铁死亡在子宫内膜异位症中的研究进展

子宫内膜异位症（endometriosis,EMs）虽为一种常见的妇科良性疾病,却有侵袭、浸润、远处转移等恶性行为。铁死亡（ferroptosis）是一种新发现的程序性细胞死亡,主要特征表现为细胞内游离二价铁（Fe²⁺）过量介导芬顿反应产生羟基自由基,细胞内抗氧化酶谷胱甘肽过氧化物酶4受抑制,细胞膜脂质发生过氧化导致细胞死亡。EMs病灶表现为铁死亡抵抗,这一特征导致异位内膜清除障碍并促进其增殖与迁移;而部分细胞又可通过铁死亡促进血管生成。铁死亡导致的精子和卵细胞损伤及胚胎毒性则进一步导致EMs相关性不孕。     

miR⁃449a通过NOTCH1介导铁死亡调控非小细胞肺癌细胞增殖和凋亡

目的 探讨miR⁃449a对非小细胞肺癌细胞增殖和凋亡的调控作用及其分子机制。方法 用miR⁃499a过表达类似物Agomir⁃499a（Agomir⁃499a组）及其阴性对照（NC组）分别转染非小细胞肺癌NCI⁃H1975细胞,采用qRT⁃PCR检测转染细胞中miR⁃499a的表达水平,CCK⁃8和Ki67染色法检测细胞增殖,Annexin V染色法检测细胞凋亡。采用铁死亡抑制剂ferrostatin⁃1（Fer⁃1）和谷胱甘肽（GSH）分别处理转染Agomir⁃499a的NCI⁃H1975细胞（依次记为Agomir⁃499a+Fer⁃1组和Agomir⁃499a+GSH组）,采用荧光探针法检测细胞内的Fe2+ 水平,光学比色法检测细胞内的GSH含量,qRT⁃PCR检测细胞内铁死亡和铁稳态相关基因的mRNA表达,Western blot检测NOTCH1信号通路相关蛋白的表达。结果 与NC组比较,Agomir⁃499a组NCI⁃H1975细胞的miR⁃449a表达水平明显增加（P=0.001）,细胞增殖活力明显降低（P<0.05）,细胞凋亡比例明显增加（P=0.004）;铁死亡相关因子PTGS2、ACSL4、SLC7A11和COX2的表达水平,Fe2+细胞比例以及铁稳态相关基因TF、STEAP3、TFRC和DMT1的表达水平均明显增加（均P<0.05）,但GSH含量以及NOTCH1信号通路相关分子NOTCH1、NICD、JAG1、JAG2、DLL1和HES1的表达水平均明显降低（均P<0.05）。与Agomir⁃449a组比较,Agomir⁃449a+Fer⁃1组铁死亡相关因子PTGS2、ACSL4、COX2和SLC7A11的表达水平,Fe2+细胞比例以及铁稳态相关基因TF和STEAP3的表达水平均明显降低（均P<0.05）,但GSH含量和NOTCH1信号通路相关分子NICD、JAG1和DLL1的表达水平均明显增加（均P<0.05）;Agomir⁃449a+GSH组SLC7A11、COX2和ACSL4的表达水平也较Agomir⁃449a组明显降低（均P<0.05）。 结论 miR⁃449a可诱导非小细胞肺癌NCI⁃H1975细胞凋亡和增殖抑制,其作用机制可能与抑制NOTCH1信号介导的铁死亡有关。     

Molecular regulatory mechanism of ferroptosis and its role in gastrointestinal oncology: Progress and updates

Gastrointestinal (GI) tumors, including liver, pancreatic, gastric, and colorectal cancers, have a high incidence rate and low survival rate due to the lack of effective therapeutic methods and frequent relapses. Surgery and postoperative chemoradiotherapy have largely reduced the fatality rates for most GI tumors, but these therapeutic approaches result in poor prognoses due to severe adverse reactions and the development of drug resistance. Recent studies have shown that ferroptosis plays an important role in the onset and progression of GI tumors. Ferroptosis is a new non-apoptotic form of cell death, which is iron-dependent, non-apoptotic cell death characterized by the accumulation of lipid reactive oxygen species (ROS). The activation of ferroptosis can lead to tumor cell death. Thus, regulating ferroptosis in tumor cells may become a new therapeutic approach for tumors, making it become a research hotspot. Current studies suggest that ferroptosis is mainly triggered by the accumulation of lipid ROS. Furthermore, several studies have indicated that ferroptosis may be a new approach for the treatment of GI tumors. Here, we review current research progress on the mechanism of ferroptosis, current inducers and inhibitors of ferroptosis, and the role of ferroptosis in GI tumors to propose new methods for the treatment of such tumors.     

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。     

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.     

针刺调控铁死亡治疗脑卒中的信号通路研究进展

脑卒中的发病机制是一个动态演变过程,表现为一系列神经毒性和神经保护相互作用的反应,参与反应的蛋白质作为信号通路通常在外界刺激下激活。目前已明确针刺能通过抑制脑卒中后脑组织神经细胞铁死亡从而促进神经功能修复,近年来针刺通过调控铁死亡治疗脑卒中的相关信号通路研究取得了显著进展,主要包括以下几方面：miR-23a-3p和核转录因子红系2样2(NFE2L2)信号通路;p62/Kelch样ECH关联蛋白1/核因子E2相关因子2(p62/Keap1/Nrf2)信号通路;α7nAChR介导的Janus激酶2/信号转导及转录激活因子3(JAK2/STAT3)信号通路;环磷酸腺苷/cAMP依赖性蛋白激酶/cAMP反应元件结合蛋白(cAMP/PKA/CREB)信号通路;磷脂酰肌醇-3激酶/蛋白激酶B(PI3K/AKT)信号通路;p38丝裂原活化蛋白激酶(MAPK)信号通路;过氧化物酶体增殖物激活受体γ辅激活因子1α/线粒体转录因子A(PGC-1α/TFAM)信号通路;Notch信号通路和脑源性神经营养因子(BDNF)介导的Nrf2信号通路。其中有已被证实的信号通路,亦有待研究的信号通路。     

Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1

Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation. Currently, the therapeutic role of ferroptosis on cancer is gaining increasing interest. Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types; however, the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown. In the study, we investigated the effect of baicalin on bladder cancer cells 5637 and KU-19-19. As a result, we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells. Subsequently, we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo, accompanied by reactive oxygen species (ROS) accumulation and intracellular chelate iron enrichment. The ferroptosis inhibitor deferoxamine but not necrostatin-1, chloroquine (CQ), N-acetyl-l-cysteine, l-glutathione reduced, or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK) rescued baicalin-induced cell death, indicating ferroptosis contributed to baicalin-induced cell death. Mechanistically, we show that ferritin heavy chain 1 (FTH1) was a key determinant for baicalin-induced ferroptosis. Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells. Taken together, our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis, which will hopefully provide a prospective compound for bladder cancer treatment.     

Role of ferroptosis in colorectal cancer

Colorectal cancer (CRC) is the second deadliest cancer and the third-most common malignancy in the world. Surgery, chemotherapy, and targeted therapy have been widely used to treat CRC, but some patients still develop resistance to these treatments. Ferroptosis is a novel non-apoptotic form of cell death. It is an iron-dependent non-apoptotic cell death characterized by the accumulation of lipid reactive oxygen species and has been suggested to play a role in reversing resistance to anticancer drugs. This review summarizes recent advances in the prognostic role of ferroptosis in CRC and the mechanism of action in CRC.     

谷胱甘肽过氧化物酶4介导的铁死亡参与阿霉素对乳腺癌细胞抑制作用研究

目的:探讨谷胱甘肽过氧化物酶4(GPX4)介导的铁死亡是否参与阿霉素对乳腺癌的抑制过程,并探讨其增加阿霉素敏感性的可能机制。方法:通过实时荧光定量逆转录聚合酶链反应(qRT-PCR)实验和免疫蛋白印迹法(Western Blot),检测正常乳腺细胞MCF10A、HCC1937细胞和乳腺癌细胞MCF-7、MDA-MB-231细胞中GPX4的表达水平;通过慢病毒转染技术构建稳定敲低GPX4的乳腺癌细胞MCF-7,并通过qRT-PCR和Western Blot实验检测敲低效率;通过CCK8实验检测阿霉素对乳腺癌细胞的细胞毒性;通过谷胱甘肽(GSH)检测试剂盒、丙二醛(MDA)检测试剂盒、铁离子(Fe²⁺)浓度检测试剂盒检测敲低GPX4后乳腺癌细胞的铁死亡水平。结果:乳腺癌细胞中GPX4的蛋白水平及mRNA水平高于正常乳腺细胞(P<0.05);与对照组细胞相比,敲低GPX4表达的乳腺癌细胞中GSH水平降低(P<0.05),MDA和Fe²⁺水平升高(P<0.05),阿霉素作用后细胞增殖能力下降(P<0.05),而铁死亡抑制剂fe...     

铁死亡在肝缺血—再灌注损伤大鼠肠损伤中的作用

目的 探究铁死亡在肝缺血-再灌注损伤(HIR)大鼠肠损伤中的作用。方法 选择健康清洁级雄性SD大鼠40只,周龄8～10周,体重220～260 g。采用随机数字表法将大鼠分成四组：假手术组(S组)、铁死亡抑制剂Ferrostatin-1+假手术组(SF组)、HIR模型组(IR组)和铁死亡抑制剂Ferrostatin-1+HIR模型组(IF组),每组10只。S组腹腔注射等容量0.02%DMSO,30 min后行假手术,仅进行开腹、分离第一肝门和关腹处理。SF组腹腔注射Ferrostatin-1(溶于0.02%DMSO)5 mg/kg, 30 min后行假手术。IR组腹腔注射等容量0.02%DMSO,30 min后制备HIR模型。IF组腹腔注射Ferrostatin-1(溶于0.02%DMSO)5 mg/kg, 30 min后制备HIR模型。于再灌注后8 h处死大鼠,取小肠组织,采用ELISA法检测肠组织丙二醛(MDA)、谷胱甘肽(GSH)和铁(Fe²⁺)浓度;采用速率法检测血清中ALT和AST活性;采用Western blot法检测谷胱甘肽过氧化物酶4(GPX4)、铁...