Experimental cell research最新文献_第5页

METTL14-mediated m6A methylation regulates pathological retinal neovascularization by targeting autophagy METTL14 介导的 m6A 甲基化通过靶向自噬调节病理性视网膜新生血管。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-24 DOI: 10.1016/j.yexcr.2024.114291

Yang Yu , Huiling Nie , Xun Qin , Xi Chen , Xiumiao Li , Jin Yao

Pathological retinal neovascularization (RNV) is a prevalent characteristic of various ocular diseases, including proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and retinal vein occlusion (RVO). While the importance of N6-methyladenosine (m6A) modification in diverse disease contexts is well-established, its functional role in pathological RNV remains unclear. Herein, we investigated the involvement of m6A modification and its core methyltransferase, METTL14, in a model of oxygen-induced retinopathy (OIR) to elucidate their contribution to retinal angiogenesis. In this study, we observed heightened levels of m6A modification and elevated expression of METTL14 in the OIR model, suggesting their potential implication in pathological RNV. Employing targeted knockdown of METTL14, we revealed that its depletion activated autophagy flux in human retinal vascular endothelial cells (HRVECs), consequently inhibiting the angiogenic capacity of endothelial cells. Mechanistically, we demonstrated that METTL14 exerts its regulatory influence on autophagy flux by modulating the stability of ATG7, a pivotal protein involved in autophagy. Specifically, METTL14 knockdown led to increased ATG7 expression at both mRNA and protein levels, accompanied by reduced m6A methylation of ATG7 mRNA and enhanced mRNA stability. Moreover, silencing of ATG7 counteracted the effects of METTL14 knockdown on endothelial cell functions, emphasizing ATG7 as a downstream target of METTL14-mediated autophagy in HRVECs. After all, our findings provide valuable insights into the pathogenesis of retinal pathological angiogenesis and potential therapeutic targets for the treatment of ocular neovascular diseases.

病理性视网膜新生血管（RNV）是包括增殖性糖尿病视网膜病变（PDR）、早产儿视网膜病变（ROP）和视网膜静脉闭塞（RVO）在内的多种眼部疾病的普遍特征。虽然 N6-甲基腺苷（m6A）修饰在各种疾病中的重要性已得到证实，但其在病理性 RNV 中的功能作用仍不清楚。在此，我们研究了氧诱导视网膜病变（OIR）模型中 m6A 修饰及其核心甲基转移酶 METTL14 的参与情况，以阐明它们对视网膜血管生成的贡献。在这项研究中，我们观察到 OIR 模型中 m6A 修饰水平升高和 METTL14 表达升高，这表明它们可能与病理 RNV 有关。通过靶向敲除 METTL14，我们发现其消耗激活了人视网膜血管内皮细胞（HRVECs）的自噬通量，从而抑制了内皮细胞的血管生成能力。从机理上讲，我们证明了METTL14是通过调节参与自噬的关键蛋白ATG7的稳定性来对自噬通量施加调控影响的。具体来说，敲除 METTL14 会导致 ATG7 在 mRNA 和蛋白质水平上的表达增加，同时 ATG7 mRNA 的 m6A 甲基化减少，mRNA 的稳定性增强。此外，ATG7的沉默抵消了METTL14敲除对内皮细胞功能的影响，强调了ATG7是METTL14介导的HRVECs自噬的下游靶点。总之，我们的研究结果为了解视网膜病理性血管生成的发病机制以及治疗眼部新生血管疾病的潜在治疗靶点提供了宝贵的见解。

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引用次数: 0

Downregulation of heat shock protein 47 caused lysosomal dysfunction leading to excessive chondrocyte apoptosis 热休克蛋白 47 的下调会导致溶酶体功能障碍，从而导致软骨细胞过度凋亡。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-22 DOI: 10.1016/j.yexcr.2024.114294

Yawen Shi , Ying He , Yanan Li , Meng Zhang , Yinan Liu , Hui Wang , Zhiran Shen , Xiaoru Zhao , Rui Wang , Tianyou Ma , Pinglin Yang , Jinghong Chen

Heat shock protein 47 (HSP47) is a collagen-specific chaperone present in several regions of the endoplasmic reticulum and cytoplasm. Elevated HSP47 expression in cells causes various cancers and fibrotic disorders. However, the consequences of HSP47 downregulation leading to chondrocyte death, as well as the underlying pathways, remain largely unclear. This study presents the first experimental evidence of the localization of HSP47 on lysosomes. Additionally, it successfully designed and generated shRNA HSP47 target sequences to suppress the expression of HSP47 in ATDC5 chondrocytes using lentiviral vectors. By employing a chondrocyte model that has undergone stable downregulation of HSP47, we observed that HSP47 downregulation in chondrocytes, disturbs the acidic homeostatic environment of chondrocyte lysosomes, causes hydrolytic enzyme activity dysregulation, impairs the lysosome-mediated autophagy-lysosome pathway, and causes abnormal expression of lysosomal morphology, number, and functional effector proteins. This implies the significance of the presence of HSP47 in maintaining proper lysosomal function. Significantly, the inhibitor CA-074 Me, which can restore the dysfunction of lysosomes, successfully reversed the negative effects of HSP47 on the autophagy-lysosomal pathway and partially reduced the occurrence of excessive cell death in chondrocytes. This suggests that maintaining proper lysosomal function is crucial for preventing HSP47-induced apoptosis in chondrocytes. The existence of HSP47 is crucial for preserving optimal lysosomal function and autophagic flux, while also inhibiting excessive apoptosis in ATDC5 chondrocytes.

热休克蛋白 47（HSP47）是一种胶原蛋白特异性伴侣蛋白，存在于内质网和细胞质的多个区域。细胞中 HSP47 表达升高会导致各种癌症和纤维化疾病。然而，HSP47 下调导致软骨细胞死亡的后果以及潜在的途径在很大程度上仍不清楚。本研究首次通过实验证明了 HSP47 在溶酶体上的定位。此外，该研究还成功设计并生成了 shRNA HSP47 靶序列，利用慢病毒载体抑制 HSP47 在 ATDC5 软骨细胞中的表达。通过采用稳定下调 HSP47 的软骨细胞模型，我们观察到软骨细胞中 HSP47 的下调会扰乱软骨细胞溶酶体的酸性平衡环境，导致水解酶活性失调，损害溶酶体介导的自噬-溶酶体通路，并引起溶酶体形态、数量和功能效应蛋白的异常表达。这意味着 HSP47 的存在对维持溶酶体的正常功能具有重要意义。值得注意的是，能恢复溶酶体功能障碍的抑制剂 CA-074 Me 成功逆转了 HSP47 对自噬-溶酶体通路的负面影响，并部分减少了软骨细胞过度细胞死亡的发生。这表明，维持溶酶体的正常功能对于防止 HSP47 诱导的软骨细胞凋亡至关重要。HSP47的存在对保持最佳溶酶体功能和自噬通量至关重要，同时还能抑制ATDC5软骨细胞的过度凋亡。

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引用次数: 0

ALKBH5 promotes T-cell acute lymphoblastic leukemia growth via m⁶A-guided epigenetic inhibition of miR-20a-5p. ALKBH5 通过 m6A 引导的 miR-20a-5p 表观遗传抑制作用促进 T 细胞急性淋巴细胞白血病的生长。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-21 DOI: 10.1016/j.yexcr.2024.114293

Jiazhuo Liu, Xin Zhang, Yi Liao, Chunlan Zhang, Leiwen Peng

This study investigates the role of ALKBH5-mediated m⁶A demethylation in T-cell acute lymphoblastic leukemia (T-ALL). T-ALL cell lines (HPB-ALL, MOLT4, Jurkat, CCRF-CEM) and human T cells were analyzed. CCRF-CEM and Jurkat cells were transfected with si-ALKBH5, miR-20a-5p-inhibitor, and pcDNA3.1-DDX5. The expression levels of ALKBH5, miR-20a-5p, and DDX5 in these cells were determined using qRT-PCR and Western blotting. Cell viability, proliferation, colony formation, and apoptosis were assessed using CCK-8, EdU staining, colony formation assay, and flow cytometry. mRNA m6A levels were quantified with an m6A RNA methylation detection reagent, and RNA immunoprecipitation was employed to measure the enrichment of DGCR8 and m6A on the primary transcript pri-miR-20a of miR-20a-5p. Dual-luciferase assay confirmed the binding relationship between miR-20a-5p and DDX5. Results showed that ALKBH5 and DDX5 were upregulated in T-ALL tissues and cells, whereas miR-20a-5p was downregulated. Silencing ALKBH5 inhibited T-ALL cell viability, colony formation, and proliferation, while promoting apoptosis. These effects were reversed by miR-20a-5p inhibition or DDX5 overexpression. ALKBH5 reduced the relative m⁶A level in T-ALL cells and decreased miR-20a-5p expression by reducing DGCR8 binding to pri-miR-20a-5p. miR-20a-5p suppressed DDX5 transcription. In conclusion, ALKBH5-mediated m⁶A demethylation decreases DGCR8 binding to pri-miR-20a, thereby repressing miR-20a-5p expression and enhancing DDX5 expression, ultimately inhibiting T-ALL cell apoptosis and promoting proliferation.

本研究探讨了 ALKBH5 介导的 m6A 去甲基化在 T 细胞急性淋巴细胞白血病（T-ALL）中的作用。研究分析了 T-ALL 细胞系（HPB-ALL、MOLT4、Jurkat、CCRF-CEM）和人类 T 细胞。用 si-ALKBH5、miR-20a-5p 抑制剂和 pcDNA3.1-DDX5 转染 CCRF-CEM 和 Jurkat 细胞。采用 qRT-PCR 和 Western 印迹法测定这些细胞中 ALKBH5、miR-20a-5p 和 DDX5 的表达水平。使用 m6A RNA 甲基化检测试剂量化了 mRNA m6A 水平，并采用 RNA 免疫沉淀法测定了 miR-20a-5p 的主转录本 pri-miR-20a 上 DGCR8 和 m6A 的富集情况。双荧光素酶测定证实了 miR-20a-5p 与 DDX5 的结合关系。结果显示，ALKBH5和DDX5在T-ALL组织和细胞中上调，而miR-20a-5p则下调。沉默 ALKBH5 会抑制 T-ALL 细胞的活力、集落形成和增殖，同时促进细胞凋亡。抑制 miR-20a-5p 或过表达 DDX5 可逆转这些影响。ALKBH5 降低了 T-ALL 细胞中 m6A 的相对水平，并通过减少 DGCR8 与 pri-miR-20a-5p 的结合降低了 miR-20a-5p 的表达。总之，ALKBH5 介导的 m6A 去甲基化减少了 DGCR8 与 pri-miR-20a 的结合，从而抑制了 miR-20a-5p 的表达，增强了 DDX5 的表达，最终抑制了 T-ALL 细胞的凋亡，促进了细胞的增殖。

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引用次数: 0

TIPE2 aggravates experimental colitis and disrupts intestinal epithelial barrier integrity by activating JAK2/STAT3/SOCS3 signal pathway TIPE2 通过激活 JAK2/STAT3/SOCS3 信号通路，加重实验性结肠炎并破坏肠上皮屏障的完整性。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-18 DOI: 10.1016/j.yexcr.2024.114287

Lingli Zeng , Yuping Wang , Jiaxin Shen , Xujin Wei , Yilong Wu , Xintong Chi , Xueyan Zheng , Xing Yu , Ying Shi , Wenming Liu

Ulcerative colitis (UC) is a chronic relapsing and progressive inflammatory disease of the colon. TIPE2 is a negative regulator of innate and adaptive immunity that maintains immune homeostasis. We found that TIPE2 was highly expressed in mucosa of mice with colitis. However, the role of TIPE2 in colitis remains unclear. We induced colitis in mice with dextran sulfate sodium (DSS) and treated them with TIPE2, and investigated the inflammatory activity of the colon in vivo by cytokines detection and histopathological analyses. We also measured inflammatory alteration and tight junctions induced by DSS in vitro. The results demonstrated that administration of TIPE2 promoted the severity of colitis in mice and human colon epithelial cells. Furthermore, TIPE2 aggravated intestinal epithelial barrier dysfunction by decreasing the expression of the tight junction proteins Occludin, Claudin-1 and ZO-1. In addition, TIPE2 exacerbated intestinal inflammatory response by inhibiting the expression of SOCS3, remarkably activating JAK2/STAT3 signaling pathway, and increasing the translocation of phosphorylated STAT3 into the nucleus. Silencing of TIPE2 attenuated the DSS-induced activation of JAK2/STAT3, thereby rescuing epithelial inflammatory injury and restoring barrier dysfunction. These results indicate that TIPE2 augments experimental colitis and disrupted the integrity of the intestinal epithelial barrier by activating the JAK2/STAT3/SOCS3 signaling pathway.

溃疡性结肠炎（UC）是一种慢性复发性和进行性结肠炎性疾病。TIPE2 是先天性免疫和适应性免疫的负调控因子，可维持免疫平衡。我们发现 TIPE2 在结肠炎小鼠粘膜中高表达。然而，TIPE2 在结肠炎中的作用仍不清楚。我们用葡聚糖硫酸钠（DSS）诱导小鼠结肠炎，并用 TIPE2 治疗小鼠，通过细胞因子检测和组织病理学分析研究体内结肠的炎症活动。我们还在体外测量了 DSS 诱导的炎症改变和紧密连接。结果表明，服用 TIPE2 会加重小鼠和人类结肠上皮细胞结肠炎的严重程度。此外，TIPE2 通过降低紧密连接蛋白 Occludin、Claudin-1 和 ZO-1 的表达，加剧了肠上皮屏障功能障碍。此外，TIPE2 通过抑制 SOCS3 的表达、显著激活 JAK2/STAT3 信号通路以及增加磷酸化 STAT3 向细胞核的转位，加剧了肠道炎症反应。沉默 Tipe2 可减轻 DSS 诱导的 JAK2/STAT3 激活，从而挽救上皮炎症损伤并恢复屏障功能障碍。这些结果表明，TIPE2通过激活JAK2/STAT3/SOCS3信号通路，加剧了实验性结肠炎并破坏了肠上皮屏障的完整性。

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引用次数: 0

Cellular resiliency and survival of Neuro-2a cells under extreme stress 神经-2a 细胞系在极端压力下的细胞恢复能力和存活率

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-09 DOI: 10.1016/j.yexcr.2024.114275

Randall Hernandez-Jimenez , Ankit Patel , Ana Machado-Olavarria , Hailey Mathieu , Jessica Wohlfahrt , Jennifer Guergues , Stanley M. Stevens , Ashutosh Dharap

Stressors such as hypoxia, hypothermia, and acute toxicity often result in widespread cell death. This study investigated the outcomes of Neuro-2a (N2a; mouse neuroblastoma) cells following a cryogenic storage failure that exposed them to a combination of these stressors over a period of approximately 24-30 hours. Remarkably, a small fraction of the cells survived the event, underwent a period of dormancy, and eventually recovered to a healthy state. To understand the underlying resilience mechanisms, we created a model to replicate the dewar failure event and examined changes in phenotype, transcriptomics, proteomics, and mitochondrial activity of the surviving cells during recovery. We found that the surviving cells initially displayed a stressed morphology with irregular membranes and a clustered apperance. They showed an increased expression of proteins related to DNA repair and chromatin modification pathways as well as heightened mitochondrial function shortly after the stress event. As recovery progressed, the stress-responsive pathways, mitochondrial activity, and growth rates normalized toward that of healthy controls, indicating a return to a stable baseline state. These findings suggest that an initial robust energetic state supports key stress-responsive and repair pathways at the early stages of recovery, facilitating cell survival and resiliency after extreme stress. This work provides valuable insights into cellular resilience mechanisms with potential implications for improving cell preservation and recovery in biomedical applications and developing therapeutic strategies for conditions involving cell damage and stress.

这项研究调查了神经-2a（N2a）细胞在低温储存失败后的存活和恢复情况，低温储存失败使这些细胞暴露在极端应激条件下，如缺氧、低体温和急性中毒。值得注意的是，一小部分细胞存活下来并最终恢复。为了了解潜在的恢复机制，我们创建了一个模型来复制脱水失败事件，并研究了存活细胞在恢复过程中表型、转录组学、蛋白质组学和线粒体活性的变化。结果发现，存活的细胞最初表现出受压形态，细胞膜不规则，细胞聚集。在应激事件发生后不久，它们显示出与DNA修复和染色质修饰途径相关的蛋白质表达增加，线粒体功能增强。随着恢复的进行，这些应激反应途径和线粒体活性趋于正常，表明已恢复到稳定状态。这些研究结果表明，最初强大的能量状态支持关键的应激反应途径，有利于细胞在极端应激后存活和恢复。这项工作为了解细胞恢复机制提供了宝贵的见解，对改善生物医学应用中的细胞保存和恢复，以及针对涉及细胞损伤和应激的病症制定治疗策略具有潜在的意义。

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引用次数: 0

Deficiency in the Rab25 gene leads to a decline in male fertility and testicular injury: Impact on the regulation of germ cell proliferation and apoptosis Rab25 基因缺陷会导致男性生育能力下降和睾丸损伤：对生殖细胞增殖和凋亡调控的影响

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-01 DOI: 10.1016/j.yexcr.2024.114285

Qiang Zhang , Zhicheng Zhang , Zhenmin Liu , Chong Wang , Hongsong Chen , Lianju Shen , Chunlan long , Guanghui Wei , Xing Liu

Background

Rab25 is a member of the Rab family, functioning as a regulatory molecule in intracellular transport. Although its involvement in cellular functions and disease development is well-established, its precise roles in male reproductive physiology remain elusive.

Methods

To explore the specific roles of Rab25 in testicular development and spermatogenesis, we established the Rab25^−/− mouse model and Rab25 knockdown germ cell line (GC-2). We compared the fertility, sperm analysis, and testicular tissues between Rab25^−/− and wild-type male mice. To delve deeper into potential mechanisms, we employed immunohistochemistry, TUNEL assay, Western Blotting, CCK-8 assay, etc. to evaluate cell proliferation and apoptosis in testicular tissues and GC-2 cells.

Results

Our findings indicated that Rab25 was expressed in germ cells and Leydig cells in the testes. Although the weight of Rab25^−/− mice testes exhibited no significant changes, fertility was compromised, with a decrease in sperm quantity and reduced motility. HE staining revealed a disorganized arrangement of germ cells and vacuolization. Additionally, chromatin marginalization and nuclear pyknosis were observed in the Rab25^−/− mice. In both Rab25^−/− mice testes and Rab25 knockdown GC-2 cells, we found that germ cell proliferation was reduced, while apoptosis was increased.

Conclusions

In conclusion, our study proposes that Rab25 plays a vital role in spermatogenesis by regulating the proliferation and apoptosis of germ cells.

背景Rab25是Rab家族的成员，是细胞内运输的调控分子。尽管Rab25参与细胞功能和疾病发展的作用已得到证实，但其在男性生殖生理中的确切作用却仍然难以捉摸：为了探索 Rab25 在睾丸发育和精子发生中的具体作用，我们建立了 Rab25-/- 小鼠模型和 Rab25 基因敲除生殖细胞系（GC-2）。我们比较了 Rab25-/- 和野生型雄性小鼠的生育能力、精子分析和睾丸组织。为了深入研究潜在的机制，我们采用了免疫组化、TUNEL 检测、Western 印迹、CCK-8 检测等方法来评估睾丸组织和 GC-2 细胞的细胞增殖和凋亡情况：结果：我们的研究结果表明，Rab25在睾丸的生殖细胞和Leydig细胞中表达。虽然 Rab25-/- 小鼠睾丸的重量没有发生显著变化，但生育能力却受到了影响，精子数量减少，活力降低。HE 染色显示生殖细胞排列紊乱并出现空泡化。此外，在 Rab25-/- 小鼠体内还观察到染色质边缘化和核焦变。在Rab25-/-小鼠睾丸和Rab25敲除的GC-2细胞中，我们发现生殖细胞增殖减少，而凋亡增加：总之，我们的研究提出，Rab25通过调节生殖细胞的增殖和凋亡，在精子发生过程中发挥着重要作用。

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引用次数: 0

Exercise training alleviates cholesterol and lipid accumulation in mice with non-alcoholic steatohepatitis: Reduction of KMT2D-mediated histone methylation of IDI1 运动训练可减轻非酒精性脂肪性肝炎小鼠的胆固醇和脂质积累：减少 KMT2D 介导的 IDI1 组蛋白甲基化。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-01 DOI: 10.1016/j.yexcr.2024.114265

Xiuqin Fan , Hongshi Wang , Weiwei Wang , Jiayan Shen , Zejun Wang

Exercise training is a cornerstone treatment for non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the effects of exercises on lipid accumulation in non-alcoholic steatohepatitis (NASH) and to explore the molecular mechanism. Established NASH mice were remained sedentary or subjected to moderate-intensity continuous training or high-intensity interval training (HIIT). The two training regimens, especially the latter one, reduced liver weight, steatosis, inflammation, lipid accumulation, collagen deposition, and cholesterol content in the mouse liver. Similarly, the HIIT regimen improved clinical presentation of NAFLD patients. RNA sequencing analysis revealed lysine methyltransferase 2D (Kmt2d) and isopentenyl-diphosphate delta isomerase 1 (Idi1) as two important genes downregulated in mice underwent HIIT. By using mouse hepatocytes AML12, we found that KMT2D promoted Idi1 expression by catalyzing H3K4me1 modification near its promoter. Upregulation of either KMT2D or IDI1 blocked the ameliorating effects of HIIT on mice. Meanwhile, in AML12 cells modeled by palmitic acid and oleic acid treatment, KMT2D and IDI1 were found to be correlated with lipid accumulation, cholesterol content, inflammation, and cell death and senescence. In conclusion, this study demonstrates that the ameliorating effects of exercise training on NASH might involve the downregulation of the KMT2D/IDI1 axis.

运动训练是治疗非酒精性脂肪肝（NAFLD）的基础疗法。本研究旨在探讨运动对非酒精性脂肪性肝炎（NASH）脂质积累的影响，并探索其分子机制。研究人员让已确诊为非酒精性脂肪性肝炎的小鼠保持静坐或接受中等强度的持续训练或高强度间歇训练（HIIT）。两种训练方案，尤其是后一种，都减轻了小鼠肝脏的重量、脂肪变性、炎症、脂质积累、胶原沉积和胆固醇含量。同样，HIIT疗法也改善了非酒精性脂肪肝患者的临床表现。RNA测序分析表明，赖氨酸甲基转移酶2D（Kmt2d）和异戊烯基二磷酸δ异构酶1（Idi1）是接受HIIT的小鼠体内两个重要的下调基因。通过使用小鼠肝细胞 AML12，我们发现 KMT2D 通过催化 Idi1 启动子附近的 H3K4me1 修饰促进了 Idi1 的表达。KMT2D或IDI1的上调会阻止HIIT对小鼠的改善作用。同时，在棕榈酸和油酸处理的 AML12 细胞模型中，发现 KMT2D 和 IDI1 与脂质积累、胆固醇含量、炎症、细胞死亡和衰老相关。总之，本研究表明，运动训练对NASH的改善作用可能涉及KMT2D/IDI1轴的下调。

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引用次数: 0

The emerging role of miRNAs in pituitary adenomas: From molecular signatures to diagnostic potential miRNA 在垂体腺瘤中的新作用：从分子特征到诊断潜力。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-01 DOI: 10.1016/j.yexcr.2024.114279

Ahmed S. Doghish , Gharieb S. El-Sayyad , Sherif S. Abdel Mageed , Mai A. Abd-Elmawla , Al-Aliaa M. Sallam , Manar Mohammed El Tabaa , Nehal I. Rizk , Alaa Ashraf , Osama A. Mohammed , Safwat Abdelhady Mangoura , Tohada M. AL-Noshokaty , Mohamed Bakr Zaki , Walaa A. El-Dakroury , Mahmoud A. Elrebehy , Mustafa Ahmed Abdel-Reheim , Mohammed S. Elballal , Ahmed I. Abulsoud

Pituitary adenomas (PAs) are an array of tumors originating from the pituitary gland. PAs are sorted as functional or nonfunctional according to their hormonal activity and classified according to size into microadenomas and macroadenomas. Still, the cellular events that trigger the transformations in pituitary neoplasms are not fully understood, and the current classification methods do not precisely predict clinical behavior. A rising number of researches have emphasized the role of miRNAs, that drawn more attention as oncogenic molecules or tumor suppressors. The etiopathological mechanisms of PAs include multiple molecular cascades that are influenced by different miRNAs. miRNAs control the cell cycle control, pro- or antiapoptotic processes, and tumor invasion and metastasis. miRNAs offer a novel perspective on tumor features and behaviors and might be valuable in prognostication and therapeutic plans. In pituitary adenomas, miRNAs showed a specific expression pattern depending on their size, cell origin, remission, and treatments. Screening miRNA expression patterns is promising to monitor and evaluate recurrence, as well as to investigate the efficacy of radiation and chemotherapy for PAs exhibiting aggressive behavior. Thus, the current review investigated the interplay of the miRNAs' pivotal role in offering new opportunities to translate these innovative epigenetic tools into healthcare applications.

垂体腺瘤（PAs）是源自垂体的一系列肿瘤。垂体腺瘤根据其激素活性分为功能性和非功能性两种，并根据大小分为微腺瘤和大腺瘤。然而，引发垂体肿瘤转变的细胞事件尚未完全明了，目前的分类方法也不能准确预测临床表现。越来越多的研究强调了 miRNA 的作用，它们作为致癌分子或肿瘤抑制因子引起了更多关注。miRNAs控制着细胞周期控制、促凋亡或抗凋亡过程，以及肿瘤的侵袭和转移。miRNAs为肿瘤特征和行为提供了一个新的视角，可能对预后和治疗方案有重要价值。在垂体腺瘤中，miRNAs表现出特定的表达模式，这取决于肿瘤的大小、细胞来源、缓解程度和治疗方法。筛选 miRNA 表达模式有望监测和评估复发情况，以及研究放疗和化疗对具有侵袭性的 PA 的疗效。因此，本综述研究了 miRNA 在提供新机会将这些创新的表观遗传工具转化为医疗应用方面的关键作用。

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引用次数: 0

Exosomal microRNA-363 mediates the destructive effect of M1 macrophages on chondrocytes by repressing G3BP2 外泌体 microRNA-363 通过抑制 G3BP2 来介导 M1 巨噬细胞对软骨细胞的破坏作用。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-01 DOI: 10.1016/j.yexcr.2024.114276

Wenteng Si , Hongchao Wei , Wenzhong Chen , Bin Chen , Yu Zhou , Huaguo Zhang

M1 polarization of synovial macrophages contributes to cartilage degeneration and osteoarthritis (OA) development. However, limited knowledge is available about how M1 macrophages affect the biological properties of chondrocytes. This study aimed to explore the role of exosomal microRNAs (miRs) released from M1 macrophages in modulating the proliferation and survival of chondrocytes. Through bioinformatic analysis and experimental validation, we indicated that miR-363 was selectively induced in M1 macrophages (CD68⁺CD80⁺) but not M2 macrophages (CD68⁺CD206⁺). The upregulation of miR-363 in M1 macrophages depended on the activation of STAT1 signaling. Clinically, OA patients had a significantly higher miR-363 level in synovial fluid than control individuals without OA. Functional studies revealed that inhibition of miR-363 blocked the M1 macrophage polarization induced by lipopolysaccharide and IFN-γ. Moreover, exosomal miR-363 released from M1 macrophages significantly suppressed the proliferation and survival and induced inflammatory gene expression in chondrocytes. G3BP2 was identified as a target gene for miR-363 and could be negatively regulated by miR-363. Knockdown of G3BP2 recapitulated the effect of miR-363 overexpression on chondrocytes. Most importantly, enforced expression of G3BP2 attenuated miR-363-induced apoptosis and inflammatory response in chondrocytes. In conclusion, miR-363 plays an indispensable role in M1 macrophage polarization and can be released from M1 macrophages via exosomes to cause chondrocyte injury and inflammation. The miR-363/G3BP2 axis may represent a promising target for the prevention of OA development.

滑膜巨噬细胞的 M1 极化有助于软骨退化和骨关节炎（OA）的发展。然而，关于 M1 巨噬细胞如何影响软骨细胞生物特性的知识却很有限。本研究旨在探索 M1 巨噬细胞释放的外泌体微RNA（miRs）在调节软骨细胞增殖和存活方面的作用。通过生物信息学分析和实验验证，我们发现 miR-363 在 M1 巨噬细胞（CD68+CD80+）而非 M2 巨噬细胞（CD68+CD206+）中被选择性诱导。miR-363 在 M1 巨噬细胞中的上调取决于 STAT1 信号的激活。临床上，OA 患者滑液中的 miR-363 水平明显高于无 OA 的对照组。功能研究显示，抑制 miR-363 能阻止脂多糖和 IFN-γ 诱导的 M1 巨噬细胞极化。此外，M1 巨噬细胞释放的外泌体 miR-363 能显著抑制软骨细胞的增殖和存活，并诱导炎症基因的表达。G3BP2被鉴定为miR-363的靶基因，可被miR-363负调控。敲除 G3BP2 重现了 miR-363 过表达对软骨细胞的影响。最重要的是，强化 G3BP2 的表达可减轻 miR-363 诱导的软骨细胞凋亡和炎症反应。总之，miR-363 在 M1 巨噬细胞极化过程中发挥着不可或缺的作用，并可通过外泌体从 M1 巨噬细胞中释放出来，导致软骨细胞损伤和炎症反应。miR-363/G3BP2轴可能是预防OA发展的一个有希望的靶点。

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引用次数: 0

Particular exosomal micro-RNAs and gastrointestinal (GI) cancer cells' roles: Current theories 特殊外泌体微RNA与胃肠道（GI）癌细胞的作用：目前的理论。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2024-10-01 DOI: 10.1016/j.yexcr.2024.114278

Bandar Almutairy , Mohammad S. Alzahrani , Dania S. Waggas , Hashem O. Alsaab

A diverse range of gastrointestinal tract disorders are called gastrointestinal (GI) malignancies. The transformation of normal cells into precursor cells, precursor cells into premalignant cells, and premalignant cells into cancerous cells is facilitated by the interaction of many modifiable and non-modifiable risk factors. Developing relevant therapy alternatives based on a better knowledge of the illness's aetiology is essential to enhance patient outcomes. The exosome is crucial in regulating intercellular interaction because it may send molecular signals to nearby or distant cells. Exosomes produced from cancer can introduce a variety of chemicals and vast concentrations of microRNA (miRNA) into the tumour microenvironment. These miRNAs significantly impact immunological evasion, metastasis, apoptosis resistance, and cell growth. Exosomal miRNAs, or exosomal miRNAs, are essential for controlling cancer resistance to apoptosis, according to mounting data. Exosomal miRNAs function as an interaction hub between cancerous cells and the milieu around them, regulating gene expression and various signalling pathways. Our research examines the regulatory function of exosomal miRNAs in mediating interactions between cancer cells and the stromal and immunological cells that make up the surrounding milieu.

多种多样的胃肠道疾病被称为胃肠道（GI）恶性肿瘤。正常细胞转化为前体细胞、前体细胞转化为恶性前体细胞、恶性前体细胞转化为癌细胞的过程是由许多可改变和不可改变的风险因素相互作用促成的。在更好地了解疾病病因的基础上开发相关的替代疗法，对于提高患者的治疗效果至关重要。外泌体在调节细胞间相互作用方面至关重要，因为它可以向邻近或远处的细胞发送分子信号。癌症产生的外泌体可将多种化学物质和高浓度的微RNA（miRNA）引入肿瘤微环境。这些 miRNA 对免疫逃避、转移、抗凋亡和细胞生长有重大影响。越来越多的数据表明，外泌体miRNA（或称外泌体miRNA）对于控制癌症对凋亡的抵抗至关重要。外泌体miRNA是癌细胞与其周围环境相互作用的枢纽，可调控基因表达和各种信号通路。我们的研究探讨了外泌体 miRNA 在介导癌细胞与构成周围环境的基质细胞和免疫细胞之间的相互作用方面的调节功能。

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引用次数: 0