Experimental cell research最新文献

Investigation of the regulation of EGF signaling by miRNAs, delving into the underlying mechanism and signaling pathways in cancer 研究 miRNA 对 EGF 信号的调控，深入探讨癌症的内在机制和信号通路。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-21 DOI: 10.1016/j.yexcr.2024.114267

The EGF receptors (EGFRs) signaling pathway is essential for tumorigenesis and progression of cancer. Emerging evidence suggests that miRNAs are essential regulators of EGF signaling, influencing various pathway components and tumor behavior. This article discusses the underlying mechanisms and clinical implications of miRNA-mediated regulation of EGF signaling in cancer. miRNAs utilize multiple mechanisms to exert their regulatory effects on EGF signaling. They can target EGF ligands, including EGF and TGF-directly, inhibiting their expression and secretion. In addition, miRNAs can modulate EGF signaling indirectly by targeting EGF receptors, downstream signaling molecules, and transcription factors implicated in regulating the EGF pathway. These miRNAs can disrupt the delicate equilibrium of EGF signaling, resulting in aberrant activation and fostering tumor cell proliferation, survival, angiogenesis, and metastasis. The dysregulation of the expression of specific miRNAs has been linked to clinical outcomes in numerous types of cancer. Specific profiles of miRNA expression have been identified as prognostic markers, reflecting tumor characteristics, invasiveness, metastatic potential, and therapeutic response. These miRNAs can serve as potential therapeutic targets for interventions that modulate EGF signaling and improve patient outcomes. Understanding the intricate relationship between miRNAs and EGF signaling in cancer can transform cancer diagnosis, prognosis, and treatment. The identification of specific miRNAs involved in the regulation of the EGF pathway opens the door to the development of targeted therapies and personalized medicine approaches. In addition, miRNA-based interventions promise to overcome therapeutic resistance and improve the efficacy of existing treatments. miRNAs are crucial regulators of EGF signaling in cancer, affecting tumor behavior and clinical outcomes. Further research is required to decipher the complex network of miRNA-mediated EGF signaling regulation and translate these findings into clinically applicable strategies for enhanced cancer treatment.

表皮生长因子受体（表皮生长因子受体）信号通路对肿瘤的发生和发展至关重要。新的证据表明，miRNA 是表皮生长因子受体信号通路的重要调控因子，可影响信号通路的各种成分和肿瘤行为。本文探讨了 miRNA 介导的癌症中 EGF 信号转导调控的内在机制和临床意义。它们可以直接靶向 EGF 配体，包括 EGF 和 TGF，抑制它们的表达和分泌。此外，miRNAs 还可以通过靶向 EGF 受体、下游信号分子和参与调节 EGF 通路的转录因子，间接调节 EGF 信号。这些 miRNA 可破坏 EGF 信号的微妙平衡，导致异常激活，促进肿瘤细胞增殖、存活、血管生成和转移。特定 miRNA 的表达失调与多种癌症的临床结果有关。特定的 miRNA 表达谱已被确定为预后标志物，可反映肿瘤特征、侵袭性、转移潜力和治疗反应。这些 miRNA 可作为潜在的治疗靶点，用于调节表皮生长因子信号转导和改善患者预后的干预措施。了解癌症中 miRNA 与表皮生长因子信号转导之间错综复杂的关系可以改变癌症诊断、预后和治疗。确定参与 EGF 通路调控的特定 miRNA 为开发靶向疗法和个性化医疗方法打开了大门。此外，基于 miRNA 的干预措施有望克服治疗耐药性，提高现有疗法的疗效。miRNA 是癌症中表皮生长因子信号转导的关键调控因子，会影响肿瘤行为和临床结果。要破译 miRNA 介导的表皮生长因子信号调控的复杂网络，并将这些发现转化为临床适用的策略以加强癌症治疗，还需要进一步的研究。

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引用次数: 0

Excess glucose alone induces hepatocyte damage due to oxidative stress and endoplasmic reticulum stress 由于氧化应激和内质网应激，仅过量葡萄糖就会诱发肝细胞损伤。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-21 DOI: 10.1016/j.yexcr.2024.114264

Type 2 diabetes mellitus (DM) is a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). With the increasing prevalence of type 2 DM and MASLD due to lifestyle changes, understanding their impact on liver health is crucial. However, the hepatocellular damage caused by glucose alone is unknown. This study investigates the effect of excess glucose on hepatocytes, focusing on oxidative stress, endoplasmic reticulum stress (ER stress), apoptosis, autophagy, and cell proliferation. We treated an immortalized-human hepatocyte cell line with excess glucose and analyzed. Excess glucose induced oxidative stress and ER stress in a time- and concentration-dependent manner, leading to apoptosis. Oxidative stress and ER stress were independently induced by excess glucose. Proteasome inhibitors and palmitic acid exacerbated glucose-induced stress, leading to the formation of Mallory-Denk body-like inclusion bodies. Despite these stresses, autophagic flux was not altered. Excess glucose also caused DNA damage but did not affect cell proliferation. This suggests that glucose itself can contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH) and carcinogenesis of HCC in patients with type 2 DM. Managing blood glucose levels is crucial to prevent hepatocyte damage and associated complications.

2 型糖尿病（DM）是代谢功能障碍相关性脂肪性肝病（MASLD）和肝细胞癌（HCC）的重要危险因素。随着生活方式的改变，2 型糖尿病和代谢性脂肪肝的发病率不断上升，了解它们对肝脏健康的影响至关重要。然而，仅由葡萄糖引起的肝细胞损伤尚不清楚。本研究调查了过量葡萄糖对肝细胞的影响，重点关注氧化应激、内质网应激（ER应激）、细胞凋亡、自噬和细胞增殖。我们用过量葡萄糖处理了永生化人肝细胞系，并对其进行了分析。过量葡萄糖以时间和浓度依赖的方式诱导氧化应激和ER应激，导致细胞凋亡。过量葡萄糖可独立诱导氧化应激和ER应激。蛋白酶体抑制剂和棕榈酸加剧了葡萄糖诱导的应激，导致马洛里-登克体样包涵体的形成。尽管存在这些应激，自噬通量并没有改变。过量的葡萄糖也会造成 DNA 损伤，但不会影响细胞增殖。这表明，葡萄糖本身可导致 2 型糖尿病患者代谢功能障碍相关性脂肪性肝炎（MASH）和 HCC 癌变的进展。控制血糖水平对于预防肝细胞损伤和相关并发症至关重要。

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引用次数: 0

A novel molecular target, superoxide dismutase 1, in ALK inhibitor-resistant lung cancer cells, detected through proteomic analysis 通过蛋白质组分析发现ALK抑制剂耐药肺癌细胞中的新分子靶点--超氧化物歧化酶1。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-21 DOI: 10.1016/j.yexcr.2024.114266

Backgrounds

To the best of our knowledge, there are no reports of proteomic analysis for the identification of unknown proteins involved in resistance to anaplastic lymphoma kinase (ALK) inhibitors. In this study, we investigated the proteins involved in resistance to alectinib, a representative ALK inhibitor, through proteomic analysis and the possibility of overcoming resistance.

Methods

An ALK-positive lung adenocarcinoma cell line (ABC-11) and the corresponding alectinib-resistant cell line (ABC-11/CHR2) were used. Two-dimensional difference gel electrophoresis (2D DIGE) was performed; the stained gel was scanned and the spots were analyzed using DeCyder TM2D 7.0. Mass spectrometry (MS) with the UltraﬂeXtreme matrix-assisted laser desorption ionization-tandem time-of-flight (MALDI-TOF/TOF) MS system was performed. For the MS/MS analysis, the samples were spotted on an AnchorChipTM 600 TF plate. The peptide masses obtained in the reﬂector positive mode were acquired at m/z of 400−6000. MS/MS data were searched against the NCBI protein databases. Growth inhibition was measured using an MTT assay. The isobologram and combination index were calculated based on the median-effect analysis. Western blotting was performed using antibodies, including superoxide dismutase (SOD) 1, MET, ERK, PARP, AKT, and BRCA1.

Results

The 2D DIGE for ABC-11 and ABC-11/CHR2 showed different expression levels in about 2000 spots. SOD was identified from spots highly expressed in resistant strains. Western blotting also confirmed SOD1 overexpression in ABC-11/CHR2. siSOD1 enhanced the growth inhibitory effects of alectinib, increased cleaved PARP levels, and decreased pERK, pAKT, and BRCA1 levels with a combination of alectinib. In addition, the combination of LCS-1, an SOD1 inhibitor, and alectinib synergistically suppressed the growth in ABC-11/CHR2, but not in ABC-11.

Conclusions

SOD1 overexpression is thought to be a mechanism for alectinib resistance, suggesting the possibility of overcoming resistance using SOD1 inhibitors.

背景：据我们所知，目前还没有关于通过蛋白质组学分析鉴定参与无性淋巴瘤激酶（ALK）抑制剂耐药性的未知蛋白质的报道。在这项研究中，我们通过蛋白质组学分析研究了参与ALK抑制剂阿来替尼耐药性的蛋白质以及克服耐药性的可能性：方法：采用ALK阳性肺腺癌细胞株（ABC-11）和相应的阿来替尼耐药细胞株（ABC-11/CHR2）。进行二维差异凝胶电泳（2D DIGE）；使用 DeCyder TM2D 7.0 扫描染色凝胶并分析斑点。使用 UltraﬂeXtreme 矩阵辅助激光解吸电离-串联飞行时间质谱（MALDI-TOF/TOF）系统进行质谱分析。在进行 MS/MS 分析时，样品被置于 AnchorChipTM 600 TF 平板上。在重扫描正向模式下获得的肽段质量的 m/z 为 400-6,000。根据 NCBI 蛋白质数据库搜索 MS/MS 数据。使用 MTT 法测量生长抑制作用。根据中位效应分析计算等全息图和组合指数。使用超氧化物歧化酶（SOD）1、MET、ERK、PARP、AKT 和 BRCA1 等抗体进行了 Western 印迹分析：ABC-11和ABC-11/CHR2的二维DIGE在约2000个点上显示出不同的表达水平。在抗性菌株的高表达点中发现了 SOD。siSOD1 增强了阿来替尼的生长抑制作用，提高了裂解 PARP 水平，降低了 pERK、pAKT 和 BRCA1 水平。此外，SOD1抑制剂LCS-1和阿来替尼联合使用能协同抑制ABC-11/CHR2的生长，但不能抑制ABC-11的生长：结论：SOD1过表达被认为是阿来替尼耐药的一个机制，这表明使用SOD1抑制剂有可能克服耐药性。

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引用次数: 0

Influence of mesenchymal stem cells from different origins on the therapeutic effectiveness of systemic lupus erythematosus 不同来源的间充质干细胞对系统性红斑狼疮疗效的影响

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-20 DOI: 10.1016/j.yexcr.2024.114263

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune inflammatory disorder characterized by alterations in the balance between inflammatory and regulatory cytokines. Mesenchymal stem cells (MSCs), which are non-hematopoietic stem cells with multipotent differentiation potential, due to their immunomodulatory, tissue repair, low immunogenicity, and chemotactic properties, have garnered increasing interest in SLE treatment. Studies increasingly reveal the heterogeneous nature of MSC populations. With sources including dental pulp, adipose tissue, bone marrow, and umbilical cord, the therapeutic effects of MSCs on SLE vary depending on their origin. This review consolidates clinical research on MSCs from different sources in treating SLE and analyzes the possible causes underlying these variable outcomes. Additionally, it elucidates five potential factors impacting the outcomes of MSC therapy in SLE: the influence of the microenvironment on MSCs, the complexity and paradoxical aspects of MSC mechanisms in SLE treatment, the heterogeneity of MSCs, the in vivo differentiation potential and post-transplant survival rates of MSCs, and disparities in MSC preparation conditions.

系统性红斑狼疮（SLE）是一种慢性自身免疫性炎症性疾病，其特点是炎性细胞因子和调节性细胞因子之间的平衡发生改变。间充质干细胞（MSCs）是一种具有多能分化潜能的非造血干细胞，具有免疫调节、组织修复、低免疫原性和趋化特性，在系统性红斑狼疮治疗中越来越受到关注。越来越多的研究揭示了间充质干细胞群体的异质性。间充质干细胞的来源包括牙髓、脂肪组织、骨髓和脐带，其对系统性红斑狼疮的治疗效果因来源而异。本综述整合了不同来源的间充质干细胞在治疗系统性红斑狼疮方面的临床研究，并分析了造成这些不同结果的可能原因。此外，它还阐明了影响间充质干细胞治疗系统性红斑狼疮效果的五个潜在因素：微环境对间充质干细胞的影响、间充质干细胞治疗系统性红斑狼疮机制的复杂性和矛盾性、间充质干细胞的异质性、间充质干细胞的体内分化潜力和移植后存活率以及间充质干细胞制备条件的差异。

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引用次数: 0

m6A methyltransferase ZC3H13 improves pulmonary fibrosis in mice through regulating Bax expression m6A 甲基转移酶 ZC3H13 通过调节 Bax 的表达改善小鼠肺纤维化。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-20 DOI: 10.1016/j.yexcr.2024.114255

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease. N6-methyladenosine (m⁶A) is a reversible RNA modification that was shown to be associated with IPF development. The present study aimed to explore the function and potential mechanism of the m⁶A methylation enzyme zinc finger CCCH-type containing 13 (ZC3H13) in IPF. In the study, bioinformatic screening yielded a differentially expressed m⁶A gene, ZC3H13, which was down-regulated in GEO microarrays, BLM-induced mouse models, and cellular models. Overexpression of ZC3H13 reduced histopathological damage of lung tissues in mice, mitigated fibrosis (including reduced α-SMA, collagen Ⅰ, and Vimentin levels, and elevated E-cadherin levels), decreased lung/body weight ratio and lung hydroxyproline levels, reduced oxidative stress (increased SOD activity and GSH-Px activity and decreased MDA levels), suppressed apoptosis within lung tissues and MLE-12 cells, promoted Bcl-2 expression, and inhibited Bax expression. Bax expression was found to be negatively correlated with ZC3H13 expression by correlation analysis. ZC3H13 could bind Bax mRNA and promote its m⁶A methylation through reading protein YTHDC1, thereby inhibiting its stability. Bax inhibition ameliorated BLM-induced MLE-12 cell dysfunction and partially abrogated the inhibition of MLE-12 cell function by ZC3H13 downregulation. In conclusion, m⁶A methyltransferase ZC3H13 impedes lung epithelial cell apoptosis and thus improves pulmonary fibrosis by promoting Bax mRNA m⁶A methylation and down-regulating Bax expression through reading protein YTHDC1.

特发性肺纤维化（IPF）是一种进行性致命肺病。N6-甲基腺苷（m6A）是一种可逆的 RNA 修饰，已被证明与 IPF 的发展有关。本研究旨在探索 m6A 甲基化酶锌指 CCCH 型含 13（ZC3H13）在 IPF 中的功能和潜在机制。研究通过生物信息学筛选发现了一个差异表达的 m6A 基因 ZC3H13，该基因在 GEO 微阵列、BLM 诱导的小鼠模型和细胞模型中均呈下调表达。过表达 ZC3H13 可减少小鼠肺组织的组织病理学损伤，减轻纤维化（包括降低 α-SMA、胶原蛋白Ⅰ和 Vimentin 水平，升高 E-cadherin 水平），降低肺/体重比和肺羟脯氨酸水平，减少氧化应激（提高 SOD 活性和 GSH-Px 活性，降低 MDA 水平），抑制肺组织和 MLE-12 细胞的凋亡，促进 Bcl-2 的表达，抑制 Bax 的表达。相关分析发现，Bax 的表达与 ZC3H13 的表达呈负相关。ZC3H13可结合Bax mRNA，并通过阅读蛋白YTHDC1促进其m6A甲基化，从而抑制其稳定性。抑制Bax可改善BLM诱导的MLE-12细胞功能障碍，并部分缓解ZC3H13下调对MLE-12细胞功能的抑制作用。总之，m6A甲基转移酶ZC3H13通过阅读蛋白YTHDC1促进Bax mRNA m6A甲基化并下调Bax表达，从而阻碍肺上皮细胞凋亡，进而改善肺纤维化。

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引用次数: 0

Architecture of CTPS filament networks revealed by cryo-electron tomography 低温电子断层扫描揭示的 CTPS 纤维网络结构。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-19 DOI: 10.1016/j.yexcr.2024.114262

The cytoophidium is a novel type of membraneless organelle, first observed in the ovaries of Drosophila using fluorescence microscopy. In vitro, purified Drosophila melanogaster CTPS (dmCTPS) can form metabolic filaments under the presence of either substrates or products, and their structures that have been analyzed using cryo-electron microscopy (cryo-EM). These dmCTPS filaments are considered the fundamental units of cytoophidia. However, due to the resolution gap between light and electron microscopy, the precise assembly pattern of cytoophidia remains unclear. In this study, we find that dmCTPS filaments can spontaneously assemble in vitro, forming network structures that reach micron-scale dimensions. Using cryo-electron tomography (cryo-ET), we reconstruct the network structures formed by dmCTPS filaments under substrate or product binding conditions and elucidate their assembly process. The dmCTPS filaments initially form structural bundles, which then further assemble into larger networks. By identifying, tracking, and statistically analyzing the filaments, we observed distinct characteristics of the structural bundles formed under different conditions. This study provides the first systematic analysis of dmCTPS filament networks, offering new insights into the relationship between cytoophidia and metabolic filaments.

嗜细胞器是一种新型的无膜细胞器，最早是在果蝇的卵巢中利用荧光显微镜观察到的。在体外，纯化的黑腹果蝇 CTPS（dmCTPS）可以在底物或产物存在的情况下形成代谢丝，其结构已通过冷冻电镜（cryo-EM）进行了分析。这些 dmCTPS 丝被认为是细胞噬菌体的基本单位。然而，由于光学显微镜和电子显微镜之间的分辨率差距，细胞噬纤维的精确组装模式仍不清楚。在这项研究中，我们发现 dmCTPS 细丝可在体外自发组装，形成达到微米级尺寸的网络结构。我们利用低温电子断层扫描（cryo-ET）重建了 dmCTPS 细丝在底物或产物结合条件下形成的网络结构，并阐明了它们的组装过程。dmCTPS 细丝最初形成结构束，然后进一步组装成更大的网络。通过识别、跟踪和统计分析这些丝状物，我们观察到在不同条件下形成的结构束具有不同的特征。这项研究首次对 dmCTPS 细丝网络进行了系统分析，为了解细胞膜和代谢细丝之间的关系提供了新的视角。

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引用次数: 0

NONRATT000538.2 promotes vascular smooth muscle cell phenotypic switch and in-stent restenosis Nonratt000538.2 可促进血管平滑肌细胞表型转换和支架内再狭窄。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-18 DOI: 10.1016/j.yexcr.2024.114260

Vascular smooth muscle cell (VSMC) excessive proliferation and migration are considered the main pathological process in in-stent restenosis (ISR) following vascular intervention. Certain long noncoding RNAs play vital roles in this process. Therefore, this study aimed to explore novel regulators for ISR and further uncover the mechanism. Using a rat abdominal aorta stent implantation model, we observed that NONRATT000538.2 (NR538.2) served as a positive regulator for VSMC proliferation and migration. By manipulating NR538.2 expression via adenoviral overexpression or siRNA knockdown, we noted that NR538.2 promoted VSMC phenotypic switching, thereby inducing proliferation and migration. Significantly, the local delivery of siRNA of NR538.2 via adeno-associated virus vector suppressed balloon injury-induced neointima formation. Our study demonstrated for the first time that NR538.2 positively influenced VSMC proliferation during ISR.

血管平滑肌细胞（VSMC）过度增殖和迁移被认为是血管介入治疗后支架内再狭窄（ISR）的主要病理过程。某些长非编码 RNA 在这一过程中发挥着重要作用。因此，本研究旨在探索ISR的新型调控因子，并进一步揭示其机制。我们利用大鼠腹主动脉支架植入模型观察到，NONRATT000538.2（NR538.2）是VSMC增殖和迁移的正向调节因子。通过腺病毒过表达或 siRNA 敲除操纵 NR538.2 的表达，我们注意到 NR538.2 促进了 VSMC 表型的转换，从而诱导了增殖和迁移。值得注意的是，通过腺相关病毒载体局部递送 NR538.2 siRNA 可抑制球囊损伤诱导的新生血管形成。我们的研究首次证明了 NR538.2 对 ISR 期间 VSMC 的增殖有积极影响。

引用次数: 0

The reduction of imidazole propionate induced by intermittent fasting promotes recovery of peripheral nerve injury by enhancing migration of Schwann cells 间歇性禁食诱导咪唑丙酸盐减少，通过增强许旺细胞的迁移促进周围神经损伤的恢复

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-18 DOI: 10.1016/j.yexcr.2024.114261

Peripheral nerve injury (PNI) accompanied with sensory and motor dysfunction has serious effect on the quality of life of patients. Intermittent fasting (IF), as a dietary pattern, has rarely been reported to influence imidazole propionate (ImP), a microbial metabolite, in vivo. To date, the link between ImP and PNI is unknown. This study aimed to explore the impact of ImP on the recovery after PNI and determine whether IF could reduce the concentration of ImP in vivo. Sciatic nerve injury rat model and RSC96 cells were utilized with 16s RNA seq, HE staining, CCK-8 assay, Western blot (WB), Transmission electron microscopy (TEM), immunofluorescence, transwell and scratch wound healing assays as read outs. WB, TEM, transwell and wound healing assay showed an inhibitory effect of ImP on autophagy and migration of Schwann cells. This negative effect on migration was reversed by rapamycin. Detection of p-Erk and p-mTOR confirmed that the MAPK/Erk/mTOR pathway was involved in this process. In vivo, IF changed the composition of gut microbiome, including bacteria related to ImP production and reduced the concentration of ImP in serum. In sum, IF influenced the composition of gut microbiome and reduced the concentration of ImP in vivo. The reduction of ImP promoted migration of SCs through enhancing autophagy which involved MAPK/Erk/mTOR pathway.

伴有感觉和运动功能障碍的周围神经损伤（PNI）严重影响患者的生活质量。间歇性禁食（IF）作为一种饮食模式，很少有报道称它会影响体内微生物代谢产物咪唑丙酸盐（ImP）。迄今为止，ImP 与 PNI 之间的联系尚不清楚。本研究旨在探讨 ImP 对坐骨神经损伤后恢复的影响，并确定 IF 是否能降低体内 ImP 的浓度。研究利用坐骨神经损伤大鼠模型和 RSC96 细胞，采用 16s RNA seq、HE 染色、CCK-8 检测、Western 印迹（WB）、透射电子显微镜（TEM）、免疫荧光、transwell 和划痕伤口愈合检测等方法进行检测。WB、TEM、transwell 和伤口愈合试验表明，ImP 对许旺细胞的自噬和迁移有抑制作用。雷帕霉素可逆转这种对迁移的负面影响。p-Erk和p-mTOR的检测证实，MAPK/Erk/mTOR通路参与了这一过程。在体内，IF 改变了肠道微生物群的组成，包括与 ImP 生成有关的细菌，并降低了血清中 ImP 的浓度。总之，IF 影响了肠道微生物群的组成，降低了体内 ImP 的浓度。ImP的减少通过增强自噬作用促进了SCs的迁移，而自噬作用涉及MAPK/Erk/mTOR途径。

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引用次数: 0

MSC-derived exosomes attenuates pulmonary hypertension via inhibiting pulmonary vascular remodeling 间充质干细胞衍生的外泌体通过抑制肺血管重塑减轻肺动脉高压

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-17 DOI: 10.1016/j.yexcr.2024.114256

Background

Pulmonary hypertension (PH) is a serious cardiopulmonary disease with significant morbidity and mortality. Vascular obstruction leads to a continuous increase in pulmonary vascular resistance, vascular remodeling, and right ventricular hypertrophy and failure, which are the main pathological features of PH. Currently, the treatments for PH are very limited, so new methods are urgently needed. Msenchymal stem cells-derived exosomes have been shown to have significant therapeutic effects in PH, however, the mechanism still very blurry. Here, we investigated the possible mechanism by which umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSC-EXO) inhibited monocrotaline (MCT)-induced pulmonary vascular remodeling in a rat model of PH by regulating the NF-κB/BMP signaling pathway. Our data revealed that hUC-MSC-EXO could significantly attenuate MCT-induced PH and right ventricular hypertrophy. Moreover, the protein expression level of BMPR2, BMP-4, BMP-9 and ID1 was significantly increased, but NF-κB p65, p-NF-κB-p65 and BMP antagonists Gremlin-1 was increased in vitro and vivo. Collectively, this study revealed that the mechanism of hUC-MSC-EXO attenuates pulmonary hypertension may be related to inhibition of NF-κB signaling to further activation of BMP signaling. The present study provided a promising therapeutic strategy for PH vascular remodeling.

背景肺动脉高压（PH）是一种严重的心肺疾病，发病率和死亡率都很高。血管阻塞导致肺血管阻力持续上升、血管重塑、右心室肥大和衰竭，这是 PH 的主要病理特征。目前，治疗 PH 的方法非常有限，因此迫切需要新的方法。骨髓干细胞衍生的外泌体已被证明对PH有显著的治疗效果，但其机制仍然非常模糊。在这里，我们研究了脐带间充质干细胞衍生的外泌体（hUC-MSC-EXO）通过调节NF-κB/BMP信号通路抑制单克隆（MCT）诱导的PH大鼠模型肺血管重塑的可能机制。我们的数据显示，hUC-间充质干细胞-EXO能显著减轻MCT诱导的PH和右心室肥厚。此外，在体外和体内，BMPR2、BMP-4、BMP-9和ID1的蛋白表达水平明显升高，但NF-κB p65、p-NF-κB-p65和BMP拮抗剂Gremlin-1的蛋白表达水平升高。综上所述，本研究揭示了 hUC-MSC-EXO 减轻肺动脉高压的机制可能与抑制 NF-κB 信号转导进一步激活 BMP 信号转导有关。本研究为肺动脉高压血管重塑提供了一种前景广阔的治疗策略。

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引用次数: 0

Small leucine zipper protein negatively regulates liver fibrosis by suppressing the expression of plasminogen activator inhibitor-1 亮氨酸拉链小蛋白通过抑制纤溶酶原激活剂抑制因子-1的表达负向调节肝纤维化。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-09-16 DOI: 10.1016/j.yexcr.2024.114258

Liver fibrosis, which is caused by viral infection, toxic exposure, and autoimmune diseases, is a chronic liver disease. Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor of tissue-type plasminogen activator (tPA) and urokinase plasminogen activator, which convert plasminogen into plasmin. Therefore, PAI-1 suppresses fibrinolysis by blocking plasmin synthesis and is involved in liver fibrosis via extracellular matrix deposition. Small leucine zipper protein (sLZIP) acts as a transcription factor and plays critical roles in many cellular processes. However, the role of sLZIP in liver fibrosis remains unclear. In this study, we investigated the role of sLZIP in regulating PAI-1 transcription and liver fibrosis. sLZIP knockdown enhanced the expression of PAI-1 at the mRNA and protein levels. sLZIP knockdown also increased PAI-1 secretion and suppressed blood clot lysis by blocking tPA activity. Moreover, conditioned medium derived from sLZIP knockdown cells downregulated the expression of matrix metalloprotease (MMP)-2 and MMP-9 in the presence of tPA in hepatic stellate cells (HSCs). Liver-specific sLZIP knockout mice showed deteriorated liver fibrosis compared to control mice in a bile duct ligation-induced fibrosis model. These findings demonstrate that sLZIP functions as a negative regulator of liver fibrosis by suppressing PAI-1 transcription and HSC activation.

肝纤维化是一种慢性肝病，由病毒感染、毒性暴露和自身免疫性疾病引起。纤溶酶原激活物抑制剂-1（PAI-1）是组织型纤溶酶原激活物（tPA）和尿激酶纤溶酶原激活物的一种丝氨酸蛋白酶抑制剂，而组织型纤溶酶原激活物和尿激酶纤溶酶原激活物可将纤溶酶原转化为纤溶酶。因此，PAI-1 通过阻断纤溶酶的合成来抑制纤溶，并通过细胞外基质沉积参与肝纤维化。小亮氨酸拉链蛋白（sLZIP）是一种转录因子，在许多细胞过程中发挥关键作用。然而，sLZIP 在肝纤维化中的作用仍不清楚。本研究调查了 sLZIP 在调节 PAI-1 转录和肝纤维化中的作用。sLZIP 敲除可提高 PAI-1 在 mRNA 和蛋白水平的表达。此外，在有tPA存在的情况下，sLZIP敲除细胞产生的条件培养基会下调肝星状细胞（HSCs）中基质金属蛋白酶（MMP）-2和MMP-9的表达。在胆管结扎诱导的肝纤维化模型中，肝特异性sLZIP基因敲除小鼠的肝纤维化程度比对照小鼠更严重。这些研究结果表明，sLZIP通过抑制PAI-1转录和造血干细胞活化，起到肝纤维化负调控因子的作用。

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