Life sciences最新文献_第2页

Hypoxanthine ameliorates diet-induced insulin resistance by improving hepatic lipid metabolism and gluconeogenesis via AMPK/mTOR/PPARα pathway 次黄嘌呤通过AMPK/mTOR/PPARα途径改善肝脏脂质代谢和葡萄糖生成，从而改善饮食引起的胰岛素抵抗。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123096

Aim

Insulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism.

Methods

We utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism.

Key findings

Hx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway.

Significance

This study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications.

目的：胰岛素抵抗（IR）是一种与2型糖尿病和代谢综合征相关的重要代谢紊乱。本研究探讨了次黄嘌呤（Hx）--一种嘌呤代谢物和尿酸前体--在改善胰岛素抵抗、调节肝脏葡萄糖和脂质代谢方面的潜力：我们利用体外 IR-HepG2 细胞和体内饮食诱导 IR 小鼠来研究 Hx 的影响。用 Hx 处理 HepG2 细胞，以评估其对葡萄糖生成和脂质沉积的影响。应用基于活性的蛋白质谱分析（ABPP）来确定 Hx 靶蛋白及其相关通路。体内研究包括给红外小鼠注射 Hx，然后评估红外相关指数，探讨肝糖和脂质代谢的潜在调节机制：Hx干预以剂量依赖的方式大大降低了IR-HepG2细胞的葡萄糖生成和脂质沉积，而不影响细胞活力。ABPP 确定了参与脂肪酸和丙酮酸代谢的关键 Hx 靶蛋白。在体内，Hx 治疗降低了 IR 的严重程度，这体现在 HOMA-IR、空腹血糖和血清脂质谱的降低上。组织学评估证实肝脏脂质沉积减少。机理研究发现，Hx 通过 AMPK/mTOR/PPARα 通路抑制肝糖原生成和脂肪酸合成，促进脂肪酸氧化：本研究揭示了 Hx 在调节肝脏代谢中的新作用，为红外及相关代谢紊乱提供了一种潜在的治疗策略。研究结果为进一步研究嘌呤代谢物在代谢调节中的作用及其临床意义奠定了基础。

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引用次数: 0

Inhibition of the FOXO1–ROCK1 axis mitigates cardiomyocyte injury under chronic hypoxia in Tetralogy of Fallot by maintaining mitochondrial quality control 通过维持线粒体质量控制，抑制 FOXO1-ROCK1 轴可减轻法洛氏四联症慢性缺氧对心肌细胞的损伤。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123084

Introduction

Persistent chronic myocardial hypoxia causes disturbances in mitochondrial quality control (MQC), ultimately leading to increased cardiomyocyte injury in patients with Tetralogy of Fallot (TOF). The present study aimed to identify the key effector molecules of cardiomyocyte injury under chronic hypoxia in TOF.

Methods

Clinical data from TOF patients were collected and whole transcriptome sequencing was performed on myocardial samples. Chronic hypoxia models were established in cardiac-specific knockout mice and cardiomyocytes, and a series of molecular experiments were used to determine the specific mechanisms involved.

Results

Clinical cohort data and whole-transcriptome sequencing analysis of myocardial samples from TOF patients revealed that forkhead box O1 (FOXO1) plays an important role in chronic hypoxic cardiomyocyte injury. In a model of chronic hypoxia established in FOXO1 cardiac-specific knockout mice and FOXO1 gene-deficient cardiomyocytes, the AMPK signaling pathway regulates the expression of FOXO1, which in turn disrupts MQC by regulating the transcriptional activation of Rho-associated protein kinase 1 (ROCK1), and increasing the production of mitochondrial ROS, thereby exacerbating damage to cardiomyocytes. Excessive reactive oxygen species (ROS) production during MQC dysfunction further activates Cox7a2L to increase the assembly of the respiratory chain supercomplex. In addition, we found that miR-27b-3p partially binds to the 3′ untranslated region of FOXO1 to exert a protective effect.

Conclusions

Maintenance of MQC under chronic hypoxia is achieved through a series of injury-protection mechanisms, suggesting that FOXO1 inhibition may be crucial for future mitigation of chronic hypoxic cardiomyocyte injury in TOF.

导言：持续的慢性心肌缺氧会引起线粒体质量控制（MQC）紊乱，最终导致法洛氏四联症（TOF）患者心肌细胞损伤加重。本研究旨在确定TOF患者在慢性缺氧条件下心肌细胞损伤的关键效应分子：方法：收集 TOF 患者的临床数据，并对心肌样本进行全转录组测序。在心脏特异性基因敲除小鼠和心肌细胞中建立慢性缺氧模型，并通过一系列分子实验来确定其中的具体机制：结果：临床队列数据和对TOF患者心肌样本的全转录组测序分析表明，叉头盒O1（FOXO1）在慢性缺氧性心肌细胞损伤中起着重要作用。在FOXO1心脏特异性基因敲除小鼠和FOXO1基因缺陷心肌细胞建立的慢性缺氧模型中，AMPK信号通路调节FOXO1的表达，而FOXO1又通过调节Rho相关蛋白激酶1（ROCK1）的转录激活破坏MQC，增加线粒体ROS的产生，从而加剧心肌细胞的损伤。MQC 功能障碍时产生的过多活性氧（ROS）会进一步激活 Cox7a2L，增加呼吸链超级复合物的组装。此外，我们还发现，miR-27b-3p与FOXO1的3'非翻译区部分结合，从而发挥保护作用：结论：MQC在慢性缺氧条件下的维持是通过一系列损伤保护机制实现的，这表明抑制FOXO1可能是未来缓解TOF慢性缺氧性心肌细胞损伤的关键。

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引用次数: 0

TFF3 and PVRL2 co-targeting identified by multi-omics approach as an effective cancer immunosuppression strategy 通过多组学方法发现 TFF3 和 PVRL2 共同靶向是一种有效的癌症免疫抑制策略。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123113

Background

The immunosuppressive tumour microenvironment (TME) plays a critical role in cancer progression and relapse by significantly influencing cancer pathogenesis through autocrine and paracrine signalling. Trefoil factor 3 (TFF3), a secreted protein, has been implicated in modulating the TME to promote cancer advancement. Herein, we investigated the potential association between TFF3 and key immunosuppressive TME components to distinguish a co-targetable oncotherapeutic strategy.

Methods

The TFF3-PVRL2 association were identified and investigated by integrating multiple bioinformatic-tools. The virtual compound screening for PVRL2 inhibitors was done with EasyVS. The TFF3-PVRL2 protein-level correlation was validated by immunoblotting, and the effectiveness of co-inhibiting TFF3 and PVRL2 was assessed using siRNA and AMPC (a TFF3 inhibitor).

Results

Analysis of the TISIDB database revealed a positive correlation between TFF3 and PVRL2 mRNA levels across multiple cancer types. This correlation was confirmed at the protein level through immunoblot analysis. Further evaluation using TCGA pan-cancer datasets demonstrated that TFF3 and PVRL2 interact to establish an immunosuppressive TME, promoting cancer progression in BRCA, LUAD, PAAD, PRAD, and STAD. Enrichment analyses of positively correlated genes, PPI network hub proteins, and ceRNA networks involving TFF3 and PVRL2, conducted using LinkedOmics, STRING, and Cytoscape, provided insights into their potential co-functions in cancer. A cell-based assay was performed to evaluate the combined therapeutic efficacy of targeting both, TFF3 and PVRL2 and virtual screening identified potential drugs for inhibiting PVRL2.

Conclusion

PVRL2 has emerged as a promising immunoinhibitory target with significant associations with TFF3 and represents a key co-targetable molecule for effective oncotherapeutic strategies.

背景：免疫抑制性肿瘤微环境（TME）通过自分泌和旁分泌信号显著影响癌症发病机制，在癌症进展和复发中发挥着关键作用。三叶草因子 3（TFF3）是一种分泌蛋白，被认为可调节肿瘤微环境以促进癌症进展。在此，我们研究了TFF3与TME关键免疫抑制成分之间的潜在关联，以区分可共同靶向的肿瘤治疗策略：方法：通过整合多种生物信息学工具，发现并研究了TFF3与PVRL2的关联。利用 EasyVS 对 PVRL2 抑制剂进行虚拟化合物筛选。通过免疫印迹验证了TFF3-PVRL2蛋白水平的相关性，并使用siRNA和AMPC（一种TFF3抑制剂）评估了共同抑制TFF3和PVRL2的效果：结果：对 TISIDB 数据库的分析表明，在多种癌症类型中，TFF3 和 PVRL2 mRNA 水平呈正相关。这种相关性通过免疫印迹分析在蛋白质水平上得到了证实。使用 TCGA 泛癌症数据集进行的进一步评估表明，TFF3 和 PVRL2 相互作用建立了免疫抑制 TME，促进了 BRCA、LUAD、PAAD、PRAD 和 STAD 中癌症的进展。利用LinkedOmics、STRING和Cytoscape对涉及TFF3和PVRL2的正相关基因、PPI网络中心蛋白和ceRNA网络进行了富集分析，从而深入了解了它们在癌症中的潜在共同功能。通过基于细胞的试验评估了靶向 TFF3 和 PVRL2 的综合疗效，并通过虚拟筛选确定了抑制 PVRL2 的潜在药物：结论：PVRL2与TFF3密切相关，是一种很有前景的免疫抑制靶点，是有效肿瘤治疗策略的关键共靶分子。

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引用次数: 0

Advancing thyroid disease research: The role and potential of zebrafish model 推进甲状腺疾病研究：斑马鱼模型的作用和潜力

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123099

Thyroid disorders significantly affect human metabolism, cardiovascular function, skeletal health, and reproductive systems, presenting a complex challenge due to their multifactorial nature. Understanding the underlying mechanisms and developing novel therapeutic approaches require appropriate models. Zebrafish, with their genetic tractability, short life cycle, and physiological relevance, have emerged as a valuable model for investigating thyroid diseases. This review provides a comprehensive analysis of the zebrafish thyroid gland's structure and function, explores its application in modeling thyroid pathologies such as hypothyroidism, hyperthyroidism, and thyroid cancer, and discusses current limitations and possible improvements. Furthermore, it outlines future directions for zebrafish-based research, focusing on enhancing the model's relevance to human thyroid disease and its potential to expedite the development of clinical therapies.

甲状腺疾病严重影响人类的新陈代谢、心血管功能、骨骼健康和生殖系统，由于其多因素的性质，带来了复杂的挑战。了解其潜在机制和开发新型治疗方法需要适当的模型。斑马鱼具有遗传易感性、生命周期短和生理相关性等特点，已成为研究甲状腺疾病的重要模型。这篇综述全面分析了斑马鱼甲状腺的结构和功能，探讨了它在甲状腺功能减退症、甲状腺功能亢进症和甲状腺癌等甲状腺疾病模型中的应用，并讨论了目前的局限性和可能的改进。此外，它还概述了基于斑马鱼的研究的未来方向，重点是提高该模型与人类甲状腺疾病的相关性及其加快临床疗法开发的潜力。

引用次数: 0

Unveiling the roles of LEMD proteins in cellular processes 揭示 LEMD 蛋白在细胞过程中的作用。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123116

Proteins localized in the inner nuclear membrane (INM) engage in various fundamental cellular processes via their interactions with outer nuclear membrane (ONM) proteins and nuclear lamina. LAP2-emerin-MAN1 domain (LEMD) family proteins, predominantly positioned in the INM, participate in the maintenance of INM functions, including the reconstruction of the nuclear envelope during mitosis, mechanotransduction, and gene transcriptional modulation. Malfunction of LEMD proteins leads to severe tissue-restricted diseases, which may manifest as fatal deformities and defects. In this review, we summarize the significant roles of LEMD proteins in cellular processes, explains the mechanisms of LEMD protein-related diseases, and puts forward questions in less-explored areas like details in tissue-restricted phenotypes. It intends to sort out previous works about LEMD proteins and pave way for future researchers who might discover deeper mechanisms of and better treatment strategies for LEMD protein-related diseases.

定位于核内膜（INM）的蛋白质通过与核外膜（ONM）蛋白质和核薄层的相互作用参与各种基本的细胞过程。LAP2-emerin-MAN1结构域（LEMD）家族蛋白主要定位于INM，参与维持INM的功能，包括有丝分裂过程中核包膜的重建、机械传导和基因转录调控。LEMD 蛋白的功能失常会导致严重的组织限制性疾病，可能表现为致命的畸形和缺陷。在这篇综述中，我们总结了LEMD蛋白在细胞过程中的重要作用，解释了LEMD蛋白相关疾病的发生机制，并提出了组织受限表型细节等较少探讨的领域的问题。该报告旨在梳理以往有关LEMD蛋白的研究成果，为未来研究人员发现LEMD蛋白相关疾病的深层机制和更好的治疗策略铺平道路。

引用次数: 0

Exosomes from human bone marrow MSCs alleviate PD-1/PD-L1 inhibitor-induced myocardial injury in melanoma mice by regulating macrophage polarization and pyroptosis 来自人骨髓间充质干细胞的外泌体通过调节巨噬细胞的极化和热解作用减轻了PD-1/PD-L1抑制剂诱发的黑色素瘤小鼠心肌损伤。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123108

Myocarditis, which can be triggered by immune checkpoint inhibitor (ICI) treatment, represents a critical and severe adverse effect observed in cancer therapy. Thus, elucidating the underlying mechanism and developing effective strategies to mitigate its harmful impact is of utmost importance. The objective of this study is to investigate the potential role and regulatory mechanism of exosomes derived from human bone marrow mesenchymal stem cells (hBMSC-Exos) in providing protection against myocardial injury induced by ICIs. We observed that the administration of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor BMS-1 in tumor-bearing mice led to evident cardiac dysfunction and myocardial injury, which were closely associated with M1 macrophage polarization and cardiac pyroptosis. Remarkably, these adverse effects were significantly alleviated through tail-vein injection of hBMSC-Exos. Moreover, either BMS-1 or hBMSC-Exos alone demonstrated the ability to reduce tumor size, while the combination of hBMSC-Exos with BMS-1 treatment not only effectively improved the probability of tumor inhibition but also alleviated cardiac anomalies induced by BMS-1.

心肌炎可由免疫检查点抑制剂（ICI）治疗引发，是癌症治疗中观察到的一种严重不良反应。因此，阐明其潜在机制并制定有效策略以减轻其有害影响至关重要。本研究的目的是探究从人类骨髓间充质干细胞（hBMSC-Exos）中提取的外泌体在保护心肌免受ICI诱导的心肌损伤方面的潜在作用和调节机制。我们观察到，肿瘤小鼠服用程序性死亡1/程序性死亡配体1（PD-1/PD-L1）抑制剂BMS-1会导致明显的心功能障碍和心肌损伤，这与M1巨噬细胞极化和心脏脓毒症密切相关。值得注意的是，通过尾静脉注射 hBMSC-Exos 可以明显缓解这些不良反应。此外，单独使用BMS-1或hBMSC-Exos都能缩小肿瘤体积，而将hBMSC-Exos与BMS-1联合治疗不仅能有效提高肿瘤抑制率，还能缓解BMS-1诱发的心脏异常。

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引用次数: 0

Formononetin alleviates no reflow after myocardial ischemia-reperfusion via modulation of gut microbiota to inhibit inflammation 福莫西汀通过调节肠道微生物群来抑制炎症，从而缓解心肌缺血再灌注后的无回流现象。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123110

Gut microflora plays an important role in relieving myocardial no-reflow (NR), formononetin (FMN) has potential effects on NR, however, the relationship between this effect and gut microflora remains unclear. This study aimed to evaluate the role of FMN in alleviating NR by regulating gut microflora. We used a myocardial NR rat model to confirm the effect and mechanism of action of FMN in alleviating NR. The rats were randomly divided into sham operation group (Sham), NR group, FMN group and sodium nitroprusside (SNP) group. Thioflavin S staining, Hematoxylin Eosin (HE), myocardial enzyme activity, ultrasonic cardiogram and RT-PCR detection showed that FMN could effectively reduce inflammatory cell infiltration, NR and ischemic area, improve cardiac structure and function and reduce TNF-α and NF-κB gene expression in NR rats. The results of 16S rRNA high-throughput sequencing showed that FMN could increase the abundance of anti-inflammatory bacteria such as Ligilactobacillus, Coprococcus, Blautia and Muribaculaceae and decrease the abundance of pro-inflammatory bacteria such as Treponema in Spirochaetota and Campylobacterota. The correlation between the differential bacteria in the gut microflora(anti-inflammatory bacteria and pro-inflammatory bacteria) and TNF-α and NF-κB, showed that they had a strong correlation. Therefore, the anti-NR mechanism of FMN may be related to increasing the abundance of anti-inflammatory bacteria and reducing the abundance of pro-inflammatory bacteria to inhibit inflammation. This study provides innovative mechanistic insights into the relationship between gut microbiota and myocardial protection, suggesting potential strategy for future treatment of NR.

肠道微生物菌群在缓解心肌无回流（NR）方面发挥着重要作用，甲萘素（FMN）对NR有潜在影响，但这种影响与肠道微生物菌群之间的关系仍不清楚。本研究旨在评估 FMN 在通过调节肠道微生物菌群减轻 NR 影响方面的作用。我们使用心肌 NR 大鼠模型来证实 FMN 在缓解 NR 方面的作用和作用机制。大鼠随机分为假手术组（Sham）、NR 组、FMN 组和硝普钠组（SNP）。硫黄素 S 染色、苏木精（HE）、心肌酶活性、超声心动图和 RT-PCR 检测结果表明，FMN 能有效减少 NR 大鼠炎症细胞浸润、NR 和缺血面积，改善心脏结构和功能，降低 TNF-α 和 NF-κB 基因表达。16S rRNA高通量测序结果表明，FMN能提高抗炎菌如Ligilaculum、Coprococcus、Blautia和Muribaculaceae的丰度，降低促炎菌如Treponema in Spirochaetota和Campylobacterota的丰度。肠道微生物区系中的不同细菌（抗炎细菌和促炎细菌）与 TNF-α 和 NF-κB 的相关性表明，它们之间有很强的相关性。因此，FMN 的抗 NR 机制可能与增加抗炎细菌的数量和减少促炎细菌的数量以抑制炎症有关。这项研究为肠道微生物群与心肌保护之间的关系提供了创新性的机制见解，为未来治疗 NR 提出了潜在的策略。

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引用次数: 0

Innovative mechanisms of micro- and nanoplastic-induced brain injury: Emphasis on the microbiota-gut-brain axis 微塑料和纳米塑料诱发脑损伤的创新机制：强调微生物群-肠-脑轴。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123107

Micro- and nanoplastics (MNPs), emerging environmental pollutants, infiltrate marine, terrestrial, and freshwater systems via diverse pathways, culminating in their accumulation in the human body through food chain transmission, posing potential health risks. Researches have demonstrated that MNPs disrupt gut microbiota equilibrium and compromise intestinal barrier integrity, as well as traverse the blood-brain barrier, leading to brain damage. Moreover, the complex interaction between the gut and the nervous system, facilitated by the “gut-brain axis,” indicates an additional pathway for MNPs-induced brain damage. This has intensified scientific interest in the intercommunication between MNPs and the gut-brain axis. While existing studies have documented microbial imbalances and metabolic disruptions subsequent to MNPs exposure, the precise mechanisms by which the microbiota-gut-brain axis contributes to MNPs-induced central nervous system damage remain unclear. This review synthesizes current knowledge on the microbiota-gut-brain axis, elucidating the pathogenesis of MNPs-induced gut microbiota dysbiosis and its consequent brain injury. It emphasizes the complex interrelation between MNPs and the microbiota-gut-brain axis, advocating for the gut microbiota as a novel therapeutic target to alleviate MNP-induced brain harm.

微塑料和纳米塑料（MNPs）是新出现的环境污染物，它们通过各种途径渗入海洋、陆地和淡水系统，最终通过食物链传播在人体内蓄积，对健康构成潜在风险。研究表明，MNPs 会破坏肠道微生物群的平衡，损害肠道屏障的完整性，并穿越血脑屏障，导致脑损伤。此外，"肠脑轴 "促进了肠道与神经系统之间复杂的相互作用，这表明 MNPs 引发脑损伤的另一个途径。因此，科学界对 MNPs 与肠道-大脑轴之间的相互影响产生了浓厚的兴趣。虽然现有研究已记录了暴露于 MNPs 后的微生物失衡和代谢紊乱，但微生物群-肠-脑轴导致 MNPs 引起的中枢神经系统损伤的确切机制仍不清楚。本综述综合了目前有关微生物群-肠-脑轴的知识，阐明了 MNPs 诱导的肠道微生物群失调及其导致的脑损伤的发病机制。它强调了 MNP 与微生物群-肠道-脑轴之间复杂的相互关系，主张将肠道微生物群作为一种新的治疗靶点，以减轻 MNP 引起的脑损伤。

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引用次数: 0

Exploring the characteristics and antecedents of clinically significant long COVID: A longitudinal cohort study 探索具有临床意义的长期 COVID 的特征和前因后果：一项纵向队列研究。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-04 DOI: 10.1016/j.lfs.2024.123114

Background

A significant number of coronavirus disease 2019 (COVID-19) survivors are experiencing long COVID, with symptoms lasting beyond three months. While diverse long COVID symptoms are established, there are gaps in understanding its long-term trends, intensity, and risk factors, requiring further investigation.

Aims

This study aimed to investigate the long COVID characteristics and associated factors by following COVID-19 survivors for one year post-infection and comparing them with healthy counterparts.

Main methods

In this longitudinal, correlational study, COVID-19 survivors diagnosed between November 2021 and February 2023 were monitored every three months for a year. Participants aged ≥18 years who had reported a positive COVID-19 test were recruited via social media and healthcare provider referrals.

Key findings

Out of 182 survivors who initially agreed to participate, 176 completed the study. The mean age was 47.56 years (SD = 16.2), and 51.1 % were female. There was a clinically significant decline in cognitive function and health-related quality of life over time, with symptoms like shortness of breath, reduced physical fitness, and increased health concerns. Those with severe acute COVID-19 symptoms experienced greater cognitive and physical declines and more shortness of breath a year later. Lower financial status was linked to poorer health-related quality of life and increased health concerns.

Significance

A year post-infection, COVID-19's impact on cognitive function and health-related quality of life remains significant, affecting individuals and communities. Survivors with severe initial symptoms and economic disadvantages need more attention. Future research should identify additional predictors of severe long COVID.

背景：大量2019年冠状病毒病（COVID-19）幸存者出现长COVID症状，症状持续时间超过三个月。目的：本研究旨在通过对感染后一年的COVID-19幸存者进行随访，并将他们与健康人进行比较，来研究长COVID的特征和相关因素：在这项纵向相关研究中，2021年11月至2023年2月期间确诊的COVID-19幸存者每三个月接受一次监测，为期一年。年龄≥18岁、COVID-19检测呈阳性的参与者是通过社交媒体和医疗机构转介招募的：在最初同意参与研究的 182 名幸存者中，有 176 人完成了研究。平均年龄为 47.56 岁（SD = 16.2），51.1% 为女性。随着时间的推移，认知功能和与健康相关的生活质量出现了明显的临床下降，并伴有呼吸急促、体能下降和健康问题增加等症状。那些有严重急性 COVID-19 症状的人在一年后的认知功能和体能下降幅度更大，呼吸急促的程度更严重。较低的经济状况与较差的健康相关生活质量和更多的健康问题有关：感染一年后，COVID-19 对认知功能和健康相关生活质量的影响仍然很大，对个人和社区都有影响。初期症状严重且经济条件较差的幸存者需要更多关注。未来的研究应确定更多预测严重长期COVID的因素。

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引用次数: 0

AP-2α decreases TMZ resistance of recurrent GBM by downregulating MGMT expression and improving DNA damage AP-2α 通过下调 MGMT 表达和改善 DNA 损伤，降低复发性 GBM 对 TMZ 的耐药性。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-04 DOI: 10.1016/j.lfs.2024.123111

Aims

The incidence of recurrent gliomas is high, exerting low survival rates and poor prognoses. Transcription factor AP-2α has been reported to regulate the progression of primary glioblastoma (GBM). However, the function of AP-2α in recurrent gliomas is largely unclear.

Methods

The expression of AP-2α and O6-methylguanine DNA-methyltransferase (MGMT) was detected in recurrent glioma tissues and cell lines by Western blots, the regulation mechanisms between AP-2α/MGMT promoter and RA/AP-2α promoter were studied by luciferase reporter assays, EMSA, and chIP assays. The effects of AP-2α and TMZ/RA treatment on cell viability in vitro and in vivo were investigated by MTT assays, γH₂AX staining, comet assays and intracranial injection.

Key findings

AP-2α expression negatively correlates with the expression of MGMT in glioma samples. AP-2α could directly bind with the promoter of the MGMT gene, suppresses transcriptional levels of MGMT and downregulate MGMT expression in TMZ-resistant U87MG-R and T98G cells, but TMZ treatment decreases AP-2α expression and increases MGMT expression. The extended TMZ treatment and increased TMZ concentrations reversed these effects. Moreover, AP-2α overexpression combines with TMZ to decrease cell viability, concurrently with improved DNA damage marker γH₂AX. Furthermore, retinoic acid (RA) activates RAR/RXR heterodimers, which bind to RA-responsive elements (RAREs) of the AP-2α promoter, and activates AP-2α expression in recurrent glioma cells. Finally, in intracranial relapsed glioma mouse model, both RA and TMZ could retard tumor development and prolong the mouse survival.

Significance

AP-2α activation by gene overexpression or RA treatment reveals the suppressive effects on glioma relapse, providing a novel therapeutic strategy against malignant refractory gliomas.

目的：复发性胶质瘤发病率高，存活率低，预后差。据报道，转录因子 AP-2α 可调控原发性胶质母细胞瘤（GBM）的进展。然而，AP-2α在复发性胶质瘤中的功能尚不明确：方法：通过Western印迹检测AP-2α和O6-甲基鸟嘌呤DNA-甲基转移酶（MGMT）在复发性胶质瘤组织和细胞系中的表达，并通过荧光素酶报告实验、EMSA和chIP实验研究AP-2α/MGMT启动子和RA/AP-2α启动子之间的调控机制。通过MTT试验、γH2AX染色、彗星试验和颅内注射，研究了AP-2α和TMZ/RA处理对体外和体内细胞活力的影响：主要发现：AP-2α的表达与胶质瘤样本中MGMT的表达呈负相关。AP-2α可直接与MGMT基因启动子结合，抑制MGMT的转录水平，下调TMZ耐药的U87MG-R和T98G细胞中MGMT的表达，但TMZ治疗可降低AP-2α的表达，增加MGMT的表达。延长TMZ处理时间和增加TMZ浓度可逆转这些效应。此外，AP-2α过表达与TMZ结合会降低细胞活力，同时DNA损伤标记物γH2AX也会得到改善。此外，视黄酸（RA）可激活RAR/RXR异二聚体，使其与AP-2α启动子的RA反应元件（RAREs）结合，并激活复发性胶质瘤细胞中AP-2α的表达。最后，在颅内复发胶质瘤小鼠模型中，RA和TMZ都能延缓肿瘤的发展，延长小鼠的生存期：意义：通过基因过表达或RA治疗激活AP-2α可抑制胶质瘤复发，为恶性难治性胶质瘤提供了一种新的治疗策略。

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引用次数: 0