ACS Applied Materials & Interfaces
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2023
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IF 9.5
Junfeng Liu,Xi Li,Jiayao Chen,Xiaoting Zhang,Jingpei Guo,Jinyan Gu,Chaoming Mei,Yitai Xiao,Chao Peng,Junbin Liu,Xiaojun Hu,Ke Zhang,Dan Li,Bin Zhou
Hepatocellular carcinoma (HCC) has a poor response to most available systemic therapies due to intrinsic or acquired resistance to apoptosis. Ferroptosis-based therapy is expected to circumvent those limitations. Therefore, the rational design of ferroptosis-based therapies with targeted delivery of ferroptosis inducers for HCC is in need. In this study, we found that arsenic trioxide (ATO) can efficiently induce ferroptosis in HCC cells, and this effect could be reversed by the iron chelator deferoxamine. On this basis, a drug delivery system was constructed to enhance the therapeutic efficacy of ATO by camouflaging ATO-loaded magnetic nanoparticles (Fe3O4) with HCC cell membranes, termed AFN@CM. After AFN@CM treatment, glutathione peroxidase 4 was strongly inhibited and intracellular lipid peroxide species were significantly increased in HCC cells. In addition, enhanced ferroptosis and tumor suppression were observed both in vitro and in vivo. The bio-safety of AFN@CM was also demonstrated by the in vivo toxicity evaluation. In addition, benefiting from the cell membrane coating, AFN@CM showed enhanced accumulation at tumor sites and achieved continuous tumor elimination in the mouse model. In conclusion, AFN@CM exhibited satisfactory therapeutic efficacy in the treatment of HCC and provided a desirable ferroptosis-based strategy for safe and reliable HCC therapeutics.
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高影响因子
Food & Function
·
2023
·Vol. 14
·期 4
·1884-1896
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IF 6.1
Huiyi Li,Qiqing Weng,Shuai Gong,Weixian Zhang,Jiaqi Wang,Yuqiao Huang,Yuanjun Li,Jiao Guo,Tian Lan
Acetaminophen (APAP)-induced liver injury (AILI) has become a growing public health problem. Ferroptosis, an iron-dependent form of cell death associated with lipid peroxide accumulation, has been recently implicated in AILI. The activation of the Nrf2 signaling pathway is a potential therapy for AILI. Kaempferol (KA), a flavonoid widely existing in edible plants, has been reported to exert profound anti-inflammatory and antioxidant activities. This study aimed to investigate whether KA exerts anti-AILI effects via the Nrf2 signaling pathway. Mice were fasted for 22 h and injected intraperitoneally with APAP (250 mg kg−1) to induce AILI. Mice were pre-injected intragastrically with KA for 2 h followed by APAP injection. The hepatic injury was observed by H&E staining. Biochemical parameters of the serum and liver were measured using kits. KA alleviated hepatic injury and inflammatory response in AILI mice and ameliorated APAP-induced hepatic iron overload and oxidative stress in mice. In addition, the protective effects of KA against APAP-induced hepatotoxicity were examined in L02 cells in vitro. Cell viability was assayed by the CCK8 assay. Mitochondrial reactive oxygen species (ROS) in L02 cells were detected by MitoSox fluorescence. KA reversed the APAP-induced decrease in cell viability and GSH levels and inhibited the accumulation of intracellular ROS. Furthermore, KA activated the Nrf2 pathway and upregulated Gpx4 in mouse livers and L02 cells to inhibit ferroptosis induced by APAP. Finally, molecular docking indicated the potential interaction of KA with Keap1. Taken together, KA ameliorated oxidative stress and ferroptosis-mediated AILI by activating Nrf2 signaling.
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Environmental Science-Nano
·
2023
·Vol. 10
·期 2
·640-655
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IF 7.3
Zuo Wang,Yi Bi,Kemin Li,Zan Song,Chuanying Pan,Shengxiang Zhang,Xianyong Lan,Nicholas S. Foulkes,Haiyu Zhao
Nickel oxide nanoparticles (NiO-NPs) with unique characteristics have been widely utilized in numerous manufacturing processes, which have inevitably led to environmental pollution and health hazards. Previous studies have shown that nanoparticles may enter the central nervous system (CNS) and trigger off various adverse effects, however, the NiO-NPs induced neurotoxic effects as well as the underlying mechanisms remain unclear yet. In the present study, by taking advantage of the zebrafish model system for genetic analyses, in vivo neuroimaging, and neurobehavioral studies, we have investigated how early-life exposure to environmental levels of NiO-NPs (0, 5, 20, 50, 100 mg L−1) affects embryonic development, neurobehavior and neurodevelopment of zebrafish larvae. Our results reveal that the observed neurobehavioral and neurodevelopmental disorders induced by environmental NiO-NPs exposure are closely related to ROS-mediated apoptosis and iron-mediated ferroptosis, the two main forms of programmed cell death which have been strongly implicated in many types of CNS injuries and diseases. Furthermore, pharmacological interventions of apoptosis and ferroptosis pathways via N-acetylcysteine (NAC) and deferoxamine (DFO) respectively, have strongly implicated apoptosis and ferroptosis in these NiO-NPs induced neurotoxic effects. Thus, this study elucidates the potential cellular and molecular mechanisms underlying NiO-NPs induced neurotoxicity, with implications for our understandings as well as pharmacotherapies of the physiologically damaging effects of other environmental nano-pollutants.
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ADVANCED FUNCTIONAL MATERIALS
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2023
·
IF 19
Yongjuan Li,Ningjing Lei,Xiaohan Yao,Yu Zhang,Ya Dong,Jinmeng Yi,Xinyan Li,Wenjing Deng,Guangjun Nie,Zhihai Qin
The clinical application of ferroptosis, characterized by iron-dependent lipid peroxidation, is limited because of the serious side effects of using toxic-dose iron. Herein, a polyvalent ferroptosis agonist-a hypoxia responsive polymer bearing 18-crown-6 ring (hPPAA18C6) is developed. In contrast to the natural ferroptosis agonists (erastin, RSL3, and sorafenib), hPPAA18C6 stimulates the ferroptosis by releasing endogenous iron stored in the natural “iron pools” of cellular organelles and depleting glutathione (GSH) via the benzoquinone generated from the cascade decaging reactions in hypoxia. hPPAA18C6 nanoparticle is loaded with photosensitizer-chlorine e6 (Ce6) (hPPAA18C6@Ce6) due to the inhomogeneous hypoxia microenvironment. Moreover, the exposed positively charged primary amine (NH 2 ) from hPPAA18C6 acts as an immune adjuvant, facilitating dendritic cells maturation, antigen presentation, and cytotoxic T lymphocyte activation. hPPAA18C6@Ce6 induces anti-tumor responses that are dependent on ferroptosis, photodynamics therapy (PDT), and CD8 + T-cell activity. In addition, the combination of hPPAA18C6 and Ce6 leads to combined therapeutic outcomes in primary, distant, and metastatic tumors. The activation of the ferroptosis pathway through functional polymer-hijacking endogenous iron and GSH may offer new therapeutic opportunities.
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CHEMICAL ENGINEERING JOURNAL
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2023
·
IF 15.1
Kai Sun,Jiaying Yu,Jinzhong Hu,Wanxiang Yang,Xianfeng Chu,Lucheng Chen,Xiongwei Deng,Baiwang Sun,Zhifei Wang
Ferroptosis is an emerging antitumor treatment modality with the superiority for evading apoptotic cell death pathway. However, how to elevate catalytic efficacy of Fe 2+ -mediated Fenton reaction and efficiently elicit ferroptosis remain enormously challenging. Herein, inspired by hyperthermia-enhanced Fenton reaction kinetics, we firstly designed iron-polyphenol-aspirin-coordinated nanochelates for photothermal-enhanced ferroptosis antitumor immunotherapy. Specifically, we modulated optimal mass feeding ratio of gallic acid (GA), aspirin (ASA), Fe (II) and polyvinylpyrrolidone (PVP) to construct novel nanofibrous GA-ASA-Fe (II) metalchelates named GAFs. The variations in size and structure allowed the nanomedicines to avoid the risk of premature renal clearance in vivo, compared with the reported ultrasmall GA-Fe (II) nanocomplexes (GFs). Under NIR laser irradiation, GAFs could constantly amplify toxic hydroxyl radicals ( OH) generation and deplete excessive GSH to induce more accumulation of lethal lipid peroxidation (LPO), thereby triggering ferroptosis pathway in vitro and in vivo. Besides, the introduction of ASA could inhibit cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ), in combination with photothermal-enhanced ferroptosis tumor therapy to induce immunogenic cell death (ICD), promote maturation of dendritic cells (DCs) and activate cytotoxic T cells for synergistic antitumor immunotherapy. GAFs with laser irradiation exhibited the capacity of inhibition of pulmonary metastasis. This work presented a strategy for incorporating small molecule immunomodulator into the metal-polyphenolic coordination to ameliorate its deficiencies, thereby inspiring a new design concept for tumor treatment.
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APPLIED SURFACE SCIENCE
·
2022
·
IF 7.392
Ziqi Cao,Di Sun,Hai Hu,Wenxin Li,Ziying Xiong,Maofen He,Shuqi Cai,Yan Fan,Lulu Zheng,Shifei Kang
The exclusive Fenton activity of iron ions has initiated wide investigation into tumor microenvironment-activated tumor therapy owing to the production of toxic ·OH and extra oxygen for chemodynamic therapy (CDT) and photodynamic therapy (PDT) respectively. However, the sensitivity of the labile iron pool (LIP) is unsatisfactory even when iron ions are placed in the tumor microenvironment. Herein, we constructed ferrous oxalate (FeC 2 O 4 ) self-assembled nanorods loaded with a graphitic carbon nitride (g-C 3 N 4 ) photo-Fenton catalyst, which can catalyze H 2 O 2 to continuously generate abundant ·OH under visible light irradiation. The FeC 2 O 4 self-assembled nanorods also dramatically accelerated O 2 production (catalase activity) to improve the PDT of C 3 N 4 . Furthermore, the photo-Fenton catalyst under excitation also open ion channels and release free iron to increase LIP to exploit the joint CDT and PDT. Characterizations proved the self-assembled nanorods outperformed conventional Fenton catalysts in terms of stability, photoelectric response performance and photo-Fenton catalytic ability, which can be ascribed to the optimized band structure and charge isolating capability. Remarkably, the self-assembled nanorods coated with g-C 3 N 4 also showed excellent biocompatibility during the fluorescence tracing cell phagocytosis experiment, suggesting great in-vivo application potential. The results of enhanced generation of reactive oxygen species, reduction of glutathione, consumption of lipid peroxidation, and reduced cell viability verified the typical ferroptosis mechanism of the FeC 2 O 4 /g-C 3 N 4 self-assemble system as-developed. These results demonstrate the great potential of the biocompatible self-assembly photo-Fenton system for rational control of tumor behaviors.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2022
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IF 5.168
Yi Yang,Xiangjie Wang,Haolin Zhang,Jiali Li,Jingyi Chen,Miao Yu,Guangxing Li,Ruili Zhang,Ming Ge
Organophosphorus flame retardants (OPFRs) are increasingly being used in many industries since brominated flame retardants (BFRs) have been phase-out. However, OPFRs are associated with environmental pollution and animal health risks, especially in the farming industry. Nevertheless, no study has evaluated the toxicity of OPFRs, as a new flame retardant, on avian species. In order to investigate the specific toxic effects of 2-ethylhexyl diphenyl phosphate (EHDPHP) exposure on chickens and the molecular biological mechanisms that cause damage to the organism, the chicken liver has been studied as a potential target organ for toxic effects. In this study, 7-day-old male chickens were treated with different concentrations of EHDPHP to further investigate the toxicity and mechanisms of OPRs on birds. The samples were taken at 14 d, 28 d, and 42 d for analysis. EHDPHP exposure affected the growth and development of chickens. Furthermore, the microstructural and ultrastructural observations clearly reflected the damage caused by EHDPHP exposure to the livers. The levels of the liver tissue asparate aminotransferase (AST) and alanine aminotransferase (ALT) decreased with increasing gavage dose. In contrast, the levels of oxidative stress in chicken liver and the mRNA expression of related factors increased with increasing gavage dose. In addition, EHDPHP exposure increased liver tissue iron content and affected mRNA expression and protein levels of ferroptosis-related factors in livers. Besides, ferroptosis causes inflammation, thus promoting the synthesis and release of inflammatory factors. This research indicates that EHDPHP can damage chicken livers through oxidative stress and ferroptosis.
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高影响因子
Journal of Pharmaceutical Analysis
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2022
·
IF 14.026
Min Mu,Xiaoyan Liang,Na Zhao,Di Chuan,Bo Chen,Shasha Zhao,Guoqing Wang,Rangrang Fan,Bingwen Zou,Bo Han,Gang Guo
Traditional microtubule inhibitors fail to significantly enhance the effect of colorectal cancer; hence, new and efficient strategies are necessary. In this study, a supramolecular nanoreactor ( [email protected] 3+ ) based on tannic acid (TA), iron ion (Fe 3+ ), and docetaxel (DOC) with microtubule inhibition, reactive oxygen species (ROS) generation, and glutathione peroxidase 4 (GPX4) inhibition, is prepared for ferroptosis/apoptosis treatment. After internalization by CT26 cells, the [email protected] 3+ nanoreactor escapes from the lysosomes to release payloads. The subsequent Fe 3+ /Fe 2+ conversion mediated by TA reducibility can trigger the Fenton reaction to enhance the ROS concentration. Additionally, Fe 3+ can consume glutathione to repress the activity of GPX4 to induce ferroptosis. Meanwhile, the released DOC controls microtubule dynamics to activate the apoptosis pathway. The superior in vivo antitumor efficacy of [email protected] 3+ nanoreactor in terms of tumor growth inhibition and improved survival is verified in CT26 tumor-bearing mouse model. Therefore, the nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer therapy.
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PHYTOMEDICINE
·
2022
·
IF 6.656
Xun Sun,Xinyu Zhang,Hui Yan,Hongfei Wu,Shijian Cao,Wenchen Zhao,Ting Dong,An Zhou
Background Hepatolenticular degeneration (HLD) is an autosomal recessive disorder concerning copper metabolism . Copper overload is also accompanied by iron overload in HLD patients , which can lead to ferroptosis . Curcumin , the active component in turmeric, has the potential to inhibit ferroptosis. Purpose The current study proposed a systematic investigation of the protective effects of curcumin against HLD and the underlying mechanisms. Methods The protective effect of curcumin on toxic milk (TX) mice was studied. Liver tissue was observed via hematoxylin-eosin (H&E) staining and the ultrastructure of the liver tissue was observed through transmission electron microscopy . Copper levels in the tissues, serum, and metabolites were measured by atomic absorption spectrometry (AAS). In addition, serum and liver indicators were evaluated. In cellular experiments, the effect of curcumin on the viability of rat normal liver cells (BRL-3A) was determined via the 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyltetrazolium bromide (MTT) assay. Cell and mitochondrial morphology were observed in curcumin-mediated HLD model cells. The intracellular copper ion fluorescence intensity was observed via fluorescence microscopy , and intracellular copper iron content was detected using AAS. Further, oxidative stress indicators were evaluated. Cellular reactive oxygen species (ROS) and cellular mitochondrial membrane potential were examined via flow cytometry. Furthermore, the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) were determined via western blotting (WB). Results The histopathology of the liver confirmed the hepatoprotective effects of curcumin. Curcumin improved copper metabolism in TX mice. Both serum liver enzyme markers and antioxidant enzyme levels indicated the protective effect of curcumin against HLD-related liver injury. The MTT assay results showed that curcumin was protective against excess copper-induced injury. Curcumin improved the morphology of HLD model cells and their mitochondrial morphology. The Cu 2+ fluorescent probe and the AAS results indicated that curcumin reduced Cu 2+ content in HLD hepatocytes. In addition, curcumin improved oxidative stress levels and prevented the decline of mitochondrial membrane potential in HLD model cells. The ferroptosis inducer Erastin reversed these effects of curcumin. WB revealed that curcumin promoted Nrf2, HO-1, and GPX4 protein expression in HLD model cells, and the Nrf2 inhibitor ML385 reversed the effects of curcumin. Conclusion Curcumin demonstrates a protective role by expelling copper and inhibiting ferroptosis, activating the Nrf2/HO-1/GPX4 signaling pathway in HLD.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Hao Chi,Guang Zhu,Yalin Yin,He Diao,Zicheng Liu,Shibo Sun,Zhaoming Guo,Weiping Xu,Jianqiang Xu,Changhao Cui,Xiao-Jin Xing,Kun Ma
Ferroptosis is a newly found promising cell death pathway, which bypasses apoptosis and overcomes multidrug resistance of tumor. In this study, acid and redox dual-responsive multifunctional magnetic nanoparticles loading with Sorafenib (Sor), namely FMMHG/Sor, were prepared for tumor ferroptosis therapy. Fe 3 O 4 nanoparticles as the core provided sufficient iron ion for ferroptosis and magnetic targeting. Mesoporous organosilica nanoparticles (MON) was coated on the outside of Fe 3 O 4 to form “core–shell” structure, which contained the disulfide bond with redox-responsive. MnO 2 was dropped on the surface of MON as gatekeeper, which was decomposed at low pH into O 2 to promote drug release. Glucose oxidase (GOD) catalyzed glucose to produce H 2 O 2 , which reacted with iron ion to generate hydroxyl radical (OH•) vie Fenton reaction. OH• inhibited GPX4 expression to induce ferroptosis with Sor as a synergistic inducer. Hyaluronic acid (HA) protected nanoparticles from removed by immune system and actively targeted to tumor cells. Overall, pH and redox dual-responsive FMMHG/Sor is a promising antitumor nanomedicine with magnetic targeting and active targeting for efficient tumor ferroptosis therapy.
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高影响因子
ORAL DISEASES
·
2022
·
IF 4.068
Shuwei Qiao,Baosheng Li,Qing Cai,Zhen Li,Zhaoyi Yin,Jie He,Yuyang Li,Weiyan Meng
Objectives Ferroptosis is associated with multiple inflammatory diseases. Periodontitis is an inflammatory disease mainly caused by oral opportunistic pathogens. However, the ferroptosis–periodontitis relationship has not been thoroughly described. We here analyzed whether ferroptosis is involved in periodontitis. Materials and methods Human gingival fibroblasts (HGFs) were stimulated with P. gingivalis -LPS and ferrostatin-1 (Fer-1, a ferroptosis inhibitor), and changes in mitochondrial morphology, ferroptosis-related factors, and inflammation levels were detected. After the rat experimental periodontitis model was established, changes in ferroptosis-related factors and inflammation levels were re-evaluated in the same manner. Results Porphyromonas gingivalis -LPS-induced mitochondrial shrinkage, an increase in mitochondrial membrane density, and upregulation of reactive oxygen species in HGFs. The expression of prostaglandin-endoperoxide synthase 2, transferrin receptor 1, and malondialdehyde and inflammation levels were upregulated, whereas the expression of solute carrier family seven member 11, glutathione peroxidase 4, superoxide dismutase, and glutathione were downregulated. Fer-1 attenuated these aforementioned changes and inflammation levels induced by P. gingivalis -LPS. The in vivo experiment results were consistent with the in vitro experiment results. Conclusions Ferroptosis is involved in inflammatory processes in HGFs upon P. gingivalis -LPS stimulation. Ferroptosis is observed in the gingival tissue of periodontitis rats.
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高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Shuting Lu,Wei Feng,Xijuan Yao,Xinran Song,Jinhe Guo,Yu Chen,Zhongqian Hu
Nanodynamic therapy (NDT) based on reactive oxygen species (ROS) generation has been envisioned as a distinct modality for efficient cancer treatment. However, insufficient ROS generation and partial ROS consumption frequently limit the theraputic effect and outcome of NDT owing to the low oxygen (O 2 ) tension and high glutathione (GSH) level in tumor microenvironment (TME). To circumvent these critical issues, we herein proposed and engineered the biodegradable GSH-depletion Mn(III)-riched manganese oxide nanospikes (MnO x NSs) with the photosynthetic bacterial cyanobacteria (Cyan) as a high-efficient and synergistic platform to reshape TME by simultaneously increasing oxygen content and decreasing GSH level. Specifically, under the trigger of acidity, MnO x NSs reacted with photosynthetic oxygen can generate toxic singlet oxygen ( 1 O 2 ). Moreover, MnO x NSs significantly reduced intracellular GSH, resulting in decreased GPX4 activity, which induced tumor cell non-apoptotic ferroptosis . Consequently, this combined strategy based on coadministration with Cyan and MnO x NSs demonstrated the superior antitumor efficacy via amplification of oxidative stress in 4T1 tumor-bearing mice for the synergetic oxygen-augmented nanodynamic/ferroptosis therapy. This work highlights a facile synergistic micro-/nano-system with the specific capability of reshaping TME to augment the sensitivity and therapeutic efficacy of NDT in solid hypoxic tumor therapy.
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