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Loss of glucose-stimulated β-cell Nr4a1 expression impairs insulin secretion and glucose homeostasis. 葡萄糖刺激的β细胞Nr4a1表达缺失会损害胰岛素分泌和葡萄糖稳态。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-09-02 DOI: 10.1152/ajpcell.00315.2024
Jacob A Herring, Jacqueline E Crabtree, Jonathon T Hill, Jeffery S Tessem

A central aspect of type 2 diabetes is decreased functional β-cell mass. The orphan nuclear receptor Nr4a1 is critical for fuel utilization, but little is known regarding its regulation and function in the β-cell. Nr4a1 expression is decreased in type 2 diabetes rodent β-cells and type 2 diabetes patient islets. We have shown that Nr4a1-deficient mice have reduced β-cell mass and that Nr4a1 knockdown impairs glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 β-cells. Here, we demonstrate that glucose concentration directly regulates β-cell Nr4a1 expression. We show that 11 mM glucose increases Nr4a1 expression in INS-1 832/13 β-cells and primary mouse islets. We show that glucose functions through the cAMP/PKA/CREB pathway to regulate Nr4a1 mRNA and protein expression. Using Nr4a1-/- animals, we show that Nr4a1 is necessary for GSIS and systemic glucose handling. Using RNA-seq, we define Nr4a1-regulated pathways in response to glucose in the mouse islet, including Glut2 expression. Our data suggest that Nr4a1 plays a critical role in the β-cells response to the fed state.NEW & NOTEWORTHY Nr4a1 has a key role in fuel metabolism and β-cell function, but its exact role is unclear. Nr4a1 expression is regulated by glucose concentration using cAMP/PKA/CREB pathway. Nr4a1 regulates Glut2, Ndufa4, Ins1, In2, Sdhb, and Idh3g expression in response to glucose treatment. These results suggest that Nr4a1 is necessary for proper insulin secretion both through glucose uptake and metabolism machinery.

2 型糖尿病的一个核心问题是功能性 β 细胞数量减少。孤儿核受体 Nr4a1 对燃料利用至关重要,但人们对它在β细胞中的调节和功能知之甚少。Nr4a1在2型糖尿病啮齿动物β细胞和2型糖尿病患者胰岛中的表达减少。我们已经证明,Nr4a1缺陷小鼠的β细胞质量减少,而且Nr4a1基因敲除会损害INS-1 832/13 β细胞的葡萄糖刺激胰岛素分泌(GSIS)。在这里,我们证明了葡萄糖浓度直接调节β细胞Nr4a1的表达。我们发现 11 mM 葡萄糖能增加 INS-1 832/13 β 细胞和原代小鼠胰岛中 Nr4a1 的表达。我们发现葡萄糖通过 cAMP/PKA/CREB 途径调节 Nr4a1 mRNA 和蛋白质的表达。我们利用 Nr4a1-/- 动物表明,Nr4a1 是 GSIS 和全身葡萄糖处理所必需的。利用 RNA-seq 技术,我们确定了 Nr4a1 调节的小鼠胰岛葡萄糖反应通路,包括 Glut2 的表达。我们的数据表明,Nr4a1 在β细胞对进食状态的反应中起着关键作用。
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引用次数: 0
Na-caprate-induced increase in MDCK II epithelial cell leak pathway permeability and opening number is associated with disruption of basal F-actin organization. Na-Caprate 诱导的 MDCK II 上皮细胞漏孔通路通透性和开口数量的增加与基础 F-Actin 组织的破坏有关。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-19 DOI: 10.1152/ajpcell.00534.2023
Shivani Rana, Leyla Nasr, Daniel Chang, Josephine Axis, Kurt Amsler

Confluent populations of the epithelial cell line, MDCK II, develop circumferential tight junctions joining adjacent cells to create a barrier to the paracellular movement of solutes and water. Treatment of MDCK II cell populations from the apical surface with 1 mM Na-caprate increased permeability to macromolecules (Leak Pathway) without increasing monolayer disruption or cell death. Graphical analysis of the apparent permeability versus solute Stokes radius for a size range of fluorescein-dextran species indicates apical 1 mM Na-caprate enhances Leak Pathway permeability by increasing the number of Leak Pathway openings without significantly affecting opening size. Na-caprate treatment did not alter the content of any tight junction protein examined. Treatment of MDCK II cell populations with apical 1 mM Na-caprate disrupted basal F-actin stress fibers and decreased the tortuosity of the tight junctions. Treatment of MDCK II cell populations with blebbistatin, a myosin ATPase inhibitor, alone had little effect on Leak Pathway permeability but synergistically increased Leak Pathway permeability when added with 1 mM Na-caprate. Na-caprate exhibited a similar ability to increase Leak Pathway permeability in wild-type MDCK II cell monolayers and ZO-1 knockdown MDCK II cell monolayers but an enhanced ability to increase Leak Pathway permeability in monolayers of TOCA-1 knockout MDCK II cells. These results demonstrate that Na-caprate increases MDCK II cell population Leak Pathway permeability by increasing the number of Leak Pathway openings. This action is likely mediated by alterations in F-actin organization, primarily involving disruption of basal F-actin stress fibers.NEW & NOTEWORTHY This study determines the underlying change in the openings in the epithelial tight junction permeability barrier structure that leads to a change in the paracellular permeability to macromolecules (the Leak Pathway) and connects this to disruption of specific F-actin structures within the cells. It provides important and novel insights into how tight junction permeability to macromolecules is modulated by specific changes to cellular and tight junction composition/organization.

上皮细胞系 MDCK II 的汇合细胞群会形成周向紧密连接,将相邻细胞连接在一起,从而为溶质和水分的细胞旁运动提供屏障。用 1 mM Na-caprate从顶端表面处理 MDCK II 细胞群,可增加其对大分子的通透性(渗漏途径),但不会增加单层破坏或细胞死亡。对荧光素-葡聚糖大小范围的表观通透性与溶质斯托克斯半径的图表分析表明,顶端 1 mM Na-caprate可通过增加泄漏通路开口的数量来提高泄漏通路的通透性,而不会显著影响开口的大小。Na-caprate处理不会改变所检测的任何紧密连接蛋白的含量。用顶端 1 mM Na-caprate处理 MDCK II 细胞群会破坏基底 F-肌动蛋白应力纤维,并降低紧密连接的迂曲度。单独用肌球蛋白 ATP 酶抑制剂 blebbistatin 处理 MDCK II 细胞群对泄漏通路的通透性几乎没有影响,但如果加入 1 mM Na-caprate,则会协同增加泄漏通路的通透性。在野生型 MDCK II 细胞单层和 ZO-1 基因敲除的 MDCK II 细胞单层中,Na-caprate 增加漏孔通路通透性的能力相似,但在 TOCA-1 基因敲除的 MDCK II 细胞单层中,Na-caprate 增加漏孔通路通透性的能力增强。这些结果表明,Na-caprate 可通过增加泄漏通路开口的数量来增加 MDCK II 细胞群的泄漏通路通透性。这种作用可能是由 F-肌动蛋白组织的改变介导的,主要涉及基底 F-肌动蛋白应力纤维的破坏。
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引用次数: 0
New insights into the cellular and molecular mechanisms of skeletal muscle fatigue: the Marion J. Siegman Award Lectureships. 骨骼肌疲劳的细胞和分子机制新见解:玛丽恩-西格曼奖讲座。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-29 DOI: 10.1152/ajpcell.00213.2024
Edward P Debold, Håkan Westerblad

Skeletal muscle fibers need to have mechanisms to decrease energy consumption during intense physical exercise to avoid devastatingly low ATP levels, with the formation of rigor cross bridges and defective ion pumping. These protective mechanisms inevitably lead to declining contractile function in response to intense exercise, characterizing fatigue. Through our work, we have gained insights into cellular and molecular mechanisms underlying the decline in contractile function during acute fatigue. Key mechanistic insights have been gained from studies performed on intact and skinned single muscle fibers and more recently from studies performed and single myosin molecules. Studies on intact single fibers revealed several mechanisms of impaired sarcoplasmic reticulum Ca2+ release and experiments on single myosin molecules provide direct evidence of how putative agents of fatigue impact myosin's ability to generate force and motion. We conclude that changes in metabolites due to an increased dependency on anaerobic metabolism (e.g., accumulation of inorganic phosphate ions and H+) act to directly and indirectly (via decreased Ca2+ activation) inhibit myosin's force and motion-generating capacity. These insights into the acute mechanisms of fatigue may help improve endurance training strategies and reveal potential targets for therapies to attenuate fatigue in chronic diseases.

骨骼肌纤维需要具备在剧烈运动中减少能量消耗的机制,以避免出现破坏性的低 ATP 水平,形成僵硬交桥和离子泵缺陷。这些保护机制不可避免地会导致肌肉在剧烈运动时收缩功能下降,从而产生疲劳。通过我们的工作,我们深入了解了急性疲劳时收缩功能下降的细胞和分子机制。我们从对完整的单个肌纤维和带皮单个肌纤维的研究中,以及最近对单个肌球蛋白分子的研究中,获得了关键的机理认识。对完整单纤维的研究揭示了肌质网(SR)Ca2+释放受损的几种机制,而对单个肌球蛋白分子的实验则提供了直接证据,证明了假定的疲劳因子如何影响肌球蛋白产生力量和运动的能力。我们的结论是,由于对无氧代谢的依赖性增加(如无机磷酸盐离子和 H+ 的积累),代谢物发生了变化,从而直接或间接(即通过 Ca2+ 激活的减少)抑制了肌球蛋白产生力和运动的能力。这些关于疲劳急性机制的见解可能有助于改进耐力训练策略,并揭示减轻慢性疾病疲劳的潜在治疗目标。
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引用次数: 0
Iron-laden macrophage-mediated paracrine profibrotic signaling induces lung fibroblast activation. 含铁巨噬细胞介导的旁分泌性纤维化信号诱导肺成纤维细胞活化。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-26 DOI: 10.1152/ajpcell.00675.2023
Yunqi Li, Xinqian Du, Yue Hu, Dan Wang, Luo Duan, Hanxiao Zhang, Ruoyang Zhang, Yingjie Xu, Ruonan Zhou, Xinyu Zhang, Muzhi Zhang, Jie Liu, Zhe Lv, Yan Chen, Wei Wang, Ying Sun, Ye Cui

Idiopathic pulmonary fibrosis (IPF) is a devastating condition characterized by progressive lung scarring and uncontrolled fibroblast proliferation, inevitably leading to organ dysfunction and mortality. Although elevated iron levels have been observed in patients and animal models of lung fibrosis, the mechanisms linking iron dysregulation to lung fibrosis pathogenesis, particularly the role of macrophages in orchestrating this process, remain poorly elucidated. Here we evaluate iron metabolism in macrophages during pulmonary fibrosis using both in vivo and in vitro approaches. In murine bleomycin- and amiodarone-induced pulmonary fibrosis models, we observed significant iron deposition and lipid peroxidation in pulmonary macrophages. Intriguingly, the ferroptosis regulator glutathione peroxidase 4 (GPX4) was upregulated in pulmonary macrophages following bleomycin instillation, a finding corroborated by single-cell RNA sequencing analysis. Moreover, macrophages isolated from fibrotic mouse lungs exhibited increased transforming growth factor (TGF)-β1 expression that correlated with lipid peroxidation. In vitro, iron overload in bone marrow-derived macrophages triggered lipid peroxidation and TGF-β1 upregulation, which was effectively suppressed by ferroptosis inhibitors. When cocultured with iron-overloaded macrophages, lung fibroblasts exhibited heightened activation, evidenced by increased α-smooth muscle actin and fibronectin expression. Importantly, this profibrotic effect was attenuated by treating macrophages with a ferroptosis inhibitor or blocking TGF-β receptor signaling in fibroblasts. Collectively, our study elucidates a novel mechanistic paradigm in which the accumulation of iron within macrophages initiates lipid peroxidation, thereby amplifying TGF-β1 production, subsequently instigating fibroblast activation through paracrine signaling. Thus, inhibiting iron overload and lipid peroxidation warrants further exploration as a strategy to suppress fibrotic stimulation by disease-associated macrophages. NEW & NOTEWORTHY This study investigates the role of iron in pulmonary fibrosis, specifically focusing on macrophage-mediated mechanisms. Iron accumulation in fibrotic lung macrophages triggers lipid peroxidation and an upregulation of transforming growth factor (TGF)-β1 expression. Coculturing iron-laden macrophages activates lung fibroblasts in a TGF-β1-dependent manner, which can be mitigated by ferroptosis inhibitors. These findings underscore the potential of targeting iron overload and lipid peroxidation as a promising strategy to alleviate fibrotic stimulation provoked by disease-associated macrophages.

特发性肺纤维化(IPF)是一种破坏性疾病,其特点是进行性肺部瘢痕和不受控制的成纤维细胞增殖,不可避免地导致器官功能障碍和死亡。虽然已在肺纤维化患者和动物模型中观察到铁水平升高,但铁失调与肺纤维化发病机制的关联机制,尤其是巨噬细胞在协调这一过程中的作用,仍未得到充分阐明。在此,我们采用体内和体外方法评估了肺纤维化过程中巨噬细胞的铁代谢情况。在小鼠博莱霉素和胺碘酮诱导的肺纤维化模型中,我们观察到肺巨噬细胞中有明显的铁沉积和脂质过氧化反应。耐人寻味的是,注射博莱霉素后,肺巨噬细胞中的铁沉积调节因子谷胱甘肽过氧化物酶4(GPX4)上调,单细胞RNA测序分析证实了这一发现。此外,从纤维化小鼠肺中分离出的巨噬细胞显示出转化生长因子(TGF)-β1 表达的增加,这与脂质过氧化有关。在体外,骨髓巨噬细胞铁超载会引发脂质过氧化反应和 TGF-β1 上调,而铁氧化抑制剂能有效抑制这种反应。当与铁超载巨噬细胞共同培养时,肺成纤维细胞表现出更强的活化能力,α-平滑肌肌动蛋白和纤连蛋白的表达增加就是证明。重要的是,用铁蛋白抑制剂处理巨噬细胞或阻断成纤维细胞中的 TGF-β 受体信号传导可减轻这种促纤维化效应。总之,我们的研究阐明了一种新的机制范式,即巨噬细胞内铁的积累会引发脂质过氧化反应,从而扩大 TGF-β1 的产生,随后通过旁分泌信号唆使成纤维细胞活化。因此,抑制铁超载和脂质过氧化值得进一步探索,以作为抑制疾病相关巨噬细胞刺激纤维化的一种策略。
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引用次数: 0
Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis. 微环境酸中毒对癌细胞脂质代谢和氧化磷酸化的调控
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-05 DOI: 10.1152/ajpcell.00429.2024
Michala G Rolver, Marc Severin, Stine F Pedersen

The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia, and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increase susceptibility to oxidative stress, lipotoxicity, and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions and of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis, and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells.

实体瘤中癌细胞体积的扩大产生了一个恶劣的环境,其特点是动态变化的酸中毒、缺氧和营养匮乏水平。由于酸中毒会抑制糖酵解代谢,而缺氧会抑制氧化磷酸化,因此在这些环境中生存和生长的癌细胞必须重新连接其代谢,并发展出高度的代谢可塑性,以满足其能量和生物合成需求。癌细胞经常通过上调途径来吸收和利用从死亡或招募的基质细胞中获得的脂质和其他营养物质,尤其是在酸性微环境中,脂质的吸收会大大增强。由此产生的脂质积累和对β-氧化和线粒体代谢的依赖性增加,从而增加了对氧化应激、脂毒性和铁中毒的易感性,反过来又推动了可能减轻这些风险的变化。因此,时空异质性的肿瘤微环境选择了具有侵袭性、代谢灵活和复原能力强的癌细胞,这些细胞既能利用局部条件,又能寻找更有利的环境。这种表型依赖于新陈代谢、酸中毒和致癌突变之间的相互作用,并驱动过氧化物酶体增殖激活受体(PPARs)等新陈代谢信号通路。了解这类细胞的特殊脆弱性,可能会发现最具侵袭性癌细胞的新型治疗弱点。
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引用次数: 0
Clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis. Clitocine 通过抑制 A2B/cAMP/ERK 轴促进 FBXW7 介导的 MCL-1 降解,从而增强结肠癌细胞对药物的敏感性。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1152/ajpcell.00310.2024
Feng Ruan, Yanyun Ruan, Huamin Gu, Jianguo Sun, Qi Chen

Chemotherapy resistance to colon cancer is an unavoidable obstacle in the clinical management of the disease. Clitocine, an adenosine analog, played a significant role in the chemosensitivity of human colon cancer cells by promoting myeloid cell leukemia 1 (MCL-1) protein degradation. However, the detailed mechanism remains to be further elucidated. We found that clitocine upregulates the expression of F-box and WD repeat domain containing 7 (FBXW7), a ubiquitin ligase involved in the MCL-1 degradation. Transcriptome sequencing analysis revealed that clitocine significantly inhibits the cyclic adenosine monophosphate (cAMP) and extracellular regulated protein kinases (ERK) downstream signaling pathways in colon cancer cells, thereby enhancing FBXW7 expression and subsequently promoting the ubiquitination degradation of MCL-1 protein. We verified that clitocine regulated intracellular cAMP levels by competitive binding with the adenosine receptor A2B. A molecular docking assay also verified the binding relationship. By decreasing intracellular cAMP levels, clitocine blocks the activation of downstream signaling pathways, which ultimately enhances the drug sensitivity of colon cancer cells through increased FBXW7 expression due to the inhibition of its promoter DNA methylation. Both knockout of the adenosine receptor A2B and Br-cAMP treatment can effectively attenuate the function of clitocine in vitro and in vivo. This study clarified that clitocine enhanced the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis, providing further knowledge of the clinical application for clitocine.NEW & NOTEWORTHY Our study found that clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis.

结肠癌的化疗耐药性是临床治疗中不可避免的障碍。腺苷类似物 Clitocine 通过促进 MCL-1 蛋白降解,在人类结肠癌细胞的化疗敏感性方面发挥了重要作用。然而,其具体机制仍有待进一步阐明。我们发现,氯托辛可上调参与MCL-1降解的泛素连接酶FBXW7的表达。转录组测序分析表明,氯托辛能显著抑制结肠癌细胞中的cAMP和ERK下游信号通路,从而提高FBXW7的表达,进而促进MCL-1蛋白的泛素化降解。我们验证了氯妥辛通过与腺苷受体 A2B 竞争性结合来调节细胞内 cAMP 水平。分子对接试验也验证了这种结合关系。通过降低细胞内cAMP水平,氯托辛阻断了下游信号通路的激活,最终通过抑制启动子DNA甲基化导致的FBXW7表达增加来提高结肠癌细胞对药物的敏感性。腺苷受体A2B的敲除和Br-cAMP处理都能有效地减弱氯托辛在体外和体内的作用。该研究阐明了氯妥辛通过抑制A2B/cAMP/ERK轴促进FBXW7介导的MCL-1降解,从而增强了结肠癌细胞对药物的敏感性,为氯妥辛的临床应用提供了进一步的知识。
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引用次数: 0
Diverse calcium signaling profiles regulate migratory behavior in avascular wound healing and aberrant signal hierarchy occurs early in diabetes. 在血管性伤口愈合过程中,不同的钙信号谱调控着迁移行为,而在糖尿病早期,信号层次结构会发生异常。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI: 10.1152/ajpcell.00249.2024
Kristen L Segars, Nicholas Azzari, Malia Cole, Landon Kushimi, Srikar Rapaka, Celeste B Rich, Vickery Trinkaus-Randall

In avascular wound repair, calcium signaling events are the predominant mechanism cells use to transduce information about stressors in the environment into an effective and coordinated migratory response. Live cell imaging and computational analysis of corneal epithelial wound healing revealed that signal initiation and propagation at the wound edge are highly ordered, with groups of cells engaging in cyclical patterns of initiation and propagation. The cells in these groups exhibit a diverse range of signaling behavior, and dominant "conductor cells" drive activity in groups of lower-signaling neighbors. Ex vivo model systems reveal that conductor cells are present in wing cell layers of the corneal epithelium and that signaling propagates both within and between wing and basal layers. There are significant aberrations in conductor phenotype and interlayer propagation in type II diabetic murine models, indicating that signal hierarchy breakdown is an early indicator of disease. In vitro models reveal that signaling profile diversity and conductor cell phenotype is eliminated with P2X7 inhibition and is altered in Pannexin-1 or P2Y2 but not Connexin-43 inhibition. Conductor cells express significantly less P2X7 than their lower-signaling neighbors and exhibit significantly less migratory behavior after injury. Together, our results show that the postinjury calcium signaling cascade exhibits significantly more ordered and hierarchical behavior than previously thought, that proteins previously shown to be essential for regulating motility are also essential for determining signaling phenotype, and that loss of signal hierarchy integrity is an early indicator of disease state. NEW & NOTEWORTHY Calcium signaling in corneal epithelial cells after injury is highly ordered, with groups of cells engaged in cyclical patterns of event initiation and propagation driven by high-signaling cells. Signaling behavior is determined by P2X7, Pannexin-1, and P2Y2 and influences migratory behavior. Signal hierarchy is observed in healthy ex vivo models after injury and becomes aberrant in diabetes. This represents a paradigm shift, as signaling was thought to be random and determined by factors in the environment.

在无血管伤口修复中,钙信号事件是细胞用于将环境中的压力信息转化为有效和协调的迁移反应的主要机制。角膜上皮伤口愈合的活细胞成像和计算分析表明,伤口边缘的信号启动和传播是高度有序的,细胞群参与启动和传播的循环模式。这些细胞群中的细胞表现出多种多样的信号传导行为,占主导地位的 "传导细胞 "会带动信号传导能力较弱的邻近细胞群的活动。体外模型系统显示,导体细胞存在于角膜上皮的翼细胞层,信号在翼细胞层和基底层内部和之间传播。在 II 型糖尿病小鼠模型中,导体表型和层间传播出现了明显的畸变,这表明信号层次结构的破坏是疾病的早期指标。体外模型显示,抑制 P2X7 会消除信号谱多样性和导体细胞表型,并改变 Pannexin-1 或 P2Y2,但不抑制 Connexin-43。导体细胞表达的 P2X7 明显少于其信号较低的邻近细胞,在损伤后表现出的迁移行为也明显较少。总之,我们的研究结果表明,损伤后的钙信号级联表现出的有序性和层次性比以前认为的要强得多,以前被证明对调节运动至关重要的蛋白质也对决定信号表型至关重要,信号层次完整性的丧失是疾病状态的早期指标。
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引用次数: 0
Hypomethylation-associated ELF3 helps nasopharyngeal carcinoma to escape immune surveillance via MUC16-mediated glycolytic metabolic reprogramming. 与低甲基化相关的ELF3通过MUC16介导的糖酵解代谢重编程帮助鼻咽癌逃避免疫监视。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-09-02 DOI: 10.1152/ajpcell.00438.2024
Yueyang Liu, Hong Zhou, Qi Yu, Qiang Wang

Immune escape and metabolic reprogramming are two essential hallmarks of cancer. Mucin-16 (MUC16) has been linked to glycolysis and immune response in different cancers. However, its involvement in nasopharyngeal carcinoma (NPC) has not been well described. We seek to dissect the functions and detailed mechanisms of MUC16 in NPC. Bioinformatics prediction was performed to identify NPC-related molecules. MUC16 was significantly enhanced in NPC tissues, which was correlated with the advanced tumor stage of patients. Lentiviral plasmids-mediated MUC16 deletion inhibited the malignant behavior of NPC cells, and glycolysis inhibition by MUC16 deletion blocked immune escape in NPC cells. E74-like factor 3 (ELF3) bound to the MUC16 promoter promotes the transcription of MUC16. MUC16 overexpression reversed the repressive effect of ELF3 silencing on glycolysis and immune escape in NPC and accelerated tumor growth in vivo. Overexpression of ELF3 in NPC was associated with reduced DNA methylation in its promoter. Our findings revealed the role of the ELF3/MUC16 axis in the immune escape and metabolic reprogramming of NPC, providing potential therapeutic targets for NPC.NEW & NOTEWORTHY We identified the functions of E74-like factor 3 (ELF3) in glycolysis and immune escape of nasopharyngeal carcinoma cells for the first time. As a transcription factor, ELF3 promoted mucin-16 (MUC16) expression by binding to its promoter, leading to the glycolysis-mediated immune escape of nasopharyngeal carcinoma (NPC) cells. Targeting the ELF3/MUC16 axis generates a superior antitumor immune response, which will help establish a novel approach to restore protective antitumor immunity for NPC immunotherapy.

免疫逃逸和代谢重编程是癌症的两个基本特征。粘蛋白-16(MUC16)与不同癌症中的糖酵解和免疫反应有关。然而,它在鼻咽癌(NPC)中的参与尚未得到很好的描述。我们试图剖析 MUC16 在鼻咽癌中的功能和详细机制。我们进行了生物信息学预测,以确定鼻咽癌相关分子。MUC16在鼻咽癌组织中明显增强,这与患者的肿瘤晚期相关。慢病毒质粒介导的MUC16缺失抑制了鼻咽癌细胞的恶性行为,通过MUC16缺失抑制糖酵解阻断了鼻咽癌细胞的免疫逃逸。E74样因子3(ELF3)与MUC16启动子结合,促进MUC16的转录。MUC16的过表达逆转了ELF3沉默对鼻咽癌细胞糖酵解和免疫逃逸的抑制作用,并加速了肿瘤在体内的生长。ELF3在鼻咽癌中的过表达与其启动子中DNA甲基化的减少有关。我们的研究结果揭示了ELF3/MUC16轴在鼻咽癌的免疫逃逸和代谢重编程中的作用,为鼻咽癌提供了潜在的治疗靶点。
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引用次数: 0
Modulating endothelial cell dynamics in fat grafting: the impact of DLL4 siRNA via adipose stem cell extracellular vesicles. 调节脂肪移植中的内皮细胞动力学:DLL4 siRNA 通过脂肪干细胞胞外囊泡的影响
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-05 DOI: 10.1152/ajpcell.00186.2024
Sen-Lin Deng, Qiang Fu, Qing Liu, Fu-Jun Huang, Miao Zhang, Xun Zhou

In the context of improving the efficacy of autologous fat grafts (AFGs) in reconstructive surgery, this study delineates the novel use of adipose-derived mesenchymal stem cells (ADSCs) and their extracellular vesicles (EVs) as vehicles for delivering delta-like ligand 4 (DLL4) siRNA. The aim was to inhibit DLL4, a gene identified through transcriptome analysis as a critical player in the vascular endothelial cells of AFG tissues, thereby negatively affecting endothelial cell functions and graft survival through the Notch signaling pathway. By engineering ADSC EVs to carry DLL4 siRNA (ADSC EVs-siDLL4), the research demonstrated a marked improvement in endothelial cell proliferation, migration, and lumen formation, and enhanced angiogenesis in vivo, leading to a significant increase in the survival rate of AFGs. This approach presents a significant advancement in the field of tissue engineering and regenerative medicine, offering a potential method to overcome the limitations of current fat grafting techniques.NEW & NOTEWORTHY This study introduces a groundbreaking method for enhancing autologous fat graft survival using adipose-derived stem cell extracellular vesicles (ADSC EVs) to deliver DLL4 siRNA. By targeting the delta-like ligand 4 (DLL4) gene, crucial in endothelial cell dynamics, this innovative approach significantly improves endothelial cell functions and angiogenesis, marking a substantial advancement in tissue engineering and regenerative medicine.

为了提高自体脂肪移植(AFG)在整形手术中的疗效,本研究界定了脂肪间充质干细胞(ADSCs)及其细胞外囊泡(EVs)作为递送 DLL4 siRNA 载体的新用途。DLL4是通过转录组分析确定的AFG组织血管内皮细胞中的一个关键基因,目的是抑制DLL4,从而通过Notch信号通路对内皮细胞功能和移植物存活产生负面影响。通过对携带 DLL4 siRNA 的 ADSC EVs(ADSC EVs-siDLL4)进行工程化处理,研究表明内皮细胞的增殖、迁移和管腔形成得到了明显改善,体内血管生成也得到了增强,从而显著提高了 AFG 的存活率。这种方法是组织工程和再生医学领域的一大进步,为克服当前脂肪移植技术的局限性提供了一种潜在的方法。
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引用次数: 0
PALMD haploinsufficiency aggravates extracellular matrix remodeling in vascular smooth muscle cells and promotes calcification. PALMD 单倍体缺陷会加剧血管平滑肌细胞细胞外基质的重塑并促进钙化。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-09-09 DOI: 10.1152/ajpcell.00217.2024
Jichao Zhang, Zhao Yang, Congcong Zhang, Shijuan Gao, Yan Liu, Yingkai Li, Songyuan He, Jing Yao, Jie Du, Bin You, Yingchun Han

Reduced PALMD expression is strongly associated with the development of calcified aortic valve stenosis; however, the role of PALMD in vascular calcification remains unknown. Calcified arteries were collected from mice to detect PALMD expression. Heterozygous Palmd knockout (Palmd+/-) mice were established to explore the role of PALMD in subtotal nephrectomy-induced vascular calcification. RNA sequencing was applied to detect molecular changes in aortas from Palmd+/- mice. Primary Palmd+/- vascular smooth muscle cells (VSMCs) or PALMD-silenced VSMCs by short interfering RNA were used to analyze PALMD function in phenotypic changes and calcification. PALMD haploinsufficiency aggravated subtotal nephrectomy-induced vascular calcification. RNA sequencing analysis showed that loss of PALMD disturbed the synthesis and degradation of the extracellular matrix (ECM) in aortas, including collagens and matrix metalloproteinases (Col6a6, Mmp2, Mmp9, etc.). In vitro experiments revealed that PALMD-deficient VSMCs were more susceptible to high phosphate-induced calcification. Downregulation of SMAD6 expression and increased levels of p-SMAD2 were detected in Palmd+/- VSMCs, suggesting that transforming growth factor-β signaling may be involved in PALMD haploinsufficiency-induced vascular calcification. Our data revealed that PALMD haploinsufficiency causes ECM dysregulation in VSMCs and aggravates vascular calcification. Our findings suggest that reduced PALMD expression is also linked to vascular calcification, and PALMD may be a potential therapeutic target for this disease. NEW & NOTEWORTHY We found that PALMD haploinsufficiency causes extracellular matrix dysregulation, reduced PALMD expression links to vascular calcification, and PALMD mutations may lead to the risk of both calcific aortic valve stenosis and vascular calcification.

背景:PALMD表达的降低与主动脉瓣狭窄钙化的发生密切相关;然而,PALMD在血管钙化中的作用仍然未知:方法:收集小鼠的钙化动脉以检测PALMD的表达。方法:收集小鼠钙化动脉以检测PALMD的表达,并建立杂合子Palmd基因敲除(Palmd+/-)小鼠以探索PALMD在肾脏次全切除术诱导的血管钙化中的作用。应用RNA测序技术检测Palmd+/-小鼠主动脉的分子变化。使用原代Palmd+/-血管平滑肌细胞(VSMC)或通过短干扰RNA(siRNA)沉默PALMD的VSMC分析PALMD在表型变化和钙化中的功能:结果:PALMD单倍体缺陷会加重肾次全切诱导的血管钙化。RNA测序分析表明,PALMD的缺失干扰了主动脉细胞外基质(ECM)的合成和降解,包括胶原和基质金属蛋白酶(Col6a6、Mmp2、Mmp9等)。体外实验显示,缺乏 PALMD 的 VSMC 更易受高磷酸盐诱导的钙化影响。在Palmd+/- VSMCs中检测到SMAD6表达下调和p-SMAD2水平升高,这表明TGF-β信号传导可能参与了PALMD单倍体缺陷诱导的血管钙化:我们的数据显示,PALMD单倍体缺陷会导致VSMCs中的ECM失调,并加剧血管钙化。我们的研究结果表明,PALMD表达的减少也与血管钙化有关,PALMD可能是该疾病的潜在治疗靶点。
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引用次数: 0
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American journal of physiology. Cell physiology
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