Redox Biology
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2024
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IF 10.7
Liyong Huang,Xue Wang,Yanning Zheng,Dongcen Lang,Jian Wang,Shuaiguo Yan,Ying Chen
Subarachnoid hemorrhage (SAH), a devastating disease with a high mortality rate and poor outcomes, tightly associated with the dysregulation of iron metabolism and ferroptosis. (-)-Epigallocatechin-3-gallate (EGCG) is one of major bioactive compounds of tea catechin because of its well-known iron-chelating and antioxidative activities. However, the findings of iron-induced cell injuries after SAH remain controversial and the underlying therapeutic mechanisms of EGCG in ferroptosis is limited. Here, the ability of EGCG to inhibit iron-induced cell death following the alleviation of neurological function deficits was investigated by using in vivo SAH models. As expected, EGCG inhibited oxyhemoglobin (OxyHb)-induced the over-expression of HO-1, which mainly distributed in astrocytes and microglial cells. Subsequently, EGCG blocked ferrous iron accumulation through HO-1-mediated iron metabolic reprogramming. Therefore, oxidative stress and mitochondrial dysfunction was rescued by EGCG, which resulted in the downregulation of ferroptosis and ferritinophagy rather than apoptosis after SAH. As a result, EGCG exerted the superior therapeutic effects in the maintenance of iron homeostasis in glial cells, such as astrocytes and microglial cells, as well as in the improvement of functional outcomes after SAH. These findings highlighted that glial cells were not only the iron-rich cells in the brain but also susceptible to ferroptosis and ferritinophagy after SAH. The detrimental role of HO-1-mediated ferroptosis in glial cells can be regarded as an effective therapeutic target of EGCG in the prevention and treatment of SAH.
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JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Yingying Xu,Liu Yang,Chengyan Wang,Weiming Sun,Yijing Zheng,Beiwei Ou,Lixian Wu,Leilei Shi,Xi Lin,Wei Chen
Oral cancer is a disease with high morbidity and mortality worldwide and greatly impacts the quality of life, especially in patients with advanced stages. Photodynamic therapy (PDT) is one of the most effective clinical treatments for oral cancers. However, most clinically applied photosensitizers have several deficiencies, including oxygen dependence, poor aqueous solubility, and a lack of tumor-targeting ability. Herein, the carrier-free multifunctional Sorafenib (Sor), chlorin e6 (Ce6), and Fe 3+ self-assembly co-delivery nanoparticles (Sor-Ce6 NPs) were constructed via combining a ferroptosis inducer Sor and a photosensitizer Ce6 for synergetic therapy. The as-synthesized Sor-Ce6 NPs presented excellent colloidal stability and water dispersity with good in vivo tumor-targeting ability. More significantly, the low dose of Sor-Ce6 NPs had little dark toxicity but produced significantly enhanced ROS and supplied O 2 sustainably to increase phototoxicity through ferroptosis pathway. Notably, the Sor-Ce6 NPs showed significantly higher in vitro and in vivo anti-tumor efficacy than the Sor/Ce6 mixture due to the improvement of cellular uptake and the incorporation of foreign Fe ions in the system, which also confer the T 1 magnetic resonance-guided imaging ability to the formed Sor-Ce6 NPs. Our study demonstrates a promising self-assembled strategy for overcoming hypoxia-related PDT resistance for oral cancer treatment.
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Chemical Science
·
2024
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IF 7.6
Dan Li,Minghui Fan,Haobing Wang,Yongjie Zhu,Bole Yu,Pingyu Zhang,Huaiyi Huang
Sonodynamic therapy (SDT), as a novel non-invasive cancer treatment modality derived from photodynamic therapy (PDT), has drawn much attention due to its unique advantages for the treatment of deep tumors. Zinc-based complexes have shown great clinical prospect in PDT due to their excellent photodynamic activity and biosafety. However, their application in SDT has lagged seriously behind. Exploring efficient zinc-based complexes as sono-sensitizers remains an appealing but significantly challenging task. Herein, we develop a hydrazone ligand-based zinc complex (ZnAMTC) for SDT of tumors in vitro and in vivo. ZnAMTC was facilely synthesized via a two-step reaction from low-cost raw materials without tedious purification. It shows negligible dark toxicity and can produce singlet oxygen (1O2) under ultrasound (US) irradiation, exhibiting high sono-cytotoxicity to various cancer cells. Mechanism studies show that ZnAMTC can effectively reduce the levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4) under US irradiation and later cause ferroptosis of cancer cells. In vivo studies further demonstrate that ZnAMTC exhibits efficient tumor growth inhibition under US irradiation and has good biosafety. This work provides useful insights into the design of first-row transition metal complexes for SDT application.
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Materials Horizons
·
2024
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IF 12.2
Anni Zhu,Shuai Shao,Jinyuan Hu,Wenzhi Tu,Zheming Song,Yue Liu,Jiansheng Liu,Qin Zhang,Jingchao Li
A variety of therapeutic strategies are available to treat glioblastoma (GBM), but the tumor remains one of the deadliest due to its aggressive invasiveness, restrictive blood-brain barrier (BBB), and exceptional resistance to drugs. In this study, we present a hydrogen sulfide (H2S)-generating semiconducting polymer nanoparticle (PFeD@Ang) for amplified radiodynamic-ferroptosis therapy of orthotopic glioblastoma. Our results showed that in acidic tumor microenvironment (TME), H₂S donors produce large amounts of H2S, which inhibits mitochondrial respiration and alleviates cellular hypoxia, thus enhancing the radiodynamic effect during X-ray irradiation; meanwhile, Fe3⁺ is reduced to Fe²⁺ by tannic acid in acidic TME, which promotes iron-dependent cell death process in tumors. H2S facilitates the ferroptosis process by increasing local H2O2 concentration via inhibiting catalase activity. Such an amplified radiodynamic-ferroptosis therapeutic strategy could remarkably inhibit glioma progression in an orthotopic GBM mouse model. Our study demonstrates the potential of PFeD@Ang for GBM treatment via targeted delivery and combinational therapeutic actions of RDT and ferroptosis therapy.
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Theranostics
·
2025
·Vol. 15
·期 1
·68
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IF 13.3
Mingbo Wu,Zhanlin Zhang,Dong Li,Xiaomiao Ruan,Jingwen Yang,Siyi Chen,Xin Li,Wenwu Ling
Rationale: Ferroptosis and sonodynamic therapy (SDT) are both promising therapeutic modalities, but their clinical application remains challenging due to the hypoxic tumor microenvironment and limited supply of polyunsaturated fatty acids. Developing an agent with oxygen-enhanced SDT and increased ferroptosis sensitivity is crucial for advancing tumor therapy. Methods: In this study, catalase (Cat) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) highly expressed 4T1 cells were constructed via lentivirus transfection. Cat and ACSL4 enriched exosomes (EXO@CA) were then extracted and loaded with the sonosensitizer tetrakis (4-carboxyphenyl) porphyrin (TCPP) through electroporation to create engineered exosomes (EXO@CAT). We evaluated the ability of EXO@CAT to generate oxygen in a hydrogen peroxide environment and investigated its effect on motion profiles and permeability of EXO@CAT. The in vitro antitumor activity was assessed via cytotoxicity, ROS levels, live/dead staining, and apoptosis, with ferroptosis biomarkers confirming ferroptosis activation. We also evaluated the in vivo anticancer efficacy of EXO@CAT by tumor growth analysis and histological and immunohistochemical staining in mouse models bearing breast tumor. Results: EXO@CAT harnesses ultrasound stimulation to facilitate oxygen-enriched SDT, demonstrating significant capacity for singlet oxygen ( 1 O 2 ) generating, which promotes the accumulation of lipid peroxidation (LPO), ultimately leading to the induction of ferroptosis. Concurrently, ACSL4 released from EXO@CAT also increases LPO accumulation by modifying cellular lipid composition, thereby enhancing cellular sensitivity to ferroptosis. Moreover, both in vitro and in vivo experiments demonstrate that the homologous targeting ability of EXO@CAT enables its efficient accumulation in tumor tissues, and the oxygen generation catalyzed by Cat not only alleviates tumor hypoxia but also facilitates the penetration of EXO@CAT into deeper layers of tumor tissue. Conclusions: EXO@CAT combines endogenous proteins, which are prone to inactivation, with an exogenous sonosensitizer, allowing synergistic anticancer treatment of both ferroptosis and SDT with improved efficacy.
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Materials Today Nano
·
2024
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IF 8.2
Baoyue Zhang,Jiang Yu,Ruiping Huang,Jianying Ye,Fanlin Meng,Zhaochu Xu,Wenwen Cui,Jia Song,Siqi Wang,Yanjun Du,Qingzhi Lv,Wanling Zhu,Dan Liu,Yongjun Wang
Liposomes, particularly those designed for remote drug loading, have achieved remarkable success as drug-delivery vehicles in clinical settings. However, the lack of ionizable or coordinative groups prevents many promising drugs from being remotely loaded into liposomes for cancer therapy. Herein, to provide a universal remote loading approach, we chose cabazitaxel (CTX) as a model drug to modify galloyl group bridged by different lengths of alkyl chain. Fortunately, all the synthesized prodrugs could be actively loaded into liposomes via Fe 3+ gradient with high encapsulation efficiency and loading capacity. As the intraliposomal aqueous phase, Fe 3+ was not only served as the driving force of prodrugs remote loading, but also regarded as an exogenous replenishment to strengthen iron-dependent ferroptosis for multimodal therapy. The length of linkage between CTX and galloyl group played a crucial role in the chemical stability of prodrugs, in vitro drug release rate and in vivo pharmacokinetics behavior of prodrug liposomes. Among three prodrug liposomes, only decylene glycol-bridged CTX-gallic acid (CTX-DC-GA) liposomes kept a good balance between drug leakage during circulation and specific drug release under tumor microenvironment. Ultimately, CTX-DC-GA liposomes displayed optimal antitumor efficacy with good safety. We proposed Fe 3+ -based galloylated prodrug liposomes give new horizons for achieving the combination of ferroptosis and chemotherapy.
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Biomaterials Advances
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2024
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IF 5.5
Wenying Wei,Haifei Kang,Chenxi Lian,Jiawei Liu,Jinwei Lin,Junwei Yang,Zhangmancang Xu,Ziqi Wang,Meizhen Yin,Honglian Dai
Chemodynamic therapy (CDT) guided by Fenton chemistry and iron-containing materials can induce ferroptosis as a prospective cancer treatment method, but the inefficient Fe 3+ /Fe 2+ conversion restricts the monotherapeutic performances. Here, an iron-based nanoplatform (Fe 3 O 4 -SRF@FeTA) including a magnetic core and a reductive film is developed for combined CDT and photothermal therapy (PTT) through ferroptosis augmentation. The inner iron oxide core serves as a photothermal transducer, a magnet-responsive module, and an iron reservoir for CDT. The coated Fe 3+ -tannic acid film (FeTA) provides extra iron and reductants for Fe 3+ /Fe 2+ conversion acceleration, and functions as a door keeper for the pH- and light-responsive release of the embedded ferroptosis inducer sorafenib (SRF). The in vitro results demonstrate that the iron-based nanocomplexes promote the production of lipid peroxide through the amplified Fenton activity, and downregulate glutathione involved in lipid peroxide repair system through the responsively released SRF. Upon accumulation in tumor by magnetic targeting and sequential laser irradiation locoregionally, Fe 3 O 4 -SRF@FeTA nanocomplexes present prominent in vivo anticancer efficacy by leveraging PTT and CDT-enhanced ferroptosis.
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RSC Advances
·
2024
·Vol. 14
·期 21
·14934-14941
·
IF 3.9
Li Lei,Jiali Yuan,Qingqing Yang,Qiuxia Tu,Haijun Yu,Liangzhao Chu,Lei Tang,Chunlin Zhang
Ferroptosis, characterized by elevated iron levels and lipid peroxidation (LPO), is a recently identified regulatory mechanism of cell death. Its substantial involvement in ischemic tissue injury, neurodegenerative disorders, and cancer positions ferroptosis inhibition as a promising strategy for managing these diverse diseases. In this study, we introduce curcumin–polydopamine nanoparticles (Cur–PDA NPs) as an innovative ferroptosis inhibitor. Cur–PDA NPs demonstrate remarkable efficacy in chelating both Fe2+ and Fe3+ in vitro along with scavenging free radicals. Cur–PDA NPs were found to efficiently mitigate reactive oxygen species, reduce Fe2+ accumulation, suppress LPO, and rejuvenate mitochondrial function in PC12 cells. Thus, these NPs can act as potent therapeutic agents against ferroptosis, primarily via iron chelation and reduction of oxidative stress.
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SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Xu Huang,Yan Fu,Siyuan Wang,Qitong Guo,Yuhao Wu,Xiangqin Zheng,Junke Wang,Shengde Wu,Lianju Shen,Guanghui Wei
2,2′,4,4′-Tetrabromodiphenyl ether (PBDE-47), being the most prevalent congener of polybrominated diphenyl ethers (PBDEs), has been found to accumulate greatly in the environment and induce spermatogenesis dysfunction. However, the specific underlying factors and mechanisms have not been elucidated. Herein, male Sprague-Dawley (SD) rats were exposed to corn oil, 10 mg/kg body weight (bw) PBDE-47 or 20 mg/kg bw PBDE-47 by gavage for 30 days. PBDE-47 exposure led to blood-testis barrier (BTB) integrity disruption and aberrant spermatogenesis. Given that Sertoli cells are the main toxicant target, to explore the potential mechanism involved, we performed RNA sequencing (RNA-seq) in Sertoli cells, and the differentially expressed genes were shown to be enriched in ferroptosis and lysosomal pathways. We subsequently demonstrated that ferroptosis was obviously increased in testes and Sertoli cells upon exposure to PBDE-47, and the junctional function of Sertoli cells was restored after treatment with the ferroptosis inhibitor ferrostatin-1. Since glutathione peroxidase 4 (GPX4) was dramatically reduced in PBDE-47-exposed testes and Sertoli cells and considering the RNA-sequencing results, we examined the activity of chaperone-mediated autophagy (CMA) and verified that the expression of LAMP2a and HSC70 was upregulated significantly after PBDE-47 exposure. Notably, Lamp2a knockdown not only inhibited ferroptosis by suppressing GPX4 degradation but also restored the impaired junctional function induced by PBDE-47. These collective findings strongly indicate that PBDE-47 induces Sertoli cell ferroptosis through CMA-mediated GPX4 degradation, resulting in decreased BTB-associated protein expression and eventually leading to BTB integrity disruption and spermatogenesis dysfunction.
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CANCER CHEMOTHERAPY AND PHARMACOLOGY
·
2024
·
IF 2.7
Ma Xuan,Sun Zhenou,Chen Hui,Cao Lixing,Zhao Shuang,Fan Lihong,Zhao Chong,Yin Shutao,Hu Hongbo
Purpose 18β-glycyrrhetinic acid (GA), the main metabolite of glycyrrhizic acid extracted from the root of licorice, has been reported to possess anti-cancer and immunomodulatory activity, but the mechanisms are not well understood. Recent studies have shown that ferroptosis of immune cells is involved in tumor-associated immune suppression. The purpose of this study was to investigate whether the enhanced immune response via inhibiting immune cell ferroptosis contributed to the anticancer effect of 18β-GA. Methods Lewis Lung carcinoma mouse model and Murine CD8 + T cell culture model were used to examine the changes of immune response and ferroptosis of immune cells. Results We found that 18β-GA was effective against lung cancer accompanied by enhanced activation of tumor-infiltrating CD8 + T cells in Lewis Lung carcinoma mouse model. Furthermore, we demonstrated that the boosted immune response by GA was attributed to its ability to inhibit arachidonic acid (AA)-mediated CD8 + T ferroptosis via suppressing CD36 expression. Conclusion The findings of the present study unraveled a novel mechanism underlying the anti-cancer and immunomodulatory activity of 18β-GA and support that 18β-GA holds potential to be used as an immune enhancer for lung cancer prevention or treatment.
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JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Xuerong Zhao,Zhuoya Wang,Guanlin Wu,Lianhong Yin,Lina Xu,Ning Wang,Jinyong Peng
Intestinal ischemia reperfusion injury (II/R injury) is a common and intractable pathophysiological process in critical patients, for which exploring new treatments and mechanisms is of great importance to improve treatment outcomes. Apigenin-7-O-Glucoside (AGL) is a sugar derivative of apigenin natural product with various pharmacological activities to protect against intestinal diseases . In this study, we synthesized two amphiphilic molecules, namely DTPA-N10–10 and mPEG-TK-DA, which can scavenge free radicals and reactive oxygen species (ROS). They were successfully encapsulated AGL through self-assembly, resulting in the formation of multi-site ROS scavenging nanoparticles called PDN@AGL. In vitro and in vivo experiments demonstrated that PDN@AGL could protect intestinal tissues by reducing lipid peroxidation, lowering ROS levels and inhibiting ferroptosis during II/R injury. Furthermore, our study revealed, for the first time, that the regulation of the ATF3/SLC7A11 pathway by PDN@AGL may play a crucial role in mitigating II/R injury. In conclusion, our study confirmed the beneficial effects of PDN@AGL in combating II/R injury through the ATF3/SLC7A11-mediated regulation of ferroptosis and oxidative stress. These findings lay the groundwork for the potential application of PDN@AGL in the treatment of II/R injury.
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PHYTOMEDICINE
·
2024
·
IF 6.7
Peipei Cheng,Xinting Wang,Qian Liu,Tianshu Yang,Enrui Dai,Wanjing Sha,Huiyan Qu,Hua Zhou
ABSTRACT Background The terminal stage of all cardiovascular diseases typically culminates in heart failure (HF), with no effective intervention available to halt its progression. LuQi formula (LQF) has been employed in clinical for numerous years to significantly ameliorate cardiac function in HF patients. Nevertheless, the underlying mechanism of LQF's efficacy remains inadequately comprehended. Cardiomyocyte ferroptosis has served as a pathogenic mechanism in HF. The goal of the current experiment was to ascertain whether LQF ameliorates HF by preventing cardiomyocyte ferroptosis and to elucidate the intrinsic mechanism involved. Purpose This research objective is to investigate the impact and underlying mechanism of LQF attenuating cardiomyocyte ferroptosis in heart failure. Methods Transverse aortic constriction (TAC) was performed to construct the HF mouse model. Neonatal rat cardiomyocytes (NRCMs) were subjected to in vitro experiments. High-performance liquid chromatography (HPLC) identified the bioactive compounds in LQF. Transcriptomic and quantitative proteomic analyses revealed the potential targets of LQF anti-HF. Specifically, histological staining evaluated cardiac hypertrophy and fibrosis. Transmission electron microscopy (TEM) observed mitochondrial morphology. The content of Fe 2+ , ROS, MDA, GSH, and GSSH was detected using kits. Molecular docking evaluated the binding activities between essential active ingredients of LQF and critical proteins of cardiomyocyte ferroptosis. Mechanistically, the expression levels of Nrf2, Keap1, HO-1, SLC7A11, and GPX4 were evaluated using qPCR, Western blot (WB), or immunohistochemical staining. Results The primary nine active ingredients in LQF were detected. Transcriptomic and proteomic analyses demonstrated that LQF may ameliorate HF by preventing cardiomyocyte ferroptosis. Histomorphometric analyses revealed that LQF attenuates myocardial hypertrophy and fibrosis. TEM revealed that LQF diminished mitochondrial shrinkage and increased membrane density in myocardial tissue. Additionally, LQF diminished reactive oxygen species (ROS) generation in cardiomyocytes and suppressed cardiomyocyte ferroptosis. Furthermore, the molecular docking technique revealed that the primary active ingredients of LQF had suitable binding activities with Nrf2, GPX4, and SLC7A11. Western analysis further verified that LQF activated the Nrf2/GPX4 signaling axis. decreased SLC7A11 and HO-1 expression. Conclusions These results demonstrated that LQF prevents cardiomyocyte ferroptosis via activating Nrf2/GPX4 signaling axis and suppressing SLC7A11 and HO-1 expression. Concurrently, it contributed to elucidating the intrinsic mechanism of LQF and provided a scientific rationale for its development as a novel cardiovascular therapeutic drug.
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