JOURNAL OF CONTROLLED RELEASE
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2022
·
IF 11.467
Jiamei Li,Yang Zhou,Jiaqi Liu,Xiaotong Yang,Kai Zhang,Lei Lei,Haili Hu,Huilin Zhang,Liang Ouyang,Huile Gao
As an endogenous gasotransmitter , CO has achieved tremendous advances in cancer treatment through selectively killing cancer cells. However, the application of CO in tumor immunotherapy has not been reported and the tumor targeting delivery is still a tremendous challenge. Herein, thermosensitive boronic acid group-containing CO prodrug was synthesized and fabricated with tannic acid (TA) and iron (Fe) to form metal-phenolic networks, and then loaded with near-infrared (NIR) photothermal agent IR820 to form [email protected] III TA for combinational therapy of CO and photothermal therapy . Ferroptosis can also be enhanced due to the Fe 3+ incorporation. After TA reduced Fe 3+ into Fe 2+ , Fe 2+ might lead to intracellular Fenton reaction. Furthermore, in combination with CTLA-4 blockade immunotherapy, [email protected] III TA remarkably inhibited breast tumor growth, suppressed the lung metastasis and improved the antitumor immune response. To summarize, [email protected] III TA provides a potential novel option for CO/photothermal/immune synergistic therapy with enhanced ferroptosis through simple compositions and facile synthesis process.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
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IF 6.1
Ming-Shan Chen,Jia-Xin Wang,Hao Zhang,Jia-Gen Cui,Yi Zhao,Jin-Long Li
Phthalates are widely used to improve the flexibility of poly(vinyl chloride) (PVC) polymer agriculture products. Di(2-ethylhexyl) phthalate (DEHP) is a type of addition to plastic and can lead to many health problems. Hemeoxygenase-1 (HO-1) is an extremely important molecule that releases enzymatic products to promote ferroptosis. This research aimed to explore the function of HO-1 in DEHP-induced renal proximal tubule cell ferroptosis. In the experiment, ICR male mice are exposed to (0, 50, 200, and 500 mg/kg BW/day) DEHP for 28 days. Here, we observed that DEHP induced glomeruli atrophy and the tubules swell. Furthermore, DEHP exposure could increase ferrous iron content and decrease antioxidant activity. We also found that DEHP exposure increased the expression of nuclear factor-erythroid 2 p45-related factor 2 (NFE2L2) in the nucleus. In particular, the expression of (HO-1) is significantly increased both in protein and mRNA levels. Glutathione peroxidase 4 (GPX4) as an endogenous control of ferroptosis was downregulated, which proved the occurrence of ferroptosis. In the study, exposure to DEHP activated the NFE2L2/HO-1 signaling pathway and resulted in ferroptosis of the proximal tubule. This research connects ferroptosis with HO-1, providing new insights into the potential roles of phthalates in nephrotoxicity.
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Acta Biomaterialia
·
2023
·
IF 9.7
Yang Lin,Xiangwu Chen,Cancan Yu,Guixiang Xu,Xinxin Nie,Yufeng Cheng,Yuxia Luan,Qingxu Song
Ferroptosis has received increasing attentions in cancer therapy owing to its unique advantages over apoptosis. However, ferroptosis is governed by the efficiency of reactive oxygen species (ROS) production and the tumor cell antioxidant microenvironment that compromises therapeutic efficacy of ferroptosis. It is of great significance to develop a strategy that can both achieve high-efficiency ROS production and modulate tumor cell antioxidant microenvironment to amplify ferroptosis. However, until now, such a strategy has rarely been realized. Here, we, for the first time, reported a radiotherapy -mediated redox homeostasis-controllable nanomedicine for amplifying ferroptosis sensitivity in tumor therapy. The nanomedicine is constructed by co-assembling a ferroptosis inducer hemin and a thioredoxin 1 (Trx-1) inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) with human serum albumin . For our nanomedicine, hemin converts H 2 O 2 to ROS via Fenton reaction to induce ferroptosis while PX-12 effectively inhibits the activity of antioxidant Trx-1 to suppress ROS depletion, resulting in amplified ferroptosis. Particularly, combining radiotherapy with the nanomedicine, radiotherapy depletes the other key antioxidant glutathione and generates additional radiotherapy-induced ROS, further boosting the ferroptosis effect. Therefore, our strategy can simultaneously ensure efficient ROS production and regulation of tumor cell antioxidant microenvironment, thereby enhancing efficacy of ferroptosis in tumor therapy. Our work offers an innovative approach to amplify ferroptosis sensitivity against tumors by simultaneously promoting ROS production and regulating redox homeostasis . Statement of significance The antioxidants such as thioredoxin 1 (Trx-1) and glutathione (GSH) in tumor cells, are significantly upregulated by the innate cancer cellular redox homeostasis, severely restricting the reactive oxygen species (ROS)-based therapy and compromising the effect of Fenton reaction-induced ferroptosis against tumors. It is urgent to develop a strategy to simultaneously achieve Fenton reaction-induced ferroptosis and regulate the cancer cellular redox homeostasis against upregulated levels of Trx-1 and GSH. A radiotherapy-mediated redox homeostasis-regulatable nanomedicine was designed for amplifying ferroptosis sensitivity in tumor therapy, where the therapeutic efficacy of ferroptosis against tumors can be significantly amplified by integrating Fenton reaction-induced and radiotherapy-induced ferroptosis as well as PX-12-enabled inhibition of antioxidant Trx-1 and radiotherapy-induced downregulation of antioxidant GSH levels.
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Frontiers in Endocrinology
·
2022
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IF 6.055
Shuqin Du,Hanqiang Shi,Lie Xiong,Ping Wang,Yanbo Shi
Canagliflozin (Cana), an anti-diabetes drug belongs to sodium-glucose cotransporter 2 inhibitor, is gaining interest because of its extra cardiovascular benefits. Ferroptosis is a new mode of cell death, which can promote the occurrence of diabetic cardiomyopathy (DCM). Whether Cana can alleviate DCM by inhibiting ferroptosis is the focus of this study. Here, we induced DCM models in diabetic C57BL6 mice and treated with Cana. Meanwhile, in order to exclude its hypoglycemic effect, the high glucose model in H9C2 cells were established. In the in vivo study, we observed that Cana could effectively alleviate the damage of cardiac function in DCM mice, including the increasing of lactate dehydrogenase (LDH) and cardiac troponin I (cTnI), the alleviating of myocardial fiber breakage, inflammation, collagen fiber deposition and mitochondrial structural disorder. We evaluated reactive oxygen species (ROS) levels by DCFH-DA and BODIPY 581/591 C11, in vitro Cana reduced ROS and lipid ROS in H9C2 cells induced by high glucose. Meanwhile, JC-1 fluorochrome assay showed that the decreased mitochondrial membrane potential (MMP) was increased by Cana. Furthermore, the inhibitory effects of Cana on myocardial oxidative stress and ferroptosis were verified in vivo and in vitro by protein carbonyl (PCO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH). As a key inducer of ferroptosis, the deposition of total iron and Fe 2+ can be inhibited by Cana both in vivo and in vitro . In addition, western blot results indicated that the expression of ferritin heavy-chain (FTN-H) was down-regulated, and cystine-glutamate antiporter (xCT) was up-regulated by Cana in DCM mice and cells, suggesting that Cana inhibit ferroptosis by balancing cardiac iron homeostasis and promoting the system Xc - /GSH/GPX4 axis in DCM. These findings underscore the fact that ferroptosis plays an important role in the development and progression of DCM and targeting ferroptosis may be a novel strategy for prevention and treatment. In conclusion, Cana may exert some of its cardiovascular benefits by attenuating ferroptosis.
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NEUROCHEMICAL RESEARCH
·
2022
·Vol. 48
·期 2
·570-578
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IF 4.414
Guo Shenglong,Lei Qi,Guo Hena,Yang Qian,Xue Yanli,Chen Ruili
Ferroptosis and neuroinflammation play a crucial role in the pathogenesis of Alzheimer’s disease (AD), and Edaravone (EDA) has been demonstrated to have anti-inflammatory, antioxidant and neuroprotective effects in neurodegenerative diseases. However, the relationship between EDA and ferroptosis in AD is unidentified. This research aimed to elucidate the mechanism of EDA in AD with Aβ 1-42-induced HT22 cells as in vitro cell model. The results showed that EDA could significantly reduce Aβ 1-42 -induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-α, IL-1β and IL-6, prevent the activation of TLR4/NF-κB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in Aβ 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Lijuan Ma,Xueqi Liu,Mengya Zhang,Lang Zhou,Ling Jiang,Li Gao,Xian Wang,Yuebo Huang,Hanxu Zeng,Yonggui Wu
The pathophysiological mechanism of acute kidney injury (AKI) is complicated, and effective drugs are still lacking. Ferroptosis is a newly discovered regulatory cell death mode characterized by the lethal accumulation of iron and reactive oxygen species-(ROS-)-dependent lipid hydroperoxides. In recent years, ferroptosis has been confirmed to be involved in the progression of AKI. Paeoniflorin (PF) is a traditional Chinese medicine that has protective effects on a variety of kidney diseases including AKI. However, the mechanism by which PF attenuates AKI is unclear. We detected that PF attenuated serum biochemical markers, histological damage, ferroptosis and inflammation in a dose-dependent manner in a mouse AKI model with bilateral renal artery ischemia–reperfusion (IR). Hypoxia-reoxygenation (HR)-induced ferroptosis and inflammation was also inhibited by PF in human renal tubular epithelial cells (HK2). RNA sequence analysis revealed that PF inhibited ferroptosis in HK2 cells by upregulating Slc7a11 in the glutathione pathway after HR treatment. PF failed to further protect cells with specific knockdown of Slc7a11 from ferroptosis under HR conditions. Consequently, these data indicated that PF prevention of ferroptosis in AKI requires dependence on Slc7a11. This study provided a scientific basis for the clinical search for drugs to prevent IR induced AKI.
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ENVIRONMENTAL TOXICOLOGY
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2022
·Vol. 37
·期 5
·1093-1103
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IF 4.109
Fengfan Liu,Xiang Cheng,Shuang Wu,Bei Hu,Chen Yang,Shufen Deng,Qiwen Shi
Exposure to nickel oxide nanoparticles (NiONPs), which have been widely produced and applied in industry, leads to adverse pulmonary and systemic effects. The aim of this study is to investigate the involvement of apoptosis and ferroptosis in NiONPs-induced acute lung injury (ALI). Intratracheal instillation of NiONPs into mice elevated the levels of pro-inflammatory cytokines, neutrophils, and proteins in the bronchoalveolar lavage fluid, and triggered apoptosis and ferroptosis in the lung tissues. Consistently, NiONPs-induced apoptosis and ferroptosis were observed in in vitro experiments using human lung epithelial cells. Activating transcription factor 3 (ATF3), a stress-inducible transcription factor, was upregulated by NiONPs exposure in both murine lung tissues and human lung epithelial cells. Moreover, human lung epithelial cells with ATF3 deficiency exhibited a lower level of apoptosis and ferroptosis when exposed to NiONPs. Collectively, our findings demonstrated that ATF3 was responsive to NiONPs exposure, and promoted NiONPs-induced apoptosis and ferroptosis in lung epithelial cells, indicating that ATF3 is a potential biomarker and therapeutic target for NiONPs-associated ALI.
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JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-20
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IF 9.429
Chen Minjiang,Li Jie,Shu Gaofeng,Shen Lin,Qiao Enqi,Zhang Nannan,Fang Shiji,Chen Xiaoxiao,Zhao Zhongwei,Tu Jianfei,Song Jingjing,Du Yongzhong,Ji Jiansong
Transcatheter arterial chemoembolization (TACE) is one of the main palliative therapies for advanced hepatocellular carcinoma (HCC), which is also regarded as a promising therapeutic strategy for cancer treatment. However, drug-loaded microspheres (DLMs), as commonly used clinical chemoembolization drugs, still have the problems of uneven particle size and unstable therapeutic efficacy. Herein, gelatin was used as the wall material of the microspheres, and homogenous gelatin microspheres co-loaded with adriamycin and Fe 3 O 4 nanoparticles (ADM/Fe 3 O 4 -MS) were further prepared by a high-voltage electrospray technology. The introduction of Fe 3 O 4 nanoparticles into DLMs not only provided excellent T2-weighted magnetic resonance imaging (MRI) properties, but also improved the anti-tumor effectiveness under microwave-induced hyperthermia. The results showed that ADM/Fe 3 O 4 -MS plus microwave irradiation had significantly better antitumor efficacy than the other types of microspheres at both cell and animal levels. Our study further confirmed that ferroptosis was involved in the anti-tumor process of ADM/Fe 3 O 4 -MS plus microwave irradiation, and ferroptosis marker GPX4 was significantly decreased and ACSL4 was significantly increased, and ferroptosis inhibitors could reverse the tumor cell killing effect caused by ADM/Fe 3 O 4 -MS to a certain extent. Our results confirmed that microwave mediated hyperthermia could amplify the antitumor efficacy of ADM/Fe 3 O 4 -MS by activating ferroptosis and the introduction of Fe 3 O 4 nanoparticles can significantly improve TACE for HCC. This study confirmed that it was feasible to use uniform-sized gelatin microspheres co-loaded with Fe 3 O 4 nanoparticles and adriamycin to enhance the efficacy of TACE for HCC. Graphical Abstract
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Biomaterials Science
·
2022
·Vol. 10
·期 14
·3911-3923
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IF 7.59
Mingting Zhu,Pengying Wu,Yan Li,Lei Zhang,Yujin Zong,Mingxi Wan
Ferroptosis is an emerging form of programmed cell death, and its combination with sonodynamic therapy (SDT) for anti-tumor activity is gradually attracting attention. However, their application against gliomas has not been studied. Herein, multifunctional cancer homologous targeting biomimetic nanoparticles (PIOC@CM NPs) encapsulating both Fe3O4 and Ce6 were constructed as a nanosonosensitizer. Based on focused ultrasound (US) combined with circulating microbubbles (MBs) to open the blood–brain barrier (BBB) in a safe and transient manner, the development of a therapeutic strategy to integrate the biomimetic nanosonosensitizer-mediated SDT and ferroptosis could achieve synergistic therapeutic effects against gliomas. We demonstrated that the glioma C6 cell membrane (CM) on the surface of the NPs allowed the nanosonosensitizer to accumulate selectively in tumors through homologous targeting in vitro. After efficient internalization in C6 cells, the PIOC@CM NPs could significantly increase the level of reactive oxygen species (ROS) and deplete glutathione (GSH) upon ultrasonic irradiation, resulting in the loss of glutathione peroxidase-4 (GPX4) activity, which facilitated SDT and ferroptosis to kill glioma C6 cells. Furthermore, the PIOC@CM NPs were intravenously injected after noninvasively opening the BBB via US-MBs, which enhanced the accumulation of the nanosonosensitizer in tumor tissues. Crucially, an attractive phenomenon of the significant reduction in orthotopic gliomas after the second US pulse-triggered SDT and ferroptosis was observed. Taken together, this study presents a novel combinatorial glioma therapeutic strategy based on noninvasive BBB opening with a biomimetic sonotheranostic system-mediated SDT and ferroptosis.
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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.
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ACS Applied Materials & Interfaces
·
2022
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IF 10.383
Wenjie Feng,Wanrui Shi,Ze Wang,Yanqi Cui,Xinxin Shao,Shuwei Liu,Li Rong,Yi Liu,Hao Zhang
Ferroptosis has been considered as a promising pathway to overcome apoptosis-induced tumor chemoresistance. However, the antitumor efficacy of ferroptosis-inducing agents is still limited because of the complexity and diversity of tumor microenvironments. Herein, we demonstrate a triple ferroptosis amplification strategy for tumor therapy by associating iron-based nanocarriers, ferroptosis molecular drugs, and H2O2-producing enzymes. Fe(III)-Shikonin (FeShik) metal-polyphenol-coordinated networks are employed to load a ferroptosis inducer of sorafenib (SRF) inside and glucose oxidase (GOx) outside, thus producing SRF@FeShik-GOx supramolecular nanomedicines (SNs). After delivering into glutathione (GSH)-overexpressed tumor cells, FeShik will disassemble and release Fe2+ to induce cell death via ferroptosis. At the same time, GOx executes its catalytic activity to produce an acid environment and plenty of H2O2 for stimulating •OH generation via the Fenton reaction. Moreover, SRF will suppress the biosynthesis of GSH by inhibiting system Xc–, further deactivating the enzymatic activity of glutathione peroxidase 4 (GPX4). Up-regulation of the oxidative stress level and down-regulation of GPX4 expression can dramatically accelerate the accumulation of lethal lipid peroxides, leading to ferroptosis amplification of tumor cells. The current strategy that utilizes ferroptosis-inducing agents as both nanocarriers and cargoes provides a pathway to enhance the efficacy of ferroptosis-based tumor therapy.
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Materials Today Bio
·
2021
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IF 7.348
Xiaomin Su,Yongbin Cao,Yao Liu,Boshu Ouyang,Bo Ning,Yang Wang,Huishu Guo,Zhiqing Pang,Shun Shen
Ferroptosis has received ever-increasing attention due to its unparalleled mechanism in eliminating resistant tumor cells. Nevertheless, the accumulation of toxic lipid peroxides (LPOs) at the tumor site is limited by the level of lipid oxidation. Herein, by leveraging versatile sodium alginate (ALG) hydrogel, a localized ferroptosis trigger consisting of gambogic acid (GA), 2,2′-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH), and Ink (a photothermal agent), was constructed via simple intratumor injection. Upon 1064 nm laser irradiation, the stored AIPH rapidly decomposed into alkyl radicals (R•), which aggravated LPOs in tumor cells. Meanwhile, GA could inhibit heat shock protein 90 (HSP90) to reduce the heat resistance of tumor cells, and forcefully consume glutathione (GSH) to weaken the antioxidant capacity of cells. Systematic in vitro and in vivo experiments have demonstrated that synchronous consumption of GSH and increased reactive oxygen species (ROS) facilitated reduced expression of glutathione peroxidase 4 (GPX4), which further contributed to disruption of intracellular redox homeostasis and ultimately boosted ferroptosis. This all-in-one strategy has a highly effective tumor suppression effect by depleting and generating fatal active compounds at tumor sites, which would pave a new route for the controllable, accurate, and coordinated tumor treatments.
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