Abrogation of ARF6 in promoting erastin-induced ferroptosis and mitigating capecitabine resistance in gastric cancer cells

BackgroundADP ribosylation factor 6 (ARF6) is a member of the Rat sarcoma virus (RAS) superfamily that is involved in the regulation of vesicular trafficking, membrane lipid remodeling, and signaling pathways. Our earlier work discovered that ARF6, as a downstream effector of the Kirsten rat sarcoma viral oncogene (Kras)/extracellular signal-regulated kinases (ERK) signaling pathway, may increase proliferation and induce the Warburg effect in gastric cancer (GC) cells. Additionally, ARF6 appears to be a potential biomarker for predicting the prognosis of GC. Ferroptosis has recently been described as a type of nonapoptotic iron-dependent cell death that is strongly associated with the Kras mutation. Therefore, it is critical to continue investigating the link between ARF6 and ferroptosis.MethodsWe first created ARF6 silenced cancer cell lines with lentivirus transfection. The knockdown efficiency was confirmed through quantitative polymerase chain reaction (qPCR) and western blotting. Subsequently, we used Cell Counting Kit-8 (CCK-8) and malondialdehyde (MDA) assay for lipid peroxidation measurement. Following this, qPCR and western blotting were conducted to clarify the mechanism involved. Finally, immunohistochemistry was used to stain human GC samples.ResultsOur findings established that, whereas ARF6 did not directly regulate lipid peroxidation, it did render GC cells susceptible to oxidative stress, particularly erastin-induced lipid peroxidation. Additionally, our research demonstrated that ARF6 may control capecitabine resistance via several routes.ConclusionsARF6 may play a critical role in the development of GC.     

不安运动阶段对早产儿运动发育结局的预测价值

目的比较全身运动质量评估(General movements assessment,GMs)不安运动阶段和Gesell发育量表(Gesell Developmental Test Scales,GDS)对早产儿运动发育结局的预测效度,及对两种评估方法和发育结局的一致性检测。方法对2011年6月-2013年6月共226例在本院儿童保健科随访的早产儿,在纠正5个月内采用GMs和GDS进行评估,在纠正12个月时临床诊断是否为脑瘫,并使用Peabody运动发育量表(Peabody Development Motor Scale 2,PDMS-2)确定其运动发育结局。对比分析两种评估方法的预测效度(包括敏感度、特异度、阳性预测值和阴性预测值),及与发育结局的相关性。结果 226例早产儿发育结局中运动发育正常176例,运动发育迟缓22例,脑瘫28例。不安运动阶段评估结果为正常者168例,异常为58例;GDS评估结果为正常者140例,异常为86例。不安运动及GDS预测脑瘫敏感度92.9%、71.4%,特异度83.8%、66.7%,阳性预测值44.8%、23.3%,阴性预测值98.8%、94.3%。不安运动及GDS预测运动发育结局敏感度88.0%、68.0%,特异度92.0%、70.4%,阳性预测值75.9%、39.5%,阴性预测值96.4%、88.6%。GDS和PDMS-2的一致性检验Kappa值0.306,P0.05,GMs和PDMS-2评估的一致性检验Kappa值0.757,P0.05,提示GMs、GDS对运动发育预测与发育结局均具有良好的一致性,GMs中不安运动阶段的预测与发育结局的一致性更高。结论 GMs的不安运动阶段能够超早期预测脑瘫等不良运动发育结局,在预测预后方面要优于GDS,能更早期的做出预测。     

靶向铁死亡的癌症疗法

铁死亡是一种铁依赖性的,由脂质活性氧累积所引发的调节性细胞死亡方式。铁死亡的启动和执行取决于铁稳态、脂质代谢和抗氧化系统的交集。基于对铁死亡与癌症相关信号通路之间交互作用的深入了解,已设计和开发了一系列诱导癌细胞铁死亡的试剂,包括实验性化合物、临床药物和纳米材料。本文综述了铁死亡的调节机制和靶向铁死亡的癌症疗法。     

Iron homeostasis in arthropathies: From pathogenesis to therapeutic potential

Iron is an essential element for proper functioning of cells within mammalian organ systems; in particular, iron homeostasis is critical for joint health. Excess iron can induce oxidative stress damage, associated with the pathogenesis of iron-storage and ageing-related diseases. Therefore, iron levels in body tissues and cells must be tightly regulated. In the past decades, excess iron content within joints has been found in some patients with joint diseases including hemophilic arthropathy, hemochromatosis arthropathy, and osteoarthritis (OA). Currently, increased evidence has shown that iron accumulation is closely associated with multiple pathological changes of these arthropathies. This review summarizes system-level and intracellular regulation of iron homeostasis, and emphasizes the role of iron in synovial alterations, cartilage degeneration, and subchondral bone of several arthropathies. Of note, we discuss the potential link between iron homeostasis and OA pathogenesis. Finally, we discuss the therapeutic potential of maintaining iron homeostasis in these arthropathies.     

铁死亡与重大慢性疾病

铁死亡是近年发现的一种铁依赖的新型细胞死亡方式，其特征是脂质过氧化物和活性氧簇的过量蓄积。大量研究表明，铁死亡不仅在重大慢性疾病的发生发展过程中发挥重要作用，而且在不同的疾病背景下扮演不同角色。目前认为，铁死亡可抑制肿瘤生长并增加多种肿瘤对化疗药物和免疫治疗的敏感性，因此诱导铁死亡的发生拓展了肿瘤治疗思路。然而，在心脑血管疾病和神经退行性疾病中，铁死亡的发生通过引发正常组织器官损伤和功能丧失直接参与疾病的发生、发展及转归，因此针对心脑血管疾病和神经退行性疾病，抑制铁死亡的发生能够有效预防并延缓这些疾病的发生和发展。本文综述了铁死亡在恶性肿瘤、神经退行性疾病和心脑血管疾病三类不同重大慢性疾病中的最新研究进展及其潜在的作用机制，系统讨论了靶向铁死亡在防治重大慢性疾病中的临床应用前景，为重大慢性疾病的防治提供新的依据。     

IFNγ signaling integrity in colorectal cancer immunity and immunotherapy

The majority of colorectal cancer patients are not responsive to immune checkpoint blockade (ICB). The interferon gamma (IFNγ) signaling pathway drives spontaneous and ICB-induced antitumor immunity. In this review, we summarize recent advances in the epigenetic, genetic, and functional integrity of the IFNγ signaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ICB. Moreover, we discuss how to target IFNγ signaling to inform novel clinical trials to treat patients with colorectal cancer.     

铁死亡相关机制与子宫内膜癌

子宫内膜癌是女性生殖系统三大恶性肿瘤之一,严重危害女性健康。近年研究发现,铁死亡在子宫内膜癌的发生、发展中起到重要作用。作为一种细胞程序性死亡方式,铁死亡与铁代谢、脂质代谢和氧化应激等生物过程密切相关。研究发现通过调控子宫内膜癌细胞铁代谢及氧化应激,可以促进癌细胞铁死亡,抑制肿瘤细胞增殖,且调控铁死亡的相关通路可以影响子宫内膜癌患者化疗敏感性,分析铁死亡相关基因表达可以预测子宫内膜癌患者预后。因此,铁死亡通路相关蛋白有望成为子宫内膜癌治疗新靶点。综述铁死亡的发生机制及其在子宫内膜癌的发生、治疗中的作用,并分析铁死亡相关分子作为一种新型的分子分型预测子宫内膜癌预后的潜在应用价值,为铁死亡在子宫内膜癌治疗领域中的应用提供新思路。     

脊髓损伤“气滞血瘀”病机理论与铁死亡的关系

“气滞血瘀”是脊髓损伤重要的中医病机理论,其科学内涵有待进一步阐释。铁死亡作为脊髓损伤重要的病理,其分子生物学和病理学或许与“气滞血瘀”病机理论有密切相关性。从铁死亡的调控机制入手,揭示活血化瘀中药治疗脊髓损伤的分子机制,为中医药治疗脊髓损伤提供分子生物学依据,丰富中医药现代化的研究思路和手段。     

铁自噬及相关基因NCOA4、FTH1在口腔鳞癌中的研究进展

铁自噬(ferritinophagy)是一种与铁死亡关系密切的自噬类型,由核受体共激活因子4 (nuclear receptor coativator 4,NCOA4)介导铁蛋白在自噬溶酶体中降解,然后使铁蛋白结合的铁降解释放出游离铁,是铁代谢的重要途径。近年来,越来越多的研究表明,铁自噬和铁死亡在肿瘤发生发展中起着重要作用。但目前铁自噬在口腔鳞癌中的作用机制尚未完全阐明,对口腔鳞癌中铁自噬机制的深入研究,有望帮助寻找此类疾病治疗的新靶点。本文对铁自噬在口腔鳞癌中作用研究的最新进展作一综述。     

短波紫外线与交联淀粉碘联用法对血浆中病毒灭活的研究

采用细胞感染试验、全自动生化分析仪、ＳＤＳ－ＰＡＧＥ等技术，观察短波紫外线（ＵＶＣ）与交联淀粉碘（ＣＳＩ）联用对血浆中辛德比斯病毒（ＳＶ）的灭活效果及血浆成分的变化。结果，以７１７０Ｊ／ｍ２ＵＶＣ照射后再经１００ｍｇ／ｍｌＣＳＩ处理６０ｍｉｎ，血浆中病毒的灭活可达６个对数级，且两消毒因子有协同增效作用。消毒后的血浆，除乳酸脱氢酶完全消失，总胆红素含量明显下降，钾离子含量比对照增加５２倍外，多种蛋白含量、蛋白分子量和生化指标均维持在正常值范围。