Life sciences最新文献_第7页

Early-life sex hormone deficiency promotes beneficial remodeling in white adipose tissue and whole-body metabolism 早期性激素缺乏促进白色脂肪组织和全身代谢的有益重塑。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-03 DOI: 10.1016/j.lfs.2025.124184

Ignacio Miguel , Ana Alzamendi , Alejandro Ezequiel Harnichar , Alejandra Paula Giordano , Carolina Carla Garraza , Eduardo Julio Spinedi , Andrés Giovambattista

Aims

This study investigates the impact of female sex hormone deficiency (FSHD) on white adipose tissue (WAT) development, focusing on two distinct depots: retroperitoneal adipose tissue (RPAT) and inguinal adipose tissue (IAT).

Materials and methods

Prepubertal ovariectomy was performed, and animals were pair-fed (FSHD-PF) to account for hyperphagia.

Key findings

FSHD-PF animals exhibited reduced plasma triglyceride and insulin levels, with improved glucose handling. A redistribution of adipose tissue was observed, with increased IAT mass and decreased RPAT mass, accompanied by a reduction in adipocyte size in RPAT. Expression markers of inflammation, such as ob and tnf-α, were significantly decreased in RPAT of FSHD-PF, suggesting a potential reduction in the inflammatory state. Likewise, we found that prepubertal ovariectomy also modulated adipocyte precursor cells (APCs), leading to increased cd34 expression in both depots, indicative of greater competency. However, RPAT showed elevated pparγ-2 levels, while IAT exhibited increased wnt10b, suggesting a depot-specific regulation. Notably, IAT-derived APCs from FSHD-PF animals display enhanced differentiation capacity in vitro. Cold exposure further modulated WAT browning, with a notable increase in UCP-1 protein expression although observed in IAT from FSHD-PF rats only.

Significance

This study is the first to examine FSHD in the context of WAT development, identifying early-life ovarian hormone loss as a critical and previously underexplored determinant of metabolic regulation. Accordingly, the consequences of early FSHD, together with its association with non-shivering thermogenesis, emerge as promising areas for further investigation with potential therapeutic relevance.

目的：本研究探讨女性性激素缺乏（FSHD）对白色脂肪组织（WAT）发育的影响，重点研究两个不同的部位：腹膜后脂肪组织（RPAT）和腹股沟脂肪组织（IAT）。材料和方法：行青春期前卵巢切除术，并对动物进行配对喂养（FSHD-PF）以解释贪食。主要发现：FSHD-PF动物表现出血浆甘油三酯和胰岛素水平降低，葡萄糖处理能力改善。观察到脂肪组织的重新分布，IAT质量增加，RPAT质量减少，同时RPAT中脂肪细胞大小减少。炎症标志物，如ob和tnf-α在FSHD-PF的RPAT中显著降低，提示炎症状态可能减轻。同样，我们发现青春期前卵巢切除术也会调节脂肪细胞前体细胞（APCs），导致cd34在两个库中的表达增加，表明更强的能力。然而，RPAT显示pparγ-2水平升高，而IAT显示wnt10b水平升高，提示储罐特异性调节。值得注意的是，来自FSHD-PF动物的iat衍生apc在体外表现出增强的分化能力。冷暴露进一步调节WAT褐变，UCP-1蛋白表达显著增加，尽管仅在FSHD-PF大鼠的IAT中观察到。意义：本研究首次在WAT发展的背景下检查FSHD，确定早期卵巢激素损失是代谢调节的关键因素，但以前未被充分探索。因此，早期FSHD的后果及其与非寒颤产热的关联，成为进一步研究的有希望的领域，具有潜在的治疗意义。

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引用次数: 0

The emerging role of decorin in pancreatic islet biology: From development to degeneration 装饰素在胰岛生物学中的新作用：从发育到退化。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-01 DOI: 10.1016/j.lfs.2025.124185

Huanjing Bi , Ruiyang Ma , Zuhan Chen , Yang Li , Xiaoming Ding

Decorin, a small leucine-rich proteoglycan, has emerged as a multifunctional signaling molecule with critical implications for pancreatic islet biology beyond its canonical role in extracellular matrix organization. Despite extensive characterization of decorin's functions in matrix architecture and growth factor sequestration across various tissues, its specific contributions to pancreatic islet development and homeostasis remain insufficiently explored. Current evidence demonstrates decorin's molecular structure and post-translational modifications enable modulation of signaling pathways through pan-receptor tyrosine kinase inhibition and transforming growth factor-beta sequestration, with regulatory activities that vary substantially across distinct cellular and pathological environments. Within the pancreatic islet microenvironment, decorin influences pancreatic islet morphogenesis and beta-cell differentiation through modulation of local matrix composition and growth factor bioavailability, while conferring protection against diabetic complications through anti-fibrotic properties that mitigate peri-islet extracellular matrix remodeling observed in progressive islet dysfunction. By synthesizing findings from developmental biology, matrix biochemistry, and diabetes research, we address this critical knowledge gap and position decorin as an underrecognized regulator of pancreatic islet biology whose multifaceted mechanisms warrant investigation to reveal therapeutic strategies for preserving beta-cell function and preventing diabetes-associated fibrotic pathology.

Decorin是一种富含亮氨酸的小蛋白多糖，它是一种多功能信号分子，除了在细胞外基质组织中的典型作用外，还对胰岛生物学具有重要意义。尽管广泛表征了decorin在基质结构和生长因子在各种组织中的隔离中的功能，但其对胰岛发育和稳态的具体贡献仍未得到充分探讨。目前的证据表明，decorin的分子结构和翻译后修饰能够通过泛受体酪氨酸激酶抑制和转化生长因子- β隔离来调节信号通路，其调节活性在不同的细胞和病理环境中存在很大差异。在胰岛微环境中，decorin通过调节局部基质组成和生长因子的生物利用度来影响胰岛形态发生和β细胞分化，同时通过抗纤维化特性，减轻进行性胰岛功能障碍中观察到的胰岛周围细胞外基质重塑，从而保护胰岛免受糖尿病并发症的侵害。通过综合发育生物学、基质生物化学和糖尿病研究的发现，我们解决了这一关键的知识缺口，并将decorin定位为胰岛生物学中未被充分认识的调节因子，其多方面的机制值得研究，以揭示保护β细胞功能和预防糖尿病相关纤维化病理的治疗策略。

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引用次数: 0

Retraction notice to “Baicalin may alleviate inflammatory infiltration in dextran sodium sulfate-induced chronic ulcerative colitis via inhibiting IL-33 expression” [Life Sci. 186 (2017) 125–132] “黄芩苷通过抑制IL-33表达减轻葡聚糖硫酸钠诱导的慢性溃疡性结肠炎的炎症浸润”的撤回通知[生命科学]. 186(2017)125-132。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-12-30 DOI: 10.1016/j.lfs.2025.124177

Cheng-Liang Zhang , Si Zhang , Wen-Xi He , Jing-Li Lu , Yan-Jiao Xu , Jin-Yu Yang , Dong Liu

引用次数: 0

Retraction notice to “A novel approach to bladder dysfunction induced by bladder outlet obstruction: Low-intensity extracorporeal shock wave therapy promotes bladder regeneration” [Life Sci. 378 (2025) 123799] “膀胱出口梗阻致膀胱功能障碍的新方法：低强度体外冲击波治疗促进膀胱再生”[生命科学]. 378(2025):123799]。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-12-30 DOI: 10.1016/j.lfs.2025.124178

Sheng-Tang Wu , Tai-Jui Juan , Jian-He Lu , Kuang-Shun Chueh , Jing-Wen Mao , Cheng-Yu Long , Shu-Mien Chuang , Mei-Chen Shen , Ting-Wei Sun , Chiang-Ting Wang , Yung-Shun Juan

引用次数: 0

Advances in AI for predicting pharmacological properties of natural medicines 人工智能预测天然药物药理性质的研究进展

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-12-29 DOI: 10.1016/j.lfs.2025.124180

Tianyu Xu , Yuemiao Xu , Jinger Zhang , Yuchen Zhou , Huiying Feng , Aiqin Zhang , Yuhua Zhang

Artificial intelligence (AI), which includes machine learning (ML) and deep learning (DL), has become an important tool in drug development. An increasing number of studies have discovered pharmacologically active compounds in natural products, and AI's high-throughput capabilities have accelerated the drug discovery process. In the development of natural medicines, AI can use existing datasets and experimental data to screen for lead compounds with potential activity and predict disease-associated drug targets. Furthermore, using AI to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of lead compounds early in the drug discovery process can save time and money. This review introduces AI applications for predicting the pharmacological properties of natural drugs by outlining model construction principles and recent advances, summarizing key aspects such as feature selection and evaluation metrics, and discussing natural drug development challenges and opportunities.

人工智能（AI），包括机器学习（ML）和深度学习（DL），已经成为药物开发的重要工具。越来越多的研究在天然产物中发现了药理活性化合物，人工智能的高通量能力加速了药物发现过程。在天然药物的开发中，人工智能可以利用现有的数据集和实验数据来筛选具有潜在活性的先导化合物，并预测与疾病相关的药物靶点。此外，在药物发现过程的早期使用人工智能来预测先导化合物的吸收、分布、代谢、排泄和毒性（ADMET）特性可以节省时间和金钱。本文介绍了人工智能在预测天然药物药理学性质方面的应用，概述了模型构建原则和最新进展，总结了特征选择和评价指标等关键方面，并讨论了天然药物开发的挑战和机遇。

引用次数: 0

Adiponectin receptor agonist, AdipoRon, reduces the growth of prostate cancer cells and patient-derived organoids 脂联素受体激动剂，AdipoRon，减少前列腺癌细胞和患者来源的类器官的生长。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-12-26 DOI: 10.1016/j.lfs.2025.124175

Francielle C. Mosele , Ana Luiza Romano Gabriel , Nilton José dos Santos , Caroline Nascimento Barquilha , Caio Cesar Damasceno Monção , Micheli Canuto de Lima , Mark A. Rubin , Sérgio Luis Felisbino , Joanna Triscott

Low adiponectin levels in obese men are associated with an incidence of aggressive prostate cancer (PCa). Despite significant advances in PCa treatment, some cases become resistant, making the development of new therapies crucial. An alternative treatment is the use of agonists, such as AdipoRon. Here, we elucidate the antitumor effects of AdipoRon on PCa models and demonstrate reduced cell proliferation, migration, and invasion in vitro. AdipoRon impaired mitochondrial respiration of androgen-dependent and castration-resistant cells. We show that this agonist reduces AR and PSA expression in androgen-dependent prostate cells. Adiponectin receptors (AdipoR1 and AdipoR2) were upregulated in PC3 and DU-145 cells. We hypothesize that the alteration of PPAR alpha could explain the effects of AdipoRon. Additionally, the antigrowth effects of AdipoRon were observed in the patient-derived organoids PM154 and MSK-PCa16. Our findings reveal that AdipoRon has strong in vitro antitumor effects on PCa, supporting its potential as a promising therapeutic candidate. Future studies should focus on in vivo models to validate these effects and explore the underlying mechanisms, which may open new therapies for PCa.

Statement of implication

AdipoRon decreases prostate cancer cell growth.

肥胖男性低脂联素水平与侵袭性前列腺癌（PCa）的发病率相关。尽管前列腺癌治疗取得了重大进展，但一些病例变得耐药，这使得开发新的治疗方法至关重要。另一种治疗方法是使用激动剂，如AdipoRon。在这里，我们阐明了AdipoRon对PCa模型的抗肿瘤作用，并在体外证明了细胞增殖、迁移和侵袭的减少。AdipoRon损害雄激素依赖细胞和去势抵抗细胞的线粒体呼吸。我们发现这种激动剂可以降低雄激素依赖性前列腺细胞中AR和PSA的表达。脂联素受体AdipoR1和AdipoR2在PC3和DU-145细胞中表达上调。我们假设PPAR α的改变可以解释AdipoRon的作用。此外，在患者来源的类器官PM154和MSK-PCa16中观察到AdipoRon的抗生长作用。我们的研究结果表明，AdipoRon对PCa具有很强的体外抗肿瘤作用，支持其作为有希望的治疗候选药物的潜力。未来的研究应该集中在体内模型上，以验证这些效应并探索潜在的机制，这可能会为PCa开辟新的治疗方法。结论：脂肪素可降低前列腺癌细胞的生长。

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引用次数: 0

Adventitial fibroblast-derived NAMPT is associated with vascular remodeling in erythropoietin-induced abdominal aortic aneurysm 内皮成纤维细胞衍生的NAMPT与促红细胞生成素诱导的腹主动脉瘤血管重构相关。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-12-26 DOI: 10.1016/j.lfs.2025.124179

Xinyi Lyu , Shuqin Ding , Chongqing Jiang , Yile Zhou , Jiahao Shi , Qi Liu , Yajun Chen , Xianpeng Dai

Abdominal aortic aneurysm (AAA) remains a life-threatening condition with limited pharmacological interventions. While erythropoietin (EPO) has been implicated in AAA pathogenesis, its cell-type-specific effects on nicotinamide phosphoribosyltransferase (NAMPT)-mediated vascular remodeling remain unexplored. This study demonstrates that EPO administration in mice significantly induces AAA formation, characterized by aortic dilation, straightening of elastic laminae, and adventitial thickening. Through integrated in vivo and in vitro analyses, we identified that EPO differentially regulates NAMPT expression across vascular cell types: downregulating it in endothelial cells while robustly upregulating it in adventitial fibroblasts and infiltrating macrophages. Notably, EPO promoted proliferation of adventitial fibroblasts but suppressed endothelial cell growth. Mechanistically, the vascular adventitia emerged as the primary locus of NAMPT-driven pathology, where fibroblast-derived NAMPT creates a pro-inflammatory and pro-remodeling niche. These findings reveal a previously unrecognized role of adventitial fibroblasts in EPO-induced AAA through NAMPT dysregulation, suggesting novel therapeutic targets for AAA treatment. The study shifts therapeutic focus toward the adventitia as a key regulator of AAA progression.

腹主动脉瘤（AAA）仍然是一种危及生命的疾病，药物干预有限。虽然促红细胞生成素（EPO）与AAA发病机制有关，但其对烟酰胺磷酸核糖基转移酶（NAMPT）介导的血管重构的细胞类型特异性作用仍未被探索。本研究表明，EPO给药小鼠可显著诱导AAA形成，其特征是主动脉扩张、弹性膜拉直和外膜增厚。通过体内和体外综合分析，我们发现EPO对不同血管细胞类型的NAMPT表达有不同的调节：内皮细胞下调NAMPT表达，而内皮细胞和浸润性巨噬细胞则大幅上调NAMPT表达。值得注意的是，EPO促进了上皮成纤维细胞的增殖，但抑制了内皮细胞的生长。从机制上讲，血管外膜是NAMPT驱动病理的主要位点，其中成纤维细胞衍生的NAMPT创造了促炎症和促重塑的生态位。这些发现揭示了以前未被认识到的内皮成纤维细胞通过NAMPT失调在epo诱导的AAA中所起的作用，为AAA治疗提供了新的治疗靶点。该研究将治疗重点转向作为AAA进展关键调节因子的外膜。

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引用次数: 0

O-GlcNAcylation stabilizes c-MYC to upregulate xCT and inhibit ferroptosis in ovarian cancer o - glcn酰化稳定c-MYC上调xCT并抑制卵巢癌中的铁下垂。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-12-26 DOI: 10.1016/j.lfs.2025.124172

Ying Tang , Yaru Zhang , Xinmei Chen , Xiaotong Li , Jingyuan Pei , Ao Wang , Zhengqing Luo , Hongshuo Zhang , Tonghui Ma , Jianhui Fan , Ying Kong

Aims

Ovarian cancer (OV) is one of the most prevalent and life-threatening malignancies among women worldwide. Resistance to conventional therapies poses a major challenge in OV treatment. Ferroptosis, a type of programmed cell death driven by iron accumulation and marked by lipid peroxidation, has garnered significant attention in cancer research. The regulation of ferroptosis involves intricate epigenetic, transcriptional, and post-translational modification (PTM) processes. O-GlcNAcylation, a reversible PTM occurring on serine/threonine hydroxyl groups of proteins, has been connected with the regulation of apoptosis, autophagy, and necroptosis. However, its role in ferroptosis is still poorly understood.

Materials and methods

O-GlcNAcylation levels and ferroptosis-associated markers were compared between normal and OV tissues. OV cells were subjected to ferroptosis induction using Erastin or RSL3, while O-GlcNAcylation was modulated via the OGT inhibitor OSMI-1 or the OGA inhibitor Thiamet-G. Subsequent analyses were performed to assess ferroptotic phenotypes and the c-MYC/xCT/GSH/GPX4 signaling pathway. In vitro findings were validated using a nude mouse xenograft model.

Key findings

In this study, we observed elevated O-GlcNAcylation, higher protein levels of xCT, GPX4, and FTH1, as well as increased antioxidant capacity in ovarian cancer tissues compared with normal ovarian tissues. Modulating O-GlcNAcylation levels in OV cells revealed that its downregulation enhanced ferroptosis, whereas upregulation inhibited it. Further investigation revealed that c-MYC protein levels were regulated by O-GlcNAcylation. The O-GlcNAcylation-mediated stabilization of c-MYC led to increased xCT expression, thereby enhancing the xCT/GSH/GPX4 antioxidant axis and suppressing ferroptosis in OV.

Significance

Our research may provide intervention strategies for the treatment of OV.

目的：卵巢癌（OV）是全世界妇女中最常见和危及生命的恶性肿瘤之一。对常规疗法的耐药性是OV治疗的主要挑战。铁凋亡是一种由铁积累驱动的程序性细胞死亡，以脂质过氧化为特征，在癌症研究中引起了极大的关注。铁下垂的调控涉及复杂的表观遗传、转录和翻译后修饰（PTM）过程。o - glcn酰化是一种发生在蛋白质丝氨酸/苏氨酸羟基上的可逆PTM，与细胞凋亡、自噬和坏死坏死的调节有关。然而，其在铁下垂中的作用仍然知之甚少。材料和方法：比较正常和OV组织中o - glcnac酰化水平和凋亡相关标志物。使用Erastin或RSL3诱导OV细胞铁下垂，而通过OGT抑制剂OSMI-1或OGA抑制剂Thiamet-G调节o - glcn酰化。随后进行分析以评估铁致表型和c-MYC/xCT/GSH/GPX4信号通路。体外研究结果通过裸鼠异种移植模型得到验证。主要发现：在本研究中，我们观察到与正常卵巢组织相比，卵巢癌组织中o - glcnac酰化升高，xCT、GPX4和FTH1蛋白水平升高，抗氧化能力增强。在OV细胞中调节o - glcnac酰水平表明其下调可增强铁下垂，而上调可抑制铁下垂。进一步研究发现c-MYC蛋白水平受o - glcnac酰化调节。o - glcn酰化介导的c-MYC稳定导致xCT表达增加，从而增强xCT/GSH/GPX4抗氧化轴，抑制OV中的铁凋亡。意义：本研究可为OV的治疗提供干预策略。

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引用次数: 0

RUVBL1-mediated mTORC1 activation drives tumour progression and immune evasion for oral squamous cell carcinoma ruvbl1介导的mTORC1激活驱动口腔鳞状细胞癌的肿瘤进展和免疫逃避。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-12-25 DOI: 10.1016/j.lfs.2025.124171

Xinpei Wang , Zuxuan Zhao , Fengyang Jing , Bingzhi Wang , Meng Wang , Jianming Ying , Tiejun Li

Background and aims

Oral squamous cell carcinoma (OSCC) is a prevalent head and neck malignancy for which surgical resection remains the primary therapeutic approach. Although immunotherapy, particularly immune checkpoint blockade targeting PD-1/PD-L1, has been revolutionary, only a small number of patients with OSCC have clinically benefited from it. Therefore, elucidating the molecular mechanisms underlying OSCC progression and immune evasion is crucial. RuvB-like AAA ATPase 1 (RUVBL1) has been implicated in diverse biological processes and modulates tumour immunity. Little is known regarding the function of RUVBL1 and its mechanism of action in OSCC. In this study, we aimed to understand RUVBL1 regulation in OSCC tissues and how expression correlates with patient prognosis.

Materials and methods

We conducted bioinformatics analysis, functional assays in vitro, co-culture experiments, and murine xenograft models, along with validation in clinical samples. To investigate the underlying mechanism, transcriptome sequencing and biochemical as well as molecular analyses were utilized.

Key findings

RUVBL1 promotes tumour growth and regulates the tumour microenvironment by controlling PD-L1 expression by targeting the rapamycin kinase (mTOR) pathway, thereby impairing both the infiltration and effector function of T cells in OSCC. Pharmacological inhibition of RUVBL1 with CB6644 suppressed tumour growth and synergised with PD-L1 blockade and conventional therapy. Collectively, these findings identify RUVBL1 as a critical driver of OSCC progression and immune modulation.

Significance

Our findings highlight the potential of RUVBL1 as a prognostic biomarker and therapeutic target to enhance treatment efficacy.

背景和目的：口腔鳞状细胞癌（OSCC）是一种常见的头颈部恶性肿瘤，手术切除仍然是主要的治疗方法。尽管免疫疗法，特别是针对PD-1/PD-L1的免疫检查点阻断疗法是革命性的，但只有少数OSCC患者在临床上受益。因此，阐明OSCC进展和免疫逃避的分子机制至关重要。ruvb样AAA atp酶1 （RUVBL1）参与多种生物过程并调节肿瘤免疫。RUVBL1在OSCC中的功能及其作用机制尚不清楚。在本研究中，我们旨在了解RUVBL1在OSCC组织中的调控及其表达与患者预后的关系。材料和方法：我们进行了生物信息学分析、体外功能分析、共培养实验和小鼠异种移植物模型，并在临床样本中进行了验证。为了研究其潜在的机制，利用转录组测序和生化及分子分析。关键发现：RUVBL1通过靶向雷帕霉素激酶（rapamycin kinase, mTOR）通路，控制PD-L1表达，促进肿瘤生长，调节肿瘤微环境，从而损害T细胞在OSCC中的浸润和效应功能。CB6644对RUVBL1的药理学抑制抑制肿瘤生长，并与PD-L1阻断和常规治疗协同作用。总之，这些发现确定RUVBL1是OSCC进展和免疫调节的关键驱动因素。意义：我们的研究结果强调了RUVBL1作为预后生物标志物和治疗靶点的潜力，以提高治疗疗效。

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引用次数: 0

FOSL2+ macrophages drive pro-inflammatory phenotype via miR-92a-3p/FOSL2/NF-κB axis to mediate endothelial cell injury in aortic dissection FOSL2+巨噬细胞通过miR-92a-3p/FOSL2/NF-κB轴驱动促炎表型介导主动脉夹层内皮细胞损伤。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-12-24 DOI: 10.1016/j.lfs.2025.124174

Zhenpeng Yuan , Ruihan Chen , Rong Fan , Zhenyu Yang , Qianqian Zhu , Chenyang Qiu , Ziheng Wu , Donglin Li , Yangyan He , Hongkun Zhang

Background

In aortic dissection, macrophages play a critical role; however, the impact of macrophages on vascular endothelial cells remains unclear.

Methods

By constructing macrophage cell lines with stable overexpression and knockdown of FOSL2, M1 polarization was induced to evaluate the effects of FOSL2 on macrophage polarization, pro-inflammatory cytokine expression, macrophage migration, apoptosis, reactive oxygen species (ROS) generation, and mitochondrial function. Additionally, co-culture experiments were conducted to study the effects of macrophages with FOSL2 overexpression and knockdown on the proliferation, migration, apoptosis, and signaling pathways of mouse aortic endothelial cells (MAECs). Furthermore, miRNA prediction and validation experiments were performed to explore the regulatory mechanism of miR-92a-3p on FOSL2 and its role in macrophage-endothelial cell interactions.

Results

Overexpression of FOSL2 enhanced the expression and secretion of pro-inflammatory cytokines, promoting the M1 phenotype. It also increased macrophage migration, apoptosis, and ROS generation while suppressing mitochondrial membrane potential and activating the MYD88/TLR4/NF-κB signaling pathway. In co-culture experiments, FOSL2 overexpression in macrophages inhibited the proliferation and migration of co-cultured MAECs, promoted apoptosis and mitochondrial dysfunction, and upregulated endothelial injury markers and the PI3K/AKT/NF-κB signaling pathway. miR-92a-3p was downregulated during M1 polarization and directly targeted FOSL2, inhibiting its expression. Overexpression of miR-92a-3p reversed the FOSL2-mediated M1 polarization of macrophages and the functional impairment of co-cultured endothelial cells.

Conclusion

FOSL2 promotes macrophage M1 polarization by regulating the MYD88/TLR4/NF-κB signaling pathway, enhancing pro-inflammatory responses, and inhibiting the function of co-cultured endothelial cells. miR-92a-3p exerts the opposite effect by targeting FOSL2, suppressing M1 polarization and endothelial cell injury.

背景：巨噬细胞在主动脉夹层中起关键作用；然而，巨噬细胞对血管内皮细胞的影响尚不清楚。方法：通过构建稳定过表达和低表达FOSL2的巨噬细胞细胞系，诱导M1极化，评估FOSL2对巨噬细胞极化、促炎细胞因子表达、巨噬细胞迁移、凋亡、活性氧（ROS）生成和线粒体功能的影响。此外，通过共培养实验研究了FOSL2过表达和敲低巨噬细胞对小鼠主动脉内皮细胞（MAECs）增殖、迁移、凋亡和信号通路的影响。此外，我们还进行了miRNA预测和验证实验，探索miR-92a-3p对FOSL2的调控机制及其在巨噬细胞-内皮细胞相互作用中的作用。结果：过表达FOSL2可增强促炎细胞因子的表达和分泌，促进M1表型。同时抑制线粒体膜电位，激活MYD88/TLR4/NF-κB信号通路，增加巨噬细胞迁移、凋亡和ROS生成。共培养实验中，巨噬细胞中FOSL2过表达抑制共培养MAECs的增殖和迁移，促进细胞凋亡和线粒体功能障碍，上调内皮损伤标志物和PI3K/AKT/NF-κB信号通路。miR-92a-3p在M1极化过程中下调，直接靶向FOSL2，抑制其表达。过表达miR-92a-3p逆转了fosl2介导的巨噬细胞M1极化和共培养内皮细胞的功能损伤。结论：FOSL2通过调节MYD88/TLR4/NF-κB信号通路，增强促炎反应，抑制共培养内皮细胞功能，促进巨噬细胞M1极化。miR-92a-3p通过靶向FOSL2发挥相反的作用，抑制M1极化和内皮细胞损伤。

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引用次数: 0