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Exploring the black box of human reproduction: endometrial organoids and assembloids - generation, implantation modeling, and future clinical perspectives. 探索人类生殖的黑匣子:子宫内膜有机体和组装体--生成、植入模型和未来临床前景。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-23 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1482054
Mária Kleinová, Ivan Varga, Michaela Čeháková, Martin Valent, Martin Klein

One of the critical processes in human reproduction that is still poorly understood is implantation. The implantation of an early human embryo is considered a significant limitation of successful pregnancy. Therefore, researchers are trying to develop an ideal model of endometrium in vitro that can mimic the endometrial micro-environment in vivo as much as possible. The ultimate goal of endometrial modeling is to study the molecular interactions at the embryo-maternal interface and to use this model as an in vitro diagnostic tool for infertility. Significant progress has been made over the years in generating such models. The first experiments of endometrial modeling involved animal models, which are undoubtedly valuable, but at the same time, their dissimilarities with human tissue represent a significant obstacle to further research. This fact led researchers to develop basic monolayer coculture systems using uterine cells obtained from biopsies and, later on, complex and multilayer coculture models. With successful tissue engineering methods and various cultivation systems, it is possible to form endometrial two-dimensional (2D) models to three-dimensional (3D) organoids and novel assembloids that can recapitulate many aspects of endometrial tissue architecture and cell composition. These organoids have already helped to provide new insight into the embryo-endometrium interplay. The main aim of this paper is a comprehensive review of past and current approaches to endometrial model generation, their feasibility, and potential clinical application for infertility treatment.

人类生殖的关键过程之一是植入,但人们对这一过程的了解仍然很少。人类早期胚胎的植入被认为是成功怀孕的重要限制因素。因此,研究人员正试图在体外开发一种理想的子宫内膜模型,以尽可能模拟体内的子宫内膜微环境。子宫内膜建模的最终目标是研究胚胎与母体界面的分子相互作用,并将该模型用作不孕症的体外诊断工具。多年来,在生成此类模型方面取得了重大进展。最初的子宫内膜建模实验涉及动物模型,动物模型无疑是有价值的,但与此同时,动物模型与人体组织的不相似性也成为进一步研究的重大障碍。这一事实促使研究人员利用从活体组织中获取的子宫细胞开发了基本的单层细胞培养系统,后来又开发了复杂的多层细胞培养模型。有了成功的组织工程方法和各种培养系统,就有可能将子宫内膜二维(2D)模型发展成三维(3D)有机体和新型组装体,从而再现子宫内膜组织结构和细胞组成的许多方面。这些器官组织已经帮助人们对胚胎-子宫内膜的相互作用有了新的认识。本文的主要目的是全面回顾过去和当前生成子宫内膜模型的方法、其可行性以及在不孕症治疗中的潜在临床应用。
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引用次数: 0
Mechanosensory entities and functionality of endothelial cells. 内皮细胞的机械感觉实体和功能。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-23 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1446452
Claudia Tanja Mierke

The endothelial cells of the blood circulation are exposed to hemodynamic forces, such as cyclic strain, hydrostatic forces, and shear stress caused by the blood fluid's frictional force. Endothelial cells perceive mechanical forces via mechanosensors and thus elicit physiological reactions such as alterations in vessel width. The mechanosensors considered comprise ion channels, structures linked to the plasma membrane, cytoskeletal spectrin scaffold, mechanoreceptors, and junctional proteins. This review focuses on endothelial mechanosensors and how they alter the vascular functions of endothelial cells. The current state of knowledge on the dysregulation of endothelial mechanosensitivity in disease is briefly presented. The interplay in mechanical perception between endothelial cells and vascular smooth muscle cells is briefly outlined. Finally, future research avenues are highlighted, which are necessary to overcome existing limitations.

血液循环中的内皮细胞会受到血液动力的影响,如循环应变、静水压和由血液流体摩擦力引起的剪切应力。内皮细胞通过机械传感器感知机械力,从而引起生理反应,如血管宽度的改变。机械传感器包括离子通道、与质膜相连的结构、细胞骨架谱蛋白支架、机械感受器和连接蛋白。本综述将重点讨论内皮机械传感器及其如何改变内皮细胞的血管功能。本文简要介绍了疾病中内皮机械敏感性失调的知识现状。简要概述了内皮细胞和血管平滑肌细胞在机械感知方面的相互作用。最后,强调了克服现有局限性所必需的未来研究途径。
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引用次数: 0
Chondrocyte autophagy mechanism and therapeutic prospects in osteoarthritis. 骨关节炎的软骨细胞自噬机制和治疗前景
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-23 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1472613
Lan Li, Jie Li, Jian-Jiang Li, Huan Zhou, Xing-Wang Zhu, Ping-Heng Zhang, Bo Huang, Wen-Ting Zhao, Xiao-Feng Zhao, En-Sheng Chen

Osteoarthritis (OA) is the most common type of arthritis characterized by progressive cartilage degradation, with its pathogenesis closely related to chondrocyte autophagy. Chondrocytes are the only cells in articular cartilage, and the function of chondrocytes plays a vital role in maintaining articular cartilage homeostasis. Autophagy, an intracellular degradation system that regulates energy metabolism in cells, plays an incredibly important role in OA. During the early stages of OA, autophagy is enhanced in chondrocytes, acting as an adaptive mechanism to protect them from various environmental changes. However, with the progress of OA, chondrocyte autophagy gradually decreases, leading to the accumulation of damaged organelles and macromolecules within the cell, prompting chondrocyte apoptosis. Numerous studies have shown that cartilage degradation is influenced by the senescence and apoptosis of chondrocytes, which are associated with reduced autophagy. The relationship between autophagy, senescence, and apoptosis is complex. While autophagy is generally believed to inhibit cellular senescence and apoptosis to promote cell survival, recent studies have shown that some proteins are degraded by selective autophagy, leading to the secretion of the senescence-associated secretory phenotype (SASP) or increased SA-β-Gal activity in senescent cells within the damaged region of human OA cartilage. Autophagy activation may lead to different outcomes depending on the timing, duration, or type of its activation. Thus, our study explored the complex relationship between chondrocyte autophagy and OA, as well as the related regulatory molecules and signaling pathways, providing new insights for the future development of safe and effective drugs targeting chondrocyte autophagy to improve OA.

骨关节炎(OA)是最常见的关节炎类型,以软骨进行性退化为特征,其发病机制与软骨细胞自噬密切相关。软骨细胞是关节软骨中唯一的细胞,软骨细胞的功能对维持关节软骨的平衡起着至关重要的作用。自噬是一种调节细胞能量代谢的细胞内降解系统,在 OA 中发挥着极其重要的作用。在 OA 的早期阶段,软骨细胞中的自噬作用增强,这是一种保护软骨细胞免受各种环境变化影响的适应机制。然而,随着 OA 的进展,软骨细胞的自噬作用逐渐减弱,导致细胞内受损细胞器和大分子的积累,促使软骨细胞凋亡。大量研究表明,软骨降解受软骨细胞衰老和凋亡的影响,而软骨细胞衰老和凋亡与自噬减少有关。自噬、衰老和凋亡之间的关系非常复杂。虽然自噬通常被认为能抑制细胞衰老和凋亡以促进细胞存活,但最近的研究表明,一些蛋白质会被选择性自噬降解,导致衰老相关分泌表型(SASP)的分泌或人类OA软骨受损区域内衰老细胞的SA-β-Gal活性增加。自噬激活的时间、持续时间或类型不同,可能导致不同的结果。因此,我们的研究探讨了软骨细胞自噬与OA之间的复杂关系,以及相关的调控分子和信号通路,为将来开发针对软骨细胞自噬的安全有效的药物以改善OA提供了新的见解。
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引用次数: 0
First photon-counting detector computed tomography in the living crocodile: a 3D-Imaging study with special reference to amphibious hearing. 活体鳄鱼的首次光子计数探测器计算机断层扫描:三维成像研究,特别是两栖听觉。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-23 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1471983
Karl-Gunnar Melkersson, Hao Li, Helge Rask-Andersen

Background: Crocodiles are semi-aquatic animals well adapted to hear both on land and under water. Currently, there is limited information on how their amphibious hearing is accomplished. Here, we describe, for the first time, the ear anatomy in the living crocodile using photon-counting detector computed tomography (PCD-CT) and 3D rendering. We speculate on how crocodiles, despite their closed ear canals, can use tympanic hearing in water that also provides directional hearing.

Material and methods: A Cuban crocodile (Crocodylus rhombifer) underwent photon-counting detector computed tomography (PCD-CT), under anesthesia and spontaneous respiration. In addition two seven-month-old C. rhombifer and a juvenile Morelet´s crocodile (Crocodylus moreletii) underwent micro-computed tomography (µCT) and endoscopy. One adult Cuviérs dwarf caiman (Paleosuchus palpebrosus) was micro-dissected and video-recorded. Aeration, earflap, and middle ear morphology were evaluated and compared after 3D modeling.

Results and discussion: PCD-CT and µCT with 3D rendering and segmentation demonstrated the anatomy of the external and middle ears with high resolution in both living and expired crocodiles. Based on the findings and comparative examinations, we suggest that the superior earflap, by modulating the meatal recess together with local bone conduction, may implement tympanic hearing in submerged crocodiles, including directional hearing.

背景介绍鳄鱼是一种半水生动物,非常适合在陆地和水下都能听到声音。目前,有关鳄鱼两栖听觉如何实现的信息非常有限。在这里,我们首次使用光子计数探测器计算机断层扫描(PCD-CT)和三维渲染技术描述了活体鳄鱼的耳部解剖结构。我们推测,尽管鳄鱼的耳道是封闭的,但它们是如何在水中利用鼓膜听力同时提供定向听力的:一条古巴鳄鱼(Crocodylus rhombifer)在麻醉和自主呼吸状态下接受了光子计数探测器计算机断层扫描(PCD-CT)。此外,两只七个月大的鳄鱼和一只幼年莫莱特鳄(Crocodylus moreletii)也接受了微型计算机断层扫描(µCT)和内窥镜检查。对一条成年库维耶尔斯侏儒凯门鳄(Paleosuchus palpebrosus)进行了显微解剖和录像。结果和讨论:带有三维渲染和分割功能的 PCD-CT 和 µCT 高分辨率地展示了活体鳄鱼和过期鳄鱼的外耳和中耳解剖结构。根据研究结果和对比检查,我们认为上耳瓣通过调节肉腔凹陷和局部骨传导,可以实现水下鳄鱼的鼓室听力,包括定向听力。
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引用次数: 0
Single-cell transcriptome analysis identifies a novel tumor-associated macrophage subtype predicting better prognosis in pancreatic ductal adenocarcinoma. 单细胞转录组分析发现了一种新型肿瘤相关巨噬细胞亚型,可预测胰腺导管腺癌的较佳预后。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-23 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1466767
Xiaonan Wang, Dongyi Li, Bo Zhu, Zichun Hua

Background: Characterized by an immune-suppressive tumor microenvironment (TME), pancreatic ductal adenocarcinoma (PDAC) is well-known for its poor prognosis. Tumor associated macrophages (TAMs) play a critical role in PDAC TME. An in-depth understanding of TAMs is helpful to develop new strategies for immunotherapy.

Methods: A large number of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC were collected for systematic bioinformatics analysis. Characterize subtypes of TAMs at single-cell resolution and its effect on prognosis. Differential gene analysis and cell-cell communication were used to describe the effect on prognosis and validated by the TCGA dataset.

Results: We used two prognosis-favorable genes, SLC12A5 and ENPP2, to identify a benign M2-like TAMs (bM2-like TAMs), which shared similarities with C1QC + TAMs, CXCL9+ TAMs and CD169+ TAMs, by analyzing scRNA-seq data and bulk RNA data of PDAC. The bM2-like TAMs were revealed to promote T cell activation and proliferation through ALCAM/CD6 interaction. Meanwhile, the bM2-like TAMs were responsible for stroma modeling by altering αSMA+/αSMA-cell ratio. On the contrast, the rest of the M2-like TAMs were defined as malignant M2-like TAMs (mM2-like TAMs), partly overlapping with SPP1+ TAMs. mM2-like TAMs were revealed to promote tumor progression by secretion of MIF and SPP1.

Conclusion: Our study used two prognosis-favorable genes to divide M2-like TAMs of PDAC into anti-tumor bM2-like TAMs and pro-tumor mM2-like TAMs. The bM2-like TAMs activate T cells through ALCAM/CD6 and generate prognosis-favorable αSMA+ myofibroblasts through secreting TGFβ, which brings insight into heterogeneity of TAMs, prognosis prediction and immunotherapy of PDAC.

背景:胰腺导管腺癌(PDAC)以免疫抑制性肿瘤微环境(TME)为特征,以预后不良而闻名。肿瘤相关巨噬细胞(TAMs)在 PDAC TME 中发挥着关键作用。深入了解 TAMs 有助于开发新的免疫疗法策略:方法:收集大量 PDAC 的单细胞 RNA 测序数据和批量 RNA 测序数据,进行系统的生物信息学分析。以单细胞分辨率描述TAMs亚型及其对预后的影响。使用差异基因分析和细胞间通讯来描述对预后的影响,并通过 TCGA 数据集进行验证:通过分析PDAC的scRNA-seq数据和大量RNA数据,我们利用SLC12A5和ENPP2这两个对预后有利的基因鉴定出了良性M2样TAMs(bM2-like TAMs),它们与C1QC + TAMs、CXCL9+ TAMs和CD169+ TAMs有相似之处。研究发现,bM2 样 TAMs 可通过 ALCAM/CD6 相互作用促进 T 细胞的活化和增殖。同时,bM2-like TAMs通过改变αSMA+/αSMA-细胞的比例负责基质的建模。相比之下,其余的M2样TAMs被定义为恶性M2样TAMs(mM2样TAMs),与SPP1+ TAMs部分重叠:我们的研究利用两个对预后有利的基因将PDAC的M2样TAMs分为抗肿瘤的bM2样TAMs和促肿瘤的mM2样TAMs。bM2样TAMs通过ALCAM/CD6激活T细胞,并通过分泌TGFβ生成预后良好的αSMA+肌成纤维细胞,这为TAMs的异质性、预后预测和PDAC的免疫治疗带来了启示。
{"title":"Single-cell transcriptome analysis identifies a novel tumor-associated macrophage subtype predicting better prognosis in pancreatic ductal adenocarcinoma.","authors":"Xiaonan Wang, Dongyi Li, Bo Zhu, Zichun Hua","doi":"10.3389/fcell.2024.1466767","DOIUrl":"10.3389/fcell.2024.1466767","url":null,"abstract":"<p><strong>Background: </strong>Characterized by an immune-suppressive tumor microenvironment (TME), pancreatic ductal adenocarcinoma (PDAC) is well-known for its poor prognosis. Tumor associated macrophages (TAMs) play a critical role in PDAC TME. An in-depth understanding of TAMs is helpful to develop new strategies for immunotherapy.</p><p><strong>Methods: </strong>A large number of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC were collected for systematic bioinformatics analysis. Characterize subtypes of TAMs at single-cell resolution and its effect on prognosis. Differential gene analysis and cell-cell communication were used to describe the effect on prognosis and validated by the TCGA dataset.</p><p><strong>Results: </strong>We used two prognosis-favorable genes, SLC12A5 and ENPP2, to identify a benign M2-like TAMs (bM2-like TAMs), which shared similarities with C1QC + TAMs, CXCL9+ TAMs and CD169+ TAMs, by analyzing scRNA-seq data and bulk RNA data of PDAC. The bM2-like TAMs were revealed to promote T cell activation and proliferation through ALCAM/CD6 interaction. Meanwhile, the bM2-like TAMs were responsible for stroma modeling by altering αSMA+/αSMA-cell ratio. On the contrast, the rest of the M2-like TAMs were defined as malignant M2-like TAMs (mM2-like TAMs), partly overlapping with SPP1+ TAMs. mM2-like TAMs were revealed to promote tumor progression by secretion of MIF and SPP1.</p><p><strong>Conclusion: </strong>Our study used two prognosis-favorable genes to divide M2-like TAMs of PDAC into anti-tumor bM2-like TAMs and pro-tumor mM2-like TAMs. The bM2-like TAMs activate T cells through ALCAM/CD6 and generate prognosis-favorable αSMA+ myofibroblasts through secreting TGFβ, which brings insight into heterogeneity of TAMs, prognosis prediction and immunotherapy of PDAC.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590462","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
Metabolic biomarkers of neonatal sepsis: identification using metabolomics combined with machine learning. 新生儿败血症的代谢生物标志物:利用代谢组学与机器学习相结合进行鉴定。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-21 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1491065
Zhaonan Bian, Xinyi Zha, Yanru Chen, Xuting Chen, Zhanghua Yin, Min Xu, Zhongxiao Zhang, Jihong Qian
<p><strong>Background: </strong>Sepsis is a common disease associated with neonatal and infant mortality, and for diagnosis, blood culture is currently the gold standard method, but it has a low positivity rate and requires more than 2 days to develop. Meanwhile, unfortunately, the specific biomarkers for the early and timely diagnosis of sepsis in infants and for the determination of the severity of this disease are lacking in clinical practice.</p><p><strong>Methods: </strong>Samples from 18 sepsis infants with comorbidities, 25 sepsis infants without comorbidities, and 25 infants with noninfectious diseases were evaluated using a serum metabolomics approach based on liquid chromatography‒mass spectrometry (LC‒MS) technology. Differentially abundant metabolites were screened via multivariate statistical analysis. In addition, least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) analyses were conducted to identify the key metabolites in infants with sepsis and without infections. The random forest algorithm was applied to determine key differentially abundant metabolites between sepsis infants with and without comorbidities. Receiver operating characteristic (ROC) curves were generated for biomarker value testing. Finally, a metabolic pathway analysis was conducted to explore the metabolic and signaling pathways associated with the identified differentially abundant metabolites.</p><p><strong>Results: </strong>A total of 189 metabolites exhibited significant differences between infectious infants and noninfectious infants, while 137 distinct metabolites exhibited differences between septic infants with and without comorbidities. After screening for the key differentially abundant metabolites using LASSO and SVM-RFE analyses, hexylamine, psychosine sulfate, LysoPC (18:1 (9Z)/0:0), 2,4,6-tribromophenol, and 25-cinnamoyl-vulgaroside were retained for the diagnosis of infant sepsis. ROC curve analysis revealed that the area under the curve (AUC) was 0.9200 for hexylamine, 0.9749 for psychosine sulfate, 0.9684 for LysoPC (18:1 (9Z)/0:0), 0.7405 for 2,4,6-tribromophenol, 0.8893 for 25-cinnamoyl-vulgaroside, and 1.000 for the combination of all metabolites. When the septic infants with comorbidities were compared to those without comorbidities, four endogenous metabolites with the greatest importance were identified using the random forest algorithm, namely, 12-oxo-20-trihydroxy-leukotriene B4, dihydrovaltrate, PA (8:0/12:0), and 2-heptanethiol. The ROC curve analysis of these four key differentially abundant metabolites revealed that the AUC was 1 for all four metabolites. Pathway analysis indicated that phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, and porphyrin metabolism play important roles in infant sepsis.</p><p><strong>Conclusion: </strong>Serum metabolite profiles were identified, and machine learning was applied to identify the key differen
背景:败血症是一种与新生儿和婴儿死亡相关的常见疾病,目前,血液培养是诊断败血症的金标准方法,但其阳性率较低,且需要2天以上的时间才能培养出来。同时,令人遗憾的是,临床上还缺乏用于早期及时诊断婴儿败血症和判断该疾病严重程度的特异性生物标志物:方法:采用基于液相色谱-质谱联用技术(LC-MS)的血清代谢组学方法,对 18 名患有合并症的败血症婴儿、25 名无合并症的败血症婴儿和 25 名患有非感染性疾病的婴儿的样本进行了评估。通过多变量统计分析筛选出了含量不同的代谢物。此外,还进行了最小绝对收缩和选择算子(LASSO)和支持向量机递归特征消除(SVM-RFE)分析,以确定患败血症和未感染婴儿的关键代谢物。采用随机森林算法确定有合并症和无合并症脓毒症婴儿的主要不同含量代谢物。生成接收者操作特征曲线(ROC)用于生物标记物价值测试。最后,进行了代谢通路分析,以探索与已确定的差异丰富代谢物相关的代谢和信号通路:结果:共有189种代谢物在感染性婴儿和非感染性婴儿之间存在显著差异,137种代谢物在有合并症和无合并症的败血症婴儿之间存在差异。利用 LASSO 和 SVM-RFE 分析筛选出主要的差异丰富代谢物后,保留了己胺、硫酸精神苷、溶菌酶 (18:1(9Z)/0:0)、2,4,6-三溴苯酚和 25-肉桂酰-伏尔加苷用于婴儿败血症的诊断。ROC曲线分析显示,己胺的曲线下面积(AUC)为0.9200,硫酸精神苷为0.9749,溶菌酶(18:1 (9Z)/0:0)为0.9684,2,4,6-三溴苯酚为0.7405,25-肉桂酰伏尔加苷为0.8893,所有代谢物的组合为1.000。将有合并症的脓毒症婴儿与无合并症的脓毒症婴儿进行比较,利用随机森林算法确定了四种最重要的内源性代谢物,即 12-氧代-20-三羟基白三烯 B4、二氢缬氨酸、PA(8:0/12:0)和 2-庚硫醇。对这四种关键的差异丰度代谢物进行的 ROC 曲线分析表明,这四种代谢物的 AUC 均为 1。通路分析表明,苯丙氨酸、酪氨酸和色氨酸的生物合成、苯丙氨酸代谢和卟啉代谢在婴儿败血症中发挥着重要作用:通过对血清代谢物谱进行鉴定,并应用机器学习方法确定了有合并症的脓毒症婴儿、无合并症的脓毒症婴儿和无感染性疾病的婴儿中主要的不同含量的代谢物。这些研究结果有望促进婴儿败血症的早期诊断并确定疾病的严重程度。
{"title":"Metabolic biomarkers of neonatal sepsis: identification using metabolomics combined with machine learning.","authors":"Zhaonan Bian, Xinyi Zha, Yanru Chen, Xuting Chen, Zhanghua Yin, Min Xu, Zhongxiao Zhang, Jihong Qian","doi":"10.3389/fcell.2024.1491065","DOIUrl":"10.3389/fcell.2024.1491065","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Sepsis is a common disease associated with neonatal and infant mortality, and for diagnosis, blood culture is currently the gold standard method, but it has a low positivity rate and requires more than 2 days to develop. Meanwhile, unfortunately, the specific biomarkers for the early and timely diagnosis of sepsis in infants and for the determination of the severity of this disease are lacking in clinical practice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Samples from 18 sepsis infants with comorbidities, 25 sepsis infants without comorbidities, and 25 infants with noninfectious diseases were evaluated using a serum metabolomics approach based on liquid chromatography‒mass spectrometry (LC‒MS) technology. Differentially abundant metabolites were screened via multivariate statistical analysis. In addition, least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) analyses were conducted to identify the key metabolites in infants with sepsis and without infections. The random forest algorithm was applied to determine key differentially abundant metabolites between sepsis infants with and without comorbidities. Receiver operating characteristic (ROC) curves were generated for biomarker value testing. Finally, a metabolic pathway analysis was conducted to explore the metabolic and signaling pathways associated with the identified differentially abundant metabolites.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A total of 189 metabolites exhibited significant differences between infectious infants and noninfectious infants, while 137 distinct metabolites exhibited differences between septic infants with and without comorbidities. After screening for the key differentially abundant metabolites using LASSO and SVM-RFE analyses, hexylamine, psychosine sulfate, LysoPC (18:1 (9Z)/0:0), 2,4,6-tribromophenol, and 25-cinnamoyl-vulgaroside were retained for the diagnosis of infant sepsis. ROC curve analysis revealed that the area under the curve (AUC) was 0.9200 for hexylamine, 0.9749 for psychosine sulfate, 0.9684 for LysoPC (18:1 (9Z)/0:0), 0.7405 for 2,4,6-tribromophenol, 0.8893 for 25-cinnamoyl-vulgaroside, and 1.000 for the combination of all metabolites. When the septic infants with comorbidities were compared to those without comorbidities, four endogenous metabolites with the greatest importance were identified using the random forest algorithm, namely, 12-oxo-20-trihydroxy-leukotriene B4, dihydrovaltrate, PA (8:0/12:0), and 2-heptanethiol. The ROC curve analysis of these four key differentially abundant metabolites revealed that the AUC was 1 for all four metabolites. Pathway analysis indicated that phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, and porphyrin metabolism play important roles in infant sepsis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Serum metabolite profiles were identified, and machine learning was applied to identify the key differen","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575588","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
A differentiation protocol for generating pancreatic delta cells from human pluripotent stem cells. 从人类多能干细胞生成胰腺三角洲细胞的分化方案。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-18 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1490040
Tongran Zhang, Nannan Wang, Zhiying Liao, Jingyi Chen, Hao Meng, Haopeng Lin, Tao Xu, Lihua Chen, Ling-Qiang Zhu, Huisheng Liu

In this protocol, we detail a seven-stage differentiation methodology for generating pancreatic delta cells (SC-delta cells) from human pluripotent stem cells (hPSCs). In the first step, definitive endoderm is generated by activin A and CHIR99021, followed by induction of primitive gut tube and posterior foregut by treatment with FGF7, SANT1, LDN193189, PdBU, and retinoic acid (RA). The subsequent endocrine generation and directed SC-delta cell induction is achieved by a combined treatment of the FGF7 with FGF2 during stage 4 and 5, together with RA, XXI, ALK5 inhibitor II, SANT1, Betacellulin and LDN193189. The planar cultivation is converted to a suspended system after stage 5, allowing cells to aggregate into delta cell-containing spheroids. The differentiation takes approximately 4-5 weeks for delta cell generation and an additional 1-2 weeks for cell expansion and evaluation. We believe that this amenable and simplified protocol can provide a stable source of SC-delta cells from efficient differentiation, facilitating further investigation of the physiological role of delta cells as well as refinement of islet cell therapeutic strategies.

在本方案中,我们详细介绍了用人多能干细胞(hPSCs)生成胰腺三角洲细胞(SC-三角洲细胞)的七阶段分化方法。第一步,通过活化素A和CHIR99021生成明确的内胚层,然后通过FGF7、SANT1、LDN193189、PdBU和维甲酸(RA)诱导原始肠管和后前肠。在第 4 和第 5 阶段,FGF7 与 FGF2 以及 RA、XXI、ALK5 抑制剂 II、SANT1、Betacellulin 和 LDN193189 的联合处理可实现随后的内分泌生成和定向 SC-delta 细胞诱导。第 5 阶段后,平面培养转换为悬浮系统,使细胞聚集成含有 delta 细胞的球体。产生三角细胞的分化过程大约需要 4-5 周,细胞扩增和评估则需要 1-2 周。我们相信,这种简便易行的方案能为高效分化提供稳定的 SC 三角洲细胞来源,有助于进一步研究三角洲细胞的生理作用,并完善胰岛细胞治疗策略。
{"title":"A differentiation protocol for generating pancreatic delta cells from human pluripotent stem cells.","authors":"Tongran Zhang, Nannan Wang, Zhiying Liao, Jingyi Chen, Hao Meng, Haopeng Lin, Tao Xu, Lihua Chen, Ling-Qiang Zhu, Huisheng Liu","doi":"10.3389/fcell.2024.1490040","DOIUrl":"10.3389/fcell.2024.1490040","url":null,"abstract":"<p><p>In this protocol, we detail a seven-stage differentiation methodology for generating pancreatic delta cells (SC-delta cells) from human pluripotent stem cells (hPSCs). In the first step, definitive endoderm is generated by activin A and CHIR99021, followed by induction of primitive gut tube and posterior foregut by treatment with FGF7, SANT1, LDN193189, PdBU, and retinoic acid (RA). The subsequent endocrine generation and directed SC-delta cell induction is achieved by a combined treatment of the FGF7 with FGF2 during stage 4 and 5, together with RA, XXI, ALK5 inhibitor II, SANT1, Betacellulin and LDN193189. The planar cultivation is converted to a suspended system after stage 5, allowing cells to aggregate into delta cell-containing spheroids. The differentiation takes approximately 4-5 weeks for delta cell generation and an additional 1-2 weeks for cell expansion and evaluation. We believe that this amenable and simplified protocol can provide a stable source of SC-delta cells from efficient differentiation, facilitating further investigation of the physiological role of delta cells as well as refinement of islet cell therapeutic strategies.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568136","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
N-acetyl-L-cysteine reduces testis ROS in obese fathers but fails in protecting offspring from acquisition of epigenetic traits at cyp19a1 and IGF11/H19 ICR loci. N-乙酰-L-半胱氨酸可减少肥胖父亲睾丸中的ROS,但不能保护后代免受cyp19a1和IGF11/H19 ICR位点表观遗传特征的影响。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-18 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1450580
Arianna Pastore, Nadia Badolati, Francesco Manfrevola, Serena Sagliocchi, Valentina Laurenzi, Giorgia Musto, Veronica Porreca, Melania Murolo, Teresa Chioccarelli, Roberto Ciampaglia, Valentina Vellecco, Mariarosaria Bucci, Monica Dentice, Gilda Cobellis, Mariano Stornaiuolo

Introduction: Paternal nutrition before conception has a marked impact on offspring's risk of developing metabolic disorders during adulthood. Research on human cohorts and animal models has shown that paternal obesity alters sperm epigenetics (DNA methylation, protamine-to-histone replacement, and non-coding RNA content), leading to adverse health outcomes in the offspring. So far, the mechanistic events that translate paternal nutrition into sperm epigenetic changes remain unclear. High-fat diet (HFD)-driven paternal obesity increases gonadic Reactive Oxygen Species (ROS), which modulate enzymes involved in epigenetic modifications of DNA during spermatogenesis. Thus, the gonadic pool of ROS might be responsible for transducing paternal health status to the zygote through germ cells.

Methods: The involvement of ROS in paternal intergenerational transmission was assessed by modulating the gonadic ROS content in male mice. Testicular oxidative stress induced by HFD was counterbalanced by N-acetylcysteine (NAC), an antioxidant precursor of GSH. The sires were divided into four feeding groups: i) control diet; ii) HFD; iii) control diet in the presence of NAC; and iv) HFD in the presence of NAC. After 8 weeks, males were mated with females that were fed a control diet. Antioxidant treatment was then evaluated in terms of preventing the HFD-induced transmission of dysmetabolic traits from obese fathers to their offspring. The offspring were weaned onto a regular control diet until week 16 and then underwent metabolic evaluation. The methylation status of the genomic region IGFII/H19 and cyp19a1 in the offspring gDNA was also assessed using Sanger sequencing and methylation-dependent qPCR.

Results: Supplementation with NAC protected sires from HFD-induced weight gain, hyperinsulinemia, and glucose intolerance. NAC reduced oxidative stress in the gonads of obese fathers and improved sperm viability. However, NAC did not prevent the transmission of epigenetic modifications from father to offspring. Male offspring of HFD-fed fathers, regardless of NAC treatment, exhibited hyperinsulinemia, glucose intolerance, and hypoandrogenism. Additionally, they showed altered methylation at the epigenetically controlled loci IGFII/H19 and cy19a1.

Conclusion: Although NAC supplementation improved the health status and sperm quality of HFD-fed male mice, it did not prevent the epigenetic transmission of metabolic disorders to their offspring. Different NAC dosages and antioxidants other than NAC might represent alternatives to stop the intergenerational transmission of paternal dysmetabolic traits.

简介受孕前父亲的营养状况对后代成年后患代谢性疾病的风险有显著影响。对人类队列和动物模型的研究表明,父亲肥胖会改变精子的表观遗传学(DNA甲基化、原胺-组蛋白置换和非编码RNA含量),从而导致后代的不良健康结果。迄今为止,将父亲的营养转化为精子表观遗传学变化的机理事件仍不清楚。高脂饮食(HFD)导致的父亲肥胖会增加性腺活性氧(ROS),而ROS会调节精子发生过程中参与DNA表观遗传修饰的酶。因此,生殖腺的ROS池可能负责通过生殖细胞将父亲的健康状况传递给胚胎:方法:通过调节雄性小鼠性腺中的 ROS 含量,评估了 ROS 在父系代际传递中的作用。N-乙酰半胱氨酸(NAC)是一种抗氧化剂 GSH 的前体,它能抵消高氟酸睾丸氧化应激。雄性小鼠被分为四个饲喂组:i) 对照组;ii) 高纤维食物组;iii) NAC存在下的对照组;iv) NAC存在下的高纤维食物组。8 周后,雄性与喂食对照组饲料的雌性交配。然后评估抗氧化剂治疗是否能防止肥胖的父亲将高氟酸诱导的代谢紊乱性状遗传给后代。后代断奶后食用常规控制饮食至第 16 周,然后进行代谢评估。此外,还利用桑格测序和甲基化依赖性 qPCR 评估了子代 gDNA 中基因组区域 IGFII/H19 和 cyp19a1 的甲基化状态:结果:补充 NAC 可保护母鼠免受高纤维食物诱导的体重增加、高胰岛素血症和葡萄糖不耐受的影响。NAC 降低了肥胖父亲性腺中的氧化应激,提高了精子活力。然而,NAC 并不能阻止表观遗传修饰从父亲传给后代。无论 NAC 治疗与否,喂食高密度脂蛋白胆固醇的父亲的雄性后代都表现出高胰岛素血症、葡萄糖不耐受和雄性激素过低。此外,他们还表现出表观遗传控制位点 IGFII/H19 和 cy19a1 的甲基化改变:结论:虽然补充 NAC 可改善高密度脂蛋白喂养雄性小鼠的健康状况和精子质量,但并不能防止代谢紊乱的表观遗传传递给后代。不同剂量的 NAC 和 NAC 以外的抗氧化剂可能是阻止父代代谢紊乱性状代际传递的替代品。
{"title":"N-acetyl-L-cysteine reduces testis ROS in obese fathers but fails in protecting offspring from acquisition of epigenetic traits at <i>cyp19a1</i> and <i>IGF11/H19</i> ICR loci.","authors":"Arianna Pastore, Nadia Badolati, Francesco Manfrevola, Serena Sagliocchi, Valentina Laurenzi, Giorgia Musto, Veronica Porreca, Melania Murolo, Teresa Chioccarelli, Roberto Ciampaglia, Valentina Vellecco, Mariarosaria Bucci, Monica Dentice, Gilda Cobellis, Mariano Stornaiuolo","doi":"10.3389/fcell.2024.1450580","DOIUrl":"10.3389/fcell.2024.1450580","url":null,"abstract":"<p><strong>Introduction: </strong>Paternal nutrition before conception has a marked impact on offspring's risk of developing metabolic disorders during adulthood. Research on human cohorts and animal models has shown that paternal obesity alters sperm epigenetics (DNA methylation, protamine-to-histone replacement, and non-coding RNA content), leading to adverse health outcomes in the offspring. So far, the mechanistic events that translate paternal nutrition into sperm epigenetic changes remain unclear. High-fat diet (HFD)-driven paternal obesity increases gonadic Reactive Oxygen Species (ROS), which modulate enzymes involved in epigenetic modifications of DNA during spermatogenesis. Thus, the gonadic pool of ROS might be responsible for transducing paternal health status to the zygote through germ cells.</p><p><strong>Methods: </strong>The involvement of ROS in paternal intergenerational transmission was assessed by modulating the gonadic ROS content in male mice. Testicular oxidative stress induced by HFD was counterbalanced by N-acetylcysteine (NAC), an antioxidant precursor of GSH. The sires were divided into four feeding groups: i) control diet; ii) HFD; iii) control diet in the presence of NAC; and iv) HFD in the presence of NAC. After 8 weeks, males were mated with females that were fed a control diet. Antioxidant treatment was then evaluated in terms of preventing the HFD-induced transmission of dysmetabolic traits from obese fathers to their offspring. The offspring were weaned onto a regular control diet until week 16 and then underwent metabolic evaluation. The methylation status of the genomic region <i>IGFII/H19</i> and <i>cyp19a1</i> in the offspring gDNA was also assessed using Sanger sequencing and methylation-dependent qPCR.</p><p><strong>Results: </strong>Supplementation with NAC protected sires from HFD-induced weight gain, hyperinsulinemia, and glucose intolerance. NAC reduced oxidative stress in the gonads of obese fathers and improved sperm viability. However, NAC did not prevent the transmission of epigenetic modifications from father to offspring. Male offspring of HFD-fed fathers, regardless of NAC treatment, exhibited hyperinsulinemia, glucose intolerance, and hypoandrogenism. Additionally, they showed altered methylation at the epigenetically controlled loci <i>IGFII/H19</i> and <i>cy19a1.</i></p><p><strong>Conclusion: </strong>Although NAC supplementation improved the health status and sperm quality of HFD-fed male mice, it did not prevent the epigenetic transmission of metabolic disorders to their offspring. Different NAC dosages and antioxidants other than NAC might represent alternatives to stop the intergenerational transmission of paternal dysmetabolic traits.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568141","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
Guanine nucleotide exchange factors and colon neoplasia. 鸟嘌呤核苷酸交换因子与结肠肿瘤。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-18 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1489321
Lea-Pearl Njei, Natalia Sampaio Moura, Alyssa Schledwitz, Kelly Griffiths, Kunrong Cheng, Jean-Pierre Raufman

Despite many diagnostic and therapeutic advances, colorectal cancer (CRC) remains the second leading cause of cancer death for men and women in the United States. Alarmingly, for reasons currently unknown, the demographics of this disease have shifted towards a younger population. Hence, understanding the molecular mechanisms underlying CRC initiation and progression and leveraging these findings for therapeutic purposes remains a priority. Here, we review critically the evidence that canonical and noncanonical actions of guanine nucleotide exchange factors (GEFs) play important roles in CRC evolution. Rho GEF GTPases, which switch between inactive GDP-bound and active GTP-bound states, are commonly overexpressed and activated in a variety of cancers, including CRC, and may be tractable therapeutic targets. In addition to comprehensively reviewing this field, we focus on Rho/Rac GEFs that are involved in regulating key functions of normal and neoplastic cells like cell polarity, vesicle trafficking, cell cycle regulation, and transcriptional dynamics. Prime examples of such Rho/Rac GEFs include βPak-interacting exchange factor (βPix), a Rho family GEF for Cdc42/Rac1, Tiam1, GEF-H1, RGNEF, and other GEFs implicated in CRC development and progression. Throughout this analysis, we explore how these findings fill key gaps in knowledge regarding the molecular basis of colon carcinogenesis and how they may be leveraged to treat advanced CRC. Lastly, we address potential future directions for research into the role of GEFs as CRC biomarkers and therapeutic targets. In this regard, leveraging the noncanonical actions of GEFs appears to provide a relatively unexplored opportunity requiring further investigation.

尽管在诊断和治疗方面取得了许多进步,但结直肠癌(CRC)仍然是美国男性和女性癌症死亡的第二大原因。令人担忧的是,由于目前尚不清楚的原因,这种疾病的发病人群已转向年轻人。因此,了解 CRC 发病和进展的分子机制并将这些发现用于治疗仍是当务之急。在此,我们对鸟嘌呤核苷酸交换因子(GEFs)的规范和非规范作用在 CRC 演变中发挥重要作用的证据进行了批判性回顾。Rho GEF GTPases 可在非活性 GDP 结合态和活性 GTP 结合态之间切换,在包括 CRC 在内的多种癌症中普遍存在过表达和激活现象,可能是可治疗的靶点。除了全面回顾这一领域,我们还重点研究了参与调节正常细胞和肿瘤细胞关键功能的 Rho/Rac GEFs,如细胞极性、囊泡贩运、细胞周期调控和转录动态。这类 Rho/Rac GEF 的主要例子包括 Cdc42/Rac1 的 Rho 家族 GEF βPak-interacting 交换因子(βPix)、Tiam1、GEF-H1、RGNEF 以及与 CRC 的发展和进程有关的其他 GEF。通过分析,我们探讨了这些发现如何填补了结肠癌发生的分子基础方面的知识空白,以及如何利用这些发现治疗晚期 CRC。最后,我们探讨了 GEFs 作为 CRC 生物标记物和治疗靶点的潜在未来研究方向。在这方面,利用 GEFs 的非规范作用似乎提供了一个相对尚未开发的机会,需要进一步研究。
{"title":"Guanine nucleotide exchange factors and colon neoplasia.","authors":"Lea-Pearl Njei, Natalia Sampaio Moura, Alyssa Schledwitz, Kelly Griffiths, Kunrong Cheng, Jean-Pierre Raufman","doi":"10.3389/fcell.2024.1489321","DOIUrl":"10.3389/fcell.2024.1489321","url":null,"abstract":"<p><p>Despite many diagnostic and therapeutic advances, colorectal cancer (CRC) remains the second leading cause of cancer death for men and women in the United States. Alarmingly, for reasons currently unknown, the demographics of this disease have shifted towards a younger population. Hence, understanding the molecular mechanisms underlying CRC initiation and progression and leveraging these findings for therapeutic purposes remains a priority. Here, we review critically the evidence that canonical and noncanonical actions of guanine nucleotide exchange factors (GEFs) play important roles in CRC evolution. Rho GEF GTPases, which switch between inactive GDP-bound and active GTP-bound states, are commonly overexpressed and activated in a variety of cancers, including CRC, and may be tractable therapeutic targets. In addition to comprehensively reviewing this field, we focus on Rho/Rac GEFs that are involved in regulating key functions of normal and neoplastic cells like cell polarity, vesicle trafficking, cell cycle regulation, and transcriptional dynamics. Prime examples of such Rho/Rac GEFs include βPak-interacting exchange factor (βPix), a Rho family GEF for Cdc42/Rac1, Tiam1, GEF-H1, RGNEF, and other GEFs implicated in CRC development and progression. Throughout this analysis, we explore how these findings fill key gaps in knowledge regarding the molecular basis of colon carcinogenesis and how they may be leveraged to treat advanced CRC. Lastly, we address potential future directions for research into the role of GEFs as CRC biomarkers and therapeutic targets. In this regard, leveraging the noncanonical actions of GEFs appears to provide a relatively unexplored opportunity requiring further investigation.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570928","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
Glioma-associated oncogene homolog 1 in breast invasive carcinoma: a comprehensive bioinformatic analysis and experimental validation. 乳腺浸润癌中的胶质瘤相关癌基因同源物 1:全面的生物信息学分析和实验验证。
IF 4.6 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-17 eCollection Date: 2024-01-01 DOI: 10.3389/fcell.2024.1478478
Teng Qi, Yujie Hu, Junhao Wan, Bo Zhao, Jinsuo Xiao, Jie Liu, Ye Cheng, He Wu, Yonggang Lv, Fuqing Ji

Background: Breast cancer, despite significant advancements in treatment, remains a major cause of cancer-related deaths among women. Immunotherapy, an emerging therapeutic strategy, offers promise for better outcomes, particularly through the modulation of immune functions. Glioma-Associated Oncogene Homolog 1 (GLI1), a transcription factor implicated in cancer biology, has shown varying roles in different cancers. However, its immunoregulatory functions in breast invasive carcinoma (BRCA) remain elusive. The current study aimed to unravel the expression patterns and immune-regulatory roles of GLI1 in BRCA.

Methods: Utilizing multiple bioinformatic platforms (TIMER2.0, GEPIA2, and R packages) based on The Cancer Genome Atlas (TCGA) and/or Genotype-Tissue Expression (GTEx) databases, we analyzed the expression of GLI1 in BRCA and its pan-cancer expression profiles. We further validated these findings by conducting qPCR and immunohistochemical staining on clinical BRCA samples. Kaplan-Meier analysis and Cox proportional hazards regression were performed to assess the prognostic value of GLI1. Additionally, the association between GLI1 expression and immune infiltration within the tumor immune microenvironment (TMIE) was examined.

Results: The findings reveal dysregulated expression of GLI1 in numerous cancers, with a significant decrease observed in BRCA. High GLI1 expression indicated better survival outcomes and was correlated with the age and stage of BRCA patients. GLI1 was involved in immune status, as evidenced by its strong correlations with immune and stromal scores and the infiltration levels of multiple immune cells. Meanwhile, GLI1 was co-expressed with multiple immune-related genes, and high GLI1 expression was associated with the activation of immune-related pathways, such as binding to proteasome and mismatch repair and retinol metabolism signaling pathways. Additionally, the differential expression of GLI1 may be related to the effect of immunotherapy on CTLA-4, PD-1, and other signals, and can effectively predict the immune efficacy.

Conclusion: Our study underscores the critical role of GLI1 in BRCA, both as a potential tumor suppressor and an immune regulator. The association between GLI1 expression and favorable prognosis suggests its potential as a prognostic biomarker and immunotherapeutic target in BRCA.

背景:尽管乳腺癌的治疗取得了重大进展,但它仍然是妇女死于癌症的主要原因。免疫疗法是一种新兴的治疗策略,有望取得更好的疗效,特别是通过调节免疫功能。胶质瘤相关癌基因同源物 1(GLI1)是一种与癌症生物学有关联的转录因子,在不同癌症中的作用各不相同。然而,它在乳腺浸润癌(BRCA)中的免疫调节功能仍然难以捉摸。本研究旨在揭示 GLI1 在 BRCA 中的表达模式和免疫调节作用:利用基于癌症基因组图谱(TCGA)和/或基因型-组织表达(GTEx)数据库的多种生物信息平台(TIMER2.0、GEPIA2和R软件包),我们分析了GLI1在BRCA中的表达及其泛癌表达谱。通过对临床 BRCA 样本进行 qPCR 和免疫组化染色,我们进一步验证了这些发现。为了评估 GLI1 的预后价值,我们进行了 Kaplan-Meier 分析和 Cox 比例危险度回归。此外,还研究了GLI1表达与肿瘤免疫微环境(TMIE)中免疫浸润之间的关系:结果:研究结果表明,GLI1在多种癌症中表达失调,在BRCA中的表达明显下降。GLI1的高表达预示着更好的生存结果,并与BRCA患者的年龄和分期相关。GLI1 与免疫和基质评分以及多种免疫细胞的浸润水平密切相关,这证明它与免疫状态有关。同时,GLI1与多个免疫相关基因共表达,GLI1的高表达与免疫相关通路的激活有关,如与蛋白酶体、错配修复和视黄醇代谢信号通路的结合。此外,GLI1的差异表达可能与免疫疗法对CTLA-4、PD-1等信号的影响有关,可以有效预测免疫效果:我们的研究强调了 GLI1 在 BRCA 中的关键作用,它既是潜在的肿瘤抑制因子,也是免疫调节因子。结论:我们的研究强调了 GLI1 在 BRCA 中的关键作用,它既是潜在的肿瘤抑制因子,又是免疫调节因子。GLI1 的表达与良好预后之间的关联表明,它有可能成为 BRCA 的预后生物标志物和免疫治疗靶点。
{"title":"Glioma-associated oncogene homolog 1 in breast invasive carcinoma: a comprehensive bioinformatic analysis and experimental validation.","authors":"Teng Qi, Yujie Hu, Junhao Wan, Bo Zhao, Jinsuo Xiao, Jie Liu, Ye Cheng, He Wu, Yonggang Lv, Fuqing Ji","doi":"10.3389/fcell.2024.1478478","DOIUrl":"10.3389/fcell.2024.1478478","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer, despite significant advancements in treatment, remains a major cause of cancer-related deaths among women. Immunotherapy, an emerging therapeutic strategy, offers promise for better outcomes, particularly through the modulation of immune functions. Glioma-Associated Oncogene Homolog 1 (GLI1), a transcription factor implicated in cancer biology, has shown varying roles in different cancers. However, its immunoregulatory functions in breast invasive carcinoma (BRCA) remain elusive. The current study aimed to unravel the expression patterns and immune-regulatory roles of GLI1 in BRCA.</p><p><strong>Methods: </strong>Utilizing multiple bioinformatic platforms (TIMER2.0, GEPIA2, and R packages) based on The Cancer Genome Atlas (TCGA) and/or Genotype-Tissue Expression (GTEx) databases, we analyzed the expression of GLI1 in BRCA and its pan-cancer expression profiles. We further validated these findings by conducting qPCR and immunohistochemical staining on clinical BRCA samples. Kaplan-Meier analysis and Cox proportional hazards regression were performed to assess the prognostic value of GLI1. Additionally, the association between GLI1 expression and immune infiltration within the tumor immune microenvironment (TMIE) was examined.</p><p><strong>Results: </strong>The findings reveal dysregulated expression of GLI1 in numerous cancers, with a significant decrease observed in BRCA. High GLI1 expression indicated better survival outcomes and was correlated with the age and stage of BRCA patients. GLI1 was involved in immune status, as evidenced by its strong correlations with immune and stromal scores and the infiltration levels of multiple immune cells. Meanwhile, GLI1 was co-expressed with multiple immune-related genes, and high GLI1 expression was associated with the activation of immune-related pathways, such as binding to proteasome and mismatch repair and retinol metabolism signaling pathways. Additionally, the differential expression of GLI1 may be related to the effect of immunotherapy on CTLA-4, PD-1, and other signals, and can effectively predict the immune efficacy.</p><p><strong>Conclusion: </strong>Our study underscores the critical role of GLI1 in BRCA, both as a potential tumor suppressor and an immune regulator. The association between GLI1 expression and favorable prognosis suggests its potential as a prognostic biomarker and immunotherapeutic target in BRCA.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557570","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
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