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Two-pore channel 2 is required for soluble adenylyl cyclase-dependent regulation of melanosomal pH and melanin synthesis 可溶性腺苷酸环化酶依赖性调节黑色素体pH值和黑色素合成需要双孔通道2。
IF 3.9 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-06-06 DOI: 10.1111/pcmr.13177
Dalee Zhou, Zuhal Eraslan, Dawson Miller, Isobel Taylor, Jaewon You, Samuel J. Grondin, Martha Vega, Prashiela Manga, Philip S. Goff, Elena V. Sviderskaya, Steven S. Gross, Qiuying Chen, Jonathan H. Zippin

Melanosomal pH is important for the synthesis of melanin as the rate-limiting enzyme, tyrosinase, is very pH-sensitive. The soluble adenylyl cyclase (sAC) signaling pathway was recently identified as a regulator of melanosomal pH in melanocytes; however, the melanosomal proteins critical for sAC-dependent regulation of melanosomal pH were undefined. We now systematically examine four well-characterized melanosomal membrane proteins to determine whether any of them are required for sAC-dependent regulation of melanosomal pH. We find that OA1, OCA2, and SLC45A2 are dispensable for sAC-dependent regulation of melanosomal pH. In contrast, TPC2 activity is required for sAC-dependent regulation of melanosomal pH and melanin synthesis. In addition, activation of TPC2 by NAADP-AM rescues melanosomal pH alkalinization and reduces melanin synthesis following pharmacologic or genetic inhibition of sAC signaling. These studies establish TPC2 as a critical melanosomal protein for sAC-dependent regulation of melanosomal pH and pigmentation.

黑色素体的pH值对黑色素的合成非常重要,因为限速酶酪氨酸酶对pH值非常敏感。可溶性腺苷酸环化酶(sAC)信号通路最近被确定为黑色素细胞中黑色素体pH值的调节因子;然而,依赖于sAC调节黑色素体pH值的黑色素体蛋白尚未确定。现在,我们系统地研究了四种特征明确的黑色素体膜蛋白,以确定它们中是否有任何一种是sAC依赖性调节黑色素体pH值所必需的。我们发现,OA1、OCA2 和 SLC45A2 在依赖 sAC 调节黑色素体 pH 的过程中是不可或缺的。相反,TPC2的活性则是依赖sAC调节黑色素体pH值和黑色素合成所必需的。此外,NAADP-AM 对 TPC2 的激活可在药物或基因抑制 sAC 信号传导后挽救黑色素体 pH 碱化并减少黑色素合成。这些研究确定了 TPC2 是依赖 sAC 调节黑色素体 pH 值和色素沉着的关键黑色素体蛋白。
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引用次数: 0
The effect of oxidative degradation of Dopa-melanin on its basic physicochemical properties and photoreactivity 多巴-黑色素氧化降解对其基本理化特性和光活性的影响。
IF 3.9 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-05-27 DOI: 10.1111/pcmr.13176
Krystian Mokrzyński, Andrzej Żądło, Grzegorz Szewczyk, Michal Sarna, Theodore G. Camenisch, Shosuke Ito, Kazumasa Wakamatsu, Tadeusz Sarna

Melanin, particularly eumelanin, is commonly viewed as an efficient antioxidant and photoprotective pigment. Nonetheless, the ability of melanin to photogenerate reactive oxygen species and sensitize the formation of cyclobutane pyrimidine dimers may contribute to melanin-dependent phototoxicity. The phototoxic potential of melanin depends on a variety of factors, including molecular composition, redox state, and degree of aggregation. Using complementary spectroscopic and analytical methods we analyzed the physicochemical properties of Dopa-melanin, a synthetic model of eumelanin, subjected to oxidative degradation induced by aerobic photolysis or exposure to 0.1 M hydrogen peroxide. Both modes of oxidative degradation were accompanied by dose-dependent bleaching of melanin and irreversible modifications of its paramagnetic, ion- and electron-exchange and antioxidant properties. Bleached melanin exhibited enhanced efficiency to photogenerate singlet oxygen in both UVA and short-wavelength visible light. Although chemical changes of melanin subunits, including a relative increase of DHICA content and disruption of melanin polymer induced by oxidative degradation were considered, these two mechanisms may not be sufficient for a satisfactory explanation of the elevated photosensitizing ability of the bleached eumelanin. This study points out possible adverse changes in the photoprotective and antioxidant properties of eumelanin that could occur in pigmented tissues after exposure to high doses of intense solar radiation.

黑色素,尤其是黑色素,通常被视为一种高效的抗氧化剂和光保护色素。然而,黑色素在光照下生成活性氧和敏化环丁烷嘧啶二聚体的能力可能会导致黑色素依赖性光毒性。黑色素的光毒性潜力取决于多种因素,包括分子组成、氧化还原状态和聚集程度。我们使用互补光谱和分析方法分析了多巴黑色素的理化特性,多巴黑色素是一种合成的黑色素模型,在有氧光解或暴露于 0.1 M 过氧化氢的条件下会发生氧化降解。在这两种氧化降解模式下,黑色素都会发生剂量依赖性漂白,其顺磁性、离子和电子交换性以及抗氧化性也会发生不可逆的改变。漂白后的黑色素在 UVA 和短波长可见光下光生成单线态氧的效率都有所提高。虽然考虑到了黑色素亚基的化学变化,包括 DHICA 含量的相对增加和氧化降解引起的黑色素聚合物的破坏,但这两种机制可能不足以令人满意地解释漂白后黑色素光敏能力的提高。这项研究指出,色素组织在暴露于高强度太阳辐射后,黑色素的光保护和抗氧化特性可能会发生不利变化。
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引用次数: 0
An in vitro nevus explant model for studying the effects of ultraviolet radiation 用于研究紫外线辐射影响的体外痣外植体模型。
IF 3.9 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-05-11 DOI: 10.1111/pcmr.13173
Rui Wang, Jianglong Feng, Wei Zhang, Yu Wang, Hongguang Lu, Wen Zeng

Ultraviolet radiation (UVR) has been recognized as a potential trigger for the transformation of benign melanocytic nevi into melanoma. However, the mechanisms governing the formation and progression of melanocytic nevi remain poorly understood. This lack of understanding is partly due to the difficulty in isolating and culturing nevus tissues in vitro, resulting in a dearth of robust ex vivo models for nevi. Therefore, the establishment of a reliable melanocytic nevus model is imperative. Such a model is essential for elucidating nevus pathogenesis and facilitating the development of effective therapeutic interventions. Therefore, we have sought to establish an ex vivo nevus explant model to study UVR stimulation. And the structural integrity and tissue activity of the ex vivo nevi explant model was evaluated. We then observed melanogenesis and proliferation activity of the explants after UVR stimulation. There was less blister formation after Day 3 in nevi explants under our modified medium conditions. The nevi explant was able to maintain almost the same morphological structure and tissue activity as in vivo tissue within 24 h. Following UVR stimulation, we observed increased melanogenesis and proliferation activity in nevi explants. Nevi explants could serve as an ex vivo model for UVR-induced nevi stimulation research.

紫外线辐射(UVR)已被认为是良性黑素细胞痣转变为黑素瘤的潜在诱因。然而,人们对黑素细胞痣的形成和发展机制仍然知之甚少。造成这种认识不足的部分原因是很难在体外分离和培养痣组织,从而导致缺乏可靠的痣体外模型。因此,建立可靠的黑素细胞痣模型势在必行。这种模型对于阐明痣的发病机制和促进有效治疗干预措施的开发至关重要。因此,我们试图建立一个体外痣外植体模型来研究紫外线刺激。我们评估了体外痣外植体模型的结构完整性和组织活性。然后,我们观察了外植体在紫外线刺激后的黑色素生成和增殖活性。在我们改良的培养基条件下,黑痣外植体在第 3 天后形成的水疱较少。在紫外线照射后,我们观察到黑痣外植体的黑色素生成和增殖活性均有所提高。黑素细胞外植体可作为紫外线诱导黑素细胞刺激研究的体外模型。
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引用次数: 0
BET inhibition sensitizes innate checkpoint inhibitor resistant melanoma to anti-CTLA-4 treatment BET 抑制剂可使先天检查点抑制剂耐药的黑色素瘤对抗 CTLA-4 治疗敏感。
IF 3.9 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-05-09 DOI: 10.1111/pcmr.13174
Hsin-Yi Tseng, Sara Alavi, Stuart Gallagher, Helen M. McGuire, Peter Hersey, Abdullah Al Emran, Jessamy Tiffen

Approximately 50% of melanoma patients fail to respond to immune checkpoint blockade (ICB), and acquired resistance hampers long-term survival in about half of initially responding patients. Whether targeting BET reader proteins, implicated in epigenetic dysregulation, can enhance ICB response rates and durability, remains to be determined. Here we show elevated BET proteins correlate with poor survival and ICB responses in melanoma patients. The BET inhibitor IBET151, combined with anti-CTLA-4, overcame innate ICB resistance however, sequential BET inhibition failed against acquired resistance in mouse models. Combination treatment response in the innate resistance model induced changes in tumor-infiltrating immune cells, reducing myeloid-derived suppressor cells (MDSCs). CD4+ and CD8+ T cells showed decreased expression of inhibitory receptors, with reduced TIM3, LAG3, and BTLA checkpoint expression. In human PBMCs in vitro, BET inhibition reduced expression of immune checkpoints in CD4+ and CD8+ T cells, restoring effector cytokines and downregulating the transcriptional driver TOX. BET proteins in melanoma may play an oncogenic role by inducing immune suppression and driving T cell dysfunction. The study demonstrates an effective combination for innately unresponsive melanoma patients to checkpoint inhibitor immunotherapy, yet highlights BET inhibitors' limitations in an acquired resistance context.

大约50%的黑色素瘤患者对免疫检查点阻断疗法(ICB)无效,而获得性抗药性阻碍了大约一半初始应答患者的长期生存。靶向与表观遗传失调有关的 BET 阅读器蛋白是否能提高 ICB 的应答率和持久性仍有待确定。在这里,我们发现 BET 蛋白的升高与黑色素瘤患者的不良生存率和 ICB 反应相关。BET 抑制剂 IBET151 与抗 CTLA-4 联用可克服先天性 ICB 抗药性,但在小鼠模型中,连续的 BET 抑制却无法对抗获得性抗药性。先天耐药性模型中的联合治疗反应诱导了肿瘤浸润免疫细胞的变化,减少了髓源性抑制细胞(MDSCs)。CD4+ 和 CD8+ T 细胞的抑制性受体表达减少,TIM3、LAG3 和 BTLA 检查点表达降低。在体外人类 PBMCs 中,BET 抑制降低了 CD4+ 和 CD8+ T 细胞中免疫检查点的表达,恢复了效应细胞因子并下调了转录驱动因子 TOX。黑色素瘤中的 BET 蛋白可能通过诱导免疫抑制和驱动 T 细胞功能障碍而发挥致癌作用。这项研究展示了一种有效的联合疗法,可用于对检查点抑制剂免疫疗法无反应的先天性黑色素瘤患者,但也强调了 BET 抑制剂在获得性耐药情况下的局限性。
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引用次数: 0
Genotypic spectrum of albinism in Mali 马里白化病的基因型谱。
IF 3.9 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-05-09 DOI: 10.1111/pcmr.13175
Modibo Diallo, Ousmane Sylla, Mohamed Kole Sidibé, Claudio Plaisant, Elina Mercier, Angèle Sequeira, Sophie Javerzat, Abdelaziz Hadid, Eulalie Lasseaux, Vincent Michaud, Benoit Arveiler

Albinism is a phenotypically and genetically heterogeneous condition characterized by a variable degree of hypopigmentation and by ocular features leading to reduced visual acuity. Whereas numerous genotypic studies have been conducted throughout the world, very little is known about the genotypic spectrum of albinism in Africa and especially in sub-Saharan Western Africa. Here we report the analysis of all known albinism genes in a series a 23 patients originating from Mali. Four were diagnosed with OCA 1 (oculocutaneous albinism type 1), 17 with OCA 2, and two with OCA 4. OCA2 variant NM_000275.3:c.819_822delinsGGTC was most frequently encountered. Four novel variants were identified (two in TYR, two in OCA2). A deep intronic variant was found to alter splicing of the OCA2 RNA by inclusion of a pseudo exon. Of note, the OCA2 exon 7 deletion commonly found in eastern, central, and southern Africa was absent from this series. African patients with OCA 1 and OCA 4 had only been reported twice and once, respectively, in previous publications. This study constitutes the first report of the genotypic spectrum of albinism in a western sub-Saharan country.

白化病是一种表型和基因异质性疾病,其特征是不同程度的色素沉着和导致视力减退的眼部特征。尽管世界各地已开展了大量基因型研究,但人们对非洲,尤其是撒哈拉以南的西非地区白化病的基因型谱却知之甚少。在此,我们报告了对马里 23 名白化病患者所有已知白化病基因的分析结果。其中 4 人被确诊为 OCA 1(1 型眼皮肤白化病),17 人被确诊为 OCA 2,2 人被确诊为 OCA 4。OCA2 变体 NM_000275.3:c.819_822delinsGGTC 是最常见的变体。发现了四个新变异(两个在 TYR 中,两个在 OCA2 中)。发现一个深内含子变异通过包含一个假外显子改变了 OCA2 RNA 的剪接。值得注意的是,该系列中不存在非洲东部、中部和南部常见的 OCA2 第 7 号外显子缺失。在以前的出版物中,非洲的 OCA 1 和 OCA 4 患者只分别报道过两次和一次。本研究首次报告了撒哈拉以南西部国家白化病的基因型谱。
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引用次数: 0
Effects of EGFR-TKI on epidermal melanin unit integrity: Therapeutic implications for hypopigmented skin disorders 表皮生长因子受体-TKI 对表皮黑色素单位完整性的影响:对色素减退性皮肤病的治疗意义。
IF 4.3 3区 医学 Q1 Medicine Pub Date : 2024-05-05 DOI: 10.1111/pcmr.13171
Ping Xu, Lingli Yang, Sylvia Lai, Fei Yang, Yasutaka Kuroda, Huimin Zhang, Daisuke Tsuruta, Ichiro Katayama

Epidermal melanin unit integrity is crucial for skin homeostasis and pigmentation. Epidermal growth factor (EGF) receptor (EGFR) is a pivotal player in cell growth, wound healing, and maintaining skin homeostasis. However, its influence on skin pigmentation is relatively unexplored. This study investigates the impact and underlying mechanisms of EGFR inhibitors on skin pigmentation. We evaluated EGF and EGFR expression in various skin cells using quantitative real-time PCR, Western blot, and immunofluorescence. EGF and EGFR were predominantly expressed in epidermal keratinocytes, and treatment with the EGFR tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and PD153035 significantly increased stem cell factor (SCF) and endothelin-1 (ET-1) expression in cultured keratinocytes. Enhanced melanocyte migration and proliferation were observed in co-culture, as evidenced by time-lapse live imaging and single-cell tracking assays. Furthermore, topical application of gefitinib to guinea pig dorsal skin induced increased pigmentation and demonstrated efficacy in mitigating rhododendrol-induced leukoderma. Suppression of EGF signaling indirectly enhanced skin pigmentation by upregulating SCF and ET-1 in epidermal keratinocytes. This novel mechanism highlights the pivotal role of EGF signaling in regulating skin pigmentation, and topical EGFR-TKI therapy at an appropriate dose may be a promising approach for depigmentation disorder management.

表皮黑色素单元的完整性对皮肤的稳态和色素沉着至关重要。表皮生长因子(EGF)受体(EGFR)是细胞生长、伤口愈合和维持皮肤稳态的关键因素。然而,它对皮肤色素沉着的影响却相对较少。本研究探讨了表皮生长因子受体抑制剂对皮肤色素沉着的影响及其内在机制。我们使用实时定量 PCR、Western 印迹和免疫荧光技术评估了 EGF 和 EGFR 在各种皮肤细胞中的表达。表皮生长因子和表皮生长因子受体主要在表皮角质形成细胞中表达,表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)吉非替尼和 PD153035 能显著增加培养角质形成细胞中干细胞因子(SCF)和内皮素-1(ET-1)的表达。通过延时活体成像和单细胞跟踪检测,观察到共培养中黑色素细胞的迁移和增殖增强。此外,在豚鼠背部皮肤上局部应用吉非替尼能诱导色素沉着的增加,并能有效减轻红豆杉诱导的白皮病。通过上调表皮角质形成细胞中的 SCF 和 ET-1,抑制表皮生长因子信号间接增强了皮肤色素沉着。这一新机制凸显了表皮生长因子受体信号在调节皮肤色素沉着中的关键作用,适当剂量的表皮生长因子受体-TKI局部疗法可能是治疗色素沉着疾病的一种很有前景的方法。
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引用次数: 0
Multi-omics analysis reveals inflammatory biomarkers for skin melanoma prognosis 多组学分析揭示了皮肤黑色素瘤预后的炎症生物标志物
IF 4.3 3区 医学 Q1 Medicine Pub Date : 2024-04-28 DOI: 10.1111/pcmr.13172
Zhi-Qing Zhan, Jia-Xin Li, Xin-Lei Hu
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引用次数: 0
25th International Pigment Cell Conference, Bilbao, Spain IPCC 2023 第 25 届国际色素细胞大会,西班牙毕尔巴鄂:IPCC 2023 会议摘要。
IF 3.9 3区 医学 Q2 CELL BIOLOGY Pub Date : 2024-04-25 DOI: 10.1111/pcmr.13145
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引用次数: 0
RNA M6A modification shaping cutaneous melanoma tumor microenvironment and predicting immunotherapy response RNA M6A修饰塑造皮肤黑色素瘤肿瘤微环境并预测免疫疗法反应
IF 4.3 3区 医学 Q1 Medicine Pub Date : 2024-04-16 DOI: 10.1111/pcmr.13170
Yanhong Wu, Hongying He, Kairong Zheng, Zhenxin Qin, Naikun Cai, Shuguang Zuo, Xiao Zhu

Recent years have seen rising mortality rates linked to cutaneous melanoma (SKCM), despite advances in immunotherapy. Understanding RNA N6-methyladenosine (M6A) significance in SKCM is crucial for prognosis, tumor microenvironment (TME), immune cell presence, and immunotherapy efficacy. We analyzed 23 M6A regulators using SKCM samples from TCGA and GEO databases, identifying three M6A modification patterns linked to TME cell infiltration. Principal component analysis (PCA) yielded an M6A score for individual tumors, utilizing patient gene expression profiles and CNV data from TCGA. M6A modification patterns play a crucial role in SKCM development and progression, influencing tumor attributes such as inflammatory stage, subtype, TME interstitial activity, and genetic mutations. The M6A score independently predicts patient outcomes and correlates with improved response to immunotherapy, validated across anti-PD-1 and anti-PD-L1 therapy cohorts. M6A modifications significantly impact the TME landscape, with the M6A score serving as a predictive marker for immunotherapy response. Integrating M6A-related information into clinical practice could revolutionize SKCM management and treatment strategies.

近年来,尽管免疫疗法取得了进展,但与皮肤黑色素瘤(SKCM)相关的死亡率却在不断上升。了解RNA N6-甲基腺苷(M6A)在SKCM中的意义对预后、肿瘤微环境(TME)、免疫细胞的存在和免疫疗法的疗效至关重要。我们利用TCGA和GEO数据库中的SKCM样本分析了23种M6A调节因子,确定了三种与TME细胞浸润相关的M6A修饰模式。利用TCGA的患者基因表达谱和CNV数据,主成分分析(PCA)得出了单个肿瘤的M6A评分。M6A修饰模式在SKCM的发展和进程中起着至关重要的作用,影响着肿瘤的属性,如炎症期、亚型、TME间质活性和基因突变。经抗PD-1和抗PD-L1疗法队列验证,M6A评分可独立预测患者的预后,并与免疫疗法反应的改善相关。M6A修饰对TME格局有重大影响,M6A评分可作为免疫疗法反应的预测标志物。将M6A相关信息纳入临床实践可彻底改变SKCM的管理和治疗策略。
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引用次数: 0
Molecular heterogeneity of quiescent melanocyte stem cells revealed by single-cell RNA-sequencing 单细胞 RNA 测序揭示静止黑素细胞干细胞的分子异质性
IF 4.3 3区 医学 Q1 Medicine Pub Date : 2024-04-13 DOI: 10.1111/pcmr.13169
Joseph W. Palmer, Nilesh Kumar, Luye An, Andrew C. White, M. Shahid Mukhtar, Melissa L. Harris

Melanocyte stem cells (McSCs) of the hair follicle are a rare cell population within the skin and are notably underrepresented in whole-skin, single-cell RNA sequencing (scRNA-seq) datasets. Using a cell enrichment strategy to isolate KIT+/CD45− cells from the telogen skin of adult female C57BL/6J mice, we evaluated the transcriptional landscape of quiescent McSCs (qMcSCs) at high resolution. Through this evaluation, we confirmed existing molecular signatures for qMcCS subpopulations (e.g., Kit+, Cd34+/−, Plp1+, Cd274+/−, Thy1+, Cdh3+/−) and identified novel qMcSC subpopulations, including two that differentially regulate their immune privilege status. Within qMcSC subpopulations, we also predicted melanocyte differentiation potential, neural crest potential, and quiescence depth. Taken together, the results demonstrate that the qMcSC population is heterogeneous and future studies focused on investigating changes in qMcSCs should consider changes in subpopulation composition.

毛囊黑色素细胞干细胞(McSCs)是皮肤中的稀有细胞群,在全皮肤单细胞RNA测序(scRNA-seq)数据集中的代表性明显不足。我们采用细胞富集策略从成年雌性 C57BL/6J 小鼠的毛囊皮肤中分离出了 KIT+/CD45- 细胞,高分辨率地评估了静止毛囊干细胞(qMcSCs)的转录情况。通过这项评估,我们证实了现有的qMcSC亚群分子特征(如Kit+、Cd34+/-、Plp1+、Cd274+/-、Thy1+、Cdh3+/-),并鉴定出了新的qMcSC亚群,其中包括两个能以不同方式调节其免疫特权状态的亚群。在qMcSC亚群中,我们还预测了黑色素细胞分化潜能、神经嵴潜能和静止深度。综上所述,研究结果表明qMcSC群体是异质性的,未来重点调查qMcSC变化的研究应考虑亚群组成的变化。
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引用次数: 0
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Pigment Cell & Melanoma Research
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