ相关蛋白的表达水平，包括claudin-4、claudin-7、occludin和zonula occludens (ZO)- 1。钙三醇增强了TJ相关蛋白在细胞边界的分布，并诱导了参与调控TJ屏障功能的通路的磷酸化，如非典型蛋白激酶C（aPKC）、Ras相关的C3肉毒毒素底物1（Rac1）、磷酸肌醇3-激酶（PI3K）和蛋白激酶B（Akt），上述通路的特异性抑制剂的效果也证明了这一点。结论这些研究结果表明，钙三醇能改变角质细胞 TJ 蛋白的表达，有助于维持屏障的平衡功能。

{"title":"Calcitriol modulates epidermal tight junction barrier function in human keratinocytes","authors":"Juan Valentin Trujillo-Paez , Ge Peng , Hai Le Thanh Nguyen , Masahiro Nakamura , Yoshie Umehara , Hainan Yue , Risa Ikutama , Miho Takahashi , Shigaku Ikeda , Hideoki Ogawa , Ko Okumura , François Niyonsaba","doi":"10.1016/j.jdermsci.2024.02.001","DOIUrl":"10.1016/j.jdermsci.2024.02.001","url":null,"abstract":"<div><h3>Background</h3><p>The aberrant expression of tight junction (TJ) proteins play an important role in several diseases with impaired skin barriers, including atopic dermatitis, psoriasis, and chronic wounds. The evidence provided thus far suggests an important role of calcitriol in skin homeostasis. However, it is not known whether calcitriol improves the impaired skin barrier.</p></div><div><h3>Objective</h3><p>To investigate the effect of calcitriol on TJ barrier function in human primary keratinocytes.</p></div><div><h3>Methods</h3><p>Normal human primary keratinocytes were stimulated with calcitriol, and the expression of TJ-related proteins was measured by real-time PCR and Western blotting. Immunofluorescence was used to examine the intercellular distribution of TJ-related proteins. TJ barrier function was assessed by the transepithelial electrical resistance (TER) assay.</p></div><div><h3>Results</h3><p>We demonstrated that calcitriol increased the expression levels of TJ-related proteins, including claudin-4, claudin-7, occludin, and <em>zonula occludens</em> (ZO)− 1. Calcitriol enhanced the distribution of TJ-related proteins at cell<img>cell borders and induced the phosphorylation of pathways involved in the regulation of TJ barrier function, such as atypical protein kinase C (aPKC), Ras-related C3 botulinum toxin substrate 1 (Rac1), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt), as evidenced by the effects of specific inhibitors on the above pathways. Indeed, we confirmed that calcitriol enhanced TER in keratinocyte monolayers.</p></div><div><h3>Conclusion</h3><p>These findings showed that calcitriol could modify the expression of keratinocyte TJ proteins, contributing to the maintenance of homeostatic barrier function.</p></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139830104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting antibody-mediated complement-independent mechanism in bullous pemphigoid with diacerein 用迪卡色林靶向大疱性类天疱疮中抗体介导的补体依赖性机制

IF 4.6

Journal of dermatological science

Pub Date : 2024-04-01 DOI: 10.1016/j.jdermsci.2024.03.001

Yung-Tsu Cho , Chih-Hung Lee , Jing-Yi Lee , Chia-Yu Chu

Background

Bullous pemphigoid (BP) is an antibody-mediated blistering disease predominantly affecting the elderly. The pathogenesis involves both complement-dependent and complement-independent mechanisms. The therapeutic potential of targeting complement-independent mechanism has not yet been determined. The mainstay of treatment, corticosteroid, has many side effects, indicating the needs of better treatments.

Objective

We tempted to establish an in vitro model of BP which resembles complement-independent mechanism and to examine the therapeutic potential of a novel anti-inflammatory agent, diacerein.

Methods

Cultured HaCaT cells were treated with purified antibodies from BP patients, with or without diacerein to measure the cell interface presence of BP180, protein kinase C, and the production of proinflammatory cytokines. An open-label, randomized, phase 2 trial was conducted to compare topical diacerein and clobetasol ointments in patients with mild-to-moderate BP (NCT03286582).

Results

The reduced presentation of BP180 at cell interface after treating with BP autoantibodies was noticed in immunofluorescence and western blotting studies. The phenomenon was restored by diacerein. Diacerein also reduced the autoantibody-induced increase of pro-inflammatory cytokines. Reciprocal changes of BP180 and protein kinase C at the cell interface were found after treating with BP autoantibodies. This phenomenon was also reversed by diacerein in a dose-dependent manner. The phase 2 trial showed that topical diacerein reduced the clinical symptoms which were comparable to those of topical clobetasol.

Conclusion

Diacerein inhibited BP autoantibody-induced reduction of BP180 and production of proinflammatory cytokines in vitro and showed therapeutic potential in patients with BP. It is a novel drug worthy of further investigations.

大疱性类天疱疮（BP）是一种抗体介导的大疱性疾病，主要影响老年人。其发病机制涉及补体依赖性机制和补体非依赖性机制。针对补体无关机制的治疗潜力尚未确定。皮质类固醇激素是主要的治疗手段，但它有很多副作用，这表明需要更好的治疗方法。我们试图建立一种类似补体依赖性机制的 BP 体外模型，并研究一种新型抗炎剂 diacerein 的治疗潜力。用来自 BP 患者的纯化抗体处理培养的 HaCaT 细胞，同时使用或不使用 diacerein，以测量细胞界面是否存在 BP180、蛋白激酶 C 以及促炎细胞因子的产生。一项开放标签、随机的 2 期试验比较了轻度至中度良性前列腺增生患者外用的迪卡瑞林和氯倍他索软膏（NCT03286582）。在免疫荧光和免疫印迹研究中发现，使用 BP 自身抗体治疗后，BP180 在细胞界面的呈现减少。迪卡西林恢复了这一现象。双醋瑞因还能减少自身抗体诱导的促炎细胞因子的增加。用 BP 自身抗体处理后，发现细胞界面上的 BP180 和蛋白激酶 C 发生了相互变化。迪卡西林也能以剂量依赖的方式逆转这一现象。二期试验表明，局部使用迪卡瑞林可减轻临床症状，其效果与局部使用氯倍他索相当。迪卡瑞林可抑制 BP 自身抗体诱导的体外 BP180 减少和促炎细胞因子的产生，对 BP 患者具有治疗潜力。这是一种值得进一步研究的新型药物。

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引用次数: 0