Cellular signalling最新文献_第4页

Corrigendum to “Recent progress of protein kinase inhibitors derived from marine peptides for developing anticancer gents” [Cellular Signalling 124 (2024) 111411] 从海洋肽中提取蛋白激酶抑制剂用于开发抗癌剂的最新进展"[Cellular Signalling 124 (2024) 111411]的更正。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-10 DOI: 10.1016/j.cellsig.2024.111449

引用次数: 0

Fangchinoline inhibits metastasis and reduces inflammation-induced epithelial-mesenchymal transition by targeting the FOXM1-ADAM17 axis in hepatocellular carcinoma 方棘霉素通过靶向 FOXM1-ADAM17 轴抑制肝细胞癌转移并减少炎症诱导的上皮-间质转化

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-10 DOI: 10.1016/j.cellsig.2024.111467

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Efforts have been focused on developing new anti-HCC agents and understanding their pharmacology. However, few agents have been able to effectively combat tumor growth and invasiveness due to the rapid progression of HCC. In this study, we discovered that fangchinoline (FAN), a bisbenzylisoquinoline alkaloid derived from Stephania tetrandra S. Moore, effectively inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells. FAN treatment also led to the suppression of IL6 and IL1β release, as well as the expression of inflammation-related proteins such as COX-2 and iNOS, and the activation of the NF-κB pathway, thereby reducing inflammation-related EMT. Additionally, FAN directly bound to forkhead box protein M1 (FOXM1), resulting in decreased levels of FOXM1 proteins and disruption of the FOXM1-ADAM17 axis. Our in vivo findings confirmed that FAN effectively hindered the growth and lung metastasis of HCCLM3-xenograft tumors. Importantly, the upregulation of FOXM1 in HCC tissue suggested that targeting FOXM1 inhibition with FAN or its inhibitors could be a promising therapeutic approach for HCC. Overall, this study elucidated the anti-tumor effects and potential pharmacological mechanisms of FAN, and proposed that targeting FOXM1 inhibition may be an effective therapeutic strategy for HCC with potential clinical applications.

肝细胞癌（HCC）是全球癌症相关死亡的主要原因。人们一直致力于开发新的抗 HCC 药物并了解其药理学。然而，由于 HCC 病情进展迅速，能够有效抑制肿瘤生长和侵袭性的药物少之又少。在这项研究中，我们发现从Stephania tetrandra S. Moore中提取的一种双苄基异喹啉生物碱--fangchinoline（FAN）能有效抑制HCC细胞的迁移、侵袭和上皮-间质转化（EMT）。FAN 还能抑制 IL6 和 IL1β 的释放，以及 COX-2 和 iNOS 等炎症相关蛋白的表达和 NF-κB 通路的激活，从而减少炎症相关的 EMT。此外，FAN直接与叉头盒蛋白M1（FOXM1）结合，导致FOXM1蛋白水平下降和FOXM1-ADAM17轴的破坏。我们的体内研究结果证实，FAN 能有效抑制 HCCLM3 异种移植瘤的生长和肺转移。重要的是，FOXM1在HCC组织中的上调表明，用FAN或其抑制剂靶向抑制FOXM1可能是一种很有前景的HCC治疗方法。总之，本研究阐明了FAN的抗肿瘤作用和潜在药理机制，并提出靶向抑制FOXM1可能是一种有效的HCC治疗策略，具有潜在的临床应用前景。

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引用次数: 0

CAF-secreted LOX promotes PD-L1 expression via histone Lactylation and regulates tumor EMT through TGFβ/IGF1 signaling in gastric Cancer CAF 分泌的 LOX 通过组蛋白乳酸化促进 PD-L1 的表达，并通过 TGFβ/IGF1 信号调节胃癌中肿瘤的 EMT

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-10 DOI: 10.1016/j.cellsig.2024.111462

In gastric cancer treatment, cancer-associated fibroblasts (CAF) may significantly influence the efficacy of immune checkpoint inhibitors by modulating PD-L1 expression. However, the precise mechanisms remain unclear. This study aims to explore the relationship between CAF and PD-L1 expression, providing new insights for improving PD-L1-targeted therapies.

Using primary fibroblasts, transcriptome sequencing, ChIP-qPCR, and a lung metastasis model, we discovered that CAF secrete lysyl oxidase (LOX), which activates the TGFβ signaling pathway in gastric cancer cells, thereby promoting insulin-like growth factor 1(IGF1) expression. Upregulation of IGF1 enhances gastric cancer cell migration, epithelial-mesenchymal transition (EMT), and glycolysis. Additionally, we found that lactate accumulation leads to lysine 18 lactylation on histone H3 (H3K18la), which enriches at the PD-L1 promoter region, thus promoting PD-L1 transcription. These findings suggest that CAF may diminish the effectiveness of PD-1/PD-L1 blockade immunotherapy through LOX-induced glycolysis and lactate accumulation. Consequently, we have constructed a model of the interactions among CAF, lactate, and PD-L1 in gastric cancer progression, providing new experimental evidence for PD-L1-based immunotherapy.

在胃癌治疗中，癌相关成纤维细胞（CAF）可能会通过调节 PD-L1 的表达而显著影响免疫检查点抑制剂的疗效。然而，其确切机制仍不清楚。利用原代成纤维细胞、转录组测序、ChIP-qPCR和肺转移模型，我们发现CAF能分泌赖氨酰氧化酶（LOX），它能激活胃癌细胞的TGFβ信号通路，从而促进胰岛素样生长因子1（IGF1）的表达。IGF1 的上调增强了胃癌细胞的迁移、上皮-间质转化（EMT）和糖酵解。此外，我们还发现乳酸盐的积累会导致组蛋白 H3 上的赖氨酸 18 乳化（H3K18la），这种乳化富集在 PD-L1 启动子区域，从而促进 PD-L1 的转录。这些研究结果表明，CAF可能会通过LOX诱导的糖酵解和乳酸积累削弱PD-1/PD-L1阻断免疫疗法的效果。因此，我们构建了CAF、乳酸和PD-L1在胃癌进展中的相互作用模型，为基于PD-L1的免疫疗法提供了新的实验证据。

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引用次数: 0

Impact of the local renin–angiotensin system in perivascular adipose tissue on vascular health and disease 血管周围脂肪组织中的局部肾素-血管紧张素系统对血管健康和疾病的影响。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111461

Perivascular adipose tissue (PVAT) is found locally around blood vessels. It has the ability to release vasoactive chemicals, such as factors that relax and contract blood vessels. PVAT is now recognized as an endocrine organ with metabolic activity and as a “protagonist” for maintaining vascular homeostasis. Angiotensin II, a powerful vasoconstrictor of the renin–angiotensin system (RAS) that can increase blood pressure and vascular tone, is produced locally by PVAT. To mitigate the multiple vascular effects of angiotensin II, PVAT also generates molecules such as angiotensin (1–7), adiponectin, and nitric oxide. Reactive oxygen species and proinflammatory cytokines are produced in greater amounts when PVAT-mediated angiotensin II is present, resulting in endothelial dysfunction, inflammation, atherosclerosis, and other vascular disorders. The anticontractile and procontractile nature of PVAT is frequently disrupted in obese individuals, which increases the production of angiotensin II and decreases the production of anti-inflammatory and vasodilatory factors. These changes in turn exacerbate vascular inflammation, hypertension, and atherosclerosis. PVAT, which is crucial for maintaining vascular homeostasis, loses its anticontractile effect in obesity due to adipocyte hypertrophy, inflammation, and oxidative stress, exacerbating endothelial dysfunction. Overactive RAS in PVAT facilitates the migration and proliferation of vascular smooth muscle cells and atherosclerotic plaques, both of which accelerate the development of atherosclerosis. Targeting PVAT and the local RAS can offer therapeutic benefits in treating hypertension, atherosclerosis, and other vascular diseases. This review highlights the scientific underpinnings of the function of PVAT in regulating the autocrine and paracrine activities of vascular RAS constituents.

血管周围脂肪组织（PVAT）位于血管周围。它能够释放具有血管活性的化学物质，如放松和收缩血管的因子。目前，人们已认识到血管周围脂肪组织是一个具有新陈代谢活性的内分泌器官，也是维持血管平衡的 "主角"。血管紧张素 II 是肾素-血管紧张素系统（RAS）的一种强效血管收缩剂，可升高血压和血管张力，由 PVAT 在局部产生。为了减轻血管紧张素 II 对血管的多重影响，PVAT 还会产生血管紧张素 (1-7)、脂联素和一氧化氮等分子。当 PVAT 介导的血管紧张素 II 存在时，会产生更多的活性氧和促炎细胞因子，导致内皮功能障碍、炎症、动脉粥样硬化和其他血管疾病。肥胖者的 PVAT 的抗收缩和促收缩特性经常受到破坏，这增加了血管紧张素 II 的产生，减少了抗炎因子和血管舒张因子的产生。这些变化反过来又加剧了血管炎症、高血压和动脉粥样硬化。肥胖症患者的脂肪细胞肥大、炎症和氧化应激使对维持血管平衡至关重要的 PVAT 失去了抗收缩作用，从而加剧了内皮功能障碍。PVAT 中过度活跃的 RAS 会促进血管平滑肌细胞和动脉粥样硬化斑块的迁移和增殖，这两者都会加速动脉粥样硬化的发展。以 PVAT 和局部 RAS 为靶点可为治疗高血压、动脉粥样硬化和其他血管疾病带来疗效。本综述重点介绍了 PVAT 在调节血管 RAS 成分的自分泌和旁分泌活动方面的功能的科学依据。

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引用次数: 0

Induction, amplification, and propagation of diabetic retinopathy-associated inflammatory cytokines between human retinal microvascular endothelial and Müller cells and in the mouse retina 糖尿病视网膜病变相关炎症细胞因子在人类视网膜微血管内皮细胞和 Müller 细胞之间以及在小鼠视网膜中的诱导、放大和传播。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111454

Ocular levels of IL-1β, TNFα, IL-8, and IL-6 correlate with progression of diabetic retinopathy (DR). Müller cells (MC), which are crucial to maintaining retinal homeostasis, are targets and sources of these cytokines. We explored the relative capacities of these four DR-associated cytokines to amplify inflammatory signal expression both in and between human MC (hMC) and retinal microvascular endothelial cells (hRMEC) and in the mouse retina. Of the four cytokines, IL-1β was the most potent stimulus of transcriptomic alterations in hMC and hRMEC in vitro, as well as in the mouse retina after intravitreal injection in vivo. Stimulation with IL-1β significantly induced expression of all four transcripts in hMC and hRMEC. TNFα significantly induced expression of some, but not all, of the four transcripts in each cell, while neither IL-8 nor IL-6 showed significant induction in either cell. Similarly, conditioned media (CM) derived from hMC or hRMEC treated with IL-1β, but not TNFα, upregulated inflammatory cytokine transcripts in the reciprocal cell type. hRMEC responses to hMC-derived CM were dependent on IL-1R activation. In addition, we observed a correlation between cytokine expression changes following direct and CM stimulation and NFκB-p65 nuclear translocation in both hMC and hRMEC. Finally, in mice, intravitreal injections of IL-1β, but not TNFα, induced retinal expression of Il1b and CXCL8 homologues Cxcl1, Cxcl2, Cxcl3, and Cxcl5, encoding pro-angiogenic chemokines. Our results suggest that expression of IL-1β, TNFα, IL-8, and IL-6 may be initiated, propagated, and sustained by autocrine and paracrine signals in hRMEC and hMC through a process involving IL-1β and NFκB. Targeting these signals may help thwart inflammatory amplification, preventing progression to vision-threatening stages and preserving sight.

眼部 IL-1β、TNFα、IL-8 和 IL-6 的水平与糖尿病视网膜病变（DR）的进展相关。对维持视网膜稳态至关重要的缪勒细胞（MC）是这些细胞因子的靶点和来源。我们探讨了这四种与 DR 相关的细胞因子在人 MC（hMC）和视网膜微血管内皮细胞（hRMEC）以及小鼠视网膜中放大炎症信号表达的相对能力。在这四种细胞因子中，IL-1β是体外刺激hMC和hRMEC以及体内静脉注射后刺激小鼠视网膜转录组变化的最有效因子。IL-1β 能显著诱导 hMC 和 hRMEC 中所有四种转录本的表达。TNFα能明显诱导这四种转录本在每个细胞中的部分表达，但不是全部，而IL-8和IL-6在这两种细胞中均无明显诱导作用。同样，用 IL-1β 而不是 TNFα 处理 hMC 或 hRMEC 的条件培养基（CM）会上调对等细胞类型中的炎症细胞因子转录本。此外，我们还观察到细胞因子在直接和 CM 刺激后的表达变化与 NFκB-p65 在 hMC 和 hRMEC 中的核转位之间存在相关性。最后，在小鼠体内静脉注射 IL-1β（而非 TNFα）可诱导视网膜表达 Il1b 和 CXCL8 同源物 Cxcl1、Cxcl2、Cxcl3 和 Cxcl5（编码促血管生成趋化因子）。我们的研究结果表明，在 hRMEC 和 hMC 中，IL-1β、TNFα、IL-8 和 IL-6 的表达可能是由自分泌和旁分泌信号通过涉及 IL-1β 和 NFκB 的过程启动、传播和维持的。针对这些信号可能有助于阻止炎症的扩大，防止其发展到威胁视力的阶段并保护视力。

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引用次数: 0

Regulatory role of Heparan sulfate in leptin signaling 硫酸肝素在瘦素信号传导中的调节作用。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111456

Leptin, a hormone mainly secreted by adipocytes, has attracted significant attention since its discovery in 1994. Initially known for its role in appetite suppression and energy regulation, leptin is now recognized for its influence on various physiological processes, including immune response, bone formation, and reproduction. It exerts its effects by binding to receptors and initiating an intracellular signaling cascade. Heparan sulfate (HS) is known to regulate the intracellular signaling of various ligands. HS is present as the glycan portion of HSPGs on cell surfaces and in intercellular spaces, with diverse structures due to extensive sulfation and epimerization. Although HS chains on HSPGs are involved in many physiological processes, the detailed effects of HS chains on leptin signaling are not well understood.

This study examined the role of HS chains on HSPGs in leptin signaling using Neuro2A cells expressing the full-length leptin receptor (LepR). We showed that cell surface HS was essential for efficient leptin signaling. Enzymatic degradation of HS significantly reduced leptin-induced phosphorylation of downstream molecules, such as signal transducer and activator of transcription 3 and p44/p42 Mitogen-activated protein kinase. In addition, HS regulated LepR expression and internalization, as treatment with HS-degrading enzymes decreased cell surface LepR. HS was also found to exhibit a weak interaction with LepR. Enzymatic removal of HS enhanced the interaction between LepR and low-density lipoprotein receptor-related protein 1, suggesting that HS negatively regulates this interaction. In conclusion, HS plays a significant role in modulating LepR availability on the cell surface, thereby influencing leptin signaling. These findings provide new insights into the complex regulation of leptin signaling and highlight potential therapeutic targets for metabolic disorders and obesity.

瘦素是一种主要由脂肪细胞分泌的激素，自 1994 年被发现以来一直备受关注。瘦素最初因其在抑制食欲和能量调节方面的作用而为人所知，现在人们认识到它对免疫反应、骨骼形成和生殖等各种生理过程都有影响。瘦素通过与受体结合并启动细胞内信号级联来发挥其作用。众所周知，硫酸肝素（HS）可调节各种配体的细胞内信号传导。HS 作为 HSPGs 的聚糖部分存在于细胞表面和细胞间隙中，由于广泛的硫酸化和外嵌合作用，其结构多种多样。虽然HSPGs上的HS链参与了许多生理过程，但HS链对瘦素信号转导的具体影响还不十分清楚。本研究利用表达全长瘦素受体（LepR）的 Neuro2A 细胞研究了 HSPG 上的 HS 链在瘦素信号转导中的作用。我们的研究表明，细胞表面的HS对有效的瘦素信号转导至关重要。酶降解HS可显著减少瘦素诱导的下游分子磷酸化，如信号转导和激活转录3以及p44/p42丝裂原活化蛋白激酶。此外，HS 还能调节 LepR 的表达和内化，因为用 HS 降解酶处理后，细胞表面的 LepR 会减少。研究还发现，HS与LepR之间存在微弱的相互作用。酶法去除 HS 可增强 LepR 与低密度脂蛋白受体相关蛋白 1 之间的相互作用，这表明 HS 负向调节了这种相互作用。总之，HS在调节细胞表面LepR的可用性，从而影响瘦素信号转导方面起着重要作用。这些发现为了解瘦素信号转导的复杂调控提供了新的视角，并突出了代谢紊乱和肥胖症的潜在治疗靶点。

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引用次数: 0

Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation Rheb1 缺乏会导致线粒体功能障碍，并通过促进 Atp5f1c 乙酰化加速荚膜衰老。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111451

Podocyte senescence can cause persistent podocyte injury and albuminuria in diabetic kidney disease (DKD), but the mechanism remains obscure. In this study, podocyte senescence was confirmed by immunohistochemical staining in podocytes from patients and mice with DKD. Rheb1 knockout in podocytes aggravated podocyte senescence and injury in diabetic mice, but mitigated podocyte injury in mice with podocyte-specific mTORC1 activation induced by Tsc1 deletion. In cultured podocytes, Rheb1 knockdown remarkably accelerated podocyte senescence, independent of mTORC1. Mechanistically, PDH phosphorylation in podocyte was correlated with podocyte senescence in DKD patients. Rheb1 deficiency decreased ATP, mitochondrial membrane potential and partial components of respiratory chain complex, and enhanced ROS production and PDH phosphorylation, which indicates mitochondrial dysfunction, both in vitro and in vivo. Furthermore, Rheb1 interacted with Atp5f1c, and regulated its acetylation under a high-glucose condition. Together, Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation, in an mTORC1-independent manner, which provides experimental basis for the treatment of DKD.

荚膜细胞衰老可导致糖尿病肾病（DKD）中荚膜细胞的持续损伤和白蛋白尿，但其机制仍不清楚。本研究通过免疫组化染色证实了糖尿病肾病患者和小鼠荚膜细胞的荚膜衰老。荚膜细胞中的 Rheb1 基因敲除会加重糖尿病小鼠荚膜细胞的衰老和损伤，但在 Tsc1 基因缺失诱导荚膜细胞特异性 mTORC1 激活的小鼠中，Rheb1 基因敲除会减轻荚膜细胞损伤。在培养的荚膜细胞中，Rheb1 的敲除明显加速了荚膜细胞的衰老，这与 mTORC1 无关。从机制上讲，DKD 患者荚膜细胞中的 PDH 磷酸化与荚膜细胞衰老相关。Rheb1 缺乏会降低 ATP、线粒体膜电位和呼吸链复合物的部分成分，并增强 ROS 的产生和 PDH 磷酸化，这表明线粒体在体外和体内均存在功能障碍。此外，Rheb1 与 Atp5f1c 相互作用，并在高葡萄糖条件下调节其乙酰化。总之，Rheb1缺乏会导致线粒体功能障碍，并通过促进Atp5f1c乙酰化加速荚膜衰老，而这种方式与mTORC1无关，这为治疗DKD提供了实验依据。

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引用次数: 0

Game-changing breakthroughs to redefine the landscape of the renin-angiotensin-aldosterone system in health and disease. 改变游戏规则的突破，重新定义肾素-血管紧张素-醛固酮系统在健康和疾病中的作用。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111459

Pitchai Balakumar, Gowraganahalli Jagadeesh

Novel perspectives on the role of the renin-angiotensin-aldosterone system (RAAS) offer a groundbreaking understanding of the system's role in health and illness. Our understanding of the role of the RAAS in several diseases, such as heart failure, hypertension, metabolic disorders, and chronic renal disease, has been broadened by recent studies. Specific variations in RAAS pathways can affect the course of disease and response to treatment, as shown by genetic and molecular research. The dynamic and fast-evolving nature of RAAS research described in this special issue might transform our approach to managing renal, neurological, and cardiovascular health, among other disease conditions, including cancer.

关于肾素-血管紧张素-醛固酮系统（RAAS）作用的新观点为我们提供了对该系统在健康和疾病中作用的突破性认识。最近的研究拓宽了我们对 RAAS 在多种疾病（如心力衰竭、高血压、代谢紊乱和慢性肾病）中作用的认识。遗传和分子研究表明，RAAS通路的特定变异会影响疾病的进程和对治疗的反应。本特刊所描述的 RAAS 研究的动态性和快速发展性可能会改变我们管理肾脏、神经和心血管健康以及包括癌症在内的其他疾病的方法。

引用次数: 0

Inhibition of TREM-1 ameliorates angiotensin II-induced atrial fibrillation by attenuating macrophage infiltration and inflammation through the PI3K/AKT/FoxO3a signaling pathway 抑制 TREM-1 可通过 PI3K/AKT/FoxO3a 信号通路减轻巨噬细胞浸润和炎症，从而改善血管紧张素 II 诱导的心房颤动。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111458

Inflammation and infiltration of immune cells are intricately linked to the pathogenesis of atrial fibrillation (AF). Triggering receptor expressed on myeloid cells-1 (TREM-1), an enhancer of inflammation, is implicated in various cardiovascular disorders. However, the precise role and potential mechanisms of TREM-1 in the development of AF remain ambiguous. Atrial samples from patients with AF were used to assess the expression levels of TREM-1. An angiotensin II (Ang II)-induced AF mouse model was established to assess the functionality of TREM-1. Cardiac function and AF inducibility were assessed through echocardiography, programmed transvenous cardiac pacing, and atrial electrophysiological mapping. Peripheral blood and atrial inflammatory cells were assessed using flow cytometry. Using histology, bulk RNA sequencing, biochemical analyses, and cell cultures, the mechanistic role of TREM-1 in AF was elucidated. TREM-1 expression was upregulated and co-localized with macrophages in the atria of patients with AF. Pharmacological inhibition of TREM-1 decreased Ang II-induced atrial enlargement and electrical remodeling. TREM-1 inhibition also ameliorated Ang II-induced NLRP3 inflammasome activation, inflammatory factor release, atrial fibrosis, and macrophage infiltration. Transcriptomic analysis revealed that TREM-1 modulates Ang II-induced inflammation through the PI3K/AKT/FoxO3a signaling pathway. In vitro studies further supported these findings, demonstrating that TREM-1 activation exacerbates Ang II-induced inflammation, while overexpression of FoxO3a counteracts this effect. This study discovered the critical role of TREM-1 in the pathogenesis of AF and its underlying molecular mechanisms. Inhibition of TREM-1 provides a new therapeutic strategy for the treatment of AF.

炎症和免疫细胞浸润与心房颤动（房颤）的发病机制密切相关。髓系细胞上表达的触发受体-1（TREM-1）是一种炎症增强因子，与多种心血管疾病有关。然而，TREM-1在心房颤动发病过程中的确切作用和潜在机制仍不明确。研究人员使用房颤患者的心房样本来评估 TREM-1 的表达水平。建立了血管紧张素II（Ang II）诱导的房颤小鼠模型，以评估TREM-1的功能。通过超声心动图、程序化经静脉心脏起搏和心房电生理图评估心脏功能和房颤诱导性。使用流式细胞术评估了外周血和心房炎症细胞。通过组织学、大量 RNA 测序、生化分析和细胞培养，阐明了 TREM-1 在房颤中的机制作用。在心房颤动患者的心房中，TREM-1表达上调并与巨噬细胞共定位。药物抑制 TREM-1 可减少 Ang II 诱导的心房扩大和电重塑。抑制 TREM-1 还能改善 Ang II 诱导的 NLRP3 炎症小体激活、炎症因子释放、心房纤维化和巨噬细胞浸润。转录组分析表明，TREM-1 通过 PI3K/AKT/FoxO3a 信号通路调节 Ang II 诱导的炎症。体外研究进一步证实了这些发现，表明TREM-1的激活会加剧Ang II诱导的炎症，而过量表达FoxO3a则会抵消这种效应。这项研究发现了 TREM-1 在心房颤动发病机制中的关键作用及其潜在的分子机制。抑制 TREM-1 为治疗心房颤动提供了一种新的治疗策略。

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引用次数: 0

GDF15 enhances anoikis resistance and metastasis of gastric cancer through protective autophagy GDF15通过保护性自噬增强胃癌的抗厌氧菌性和转移性

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111457

Distant metastasis is a prevalent cause of mortality in gastric cancer (GC) patients. Anoikis, a process that induces cell death when cells get detached from the extracellular matrix (ECM), acts as a barrier to tumor metastasis. To survive in the circulatory system and metastasize, tumor cells must acquire anoikis resistance. It is crucial to identify the molecular processes that cause resistance to anoikis in GC since this might lead to the discovery of novel treatment targets and improve the long-term survival of GC patients. In this study, we employed quantitative proteomics to identify growth differentiation factor 15 (GDF15) as a key factor in GC anoikis resistance. We found that GDF15 enhances protective autophagy, thereby promoting anoikis resistance in GC cells. Furthermore, through DNA pull down assay, activating transcription factor 2 (ATF2) was found to be a critical regulator of GDF15 expression, acting as a transcriptional activator of GDF15. Collectively, these discoveries indicate that ATF2 and GDF15 have great potential as target candidates for developing therapeutic strategies to address the metastasis of GC.

远处转移是导致胃癌（GC）患者死亡的一个普遍原因。细胞脱离细胞外基质（ECM）会导致细胞死亡，而细胞抗原（anoikis）是肿瘤转移的屏障。肿瘤细胞要想在循环系统中存活并转移，就必须获得抗anoikis能力。鉴别导致 GC 耐 anoikis 的分子过程至关重要，因为这可能有助于发现新的治疗靶点并改善 GC 患者的长期生存。在这项研究中，我们采用定量蛋白质组学方法确定了生长分化因子15（GDF15）是GC耐药的关键因素。我们发现，GDF15能增强保护性自噬，从而促进GC细胞的耐厌氧菌性。此外，通过DNA牵引试验，我们发现活化转录因子2（ATF2）是GDF15表达的关键调节因子，是GDF15的转录激活因子。这些发现共同表明，ATF2 和 GDF15 具有巨大的潜力，可作为候选靶点开发治疗策略，以解决 GC 的转移问题。

引用次数: 0