MOLECULAR NEUROBIOLOGY
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2024
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IF 4.6
Chen Kechun,Xu Bingtian,Long Lu,Wen Huizhen,Zhao Qian,Tu Xingxing,Wang Jiakang,Xu Jiangping,Wang Haitao
We have previously shown that inhibition of phosphodiesterase 4 (PDE4) protects against cerebral ischemia/reperfusion injury. However, it remains unclear whether and how PDE4 affects ferroptosis under cerebral ischemia/reperfusion conditions. In this study, we found that overexpression of PDE4B in HT-22 cells exacerbated the detrimental effects of oxygen–glucose deprivation/reoxygenation (OGD/R), including a decrease in cell viability and glutathione (GSH) levels and an increase in Fe 2+ content. PDE4B knockdown mitigated the effects of OGD/R, as evidenced by decreased oxidative stress, lactate dehydrogenase (LDH) release, Fe 2+ content, and nuclear receptor coactivator 4 (NCOA4) expression. PDE4B knockdown also enhanced the levels of GSH, ferroportin (FPN), and ferritin heavy chain 1 (FTH1). Consistently, inhibition of PDE4 by roflumilast (Roflu) produced similar effects as PDE4B knockdown. Roflu also ameliorated the morphology and membrane potential of the mitochondria. Glutathione peroxidase 4 (GPX4) knockdown blocked the effects of Roflu on cell viability and lipid peroxidation. Moreover, we found that nuclear factor erythroid 2-related factor 2 (Nrf-2) knockdown decreased GPX4 expression. In addition, Nrf-2 knockdown led to enhanced lipid peroxidation, LDH release, and iron levels, while the GSH and FPN levels decreased. More crucially, PDE4 inhibition decreased infarct volume, alleviated oxidative stress, and restored the expression levels of ferroptosis-associated proteins in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Interestingly, the GPX4 inhibitor RSL3 blocked the neuroprotective effects of Roflu in rats subjected to MCAO/R. Thus, PDE4 inhibition significantly inhibits neuronal ferroptosis by activating the Nrf-2/GPX4 pathway. These data indicate the existence of a novel mechanism underlying the neuroprotective effects of PDE4 inhibition.
研究领域:
神经科学
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药理学
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细胞生物学
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神经保护
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高影响因子
Science Advances
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2024
·Vol. 10
·期 13
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IF 11.7
Qian Huang,Yi Ru,Yingli Luo,Xianyu Luo,Didi Liu,Yinchu Ma,Xinru Zhou,Maoyuan Linghu,Wen Xu,Fei Gao,Yi Huang
Ferroptosis is a form of iron-dependent, lipid peroxidation–driven regulatory cell death that has been implicated in the pathogenesis of multiple diseases, including organ injury, ischemia/reperfusion, and neurodegenerative diseases. However, inhibitors that directly and specifically target ferroptosis are not yet available. Here, we identify the compound AS-252424 (AS) as a potent ferroptosis inhibitor through kinase inhibitor library screening. Our results show that AS effectively inhibits lipid peroxidation and ferroptosis in both human and mouse cells. Mechanistically, AS directly binds to the glutamine 464 of ACSL4 to inhibit its enzymatic activity, resulting in the suppression of lipid peroxidation and ferroptosis. By using nanoparticle-based delivery systems, treatment with AS-loaded nanoparticles effectively alleviate ferroptosis-mediated organ injury in mouse models, including kidney ischemia/reperfusion injury and acute liver injury (ALI). Thus, our results identify that AS is a specific and targeted inhibitor of ACSL4 with remarkable antiferroptosis function, providing a potential therapeutic for ferroptosis-related diseases.
研究领域:
药理学
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细胞生物学
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分子生物学
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治疗学
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Materials Today Bio
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2024
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IF 8.7
Yijun Guo,Huiling Luo,Hairong Jiang,Xinxin Liu,Xinrui Long,Yinuo Hou,Zhou Chen,Yanan Sun,Dongtao Ge,Wei Shi
The short lifespan of active oxygen species and depressed O 2 level during ferroptosis treatment in tumor cells weaken ferroptosis therapy. How to improve the utilization efficiency of active oxygen species generated in real time is pivotal for anticancer treatment. Herein, the tirapazamine (TPZ) loaded polydopamine-Fe nanoparticles (PDA-Fe-TPZ) was modified with unsaturated liposome (Lip), which was constructed to overcome the drawbacks of traditional ferroptosis therapy. The Lip@PDA-Fe-TPZ nanoliposomes can react with H 2 O 2 to produce •OH by Fenton reaction, which then attacks Lip and transforms into radical intermediate (L•) and phospholipid peroxide radical (LOO•) to avoid the annihilation of •OH. The introduced Lip enhances lipid peroxidation and promotes oxygen consumption, resulting in increased hypoxia at tumor site. The introduced TPZ can be triggered by reductase in tumor cells under hypoxia, which can reduce to transient oxidative free radicals by reductase enzymes and destroy the structure of the surrounding biomacromolecules, thus achieving the synergistic treatment of ferroptosis and chemotherapy. In this work, we organically combined enhanced ferrroptosis with hypoxic activated chemotherapy to achieve efficient and specific tumor killing effect, which can sever as a promising treatment of cancer in the future.
研究领域:
纳米技术
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癌症治疗
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药物科学
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生物医学工程
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高影响因子
Scientific Reports
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2024
·Vol. 14
·期 1
·1-8
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IF 3.8
Luo Cheng,Li Xuying,Yan Hongyang,Guo Qitao,Liu Jiarong,Li Yan
Iron oxide nanoparticles (IONPs) have the potential to be utilized in a multitude of fields, including biomedicine. Consequently, the potential health risks associated with their use must be carefully considered. Most biosafety evaluations of IONPs have focused on examining the impact of the material’s distinctive physicochemical attributes. However, the specific attributes of individual cells are frequently disregarded, particularly under the oxidative stress conditions. This may result in an underestimation of potential risk and impede the clinical translation of IONPs. The present study thus sought to evaluate the potential cytotoxicity and underlying mechanisms of IONPs in a pathological state characterized by mild oxidative stress. A cell model of mild oxidative stress was initially established in vitro. Subsequently, a series of indicators, including cell viability, live/dead ratio, mitochondrial membrane potential, and oxidative damage, were measured to assess the cytotoxicity of IONPs. Finally, a series of ferroptosis regulators were used to elucidate the involvement of ferroptosis. Preincubation with IONPs resulted in a significant reduction in cellular viability, morphological degeneration, elevated numbers of dead cells, impaired mitochondrial function, and increased oxidative damage under mild oxidative stress conditions in vitro. The cytotoxic effects of IONPs under mild oxidative stress are largely dependent on ROS and iron ions and are strongly associated with ferroptosis, which is based on the effects of ferroptosis regulators. The present in vitro study indicated that IONPs are toxic to cells under mild oxidative stress, which is linked to ferroptosis.
研究领域:
纳米医学
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毒理学
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细胞生物学
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PubMed
高影响因子
ACS Applied Materials & Interfaces
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2021
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IF 9.229
Yabing Zhang,Xiangyi Ren,Yan Wang,Dongxu Chen,Ling Jiang,Xi Li,Tao Li,Minfeng Huo,Qian Li
Ferroptosis is a new form of regulated cell death depending on elevated iron (Fe2+) and lipid peroxidation levels. Myocardial ischemia/reperfusion (I/R) injury has been shown to be closely associated with ferroptosis. Therefore, antiferroptosis agents are considered to be a new strategy for managing myocardial I/R injury. Here, we developed polydopamine nanoparticles (PDA NPs) as a new type of ferroptosis inhibitor for cardioprotection. The PDA NPs features intriguing properties in inhibiting Fe2+ accumulation and restoring mitochondrial functions in H9c2 cells. Subsequently, we demonstrated that administration of PDA NPs effectively reduced Fe2+ deposition and lipid peroxidation in a myocardial I/R injury mouse model. In addition, the myocardial I/R injury in mice was alleviated by PDA NPs treatment, as demonstrated by reduced infarct size and improved cardiac functions. The present work indicates the therapeutic effects of PDA NPs against myocardial I/R injury via preventing ferroptosis.
研究领域:
药理学
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心脏病学
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纳米技术
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细胞生物学
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高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2026
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IF 3.5
Yurou Li,Zhenzhen Yan,Wanrong Zhang,Xin Zheng,Zhengping Wu,Yinjie Jiang,Jie Zhou
Sodium aescinate (SA), a triterpenoid saponin derived from Aesculus hippocastanum seeds, is widely used clinically but has been linked to hepatotoxicity, nephrotoxicity, and phlebitis. We previously reported that SA triggers hepatocyte ferroptosis, and enhancing GSH synthesis via the CTH/cysteine axis activation only partially mitigates liver injury. In this study, we showed that SA disrupted redox homeostasis, promoted lipid peroxidation (LPO), and induced ferroptosis in hepatocytes, concomitant with suppressed Nrf2/PRDX6/GPX4 pathway activity. Mechanistically, SA downregulated the expression and transcriptional activity of Nrf2, reducing its binding to antioxidant response elements (AREs) in the promoters of PRDX6 and GPX4, thereby decreasing their expression. Nrf2 overexpression restored PRDX6 and GPX4 levels, enhanced antioxidant capacity, and attenuated SA-induced ferroptosis. Notably, PRDX6 regulated GPX4 expression and activity by modulating selenium utilization and selenoprotein biosynthesis during SA-induced hepatotoxicity. Both PRDX6 overexpression and selenium supplementation rescued GPX4 and protected against SA-induced ferroptotic damage. The protection conferred by Nrf2/PRDX6 overexpression or selenium supplementation was fully abrogated upon GPX4 knockdown or inhibition with RSL3. Collectively, SA induced ferroptotic liver injury by disrupting the Nrf2/PRDX6/GPX4 axis, culminating in GPX4 deficiency and redox collapse. This study suggests that this cascade represents a promising therapeutic target for SA-induced hepatotoxicity.
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高影响因子
ADVANCED MATERIALS
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2026
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IF 29.1
Xinyu Wang,Cheng Liu,Ran Ji,Jiaxin Liu,Yuyang Shao,Shu Xia,Jingyao Li,Xiang Zhang,Lingjie Luo,Yanwei Wu,Shao Q. Yao,Chao Fang,Liang Chen,Xiao Dong
Chemotherapy remains the primary treatment modality for leukemia, yet relapse frequently occurs due to the persistence of chemoresistant leukemia cells (LCs) within the bone marrow (BM). Ferroptosis-based therapies provide a promising strategy for eliminating these resistant cells. Here, we demonstrate that cytarabine chemotherapy promotes lipid droplet (LD) accumulation in BM-resident LCs, thereby conferring resistance to ferroptosis. Based on these findings, we developed a biomimetic liposome (REM@HLipo) co-encapsulating RSL3 (a ferroptosis inducer), elacytarabine (a cytarabine prodrug), and metformin (an LD disruptor) to enhance chemo-ferroptosis therapy against leukemia. Upon targeted delivery to BM-resident LCs, metformin disrupts LDs and increases the availability of polyunsaturated fatty acids (PUFAs) for oxidation, thereby sensitizing LCs to RSL3-induced ferroptosis. This effect synergizes with cytarabine to exert potent cytotoxicity against BM-resident LCs in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) mouse models. Moreover, REM@HLipo significantly reduces leukemia stem cell populations in AML models. This study presents a novel chemo-ferroptosis therapeutic regimen for leukemia management.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2023
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IF 9.9
Lineng Wei,Ziyu Wang,Xiuxin Lu,Jingqi Chen,Yujie Zhai,Qinghua Huang,Shenglin Pei,Yan Liu,Weiqing Zhang
Noble metal nanozymes are promising therapeutic agents due to their good ability of reactive oxygen species generation in response to the tumor microenvironment (TME). Achieving optimal performance of noble metal nanozymes at a minimum dosage is crucial due to potential systemic biotoxicity. In this study, we report the successful anchoring of Ir nanoclusters on Co(OH) 2 nanosheets with an Ir content of 6.2 wt% (denoted as Ir 6.2 -Co(OH) 2 ), which exhibits remarkable peroxidase (POD)- and catalase (CAT)-like activities. The strong electronic interaction at the Ir-O-Co interface endows glutathione peroxidase (GSH-Px)-like activity to the composite, ensuring efficient generation of reactive oxygen species (ROS) and deactivation of glutathione peroxidase 4 (GPX4) by supplementing hydrogen peroxide (H 2 O 2 ) and depleting glutathione (GSH). Both in vitro and in vivo evaluations demonstrate that Ir 6.2 -Co(OH) 2 nanozymes significantly enhance antitumor efficacy through apoptosis-ferroptosis synergistic therapy. This study highlights the tremendous potential of leveraging strong electronic interactions between noble metals and oxides for modulating enzyme-like activities towards high-efficiency synergistic therapies.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2023
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IF 9.9
Zengyi Liu,Ruixin Kang,Ning Yang,Xiuhua Pan,Jie Yang,Hongjie Yu,Wanli Deng,Zengguang Jia,Jun Zhang,Qi Shen
The induction of immunogenic ferroptosis in cancer cell is limited by the complex and delicate antioxidant system in the organism. Synergistic induction of oxidative damage and inhibition of the defensive redox system in tumor cells is critical to promote lethal accumulation of lipid peroxides and activate immunogenic death (ICD). To address this challenge, we present a multifunctional and dual-responsive layered double hydroxide (LDH) nanosheet to enhance immunogenic ferroptosis. The MTX-LDH@MnO 2 nanoplatform is constructed by intercalating methotrexate (MTX) into LDH interlayers and electrostatically absorbing biomineralized ovalbumin (OVA)-MnO 2 onto the LDH surface. Specifically, the released Mn 2+ from the incorporated MnO 2 triggers a Fenton-like reaction, leading to reactive oxygen species (ROS) accumulation, while the depletion of reduced glutathione (GSH) further intensifies oxidative stress , resulting in the induction of ferroptosis. MTX is released in response to the acidic environment of tumor cells and inhibits the regeneration of tetrahydrobiopterin (BH4), modulating the GTP cyclic hydrolase 1 (GCH1)/BH4 axis. MTX disrupts the antioxidant metabolic activity regulated by GCH1/BH4 axis and inhibits ROS consumption, further boosting the ferroptosis effect, which promoted the release of damage-associated molecular patterns (DAMPs) and triggered ICD in the tumor. This activation subsequently leads to significant antitumor immune reactions, including DCs maturation, infiltration of CD4 + /CD8 + T cells and cytokines release. The redox-controllable nanoplatform demonstrates promising anticancer efficacy in a mouse breast model providing a novel strategy for cancer immunotherapy.
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EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2023
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IF 4.9
Qun-Fa Huang,Yan-Hong Li,Zeng-Jin Huang,Mei Jun,Wei Wang,Xiao-Li Chen,Guan-Hai Wang
Artesunate (ART) has potent anticancer activity but it suffers from poor stability and low bioavailability in vivo due to the special endoperoxide moiety in the molecules. In this work, we fabricated programmable enzyme/reactive oxygen species (ROS) responsive ART complex carriers with size and charge adaptive regulation in order to improve stability and overcome biochemical hurdles of solid tumor. The complex carries (ART/AA-PAMAM@HA) were created by electrostatic interaction between dendrimer-ART/arachidonic acid (AA) (ART/AA-PAMAM) and hyaluronic acid (HA), which can proactively penetrate deeply into tumors and selective drug release. Specifically, ART induced Fenton reaction and produced a mass of ROS and lipid peroxides (LPO), leading to the depressing of GSH level and glutathione peroxidase 4 (GPX4) activity. Meanwhile, exogenous AA further promoted the accumulation of LPO by cascade regulating ferroptosis pathway. In the anti-tumor efficacy in vivo, the tumor inhibition ratio was achieved to 46.92%. This work shows a new anti-tumor strategy triggering ferroptosis via regulating redox homeostasis.
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高影响因子
Experimental and Therapeutic Medicine
·
2023
·Vol. 26
·期 2
·1-15
·
IF 2.7
Jianxin Wang,Peng Guan,Yu Chen,Meng Xu,Na Wang,Ensheng Ji
Myocardial dysfunction is a frequent complication in patients with severe sepsis. However, effective drugs for the prevention of myocardial dysfunction and the molecular mechanisms of the disease remain elusive. The present study demonstrated that Cyclovirobuxine D (CVB‑D) could improve cardiac dysfunction in a cecal ligation and puncture (CLP) model in rodents and in a lipopolysaccharide (LPS) model in vitro. Echocardiography and histopathological examination were used to detect changes in cardiac structure and function. Kits were used to detect indicators of cardiac injury, transmission electron microscopy to detect structural changes in mitochondria and reverse transcription‑quantitative PCR to detect prostaglandin‑endoperoxide synthase 2 and hamp expression levels. L‑Glutathione and malondialdehyde levels and superoxide dismutase activity were measured using kits. Cell viability was measured with the Cell Counting Kit‑8. Iron metabolism‑related proteins, inflammatory factor levels and related pathway proteins were detected using western blot analysis. Changes in L‑type calcium currents were detected by membrane clamp, and contractility of cardiomyocytes was measured by Ion Optix. CVB‑D attenuated CLP‑induced cardiac malfunction in septic rats, with changes observed in myocardial pathological structure, creatine kinase isoenzyme (CK‑MB), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI). CVB‑D attenuated sepsis‑induced lipid peroxidation and iron overload. In addition, CVB‑D decreased the expression of CK‑MB, LDH and cTnI, suppressed oxidative stress index levels and reduced the production of reactive oxygen species. CVB‑D decreased LPS‑induced cytoplasmic iron overload by increasing upregulation of iron uptake molecules. Conversely, CVB‑D significantly increased the upregulation of ferroportin 1. CVB‑D pretreatment significantly reduced the levels of hamp mRNA compared with the LPS‑treated group. CVB‑D pretreatment significantly reduced inflammatory factor levels and the ratio of phosphorylated vs. total signal transducer and activator of transcription 3. The expression of SLC7A11 and GPX4 was upregulated in septic cells pretreated with CVB‑D, however treatment with ML385 largely decreased this upregulation. Of note, CVB‑D inhibited the inward flow of calcium ions through the LTCC. In conclusion, these findings suggest that CVB‑D alleviated sepsis‑induced cardiac iron toxicity by alleviating iron metabolism.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
·
IF 6.1
Tongwen Huang,Ke Zhang,Junqiao Wang,Kaihong He,Xingtao Zhou,Shaoping Nie
Acrylamide (ACR) generated in carbohydrate-rich foods during thermal processing has been demonstrated to exhibit hepatotoxicity. As one of the most consumed flavonoids with diet, quercetin (QCT) possesses the ability to protect against ACR-induced toxicity, albeit its mechanism is unclear. Herein, we discovered that QCT alleviated ACR-induced elevated levels of reactive oxygen species (ROS), AST, and ALT in mice. RNA-seq analysis revealed that QCT reversed the ferroptosis signaling pathway upregulated by ACR. Subsequently, experiments indicated that QCT inhibited ACR-induced ferroptosis through the reduction of oxidative stress. With autophagy inhibitor chloroquine, we further confirmed that QCT suppressed ACR-induced ferroptosis by inhibiting oxidative stress-driven autophagy. Additionally, QCT specifically reacted with autophagic cargo receptor NCOA4, blocked the degradation of iron storage protein FTH1, and eventually downregulated the intracellular iron levels and the consequent ferroptosis. Collectively, our results presented a unique approach to alleviate ACR-induced liver injury by targeting ferroptosis with QCT.
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