铁死亡参与四氯化碳致肝纤维化发病过程的研究

目的 探讨铁死亡是否参与CCl4致肝纤维化发病过程。方法 小鼠分为对照组和CCl4组。采用腹腔注射法造模,每隔2 d给药1次,共8次,造模完成后隔2 d处死。通过HE、MASSON和天狼星红染色评价CCl4致小鼠肝损伤及纤维化情况;铁离子检测试剂盒检测小鼠肝组织铁离子含量;MDA检测试剂盒检测小鼠肝组织MDA含量;免疫荧光法观察小鼠肝组织中MDA含量;谷胱甘肽/氧化型谷胱甘肽(GSH/GSSG)评价小鼠肝组织脂质过氧化情况;通过Western Blot和RT - qPCR评价谷胱甘肽过氧化物酶4(GPX4)、铁蛋白(Ferritin)的蛋白和mRNA表达水平。结果 通过HE染色、MASSON染色和天狼星红染色发现,CCl4引起小鼠肝细胞排列紊乱,炎症细胞浸润,纤维化隔片形成。而对照组没有显著的病理变化;CCl4组小鼠肝组织铁离子含量(2.83±0.81) μmol/g较对照组小鼠肝组织铁离子含量(1.54±0.19) μmol/g增加(t = 5.415,P＜0.001);CCl4组MDA荧光强度高于对照组;CCl4组MDA含量(0.74±0.13) nmol/mg较对照组MDA含量(0.21±0.06) nmol/mg增加(t = 15.650,P＜0.001);GSH/GSSG在CCl4组(1.29±0.19)较对照组(1.90±0.16)降低(t = 10.580,P＜0.001);在CCl4组GPX4蛋白相对表达水平(0.27±0.07)较对照组(0.42±0.10)降低(t = 3.000,P = 0.013)。CCl4组Ferritin蛋白相对表达水平(0.18±0.06)较对照组(0.30±0.06)降低(t = 3.571,P = 0.005);CCl4组Ferritin mRNA相对表达水平(1.83±0.60)较对照组(0.84±0.30)降低(t = 4.420,P＜0.001)。CCl4组GPX4 mRNA相对表达水平(1.10±0.45)较对照组(3.54±0.87)降低(t = 7.385,P＜0.001)。结论 铁死亡参与了四氯化碳致肝纤维化的发病过程。     

Exploring a 7-gene prognostic model based on ferroptosis for efficiently guiding immunotherapy in melanoma patients

PurposeAlthough skin cutaneous melanoma (SKCM) is a relatively immunotherapy-sensitive tumor type, there is still a certain fraction that benefits less from treatment. Ferroptosis has been demonstrated to modulate tumor progression in many cancer types. This study focused on ferroptosis-related genes to construct a prognostic model for SKCM patients.Materials and methodsGene expression profiles of SKCM samples were obtained from public databases. Unsupervised consensus clustering was used to determine molecular subtypes related to ferroptosis. Least absolute shrinkage and selection operator (LASSO) and stepwise Akaike information criterion (stepAIC) were applied to construct a prognostic model based on differentially expressed genes between two molecular subtypes.ResultsC1 and C2 subtypes were identified with differential prognosis and immune infiltration. A 7-gene prognostic model was constructed to classify samples into high-FPRS and low-FPRS groups. Low-FPRS group with favorable prognosis had higher immune infiltration and more enriched immune-related pathways than the high-FPRS group. The two groups showed distinct sensitivity to immunotherapy, with the low-FPRS group predicted to have more positive response to immunotherapy than the high-FPRS group. A nomogram based on the FPRS score and clinical features was built for more convenient use.ConclusionsThe critical role of ferroptosis involved in SKCM development was further validated in this study. The prognostic model was efficient and stable to be applied in clinical conditions to support clinicians in determining personalized therapy for SKCM patients especially those with metastasis.     

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。     

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。     

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。     

放射性肺损伤与铁死亡相关性研究进展

放射性肺损伤(RILI)是肺癌等胸部肿瘤放疗后的常见并发症,而铁死亡是一种由铁依赖的、膜脂质过氧化引起的调节性细胞死亡。本文主要从活性氧簇诱导的氧化损伤、核因子E2相关因子2调控的抗氧化网络和铁离子稳态以及转化生长因子 β1参与的炎性反应方面来探索RILI和铁死亡之间关系,以期通过调控铁死亡以减轻或抑制RILI发生,从而改善放疗患者预后。     

褪黑素抑制氧化应激和铁死亡缓解妊娠糖尿病大鼠病理损伤

目的:探讨褪黑素对妊娠糖尿病(GDM)大鼠的治疗作用及可能作用机制。方法:将24只雌性大鼠分成4组正常妊娠组、GDM模型组、低剂量褪黑素5mg/(kg·d)治疗组及高剂量褪黑素10mg/(kg·d)治疗组,每组6只。不同剂量褪黑素治疗14天后,检测大鼠胰腺组织形态病理变化及细胞凋亡水平,检测血清生化指标、细胞氧化应激指标及铁含量。检测胰腺组织中褪黑素受体基因及铁死亡通路相关基因的mRNA和蛋白表达水平。结果:褪黑素治疗明显减轻了大鼠胰腺组织病理损伤和细胞凋亡水平,降低了血清中葡萄糖、糖化血红蛋白及胰岛素水平,显著升高了胰腺组织中CAT、GSH-PX、SOD等抗氧化酶活性及抗氧化剂GSH水平,降低了H2O2、MDA及铁含量。褪黑素治疗显著增加了大鼠胰腺中褪黑素受体基因MTNR1B表达,同时调控铁死亡通路相关基因表达,包括增加GPX4及FTH1基因表达水平,降低ACSL4基因表达水平。结论:褪黑素可能通过褪黑素受体介导,抑制组织氧化还原水平失衡,降低组织细胞凋亡和铁死亡,进而缓解GDM所致的病理损伤。