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Cap-Specific m6Am Methyltransferase PCIF1/CAPAM Regulates mRNA Stability of RAB23 and CNOT6 through the m6A Methyltransferase Activity. 帽子特异性 m6Am 甲基转移酶 PCIF1/CAPAM 通过 m6A 甲基转移酶活性调控 RAB23 和 CNOT6 的 mRNA 稳定性
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-12 DOI: 10.3390/cells13201689
Ai Sugita, Ryoya Kano, Hiroyasu Ishiguro, Natsuki Yanagisawa, Soichiro Kuruma, Shotaro Wani, Aki Tanaka, Yoshiaki Tabuchi, Yoshiaki Ohkuma, Yutaka Hirose

Chemical modifications of cellular RNAs play key roles in gene expression and host defense. The cap-adjacent N6,2'-O-dimethyladenosine (m6Am) is a prevalent modification of vertebrate and viral mRNAs and is catalyzed by the newly discovered N6 methyltransferase PCIF1. However, its role in gene expression remains unclear due to conflicting reports on its effects on mRNA stability and translation. In this study, we investigated the impact of siRNA-mediated transient suppression of PCIF1 on global mRNA expression in HeLa cells. We identified a subset of differentially expressed genes (DEGs) that exhibited minimal overlap with previously reported DEGs. Subsequent validation revealed that PCIF1 positively and negatively regulates RAB23 and CNOT6 expression, respectively, at both the mRNA and protein levels. Mechanistic analyses demonstrated that PCIF1 regulates the stability of these target mRNAs rather than their transcription, and rescue experiments confirmed the requirement of PCIF1's methyltransferase activity for these regulations. Furthermore, MeRIP-qPCR analysis showed that PCIF1 suppression significantly reduced the m6A levels of RAB23 and CNOT6 mRNAs. These findings suggest that PCIF1 regulates the stability of specific mRNAs in opposite ways through m6A modification, providing new insights into the role of m6Am in the regulation of gene expression.

细胞 RNA 的化学修饰在基因表达和宿主防御中起着关键作用。与帽子相邻的 N6,2'-O-二甲基腺苷(m6Am)是脊椎动物和病毒 mRNA 的一种普遍修饰,由新发现的 N6 甲基转移酶 PCIF1 催化。然而,由于有关其对 mRNA 稳定性和翻译的影响的报道相互矛盾,其在基因表达中的作用仍不清楚。在本研究中,我们研究了 siRNA 介导的 PCIF1 瞬时抑制对 HeLa 细胞中全局 mRNA 表达的影响。我们发现了一组差异表达基因(DEG),它们与之前报道的 DEG 重叠极少。随后的验证显示,PCIF1 在 mRNA 和蛋白质水平上分别正向和负向调控 RAB23 和 CNOT6 的表达。机理分析表明,PCIF1 调控的是这些靶 mRNA 的稳定性,而不是它们的转录,拯救实验证实了这些调控需要 PCIF1 的甲基转移酶活性。此外,MeRIP-qPCR 分析表明,PCIF1 的抑制作用显著降低了 RAB23 和 CNOT6 mRNA 的 m6A 水平。这些发现表明,PCIF1通过m6A修饰以相反的方式调节特定mRNA的稳定性,为m6Am在基因表达调控中的作用提供了新的见解。
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引用次数: 0
The Power of Reagent Titration in Flow Cytometry. 流式细胞仪中试剂滴定的威力。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-11 DOI: 10.3390/cells13201677
Diana L Bonilla, Alberta Paul, Jesus Gil-Pulido, Lily M Park, Maria C Jaimes

Flow cytometry facilitates the detection of multiple cell parameters simultaneously with a high level of resolution and throughput, enabling in-depth immunological evaluations. High data resolution in flow cytometry depends on multiple factors, including the concentration of reagents used in the staining protocol, and reagent validation and titration should be the first step in any assay optimization. Titration is the process of finding the concentration of the reagent that best resolves a positive signal from the background, with the saturation of all binding sites, and minimal antibody excess. The titration process involves the evaluation of serial reagent dilutions in cells expressing the antigen target for the tested antibody. The concentration of antibody that provides the highest signal to noise ratio is calculated by plotting the percentage of positive cells and the intensity of the fluorescence of the stained cells with respect to the negative events, in a concentration-response curve. The determination of the optimal antibody concentration is necessary to ensure reliable and reproducible results and is required for each sample type, reagent clone and lot, as well as the methods used for cell collection, staining, and storage conditions. If the antibody dilution is too low, the signal will be too weak to be accurately determined, leading to suboptimal data resolution, high variability across measurements, and the underestimation of the frequency of cells expressing a specific marker. The use of excess antibodies could lead to non-specific binding, reagent misuse, and detector overloading with the signal off scale and higher spillover spreading. In this publication, we summarized the titration fundamentals and best practices, and evaluated the impact of using a different instrument, sample, staining, acquisition, and analysis conditions in the selection of the optimal titer and population resolution.

流式细胞术可同时检测多种细胞参数,分辨率高,通量大,可进行深入的免疫学评估。流式细胞仪的高数据分辨率取决于多种因素,包括染色方案中使用的试剂浓度,试剂验证和滴定应是任何检测优化的第一步。滴定是一个寻找试剂浓度的过程,该浓度能最好地将阳性信号从背景中分离出来,同时使所有结合位点达到饱和,并将抗体过量降至最低。滴定过程包括在表达被测抗体靶抗原的细胞中对系列试剂稀释液进行评估。将阳性细胞的百分比和染色细胞的荧光强度与阴性事件相比,绘制成浓度-反应曲线,从而计算出信噪比最高的抗体浓度。为确保结果的可靠性和可重复性,必须确定最佳的抗体浓度,这需要根据每种样本类型、试剂克隆和批次以及细胞收集、染色和储存条件所使用的方法来确定。如果抗体稀释度太低,信号就会太弱,无法准确测定,导致数据分辨率不理想、测量结果差异大以及低估表达特定标记物的细胞频率。使用过量抗体可能会导致非特异性结合、试剂误用、检测器过载、信号失衡和溢出扩散。在这篇论文中,我们总结了滴定的基本原理和最佳实践,并评估了使用不同仪器、样本、染色、采集和分析条件对选择最佳滴定度和群体分辨率的影响。
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引用次数: 0
Age-Related Homeostatic Plasticity at Rodent Neuromuscular Junctions. 啮齿动物神经肌肉接头处与年龄相关的同态可塑性
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-11 DOI: 10.3390/cells13201684
Yizhi Li, Yomna Badawi, Stephen D Meriney

Motor ability decline remains a major threat to the quality of life of the elderly. Although the later stages of aging co-exist with degenerative pathologies, the long process of aging is more complicated than a simple and gradual degeneration. To combat senescence and the associated late-stage degeneration of the neuromuscular system, it is imperative to examine changes that occur during the long process of aging. Prior to late-stage degeneration, age-induced changes in the neuromuscular system trigger homeostatic plasticity. This unique phenomenon may be important for the maintenance of the neuromuscular system during the early stages of aging. In this review, we will focus on age-induced changes in neurotransmission at the neuromuscular junction, providing the potential mechanisms responsible for these changes. The goal is to highlight these key elements and their role in regulating neurotransmission, facilitating future research efforts to combat late-stage degeneration in the neuromuscular system by preserving the functional and structural integrity of these elements prior to the late stage of aging.

运动能力下降仍然是老年人生活质量的主要威胁。虽然衰老晚期与退行性病变并存,但漫长的衰老过程比简单的渐进性退化更为复杂。要对抗衰老和与之相关的神经肌肉系统晚期退化,就必须研究在漫长的衰老过程中发生的变化。在晚期退化之前,神经肌肉系统中由衰老引起的变化会触发同态可塑性。这种独特的现象可能对衰老早期阶段神经肌肉系统的维持非常重要。在这篇综述中,我们将重点讨论由年龄引起的神经肌肉接头处神经传递的变化,并提供引起这些变化的潜在机制。目的是强调这些关键因素及其在调节神经传递中的作用,从而促进未来的研究工作,通过在衰老晚期之前保持这些因素的功能和结构完整性,来对抗神经肌肉系统的晚期退化。
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引用次数: 0
Enhanced Anti-Melanoma Activity of Nutlin-3a Delivered via Ethosomes: Targeting p53-Mediated Apoptosis in HT144 Cells. 通过 Ethosomes 递送的 Nutlin-3a 增强了抗黑色素瘤活性:靶向 p53 介导的 HT144 细胞凋亡
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-11 DOI: 10.3390/cells13201678
Arianna Romani, Giada Lodi, Fabio Casciano, Arianna Gonelli, Paola Secchiero, Giorgio Zauli, Olga Bortolini, Giuseppe Valacchi, Daniele Ragno, Agnese Bondi, Mascia Benedusi, Elisabetta Esposito, Rebecca Voltan

This study evaluated ethosomes as a novel nanodelivery system for nutlin-3a, a known MDM2 inhibitor and activator of the p53 pathway, to improve nutlin-3a's poor solubility, limiting its bio-distribution and therapeutic efficacy. The potential of nutlin-3a-loaded ethosomes was investigated on two in vitro models of melanoma: the HT144 cell line p53wild-type and the SK-MEL-28 cell line p53mutated. Nutlin-3a-loaded ethosomes were characterized for their physicochemical properties and used to treat melanoma cells at different concentrations, considering nutlin-3a solution and empty ethosomes as controls. The biological effects on cells were evaluated 24 and 48 h after treatment by analyzing the cell morphology and viability, cell cycle, and apoptosis rate using flow cytometry and the p53 pathway's activation via Western blotting. The results indicate that ethosomes are delivery systems able to maintain nutlin-3a's functionality and specific biological action, as evidenced by the molecular activation of the p53 pathway and the biological events leading to cell cycle block and apoptosis in p53wild-type cells. Nutlin-3a-loaded ethosomes induced morphological changes in the HT144 cell line, with evident apoptotic cells and a reduction in the number of viable cells of over 80%. Furthermore, nutlin-3a-loaded ethosomes successfully modulated two p53-regulated proteins involved in survival/apoptosis, with up to a 2.5-fold increase in membrane TRAIL-R2 and up to an 8.2-fold decrease in Notch-1 (Notch intracellular domain, NICD) protein expression. The expression of these molecules is known to be altered or dysfunctional in a large percentage of melanoma tumors. Notably, ethosomes, regardless of their nutlin-3a loading, exhibited the ability to reduce HT144 melanoma cellular migration, as assessed in real time using xCELLigence, likely due to the modification of lipid rafts, suggesting their potential antimetastatic properties. Overall, nutlin-3a delivery using ethosomes appears to be a significantly effective means for upregulating the p53 pathway and downregulating active Notch-1, while also taking advantage of their unexpected ability to reduce cellular migration. The findings of this study could pave the way for the development of specific nutlin-3a-loaded ethosome-based medicinal products for cutaneous use.

本研究评估了乙硫体作为一种新型纳米给药系统用于Nutlin-3a(一种已知的MDM2抑制剂和p53通路激活剂),以改善Nutlin-3a溶解度低、限制其生物分布和疗效的问题。研究人员在两种黑色素瘤体外模型(HT144细胞系p53野生型和SK-MEL-28细胞系p53突变型)上研究了装载nutlin-3a的乙硫体的潜力。对 Nutlin-3a 负载乙硫体的理化性质进行了表征,并以不同浓度的 Nutlin-3a 溶液和空乙硫体作为对照,用于处理黑色素瘤细胞。通过使用流式细胞仪分析细胞形态和存活率、细胞周期和凋亡率,以及通过 Western 印迹分析 p53 通路的激活情况,评估了处理后 24 和 48 小时对细胞的生物效应。结果表明,乙硫体是一种能够维持 nutlin-3a 功能和特定生物作用的递送系统,p53 通路的分子活化以及导致 p53 野生型细胞细胞周期阻滞和凋亡的生物事件都证明了这一点。含有Nutlin-3a的乙硫体诱导HT144细胞系发生形态变化,细胞明显凋亡,存活细胞数量减少80%以上。此外,载药乙素体成功调节了两种参与存活/凋亡的p53调控蛋白,膜TRAIL-R2蛋白表达量增加了2.5倍,Notch-1(Notch胞内结构域,NICD)蛋白表达量减少了8.2倍。已知这些分子的表达在很大比例的黑色素瘤肿瘤中发生了改变或功能失调。值得注意的是,根据使用xCELLigence进行的实时评估,乙硫体无论装载多少nutlin-3a,都能减少HT144黑色素瘤细胞的迁移,这可能是由于脂质筏的修饰,表明乙硫体具有潜在的抗转移特性。总之,使用乙硫体递送 nutlin-3a 似乎是上调 p53 通路和下调活性 Notch-1 的一种非常有效的方法,同时还能利用其意想不到的能力减少细胞迁移。这项研究的结果可为开发基于乙硫体的特定营养素-3a皮肤用药产品铺平道路。
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引用次数: 0
Podoplanin Expression in Early-Stage Colorectal Cancer-Associated Fibroblasts and Its Utility as a Diagnostic Marker for Colorectal Lesions. 早期结直肠癌相关成纤维细胞中 Podoplanin 的表达及其作为结直肠病变诊断标志物的作用
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-11 DOI: 10.3390/cells13201682
Shuichi Tsukamoto, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Tomoo Itoh, Hiroshi Yokozaki, Yu-Ichiro Koma

(Background) Cancer-associated fibroblasts (CAFs) are major cancer stromal components. CAFs have diverse functions and cell origins. Podoplanin (PDPN), a lymphatic vessel marker, is also a CAF marker in certain cancers. On daily diagnosis of early colorectal carcinoma (CRC), PDPN upregulation in the stroma is often encountered, suggesting PDPN-positive CAFs have emerged. However, PDPN-positive CAFs in early CRC have not been studied well. (Methods) On immunohistochemistry, PDPN expression in the lamina propria or stroma of adenomas, early CRCs, and neuroendocrine tumors, their normal neighbors, and non-neoplastic colorectal lesions were compared. Single-cell RNA sequencing (scRNA-seq) of CRC was used to explore PDPNhigh CAFs' cell origins. (Results) Reticular cells or pericryptal fibroblasts in the lamina propria of adenomas and early CRCs showed higher PDPN expression than did normal mucosae and non-neoplastic lesions (p < 0.01). Pericryptal PDPN expression was a diagnostic feature of adenomas and early CRCs. scRNA-seq of CRCs highlighted that PDPNhigh CAFs had distinctly higher COL4A1, COL4A2, and WNT5A expression, unlike well-known CAFs characterized by high FAP, POSTN, or ACTA2 expression. (Conclusions) We demonstrated that pericryptal fibroblasts and reticular cells in the lamina propria are origins of early-stage CRC CAFs and thus have potential as a diagnostic marker for distinguishing colorectal non-neoplastic from neoplastic lesions.

(背景)癌症相关成纤维细胞(CAFs)是癌症基质的主要组成部分。CAF 具有多种功能和细胞来源。Podoplanin(PDPN)是一种淋巴管标记物,也是某些癌症的 CAF 标记物。在早期结直肠癌(CRC)的日常诊断中,经常会发现基质中的 PDPN 上调,这表明 PDPN 阳性的 CAF 已经出现。然而,对早期 CRC 中 PDPN 阳性 CAFs 的研究还不够深入。(方法)通过免疫组化,比较腺瘤、早期 CRC 和神经内分泌肿瘤的固有膜或基质、其正常邻近组织以及非肿瘤性结直肠病变中 PDPN 的表达。利用 CRC 的单细胞 RNA 测序(scRNA-seq)来探索 PDPNhigh CAFs 的细胞起源。(结果)腺瘤和早期 CRC 固有层中的网状细胞或隐周成纤维细胞的 PDPN 表达高于正常粘膜和非肿瘤性病变(p < 0.01)。CRCs的scRNA-seq突显出PDPN高的CAFs具有明显较高的COL4A1、COL4A2和WNT5A表达,这与众所周知的以FAP、POSTN或ACTA2高表达为特征的CAFs不同。(结论)我们证明了固有层中的包膜成纤维细胞和网状细胞是早期 CRC CAFs 的起源,因此有可能成为区分结直肠非肿瘤性病变和肿瘤性病变的诊断标志物。
{"title":"Podoplanin Expression in Early-Stage Colorectal Cancer-Associated Fibroblasts and Its Utility as a Diagnostic Marker for Colorectal Lesions.","authors":"Shuichi Tsukamoto, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Tomoo Itoh, Hiroshi Yokozaki, Yu-Ichiro Koma","doi":"10.3390/cells13201682","DOIUrl":"https://doi.org/10.3390/cells13201682","url":null,"abstract":"<p><p>(Background) Cancer-associated fibroblasts (CAFs) are major cancer stromal components. CAFs have diverse functions and cell origins. Podoplanin (PDPN), a lymphatic vessel marker, is also a CAF marker in certain cancers. On daily diagnosis of early colorectal carcinoma (CRC), PDPN upregulation in the stroma is often encountered, suggesting PDPN-positive CAFs have emerged. However, PDPN-positive CAFs in early CRC have not been studied well. (Methods) On immunohistochemistry, PDPN expression in the lamina propria or stroma of adenomas, early CRCs, and neuroendocrine tumors, their normal neighbors, and non-neoplastic colorectal lesions were compared. Single-cell RNA sequencing (scRNA-seq) of CRC was used to explore <i>PDPN</i><sup>high</sup> CAFs' cell origins. (Results) Reticular cells or pericryptal fibroblasts in the lamina propria of adenomas and early CRCs showed higher PDPN expression than did normal mucosae and non-neoplastic lesions (<i>p</i> < 0.01). Pericryptal PDPN expression was a diagnostic feature of adenomas and early CRCs. scRNA-seq of CRCs highlighted that <i>PDPN</i><sup>high</sup> CAFs had distinctly higher <i>COL4A1</i>, <i>COL4A2</i>, and <i>WNT5A</i> expression, unlike well-known CAFs characterized by high <i>FAP, POSTN</i>, or <i>ACTA2</i> expression. (Conclusions) We demonstrated that pericryptal fibroblasts and reticular cells in the lamina propria are origins of early-stage CRC CAFs and thus have potential as a diagnostic marker for distinguishing colorectal non-neoplastic from neoplastic lesions.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mini-Review: Tregs as a Tool for Therapy-Obvious and Non-Obvious Challenges and Solutions. 微型评论:作为治疗工具的 Tregs--明显和不明显的挑战与解决方案
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-11 DOI: 10.3390/cells13201680
Elena I Morgun, Irina A Govorova, Maria B Chernysheva, Maria A Machinskaya, Ekaterina A Vorotelyak

Tregs have the potential to be utilized as a novel therapeutic agent for the treatment of various chronic diseases, including diabetes, Alzheimer's disease, asthma, and rheumatoid arthritis. One of the challenges associated with developing a therapeutic product based on Tregs is the non-selectivity of polyclonal cells. A potential solution to this issue is a generation of antigen-specific CAR-Tregs. Other challenges associated with developing a therapeutic product based on Tregs include the phenotypic instability of these cells in an inflammatory microenvironment, discrepancies between engineered Treg-like cells and natural Tregs, and the expression of dysfunctional isoforms of Treg marker genes. This review presents a summary of proposed strategies for addressing these challenges.

集落细胞有可能被用作治疗糖尿病、阿尔茨海默病、哮喘和类风湿性关节炎等各种慢性疾病的新型治疗剂。开发基于 Tregs 的治疗产品所面临的挑战之一是多克隆细胞的非选择性。解决这一问题的潜在办法是产生抗原特异性 CAR-Tregs。开发基于Tregs的治疗产品所面临的其他挑战包括:这些细胞在炎症微环境中的表型不稳定、工程Treg样细胞与天然Tregs之间的差异,以及Treg标记基因的功能障碍异构体的表达。本综述概述了应对这些挑战的拟议策略。
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引用次数: 0
The Role of Soluble CD163 (sCD163) in Human Physiology and Pathophysiology. 可溶性 CD163 (sCD163) 在人体生理学和病理生理学中的作用。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-11 DOI: 10.3390/cells13201679
Andriana Plevriti, Margarita Lamprou, Eleni Mourkogianni, Nikolaos Skoulas, Maria Giannakopoulou, Md Sanaullah Sajib, Zhiyong Wang, George Mattheolabakis, Antonios Chatzigeorgiou, Antonia Marazioti, Constantinos M Mikelis

Soluble CD163 (sCD163) is a circulating inflammatory mediator, indicative of acute and chronic, systemic and non-systemic inflammatory conditions. It is the cleavage outcome, consisting of almost the entire extracellular domain, of the CD163, a receptor expressed in monocytic lineages. Its expression is proportional to the abundance of CD163+ macrophages. Various mechanisms trigger the shedding of the CD163 receptor or the accumulation of CD163-expressing macrophages, inducing the sCD163 concentration in the circulation and bodily fluids. The activities of sCD163 range from hemoglobin (Hb) scavenging, macrophage marker, decoy receptor for cytokines, participation in immune defense mechanisms, and paracrine effects in various tissues, including the endothelium. It is an established marker of macrophage activation and thus participates in many diseases, including chronic inflammatory conditions, such as atherosclerosis, asthma, and rheumatoid arthritis; acute inflammatory conditions, such as sepsis, hepatitis, and malaria; insulin resistance; diabetes; and tumors. The sCD163 levels have been correlated with the severity, stage of the disease, and clinical outcome for many of these conditions. This review article summarizes the expression and role of sCD163 and its precursor protein, CD163, outlines the sCD163 generation mechanisms, the biological activities, and the known underlying molecular mechanisms, with an emphasis on its impact on the endothelium and its contribution in the pathophysiology of human diseases.

可溶性 CD163(sCD163)是一种循环炎症介质,是急性和慢性、全身性和非全身性炎症的标志。它是 CD163 的裂解产物,几乎包括 CD163 的整个胞外结构域,CD163 是一种在单核细胞系中表达的受体。它的表达与 CD163+ 巨噬细胞的数量成正比。各种机制会导致 CD163 受体脱落或表达 CD163 的巨噬细胞聚集,从而诱发血液循环和体液中的 sCD163 浓度。sCD163 的活性包括清除血红蛋白(Hb)、巨噬细胞标记物、细胞因子诱饵受体、参与免疫防御机制以及在包括内皮在内的各种组织中的旁分泌效应。它是巨噬细胞活化的既定标志物,因此参与许多疾病的治疗,包括慢性炎症,如动脉粥样硬化、哮喘和类风湿性关节炎;急性炎症,如败血症、肝炎和疟疾;胰岛素抵抗;糖尿病和肿瘤。在这些疾病中,sCD163 的水平与疾病的严重程度、阶段和临床结果相关。这篇综述文章总结了 sCD163 及其前体蛋白 CD163 的表达和作用,概述了 sCD163 的生成机制、生物活性和已知的潜在分子机制,重点介绍了它对血管内皮的影响及其在人类疾病的病理生理学中的贡献。
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引用次数: 0
Cardiac Aging in the Multi-Omics Era: High-Throughput Sequencing Insights. 多指标时代的心脏衰老:高通量测序洞察。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-11 DOI: 10.3390/cells13201683
Yiran Song, Brian Spurlock, Jiandong Liu, Li Qian

Cardiovascular diseases are a leading cause of mortality worldwide, and the risks of both developing a disease and receiving a poor prognosis increase with age. With increasing life expectancy, understanding the mechanisms underlying heart aging has become critical. Traditional techniques have supported research into finding the physiological changes and hallmarks of cardiovascular aging, including oxidative stress, disabled macroautophagy, loss of proteostasis, and epigenetic alterations, among others. The advent of high-throughput multi-omics techniques offers new perspectives on the molecular mechanisms and cellular processes in the heart, guiding the development of therapeutic targets. This review explores the contributions and characteristics of these high-throughput techniques to unraveling heart aging. We discuss how different high-throughput omics approaches, both alone and in combination, produce robust and exciting new findings and outline future directions and prospects in studying heart aging in this new era.

心血管疾病是导致全球死亡的主要原因,而随着年龄的增长,患病和预后不良的风险都会增加。随着预期寿命的延长,了解心脏衰老的内在机制变得至关重要。传统技术为研究发现心血管衰老的生理变化和标志提供了支持,包括氧化应激、大自噬功能失效、蛋白稳态丧失和表观遗传学改变等。高通量多组学技术的出现为研究心脏的分子机制和细胞过程提供了新的视角,为开发治疗靶点提供了指导。本综述探讨了这些高通量技术对揭示心脏衰老的贡献和特点。我们讨论了不同的高通量 omics 方法,无论是单独使用还是结合使用,如何产生强大而令人兴奋的新发现,并概述了在这个新时代研究心脏衰老的未来方向和前景。
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引用次数: 0
CREB Is Critically Implicated in Skin Mast Cell Degranulation Elicited via FcεRI and MRGPRX2. CREB在通过FcεRI和MRGPRX2诱发的皮肤肥大细胞脱颗粒中发挥关键作用
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-11 DOI: 10.3390/cells13201681
Zhuoran Li, Jean Schneikert, Shiva Raj Tripathi, Manqiu Jin, Gürkan Bal, Torsten Zuberbier, Magda Babina

Skin mast cells (MCs) mediate acute allergic reactions in the cutaneous environment and contribute to chronic dermatoses, including urticaria, and atopic or contact dermatitis. The cAMP response element binding protein (CREB), an evolutionarily well conserved transcription factor (TF) with over 4,000 binding sites in the genome, was recently found to form a feedforward loop with KIT, maintaining MC survival. The most selective MC function is degranulation with its acute release of prestored mediators. Herein, we asked whether CREB contributes to the expression and function of the degranulation-competent receptors FcεRI and MRGPRX2. Interference with CREB by pharmacological inhibition (CREBi, 666-15) or RNA interference only slightly affected the expression of these receptors, while KIT was strongly attenuated. Interestingly, MRGPRX2 surface expression moderately increased following CREB-knockdown, whereas MRGPRX2-dependent exocytosis simultaneously decreased. FcεRI expression and function were regulated consistently, although the effect was stronger at the functional level. Preformed MC mediators (tryptase, histamine, β-hexosaminidase) remained comparable following CREB attenuation, suggesting that granule synthesis did not rely on CREB function. Collectively, in contrast to KIT, FcεRI and MRGPRX2 moderately depend on unperturbed CREB function. Nevertheless, CREB is required to maintain MC releasability irrespective of stimulus, insinuating that CREB may operate by safeguarding the degranulation machinery. To our knowledge, CREB is the first factor identified to regulate MRGPRX2 expression and function in opposite direction. Overall, the ancient TF is an indispensable component of skin MCs, orchestrating not only survival and proliferation but also their secretory competence.

皮肤肥大细胞(MC)介导皮肤环境中的急性过敏反应,并导致慢性皮肤病,包括荨麻疹、特应性皮炎或接触性皮炎。cAMP 反应元件结合蛋白(CREB)是一种在基因组中有 4000 多个结合位点的进化保守转录因子(TF),最近发现它与 KIT 形成前馈循环,维持 MC 的存活。MC 最具选择性的功能是脱颗粒,即急性释放预先储存的介质。在此,我们询问 CREB 是否有助于脱颗粒功能受体 FcεRI 和 MRGPRX2 的表达和功能。通过药理抑制(CREBi,666-15)或 RNA 干扰对 CREB 的干扰仅轻微影响了这些受体的表达,而 KIT 的表达则受到了强烈抑制。有趣的是,在 CREB 敲除后,MRGPRX2 的表面表达适度增加,而 MRGPRX2 依赖性外渗同时减少。FcεRI 的表达和功能受到一致的调节,但在功能水平上的影响更大。CREB衰减后,预形成的MC介质(色氨酸酶、组胺、β-己糖胺酶)仍保持相似,这表明颗粒的合成并不依赖于CREB的功能。总之,与 KIT 相反,FcεRI 和 MRGPRX2 适度依赖于不受干扰的 CREB 功能。然而,无论刺激如何,CREB 都是维持 MC 释放性所必需的,这意味着 CREB 可能是通过保护脱颗粒机制来发挥作用的。据我们所知,CREB 是第一个被发现以相反方向调节 MRGPRX2 表达和功能的因子。总之,古老的 TF 是皮肤 MCs 不可或缺的组成部分,它不仅能协调 MCs 的存活和增殖,还能调节 MCs 的分泌能力。
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引用次数: 0
Autophagy-Mediated Cellular Remodeling during Terminal Differentiation of Keratinocytes in the Epidermis and Skin Appendages. 表皮和皮肤附属物角质形成细胞末期分化过程中自噬介导的细胞重塑
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-10 DOI: 10.3390/cells13201675
Leopold Eckhart, Florian Gruber, Supawadee Sukseree

The epidermis of the skin and skin appendages, such as nails, hair and sebaceous glands, depend on a balance of cell proliferation and terminal differentiation in order to fulfill their functions at the interface of the body and the environment. The differentiation of epithelial cells of the skin, commonly referred to as keratinocytes, involves major remodeling processes that generate metabolically inactive cell remnants serving as building blocks of the epidermal stratum corneum, nail plates and hair shafts. Only sebaceous gland differentiation results in cell disintegration and holocrine secretion. A series of studies performed in the past decade have revealed that the lysosome-dependent intracellular degradation mechanism of autophagy is active during keratinocyte differentiation, and the blockade of autophagy significantly alters the properties of the differentiation products. Here, we present a model for the autophagy-mediated degradation of organelles and cytosolic proteins as an important contributor to cellular remodeling in keratinocyte differentiation. The roles of autophagy are discussed in comparison to alternative intracellular degradation mechanisms and in the context of programmed cell death as an integral end point of epithelial differentiation.

皮肤表皮层以及指甲、毛发和皮脂腺等皮肤附属物依赖于细胞增殖和终端分化的平衡,以实现其在身体和环境界面上的功能。皮肤上皮细胞(通常称为角质形成细胞)的分化涉及到主要的重塑过程,产生代谢不活跃的残余细胞,作为表皮角质层、甲板和毛干的组成部分。只有皮脂腺分化才会导致细胞解体和整体分泌。过去十年间进行的一系列研究发现,依赖于溶酶体的细胞内自噬降解机制在角质形成细胞分化过程中非常活跃,阻断自噬可显著改变分化产物的性质。在这里,我们提出了一个模型,说明自噬介导的细胞器和细胞膜蛋白降解是角质形成细胞分化过程中细胞重塑的重要因素。我们将自噬的作用与其他细胞内降解机制进行了比较,并结合作为上皮细胞分化不可或缺的终点的程序性细胞死亡进行了讨论。
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