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Enhanced Late INa Induces Intracellular Ion Disturbances and Automatic Activity in the Guinea Pig Pulmonary Vein Cardiomyocytes 增强的晚期 INa 诱导豚鼠肺静脉心肌细胞的细胞内离子紊乱和自动活动
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.3390/ijms25168688
Taro Saito, Mahiru Suzuki, Aiko Ohba, Shogo Hamaguchi, Iyuki Namekata, Hikaru Tanaka
The effects of enhanced late INa, a persistent component of the Na+ channel current, on the intracellular ion dynamics and the automaticity of the pulmonary vein cardiomyocytes were studied with fluorescent microscopy. Anemonia viridis toxin II (ATX- II), an enhancer of late INa, caused increases in the basal Na+ and Ca2+ concentrations, increases in the number of Ca2+ sparks and Ca2+ waves, and the generation of repetitive Ca2+ transients. These phenomena were inhibited by eleclazine, a blocker of the late INa; SEA0400, an inhibitor of the Na+/Ca2+ exchanger (NCX); H89, a protein kinase A (PKA) inhibitor; and KN-93, a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor. These results suggest that enhancement of late INa in the pulmonary vein cardiomyocytes causes disturbance of the intracellular ion environment through activation of the NCX and Ca2+-dependent enzymes. Such mechanisms are probably involved in the ectopic electrical activity of the pulmonary vein myocardium.
荧光显微镜研究了增强的晚期INa(Na+通道电流的持久成分)对肺静脉心肌细胞胞内离子动力学和自动性的影响。晚期 INa 增强剂 Anemonia viridis 毒素 II(ATX- II)会导致基础 Na+ 和 Ca2+ 浓度增加、Ca2+ 火花和 Ca2+ 波的数量增加以及重复 Ca2+ 瞬态的产生。这些现象受到了晚期INa阻滞剂eleclazine、Na+/Ca2+交换器(NCX)抑制剂SEA0400、蛋白激酶A(PKA)抑制剂H89和Ca2+/钙调蛋白依赖性蛋白激酶II(CaMKII)抑制剂KN-93的抑制。这些结果表明,肺静脉心肌细胞晚期 INa 的增强会通过激活 NCX 和 Ca2+ 依赖性酶导致细胞内离子环境紊乱。这些机制可能参与了肺静脉心肌的异位电活动。
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引用次数: 0
Recent Technologies towards Diagnostic and Therapeutic Applications of Circulating Nucleic Acids in Colorectal Cancers 循环核酸在结直肠癌诊断和治疗中的最新应用技术
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.3390/ijms25168703
Jun Chung, Sophie Xiao, Yang Gao, Y. Soung
Liquid biopsy has emerged as a promising noninvasive approach for colorectal cancer (CRC) management. This review focuses on technologies detecting circulating nucleic acids, specifically circulating tumor DNA (ctDNA) and circulating RNA (cfRNA), as CRC biomarkers. Recent advancements in molecular technologies have enabled sensitive and specific detection of tumor-derived genetic material in bodily fluids. These include quantitative real-time PCR, digital PCR, next-generation sequencing (NGS), and emerging nanotechnology-based methods. For ctDNA analysis, techniques such as BEAMing and droplet digital PCR offer high sensitivity in detecting rare mutant alleles, while NGS approaches provide comprehensive genomic profiling. cfRNA detection primarily utilizes qRT-PCR arrays, microarray platforms, and RNA sequencing for profiling circulating microRNAs and discovering novel RNA biomarkers. These technologies show potential in early CRC detection, treatment response monitoring, minimal residual disease assessment, and tumor evolution tracking. However, challenges remain in standardizing procedures, optimizing detection limits, and establishing clinical utility across disease stages. This review summarizes current circulating nucleic acid detection technologies, their CRC applications, and discusses future directions for clinical implementation.
液体活检已成为治疗结直肠癌(CRC)的一种前景广阔的无创方法。本综述重点介绍检测循环核酸(特别是循环肿瘤 DNA (ctDNA) 和循环 RNA (cfRNA))作为 CRC 生物标记物的技术。分子技术的最新进展实现了对体液中来自肿瘤的遗传物质进行灵敏而特异的检测。这些技术包括定量实时 PCR、数字 PCR、新一代测序 (NGS) 和基于纳米技术的新兴方法。cfRNA 检测主要利用 qRT-PCR 阵列、微阵列平台和 RNA 测序来分析循环微 RNA 和发现新型 RNA 生物标志物。这些技术在早期 CRC 检测、治疗反应监测、最小残留病评估和肿瘤演变跟踪方面显示出潜力。然而,在标准化程序、优化检测限和建立跨疾病阶段的临床实用性方面仍存在挑战。本综述总结了目前的循环核酸检测技术及其在 CRC 中的应用,并讨论了临床应用的未来方向。
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引用次数: 0
Long-Term Oral Administration of Hyperimmune Egg-Based IgY-Rich Formulations Induces Mucosal Immune Response and Systemic Increases of Cytokines Involved in Th2- and Th17-Type Immune Responses in C57BL/6 Mice 长期口服高免疫蛋基富含 IgY 的制剂可诱导 C57BL/6 小鼠的粘膜免疫反应以及参与 Th2 型和 Th17 型免疫反应的细胞因子的全身性增加
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.3390/ijms25168701
V. Nastasa, B. Minea, Aurelian-Sorin Pasca, Andra-Cristina Bostanaru-Iliescu, Alina-Elena Stefan, D. Gologan, Robert Capota, L. Foia, Mihai Mares
Three hyperimmune egg-based formulations rich in immunoglobulin Y (IgY) were orally administered (daily, for up to 90 days) to C57BL/6 mice that were not microbially challenged. The serum levels of 32 cytokines were quantified every 30 days. Histopathology, hematology, and serum biochemistry investigations were also performed. As a sign of increased immune activity, lymphohistiocytic infiltrates were detected in the digestive tract and the liver after 30, 60, and 90 days of treatment. These infiltrates were also present in the lungs after 30 and 60 days, but not at 90 days. Blood analysis indicated systemic inflammation after 30 days of treatment: increases in pro-inflammatory cytokines, glycemia, total serum proteins, ALT, and ALP. After 60 and 90 days of treatment, the analyzed blood parameters showed mixed signs of both increased and decreased inflammation. The increased cytokines, which varied with formulation and time of exposure, indicated a combination of mostly Th17- and Th2-type immune responses. As the mice were healthy and housed in standardized sanitary conditions, and were not microbially challenged, the data were consistent with an interaction of IgY with the gut-associated lymphoid tissue as the main mechanism of action. This interaction generated a local immune response, which subsequently induced a systemic response.
给未受到微生物挑战的 C57BL/6 小鼠口服三种富含免疫球蛋白 Y(IgY)的超免疫蛋基制剂(每天一次,最长持续 90 天)。每 30 天对血清中 32 种细胞因子的水平进行量化。此外,还进行了组织病理学、血液学和血清生化检查。治疗 30 天、60 天和 90 天后,在消化道和肝脏中检测到淋巴组织细胞浸润,这是免疫活性增强的标志。肺部在治疗 30 天和 60 天后也出现了淋巴组织细胞浸润,但在治疗 90 天后没有发现。血液分析表明,治疗 30 天后会出现全身性炎症:促炎细胞因子、血糖、血清总蛋白、谷丙转氨酶和谷草转氨酶升高。治疗 60 天和 90 天后,分析的血液参数显示出炎症增加和减少的混合迹象。增加的细胞因子随配方和接触时间的不同而变化,表明主要是 Th17 型和 Th2 型免疫反应的结合。由于小鼠身体健康,饲养条件符合卫生标准,没有受到微生物的挑战,因此数据表明 IgY 与肠道相关淋巴组织的相互作用是主要的作用机制。这种相互作用产生了局部免疫反应,随后诱发了全身反应。
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引用次数: 0
One-Step Genetic Modification by Embryonic Doral Aorta Injection of Adenoviral CRISPR/Cas9 Vector in Chicken 通过在鸡胚胎多拉主动脉注射腺病毒 CRISPR/Cas9 载体实现一步式基因修饰
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.3390/ijms25168692
Chao Qin, Shengyao Jiang, Ke Xu, Jianshen Zhu, Liyuan Wang, Wenhao Yang, Fuquan Xiao, Kaixuan Yang, Qizhong Huang, He Meng
In the avian species, genetic modification by cell nuclear transfer is infeasible due to its unique reproductive system. The in vitro primordial germ cell modification approach is difficult and cumbersome, although it is the main method of genetic modification in chickens. In the present study, the adenoviral CRISPR/Cas9 vector was directly microinjected into the dorsal aorta of chicken embryos to achieve in vivo genetic modification. The results demonstrated that keratin 75-like 4 (KRT75L4), a candidate gene crucial for feather development, was widely knocked out, and an 8bp deletion was the predominant mutation that occurred in multiple tissues in chimeras, particularly in the gonad (2.63–11.57%). As we expected, significant modification was detected in the sperm of G0 (0.16–4.85%), confirming the potential to generate homozygous chickens and establishing this vector as a simple and effective method for genetic modification in avian species.
在禽类物种中,由于其独特的生殖系统,通过细胞核转移进行基因改造是不可行的。体外原始生殖细胞修饰方法虽然是鸡遗传修饰的主要方法,但难度大,操作繁琐。本研究将腺病毒 CRISPR/Cas9 载体直接显微注射到鸡胚的背主动脉中,实现体内基因修饰。结果表明,对羽毛发育至关重要的候选基因角蛋白75样4(KRT75L4)被广泛敲除,8bp缺失是嵌合体多个组织中发生的主要突变,尤其是在性腺中(2.63-11.57%)。正如我们所预期的那样,在 G0 的精子中也检测到了明显的基因修饰(0.16-4.85%),这证实了产生同基因鸡的潜力,并将这种载体确立为禽类物种基因修饰的一种简单而有效的方法。
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引用次数: 0
Trajectory Analysis in Single-Particle Tracking: From Mean Squared Displacement to Machine Learning Approaches 单粒子跟踪中的轨迹分析:从均方位移到机器学习方法
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-08 DOI: 10.3390/ijms25168660
Chiara Schirripa Spagnolo, S. Luin
Single-particle tracking is a powerful technique to investigate the motion of molecules or particles. Here, we review the methods for analyzing the reconstructed trajectories, a fundamental step for deciphering the underlying mechanisms driving the motion. First, we review the traditional analysis based on the mean squared displacement (MSD), highlighting the sometimes-neglected factors potentially affecting the accuracy of the results. We then report methods that exploit the distribution of parameters other than displacements, e.g., angles, velocities, and times and probabilities of reaching a target, discussing how they are more sensitive in characterizing heterogeneities and transient behaviors masked in the MSD analysis. Hidden Markov Models are also used for this purpose, and these allow for the identification of different states, their populations and the switching kinetics. Finally, we discuss a rapidly expanding field—trajectory analysis based on machine learning. Various approaches, from random forest to deep learning, are used to classify trajectory motions, which can be identified by motion models or by model-free sets of trajectory features, either previously defined or automatically identified by the algorithms. We also review free software available for some of the analysis methods. We emphasize that approaches based on a combination of the different methods, including classical statistics and machine learning, may be the way to obtain the most informative and accurate results.
单粒子跟踪是研究分子或粒子运动的一项强大技术。在这里,我们回顾了分析重建轨迹的方法,这是破译驱动运动的基本机制的第一步。首先,我们回顾了基于平均位移平方(MSD)的传统分析方法,强调了有时被忽视的可能影响结果准确性的因素。然后,我们报告了利用位移以外的参数分布(如角度、速度、到达目标的时间和概率)的方法,讨论了这些方法如何更灵敏地描述 MSD 分析中被掩盖的异质性和瞬态行为。隐马尔可夫模型也可用于此目的,这些模型可以识别不同的状态、状态群和切换动力学。最后,我们将讨论基于机器学习的快速扩展的场轨迹分析。从随机森林到深度学习等各种方法都被用来对轨迹运动进行分类,这些运动可以通过运动模型或无模型的轨迹特征集来识别,这些特征集可以是之前定义的,也可以是算法自动识别的。我们还回顾了可用于某些分析方法的免费软件。我们强调,基于不同方法(包括经典统计学和机器学习)组合的方法可能是获得最翔实、最准确结果的途径。
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引用次数: 0
Evaluation of 73 Enlisted Patients for Liver Transplant with Unknown Etiology Reveals a Late-Diagnosed Case of Lysosomal Acid Lipase Deficiency 对 73 名病因不明的入伍肝移植患者进行评估,发现一例晚期诊断的溶酶体酸性脂肪酶缺乏症病例
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-08 DOI: 10.3390/ijms25168648
K. L. M. Bastos, B. Stephan, B. Linnenkamp, Larissa Sampaio de Athayde Costa, Fabiana Roberto Lima, L. M. L. Carvalho, R. Honjo, U. Tannuri, A. Tannuri, C. A. Kim
Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP—Brazil) who were subjected to LAL activity measurement and LIPA Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years. The LALD diagnosis confirmation was conducted at 24 years old due to low levels of LAL enzyme activity. The causal homozygous variant LIPA(NM_000235.4):c.266T>C(p.Leu89Pro) was identified, but the patient had already undergone his first LT at 18 years with several rejection episodes. Despite beginning treatment with sebelipase alfa at 26 years old (total of five infusions), this patient died at 28 years from complications after his second liver transplant. LALD is an important differential diagnosis in cases presenting with hepatomegaly, elevated liver enzymes, and dyslipidemia. Detecting low/absent LAL activity and identifying the LIPA causal variant are essential for diagnosis and specific treatment, as well as for appropriate genetic counseling. Early diagnosis, along with sebelipase alfa therapy, may improve the prognosis of affected patients.
溶酶体酸性脂肪酶缺乏症(LALD)有严重的幼年发病型(沃尔曼病)和晚期发病型胆固醇酯贮积症(CESD)之分,这两种疾病都是由双倍拷贝LIPA致病变体引起的常染色体隐性遗传病。我们对巴西儿童研究所(HCFMUSP-Brazil)招募的73名肝移植(LT)患者进行了评估,对他们进行了LAL活性测定和LIPA Sanger测序分析,结果只有一人被确诊为LALD。这名 LALD 患者在 4 个月大时出现反复腹泻、发育不良、肝肿大和血脂异常,13 岁时肝功能衰竭。由于 LAL 酶活性水平较低,该患者在 24 岁时被确诊为 LALD。患者在18岁时已经接受了首次LT手术,并出现了数次排斥反应。尽管该患者在26岁时开始接受sebelipase alfa治疗(共输注5次),但在28岁时死于第二次肝移植后的并发症。在出现肝脏肿大、肝酶升高和血脂异常的病例中,LALD是一个重要的鉴别诊断。检测低/无 LAL 活性和确定 LIPA 致病变体对于诊断和具体治疗以及适当的遗传咨询至关重要。早期诊断和sebelipase alfa治疗可改善患者的预后。
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引用次数: 0
The Effect of Phototherapy on Systemic Inflammation Measured with Serum Vitamin D-Binding Protein and hsCRP in Patients with Inflammatory Skin Disease 用血清维生素 D 结合蛋白和 hsCRP 测定光疗对炎症性皮肤病患者全身炎症的影响
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-08 DOI: 10.3390/ijms25168632
Andrea Elmelid, Maria Siekkeri Vandikas, M. Gillstedt, Mikael Alsterholm, A. Osmancevic
Vitamin D plays a role in inflammatory skin disease, but the exact mechanisms and the clinical significance remain unclear. According to the free hormone hypothesis, it is the free concentration of 25-hydroxy vitamin D (25(OH)D) that is biologically active. Vitamin D-binding protein (DBP) acts as the major transporter of vitamin D in the circulation, and DBP concentration defines the free 25(OH)D levels. DBP levels are elevated in various inflammatory conditions, including psoriasis. Narrowband-ultraviolet B (NB-UVB) is the most widely used phototherapy and is an established first-line treatment for psoriasis and atopic dermatitis (AD), often used before proceeding to systemic treatment. The aim of this study was to investigate the influence of NB-UVB phototherapy on DBP and high-sensitivity C-reactive protein (hsCRP) levels, as markers of systemic inflammation, in inflammatory skin disease. Thirty adults (psoriasis (n = 20) and AD (n = 10)) were treated with NB-UVB. Serum DBP, hsCRP, total and free 25(OH)D, and 1,25-dihydroxy vitamin D (1,25(OH)2D) were measured before and after NB-UVB. Disease severity was assessed with Psoriasis Area and Severity Index (PASI), SCORing Atopic Dermatitis (SCORAD), and Visual Analogue Scale (VAS). DBP decreased in psoriasis patients and varied with no clear trend in AD patients. HsCRP decreased in both groups, but this did not reach statistical significance. PASI, SCORAD, and VAS improved, and vitamin D levels increased after NB-UVB. Sub-analysis indicated a better response to NB-UVB for patients with vitamin D deficiency and insufficiency compared to vitamin D-sufficient patients. The decrease in DBP after NB-UVB in psoriasis patients suggests a potential systemic anti-inflammatory effect of phototherapy. Measurement of vitamin D levels may potentially serve as a tool to identify patients who would derive the greatest benefit from NB-UVB phototherapy.
维生素 D 在炎症性皮肤病中发挥作用,但其确切机制和临床意义仍不清楚。根据游离激素假说,25-羟基维生素 D(25(OH)D)的游离浓度才具有生物活性。维生素 D 结合蛋白(DBP)是血液循环中维生素 D 的主要转运体,DBP 的浓度决定了游离 25(OH)D 的水平。在包括银屑病在内的各种炎症中,DBP 水平都会升高。窄带紫外线 B(NB-UVB)是应用最广泛的光疗方法,也是治疗银屑病和特应性皮炎(AD)的公认一线疗法,通常在进行全身治疗前使用。本研究旨在探讨 NB-UVB 光疗对炎症性皮肤病患者全身炎症标志物 DBP 和高敏 C 反应蛋白(hsCRP)水平的影响。30 名成年人(银屑病(20 人)和注意力缺失症(10 人))接受了 NB-UVB 治疗。在使用 NB-UVB 之前和之后测量了血清 DBP、hsCRP、总 25(OH)D 和游离 25(OH)D 以及 1,25-二羟基维生素 D (1,25(OH)2D)。疾病严重程度通过银屑病面积和严重程度指数(PASI)、SCORing 特应性皮炎(SCORAD)和视觉模拟量表(VAS)进行评估。银屑病患者的 DBP 有所下降,而 AD 患者的 DBP 有所变化,无明显趋势。两组患者的 HsCRP 均有所下降,但未达到统计学意义。NB-UVB治疗后,PASI、SCORAD和VAS有所改善,维生素D水平有所提高。子分析表明,与维生素 D 充足的患者相比,维生素 D 缺乏和不足的患者对 NB-UVB 的反应更好。银屑病患者接受 NB-UVB 治疗后,DBP 有所下降,这表明光疗具有潜在的全身抗炎作用。测量维生素 D 水平可作为一种工具,用于确定哪些患者能从 NB-UVB 光疗中获得最大益处。
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引用次数: 0
Helicase HELQ: Molecular Characters Fit for DSB Repair Function 螺旋酶 HELQ:适合 DSB 修复功能的分子角色
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-08 DOI: 10.3390/ijms25168634
Yuqin Zhao, Kai-Yuan Hou, Yu Liu, Yinan Na, Chao Li, Haoyuan Luo, Hailong Wang
The protein sequence and spatial structure of DNA helicase HELQ are highly conserved, spanning from archaea to humans. Aside from its helicase activity, which is based on DNA binding and translocation, it has also been recently reconfirmed that human HELQ possesses DNA–strand–annealing activity, similar to that of the archaeal HELQ homolog StoHjm. These biochemical functions play an important role in regulating various double–strand break (DSB) repair pathways, as well as multiple steps in different DSB repair processes. HELQ primarily facilitates repair in end–resection–dependent DSB repair pathways, such as homologous recombination (HR), single–strand annealing (SSA), microhomology–mediated end joining (MMEJ), as well as the sub-pathways’ synthesis–dependent strand annealing (SDSA) and break–induced replication (BIR) within HR. The biochemical functions of HELQ are significant in end resection and its downstream pathways, such as strand invasion, DNA synthesis, and gene conversion. Different biochemical activities are required to support DSB repair at various stages. This review focuses on the functional studies of the biochemical roles of HELQ during different stages of diverse DSB repair pathways.
从古生菌到人类,DNA螺旋酶HELQ的蛋白质序列和空间结构高度保守。除了以 DNA 结合和转位为基础的螺旋酶活性外,最近还证实人类 HELQ 具有 DNA 链断开活性,与古生菌 HELQ 同源物 StoHjm 相似。这些生化功能在调节各种双链断裂(DSB)修复途径以及不同DSB修复过程的多个步骤中发挥着重要作用。HELQ 主要促进同源重组(HR)、单链退火(SSA)、微组蛋白介导的末端连接(MMEJ)等依赖末端切除的 DSB 修复途径的修复,以及 HR 中的子途径合成依赖性链退火(SDSA)和断裂诱导复制(BIR)。HELQ 的生化功能在末端切除及其下游途径(如链侵入、DNA 合成和基因转换)中具有重要作用。支持不同阶段的 DSB 修复需要不同的生化活动。本综述将重点关注 HELQ 在不同 DSB 修复途径的不同阶段所发挥的生化作用的功能研究。
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引用次数: 0
The Impact of Serum/Plasma Proteomics on SARS-CoV-2 Diagnosis and Prognosis 血清/血浆蛋白质组学对 SARS-CoV-2 诊断和预后的影响
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-08 DOI: 10.3390/ijms25168633
M. D’Amato, M. A. Grignano, P. Iadarola, T. Rampino, M. Gregorini, S. Viglio
While COVID-19’s urgency has diminished since its emergence in late 2019, it remains a significant public health challenge. Recent research reveals that the molecular intricacies of this virus are far more complex than initially understood, with numerous post-translational modifications leading to diverse proteoforms and viral particle heterogeneity. Mass spectrometry-based proteomics of patient serum/plasma emerges as a promising complementary approach to traditional diagnostic methods, offering insights into SARS-CoV-2 protein dynamics and enhancing understanding of the disease and its long-term consequences. This article highlights key findings from three years of pandemic-era proteomics research. It delves into biomarker discovery, diagnostic advancements, and drug development efforts aimed at monitoring COVID-19 onset and progression and exploring treatment options. Additionally, it examines global protein abundance and post-translational modification profiling to elucidate signaling pathway alterations and protein-protein interactions during infection. Finally, it explores the potential of emerging multi-omics analytic strategies in combatting SARS-CoV-2.
尽管 COVID-19 自 2019 年底出现以来,其紧迫性已有所减弱,但它仍然是一项重大的公共卫生挑战。最新研究发现,这种病毒的分子结构远比人们最初了解的要复杂得多,大量的翻译后修饰导致了多种蛋白形式和病毒颗粒的异质性。基于质谱技术的病人血清/血浆蛋白质组学是对传统诊断方法的一种很有前途的补充方法,可以深入了解 SARS-CoV-2 蛋白质的动态变化,加深对该疾病及其长期后果的认识。本文重点介绍了三年来大流行病时期蛋白质组学研究的主要发现。文章深入探讨了生物标志物的发现、诊断方面的进展以及旨在监测 COVID-19 发病和进展并探索治疗方案的药物开发工作。此外,它还研究了全球蛋白质丰度和翻译后修饰剖析,以阐明感染期间信号通路的改变和蛋白质之间的相互作用。最后,它还探讨了新兴的多组学分析策略在抗击 SARS-CoV-2 方面的潜力。
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引用次数: 0
Mechanisms of Cell Death Induced by Erastin in Human Ovarian Tumor Cells 艾拉汀诱导人类卵巢肿瘤细胞死亡的机制
IF 4.9 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-08 DOI: 10.3390/ijms25168666
Birandra K. Sinha, Carri Murphy, Shalyn M. Brown, Brian B. Silver, Erik J. Tokar, Carl D. Bortner
Erastin (ER) induces cell death through the formation of reactive oxygen species (ROS), resulting in ferroptosis. Ferroptosis is characterized by an accumulation of ROS within the cell, leading to an iron-dependent oxidative damage-mediated cell death. ER-induced ferroptosis may have potential as an alternative for ovarian cancers that have become resistant due to the presence of Ras mutation or multi-drug resistance1 (MDR1) gene expression. We used K-Ras mutant human ovarian tumor OVCAR-8 and NCI/ADR-RES, P-glycoprotein-expressing cells, to study the mechanisms of ER-induced cell death. We used these cell lines as NCI/ADR-RES cells also overexpresses superoxide dismutase, catalase, glutathione peroxidase, and transferase compared to OVCAR-8 cells, leading to the detoxification of reactive oxygen species. We found that ER was similarly cytotoxic to both cells. Ferrostatin, an inhibitor of ferroptosis, reduced ER cytotoxicity. In contrast, RSL3 (RAS-Selective Ligand3), an inducer of ferroptosis, markedly enhanced ER cytotoxicity in both cells. More ROS was detected in OVCAR-8 cells than NCI/ADR-RES cells, causing more malondialdehyde (MDA) formation in OVCAR-8 cells than in NCI/ADR-RES cells. RSL3, which was more cytotoxic to NCI/ADR-RES cells, significantly enhanced MDA formation in both cells, suggesting that glutathione peroxidase 4 (GPX4) was involved in ER-mediated ferroptosis. ER treatment modulated several ferroptosis-related genes (e.g., CHAC1, GSR, and HMOX1/OX1) in both cells. Our study indicates that ER-induced ferroptotic cell death may be mediated similarly in both NCI/ADR-RES and OVCAR-8 cells. Additionally, our results indicate that ER is not a substrate of P-gp and that combinations of ER and RSL3 may hold promise as more effective treatment routes for ovarian cancers, including those that are resistant to other current therapeutic agents.
依拉斯汀(ER)通过形成活性氧(ROS)诱导细胞死亡,从而导致铁变态反应。铁变态反应的特点是细胞内 ROS 的积累,导致铁依赖性氧化损伤介导的细胞死亡。对于因存在 Ras 突变或多重耐药1(MDR1)基因表达而产生耐药性的卵巢癌,ER 诱导的铁变态反应可能是一种潜在的替代疗法。我们利用K-Ras突变的人类卵巢肿瘤OVCAR-8和表达P-糖蛋白的NCI/ADR-RES细胞来研究ER诱导细胞死亡的机制。我们使用这些细胞系,因为与 OVCAR-8 细胞相比,NCI/ADR-RES 细胞也过量表达超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶和转移酶,从而导致活性氧的解毒。我们发现,ER 对这两种细胞具有类似的细胞毒性。铁蛋白酶抑制剂 Ferrostatin 可降低 ER 的细胞毒性。与此相反,RSL3(RAS-选择性配体3)--一种铁变态反应诱导剂--明显增强了ER在两种细胞中的细胞毒性。在 OVCAR-8 细胞中检测到的 ROS 多于 NCI/ADR-RES 细胞,导致 OVCAR-8 细胞中丙二醛(MDA)的形成多于 NCI/ADR-RES 细胞。RSL3对NCI/ADR-RES细胞的细胞毒性更强,它能显著增强两种细胞中MDA的形成,这表明谷胱甘肽过氧化物酶4(GPX4)参与了ER介导的铁变态反应。ER处理调节了两种细胞中与铁突变相关的几个基因(如CHAC1、GSR和HMOX1/OX1)。我们的研究表明,ER诱导的铁突变细胞死亡可能在NCI/ADR-RES和OVCAR-8细胞中具有相似的介导作用。此外,我们的研究结果表明,ER 并不是 P-gp 的底物,ER 和 RSL3 的组合可能有望成为卵巢癌(包括对目前其他治疗药物耐药的卵巢癌)更有效的治疗途径。
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