Scientific Reports
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2025
·Vol. 15
·期 1
·1-14
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IF 3.9
Zhang Yuxi,Zhan Junbiao,Qiu Zhen,Tian Hao,Lei Shaoqing,Huang Qin,Xue Rui,Sun Qian,Xia Zhongyuan
Myocardial cold ischemia/reperfusion (I/R) injury is an inevitable consequence of heart transplantation, significantly affecting survival rates and therapeutic outcomes. Growth Differentiation Factor 15 (GDF15) has been shown to regulate GPX4-mediated ferroptosis, playing a critical role in mitigating I/R injury. Meanwhile, verbascoside (VB), an active compound extracted from the herbaceous plant, has demonstrated myocardial protective effects. In this study, heart transplantation was performed using a modified non-suture cuff technique, with VB administered at a dose of 20 mg/kg/day via intraperitoneal injection for 3 days in vivo. In vitro, cardiomyocytes were pretreated with 50 µg/ml VB for 24 h. VB treatment significantly reduced histopathological injury, decreased myocardial injury markers, and inhibited ferroptosis and oxidative stress during myocardial cold I/R injury in vivo. In vitro experiments further demonstrated that GDF15 alleviates ferroptosis induced by hypoxic reoxygenation by upregulating GPX4. Therefore, it is concluded that VB preconditioning can effectively reduce ferroptosis induced by myocardial cold I/R after heterotopic heart transplantation, possibly through up-regulation of GDF15/GPX4/SLC7A11 pathway.
研究领域:
心血管病学
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药理学
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移植学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-21
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IF 12.6
Pei Mingliang,Guan Xin,Hou Xiaodong,Niu Zhiyuan,Lyu Qi,Wang Kai,Wang Shanshan,Zhang Jingkai,Ke Yun,Zhuang Shuting,Chen Jie,Xu Huixiong,Yang Fan
Currently, given variations in the abnormal tumor microenvironment (TME), significant progress has been made in the treatment of breast cancer (BC) based on TME-responsive nanosystems-mediated ferroptosis. Due to inherent deficiencies such as the limited efficacy of Fe-induced catalysis, the lack of endogenous hydrogen peroxide (H 2 O 2 ), and the overexpression of glutathione (GSH) in tumor cells, the treatment of ferroptosis is restricted. Here, this document highlighted polymeric nanoparticles with GSH resection (ssP-tHB@Fe/DOX), demonstrating significant improvements in TME responses, biocompatibility, and anti-tumor effects. Our study offers a platform for combined BC amplification therapy involving ferroptosis and DOX-induced chemotherapy, and it highlights the use of 3,4,5-trihydroxybenzaldehyde (tHB) in a Fe(III)-Fe(II) cyclic reaction to deplete GSH and enhance ferroptosis. Notably, ssP-tHB@Fe/DOX could effectively disrupt mitochondrial structure and reduce membrane potential in tumor cells, leading to decreased ATP production, depletion of GSH via multi-channel approach, inhibition of GPX4 expression, and accumulation of lipid peroxidation, thereby inducing ferroptosis enhancement to achieve BC therapy. Meanwhile, the release of the anticancer drug DOX has dual effects: it interferes with NADPH to enhance the Fe-mediated Fenton reaction and induces apoptosis in tumor cells. Moreover, RNA sequencing (RNA-seq) analysis robustly supported the anti-tumor mechanism of ssP-tHB@Fe/DOX, confirming involvement in the amino acid metabolism ferroptosis signaling pathway and the p53 signaling pathway, etc. Therefore, in this study, we thoroughly introduced the design of intelligent nanosystems, proposed methods to enhance DOX-induced apoptosis and ferroptosis, offering a novel approach for cancer treatment.
研究领域:
肿瘤学
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生物医学工程
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药理学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
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IF 8.3
Xiaobang Liu,Jiaqun Du,Junpeng Sun,Han Wang,Jinyu An,Yingqiao Li,Yu Hu,Shuai Cheng,Huicong Feng,He Tian,Xifan Mei,Yang Qiu,Chao Wu
Spinal cord injury (SCI) is a serious neurological disease that can result in paralysis. After SCI occurs, the blood–spinal cord barrier (BSCB) is disrupted, and permeability is transiently elevated. However, the permeability of the BSCB returns to normal over time, which prevents many drugs from being used in subsequent treatments. In this study, we designed a borneol-functionalized macrophage membrane encapsulating mesoporous selenium nanoparticles loaded with resveratrol (MSe-Res-BMMs) for SCI treatment. In vivo animal experiments and in vitro cell experiments demonstrated that MSe-Res-BMMs were able to protect neurons from ferroptosis by reducing ROS levels and increasing glutathione peroxidase-4 (GPx-4) activity. In addition, this treatment also reduced ROS-induced inflammation and apoptosis by decreasing the expression of inflammatory factor IL-1β and apoptotic factor Cleaved Caspase-3 at the site of injury. Therefore, MSe-Res-BMMs are expected to provide new therapeutic options for SCI treatment.
研究领域:
神经科学
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药理学
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纳米医学
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DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Mengzhu Lv,Xiaoyu Mao,Zheng Lu,Yanzhu Yang,Jiangtao Huang,Yuqin Cheng,Chuan Ye,Zhixu He,Liping Shu,Dashuang Mo
N -(1,3-dimethylbutyl)- N′ -phenyl- p -phenylenediamine (6PPD), which is widely used as an antiozonant in rubber tires, has recently got much attention for its acute aquatic toxicity. However, the developmental toxicity of 6PPD in cerebrovascular network remains unknown. Here, we investigated the effects of 6PPD exposure in cerebral vascular using zebrafish. 6PPD would not affect the body length and shape of zebrafish larvae at the concentrations ranging from 20 μg/L to 1000 μg/L. 6PPD induced developmental defects in the brain in a concentration-dependent manner. The trunk vascular development would not be affected while the cerebrovascular network was disrupted upon 6PPD exposure. 6PPD would trigger excessive Reactive Oxygen Species (ROS) in the brain, indicating abnormal oxidative stress. Mechanistically, brain-specific transcriptome analysis showed that 6PPD could potentially cause the blockage of arachidonic acid (AA) metabolism-related genes and the upregulation of ferroptosis-related genes. Besides, treatment with ferroptosis inhibitor N -Acetyl-L-cysteine (NAC) attenuated oxidative damage and improved the construction of cerebrovascular network upon 6PPD exposure. Moreover, using a human vascular endothelial cell line, we further confirmed that 6PPD could trigger abnormal oxidative stress and defective expansion capacity, implying the conserved toxicity cross species. These findings are useful for the elucidation of toxicity underlying 6PPD in cerebrovascular systems of both zebrafish and humans.
研究领域:
毒理学
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发育生物学
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环境科学
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DOI
PubMed
高影响因子
Viruses-Basel
·
2021
·Vol. 13
·期 12
·2383
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IF 5.048
Huawei Xia,Zeming Zhang,Fuping You
Murine hepatitis virus strain A59 (MHV-A59) was shown to induce pyroptosis, apoptosis, and necroptosis of infected cells, especially in the murine macrophages. However, whether ferroptosis, a recently identified form of lytic cell death, was involved in the pathogenicity of MHV-A59 is unknown. We utilized murine macrophages and a C57BL/6 mice intranasal infection model to address this. In primary macrophages, the ferroptosis inhibitor inhibited viral propagation, inflammatory cytokines released, and cell syncytia formed after MHV-A59 infection. In the mouse model, we found that in vivo administration of liproxstatin-1 ameliorated lung inflammation and tissue injuries caused by MHV-A59 infection. To find how MHV-A59 infection influenced the expression of ferroptosis-related genes, we performed RNA-seq in primary macrophages and found that MHV-A59 infection upregulates the expression of the acyl-CoA synthetase long-chain family member 1 (ACSL1), a novel ferroptosis inducer. Using ferroptosis inhibitors and a TLR4 inhibitor, we showed that MHV-A59 resulted in the NF-kB-dependent, TLR4-independent ACSL1 upregulation. Accordingly, ACSL1 inhibitor Triacsin C suppressed MHV-A59-infection-induced syncytia formation and viral propagation in primary macrophages. Collectively, our study indicates that ferroptosis inhibition protects hosts from MHV-A59 infection. Targeting ferroptosis may serve as a potential treatment approach for dealing with hyper-inflammation induced by coronavirus infection.Keywords:coronavirus;mouse hepatitis virus (MHV);ferroptosis;therapy
研究领域:
病毒学
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免疫学
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药理学
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DOI
PubMed
高影响因子
Journal of Cancer
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2022
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IF 4.478
Kezhong Tang,Qing Chen,Yanmo Liu,Lantian Wang,Wenjie Lu
Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo . Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2023
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IF 4.4
Yiran Che,Jingying Yang,Zhenming Dong,Jianhua Wang,Xiaoqing Yan,Yu Wang,Shaomin Shuang
A novel Schiff-base fluorescent probe, 4-(N-(2- hydroxyl-1-naphthalymethylimino)-ethylamino) −7-nitro-1,2,3-benzoxadiazole (HENB) was synthesized and utilized for spectral sensing of Fe 3+ ions at neutral pH. The binding of Fe 3+ to HENB in C 2 H 5 OH-HEPES buffer (1:1 v/ v, 25 mM, pH 7.2) resulted in a pronounced emission enhancement at 530 nm, which is possibly due to the inhibition of photo-induced electron transfer (PET) process as well as the chelation enhanced fluorescence (CHEF) effect. HENB shows good selectivity and sensitivity toward Fe 3+ with the detection limit as low as 4.51 nM. Test strips made of HENB was used for rapid “naked-eye” detection of Fe 3+ ions in aqueous medium. Moreover, HENB was successfully applied in fluorescence imaging of exogenous and endogenous Fe 3+ in live Hela cells as well as zebrafish. Importantly, HENB is capable of effectively monitoring the variations of Fe 3+ in living cells during ferroptosis process.
研究领域:
分析化学
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生物医学
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细胞生物学
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DOI
PubMed
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Jiawu Yu,Yuchen Zhang,Liqi Li,Yang Xiang,Xuemei Yao,Youbo Zhao,Kaiyong Cai,Menghuan Li,Zhongjun Li,Zhong Luo
Radiotherapy is a mainstream modality for breast cancer treatment that employs ionizing radiation (IR) to damage tumor cell DNA and elevate ROS stress, which demonstrates multiple clinically-favorable advantages including localized treatment and low invasiveness. However, breast cancer cells may activate the p53-mediated cell cycle regulation in response to radiotherapy to repair IR-induced cellular damage and facilitate post-treatment survival. F-Box and WD Repeat Domain Containing 7 (FBXW7) is a promoter of p53 degradation and critical nexus of cell proliferation and survival events. Herein, we engineered a cooperative radio-ferroptosis-stimulatory nanomedicine through coordination-driven self-assembly between ferroptosis-inducing Fe 2+ ions and FBXW7-inhibiting DNAzymes and further modification of tumor-targeting dopamine-modified hyaluronic acid (HA). The nanoassembly could be selectively internalized by breast cancer cells and disintegrated in lysosomes to release the therapeutic payload. DNAzyme readily abolishes FBXW7 expression and stabilizes phosphorylated p53 to cause irreversible G2 phase arrest for amplifying post-IR tumor cell apoptosis. Meanwhile, the p53 stabilization also inhibits the SLC7A11-cystine-GSH axis, which combines with the IR-upregulated ROS levels to amplify Fe 2+ -mediated ferroptotic damage. The DNAzyme-Fe-HA nanoassembly could thus systematically boost the tumor cell damaging effects of IR, presenting a simple and effective approach to augment the response of breast cancer to radiotherapy. Statement of Significance To overcome the intrinsic radioresistance in breast cancer, we prepared co-assembly of Fe 2+ and FBXW7-targeted DNAzymes and modified surface with dopamine conjugated hyaluronic acid (HA), which enabled tumor-specific FBXW7-targeted gene therapy and ferroptosis therapy in IR-treated breast cancers. The nanoassembly could be activated in acidic condition to release the therapeutic contents. Specifically, the DNAzymes could selectively degrade FBXW7 mRNA in breast cancer cells to simultaneously induce accumulation of p53 and retardation of NHEJ repair , eventually inducing irreversible cell cycle arrest to promote apoptosis. The p53 stabilization would also inhibit the SLC7A11/GSH/GPX4 axis to enhance Fe 2+ mediated ferroptosis. These merits could act in a cooperative manner to induce pronounced tumor inhibitory effect, offering new approaches for tumor radiosensitization in the clinics.
研究领域:
肿瘤学
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分子生物学
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纳米医学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Haoze Song,Jing Liang,Yuanyuan Guo,Yang Liu,Kuiru Sa,Guohong Yan,Wen Xu,Wei Xu,Lixia Chen,Hua Li
Glutathione peroxidase 4 (GPX4) is the most promising target for inducing ferroptosis . GPX4-targeting strategies primarily focus on inhibiting its activity or adjusting its cellular level. However, small inhibitors have limitations due to the covalent reactive alkyl chloride moiety, which could lead to poor selectivity and suboptimal pharmacokinetic properties. Herein, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) by connecting RSL3, a small molecule inhibitor of GPX4, with six different ubiquitin ligase ligands. As a highly effective degrader, compound 18a is a potent degrader (DC 50, 48h = 1.68 μM, D max, 48h = 85 %). It also showed an obvious anti-proliferative effect with the IC 50 value of 2.37 ± 0.17 μM in HT1080. Mechanism research showed that compound 18a formed a ternary complex with GPX4 and cIAP and induced the degradation of GPX4 through the ubiquitin-proteasome system pathway. Furthermore, compound 18a also induced the accumulation of lipid peroxides and mitochondrial depolarization, subsequently triggering ferroptosis. Our work demonstrated the practicality and efficiency of the PROTAC strategy and offered a promising avenue for designing degraders to induce ferroptosis in cancer cells.
研究领域:
肿瘤学
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药物化学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Shi Haoyu,Song Libiao,Wu Yonghui,Shen Ruonan,Zhang Chenxu,Liao Xingzhi,Wang Qiuhong,Zhu Jie
Traumatic brain injury (TBI) is a highly severe form of trauma with complex series of reactions in brain tissue which ultimately results in neuronal damage. Previous studies proved that neuronal ferroptosis, which was induced by intracranial haemorrhage and other reasons, was one of the most primary causes of neuronal damage following TBI. However, the association between neuronal mechanical injury and ferroptosis in TBI and relevant treatments remain unclear. In the present study, we first demonstrated the occurrence of neuronal ferroptosis in the early stage of TBI and preliminarily elucidated that edaravone (EDA), a cerebroprotective agent that eliminates oxygen radicals, was able to inhibit ferroptosis induced by TBI. A cell scratching model was established in PC12 cells, and it was confirmed that mechanical injury induced ferroptosis in neurons at the early stage of TBI. Ferroptosis suppressor protein 1 (FSP1) plays a significant role in inhibiting ferroptosis, and we found that iFSP, a ferroptosis agonist which is capable to inhibit FSP1 pathway, attenuated the anti-ferroptosis effect of EDA. In conclusion, our results suggested that EDA inhibited neuronal ferroptosis induced by mechanical injury in the early phase of TBI by activating FSP1 pathway, which could provide evidence for future research on prevention and treatment of TBI.
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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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2025
·
IF 8.4
Ye Hua,Wu Lin,Liu Yan-mei,Zhang Jun-xia,Hu Huan-tao,Dong Mao-long,Ren Jun
Septic cardiomyopathy (SCM), a severe complication in sepsis, significantly increases the mortality of septic patients. Ferroptosis, an iron-regulated cell death, has been implicated in the development of SCM. Wogonin, a flavonoid from the root of the skullcap, exhibits anti-inflammatory, anti-allergic, and anti-apoptotic activities. In this study, we investigated the effects of wogonin on SCM and associated cardiomyocyte ferroptosis. Cecal ligation and puncture (CLP) surgery was performed in mice to establish a SCM model. Wogonin (20, 40 and 60 mg·kg −1 , i.p.) was administered 2 h prior to CLP surgery. We showed that wogonin pretreatment dose-dependently mitigated CLP-induced cardiac dysfunction, myocardial damage, and deranged cardiomyocyte contractility. Furthermore, wogonin pretreatment ameliorated cardiac inflammation, oxidative stress, and mitochondrial dysfunction in CLP-challenged mice. We demonstrated that wogonin exerted the cardioprotective effects through suppressing cardiomyocyte ferroptosis both in vivo and in vitro. We revealed that wogonin directly bound to and inhibited ALOX15 (arachidonic acid 15-lipoxygenase), a lipoxygenase that governed the oxidation of polyunsaturated fatty acids to initiate ferroptosis. Pharmacological inhibition of ALOX15 using a specific inhibitor ML351 (10 mg·kg −1 ·d −1 , i.p. for 7 days prior to CLP surgery) markedly diminished cardiac abnormalities and cardiomyocyte ferroptosis in CLP-challenged mice. In LPS-challenged HL-1 cardiomyocytes, overexpression of ALOX15 or supplement of its downstream metabolite 15-HpETE (1 μM) diminished the anti-ferroptotic effects of wogonin. Our results demonstrate that wogonin protects against SCM through inhibition of ALOX15-meditated ferroptosis.
研究领域:
药理学
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病理学
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心血管医学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
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IF 6.9
Weikang Guo,Wanyue Wang,Fei Lei,Ruxin Zheng,Xinyao Zhao,Yuze Gu,Mengdi Yang,Yunshun Tong,Yaoxian Wang
Cisplatin (DDP) resistance poses a significant challenge in the treatment of ovarian cancer. Studies have shown that the combination of certain polysaccharides derived from plants with DDP is an effective approach to overcoming drug resistance in some cancers. Angelica sinensis (Oliv.) Diels has been used for centuries in China to treat gynecological ailments. Numerous studies indicate that Angelica sinensis polysaccharide (ASP), an extract from Angelica sinensis , can inhibit various forms of cancer. However, the impact of ASP on ovarian cancer remains unexplored. Through both in vitro and in vivo experiments, our study revealed the capability of ASP to effectively reversing DDP resistance in cisplatin-resistant ovarian cancer cells, while exhibiting acceptable safety profiles in vivo. To elucidate the mechanism underlying drug resistance reversal, we employed RNA-seq analysis and identified GPX4 as a key gene. Considering the role of GPX4 in ferroptosis, we conducted additional research to explore the effects of combining ASP with DDP on SKOV3/DDP cells. In summary, our findings demonstrate that the combination of ASP and DDP effectively suppresses GPX4 expression in SKOV3/DDP cells, thereby reversing their resistance to DDP.
研究领域:
肿瘤学
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药理学
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分子生物学
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植物科学
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DOI
PubMed
高影响因子
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