Materials Today Bio
·
2025
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IF 10.2
Mingyue Yan,Kehao Hou,Jinpeng Zhao,Shuangshan Li,Xiaolin Wu,Shichao Bi,Jing Yu,Tianrui Wang,Yingze Zhang
The characteristic pathological manifestations of rheumatoid arthritis (RA) include inflammatory cell infiltration, abnormal synoviocyte proliferation, and progressive bone and cartilage destruction. An excessive buildup of reactive oxygen species (ROS) within the joints is a critical factor promoting RA pathological progression. In this study, we innovatively employed a hard template-restricted controlled sintering carbonization strategy to fabricate ultra-small Fe 3 O 4 @C nanoparticles with hierarchical structures. The ultra-small Fe 3 O 4 @C nanoparticles exhibit multiple natural enzyme-mimic catalytic activity, effectively diminishing intracellular ROS levels in macrophages, while also facilitating the polarization toward the M2 phenotype, and significantly suppresses the production of pro-inflammatory cytokines. Mechanistic investigations reveal that Fe 3 O 4 @C significantly suppresses ferroptosis in synoviocytes and chondrocytes through regulation of the SLC7A11/GPX4 signalling pathway, thereby alleviating synovial tissue erosion and promoting type II collagen synthesis. In the collagen-induced arthritis mouse model, Fe 3 O 4 @C exhibited remarkable anti-inflammatory and chondroprotective effects, providing an innovative nanozyme therapeutic approach for RA treatment.
研究领域:
纳米医学
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风湿病学
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免疫学
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生物医学工程
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氧化还原生物学
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Nutrients
·
2023
·Vol. 15
·期 5
·1090
·
IF 5.9
Yunpeng Zhang,Shuang Liu,Jing Peng,Shifeng Cheng,Qingling Zhang,Nan Zhang,Zandong Zhou,Yue Zhang,Yang Zhao,Tong Liu
Mitochondria-dependent ferroptosis plays an important role in the pathogenesis of doxorubicin (DOX)-induced cardiotoxicity (DIC), which remains a clinical challenge due to the lack of effective interventions. Cerium oxide (CeO2), a representative nanozyme, has attracted much attention because of its antioxidant properties. This study evaluated CeO2-based nanozymes for the prevention and treatment of DIC in vitro and in vivo by adding nanoparticles (NPs), which were synthesized by biomineralization, to the culture or giving them to the mice, and the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) was used as control. The prepared NPs exhibited an excellent antioxidant response and glutathione peroxidase 4 (GPX4)-depended bioregulation, with the additional merits of bio-clearance and long retention in the heart. The experiments showed that NP treatment could significantly reverse myocardial structural and electrical remodeling, and reduce myocardial necrosis. These cardioprotective therapeutic effects were associated with their ability to alleviate oxidative stress, mitochondrial lipid peroxidation, and mitochondrial membrane potential damage, with a superior efficiency to the Fer-1. The study also found that the NPs significantly restored the expression of GPX4 and mitochondrial-associated proteins, thereby restoring mitochondria-dependent ferroptosis. Therefore, the study provides some insights into the role of ferroptosis in DIC. It also shows that CeO2-based nanozymes could be a promising prevention and treatment candidate as a novel cardiomyocyte ferroptosis protector to mitigate DIC and improve prognosis and quality of life in cancer patients.Keywords:doxorubicin-induced cardiomyopathy;ferroptosis;mitochondria;nanozyme;oxidative stress;biomineralization
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2023
·
IF 5.8
Chan Li,Sheng Zhou,Chuncheng Chen,Lijun Zhu,Shijie Li,Zhuoyue Song,Jian Liang,Chunzhi Tang,Nenggui Xu,Tao Liu,Shihui Liu
Disulfiram (DSF), a drug for alcohol withdrawal , has attracted extensive scientific attention due to its potential to treat cancer. The metabolite of DSF, diethyl dithiocarbamate (DDTC), forms a Cu-DDTC complex in vivo with copper ions , which has been shown to be a proteasome inhibitor with high antitumor activity . However, the in vivo stability of Cu-DDTC complexes remains a challenge. In this study, the nanomedicine [email protected] with high antitumor activity was prepared by using the nanoscale metal-organic framework (MOF) Cu-BTC as a carrier and loading diethyldithiocarbamate (DDTC) through coordination interaction. The results showed that [email protected] had high drug loading and adequate stability, and exhibited DDTC-Cu(I) chemical valence characteristics and polycrystalline structure features. In vitro cytocompatibility investigation and animal xenograft tumor model evaluation demonstrated the anti-cancer potential of [email protected] , especially the combination of [email protected] with low-dose cisplatin showed significant antitumor effect and biosafety. This study provides a feasible protocol for developing antitumor drugs based on the drug repurposing strategy.
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Frontiers in Cell and Developmental Biology
·
2022
·
IF 6.081
Fan Zhang,Hualong Zhen,Hengshun Cheng,Fengying Hu,Yunfei Jia,Binbin Huang,Minmin Jiang
As one kind of endocrine disrupting chemical, di-(2-ethylhexyl) phthalate (DEHP) has been reported to cause liver dysfunction in epidemiological and experimental studies. Abnormal liver function in pregnancy is associated with adverse maternal and perinatal outcomes. Few studies have investigated the potential effect of gestational DEHP exposure on the liver in pregnant mice, and the underlying mechanisms remain unclear. In the present study, pregnant ICR mice were exposed to doses (0, 500, 1,000 mg/kg/day) of DEHP in the presence or absence of 5 mg/kg/day ferrostatin-1 (Fer-1, ferroptosis inhibitor) by oral gavage from gestation day 4 to day 18. HepG2 cells were exposed to different doses of monoethylhexyl phthalate (MEHP, a major metabolite of DEHP) in vitro . Hepatic function and pathologic changes were observed. Oxidative stress, iron metabolism, and ferroptosis-related indicators and genes were evaluated both in vivo and in vitro . The results showed that gestational DEHP exposure induced disordered liver function and hepatocyte morphology changes in pregnant mice, along with increased malondialdehyde (MDA) and Fe 2+ content and decreased glutathione (GSH) levels. The expression levels of the selected ferroptosis-related genes Slc7a11 , Gpx4 , and Nfr2 were significantly decreased, and Ptgs2 and Lpcat3 were significantly increased. Notably, Fer-1 attenuated DEHP-induced liver injury and ferroptosis. Furthermore, MEHP exhibited a synergistic effect with RSL3 (a GPX4 inhibitor) in promoting ferroptosis in vitro . Taken together, the results demonstrated that DEHP induced liver injury and ferroptosis in pregnant mice, probably by inhibiting the GPX4 pathway through lipid peroxidation and iron accumulation.
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Bioactive Materials
·
2024
·
IF 18
Chuanlu Lin,Yiqiang Hu,Ze Lin,Longyu Du,Yixin Hu,Lizhi Ouyang,Xudong Xie,Peng Cheng,Jiewen Liao,Li Lu,Ruiyin Zeng,Ping Xia,Zhiyong Hou,Guohui Liu,Hankun Hu
Ferroptosis plays a crucial role in the progression of diabetic wounds, suggesting potential therapeutic strategies to target ferroptosis. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective calcium channel that acts as a receptor for a variety of physical or chemical stimuli. Cinnamaldehyde (CA) is a specific TRPA1 agonist. In in vitro experiments, we observed that high glucose (HG) treatment induced endothelial cell ferroptosis, impairing cell function. CA successfully inhibited endothelial cell ferroptosis, improving migration, proliferation, and tube formation. Further mechanistic studies showed that CA-activated TRPA1-induced Ca 2+ influx promoted the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-E 2-related factor 2 (Nrf2) translocation, which contributed to the elevation of glutathione peroxidase 4 (GPX4), leading to the inhibition of endothelial cell ferroptosis. In addition, CA was incorporated into an MMP-9-responsive injectable duplex hybrid hydrogel (CA@HA-Gel), allowing its efficient sustained release into diabetic wounds in an inflammation-responsive manner. The results showed that CA@HA-Gel inhibited wound endothelial cell ferroptosis and significantly promoted diabetic wound healing. In summary, the results presented in this study emphasize the potential therapeutic application of CA@HA-Gel in the treatment of diseases associated with ferroptosis.
研究领域:
药理学
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生物医学工程
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细胞生物学
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伤口愈合
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Cardiovascular Diabetology
·
2024
·Vol. 23
·期 1
·1-19
·
IF 8.5
Tang Yuan-juan,Zhang Zhen,Yan Tong,Chen Ken,Xu Guo-fan,Xiong Shi-qiang,Wu Dai-qian,Chen Jie,Jose Pedro A.,Zeng Chun-yu,Fu Jin-juan
Background Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia–reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. Methods and results T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. Conclusion This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.
研究领域:
内分泌学
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心脏病学
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分子生物学
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药理学
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PATHOLOGY RESEARCH AND PRACTICE
·
2025
·
IF 3.2
Ting-Ting Yang,Xin-Xin Ma,Xuan Zhang,Zhen-Qing Han,Shuang Zhang,Qi Wang,Hong-Wei Dong,Jia-Ren Liu
β-Ionone (BI) has shown the potent inhibitory malignant progression of multiple tumors including gastric cancer in vitro and in vivo. However, the mechanism by which BI inhibits gastric cancer remains to be clarified, especially in ferroptosis, which is a new form of programmed cell death. The aim of this study was to investigate whether BI could induce ferroptosis in gastric cancer and the underlying mechanisms. The results manifested that BI obviously inhibited cell viability and increased the Fe 2 + level, total reactive oxygen species (ROS) and lipid ROS levels and the malondialdehyde (MDA) concentrations, but reduced the mitochondrial membrane potential (MMP) and the expression of SLC7A11 and GPX4 in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Besides, BI also arrested cell cycle and decreased the expression of Cyclin D1 and CDK4 ( P < 0.05 or P < 0.01). Mechanistically, BI reduced the levels of β-catenin and pGSK-3β/GSK-3β in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Nevertheless, pretreatment with lithium chloride (LiCl), an inhibitor of GSK-3β, reversed BI-induced ferroptosis and cell cycle arrested in MKN45 cells ( P < 0.05). In addition, BI effectively inhibited the growth of gastric cancer xenografts and downregulated the levels of GPX4, SLC7A11, PCNA, β-catenin and pGSK-3β/GSK-3β ( P < 0.05 or P < 0.01). Collectively, our study reveals that BI inhibits proliferation of gastric cancer cells by induction ferroptosis via the Wnt/β-catenin signaling pathway and provides a novel therapy for gastric cancer.
研究领域:
肿瘤学
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细胞生物学
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药理学
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分子生物学
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Food & Function
·
2021
·Vol. 12
·期 24
·12671-12682
·
IF 5.396
Jing-yi Ren,Bo-wen Yin,Xiang Li,Si-qi Zhu,Jin-liang Deng,Yi-ting Sun,Zhen-ao Zhang,Zi-hao Guo,Huan-ting Pei,Fan Zhang,Rui-qiang Li,Feng-ge Chen,Yu-xia Ma
Objective: This study aimed to elucidate the pharmacological effects of sesamin (Ses) and its mechanism of action towards PM2.5-induced cardiovascular injuries. Method: Forty Sprague Dawley (SD) rats were randomly divided into five groups: a saline control group; a PM2.5 exposure group; and low-, middle-, and high-dose Ses pretreatment groups. The SD rats were pretreated with different concentrations of Ses for 21 days. Afterward, the rats were exposed to ambient PM2.5 by intratracheal instillation every other day for a total of three times. The levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), and indicators related to oxidative responses, such as total superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), were measured in the blood and heart. The expression of ferroptosis-related proteins in heart tissues was determined via western blot and immunohistochemistry. Results: Ses pretreatment substantially ameliorated cardiovascular injuries in rats as evidenced by the decrease in the pathological score and collagen area. The decreased levels of SOD, GSH, and GSH-Px in the heart and serum were inhibited by Ses. In addition, Ses not only notably increased the activity of antioxidant enzymes but also reduced the levels of MDA, CK, LDH, CK-MB, IL-6, TNF-α, IL-1β, and IL-6. Furthermore, Ses pretreatment upregulated the expression levels of GPX4, SLC7A11, TFRC, and FPN1 and inhibited the expression levels of FTH1 and FTL. Conclusion: Ses pretreatment could ameliorate PM2.5-induced cardiovascular injuries perhaps by inhibiting ferroptosis. Therefore, Ses pretreatment may be a novel strategy for the prevention and treatment of PM2.5-induced cardiovascular injury.
研究领域:
药理学
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心脏病学
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毒理学
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环境健康
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CHEMICAL RESEARCH IN TOXICOLOGY
·
2024
·
IF 3.7
Xiuhao Yu,Shaokun Chen,Hailin Wang
Chlorobenzoquinones (CBQs) are a class of emerging water disinfection byproducts that pose significant risks to public health. In this study, we found that three CBQs (tetrachloro-1,4-benzoquinone, 2,5-dichloro-1,4-benzoquinone, and 2-chloro-1,4-benzoquinone) can significantly aggravate cell death caused by Ras-selective lethal small molecule 3 (RSL3). Further study showed that the cell death caused by CBQs, either alone or in combination with RSL3, was related to iron accumulation and GPX4 inactivation, suggesting the occurrence of ferroptosis. Furthermore, reactive oxygen species are found to play a potential key role in mediating the toxicity of CBQs in CBQs and RSL3-induced ferroptosis. These findings will be helpful in understanding the toxic mechanism of CBQs to mammalian cells.
研究领域:
毒理学
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细胞生物学
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环境科学
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公共卫生
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Cell Death & Disease
·
2026
·
IF 12.2
Liu Yanyan,Guan Chenxi,Xu Linlin,Yang Jianhua,Wang Jinglei,Yang Si,Chen Jiaxiang
Impaired Leydig cell function leads to low testosterone levels, which is associated with male reproductive developmental defects and functional disorders. Exposure to di(2-ethylhexyl) phthalate (DEHP), an endocrine-disrupting chemical, can cause damage to Leydig cells, yet the underlying mechanism remains unclear. In this study, we found that DEHP exposure decreased serum testosterone levels and triggered ferroptosis of mouse Leydig cells by inhibiting GPX4 expression. Subsequently, mono(2-ethylhexyl) phthalate (MEHP), the primary active metabolite of DEHP, was shown to suppress the transcription of Gpx4 gene in TM3 cells by downregulation of HOXA3, which bound to the −264 to −258 region (RE3) of Gpx4 gene promoter. Concurrently, MEHP promoted HSC70 to recognize and degradate GPX4 protein via chaperone-mediated autophagy (CMA). Furthermore, both overexpression of HOXA3 and inhibition of CMA significantly abrogated MEHP-induced ferroptosis of TM3 cells through upregulating the expression of GPX4. Ultimately, tannic acid (TA), a natural polyphenol, was identified to increase the expression of GPX4 and inhibit MEHP-induced ferroptosis of TM3 cells, thereby alleviating DEHP-caused testicular damage in mice through the upregulation of HOXA3 and inhibition of CMA.
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ENVIRONMENT INTERNATIONAL
·
2026
·
IF 10.2
Fan Yu,Shihao Luo,Zhengrong Zhou,Feixia Chen,Jiawei Ying,Qiufang Wu,Yize Wu,Shihua Chen,Xinxin Yao,Feiqin Xie,Wenhui Xu,Ke Xu,Renyi Peng
Cypermethrin (CY), a pyrethroid insecticide, accumulated in aquatic environments and exertd toxic effects on aquatic organisms, impairing their development, nervous system, and immune function. Polystyrene nanoparticles (PS-NPs) readily adsorbed organic contaminants like CY, forming complex pollution systems that resulted in synergistic toxicities. However, the mechanisms behind their hepatotoxicity remained unclear. In this study, both in vivo and in vitro experiments demonstrated that co-exposure to PS-NPs and CY significantly induced liver injury and steatosis in zebrafish larvae, while activating the key lipid synthesis regulator sterol regulatory element-binding protein 1 (SREBP1) in Hep G2 cells. This process displayed typical features of ferroptosis, including oxidative stress, mitochondrial damage, iron dysregulation, and suppression of the antioxidant enzyme glutathione peroxidase 4 (GPX4). Correlation analysis showed a close association between ferroptosis and steatosis. Physiological and genetic verification revealed that Erastin aggravated lipid accumulation by inhibiting GPX4 expression, activating the SREBP1/SCD1 lipid synthesis pathway. Conversely, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, alleviated oxidative stress, iron overload, and lipid accumulation, while GPX4 overexpression reversed SREBP1/SCD1 activation and improved lipid accumulation, peroxidation, and ferroptosis. This study revealed a novel mechanism by which PS-NPs and CY co-exposure induced ferroptosis-mediated hepatic steatosis through GPX4. These findings provided new insights into the hepatometabolic toxicity of complex pollutants and identified potential targets for preventing related liver diseases.
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Frontiers in Bioscience-Landmark
·
2025
·Vol. 30
·期 6
·36615
·
IF 3.1
Shanli Wu,Gun Yang,Xiaosha Wen,Yi Lin,Shenglong Wang,Jing Wang,Quan Liu,Dixian Luo
Background:Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B10 in the susceptibility of MDA-MB-231 cells to ferroptosis. These cells serve as a model for triple-negative breast cancer (TNBC).Methods:Lentiviral transfection was used to establish stable cell lines with high or low expression of AKR1B10. Our model of ferroptosis used the ferroptosis activator RSL3, and the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) to rescue cell death. Stable cell lines were treated with the specific inhibitor OSU-T315 directed against phosphorylation of Ser473 in protein kinase B (AKT) and Ser9 in glycogen synthase kinase 3 beta (GSK3β), either alone or in combination with RSL3. A fatty acid stress model was established using palmitic acid (PA) or arachidonic acid (AA), either in the presence or absence of serum starvation and with or without co-treatment with RSL3. Cell viability was evaluated with the cell counting kit-8 (CCK8) assay and lipid peroxidation levels by flow cytometry after staining with C11 BODIPY 581/591. Exploration of the underlying mechanisms was conducted through RNA sequencing and bioinformatics analysis. Western blotting was performed to evaluate protein levels, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate transcript levels.Results:Western blot and qPCR analyses validated the successful establishment of stable MDA-MB-231 cell lines with and without AKR1B10 overexpression. Cell viability and lipid reactive oxygen species (ROS) assays showed that AKR1B10 suppressed ferroptosis in the RSL3-induced cell death model. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses indicated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway was likely to play a role in the underlying mechanisms. AKR1B10 increased the expression of glutathione peroxidase 4 (GPX4), thus potentially implicating the AKT/GSK3β/nuclear factor erythroid 2-related factor 2 (NRF2)/GPX4 pathway in the mechanism. These changes in protein levels were also observed by Western blot analysis after 6 h of RSL3 treatment. Under the influence of RSL3, the transcript levels of NRF2-related genes including GPX4, ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were significantly elevated in the AKR1B10 overexpression cell line, whereas that of prostaglandin-endoperoxide synthase 2 (PTGS2) was significantly reduced. Similar changes were observed after treatment with OSU-T315. AKR1B10 was found to suppress the sensitivity to ferroptosis induced by treatment with OSU-T315, PA, or AA. These phenomena were rescued by the ferroptosis inhibitor Fer-1.Conclusions:AKR1B10 appears to be an important mechanism protecting MDA-MB-231 cells from ferroptosis, possibly through the AKT Ser473/GSK3β Ser9/NRF2/GPX4 pathway. AKR1B10 may be a key factor underlying the therapeutic effect of RSL3 under different exogenous fatty acid microenvironments.
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