MOLECULAR HUMAN REPRODUCTION
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2023
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IF 4
Dong Xiaoyu,Xu Le,Wang Shuang,Jiao Xue,Yan Shumin,Huang Yufei,Yuan Ming,Wang Guoyun
Ferroptosis is an iron-dependent programmed cell death process characterised by the accumulation of lethal oxidative damage. Localised iron overload is a unique clinical phenomenon in ovarian endometriosis. However, the role and mechanism of ferroptosis in the course of ovarian endometriosis remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian endometriosis and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells. Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse endometriosis model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian endometriosis can activate autophagy-related ferroptosis in endometrial stromal cells, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the endometriosis environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian endometriosis.
研究领域:
妇科学
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细胞生物学
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分子生物学
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病理生理学
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DOI
PubMed
高影响因子
BMC Complementary Medicine and Therapies
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2025
·Vol. 25
·期 1
·451
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IF 3.4
Pan Sunfeng,Xiong Lie,Li Jiakun,Wang Zhenjun,Su Yujuan,Fang Gaofeng,Zhu Minda,Shi Hanqiang,Li Jiayan,Liu Zhaoyan,Han Chunmao,Shi Yanbo
Background Venous leg ulcer (VLU) is among the most severe clinical manifestations of chronic venous disease (CVD) and imposes substantial burdens on both patients and society. VLU pathogenesis is closely associated with the impairment of vascular endothelial cells. In this study, tissue samples from the patients’ s skins around wound at different stages of CVD were collected during operation and used to elucidate the involvement of ferroptosis in the pathogenesis of VLU. Also the potential mechanism through which Huoxue Shengji (HXSJ) decoction alleviates ferroptosis in human umbilical vein endothelial cells (HUVECs) was investigated. Methods During surgical procedure such as great saphenous vein high ligation and stripping surgery, matched skin tissues from the normal, hyperpigmentation (HPT), lipodermatosclerosis (LDS), and VLU regions were collected from 10 patients with VLU, and the levels of iron and glutathione peroxidase 4 (GPX4) were quantified to evaluate ferroptosis. In vitro, HUVECs were used to iron overload induction using exogenous 100 µM ferric ammonium citrate (FAC) or 100 µM hemin, or ferroptosis induction with 10 µM erastin, and treated with 10 µg/ml HXSJ decoction for 24 h. Subsequently, lipid peroxidation (LPO) damage, mitochondrial function, and key genes involved in ferroptosis were assessed. Results Iron deposition in the affected skin of patients with CVD gradually increased before progression to VLU and significantly decreased during the VLU stage. Moreover, GPX4 expression increased significantly in the HPT stage but was gradually suppressed with further deterioration of CVD. The in vitro results indicated that in both the iron overload and ferroptosis models, HXSJ decoction effectively upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SLC7A11, xCT), and GPX4, which was accompanied by the inhibition of malondialdehyde and protein carbonylation production, the alleviation of ferrous ion accumulation, and the restoration of mitochondrial function. Conclusions This study demonstrated that iron accumulation-mediated inactivation of GPX4 serves as a crucial mechanism in VLU formation through ferroptosis induction. Notably, the therapeutic mechanism through which HXSJ decoction alleviates ferroptosis involves Nrf2/xCT/GPX4 pathway activation and a reduction in ferrous ion accumulation. These findings may provide novel insights into VLU pathogenesis and give possible reason for developing traditional Chinese medicine therapies targeting ferroptosis and VLUs. Graphical
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PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2019
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IF 8.456
Longfa Kou,Rui Sun,Shuyi Xiao,Yawen Zheng,Zhiwei Chen,Aimin Cai,Hailun Zheng,Qing Yao,Vadivel Ganapathy,Ruijie Chen
An effective steady-state redox balance is maintained in cancer cells, allowing for protection against oxidative stress and thereby enhancing cell proliferation and tumor growth. Disruption of this redox balance would increase the cellular content of reactive oxygen species (ROS) and potentiate oxidative stress-induced cell death in tumor cells, thus representing an effective strategy for cancer treatment. Glutathione (GSH) is a major reducing agent, and its cellular levels are determined at least partly by the availability of cysteine via xCT (SLC7A11)-mediated entry of cystine into cells. We developed a nanoplatform using ZnO nanoparticles (NPs) as a carrier, loaded with salicylazosulfapyridine (SASP), and stabilized with DSPE-PEG, to form ultra-small NPs (SASP/ZnO NPs). The goal of this NP strategy is to disrupt the redox balance in cells by two mechanisms: increased generation of ROS and decreased synthesis of GSH. Such an approach would be effective in killing tumor cells. As expected, the SASP/ZnO NPs enhanced ROS production because of ZnO and impaired GSH synthesis because of SASP-induced inhibition of xCT (SLC7A11) transport function. As a consequence, treatment of tumor cells with SASP/ZnO NPs in vitro and in vivo resulted in a synergistic disruptive effect on redox balance in tumor cells and induced cell death and decreased tumor growth. This ambidextrous approach has potential in cancer therapy by combining two complementary pathways to disrupt the redox balance in tumor cells.
研究领域:
肿瘤学
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纳米技术
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2020
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IF 8.758
Longfa Kou,Rui Sun,Xinyu Jiang,Xinlu Lin,Huirong Huang,Shihui Bao,Youting Zhang,Chao Li,Ruijie Chen,Qing Yao
Tumor cells usually display metabolic, genetic, and microenvironment-related alterations, which are beneficial to tumor proliferation, tumor development, and resistance occurrence. Many transporters and enzymes, including ATB0,+, xCT, and matrix metalloproteinases (MMPs), are involved in the altered cell metabolism and tumor microenvironment and often abnormally upregulated in malignant tumors. Meanwhile, these dysregulated transporters and enzymes provide targets not only for a pharmacological blockage to suppress tumor progress but also for tumor-specific delivery. Although transporters and MMPs have been widely reported for antitumor drug delivery, the feasibility of utilizing two strategies has never been elucidated yet. Herein, we developed an MMP2-activated and ATB0,+-targeted liposome with doxorubicin and sorafenib (DS@MA-LS) loaded for optimal tumor drug delivery for cancer therapy. DS@MA-LS was designed to prolong blood circulation and deshield the PEG shell from MMP2 cleavage to expose lysine and target overexpressed ATB0,+ for enhanced tumor distribution and cancer cellular uptake. Besides the anticancer effects of loaded drugs, the endocytosed liposomes could further increase ROS production and suppress the antioxidant system to amplify oxidative stress. As expected, DS@MA-LS displayed enhanced targeted drug delivery to tumor sites with the MMP2-controlled ligand exposure and ATB0,+-mediated uptake. More importantly, DS@MA-LS successfully inhibited the tumor growth and cancer cell proliferation both in vitro and in vivo by enhancing apoptosis and ferroptosis, which thanks to the increased ROS generation and impaired GSH synthesis synergistically amplified oxidative stress. Our results suggested that the tumor microenvironment-responsive, multistaged nanoplatform, DS@MA-LS, has excellent potential for optimal drug delivery and enhanced cancer treatment.
研究领域:
药学
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纳米技术
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癌症研究
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生物医学工程
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DOI
PubMed
高影响因子
ACS Nano
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2022
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IF 18.027
Wenhao Wang,Fangqin Fu,Zhengwei Huang,Wenhua Wang,Minglong Chen,Xiao Yue,Jintao Fu,Xiaoqian Feng,Ying Huang,Chuanbin Wu,Xin Pan
Ferroptosis therapy by catalyzing the Fenton reaction has emerged as a promising tumor elimination strategy for lung adenocarcinoma (ADC). However, the unsatisfactory Fenton reaction efficiency, strong intracellular antioxidant system, and insufficient lung drug accumulation limits the ferroptosis therapeutic effect. To address these issues, an inhalable nanoreactor was proposed by spontaneously adsorbing biomimetic protein corona (PC) composed of matrix metalloproteinase 2 responsive gelatin and glutamate (Glu) on the surface of cationic nanostructured lipid carriers (NLC) core loaded with ferrocene (Fc) and fluvastatin. The prepared Fc-NLC(F)@PC could be nebulized into lung lesions with 2.6 times higher drug accumulation and boost lipid peroxide production by 3.2 times to enhance ferroptosis therapy. Mechanically, fluvastatin was proved to inhibit monocarboxylic acid transporter 4 mediated lactate efflux, inducing tumor acidosis to boost Fc-catalyzing reactive oxygen species production, while the extracellular elevating Glu concentration was found to inhibit xCT (system Xc–) functions and further collapse the tumor antioxidant system by glutathione synthesis suppression. Mitochondrial dysfunction and cell membrane damage were involved in the nanoreactor-driven ferroptotic cell death process. The enhanced antitumor effects by combination of tumor acidosis and antioxidant system collapse were confirmed in an orthotopic lung ADC tumor model. Overall, the proposed nanoreactor highlights the pulmonary delivery approach for local lung ADC treatment and underscores the great potential of ferroptosis therapy.
研究领域:
癌症治疗
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纳米技术
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药学
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生物医学工程
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2023
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IF 5.1
Xi Wang,Wenjing Zhu,Miao Xing,Haiyan Zhu,Enqing Chen,Jie Zhou
Matrine (MT) is an alkaloid isolated from Sophora flavescens with various bioactivities and is widely used clinically. However, the broader its clinical use, the greater its toxicity concerns. We investigate the role of ferroptosis in MT-induced liver injury caused by an imbalance in the antioxidant pathway. Our results showed that MT could cause pathological changes in liver tissues and lead to a significant reduction in L02 cell viability. MT also reduced superoxide dismutase (SOD) and glutathione (GSH), increased malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation levels, and disrupted iron homeostasis , leading to ferroptosis. In addition, MT decreased the protein levels of FTH, Nrf2 , xCT, GPX4, HO-1 and ferroptosis suppressor protein 1 (FSP1) and increased the protein levels of TRF1 and DMT1 , characteristic indicators of ferroptosis. Interestingly, the cytotoxic effects of MT were alleviated by ferroptosis inhibitor, Nrf2 agonist, or selenium supplementation. These results revealed that MT triggers hepatocyte ferroptosis by inhibiting the Nrf2/GPX4 antioxidant system.
研究领域:
药理学
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毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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